ES2348557T3 - ANTIVIRAL COMPOUNDS. - Google Patents

Abstract

A compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, where the compound has Formula II (a) or II (b), where: R 2 and R 3 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; R 7 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl, cyanoalkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, morpholino, hydrazino, alkylaminoalkoxy, alkoxyalkylamino, and aryl; R 9 is selected from the group consisting of arylalkylamino, N- [alkylamino (arylsulfanyl) arylalkyl] -N - [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarylalkoxy, nitroarylalkoxy, cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkoxy, arylalkyl-alkylalkyl, alkylaryloxylalkyl, alkylaryloxylalkyl, alkylaryloxylalkyl, alkylaryloxylalkyl, alkyl , alkylaminoarylaminocarbonyl, and arylalkoxy; R 11 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R 12 is selected from the group consisting of arylsulfanyl, arylsulfinyl, aryloxy, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; where R 12 is optionally substituted with one or more substituents independently selected from R 16; R 16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl, alk ylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl; R 13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylalkyl alkoxy, and alkylcarbonylaminoarylalkoxy.

Description

COUNTRYSIDE

The present invention relates to compounds effective in inhibiting the replication of the Hepatitis C virus ("HCV"). The present invention also relates to methods for making such compounds, compositions comprising such compounds, and such compounds / compositions for the treatment of an HCV infection or the conditions / symptoms associated with

10 the same. In addition, the present invention relates to the use of such compounds for the manufacture of medicaments for the treatment of an HCV infection.

BACKGROUND

15 HCV, a human pathogen, is an RNA virus belonging to the genus Hepacivirus of the Flaviviridae family. As is characteristic with all other members of the Flaviviridae family, the HCV has

20 enveloped virions containing a positive strand RNA genome that encodes all known virus-specific proteins in a single open, uninterrupted reading frame. The open reading frame comprises approximately 9500 nucleotides that

25 encode a single large polyprotein of approximately 3000 amino acids. The polyprotein comprises a core protein, the envelope proteins E1 and E2, a p7 membrane binding protein, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NSSA

30 and NSSB. A cellular protease cleaves the viral protein at the NS2-NS3 junction allowing a viral protease (NS3 protease) to mediate at subsequent cleavages. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS2 and NS4A can,

35 also, be involved in proteolytic activity.

NS5A is a phosphoprotein involved in replication. NS5B is an RNA-dependent RNA polymerase. United States Patent Publication No. 2004/0265792, published on December 30, 2004, mentions that inhibition of the aforementioned non-structural proteins may inhibit HCV replication.

HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. End-stage liver disease associated with HCV is the most frequent indication of liver transplantation among adults. Chronic hepatitis C can be treated with a weekly injection of peginterferon-alpha combined with ribavirin daily. Peginterferon-alpha is interferon-alpha bound to polyethylene glycol for the slow elimination of the drug from the body. This results in increased adaptability and clinically superior anti-viral activity when compared to daily interferon-alpha injection treatments. Substantial limitations to efficacy and tolerability remain since many users suffer from side effects and viral elimination from the body is often inadequate.

Attempts have been made to design drugs that specifically inhibit the functions of the hepatitis C virus. United States Patent No.

6,323,180 to Boehringer Ingelheim mentions tripeptide compounds as HCV serine protease inhibitors proposed for the treatment of an HCV infection.

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

The inhibition of HCV translation, by a yeast RNA that binds to cellular polypeptides and prevents their interaction with the internal ribosome viral entry site (IRES), is described by Das et al, in J. VIROLOGY, 72 ( 7): 5638-5647 (1998).

Fused bicyclic heterocyclic compounds have been proposed for various uses related to life sciences. Examples of such heterocyclic compounds include naphthyridine, pyridopyrimidine, pyrimidopyrimidine, pyrazolopyrimidine and thiazolo / thienopyrimidine compounds.

Fused bicyclic compounds of the naphthyridine type have been investigated for disease treatment uses. For example, Boots WO 93/13097, published July 8, 1993, mentions [1,8] naphthyridine compounds, such as 4- (4-methoxyanilino) -6-ethoxy-7-methyl- hydrochloride Ethyl 1,8-naphthyridine-3-carboxylate, proposed for use as anti-rheumatic agents. Boots WO 95/00511, published on January 5, 1995, mentions substituted fused ring 4-aminopyridines, such as 3-ethoxy-5- (2-ethoxy-5-pyridylamino) -2-methyl-1,8- Naphthyridine, proposals for use as anti-rheumatic agents. WO 98/13350 of Zeneca, published on April 2, 1998, mentions [1,8] naphthyridine compounds, such as 2-acetamido-5- (2-fluoro-5-hydroxy-4-methylanilino) hydrochloride -1 , 8-naphthyridine, proposed as antiangiogenic agents. WO 2004/055004 from Neurogen, published on July 1, 2004, mentions naphthyridine compounds as capsaicin receptor modulators, the specific compounds being 5- (4-trifluoromethylphenylamino) -2- (3-trifluoromethylpyridine-2-) il) - [1,6] naphthyridine-7-carboxylic acid, and 2-methoxymethyl-4- (4-trifluoromethyl-phenylamino) -7- (3trifluoromethyl-pyridin-2-yl) - [1,8] naphthyridine- 3 carboxylic.

Fused bicyclic compounds of the pyridopyrimidine type have been investigated for different uses for the treatment of diseases. For example, Pfizer WO 98/05661, published on February 12, 1998, mentions substituted pyridopyrimidine compounds, such as [8- (1-ethylpropyl) -2-methyl-5,6,7,8-tetrahydropyridide (2,3-d) pyrimidin4-yl]) - (2,4,6-trimethyl-phenyl) -amine, as antagonists of the corticotropin releasing factor (hormone) CRF (CRH) proposed for the treatment of Alzheimer's disease and obesity. Pfizer WO 98/23613, published June 4, 1998, mentions fused bicyclic pyrimidine compounds, including pyridopyrimidinyl-aminophenyl compounds, such as (3-ethynyl-phenyl) -pyrido [3,4-d] pyrimidin -4-ylamine, proposed for the treatment of hyperproliferative diseases such as cancer. U.S. Patent No. 6,169,091 to Glaxo Wellcome, issued January 2, 2001, mentions bicyclic heteroaromatic compounds, such as 4- (4-benzyloxyanilino) pyrido [2,3-d] -pyrimidine, as tyrosine inhibitors kinases proposed for the treatment of fibrosis, inflammation, diseases of the nervous system and cancer. WO 01/32632 of Eli Lilly, published on May 10, 2001, mentions substituted pyrimidine compounds in position 4, including 2-trifluoromethyl-4- [2- (2- (2-chlorophenyl) ethylamino] hydrochloride] pyrido [2,3-d] pyrimidine, as mGluR1 antagonists proposed for the treatment of neurological disorders associated with glutamate dysfunction such as seizures, migraine, psychosis, anxiety and pain, WO 01/57040 of Abbott Laboratories published on August 9, 2001, mentions 6,7-disubstituted-4-amino-pyrido [2,3-d] pyrimidine compounds, such as 4-amino-6- (4-methylphenyl) -7- (4-bromophenyl) pyrido [2,3- d] pyrimidine, as adenosine kinase inhibitors proposed for the treatment of pain and inflammation, WO 2004/055004 of Neurogen, published July 1, 2004, mentions pyridopyrimidinyl aminophenyl compounds, such as 2-methyl acid -2- {4- [2-methyl-7- (3-methylpyridin2-yl) -pyrido [2,3-d] pyrimidin-4-ylamino] -phenyl} propion ico, as modulators of capsaicin receptors. United States Patent No.

6,395,733 to Pfizer, issued May 28, 2002, mentions heterocyclic fused ring pyrimidine compounds, such as 3-chloro-phenyl-pyrido [2,3d] pyrimidin-4-yl-amine, proposed for treatment of hyperproliferative diseases, such as cancer.

Fused bicyclic bicyclic compounds of the pyrimidopyrimidine type have been investigated for uses for pest control and disease treatment. For example, U.S. Patent No. 5,350,749 to Dow Elanco, issued September 27, 1994, mentions 4-substitutedpyrimido [2,3-d] pyrimidine compounds proposed for use as fungicides, insecticides and miticides . WO 95/19774 Warner-Lambert, published on July 27, 1995, mentions pyrimidopyrimidine compounds, such as 4-benzylamino-7-methylaminopyrimido [4,5-d] pyrimidine, as tyrosine kinase inhibitors proposed for the treatment of cancer, vascular restenosis and psoriasis.

Fused bicyclic compounds of thienopyrimidine have been investigated for various uses for the treatment of diseases. For example, WO 95/19774 of Warner-Lambert, published July 27, 1995, mentions fused heterocyclic pyrimidine compounds, including 4- (3-bromoanilino) thieno [2,3-d] pyrimidine, as tyrosine kinase inhibitors proposed for the treatment of cancer, vascular restenosis and psoriasis. US Patent No. 6,169,091 to Glaxo Wellcome, issued on January 2, 2001, mentions bicyclic heteroaromatic compounds, such as 5-methyl-4- (4-phenoxyanilino) thieno [2,3d] pyrimidine hydrochloride as Tyrosine kinase inhibitors, proposed for the treatment of fibrosis, inflammation, diseases of the central nervous system and cancer. WO 01/32632 by Eli Lilly, published on May 10, 2001, mentions 4-substituted-pyrimidine compounds, such as 6-methyl-4- [2,6-dichlorobenzylthio) ethylamino] thieno [2, 3-d] pyrimidine, as mGluR1 antagonists proposed for the treatment of neurological disorders associated with glutamate dysfunction such as seizures, migraine, psychosis, anxiety and pain.

WO 2004/014852 from Bristol-Myers Squibb, published on February 19, 2004, mentions iminothiazolidinones, including fused bicyclic derivatives of 2- (4-aminophenyl) -5H-thiazolo [2.36] quinazolin-3-one, as NS5A protein inhibitors

proposed to prevent HCV replication.

WO 2004/014313 from Bristol-Myers Squibb, published on February 19, 2004, mentions combined therapies for the treatment of viral diseases, including iminothiazolidinone compounds anti-HCV inhibitors of NS5A protein combined with other agents capable of interfering with HCV function.

COMPENDIUM

The present invention characterizes compounds having Formulas II (a) or II (b), tautomers of these compounds, and pharmaceutically acceptable salts of these compounds or tautomers according to the attached claims 1-3. These compounds, their tautomers or salts can be used, 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 disrupt the functions of HCV or other viruses.

The present invention also characterizes 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 different antiviral or therapeutic agents.

The compounds, tautomers or salts of the present invention, or the compositions comprising them, can be used in methods to inhibit the replication of HCV or other viruses. These methods comprise contacting HCV or another virus, or cells infected with HCV or said other virus, with an effective amount of a compound, tautomer or salt of the present invention, thereby inhibiting the replication of HCV or said another virus.

The compounds, tautomers or salts of the present invention, or the compositions comprising them, can be used in methods to inhibit proliferation.

or the transmission of HCV or other viruses. These methods comprise contacting HCV or another virus, or contacting infected cells with HCV or another virus, with an effective amount of a compound, tautomer

or salt of the present invention, thereby inhibiting the proliferation or transmission of HCV or said other virus.

The compounds, tautomers or salts of the present invention, or the compositions comprising them, can be used in methods for the treatment of 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 in blood or tissues of HCV or other viruses in the patient.

The present invention also characterizes the use 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 characterizes the processes for making the compounds, tautomers or salts of the present invention. The present invention also characterizes the use of a compound of Formula (II) (a) or (II) (b), or a tautomer of the compound, or a pharmaceutically acceptable salt of the

5 compound or tautomer, according to the attached claims 5-8 for the manufacture of a medicament for inhibiting the replication of the HCV virus or for the treatment of an HCV infection. The present invention also characterizes a compound of Formula

10 (II) (a) or (II) (b), or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, according to the appended claims 9-11 for use in the treatment of an infection by HCV

The present invention characterizes compounds having Formulas II (a) or II (b), the tautomers of these compounds, and the pharmaceutically acceptable salts of these compounds or tautomers,

twenty

image 1

where: R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylaminocarbonyl; R4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; 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 arylalkylamino, N- [alkylarylamino (arylsulfanyl) arylalkyl] -N - [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarilalcoxi, nitroarilalcoxi, cianoarilalcoxi, aryloxyalkyl, haloariloxialquilo, cyanoalkoxy, arylalkoxy, alquilarilalcoxi, haloalquilarilaminocarbonilo, alkylaminoarylaminocarbonyl, and arylalkoxy; R11 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R12 is selected from the group consisting of arylsulfanyl, arylsulfinyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; where R12 is optionally substituted with one or more substituents independently selected from R16; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroaxilcarbonilamino, heteroaxilcarbonilamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquiloarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alkoxyarylaminocarbonyl, azidoalkyl, alkylaminoarylsulfonyloxy, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arylalkoxycarbonylheterocyclocarbonylamino, aryloxyalkylalkyl, alkylalkyl alkylalkyl alkylalkyl alkylalkyl alkyl alkylalkyl

Carbonylamino, arylalkoxyalkylcarbonylamino, heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino, alkylcarbonylheterocyclocarbonylamino, amino, aminocarbonyl, alkylaminocarbonyl, hydroxyalkyl, aminoalkyl,

Alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl; R13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy,

15 haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylarylalkoxy, and alkylcarbonylaminoarylalkyl.

In a family of subgroups in Formulas II (a) or 20 II (b), R12 is selected from the group consisting of

image 1

n is an integer selected from the group consisting of

25 in zero and one; R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, hoteroarylcarbonylamino,

Hydroxyheteroarylcarbonylamino, hydroxyalkylheteroarylcarbonylamino, heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino, aryloxyarylalkylcarbonylamino, allylaminocarbonyl, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hydroxyarylaminocarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilmino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonil

Not me,

heteroarylalkylcarbonylamino, alkylcarbonyl

heterocyclocarbonylamino,

Not me, aminocarbonyl,

alkylaminocarbonyl,

hydroxyalkyl, aminoalkyl,

alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl.

In an additional subgroup in Formulas II (a) or II (b), R2 and R3 are independently selected from the group consisting of hydrogen, ethoxycarbonyl, 3-Nmethoxy-N-methylaminocarbonyl, and methyl; R4 is selected from the group consisting of hydrogen, tbutoxycarbonyl, 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-ethoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino, N, N-dimethylaminoethoxy, methoxyethylamino, and cyano-1-ethoxy- carbonylmethyl; R9 is selected from the group consisting of phenyl, phenylmethylamino, methyl [1,8] naphthyridin-4-ylamino- (2-phenylsulfanylphene-5-ylmethyl) amino- (Nt-butoxy-carbonyl-Nmethyl), methoxyphenylmethoxy, bromophenylmethoxy, nitrophenylmethoxy, cyanophenylmethoxy , phenoxymethyl, bromophenoxymethyl, phenylmethoxy, methylphenylmethoxy, methylphenylmethoxy, fluoro-3-methylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, N, N-dimethylaminophenylaminocarbonyl, fluorophenylmethoxymethoxymethyl R11 is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy, and methyl;

R12

it is described as before in relation to Formulas II (a) and II (b); R13 is selected from the group consisting of hydrogen, chloro, methyl, methylcarbonylaminophenylsulfanyl, aminophenylsulfanyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethylaminophenoxy, hydroxyphenoxy, and methylaminocarbonylphenoxy; R14 is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, hydroxy, aminocarbonyl, N-methylaminocarbonyl, N, N-dimethylaminecarbonyl, amino, t-butylcarbonylamino, 2,6-dimethylfuranyl) carbonylamino, thienylcarbonylamino, hydroxypyridinylcarbonylamino, (2-hydroxy-6-methyl-6-methyl-6-methylamino ) carbonylamino, (3-pyrazinyl) carbonylamino, furanilcarbonilaminometilcarbonilamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) fenilmetilcarbonilamino, N-alilaminocarbonilo, ethoxycarbonyl, 1hidroxietilo, aminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, hidroxifenilaminocarbonilo, 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-dimetilaminonaft-1-ilsulfoniloxi, ethylsulfonyloxy, isopropylsulfonyloxy, methylsulfonyloxy, benzylsulfonyloxy, ethoxycarbonylmethoxy, hydroxycarbonylmethoxy, tbutilcarbonilamino, cyclopropylcarbonylamino, benciloxicarbonilpirrolidinilcarbonilamino, phenoxy, methylcarbonylamino, iminoethyl, tienoetilo, (S) -1fenilpropilcarbonilamino, metilfenoximetilcarbonilamino, (R) -1-phenyl-1-metoximetilcarbonilmino, (S) -1-phenyl-1metoximetilcarbonilamino, furanilcarbonilaminometilcarbonilamino, tienilpropilcarbonilamino, metilcarbonilpiperidinilcarbonilamino, amino, aminocarbonyl, methylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy, phenylmethylsulfonyloxy, methylcarbonylamino, methylaminocarbonyl, hydroxymethyl, aminoethyl, metoxietilaminocarbonilo, propylaminocarbonyl, X-methoxy-methylaminocarbonyl, N, N-diethyl aminocarbonyl, N- (2-methoxyethyl) aminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-hydroxy-1-iminoethyl, hydroxyethyl, aminomethyl, N, N-dimethylaminocarbonyl, 2,6-dimethylfuranyl, 1H [1,2,4] triazolyl, and pyridinyl

Medical use

The present invention also characterizes the use of a compound of Formula II (a) or II (b), or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, for the manufacture of a medicament for inhibiting virus replication. HCV or for the treatment of an HCV infection, where:

image 1

R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylaminocarbonyl; R4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; 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 [alkylarylamino (arylsulfanyl) arylalkyl] -N [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarylalkoxy nitroarylalkoxy, cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkyl, cyanoalkoxy, arylalkoxy, alkylarylalkoxy, haloalkylarylaminocarbonyl, alkylaminoarylaminocarbonyl, arylalkoxy, alkyloxyloxy, and alkoxycarbonyl; R11 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R12 is selected from the group consisting of hydrogen, arylsulfanyl, arylsulfinyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; where R12 is optionally substituted with one or more substituents independently selected from

R16;

R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl, alk ylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl; R13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy,

5 haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylarylalkoxy, and alkylcarbonylaminoarylalkyl.

According to an embodiment of such use, 10 R12 is selected from the group consisting of

image 1

n is an integer selected from the group consisting of

15 in zero and one; R14 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,

Hydroxyarylaminocarbonyl, alkoxyalkyl, alkoxyarylaminocarbonyl, and azidoalkyl; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino,

30 alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi alkylsulfonyloxy. arylalkyl sulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arylalkoxycarbonylheterocyclocarbonylamino, aryloxy, iminoalkyl, alkylthiona, arylalkylcarbonylamino, alkylaxyalkylcarbonylamino, arylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkyl

Not me,

heteroarylalkylcarbonylamino, alkylcarbonyl

heterocyclocarbonylamino,

Not me, aminocarbonyl,

alkylaminocarbonyl,

hydroxyalkyl, aminoalkyl,

alkoxyalkylaminocarbonyl, hydroxylaminoalkyl, alkyl substituted heteroaryl, and heteroaryl.

According to another embodiment of such use, R2 and R3 are independently selected from the group consisting of hydrogen, ethoxycarbonyl, 3-N-methoxy-N-methylaminocarbonyl, and methyl; R4 is selected from the group consisting of hydrogen, tbutoxycarbonyl, 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-ethoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino, N, N-dimethylaminoethoxy, methoxyethylamino, and cyano-1-ethoxy- carbonylmethyl; R9 is selected from the group consisting of hydrogen, methyl, methoxy, phenyl, trifluoromethyl, phenylmethylamino, hydroxy, t-butoxycarbonylaminomethyl, carbonylamino, methylcarbonyl, amino, bromine, chlorine, fluoro, methyl [1,8] naphthyridine-4- ilamino- (2-fenilsulfanilfen-5-ylmethyl) amino- (Nt-butoxycarbonyl-N-methyl), methoxyphenylmethoxy, bromofenilmetoxi, nitrofenilmetoxi, cianofenilmetoxi, trifluoromethyl, phenoxymethyl, bromofenoximetilo, cyanomethoxy, phenylmethoxy, methylallyloxy, propoxy, metilfenilmetoxi, metilfenilmetoxi, fluoro -3-methylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, N, N-dimethylaminophenylaminocarbonyl, fluorophenylmethoxy, and chlorophenylmethoxy; R11 is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy, and methyl;

R12

it is described as before in relation to Formulas II (a) and II (b); R13 is selected from the group consisting of hydrogen, chloro, methyl, methylcarbonylaminophenylsulfanyl, aminophenylsulfanyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethylaminophenoxy, hydroxyphenoxy, and methylaminocarbonylphenoxy; R14 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-methyl-6-methyl-6-methyl-6-yl ) carbonylamino, (3-pyrazinyl) carbonylamino, furanilcarbonilaminometilcarbonilamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) fenilmetilcarbonilamino, N-alilaminocarbonilo, ethoxycarbonyl, 1hidroxietilo, aminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, hidroxifenilaminocarbonilo, 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-dimetilaminonaft-1-ilsulfoniloxi, ethylsulfonyloxy, isopropylsulfonyloxy, methylsulfonyloxy, benzylsulfonyloxy, ethoxycarbonylmethoxy, hydroxycarbonylmethoxy, tbutilcarbonilamino, cyclopropylcarbonylamino, benciloxicarbonilpirrolidinilcarbonilamino, phenoxy, methylcarbonylamino, iminoethyl, tienoetilo, (S) -1fenilpropilcarbonilamino, metilfenoximetilcarbonilamino, (R) -1-phenyl-1metoximetilcarbonilamino, (S) -1-phenyl-1metoximetilcarbonilamino, furanilcarbonilaminometilcarbonilamino, tienilpropilcarbonilamino, metilcarbonilpiperidinilcarbonilamino, amino, aminocarbonyl, Nmethylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy, phenylmethylsulfonyloxy, methylcarbonylamino, Nmethylaminocarbonyl, hydroxymethyl, aminoethyl, methoxymethylaminocarbonyl, diethylaminocarbonyl, N-methylaminocarbonyl, N-amino amino laminocarbonyl, N- (2-methoxyethyl) aminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-hydroxy-1-iminoethyl, hydroxyethyl, aminomethyl, N, N-dimethylaminocarbonyl, 2,6-dimethylfuranyl, 1H [1,2,4] triazolyl , and pyridinyl.

The present invention also characterizes such compounds according to the appended claims 9-11 for use in the treatment of an HCV infection.

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 concrete compound, a salt of the compound may be advantageous due to one or more of the physical properties of the salts, such as an increase in pharmaceutical stability at different temperatures and humidity, or a desirable solubility in water or oil. In some cases, a salt of a compound can also be used as an adjuvant for 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, the 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 by conventional methods with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.

Pharmaceutically acceptable acid addition salts of the compounds of this invention can be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, the classes of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, format, 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, sulfanilate, cyclohexylaminosulfonate, bicarboxylic acid, galactic acid galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glicoheptanoato, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

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 Ia), alkaline earth metal salts (group IIa), and other physiologically acceptable metal salts. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Non-limiting examples of the preferred organic salts can be made from tertiary amines and quaternary amine salts, such

how

tromethamine, diethylamine, N, N '

dibenzylethylenediamine,

chloroprocaine, hill,

diethanolamine,

ethylenediamine, meglumine (N

methylglucamine), and procaine. Alkaline nitrogen containing groups can be quaternized with agents such as lower alkyl (C1-C6) halides (for example, chlorides, bromides and iodides of methyl, ethyl, propyl, and butyl,), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides (e.g., chlorides, bromides, and decyl, lauryl, myristyl, and stearyl iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) , and others.

Solvates and Isomers

The compounds of the present invention, their tautomers, and their salts, may also exist in the form of solvates 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 may exist in each form of solvate or mixtures thereof.

The compounds of the invention may comprise asymmetrically substituted carbon atoms known as chiral centers. These chiral centers are designated "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" used herein are the configurations defined in the Nomenclature of Organic Chemistry, Section E: Stereochemistry, Recommendations 1974, PURE APPL. CHEM., 45: 11-40 (1976). The compounds of this invention may exist, without limitation, in the form of individual stereoisomers (eg, simple enantiomers or simple diastereomers); mixtures of stereoisomers (for example any mixture of enantiomers or diastereomers), or racemic mixtures. All these simple stereoisomers, mixtures and racemates are included within the scope of the invention. It is intended that the compounds identified in the present invention as stereoisomers describe compounds that are present in a form that is substantially free of other stereoisomers (eg, 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 more preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in a composition is the desired stereoisomer. When the stereochemistry of carbon or carbons present in a chemical structure is not specified, the chemical structure is intended to encompass compounds containing any stereoisomer of each chiral center present in the chemical structure.

Individual stereoisomers of the compounds of this invention can be prepared using many methods known in the art. These methods include, but are not limited to stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of the enantiomers of an enantiomeric mixture into diastereomers followed by chromatographic separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic resolution.

Stereospecific synthesis typically involves the use of optically pure (enantiomerically pure) or substantially optically pure substances and synthetic reactions that do not cause the racemization or inversion of stereochemistry in chiral centers. Mixtures of the stereoisomers of the compounds, including racemic mixtures, that result from a synthetic reaction can be separated, for example, by chromatographic techniques as will be appreciated by those of ordinary skill in the art. Chromatographic resolution of enantiomers can be completed on chiral chromatographic resins, many of which are commercially available. In a non-limiting example, a racemate is placed in solution and loaded into the column containing a chiral stationary phase.

The enantiomers can be separated by HPLC.

The resolution of the enantiomers can also be completed by converting the enantiomers of a mixture into diastereomers by reaction with chiral auxiliary agents. The resulting diastereomers can be separated by column chromatography or crystallization / recrystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary agent. Non-limiting examples of chiral auxiliary agents include chirally pure amino acids, organic carboxylic acids or organosulfonic acids. Once the diastereomers are separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary agent can be recovered and used again.

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

Alternatively, the salts of the enantiomers of a mixture can be prepared using any method known in the art, including the treatment of the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization / recrystallization of the enantiomerically salts. pure. Suitable methods for the 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. It is intended that all double bond isomers, such as cis (Z) and trans (E) isomers, and mixtures thereof be included within the scope of the aforementioned compound unless otherwise specified. In addition, when a compound exists in various tautomeric forms, the indicated compound is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.

Some compounds of the invention may exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotations around an asymmetric single bond, for example due to steric hindrance or ring tension, can allow the separation of different conformers. The compounds of the invention include each conformational isomer of these compounds and mixtures thereof.

Some compounds of the invention may 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 in the present invention using conventional nomenclature. For an indicated compound having one or more asymmetric centers, it should be understood that all stereoisomers of the compound and mixtures thereof are included in the present invention unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-trans isomers. When an indicated compound exists in several tauromeric forms, it is intended that the compound encompasses all tautomeric forms. Some compounds are described in the present invention using general formulas that include variables. Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that appears more than once in a formula is independently defined at each occurrence. If the substituents are described by "independently selected" from one group, each substituent is independently selected from the other. Each substituent may be identical or different from the other or the other substituents.

The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix "Cx-Cy", where x is the minimum number and the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C6 alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Further illustrated, C3-C6 cycloalkyl means a saturated hydrocarbyl ring containing 3 to 6 ring carbon atoms. A prefix attached to a multi-component substituent only applies to the first component that immediately follows the prefix. As an illustration, the term "alkylaryl" contains two components: alkyl and aryl. Thus, for example, (C1-C6) alkyl aryl refers to a C1-C6 alkyl anchored to the molecular radical of origin through an aryl group. Also, C6-C10 alkylaryl refers to an alkyl group anchored to the molecular radical of origin through a C6-C10 aryl group. Similarly, the prefix "halo" in haloalkoxyalkyl indicates that the alkoxy component is substituted with one or more halogen radicals, while the prefix "halo" in alkoxyhaloalkyl indicates that the

component

I rent is replaced with one or plus

halogen radicals.

When

be use words for describe a

connecting element between two different elements of a chemical structure represented, the most left described component of the connecting element is the component that is attached to the left element in the represented structure. As an illustration, if the chemical structure is X-L-Y and L is described as methylarylethyl, the chemical structure would be X-methylarylethyl-Y.

If a connecting element in a represented structure is a link, the left element in the represented structure joins directly to the left element in the represented structure. For example, if a chemical structure is represented as X-L-Y and L is selected as a bond, the chemical structure would be X

Y. For another example, if a chemical radical is represented as -L-X and L is selected as a bond, the chemical radical would be -X. For another example, if a chemical structure is represented as X-L1-L2-Y, X-L1-L2-L3-Y or X L1L2 -...- LN-Y, and L1, L2, L3, ... > LN are selected as links, the chemical structure would 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 fifth valence.

If a substituent is described as being "substituted," a non-hydrogen radical is instead of one or more hydrogen radicals in a carbon, nitrogen or oxygen of the substituents. Thus, for example, a substituted alkyl substituent is an alkyl substituent where at least one non-hydrogen radical is in place of one or more hydrogen radicals in the alkyl substituent. As an illustration, monofluoroalkyl is alkyl substituted with a fluorine radical, and difluoroalkyl is alkyl substituted with two fluorine radicals. It should be noted that if there are two or more substitutions in a substituent, each of the non-hydrogen radicals may be identical or different unless otherwise indicated.

A substituent is "substitutable" 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 substituted or unsubstituted. If a substituent is described as being optionally substituted with up to a specific number of non-hydrogen radicals, that substituent may be unsubstituted, or substituted with up to a specific number of non-hydrogen radicals or with up to the maximum number of substitutable positions. in the substituent, whatever the minor. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to three non-hydrogen radicals, any heteroaryl with less than three substitutable positions would be optionally substituted only with up to as many non-hydrogen radicals as substitutable positions have the heteroaryl. As an illustration, tetrazolyl (having only one substitutable position) would be optionally substituted with up to a radical that is not hydrogen. As a further illustration, if an amine nitrogen is described as being optionally substituted with up to two non-hydrogen radicals, a primary amine nitrogen will be optionally substituted with up to two non-hydrogen radicals, while a secondary amine nitrogen will be optionally substituted only with even a radical that is not hydrogen.

The term "alkenyl" (alone or in combination with another or other terms) means straight or branched chain hydrocarbyl substituent containing one or more double bonds and typically 2 to 20 carbon atoms, more typically 2 to 8 carbon atoms, and even more typically 2 to 6 carbon atoms. Each carbon-carbon double bond can have cis or trans geometry in the alkenyl radical, with respect to the groups substituted on the carbons of the double bond. Non-limiting examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.

The term "alkenylene" (alone or in combination with another or other terms) refers to a divalent unsaturated hydrocarbyl group that can be linear or branched and 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 even more 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- , -CH2C (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 or other terms) refers to an alkyl group anchored to the molecular radical of origin through an oxy radical (ie, -O-alkyl). Non-limiting examples of such substituent include methoxy (-O-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secbutoxy, and tert-butoxy.

The term "alkoxyalkyl" (alone or in combination with another or other terms) refers to an alkoxy group anchored to the molecular radical of origin 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 or other terms) refers to an alkoxy group anchored to the molecular radical of origin through a carbonyl group (ie, -C (O) -O-alkyl). Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl (

image 1

), and tert-butoxycarbonyl.

The term "alkoxycarbonylamino" (alone or in combination with other or other terms) refers to N (RARB) -, where RA is alkyl-O-C (O) -, and RB is alkyl-O-C (O) -o hydrogen. RA and RB can be identical or different.

The term "alkoxycarbonylaminoalkyl" (alone or in combination with other or other terms) refers to N (RARB) -alkylene-, where RA is alkyl-O-C (O) -, and RB is alkyl-O-C (O) -o hydrogen. RA and RB can be identical

or different.

The term "alkoxycarbonylalkyl" (alone or in combination with another or other terms) refers to an alkoxycarbonyl group anchored to the molecular radical of origin through an alkylene group. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 2-methoxy-2-oxoethyl, 2-ethoxy-2oxoethyl, 3-methoxy-3-oxopropyl, 3-ethoxy-3-oxopropyl, 4ethoxy-2- (ethoxycarbonyl) -4-oxobutyl, 5-methoxy-5oxopentyl, and 6-methoxy-6-oxohexyl.

The term "alkyl" (alone or in combination with another or other terms) means saturated linear or branched chain hydrocarbyl substituent that typically contains 1 to 20 carbon atoms, more typically 1 to 8 carbon atoms, and even more typically of 1 to 6 carbon atoms. Non-limiting examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, iso-amyl, hexyl, and octyl.

The term "alkylamino" (alone or in combination with another or other terms) refers to -NRARB, where RA is alkyl, and RB is hydrogen or alkyl. RA and RB can be identical or different. For example, (C1-C6) alkyl refers to -NRARB, where RA is C1-C6 alkyl, and RB is hydrogen or C1-C6 alkyl.

The term "alkylaminoalkyl" (alone or in combination with other or other terms) refers to N (RARB) alkylene-, where RA is alkyl, and RB is hydrogen or alkyl. RA and RB can be identical or different. Thus, (C1-C6) alkyl C1-C6 aminoalkyl refers to N (RARB) -C1-C6 alkylene-, where RA is C1-C6 alkyl, and RB is hydrogen or C1-C6 alkyl.

The term "alkylcarbonyl" (alone or in combination with another or other terms) refers to an alkyl group anchored to the molecular radical of origin through a carbonyl group (ie, -C (O) -alkyl). Representative examples of alkylcarbonyl include, but are not limited to, acetyl, ethylcarbonyl.

image 1

), 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term "alkylcarbonylalkyl" (alone or in combination with another or other terms) refers to an alkylcarbonyl group anchored to the molecular radical of origin 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 or other terms) refers to an alkylcarbonyl group anchored to the molecular radical of origin through an oxy radical. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.

The term "alkylcarbonyloxyalkyl" (alone or in combination with another or other terms) refers to an alkylcarbonyloxy group anchored to the molecular radical of origin through an alkylene radical. Representative examples of alkylcarbonyloxyalkyl include, but are not limited to, 2- (acetyloxy) ethyl, 3 (acetyloxy) propyl, and 3- (propionyloxy) propyl.

The terms "alkylene" or "alkylenyl" (alone or in combination with other or other terms) indicate a divalent group derived from a linear or branched hydrocarbon chain that typically contains 1 to 20 carbon atoms, more typically 1 to 8 atoms of carbon, and even more typically 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 or other terms) means a linear or branched chain hydrocarbyl substituent containing one or more triple bonds and typically 2 to 20 carbon atoms, more typically 2 to 8 carbon atoms. , and even more typically 2 to 6 carbon atoms. Non-limiting examples of such substituents include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decinyl, 1-butynyl, 2-butynyl, and 3-butynyl.

The terms "alkynylene" (alone or in combination with another or other terms) refers to a divalent unsaturated hydrocarbon group that can be linear

or branched and having at least one carbon-carbon triple bond. Representative alkynylene groups include, by way of example, -C≡C-, -C≡C-CH2-, -C≡C-CH2CH2-, -CH2-C≡C-CH2-, -C≡C-CH ( CH3) -, and -CH2-C≡C-CH (CH2CH3) -.

The term "amino" (alone or in combination with another or other terms) means NH2. The term "monosubstituted amino" (alone or in combination with another or other terms) means an amino substituent where one of the hydrogen radicals is replaced by a non-hydrogen substituent. The term "disubstituted amino" (alone or in combination with another or other terms) means an amino substituent where both hydrogen atoms are replaced by substituents that are not, which may be identical or different.

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

image 1

The term "aminoalkyl" (alone or in combination with another or other terms) means -alkylene-NH2,

The term "aminoalkylcarbonyl" (alone or in combination with another or other terms) means -C (O) -alkylene-NH2, for example, "aminomethylcarbonyl" can be represented as:

image 1

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

image 1

The term "aryl" (alone or in combination with another or

other terms) refers to an aromatic carbocyclyl containing from 6 to 14 annular carbon atoms. Non-limiting examples of aryls include phenyl, naphthalenyl, anthracenyl, and indenyl. An aryl group can be connected to the origin molecular radical through any substitutable carbon atom group.

The term "arylalkyl" (alone or in combination with another or other terms) refers to an aryl group anchored to the molecular radical of origin 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-5yl) -2-methylpropyl, 3- (phenoxy) benzyl, 3- (1,3-benzodioxol-5-yl) propyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthylmethyl, 3,5-diterc-butyl-2-hydroxybenzyl, 3methoxybenzyl, 3,4-dimethoxybenzyl, 4- (dimethylamino) benzyl, 4- [3- (dimethylamino) propoxy] benzyl, (6-methoxy-2naphthyl) methyl, and 2-naphth-2-ylethyl.

The term "arylalkylcarbonyl" (alone or in combination with another or other terms) refers to an arylalkyl group anchored to the molecular radical of origin through a carbonyl group (ie, arylalkyl-C (O-). Representative examples of arylalkylcarbonyl they include, but are not limited to, 2-naphthylacetyl and phenylacetyl.

The term "arylalkoxy" (alone or in combination with another or other terms) refers to an arylalkyl group anchored to the molecular radical of origin through an oxy radical (ie, arylalkyl-O-). Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.

The term "arylalkoxyalkyl" (alone or in combination with another or other terms) refers to an arylalkoxy group anchored to the molecular radical of origin 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 or other terms) refers to an arylalkoxy group anchored to the molecular radical of origin through a carbonyl group. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, and naphth-2-methoxycarbonyl.

The term "arylcarbonyl" (alone or in combination with another or other terms) refers to an aryl group anchored to the molecular radical of origin through a

group

carbonyl The examples representative from

arylcarbonyl

include, but no is it so limited to,

benzoyl and naphthoyl.

The term "aryloxy" (alone or in combination with another or other terms) refers to an aryl group anchored to the molecular radical of origin through an oxy radical. Representative examples of substituted / unsubstituted aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.

The term "aryloxyalkyl" (alone or in combination with another or other terms) refers to an aryloxy group anchored to the molecular radical of origin through an alkylene group. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyl, and phenoxymethyl.

The term "aryloxycarbonyl" (alone or in combination with another or other terms) refers to an aryloxy group anchored to the molecular radical of origin through a carbonyl group.

The term "arylthio" (alone or in combination with another or other terms) refers to an aryl group anchored to the molecular radical of origin through a sulfur atom (ie, aryl-S-). Representative examples of arylthio include, but are not limited to, phenylthio, naphthalen-1-ylthium, and naphthalen-2-ylthium.

The term "arylthioalkyl" (alone or in combination with another or other terms) refers to aryl-Salkylene. 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 or other terms) refers to an arylthioalkyl group anchored to the molecular radical of origin through an oxy group.

The term "arylthioalkoxyalkyl" (alone or in combination with another or other terms) refers to an arylthioalkoxy group anchored to the molecular radical of origin through an alkylene group.

The terms "carbocycle" or "carbocyclic" or "carbocyclyl" (alone or in combination with another or other terms) refer to a saturated ring system (for example, "cycloalkyl"), partially saturated (for example, "cycloalkenyl" or " cycloalkynyl ") or completely unsaturated (for example," aryl ") containing zero hateroatoms as ring atoms and typically 3 to 18 ring carbon atoms. "Ring atoms" or "ring members" are atoms linked 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 may contain 3 to 14 ring members (i.e., C3-C14 carbocyclyl, such as C3C14 cycloalkyl), 3 to 10 ring members (i.e., C3-C10 carbocyclyl, such as C3-C10 cycloalkyl), of 3 to 8 annular members (i.e. C3-C8 carbocyclyl, such as C3-C8 cycloalkyl), 3 to 6 annular members (i.e., C3-C6 carbocyclyl, such as C3-C6 cycloalkyl), 4 to 10 annular members (i.e., C4C10 carbocyclyl, such as C4-C10 cycloalkyl and C4-C10 cycloalkenyl), of 4 to 8 ring members (ie, C4-C8 carbocyclyl, such as C4-C8 cycloalkyl and C4-C8 cycloalkenyl), or of 5 to 7 ring members (ie, C5-C7 carbocyclyl, such as C5-C7 cycloalkyl, C5-C7 cycloalkenyl and phenyl). A substituted carbocyclyl can have cis or trans geometry. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, cyclohexenyl, cyclohexenyl, cyclohexenyl, cyclohexenyl , 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 anchored to the molecular radical of origin through any substitutable carbon atom in the group.

The term "carbocyclylalkyl" (alone or in combination with another or other terms) refers to a carbocyclyl group anchored to the molecular radical of origin through an alkylene group. For example, carbocyclyl (C3-C10) C1-C6 alkyl refers to a C3-C10 carbocyclyl group anchored to the molecular radical of origin through C1-C6 alkylene. Likewise, carbocyclyl (C5-C7) C1-C6 alkyl refers to a C5-C7 carbocyclyl group anchored to the molecular radical of origin through C1-C6 alkylene.

The term "carbocyclylalkoxy" (alone or in combination with another or other terms) refers to a carbocyclylalkyl group anchored to the molecular radical of origin through an oxy group (ie, carbocyclyl-alkylene-O-). For example, carbocyclyl (C3-C10) C1-C6 alkoxy refers to a carbocyclyl (C3-C10) C1-C6 alkyl group anchored to the molecular radical of origin through an oxy group. Also, a carbocyclyl (C5-C7) C1C6 alkoxy group refers to a carbocyclyl (C5-C7) C1-C6 alkyl group anchored to the molecular radical of origin through an oxy group.

The term "carbocyclylalkoxyalkyl" (alone or in combination with another or other terms) refers to a carbocyclylalkoxy group anchored to the molecular radical of origin through an alkylene group (ie, carbocyclyl-alkylene-O-alkylene-). For example, carbocyclyl (C3-C10) (C1-C6) alkoxy C1-C6 alkyl refers to a carbocyclyl (C3-C10) C1-C6 alkoxy group anchored to the molecular radical of origin through a C1-C6 alkylene group.

5 The term "carbocyclylalkoxycarbonyl" (alone or in combination with another or other terms) refers to a carbocyclylalkoxy group anchored to the molecular radical of origin through a carbonyl group (ie, -C (O) -Olkylene-carbocyclyl). For example, carbocyclyl (C3

C10) (C1-C6) alkoxy carbonyl refers to a carbocyclyl (C3-C10) C1-C6 alkoxy group anchored to the molecular radical of origin through a carbonyl group. As a non-limiting example, "phenylethoxycarbonyl" can be represented as:

image 1

fifteen

The term "carbocyclylalkylcarbonyl" (alone or in combination with another or other terms) refers to a carbocyclylalkyl group anchored to the molecular radical of origin through a carbonyl group (ie, -C (O)

20 alkylene-carbocyclyl). For example, "phenylethylcarbonyl" can be represented as:

image 1

The term "carbocyclylcarbonyl" (alone or in combination

with another or other terms) refers to a group

carbocyclyl anchored to the molecular radical of origin a

through a carbonyl group (ie carbocyclyl-

CO)-). For example, "phenylcarbonyl" can be

represent as:

image 1

The term "carbocyclyloxy" (alone or in combination with another or other terms) refers to a carbocyclyl group anchored to the molecular radical of origin through an oxy radical (ie, carbocyclyl-O-).

5

The term "carbocyclyloxyalkyl" (alone or in combination with another or other terms) refers to a carbocyclyloxy group anchored to the molecular radical of origin through an alkylene group (ie carbocyclyl-O

10 alkylene-).

The term "carbocyclyloxycarbonyl" (alone or

combined with other or other terms) refers to

carbocyclyloxy group anchored to the molecular radical of

15 origin through a carbonyl group (ie -C (O) -Ocarbocyclyl). For example, "phenyloxycarbonyl" can be represented as:

image 1

The term "carbocyclylthio" (alone or in combination with

20 or other terms) refers to a carbocyclyl group anchored to the molecular radical of origin through a sulfur atom (i.e., carbocyclyl-S-).

The term "carbocyclylthioalkoxy" (alone or in combination with another or other terms) refers to carbocyclylalkylene-S-.

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

The term "carbocyclylthioalkyl" (alone or in combination

with another or other terms) refers to carbocyclylthio group anchored to the molecular radical of origin through an alkylene group (ie carbocyclyl-S-alkylene-).

The term "carbocyclylcarbocyclyl" (alone or in combination with another or other terms) refers to a carbocyclyl group anchored to the molecular radical of origin through another carbocyclyl group (ie, carbocyclyl-carbocyclyl-). For example, carbocyclyl (C3C10) carbocyclyl C5-C7 refers to a C3-C10 carbocyclyl group anchored to the molecular radical of origin through a C5-C7 carbocyclyl group (i.e., carbocyclyl (C3-C10) -carbocyclyl (C5- C7) -).

The term "carbocyclylcarbocyclylalkyl" (alone or in combination with another or other terms) refers to a carbocyclylcarbocyclyl group anchored to the molecular radical of origin through an alkylene group.

The term "carbocyclylalkoxycarbocyclylalkyl" (alone or in combination with another or other terms) refers to a carbocyclyl-alkylene-Ocarbocyclyl-alkylene- group. For example, carbocyclyl (C3C10) alkoxy (C1-C6) carbocyclyl (C5-C7) C3-C4 alkyl refers to carbocyclyl (C3-C10) -alkylene (C1-C6) -Ocarbocyclyl (C5-C7) -alkylene (C3 -C4) -.

The term "(carbocyclylalkyl) carbocyclylalkyl" (alone or in combination with another or other terms) refers to carbocyclyl-alkylene-carbocyclyl-alkylene-. For example, carbocyclyl (C3-C10) alkyl (C1C6) carbocyclyl (C5-C7) C3-C4 alkyl refers to carbocyclyl (C3-C10) -alkylene (C1-C6) -carbocyclyl (C5-C7) alkylene (C3-) C4) -.

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

5

The term "carbocyclylcarbonylheterocycloalkyl"

(alone or in combination with other or other terms) does

reference to carbocyclyl-C (O) -heterocyclyl-alkylene-.

10 The term "carbocyclylheterocycloalkyl" (alone or in combination with other or other terms) refers to carbocyclyl-heterocyclyl-alkylene-.

The term "carbocyclylcarbonylcarbocyclylalkyl"

15 (alone or in combination with other or other terms) refers to carbocyclyl-C (O) -carbocyclyl-alkylene-. For example, carbocyclyl (C3-C10) carbonylcarbocyclyl (C4C8) C1-C6 alkyl refers to carbocyclyl (C3-C10) C (O) -carbocyclyl (C4-C8) -alkylene (C1-C6) -.

The term "(carbocyclylalkyl) heterocycloalkyl" (alone or in combination with another or other terms) refers to carbocyl-alkylene-heterocyclyl-alkylene.

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

image 1

The term "carboxy" (alone or in combination with another

other terms) means -C (O) -OH, which can also be

represent as:

image 1

The term "carboxy alkyl" (alone or in combination with another or other terms) refers to a carboxy group anchored to the molecular radical of origin through an alkylene group. Representative examples of carboxy alkyl include, but are not limited to, carboxymethyl, 2-carboxy ethyl, and 3-carboxypropyl.

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

The term "cycloalkenyl" (alone or in combination with another or other terms) refers to a non-aromatic partially unsaturated carbocyclyl substituent, which has zero heteroatomic ring members and typically 4 to 18 carbon ring members. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl.

The term "cycloalkyl" (alone or in combination with another or other terms) refers to a saturated carbocyclyl group containing zero heteroatomic ring members and typically 3 to 18 carbon ring members. Non-limiting examples of

cycloalkyls

include cyclopropyl, cyclobutyl,

cyclopentyl,

cyclohexyl, cycloheptyl, cyclooctyl,

decalinyl and norpinanyl.

The term "cycloalkylcarbonyl" (alone or in combination with another or other terms) refers to a cycloalkyl group anchored to the molecular radical of origin through a carbonyl group.

The term "cyano" (alone or in combination with another or other terms) means -CN, which can also be represented as

image 1

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

The term "dialkylaminocarbonyl" (alone or in combination with another or other terms) refers to a dialkylamino group anchored to the molecular radical of origin through a carbonyl group (ie, N (RARB) C (O) -, where RA and RB are independently selected from alkyl groups).

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

The term "halogen" or "halo" (alone or in combination with another or other terms) means a fluorine radical (which can be represented as -F), chlorine radical (which can be represented as -Cl), bromine radical (which is It can represent as -Br), or radical iodine (which can be represented as -I).

The "halo" prefix indicates that the substituent to which the prefix is anchored is substituted with one or more independently selected halogen radicals. For example, "haloalkyl" (alone or in combination with another or other terms) means an alkyl substituent where at least one hydrogen radical is replaced by a halogen radical. Non-limiting examples of haloalkyl include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. As a further illustration, "haloalkoxy" (alone or in combination with another or other terms) means an alkoxy substituent where 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 noted that if a substituent is substituted with more than one halogen radical, those halogen radicals may be identical or different (unless otherwise indicated).

The prefix "perhalo" indicates that each hydrogen radical in the substituent to which the prefix is anchored is replaced by independently selected halogen radicals, that is, each hydrogen radical in the substituent is replaced by 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 anchored is substituted with a fluorine radical. As an illustration, the term "perfluoroalkyl" means an alkyl substituent where a fluorine radical is in place of each hydrogen radical. Non-limiting examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluoroisopropyl, perfluorobutyl, perfluorodecyl, and perfluorododecyl. As a further illustration, the term "perfluoroalkoxy" means an alkoxy substituent where each hydrogen radical is replaced by a fluorine radical. Non-limiting examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF3), perfluoroisopropoxy, perfluorobutoxy, perfluorodekoxy, and perfluorododekoxy.

The terms "heterocycle" or "heterocycle" or "heterocyclyl" (alone or in combination with another or other terms) refer to a saturated ring system (for example, "heterocycloalkyl"), partially unsaturated (for example, "heterocycloalkenyl" or " heterocycloalkynyl ") or completely unsaturated (for example," heteroaryl ") typically containing 3 to 18 ring atoms, where at least one of the ring atoms is a heteroatom (i.e. nitrogen, oxygen

or sulfur), the remaining ring atoms being independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocyclyl group can be connected to the molecular radical of origin through any substitutable carbon or nitrogen atom in the group, provided that a stable molecule is produced.

A heterocyclyl can be, without limitation, a single ring, which typically contains from 3 to 14 ring atoms (i.e., M3-M14 heterocyclyl), from 3 to 8 ring atoms (i.e., M3-M8 heterocyclyl), from 3 to 6 ring atoms (i.e., M3-M6 heterocyclyl), or 5 to 6 ring atoms (i.e., M5-M6 heterocyclyl). Nonlimiting examples of heterocyclyls single ring they include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl , thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4oxadiazolyl (also known as "azoximyl"), 1,2,5oxadiazolyl (also known as like "furazanyl"), and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1 , 2,4-dioxazolyl, 1,3,2-dioxazolyl, and 1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also known as "1,2diazi nile "), pyrimidinyl (also known as" 1,3diazinyl "), and pyrazinyl (also known as" 1,4diazinyl ")), piperazinyl, triazinyl (including striazinyl (also known as" 1,3,5-triazinyl ")) , as-triazinyl (also known as 1,2,4-triazinyl), and v-triazinyl (also known as "1,2,3-triazinyl, oxazinyl (including 1,2,3-oxazinyl, 1,3,2 -oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, 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, tiepinil, Y

diazepinyl

A

heterocyclyl may include too, without

limitation, two or more rings fused together, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, pyrolinyl pyrrolinyl, pyrolinyl pyrinyl , 4-quinolizinyl, purinyl, pyridopyridinyl (including pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl, and pyrido [4,3-b] -pyridinyl), pyridopyrimidine, and

pteridinyl

Others examples no limiting from

heterocyclyls

from ring fused include

heterocyclyls

benzofusedados, such how indolyl,

isoindolyl,

indoloninyl (too known how

"pseudoindolyl"), isoindazolyl (also known as "benzopyrazolyl"), benzazinyl (including quinolinyl (also known as "1-benzazinyl") and isoquinolinyl (also known as "2-benzazinyl")), phthalazinyl, quinoxalinyl, benzodiazinyl (including cinolinolin (also known as "1,2-benzodiazinyl") and quinazolinyl (also known as "1,3benzodiazinyl")), benzopyranyl (including "chromenyl" and "isochromenyl"), benzothiopyranyl (also known as "thiochromenyl"), benzoxazolyl , indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanil, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", thiophenyl, benzothiophenyl) isobenzothienyl (also known as "isobenzothiophenyl", "isothionephtenyl", and "isobenzothiophuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (include endo 1,3,2-benzoxazinyl, 1,4,2benzoxazinyl, 2,3,1-benzoxazinyl, and 3,1,4benzoxazinyl), benzisoxazinyl (including 1,2benzisoxazinyl and 1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl , and acridinyl.

The term "branched ring heterocyclyl" (alone or in combination with another or other terms) means a saturated, partially saturated, or aromatic heterocyclyl containing two fused rings. Non-limiting examples of the bifusioned heterocyclyls include naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, pyrizinyl, pyrizinyl, pyrizinyl, pyrizinyl, pyrizinyl, pyrizinyl, pyrizinyl, pyrinyl, pyrinyl, pyrinyl, pyrinyl, pyrinyl, pyrinyl, pyrinyl, pyrinyl, pyrinyl, pyrininyl 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 can comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom or atoms oxidize to SO or SO2. The heteroatom or nitrogen heteroatoms in a heterocyclyl can be quaternized or not, and can be oxidized or not to an N-oxide. In addition, the heteroatom or nitrogen heteroatoms may have the N protected or not.

As used herein, the number of ring atoms in a heterocyclyl radical can be identified by the prefix "Mx-My," where x is the minimum number e and is the maximum of ring atoms in the heterocyclyl radical.

The term "heterocycloalkoxy" (alone or in combination with another or other terms) refers to a heterocycloalkyl group anchored to the molecular radical of origin through an oxy group.

The term "heterocycloalkoxyalkyl" (alone or in combination with another or other terms) refers to a heterocycloalkoxy group anchored to the molecular radical of origin through an alkylene group (ie, heterocyclyl-alkylene-O-alkylene-).

The term "heterocycloalkoxycarbonyl" (alone or in combination with another or other terms) refers to a heterocycloalkoxy group anchored to the molecular radical of origin through a carbonyl group (ie, heterocyclyl-alkylene-O-C (O) -).

The term "heterocycloalkyl" (alone or in combination with another or other terms) refers to a heterocyclyl anchored to the molecular radical of origin a

through

from a group alkylene (by example,

C1-C6 heterocycloalkyl).

He

finished "heterocycloalkylcarbonyl" (alone or

combined with another or other terms) refers to a heterocycloalkyl group anchored to the molecular radical of origin through a carbonyl group (ie, -C (O) alkylene-heterocyclyl).

The term "heterocyclocarbonyl" (alone or in combination with another or other terms) refers to a heterocyclyl anchored to the molecular radical of origin through a carbonyl group (ie, -C (O) heterocyclyl).

The terms "heterocyclyloxy" or "(heterocycle) oxy" (alone or in combination with other or other terms) refers to a heterocyclyl group anchored to the molecular radical of origin through an oxy radical.

The term "(heterocycle) oxyalkyl" (alone or in combination with another or other terms) refers to a heterocyclyloxy group anchored to the molecular radical of origin through an alkylene group (ie, heterocyclyl-O-alkylene-).

The term "(heterocycle) oxycarbonyl" (alone or in combination with another or other terms) refers to a group (heterocycle) oxy anchored to the molecular radical of origin through a carbonyl group (ie, heterocyclyl-OC (O) - ).

The term "heterocyclotium" (alone or in combination with another or other terms) refers to a heterocyclyl anchored to the molecular radical of origin through -S-.

The term "heterocyclothioalkoxy" (alone or in combination

with

other or others terms) make reference to

heterocyclyl-alq

uilen-S-.

He

finished "heterocyclyloalkoxyalkyl" (only or

combined with other or other terms) refers to heterocyclyl-alkylene-S-alkylene-.

The term "heterocyclothioalkyl" (alone or in combination with another or other terms) refers to heterocyclyl group anchored to the molecular radical of origin through an alkylene group (ie heterocyclyl-Salquilen-).

The term "heterocyclocarbocyclyl" (alone or in combination with another or other terms) refers to a heterocyclyl anchored to the molecular radical of origin through a carbocyclyl group (ie, heterocyclocarbocyclyl-).

The term "heterocyclocarbocyclylalkyl" (alone or in combination with another or other terms) refers to a heterocyclocarbocyclyl group anchored to the molecular radical of origin through an alkylene group (ie, heterocyclyl-carbocyclyl-alkylene-).

The term "(heterocycle) alkoxycarbocyclylalkyl" (alone or in combination with other or other terms) refers to heterocycle-alkylene-O-carbocyclylalkylene-.

The term "(heterocycle) carbonylcarbocyclylalkyl" (alone or in combination with other or other terms) refers to heterocycle-C (O) -carbocyclyl-alkylene-.

The term "(heterocycle) heterocycloalkyl" (alone or in combination with other or other terms) refers to heterocycle-heterocycle-alkylene-.

The term "(heterocycle) alkoxyheterocycloalkyl" (alone or in combination with other or other terms) refers to heterocycle-alkylene-O-heterocycloalkylene-.

The term "(heterocycle) carbonylheterocycloalkyl" (alone or in combination with other or other terms) refers to heterocycle-C (O) -heterocycle-alkylene-.

The term "(heterocycloalkyl) carbocyclylalkyl" (alone or in combination with other or other terms) refers to heterocycle-alkylene-carbocyclyl-alkylene-.

The term "(heterocycloalkyl) heterocycloalkyl" (alone or in combination with other or other terms) refers to heterocycle-alkylene-heterocycle-alkylene-. Thus, for example, (heterocycle (M3-M10) alkyl (C1C6)) heterocycle (M5-M6) C1-C3 alkyl means heterocycle (M3-M10) -alkylene (C1-C6) -heterocycle (M5-M6) rent (C1-C3) -.

The term "heteroaryl" (alone or in combination with another or other terms) means in aromatic heterocyclyl that typically contains 5 to 18 ring atoms. A heteroaryl can be a single ring, or two or more fused rings. Non-limiting examples of five-membered heteroaryls include imidazolyl; furanyl; thiophenyl (or thienyl or thiofuranyl); pyrazolyl; oxazolyl; isoxazolyl; thiazolyl; 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,4-oxadiazolyl; and isothiazolyl. Non-limiting examples of six-membered heteroaryls include pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; and 1,3,5-, 1,2,4-, and 1,2,3-triazinyl. Non-limiting examples of 6/5 membered fused ring heteroaryls include benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl. Non-limiting examples of the 6/6 membered fused ring heteroaryls include quinolinyl; isoquinolinyl; and benzoxazinyl (including cinolinyl and quinazolinyl).

The term "heteroarylalkoxy" (alone or in combination with another or other terms) refers to a heteroarylalkyl anchored to the molecular radical of origin 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 or other terms) refers to a heteroarylalkoxy group anchored to the molecular radical of origin through an alkylene group (ie heteroaryl-alkylene-O-alkylene-). Representative examples of heteroarylalkoxyalkyl include, but are not limited to, (2-pyridin-3-ylethoxy) methyl, (3quinolin-3-ylpropoxy) methyl, (1,3-thiazol-5-ylmethoxy) methyl, and 2- ( 5-pyridin-4-ylpentyloxy) ethyl.

The term "heteroarylalkoxycarbonyl" (alone or in combination with another or other terms) refers to a heteroarylalkoxy group anchored to the molecular radical of origin through a carbonyl group (ie heteroaryl-alkylene-O-C (O) -). Representative examples of heteroarylalkoxycarbonyl include, but are not limited to, (2-pyridin-3-ethoxy) carbonyl, (3-quinolin-3-ylpropoxy) carbonyl, 2 (1,3-thiazol-5-ylmethoxy) carbonyl, and (5 -pyridin-4-pentyloxy) carbonyl.

The term "heteroarylalkyl" (alone or in combination with another or other terms) refers to a heteroaryl group anchored to the molecular radical of origin 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-methylmethyl, pyridin-3-ylmethyl, and 2-pyrimidin- 2-ilpropyl.

The term "heteroarylalkylcarbonyl" (alone or in combination with another or other terms) refers to a heteroarylalkyl group anchored to the molecular radical of origin through a carbonyl group (ie heteroaryl-C-alkylene-O (-) -).

The term "heteroarylcarbonyl" (alone or in combination with another or other terms) refers to a heteroaryl group anchored to the molecular radical of origin through a carbonyl group. Representative examples of heteroarylcarbonyl include, but are not limited to, pyridin-3-ylcarbonyl, (1,3-thiazol-5yl) carbonyl, and quinolin-3-ylcarbonyl.

The term "heteroaryloxy" (alone or in combination with another or other terms) refers to a heteroaryl group anchored to the molecular radical of origin through an oxy radical. 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 or other terms) refers to a heteroaryloxy group anchored to the molecular radical of origin through an alkylene group (ie heteroaryl-Oalkylene-).

The term "heteroaryloxycarbonyl" (alone or in combination with another or other terms) refers to a heteroaryloxy group anchored to the molecular radical of origin through a carbonyl group (ie heteroaryl-O-C (O) -).

The term "heteroarylthio" (alone or in combination with another or other terms) refers to a heteroaryl group anchored to the molecular radical of origin through -S-.

The term "heteroarylthioalkoxy" (alone or in combination with another or other terms) refers to heteroarylalkylene-S-.

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

The term "heteroarylthioalkyl" (alone or in combination with another or other terms) refers to a heteroarylthio group anchored to the molecular radical of origin through an alkylene group (ie heteroaryl-Salquilen-).

The term "hydrogen" (alone or in combination with another or other terms) refers to a hydrogen radical, and can be represented as -H.

The term "hydroxy" (alone or in combination with another or other terms) refers to -OH.

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

The term "keto" (alone or in combination with another or other terms) means an oxo radical, and can be represented as = O.

The term "iminoalkyl" (alone or in combination with another or other terms) refers to a radical of formula

image 1

where H may be optionally substituted with alkyl or hydroxy, in which case the substituent would be alkyliminoalkyl or hydroxyiminoalkyl respectively.

The term "nitro" (alone or in combination with another or other terms) means -NO2,

10

The term "oxo" (alone or in combination with another or other terms) refers to a radical = O (that is,

image 1 ).

15 The term "oxy" (alone or in combination with another or other terms) means -O-.

The term "propargyl" (alone or in combination with another or other terms) means the monovalent radical 20 represented as: -CH2-CH≡CH.

The term "sulfonyl" (alone or in combination with another or other terms) means -S (O) 2-, which can also be represented as:

image 1

The term "sulfinyl" (alone or in combination with another

other terms) means -S (O) -, which can also be

represent as:

image 1

The term "uncle" or "aunt" (alone or in combination with another or other terms) means -S-.

The term "thiol," "mercapto" or "sulfhydryl" (only

or combined with another or other terms) means a sulfhydryl substituent, (i.e., -SH). Thus, for example, thiolalkyl means an alkyl substituent where one or more hydrogen radicals are replaced by -SH, while alkylthio means alkyl-S-.

The term "thioalkoxy" (alone or in combination with another or other terms) refers to an alkyl group anchored to the molecular radical of origin through -S-. Representative examples of thioalkoxy include, but are not limited to, methylthio, ethylthio, and butylthio.

The term "thioalkoxyalkyl" (alone or in combination with another or other terms) refers to a thioalkoxy group anchored to the molecular radical of origin through an alkylene group (ie, alkyl-S-alkylene-).

The term "thiocarbonyl" (alone or in combination with another or other terms) means a carbonyl where the oxygen atom has been replaced by a sulfur. Such substituent can be represented as -C (S) -, and can also be represented as:

image 1

The term "pharmaceutically acceptable" is used adjectively to mean that the modified noun is appropriate for use as a pharmaceutical product or as part of a pharmaceutical product.

The term "therapeutically effective amount" refers to the total amount of each active substance 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 that have chemically or metabolically cleavable groups and are converted, by solvolysis or under physiological conditions, into the compounds of the invention that are pharmaceutically active in vivo. A prodrug of a compound can be formed in a conventional manner by reacting a functional group of the compound (such as an amino, hydroxy or carboxy group). The prodrug derivative form often offers advantages of solubility, 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 by reaction of the acidic compound of origin, a suitable alcohol, or amides prepared by 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 derivatives of alcohol or amine functional groups in the compounds of the invention.

The term "solvate" refers to the physical association of a compound of this invention with one or more solvent, organic or inorganic molecules. This physical association often includes hydrogen bonds. In some cases the solvate will be susceptible to isolation, for example when one or more solvent molecules are incorporated into the crystalline lattice of the crystalline solid. "Solvato" encompasses solvates both in solution phase and insulated. Illustrative 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 superimposable on their mirror image. A chiral molecule can exist in two forms, a dextrógira and a levógira.

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 around a double bond or ring. Cistrans isomers are also called geometric isomers.

The term "enantiomer" refers to stereoisomers of a chiral substance that have a specular relationship.

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

The term "racemic mixture" refers to a

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

5

The term "tautomer" refers to isomers that are interchangeable. For example, enoles and ketones are tautomers since they are interconverted by acid or base treatment.

The term "positional isomer" refers to any two or more constitutional isomers that differ in the position of a specific substituent or group. Functional groups may be anchored to

15 structurally non-equivalent positions in the carbon skeleton. For example, [1,3] imidazole, represented as

image 1

and [1,4] imidazole, represented as

twenty

image 1

They are positional isomers.

The term "N protecting group" or "N protected" refers to those groups capable of protecting an amino group from unwanted reactions. The N-protecting groups commonly used are described by Greene and Wuts, in PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3rd ed., John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Non-limiting examples of the 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, 4bromobenzoyl, 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, pclorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, pnitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, pbromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyloxycarbonyl, 2,4-dimethoxycarbonyl, 2,4-dimethoxycarbonyl, 2,4-dimethoxycarbonyl, 2,4-dimethoxycarbonyl, 2,4-dimethoxycarbonyl, 2,4-dimethoxycarbonyl, 2,4-dimethoxycarbonyloxycarbonyl, 2,4 5dimetoxibenciloxicarbonilo, 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, pmethoxybenzyl, triphenylmethyl, or benzyloxymethyl; pmethoxyphenyl; 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 are used in the General Synthetic Methods and the examples described below: AcOH = acetic acid atm = atmospheres Boc = Nt-butoxycarbonyl (protective group) CDI = 1,1'-carbonyldiimidazole CH2Cl2 = methylene chloride (dichloromethane) CuI = cuprous iodide [copper iodide (I)] DCE = 1,2-dichloroethane DEAD = diethyl azodicarboxylate DMA = NN-dimethylacetamide DMAP = 4-dimethylaminopyridine DMF = N, N-dimethylformamide DMSO = dimethyl sulfoxide EDCI = hydrochloride of (N- ethyl-N '- (3-dimethylaminopropyl) carbodiimide EMME = diethyl ester of 2-ethoxymethylene-malonic acid Et3N = triethylamine Ether = diethyl ether EtI = ethyl iodide EtOAc = ethyl acetate EtOH = ethanol Fe = iron Fe (AcAc) 3 = iron (III) acetylacetonate Fmoc chloride = 9-fluorenylmethylchloroformate HOBt = N-Hydroxybenzotriazole Hunig Base = N, N-diisopropylethylamine IPA = isopropyl alcohol K2CO3 = potassium carbonate KOH = potassium hydroxide LDA = diisopropyl LDA = diisopropyl hydroxide lithium amide MeOH = methanol MsCl = methanesulfonyl chloride NaH = sodium hydride NH2OH · HCl = hydroxylamine hydrochloride NMP = 1-methyl-2-pyrrolidinone Mg2SO4 = magnesium sulfate Na2SO4 = sodium sulfate NH3 = ammonia NH4Cl = ammonium chloride NH4OH = ammonium hydroxide PG = protecting group such as Boc-o TrocPOCl3 = phosphorus oxychloride R-MgCl = Grignard reagent RI = alkyl iodide or substituted alkyl iodide SnCl2 = Stannous chloride (Tin Chloride (II)) TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography Triflic anhydride = trifluoromatanesulfonic anhydride Troc = 2,2,2-trichloroethoxycarbonyl- (protective 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. The starting substances can be obtained from commercial sources or prepared using methods well known to those of ordinary skill in the art. By way of example, synthetic methods similar to those shown here below may be used, together with synthetic methods known in the art of organic chemistry, or variations thereof, as those skilled in the art will appreciate.

It is intended that the present invention encompasses compounds prepared by synthetic methods

or metabolic procedures. Metabolic procedures include those that occur in the human or animal organism (in vivo), or those that occur in vitro.

If a substituent described in the present invention is not compatible with the synthetic methods of this invention, the substituent can be protected with a suitable protecting group that is stable under the conditions of

5 reaction used in these methods. The protecting group can be removed at any suitable point in the reaction sequence to provide a desired intermediate or target compound. Appropriate protecting groups and methods to protect or unprotect

10 substituents are well known in the art, examples can be found in Greene and Wuts, supra.

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

The synthesis of compounds of Formulas II (a) or II (b) generally involves the reaction of

image 1

20 with

image 1

R11 R12

where R2, R3, R7, R9,,, and R13 have the

25 meanings shown in the above embodiments or examples, and K is Cl or other halogen. Schemes 1, 2, 3 and 4 below show a representative method for the preparation of these compounds [1,8] naphthyridine.

30

The 7-substituted-4-substituted [1,8] naphthyridine compounds are generally synthesized (Scheme 4) by coupling a 7-substituted-4-chloro [1,8] naphthyridine 8 compound with a coupling compound such as 10, 11 and 12 (Scheme 3). Other 4-substituted [1,8] 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 is treated with ammonium hydroxide in a metal reactor at scale at approximately 180 ° C for approximately 40 hours. After cooling to room temperature the product is filtered producing 6-chloro-2-aminopyridine. A solution of this product and hexane-2,5-dione in benzene is treated with acetic acid, heated under reflux conditions with azeotropic removal of water for approximately 20 hours. This reaction mixture is cooled to room temperature, diluted with diethyl ether, washed with dilute hydrochloric acid and water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give 6-chloro-2- (2,5-dimethyl-pyrrol-1-yl-pyridine 1. Compound 1 is treated with (R-MgX) in dry tetrahydrofuran (THF) and 1-methyl-2-pyrrolidinone (NMP) at room temperature under a nitrogen atmosphere and iron (III) acetylacetonate [Fe (AcAo) 3] is added and the mixture is stirred at room temperature for 18 hours. the reaction is added two loads of Grignard reagent and iron catalyst.The reaction is quenched by pouring it into 5% acetic acid and extracted with ether.The ether layer is dried over sodium sulfate, filtered and concentrated in vacuo to give 6-substituted-2

(2,5-dimethyl-pyrrol-1-yl) -pyridine 2. Compound 2 can be converted directly into a 6-substituted-2-amino-pyridine 4 or can be further functionalized by reacting it with an alkyl iodide or an alkyl iodide substituted in the presence of lithium diisopropylamide (LDA). In this case, a solution of compound 2 in dry tetrahydrofuran is added dropwise over approximately 30 minutes to a stirred solution of lithium diisopropylamide in dry tetrahydrofuran at -30 ° C. An alkyl iodide or a substituted alkyl iodide (R-I) in tetrahydrofuran is then added dropwise over approximately 30 minutes, then it is quenched at room temperature. After two hours the reaction mixture is quenched by pouring it into a saturated solution of sodium chloride and extracted with ether. The ether solution is dried over magnesium sulfate, filtered and concentrated in vacuo yielding 6-substituted-2- (2,5-dimethylpyrrol-1-yl) pyridine 3. A solution of compound 20 2 or 3 and hydroxylamine hydrochloride in Ethanol and water are heated at approximately 100 ° C for approximately 16 hours, cooled to room temperature and extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated in vacuo yielding the

6-substituted-aminopyridine 4 used in Scheme 2. The substituent at position 6 in Scheme 1 is the R7 described above.

30

35

Scheme 1

image 1

5 Preparation of 7-substituted-4-Chloro- [1,8] 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 (EMME)

10 and heat to approximately 100 ° C with stirring for approximately 2.5 hours. The reaction mixture is cooled to room temperature and diluted with hexane, the resulting solid is filtered and dried in vacuo to give the aminomethylenemalonic acid ester 5. Compound 5 is

Then dissolve diphenyl ether and the resulting solution is heated at 250 ° C for approximately 30 minutes. After cooling to room temperature, diluting with hexane the resulting solid is filtered and dried in vacuo yielding the 7-substituted-4-oxo1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester "E "replaced. A solution of compound 6 and potassium hydroxide (KOH) is heated in a sealed metal reactor at 180 ° C for approximately 16 hours, cooled to

5 room temperature and adjust to pH 6 with 1N hydrochloric acid. The resulting precipitate is filtered and dried to yield 7-substituted [1,8] naphthyridin-4-ol 7. A mixture of compound 7 is mixed with phosphorus oxychloride (POCl3) and heated to approximately 50 ° C

10 stirring for 6 hours, cool by pouring it on ice. It is cooled, then adjusted to pH 10 with ammonium hydroxide and extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo yielding the 7-substituted-4-chloro

[1,8] naphthyridine 8. The substituents for compound 8 are shown in Scheme 2 as R7 which is described as before.

image2

Preparation of Aminophenyl Coupling Agents (10, 11 and 12)

A wide variety of aminophenyl coupling agents are possible. The agents of Scheme 3 are illustrative of this variety.

In a typical preparation, a dimethylformamide-substituted 2-chloronitrobenzene compound (DMF) is treated with a sodium thiophenolate at about 50 ° C for about 2 hours, cooled and diluted with methylene chloride, washed with water, washed Dry over sodium sulfate, filter and concentrate in vacuo to give the substituted compound-2-phenylsulfanylnitrobenzene. This nitrobenzene compound is then reduced with stannous chloride (SnCl2) or iron (Fe) in ethanol. The reaction mixture is adjusted to pH 12 with 1N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo yielding the substituted compound-2-phenylsulfanyl-aminobenzene 10.

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

image3

Similarly, any compound 10 where R9 is protected hydroxy- or hydroxyl can be further modified by alkylating the hydroxy group using a substituted benzyl bromide to give the compound of 5

5 substituted-phenoxy-2-substituted-phenylsulfanyl-aminobenzene corresponding 11.

X is OH, NH2, NHR, halo, alkyl, or alkoxyR is alkyl, alkoxy, bromine, fluorine, chlorine, or cyano

Preparation of 7-substituted-4-aminophenyl15 [1,8] naphthyridines

As shown in Scheme 4, the coupling agent (compound 10, 11, 12 or the like) suitable for the synthesis of 7-substituted-4-aminophenyl

[1,8] substituted naphthyridine is dissolved in ethanol and reacted with compound 8 in ethanol at 80 ° C for approximately 7 hours. The reaction mixture is concentrated in vacuo and recrystallized from tetrahydrofuran with a few drops of methanol. Filtration produces the desired 7-substituted-4-aminophenyl- [1,8] naphthyridine 13, 14

or 15.

Scheme 4

image4

X is defined as before;

R is defined as before

15 Preparation of Amide Coupling Agents

As described in Scheme 3, they are possible

a wide variety of coupling agents from

aminophenyl. These aminophenyl coupling agents

20 can be used to prepare 7-substituted-4

desired aminophenyl- [1,8] naphthyridine according to the procedures represented in Scheme 4.

In Scheme 5, aminophenyl compounds with amide substitution in the 3-phenyl position are described.

An aniline substituted in methylene chloride is treated with 4-chloro-3-nitrobenzoyl chloride and N, Ndiisopropylamine and stirred at room temperature for approximately 17 hours. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the N-substituted-phenyl-4-chloro-3- nitrobenzamide 16.

Compound 16 can be further modified by displacement of the 4-chloro group to produce the 3-amino-4-substituted-phenoxybenzamides 17 and the 3-amino-4- substituted-phenylsulfanylbenzamides 18.

Compounds 17 can typically be prepared by reacting benzamide 16 in N, anhydrous N-dimethylformamide with 4- (N-tbutoxycarbonyl) aminophenol (N-Boc-4-hydroxyaniline) and potassium carbonate at room temperature, then heated to approximately 80 ° C for about 5 hours. The reaction is cooled to room temperature, the solvent is removed in vacuo, the residue is taken up in ethyl acetate, washed with water and brine. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to yield the substituted 4-N-tbutoxycarbonylamino compound 17. The Boc protecting group can be removed with a variety of methods to produce the compounds of structure 17.

Similarly, compound 16 can be reacted with 4-aminothiophenol and anhydrous sodium acetate in anhydrous ethanol by refluxing for approximately 19 hours. After cooling to

At room temperature the ethanol is removed in vacuo, the residue is taken up in water and extracted with ethyl acetate. The organic extracts are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the solid with ethyl acetate

10 methylene chloride provided compound 18.

Some examples will require the use of protective groups followed by removal of the protective group at the appropriate time. R is defined as before

image5

The optimal reaction conditions and reaction times for each individual stage may vary depending on the specific reactants employed and the substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions can be easily selected by a person skilled in the art. The reactions can be prepared in the conventional manner, for example by removing the solvent from the residue and are further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, crushing and chromatography.

It should be understood that the embodiments and schemes described above and the following examples are given by way of illustration, not limitation.

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

Example 1a

2 - [(6-Methyl-pyridin-2-ylamino) methylene] -malonic acid diethyl ester

A mixture of 2-methyl-5-aminopyridine (12.48 g, 115 mmol) and 2-ethoxymethylenemalonic acid diethyl ester (7.46 mL, 89.2 mmol) was heated at 100 ° C with stirring for 2.5 h . It was cooled to room temperature and diluted with hexane. It was filtered and dried in vacuo yielding the title compound (21.05 g, 85%).

Example 1b 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 1a (2.50 g, 9.0 mmol) was added in several small portions over a period of approximately 5 min after it was heated to 250 ° C for 30 min. After cooling to room temperature it was diluted with hexane. The resulting solid was filtered and dried in vacuo yielding the title compound as a tan solid (1.47 g, 71%).

Example 1c

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

A solution of the product of Example 1b (1.30 g, 5.59 mmol) and NaOH (233 mg, 5.82 mmol) in 20 mL of water was heated in a sealed metal reactor at 180 ° C for 16 h. It was cooled to room temperature and adjusted to pH 6 with 1N HCl. The resulting precipitate was filtered and dried in vacuo yielding the title compound as a black solid (743 mg, 82%).

Example 1d

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

A mixture of the product of Example 1c (320 mg, 2.0 mmol) in 6 mL of POCl3 was heated at 50 ° C with stirring for 6 h. It was cooled to room temperature and suffocated by pouring it into ice. It was adjusted to pH 10 with NH4OH and extracted with CH2Cl2. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound as a tan solid (322 mg, 90%).

Example 1e

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

A solution of sodium thiophenolate (3.96 g, 30 mmol) in 60 mL of DMF was heated at 50 ° C with 4-chloro-3-nitrotoluene (2.65 mL, 20 mmol) stirring for 2 days. It was cooled to room temperature and diluted with CH2Cl2. It was washed with water and the organic layer was dried over Na2SO4. It was filtered and concentrated in vacuo yielding the title compound (4.29 g, 87%) 1 H NMR (300 MHz, CDCl3) δ ppm: 2.36 (s, 3 H) 6.76 (d, J = 8 , 09 Hz, 1H) 7.16 (d, J = 8.46 Hz, 1H) 7.45 (m, 3 H) 7.58 (m, 2 H) 8.03 (s, 1H).

Example 1f

5-Methyl-2-phenylsulfanyl-phenylamine

A solution of the product of Example 1e (1.17 g, 7.0 mmol) in 25 mL of absolute EtOH and SnCl2 (3.58 g, 29.8 mmol) was stirred at room temperature for 16

h. It was adjusted to pH 12 with 1N NaOH and extracted with EtOAc. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound (835 mg, 82%) H1 NMR (300 MHz, CDCl3) δ ppm: 2.30 (2.3 H) 6.62 (d, J = 8.83 Hz, 1H) 6.69 (s, 1H) 7.10 (m, 3 H) 7.21 (m, 2 H) 7.54 (d, J = 7.72 Hz, 2 H ).

Example 1g

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

A stirred solution of the product of Example 1d (65 mg, 0.36 mmol) and the product of Example 1f (77 mg, 0.36 mmol) in 3 mL of EtOH was heated at 80 ° C for 7

h. It was concentrated in vacuo. It was recrystallized from THF with a few drops of MeOH. Filtration produced the title compound as the hydrochloride salt as a white solid (62 mg, 43%) H1 NMR (300 MHz, CDCl3) δ ppm: 1.62 (broad s, 1H) 2, 43 (s, 3 H) 2.52 (s, 3 H) 6.02 (d, J = 7.0 Hz, 1H) 7.05-7.35 (m, 8 H) 7.70 (wide s , 1 H) 8.00 (d, J = 7.0 Hz, 1H) 8.85 (d, J = 8.5 Hz, 1H) 10.80 (wide s, 1H); MS (ESI +) m / z 358 (M-Cl) +; (ESI) m / z 356 (M-HCl) -.

Example 2

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

Example 2a

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

A solution of 2-methyl-5-aminopyridine (5.0 g, 46 mmol) and hexane-2,5-dione (5.4 mL, 46 mmol) in 60 mL benzene was treated with HOAc (0.5 mL, 7.9 mmol). The solution was heated at reflux with azeotropic removal of water for 20 h. It was cooled to room temperature and diluted with ether. It was washed with dilute HCl and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo yielding 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 while stirring to a solution of LDA (42.4 mmol) in 30 mL of dry THF at -30 ° C. It was stirred at -30 ° C for 30 min. EtI (3.42 mL, 42.0 mmol) in 20 mL of dry THF was added dropwise while stirring for 30 min then it was warmed to room temperature. After 2 h, it was quenched by pouring it into a saturated NaCl solution and extracted with ether. It was dried over MgSO4, filtered and concentrated in vacuo yielding the title compound. The product was purified by silica gel column chromatography eluting with EtOAc / hexane to give the title compound (5.21 g, 60%).

Example 2c

6-Propyl-pyridin-2-ylamine

A solution of the product of Example 2b (348 mg, 1.52 mmol) and NH2OH HCl (530 mg, 7.62 mmol) in 4 mL of EtOH / 1.5 mL water. It was heated at 100 ° C for 16 h, cooled to room temperature and extracted with CH2Cl2. It was dried over MgSO4, filtered and concentrated in vacuo yielding the title compound as an amber oil (223 mg, 100%).

2d example

2 - [(6-Propyl-pyridin-2-ylamino) methylene] -malonic acid diethyl ester

The product of Example 2c (223 mg, 1.52 mmol) was reacted with 2ethoxymethylene-malonic acid diethyl ester 0.350 mL, 1.75 mmol) following the procedure of Example 1a to give the title compound after chromatography on silica gel column 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 of Example 1b yielding the title compound as a tan solid (4.73 g, 81%).

Example 2f

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

The product of Example 2e (4.73 g, 18.1 mmol) was reacted with NaOH (756 mg, 18.9 mmol) following the procedure of Example 1c yielding the title compound as a solid (3.42 g, 100%).

Example 2g

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

The product of Example 2f (145 mg, 0.76 mmol) was reacted with 4 mL POCl3 following the procedure of Example 1d to yield the title compound as a solid (135 mg, 86%).

Example 2h

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

The product of Example 2g (65 mg, 0.31 mmol) was reacted with the product of Example 1f (68 mg, 0.31 mmol) for 24 h following the procedure of Example 1g producing the title compound as a hydrochloride salt in the form of a solid that was triturated with ether producing (110 mg, 84%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 2.38 (qnt, J = 7.35 Hz, 2 H) 2.99 (dd , J = 7.35 Hz, J = 7.72 Hz, 2 H) 6.31 (d, J = 7.35 Hz, 1H) 7.23 (s, 5 H) 7.35 (m, 4 H ) 7.79 (d, J = 8.46 Hz, 1 H) 8.38 (d, J = 6.98 Hz, 1H) 9.01 (d, J = 8.46 Hz, 1H) 11.10 (s, 1H) 14.35 (broad s, 1H); MS (ESI +) m / z 386 (M-Cl) +; (ESI-) m / z 384 (M-HCl) -.

Example 3

(7-Ethyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) -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 N2 atmosphere, n-BuLi was added dropwise in the form of a solution 2.5 M in hexanes (16 mL, 40 mmol). The resulting solution was stirred at low temperature for thirty minutes, then treated with CH3I (2.4 mL, 38.6 mmol). Once the addition was complete, the mixture was allowed to warm to -30 ° C and after 20 min at room temperature. The reaction was subsequently quenched by pouring it into a brine solution, the product was isolated by extraction with EtOAc. It was dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography eluting with EtOAc / hexane afforded the title compound (4.42 g, 60%).

Example 3b

6-Ethyl-pyridin-2-ylamine

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

Example 3c

2 - [(6-Ethyl-pyridin-2-ylamino) methylene] -malonic acid diethyl ester

The crude product of Example 3b was combined with 2-ethoxymethylene malonic acid diethyl ester (6.6 mL, 0.032 mol) and the mixture was heated under an atmosphere of N2 in an oil bath at 100 ° C for 2 h. It was purified by flash chromatography on silica gel eluting with EtOAc / hexane to yield the title compound (7.16 g, 98%).

3d illustration

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

The product of Example 3c (7.16 g, 0.024 mol) was heated in diphenyl ether following the procedure of Example 1b yielding the title compound (4.73 g, 79%) as a tan solid.

Example 3e

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

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

Example 3f

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

The product of Example 3e (200 mg, 1.14 mmol) was treated with POCl3 following the procedure of Example 1d to produce the title compound as a brown solid (183 mg, 83%).

Example 3g

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

The product of Example 3f (88 mg, 0.46 mmol) was reacted with the product of Example 1f (100 mg, 0.46 mmol) for 24 h following the procedure of Example 1f producing the title compound as a hydrochloride salt that was triturated with ether producing (134 mg, 70%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (t, J = 7.35 Hz, 3 H) 3.02 (c, J = 7.35 Hz, 2 H) 6.69 (d , J = 6.99Hz, 1 H) 6.97 (d, J = 8.82 Hz, 2 H) 7.10 (dd, J = 7.35 Hz, IH) 7.15 (d, J = 8 , 82 Hz, 2 H) 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, 1 H) 8.52 (d, J = 6.99 Hz, 1H) 9, 02 (d, J = 8.45 Hz, 1H) 11.16 (wide s, 1H) 14.56 (wide s, 1H); MS (ESI +) m / z 376 (M-Cl) +; (ESI-) m / z 374 (M-HCl) -.

Example 4

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

Example 4a

Trifluoromethanesulfonic acid 4-methyl-2-nitro-phenyl ester

A solution of 4-methyl-2-nitrophenol (6.0 g, 39.1 mmol) and Et3N (16.38 mL, 117.5 mmol) in 100 mL of CH2Cl2 in an N2 atmosphere was treated with trifluoromatanesulfonic anhydride ( 7.25 mL, 43.1 mmol) at 0 ° C for 30 min. It was quenched by the addition of MeOH. It was washed successively with 10% citric acid, 0.5 M KOH and water. It was dried over MgSO4, filtered and concentrated in vacuo yielding the title compound that was purified by silica gel column chromatography eluting with CH2Cl2 yielding an amber oil (11.22 g, 100%).

Example 4b

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

The product of Example 4a (11.22 g, 39.3 mmol) and 4-mercaptophenol (4.96 g, 39.3 mmol) in 100 mL of EtOH was treated with Na2CO3 and heated overnight at reflux. It was cooled to room temperature and suffocated with water. It was extracted with EtOAc. It was dried over MgSO4, filtered and concentrated in vacuo yielding the title compound, which was purified by silica gel column chromatography eluting with 25% EtOAc / hexane to yield a red oil (8.65 g, 85 %).

Example 4c

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

The product of Example 4b (8.65 g, 31.3 mmol) was reduced with SnCl2 following the procedure of Example 1f to produce the title compound as a white solid (8.51 g, 100%).

4d example

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

The product of Example 4c (131 mg, 0.530 mmol) was reacted with the product of Example 3f (97 mg, 0.503 mmol) for 21 h following the procedure of Example 1g yielding the title compound as a hydrochloride salt which triturated with ether / THF 5: 1 yielding (210 mg, 98%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J = 7.35 Hz, 3 H) 2.33 (s, 3 H) 3.05 (c, J = 7.35 Hz , 2 H) 6.29 (d, J = 6.99 Hz, 1H) 6.74 (d, J = 8.46 Hz, 2 H) 7.00 (m, 1H) 7.17-7.29 (m, 4 H) 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 (wide s, 1H) 14.38 (wide s, 1H); MS (ESI +) m / z 388 (M-Cl) +; (ESI-) m / z 386 (M-HCl) -.

Example 5

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

The product of Example 1d (277 mg, 0.156 mmol) was reacted with the product of Example 4c (361 mg, 0.156 mmol) for 5 h by the procedure of Example 1g producing the title compound after purification of the crude product by HPLC with TFA in the form of the trifluoroacetic acid salt (231 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3 H) 2.77 (s, 3 H) 6.29 (d, J = 6.99 Hz, 1H) 6.73 ( d, J = 8.82 Hz, 2 H) 7.01 (d, J = 7.72 Hz, 1H) 7.19 (d, J = 8.46 Hz, 2 H) 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 (wide s, 1H); MS (ESI +) m / z 374 (M + H) +.

Example 6

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

The product of Example 2g (275 mg, 0.133 mmol) was reacted with the product of Example 4c (231 mg, 0.133 mol) for 5 h following the procedure of Example 1g producing the title compound after purification of the crude product by HPLC with TFA in the form of the trifluoroacetic acid salt (288 mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 2 H) 1.85 (m, 2 H) 2.33 (s, 3 H) 3.00 (t, J = 7.35 Hz 2 H) 6.29 (d, J = 6.99 Hz, 1H) 6.73 (d, J = 8.46 Hz, 2 H) 7.00 (m, 2 H) 7.19 (d, J = 8.46 Hz, 2 H) 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 (wide s, 1H); MS (ESI +) m / z 402 (M + H) +.

Example 7

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

Example 7a

2,6-dibromo-nicotinic acid

A sample of 2,6-dichloro-nicotinic acid (2.50 g, 13.0 mmol) was reacted with 25 mL of 30% HBr / HOAc in a sealed metal reactor at 110 ° C for 2 h at 12.45 kg / cm2 It was cooled to room temperature and extracted with EtOAc and washed with water. It was dried over MgSO4, filtered and concentrated in vacuo yielding the title compound as a solid (3.22 g, 88%).

Example 7b

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

The product of Example 7a was subjected to the reaction sequence in United States Patent No.

6,818,654 to give the title compound.
Example 7c
1-Tert-Butyl-4-oxo-7-trifluoromethyl-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester
The product of Example 7b (101 mg, 0.28 mmol) was reacted with difluorofluorosulfonyl acetic acid methyl ester (0.132 mL, 1.43 mmol) in 2 mL of DMF with CuI (71 mg, 0.37 mmol) at 75 ° C for 15 h under an N2 atmosphere producing the title compound as a solid (57 mg, 59%).
Example 7d
5-Chloro-2-trifluoromethyl- [1,8] naphtinidine
The product of Example 7c was deprotected with trifluoroacetic acid following the procedure of Example 16b and then treated successively using the procedures of Examples 1b-1d to give the title compound as a solid (142 mg, 87%). The performance is for the last stage of the sequence.
Example 7e
(5-Methyl-2-phenylsulfanyl-phenyl) - (7-trifluoromethyl [1,8] naphthyridin-4-yl) -amine
The product of Example 7d (65 mg, 0.28 mmol) and the product of Example 1f (61.5 mg, 0.28 mmol) were reacted 28 h following the procedure of Example 1g yielding the title compound as a hydrochloride salt after trituration with ether producing (131 mg, 99%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 6.43 (d, J = 6.99 Hz, 1H) 7.23 (m, 4H) 7.35 (m, 4H) 8.39 (d, J = 8.82 Hz, 1H) 8.55 (d, J = 6.99 Hz, 1H) 9.48 (d, J = 8.46 Hz, 1H) 11.55 (wide s, 1H); MS (ESI +) m / z 412 (M-Cl) +; (ESI-) m / z 410 (M-HCl) -.
Example 8
(7-Isopropyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine
Example 8a
2- (2,5-Dimethyl-pyrrol-1-yl) -6-isopropyl-pyridine
The product of Example 12b (1.5 g, 7.26 mmol) was reacted with isopropyl magnesium bromide (4.35 mL, 8.7 mmol) following the procedure of Example 12c, after 1h a second charge was made of the Grignard reagent and the iron catalyst producing the title compound. The product was purified by silica gel column chromatography eluting with 2% EtOAc / hexane yielding (880 mg, 56%).
Example 8b
5-Chloro-2-isopropyl- [1,8] naphthyridine
The product of Example 8a was treated successively using the procedures of Examples 2c-2g to give the title compound.
Example 8c
(7-Isopropyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine
The product of Example 8b (0.098 g, 0.475 mmol) was reacted with the product of Example 1f (0.102 g, 0.475 mmol) for 18 h following the procedure of Example 1g to give the title compound, which was purified by HPLC with TFA It was converted into the hydrochloride salt by treatment with 4N HCl in dioxane at room temperature produced hydrochloride salt (0.076 g, 38%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (d, J = 6.99 Hz, 6 H) 2.38 (s, 3 H) 3.30 (m, 1H) 6.32 (d , J = 6.99 Hz, 1H) 7.24 (s, 5 H) 7.34 (m, 3 H) 7.86 (d, J = 8.82 Hz, 1H) 8.39 (d, J = 7.35 Hz, 1H) 9.08 (d, J = 8.46 Hz, 1H) 11.16 (s, 1H) 14.36 (m, 1H); MS (ESI +) m / z 386.0 (M + H) +.
Example 9
(5-Methoxy-2-phenylsulfanyl-phenyl) - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 9a
4-Methoxy-2-nitro-1-phenylsulfanyl-benzene
A solution of 1-Chloro-4-methoxy-2-nitro-benzene (3.75 g, 20.0 mmol) was reacted with sodium thiophenolate (3.96 g, 30.0 mmol) at 70 ° C for 70 ° C. 48 h following the procedure of Example 1e yielding the title compound as a yellow oil after silica gel column chromatography eluting with 25% EtOAc / hexane (2.70 g, 54%).
Example 9b
5-Methoxy-2-phenylsulfanyl-phenylamine
The product of Example 9a (2.70 g, 10.2 mmol) is
reacted with SnCl2 (9.40 g, 50.0 mmol) for 22 h following the procedure of Example 1f yielding the title compound as a white solid (2.28 g, 96%).
Example 9c
(5-Methoxy-2-phenylsulfanyl-phenyl) - (7-methyl [1,8] naphthyridin-4-yl) -amine
The product of Example 9b (69 mg, 0.30 mmol) was reacted with the product of Example 1d (53 mg, 0.30 mmol) following the procedure of Example 1g producing the title compound as a hydrochloride salt then of trituration with solid (119 mg, 96%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3 H) 3.83 (s, 3 H) 6.34 (d, J = 6.99 Hz, 1H) 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, 1H) 8 , 99 (d, J = 8.46 Hz, 1H) 11.16 (wide s, 1H) 14.43 (wide s, 1 H); MS (ESI +) m / z 374 (M-Cl) +; (ESI-) m / z 372 (M-HCl) -.
Example 10
7-Methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid ethyl ester
Example 10a
4-Chloro-7-methyl- [1,8] naphthyridine-3-carboxylic acid ethyl ester
The product of Example 1b (1.0 g, 4.30 mmol) was reacted with 12 mL of POCl3 for 4 h following the procedure of Example 1d yielding the title compound as a brownish pink solid (619 mg , 57%).
Example 10b
7-Methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid ethyl ester
The product of Example 10a (438 mg, 2.03 mmol) was reacted with the product of Example 1f (510 mg, 2.03 mmol) for 10 min following the procedure of Example 1g yielding the title compound that was purified by silica gel column chromatography eluting with 4% MeOH / CH2Cl2 as a solid (114 mg, 57%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (t, J = 6.99 Hz, 3 H) 2.16 (s, 3 H) 2.62 (s, 3 H) 4.29 (c, J = 7.11 Hz, 2 H) 6.86 (s, 1H) 7.04 (d, J = 8.09 Hz, 1H) 7.15 -7.34 (m, 6 H) 7 , 39 (d, J = 7.72 Hz, 1H) 7.69 (d, J = 8.82 Hz, 1H) 9.17 (s, 1H) 10.13 (s, 1H); MS (ESI +) m / z 430 (M + H) +, (ESI-) m / z 428 (MH) -.
Example 11
7-Methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid methoxymethyl-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 min. It was cooled to room temperature and diluted with water, adjusted to pH 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 methoxymethyl-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 min. N hydrochloride, Odimethylhydroxylamine (25 mg, 0.215 mmol) was added and stirred at room temperature for 24 h. The solvent was concentrated in vacuo yielding the title compound. After purification of the crude product by HPLC with AA the product was isolated as the free base (12 mg, 21%). 1 H NMR (300 MHz, DMSO-D6) δ 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, 1H) 7.15 -735 (m, 7 H) 7.44 (d, J = 8.46 Hz, 1H) 8.34 ( d, J = 8.09 Hz, 1 H) 8.67 (s, 1H); MS (ESI +) m / z 445 (M + H) +, 467 (M + Na) +, MS (ESI-) m / z 443 (MH) -.
Example 12
4- [2- (7-Isobutyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
Example 12a
6-Chloro-pyridin-2-ylamine
A solution of 2,6-dichloropyridine (500 g, 3.37 mol) was treated with NH4OH in a sealed metal reactor at 180 ° C for 40 h. After cooling to room temperature the product was isolated by suction filtration yielding the title compound as a solid (400 g, 92%).
Example 12b
2-Chloro-6- (2,5-dimethyl-pyrrol-1-yl) -pyridine
The product of Example 12a (20 g, 156 mmol) was treated with hexane-2,5-dione (18.3 mL, 156 mmol) for 2 h following the procedure of Example 2a yielding the title compound (17.7 g 55%)
Example 12c
2- (2,5-Dimethyl-pyrrol-1-yl) -6-isobutyl-pyridine
The product of Example 12b (1.0 g, 4.84 mmol) was treated with 2.0 M isobutylmagnesium chloride (2.90 mL, 5.81 mmol) in 30 mL THF and 3 mL NMP at room temperature in a atmosphere of N2. Fe (acac) 3 (85 mg, 0.242 mmol) was added and stirred at room temperature for 18 h. In the course of reaction two, two additional charges of Grignard reagent and catalyst were added. The reaction was quenched by pouring it into 5% acetic acid and extracting with ether. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound that was purified by silica gel column chromatography eluting with 10% EtOAc / hexane to give (620 mg, 56%).
Example 12d
5-Chloro-2-isobutyl- [1,8] naphthyridine
The product of Example 12c was treated successively using the procedures of Examples 2c-2g to give the title compound.
Example 12e
4- [2- (7-Isobutyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -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 h following the procedure of Example 1g producing the title compound after purification of the crude product by HPLC with TFA in the form of the trifluoroacetic acid salt (90 mg, 47%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (d, J = 6.62 Hz, 6 H), 2.13 -2.30 (m, 1H), 2.33 (s, 3 H ), 2.89 (d, J = 6.99 Hz, 2 H), 6.29 (d, J = 6.99 Hz, 1H), 6.73 (d, J = 8.46 Hz, 2 H ), 7.00 (d, J = 8.09 Hz, 1H), 7.13-7.34 (m, 4 H), 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 (wide s, 1H), 14.36 (wide s, 1H ); MS (ESI +) m / z 416 (M + H) +; (ESI-) m / z 414 (MH) -.
Example 13
4- [2- (7-Ethoxy- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
Example 13a
1-tert-Butyl-7-chloro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester
This compound was prepared from 2.6 acid
dichloro-nicotinic as described in US Patent No. 6,818,654 to give the title compound.
Example 13b
7-Chloro-4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid ethyl ester
The product of Example 13a (0.282 g, 0.91 mmol) was combined at room temperature with 2 mL of TFA containing 2 drops of sulfuric acid. The resulting mixture was heated at 70 ° C for 16.5 h. Volatile substances were removed in vacuo and the residue was suspended in water. The product was collected by vacuum filtration, washed with water and dried in vacuo to give the title compound as a cream-colored solid (0.214 g, 93%).
Example 13c
[1,8] Naphthyridine-2,5-diol
The product of Example 13b (0.208 g, 0.82 mmol) was reacted as described in Example 1c to give the title compound as a dark brown solid (0.196 g, 97%).
Example 13d
2,5-Dichloro- [1,8] naphthyridine
The product of Example 13c (0.111gm, 0.68 mmol) was reacted as described in Example 1d to give the title compound as a light yellow solid (0.124g, 91%).
Example 13e
4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
The product of Example 13d (0.67 g, 3.36 mmol) and the product of Example 4c (0.78 g, 3.36 mmol) in 10 mL ethanol were heated at reflux for 5.5 hr. The reaction mixture was cooled to room temperature and the solvent was removed, concentrated in vacuo leaving a yellow solid that was used without further purification (1.43 g, 100%).
Example 13f
4- [2- (7-Ethoxy- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
The product of Example 13e (0.025 g, 0.063 mmol) was treated with 2 mL of 21% NaOEt by weight in EtOH. The resulting mixture was heated at reflux 4 h. The solvent was concentrated in vacuo 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 produce a light brown powder (20 mg, 78%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.44 (t, J = 6.99 Hz, 3 H) 2.32 (s, 3 H) 4.56 (c, J = 6.99 Hz , 2 H) 6.24 (d, J = 6.99 Hz, 1 H) 6.68 -6.81 (m, 2 H) 6.98 (d, J = 8.09 Hz, 1H) 7, 05 -7.34 (m, 3 H) 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-methylphenylsulfanyl] -phenol
Example 14a
2,7-Dimethyl-1H- [1,8] naphthyridine-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 2h It was cooled to room temperature and poured into water, neutralized with 1N NaOH. It was extracted with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo yielding a yellow oil which was heated in diphenyl ether at 250 ° C for 1 h. It was cooled to room temperature, diluted with hexane and the product was isolated by suction filtration to yield the title compound that was used without purification.
Example 14b
4-Chloro-2,7-dimethyl- [1,8] naphthyridine
The product of Example 14a (500 mg, 2.87 mmol) was reacted with 10 mL of POCl3 for 2 h following the procedure of Example 1d yielding the title compound, which was used without purification.
Example 14c
4- [2- (2,7-Dimethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
The product of Example 14b (60 mg, 0.31 mmol) was reacted with the product of Example 4c (72 mg, 0.31 mmol) for 12 h following the procedure of Example 1g producing the title compound as a crude solid that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (45 mg, 37%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.23 (s, 3 H) 2.75 (s, 3 H) 3.43 (s, 3 H) 6.10 (s, 1H) 6, 68 (d, J = 8.82 Hz, 2 H) 6.99 -7.20 (m, 3H) 7.20 7.38 (m, 2 H) 7.75 (d, J = 8.82 Hz , 1H) 8.96 (d, J = 8.82 Hz, 1H) 9.86 (s, 1H) 10.78 (s, 1H) 14.21 (s, 1H); MS (APCI) m / z 386 (MH) -.
Example 15
4- [2- (7-Methoxy- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
Example 15a
4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
The product of Example 13e (670 mg, 3-36 mmol) was reacted with the product of Example 4c (780 mg, 3.36 mmol) for 5.5 h following the procedure of Example 1g producing the title compound as of the hydrochloride salt (1.43 g, 100%).
Example 15b
4- [2- (7-Methoxy- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
The product of Example 15a (0.100 g, 0.254 mmol)
It was treated with 5 mL of Methanol and NaOMe powder (95%, 0.27 g, 5 mmol). The resulting mixture was heated at reflux 18 h. The solvent was concentrated in vacuo leaving an oily residue orange. The crude oil was purified by HPLC (CH3CN gradient from 0 to 95% / 0.1% TFA) to yield the title compound as a trifluoroacetic acid salt which was isolated as a yellow powder (75 mg, 76%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.32 (s, 3 H) 4.10 (s, 3 H) 6.25 (d, J = 7.35 Hz, 1H) 6.65 - 6.81 (m, 3 H) 6.99 (d, J = 8.09 Hz, 1H) 7.13 -7.29 (m, 3 H) 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, 1 H); MS (ESI +) m / z 390 (M + H) +; (ESI-) m / z 388 (M + H) -.
Example 16
4- [4-Methyl-2 - ([1,8] naphthyridin-4-ylamino) -phenylsulfanyl] phenol
Example 16a
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 United States Patent No. 6,818,654 to give the title compound.
Example 16b
4-Hydroxy- [1,8] naphthyridine-3-carboxylic acid ethyl ester
The product of Example 16a (6.36 g, 23.1 mmol) was reacted with 50 mL of trifluoroacetic acid and 1 mL of H2SO4 for 1 h at room temperature. The solvent was concentrated in vacuo to yield the title compound as a solid (5.05 g, 99%).
Example 16c
4-Chloro- [1,8] naphthyridine
The product of Example 16b was subjected to the reactions following the procedures of Example 1c and Example 1d to produce the title compound as a solid (106 mg, 96%).
Example 16d
4- [4-Methyl-2 - ([1,8] naphthyridin-4-ylamino) -phenylsulfanyl] phenol
The product of Example 16c in the form of a 0.9M solution in methanol (0.080 mL, 0.07 mmol) was reacted with the product of Example 4c in the form of a 0.7M solution in ethanol (0.100 mL, 0.07 mmol) for 18 h following the procedure of Example 1g to give the crude product that was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (0.017 g, 51%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3 H) 6.33 (d, J = 6.99 Hz, 1H) 6.69-6.78 (m, 2 H) 7.02 (d, J = 8.09 Hz, 1H) 7.16 7.20 (m, 2 H) 7.23-7.29 (m, 2 H) 7.92 (dd, J = 8, 46, 4.41 Hz, 1H) 8.51 (d, J = 6.99 Hz, 1H) 9.10-9.23 (m, 2 H) 11.14 (s, 1H); MS (ESI +) m / z 360.0 (M + H) +, (ESI-) m / z 358.1 (MH) -.
Example 17
4- [2- (7-Isopropyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol
The product of Example 8b (100 mg, 0.435 mmol) was reacted with the product of Example 4c (105 mg, 0.435 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA producing the trifluoroacetic acid salt (90 mg, 47%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J = 6.62 Hz, 6 H), 2.13 -2.30 (m, 1H), 2.33 (s, 3 H), 2.89 (d, J = 6.99 Hz, 2 H), 6.29 (d, J = 6.99 Hz, 1H), 6.73 (d, J = 8.46 Hz, 2 H), 7.00 (d, J = 8.09 Hz, 1H), 7.13-7.34 (m, 4 H), 7.81 (d, J = 8.46 Hz, 1H), 8 , 43 (d, J = 6.99 Hz, 1H), 9.03 (d, J = 8.46 Hz, 1 H), 10.99 (wide s, 1H), 14.36 (wide s. , 1 HOUR); MS ESI + m / z 416 (M + H) +; ESI-m / z 414 (MH) -.
Example 18
N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
Example 18a
N- [4- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide
The product of Example 4a (1 g, 3.51 mmol) was reacted with N- (4-mercapto-phenyl) -acetamide (0.65 g, 351 mmol) for 18 h following the procedure of Example 4b producing the compound of the title (1.04 g, 98%).
Example 18b
N- [4- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -acetamide
The product of Example 18a (0.30 g, 1 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.27 g, 100%) as an amber oil which was used without further purification.
Example 18c
N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 18c (0.27 g, 1 mmol) was combined with the product of Example 1d (0.178 g, 1 mmol) and reacted according to the procedure described in Example 1g to give the crude product as a Brown solid that was purified by HPLC with TFA to provide the trifluoroacetic acid salt that was converted to the hydrochloride salt by 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-d6) δ ppm: 2.04 (s, 3 H) 2.35 (s, 3 H) 2.76 (s, 3 H) 6.29 (d, J = 6, 99 Hz, 1H) 7.24 (m, 5 H) 7.50 (d, J = 8.82 Hz, 2 H) 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 (MH) -.
Example 19
N- {4- [2- (7-Ethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The product of Example 3f (92 mg, 0.47 mmol) was reacted with the product of Example 18b (130 mg, 0.47 mmol) for 22 h following the procedure of Example 1g yielding the title compound as a solid after purification of the crude product by HPLC with TFA in the form of a trifluoroacetic acid salt (68 mg, 26%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J = 7.72 Hz, 1 H) 2.04 (s, 3 H) 2.35 (s, 3 H) 3.05 (c, J = 7.72 Hz, 2 H) 6.31 (d, J = 6.98 Hz, 1H) 7.15 (d, J = 8.83 Hz, 1H) 7.20-7.35 (m, 3 H) 7.49 (d, J = 8.83 Hz, 2 H) 7.82 (d, J = 8.82 Hz, 1H) 8.41 (d, J = 6.99 Hz, 1H) 8.99 (d, J = 8.82 Hz, 1 H) 10.04 (s, 1H) 11.01 (wide s, 1H) 14.39 (wide s, 1H). MS (ESI +) m / z 429 (M + H-Cl) +; (ESI-) m / z 427 (MH-Cl) -.
Example 20
N- {4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 2g (93 mg, 0.44 mmol) was reacted with the product of Example 18b (123 mg, 0.44 mmol) for 23 h following the procedure of Example 1g producing the title compound after purification of the crude product by HPLC with TFA in the form of a solid trifluoroacetic acid salt (72 mg, 29%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H), 1.84 (dq, J = 14.75, 7.46 Hz, 2 H) , 2.04 (s, 3 H), 2.35 (s, 3 H), 2.99 (t, J = 7.35 Hz, 2 H), 6.31 (d, J = 6.99 Hz , 1H), 7.15 (d, J = 8.09 Hz, 1H), 7.20 7.33 (m, 4 H), 7.50 (d, J = 8.46 Hz, 2 H), 7.81 (d, J = 8.46 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 9.00 (d, J = 8.46 Hz, 1H), 10, 05 (s, 1H), 11.02 (s, 1H); MS (ESI +) m / z 443 (M + H) +; (ESI-) m / z 441 (MH) -.
Example 21
N- {4- [4-Methyl-2- (7-trifluoromethyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
A solution of the product of Example 7d (50.0 mg, 0.215 mmol), and the product of Example 18b (59.0 mg, 0.215 mmol) in ethanol (2 mL) was stirred in a preheated oil bath at 80 ° C for 16 hours The mixture was then cooled to room temperature, the ethanol was removed in vacuo, and the resulting crude residue was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (22.0 mg, 22%). . 1 H NMR (300 MHz, DMSOd6) δ ppm: 2.03 (s, 3 H), 2.32 (s, 3 H), 6.33 (d, J = 5.52 Hz, 1H), 7.01 (d, J = 8.09 Hz, 1H), 7.15 (d, J = 8.46 Hz, 1H), 7.21-7.27 (m, 3 H), 7.54 (d, J = 8.82 Hz, 2 H), 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-HTFA) -.
Example 22
N- {4- [2- (7-sec-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
Example 22a
2-sec-Butyl-5-chloro- [1,8] naphthyridine
Example 22b
N- {4- [2- (7-sec-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The product of Example 22a (50 mg, 0.226 mmol) was reacted with the product of Example 18b (62 mg, 0.226 mmol) for 16 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC on TFA providing the product in the form of a trifluoroacetic acid salt (33 mg, 32%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.85 (t, J = 7.35 Hz, 3 H), 1.35 (d, J = 6.99 Hz, 3 H), 1.73 (dd, J = 13.60, 6.99 Hz, 1H), 1.79-1.90 (m, 1H), 2.03 (s, 3 H), 2.35 (s, 3 H), 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, 4 H), 7.51 (d, J = 8.82 Hz, 2 H), 7.84 (d, J = 8.46 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 9.02 (d, J = 8.46 Hz, 1H), 10.05 (s, 1H), 11.02 (s, 1H); MS (ESI +) m / z 457 (M + H) +, (ESI-) m / z 455 (MH) -.
Example 23
N- {4- [2- (7-Cyclopentyl- [1,8] naphthyridin-4-ylamino) -4methyl-phenylsulfanyl] -phenyl} -acetamide
Example 23a
S-Chloro-2-cyclopentyl- [1,8] naphthyridine
Example 23b
N- {4- [2- (7-Cyclopentyl- [1,8] naphthyridin-4-ylamino) -4methyl-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of a trifluoroacetic acid salt (29 mg, 29%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.71 1.76 (m, 3 H), 1.79 -1.93 (m, 4 H), 2.04 (s, 3 H), 2.14 (d, J = 7.72 Hz, 2 H), 2.35 (s, 3 H), 6.31 (d, J = 6.99 Hz, 1 H), 7.14 (d, J = 8.09 Hz, 1H), 7.21-7.32 (m, 4 H), 7.51 (d, J = 8.82 Hz, 2 H), 7.84 (d, J = 8 , 82 Hz, 1 H), 8.40 (d, J = 6.99 Hz, 1H), 8.99 (d, J = 8.46 Hz, 1H), 10.05 (s, 1H), 11 , 00 (s, 1 H); MS (ESI +) m / z 469 (M + H) +, (ESI-) m / z 467 (MH) -.
Example 24
N- (4- {2- [7- (2-Hydroxy-ethyl) - [1,8] naphthyridin-4-ylamino] -4methyl-phenylsulfanyl} -phenyl) -acetamide
Example 24a
N- {4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The product of Example 13d (200 mg, 1.0 mmol) and the product of Example 18b (215 mg, 1.0 mmol) were reacted following the procedure of Example 1g to produce a crude solid that was purified by HPLC with TFA to give the title compound 200 mg, 48%).
Example 24b
2- {5- [2- (4-Acetylaminophenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} malonic acid diethyl ester
To a suspension of sodium hydride (95%, 0.045 g, 1.8 mmol) in 10 mL of anhydrous THF at 0 ° C in an N2 atmosphere was added diethyl malonate (0.32 g, 2.0 mmol ) drop by drop. The mixture was stirred for 30 minutes at room temperature, treated with the product of Example 24a (0.141 g, 0.3 mmol), heated at 110 ° C for two hours, cooled and partitioned between EtOAc and water. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to yield the title compound as yellow crystals, (0.14 g, 84% yield).
Example 24c
N- (4- {2- [7- (2-Hydroxy-ethyl) - [1,8] naphthyridin-4-ylamino] -4methyl-phenylsulfanyl} -phenyl) -acetamide
The product of Example 24b (56 mg, 0.10 mmol) was reacted with NaBH4 (40 mg, 1.00 mmol) in 5 mL EtOH for 24 h. It was quenched with aqueous NH4Cl and adjusted to pH 7 with dilute HCl. It was extracted with EtOAc and dried over Na2SO4, filtered and concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA yielding the trifluoroacetic acid salt (15 mg, 25%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.04 (s, 3 H) 2.35 (s, 3 H) 3.16 (t, J = 6.43 Hz, 2 H) 3.91 (t, J = 6.25 Hz, 2 H) 6.31 (d, J = 6.99 Hz, 1H) 7.14 (d, J = 8.09 Hz, 1H) 722-7.33 (m , 4 H) 7.51 (d, J = 8.82 Hz, 2 H) 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, 1 H) 11.03 (s, 1H) 14.40 (s, 1H); MS (ESI +) m / z 445 (M + H-TFA) +.
Example 25
N- {4- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
Example 25a
2-Butyl-6- (2,5-dimethyl-pyrrol-1-yl) -pyridine
The product of Example 2a 1.0 g, 5.37 mmol) was reacted with propyl iodide 0.55 mL, 5.64 mmol) instead 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 of Examples 2b-2g to give the title compound.
Example 25c
N- {4- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The product of Example 25b (170 mg, 0.77 mmol) was reacted with the product of Example 18b (209 mg, 0.77 mmol) for 19 h following the procedure of Example 1g producing the title compound after purification of the crude product by HPLC with TFA in the form of a trifluoroacetic acid salt in the form of a solid (130 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J = 7.72 Hz, 3 H) 1.39 (sext, 2 H), J = 7.72 Hz) 1.80 ( qnt, J = 7.72 Hz, 2 H) 2.04 (s, 3 H) 2.35 (s, 3 H) 3.01 (dd, J = 7.36 Hz, 2 H) 6.81 ( d, J = 6.99 Hz, 1H) 7.15 (d, J = 8.09 Hz, 1H) 7.22-7.32 (m, 4 H) 7.50 (d, J = 8.82 Hz, 2 H) 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 (wide s, 1H) 11.02 (wide s, 1H) 14.41 (wide s, 1H); MS (ESI +) m / z 457 (M + H); (ESI-) m / z 455 (MH) -.
Example 26
N- {4- [4-Methyl-2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 16c (50 mg, 0.304 mmol) was reacted with the product of Example 18b (83 mg, 0.304 mmol) for 16 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (29 mg, 24%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.04 (s, 3 H), 2.35 (s, 3 H), 6.34 (d, J = 6.99 Hz, 1H), 7 , 17 (d, J = 7.72 Hz, 1H), 7.23 (d, J = 8.46 Hz, 2 H), 7.28-7.34 (m, 2 H), 7.49 ( d, J = 8.82 Hz, 2 H), 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, 1 H); MS (ESI +) m / z 401 (M + H) +, (ESI-) m / z 399 (MH) -.
Example 27
2- {5- [2- (4-Acetylaminophenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} malonic acid diethyl ester
The crude product of Example 24b was purified by silica gel column chromatography eluting with 3% MeOH / CH2Cl2 followed by HPLC with TFA to yield the title compound as a trifluoroacetic acid salt (70 mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.22 (t, J = 7.17 Hz, 6 H) 2.04 (s, 3 H) 2.35 (s, 3 H) 4.24 (c, J = 6.99 Hz, 4 H) 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, 4 H) 7.54 (d, J = 8.82 Hz, 2 H) 7.96 (d, J = 8.46 Hz, 1H) 8.46 (d , J = 6.99 Hz, 1H) 9.16 (d, J = 8.46 Hz, 1H) 10.06 (s, 1H) 11.20 (s, 1H) 14.53 (s, 1H); MS (ESI +) m / z 559 (M + H = TFA) +.
Example 28
{5- [2- (4-Acetylaminophenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridine-2 -lamino} -acetic acid ethyl ester
The product of Example 24a (47 mg, 0.10 mmol) was reacted with glycine ethyl ester hydrochloride (84 mg, 0.10 mmol) in 2 mL of EtOH in a sealed tube at 150 ° C for 1 h . It was cooled to room temperature and concentrated. It was adjusted to pH 7 with 1M HCl and extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA to provide the product as a solid trifluoroacetic acid (12 mg, 19%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.22 (t, J = 6.99 Hz, 3 H) 2.04 (s, 3 H) 2.33 (s, 3 H) 4.15 (c, J = 7.23 Hz, 2 H) 4.27 (d, J = 6.25 Hz, 2 H) 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, 4 H) 7.57 (d, J = 8.46 Hz, 2 H) 8.04 (t, J = 6.62 Hz, 1H) 8.53 (d, J = 9.19 Hz, 1H) 8.72 (t, J = 5.88 Hz, 1H) 10, 08 (s, 1H) 10.43 (s, 1H) 13.43 (d, J = 5.88 Hz, 1H); MS (ESI +) m / z 502 (M + H-TFA) +.
Example 29
2- {5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] [1,8] naphthyridin-2-yl} -malonic acid tert-butyl ester
To a suspension of sodium hydride (95%, 0.025 g, 1.0 mmol) in 5 mL of anhydrous THF at 0 ° C in an atmosphere of N2 was added ethyl tert-butylmalonate (0.188 g, 1.0 mmol ) drop by drop. 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 h. The solution was cooled and added to water, acidified by 1M HCl at pH 4 and extracted with EtOAc and washed with saturated brine. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the crude title compound that was purified by chromatography on silica eluting with 1% MeOH in CH2Cl2 to give the title compound as a hydrochloride salt (0.040 g, yield 64%) 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.26 (t, J = 7.11 1 Hz, 3 H) 1.49 (s, 9 H) 2.04 (s, 3 H) 2, 30 (s, 3 H) 4.16 (c, J = 7.11 Hz, 2 H) 5.76 (s, 1H) 6.07 (d, J = 5.88 Hz, 1 H) 6.98 (d, J = 7.72 Hz, 1H) 7.11 (d, J = 8.09 Hz, 1H) 7.26 (m, 4 H) 7.56 (d, J = 8.82 Hz, 2 H) 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, 1 H); MS (ESI +) m / z 587 (M + H) +.
Example 30
{5- [2- (4-Acetylaminophenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} cyanoacetic acid ethyl ester
The title compound was prepared according to the procedure of Example 27 by substituting ethyl cyanoacetate (0.240 mg, 2.1 mmol) for diethyl malonate. The crude product was purified by chromatography on silica eluting with 2% methanol in dichloromethane to give a yellow powder (0.092 g, 55% yield). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.28 (t, J = 6.99 Hz, 3 H) 03 (s, 3 H) 2.31 (s, 3 H) 4.24 (c , 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, 2 H) 7.23 (d, J = 8.46 Hz, 2 H) 7.53 (d, J = 8.82 Hz , 2 H) 8.13 (d, J = 5.88 Hz, 1 H) 8.60 (d, J = 9.56 Hz, 1 H) 9.37 (s, 1 H) 10.03 (s, 1 H) 13.09 (s, 1 H); MS (ESI +) m / z 512 (M + H) +.
Example 31
{5- [2- (4-Acetylaminophenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} cyanoacetic acid tert-butyl ester
The title compound was prepared according to the procedure of Example 27 by substituting tert-butyl cyanoacetate (0.282 mg, 2.0 mmol) with 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). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.52 (s, 9 H) 2.03 (s, 3 H) 2.30 (s, 3 H) 6.14 (d, J = 5, 88 Hz, 1H) 6.98 -7.27 (m, 6 H) 7.53 (d, J = 8.82 Hz, 2 H) 8.11 (d, J = 5.88 Hz, 1 H) 8.55 (d, J = 9.56 Hz, 1H) 9.33 (s, 1H) 10.03 (s, 1H) 13.12 (s, 1H); MS (ESI +) m / z 540 (M + H) +.
Example 32
N- {4- [2- (7-Cyanomethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The product of Example 31 (0.101 g, 0.19 mmol) was added to 5 mL trifluoroacetic acid and 5 mL of CH2Cl2. The mixture was stirred at room temperature for 2 h and concentrated in vacuo yielding 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, DMSOd6) δ ppm: 2.04 (s, 3 H) 2.35 (s, 3 H) 4.64 (s, 2 H) 6.35 (d, J = 6.99 Hz , 1H) 7.18 (d, J = 8.46 Hz, 1H) 7.23 (d, J = 8.82 Hz, 2 H) 7.30 (m, 2 H) 7.48 (d, J = 8.46 Hz, 2 H) 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 a saturated solution of sodium bicarbonate (0.5 mL) and toluene (1 mL) is treated with phenylboronic acid (14 mg, 0.11 mmol) ) and tetrakistriphenylphosphinopalladium (8 mg, 0.0074 mmol) and the mixture was heated at reflux 4 hr. 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 in vacuo leaving the crude title compound as an orange oil that was purified by HPLC with TFA to give the product as a salt of trifluoroacetic acid (15 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.06 (s, 3 H), 2.77 (s, 3 H), 6.44 (d, J = 6.99 Hz, 1H), 7 , 21 (d, J = 8.09 Hz, 1H), 7.36 (d, J = 8.46 Hz, 2 H) 7.41-7.52 (m, 3 H), 7.58 (d , J = 8.82 Hz, 2 H), 7.71 (d, J = 7.35 Hz, 2 H), 7.75-7.87 (m, 3 H), 8.44 (d, J = 6.62 Hz, 1H), 9.02 (d, J = 8.82 Hz, 1H), 10.10 (s, 1 H) 11.12 (s, 1H), 14.41 (s, 1H ); MS (ESI +) m / z 477 (M + H) +.
Example 34
N- {4- [5-Hydroxy-4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
Example 34A
N- [4- (5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl) -phenyl] acetamide
A mixture of 2-Methyl-4-nitro-5-chlorophenol (1.5 g, 8.0 mmol), 4-Acetamidothiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF (10 mL) was heated 2.5 h at 100 ° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and a 10% aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo leaving the title compound as a solid (2.5 g, 81%).
Example 34b
N- [4- (2-Amino-5-hydroxy-4-methyl-phenylsulfanyl) -phenyl] acetamide
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 a methanol solution ( 10 mL), tetrahydrofuran (10 mL), and water (5 mL) was heated at reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a bed of celite. The filtrate was concentrated in vacuo to a volume of 10 mL, the solution was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound (1.7 g, 91%).
Example 34c
N- {4- [5-Hydroxy-4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (102 mg, 0.570 mmol) was reacted in ethanol (2 mL) with the product of Example 34b (161 mg, 0.560 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound which purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (50 mg, 21%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3 H) 2.12 (s, 3 H) 2.75 (s, 3 H) 6.31 (d, J = 6, 99 Hz, 1H) 6.61 (s, 1H) 7.15 (s, 1H) 7.29 (d, J = 8.46 Hz, 2 H) 7.56 (d, J = 8.82 Hz, 2 H) 7.77 (d, J = 8.82 Hz, IH) 8.39 (d, J = 5.52 Hz, 1H) 8.96 (d, J = 8.82 Hz, 1H) 9, 90 (s, 1 H) 10.08 (s, 1 H) 10.84 (s, 1 H) 14.24 (wide s, 1 H); MS (ESI +) m / z 431 (M + H) +.
Example 35
N- {4- [2- (7-Propyl- [1,8] naphthyridin-4-ylamino) -4trifluoromethyl-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- (4mercapto-phenyl) -acetamide (185 mg, 1.11 mmol) following the procedure of Example 1e for 16 h to give the product 350 mg, 88%) which was reduced with SnCl2 following the procedure of 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) -4trifluoromethyl-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the salt of ditrifluoroacetic acid (10.5 mg, 10%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 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, 2 H), 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, 2 H), 7.69 (d, J = 8.82 Hz, 2 H), 7.78 (dd, J = 8.82, 1.47 Hz, 1H), 7.87 (d, J = 8.82 Hz, 1H), 7.91 (d, J = 1.10 Hz, 1H), 8 , 52 (d, J = 6.99 Hz, 1H), 9.03 (d, J = 8.46 Hz, 1H), 11.14 (s, 1H); MS (ESI +) m / z 497 (M + H) +, ESI-m / z 495 (MH) -.
Example 36
N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4trifluoromethyl-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (21.5 mg, 20%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.07 (s, 3 H), 2.78 (s, 3 H), 6.43 (d, J = 6.99 Hz, 1H), 7 , 09 -7.15 (m, 1H), 7.44 (d, J = 8.46 Hz, 2 H), 7.68 (d, J = 8.46 Hz, 2 H), 7.78 ( dd, J = 8.64, 1.65 Hz, 1H), 7.84 (d, J = 8.82 Hz, 1H), 7.92 (d, J = 1.84 Hz, 1H), 8, 52 (d, J = 7.35 Hz, 1H), 9.00 (d, J = 8.46 Hz, 1H), 10.19 (s, 1H), 11.12 (s, 1H); MS (ESI +) m / z 469 (M + H-TFA) +, (ESI-) m / z 467 (MH-TFA) -.
Example 37
[2- (4-Acetylaminophenylsulfanyl) -5-methyl-phenyl] - [7- (2-hydroxy-ethyl) [1,8] naphthyridin-4-yl] -carbamic acid tert-butyl ester
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 of dry THF. Et3N (8.0 mg, 0.08 mmol) and a catalytic amount of N, N-4-dimethylaminopyridine were added and stirred for 2 h. It was poured into water and neutralized with 1M HCl. It was extracted with EtOAc, dried over Na2SO4 and filtered and concentrated in vacuo to yield the crude title compound that was purified by silica gel column chromatography eluting with 1% MeOH / CH2Cl2 to give the product as a base. solid free (7.0 mg, 26%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.22 (d, J = 8.82 Hz, 2 H) 7.36 (d, J = 8.09 Hz, 1H) 7.52 (d, J = 8.82 Hz, 2 H) 7.70 (d, J = 8.46 Hz, 1H) 8.50 (d, J = 8.09 Hz, 1H) 10.00 (s, 1H); MS (ESI-) m / z 545 (M + H) +.
Example 38
N- {4- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylbenzenesulfinyl] -phenyl} -acetamide
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 provide the product as trifluoroacetic acid (34 mg, 32%). 1 H NMR (500 MHz, DMSO-d6) δ ppm: 1.07 (t, J = 7.32 Hz, 3 H), 1.91 -1.98 (m, 4 H), 2.11 (s, 3 H), 2.49 (s, 3 H), 3.05 -3.10 (m, 2 H), 6.03 (d, J = 6.84 Hz, 1H), 7.31 (d, J = 8.79 Hz, 2 H), 7.35 (s, 1H), 7.48 (d, J = 8.79 Hz, 2 H), 7.67 (d, J = 7.81 Hz, 1H), 7.83 (d, J = 8.79 Hz, 1H), 8.10 (d, J = 7.81 Hz, 1H), 8.19 (d, J = 6.84 Hz, 1H) , 9.05 (d, J = 8.79 Hz, 1H); MS (ESI +) m / z 459 (M + H-TFA) +; (ESI-) m / z 457 (MH-TFA) -.
Example 39
N- {3-Fluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4ilanino) -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 (15 mL) was added a 15% aqueous solution of NaSMe (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 H2O (twice) and brine, dried over MgSO4 and evaporated to give the crude product, which was purified by washing with cold nhexane to give the desired product as yellow crystals (1.58 g, 90%).
Example 39b
3-Fluoro-4-methylsulfanyl-phenylamine
The product of Example 39a (1.57 g, 8.4 mmol) and powder powder (1.41 g, 25.2 mmol) in a mixture of EtOH (7.5 mL) and HOAc (7.5 mL) it was gradually heated to 80 ° C and heated at the same temperature for 1 hour. The reaction mixture was evaporated. The residue was partitioned between CHCl3 and 10% NaHCO3, and then filtered through celite. The organic layer was washed with H2O, dried over MgSO4, and evaporated to give the crude product, which was purified by washing with n-hexane to give the desired product as light brown crystals (1.08 g, 82 %).
Example 39c
N- (3-Fluoro-4-methylsulfanyl-phenyl) -acetamide
The product of Example 39c (1.08 g, 6.9 mmol) and Ac2O (0.97 mL, 10.3 mmol) in pyridine (10 mL) was heated at 50 ° C for 2 hours, and then evaporated. The residue was diluted with H2O, acidified to pH 3 with 10% HCl, and then extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4 and evaporated to give the crude product, which was purified by washing with n-hexane to give the title compound as colorless crystals (1.26 g, 92% ).
Example 39d
N- [3-Fluoro-4- (4-methyl-2-nitro-phenylsulfanyl) -phenyl] acetamide
The product of Example 39c (1.00 g, 5.0 mmol) and t-BuSNa (1.88 g, 15.1 mmol) in anhydrous DMF (10 mL) was heated at 160 ° C for 4 hours in a stream of N2, and then cooled to room temperature. To the reaction mixture 1-chloro-4-methyl-2-nitrobenzene (2.36 mL, 17.6 mmol) was added at room temperature and then the mixture was heated at 80 ° C for 4 hours in a stream of N2 The mixture was diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by silica gel column chromatography eluting with 2: 1 EtOAc / hexane to give the title compound as yellow crystals (1.04 g, 65%).
Example 39e
N- [4- (2-Amino-4-methyl-phenylsulfanyl) -3-fluoro-phenyl] acetamide
The product of Example 39d was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 39f
N- {3-Fluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} acetamide
The product of Example 2g (100 mg, 0.48 mmol) was reacted with the product of Example 39e (140 mg, 0.48 mmol) for 22 h at 120 ° C following the procedure of Example 1g producing the title compound in form of a solid (120 mg, 54%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.99 (t, J = 7.3 Hz, 3 H), 1.86 (sextet, J = 7.3 Hz, 2 H), 2.06 (s, 3 H), 2.36 (s, 3 H), 3.41 (t, J = 7.3 Hz, 2 H), 6.28 (d, J = 6.9 Hz, 1H), 7,127.35 (m, 5 H), 7.55 (dd, J = 12.1, 2.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.42 ( d, J = 6.9 Hz, 1H), 9.04 (d, J = 8.8 Hz, 1H); MS (ESI +) m / z 461 (M + H) +, ESI-m / z 459 (MH)
Example 40
N- {3,5-Difluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} acetamide
Example 40a.
N- [3,5-Difluoro-4- (4-methyl-2-nitro-phenylsulfanyl) -phenyl] acetamide
The title compound was prepared using the procedure of Example 39a using 1,2,3-trifluoro5-nitrobenzene instead of 1,2-difluoro-4-nitrobenzene. The 2,6-difluoro-1-methylsulfanyl-4-nitrobenzene product 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 NH4C1 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 h at 120 ° C following the procedure of Example 1g producing the title compound in form of a salt (120 mg, 52%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.99 (t, J = 7.3 Hz, 3 H), 1.86 (sextet, J = 7.3 Hz, 2 H), 2.06 (s, 3 H), 2.36 (s, 3 H), 3.01 (t, J = 7.3 Hz, 2 H), 6.28 (d, J = 6.9 Hz, 1H), 7.12-7.35 (m, 5 H), 7.55 (dd, J = 12.1, 2.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 6.9 Hz, 1H), 9.04 (d, J = 8.8 Hz, 1H); MS (ESI +) m / z 461 (M + H) +, (ESI-) m / z 459 (MH) -.
Example 41
(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenoxy-phenyl) amine
Example 41a
4-Methyl-2-nitro-1-phenoxy-benzene
A solution of sodium phenoxide trihydrate (5.0 g, 30 mmol) and 4-chloro-3-nitrotoluene (2.65 mL, 30 mmol) was heated in 60 mL of DMF at 100 ° C for 5 days while stirring procedure of Example 1c. The product was purified by silica gel column chromatography eluting with CH2C2 to yield the title compound as an orange solid (1.36 g, 30%).
Example 41b
5-Methyl-2-phenoxy-phenylamine
The product of Example 41a (884 mg, 3.86 mmol) was treated with SnCl2 (3.5 g, 19.0 mmol) for 24 h following the procedure of Example 1f yielding the title compound as a colored oil. yellow (710 mg, 93%).
Example 41c
(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenoxy-phenyl)
amine
The product of Example 41b (65 mg, 0.36 mmol) was reacted with the product of Example 1d following the procedure of Example 1g yielding the title compound that was triturated with ether to provide the product as a hydrochloride salt (12 mg, 8.8%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J = 7.73 Hz, 3 H) 1.82 (c, J = 7.72 Hz, 2 H) 2.97 (dd , J = 7.73 Hz, 2 H) 6.68 (d, J = 6.99 Hz, 1H) 6.99 (d, J = 7.72 Hz, 2 H) 7.12 (dd, J = 8.82 Hz, 2 H) 7.30 (dd, J = 8.09 Hz, 2 H) 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 (wide s, 1H) 14.45 (wide s, 1H); MS (ESI +) m / z 390 (M-Cl) +; (ESI-) m / z 388 (M-HCl) -.
Example 42
(5-Chloro-2-phenoxy-phenyl) - (7-ethyl- [1,8] naphthyridin-4-yl) amine
Example 42a
4-Chloro-2-nitro-1-phenoxy-benzene
To a solution of DMF (50 mL) was added 1-bromo2-nitro-4-chloro-benzene (5.0 g, 21.1 mmol), phenol (1.9 g, 21.1 mmol), and Na2CO3 (2.3 g, 21.1 mmol). The solution was heated to 85 ° C and stirred overnight. The reaction was poured into water and extracted with EtOAc. It was washed with water and dried over Na2SO4, filtered and concentrated in vacuo to yield a yellow oil that was purified by silica gel column chromatography eluting with Hexanes: Ethyl acetate (90:10) to give the compound. of the title (3.8 g, 74%).
Example 42b
5-Chloro-2-phenoxy-phenylamine
The product of Example 42a (13 g, 52.1 mmol) was reacted with SnCl2 (49.3 g, 260 mmol) following the procedure of Example 1f yielding the title compound as a white solid 9.0 g, 79%).
Example 42c
(5-Chloro-2-phenoxy-phenyl) - (7-ethyl- [1,8] naphthyridin-4-yl) amine
The product of Example 42b (100 mg, 0.46 mmol) was reacted with the product of Example 3f (88 mg, 0.46 mmol) following the procedure of Example 1g yielding the title compound that was triturated with ether / THY 2: 1 providing the product in the form of a hydrochloride salt (134 mg, 70%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (t, J = 7.35 Hz, 3 H) 3.02 (c, J = 7.35 Hz, 2 H) 6.69 (d , J = 6.99Hz, 1H) 6.97 (d, J = 8.82 Hz, 2 H) 7.10 (dd, J = 7.35 Hz, 1H) 7.15 (d, J = 8, 82 Hz, 2 H) 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 (wide s, 1H) 14.56 (wide s, 1H); MS (ESI +) m / z 376 (M-Cl) +; (ESI-) m / z 374 (M-HCI) -.
Example 43
(5-Chloro-2-phenoxy-phenyl) - (7-trifluoromethyl [1,8] naphthyridin-4-yl) -amine
The product of Example 42b (60 mg, 0.27 mmol) was reacted with the product of Example 7d (63 mg, z27 mmol) for 24 h following the procedure of Example 1g yielding the crude title compound as a solid which was triturated with ether / THF 4: 1 to give the product as a hydrochloride salt (112 mg, 91%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 6.82 (d, J = 6, 99 Hz, 1H) 6.98 (d, J = 7.72 Hz, 2-H) 7.13 (m, 2 H) 7.32 (dd, J = 7.73-Hz, J = 8.82 Hz, 2 H) 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, IH) 8.69 (d, J = 6.99 Hz, 1H) 9.42 (d, J = 8.82 Hz, 1H) 11.47 (wide s, 1H) 14.40 ( s wide, 1H); MS (ESI +) m / z 416 (M-Cl) +; (ESI-) m / z 414 (M-HCl) -.
Example 44
4- [4-Benzylamino-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
Example 44a
4- (4-Amino-2-nitro-phenylsulfanyl) -phenol
A solution of 4-chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-hydroxythiophenol (0.75 g, 6.00 mmol), cesium carbonate (3.9 g, 12 mmol) in DMSO (10 mL) was heated at 100 ° C for 16 hours. After that, ice water (50 mL) was added to the solution and the resulting suspension was treated with ethyl acetate (100 mL). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and concentrated in vacuo yielding the title compound as a red solid (1.45 g, 92%).
Example 44b
4- (4-Benzylamino-2-nitro-phenylsulfanyl) -phenol
A solution of the product of Example a (0.63 g, 2.4 mmol), benzaldehyde (0.24 g, 2.3 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) in methanol (10 mL) containing 1% acetic acid was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and the resulting solution was concentrated in vacuo to a yellow solid. The solid was dissolved in ethyl acetate (50 mL), and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo leaving a light yellow oil. The oil was applied to a silica gel column and eluted with CH2Cl2 then 1% methanol in CH2Cl2. Fractions containing product were combined and evaporated to dryness to yield the title compound as a yellow solid (0.63 g, 77%).
Example 44c
4- (2-Amino-4-benzylamino-phenylsulfanyl) -phenol
The product of Example 44b was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 44d 4- [4-Benzylamino-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 2g (105 mg, 0.50 mmol) was reacted with the product of Example 44c (161 mg, 0.50 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (68 mg, 22%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.83 (sext, J = 7.35 Hz, 2 H) 2.97 (dd , J = 7.35 Hz, 2 H) 4.29 (m, 2 H) 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, 8 H) 7.78 (d, J = 8.83 Hz, 1H) 8.95 (d, J = 8.46 Hz, 1H) 9.66 (s, 1H) 10.90 (wide s, 1H) 14.21 (wide s, 1H); MS (ESI +) m / z 493 (M + HTFA) +.
Example 45
4- [4-Benzylamino-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 1d (57 mg, 0.319 mmol) was reacted with the product of Example 44c (102 mg, 0.319 mmol) for 72 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (169 mg, 91%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.74 (s, 3 H) 4.30 (s, 2 H) 6.15 (d, J = 6.99 Hz, 1H) 6.52 ( d, J = 8.46 Hz, 1H) 6.56-7.39 (m, 11 H) 7.75 (d, J = 8.46 Hz, 1 H) 8.28 (d, J = 7, 36 Hz, 1 H) 9.50 (wide s, 1 H) 10.85 (wide s, 1 H) 14.25 (wide s, 1 H); MS (ESI +) m / z 465 (M + H-TFA) +; (ESI-) m / z 463 (M-HTFA) -.
Example 46
N- {4- [4-Methyl-2- (7-morpholin-4-yl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} acetamide
Example 46a
N- {4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The product of Example 13d (200 mg, 1.0 mmol) was reacted with the product of Example 18b (215 mg, 1.0 mmol) for 24 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (200 mg, 45%).
Example 46b
N- {4- [4-Methyl-2- (7-morpholin-4-yl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} acetamide
The product of Example 46a (0.047 g, 0.1 mmol) and morpholine (0.087 g, 1.0 mmol) in ethanol (0.5 mL) were heated in a sealed tube at 110 ° C for 1 h, cooled and They 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-d6) δ 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, 1 H), 7.20-7.32 (m, 4 H), 7.54 (d , J = 8.82 Hz, 2 H), 8.07 (t, J = 6.80 Hz, 1 H), 8.64 (d, J = 9.56 Hz, 1 H), 10.06 ( s, 1 H), 10.45 (s, 1 H), 13.42 (d, J = 5.88 Hz, 1 H); MS (ESI +) m / z 486 (M + H) +.
Example 47
(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-ptolylsulfanyl-phenyl) -amine
Example 47a
4-Methyl-2-nitro-1-p-tolylsulfanyl-benzene
The product of Example 4a (5.00 g, 17.53 mmol) was reacted with 4-methylthiophenol (2.17 g, 17.53 mmol) instead of thiophenol following the procedure of Example 1e for 18 h producing the compound of the crude title that was purified by silica gel column chromatography eluting with 5% EtOAc / hexane to give a solid (3.53 g, 78%).
Example 47b
5-Methyl-2-p-tolylsulfanyl-phenylamine
The product of Example 47a was reduced with SnCl2 following the procedure of Example 1f to produce the title compound.
Example 47c
(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-ptolylsulfanyl-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (347 mg, 46%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.22 (s, 3 H) 2.37 (s, 3 H) 2.77 (s, 3 H) 6.27 (d, J = 7, 35 Hz, 1 H) 7.04 (d, J = 7.72 Hz, 2 H) 7.14 (m, 2 H) 7.29 (m, 3 H) 7.79 (d, J = 8, 82 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H) 8.95 (d, J = 8.46 Hz, IH) 11.25 (wide s, 1 H) 14, 39 (wide s., 1 H); MS (ESI +) m / z 372 (M + H) +.
Example 48
(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-mtholylsulfanyl-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) instead of thiophenol following the procedure of Example 1e for 18 h producing the compound of the crude title that was purified by silica gel column chromatography eluting with 5% EtOAc / hexane to give a solid (7.50 g, 87%).
Example 48b
5-Methyl-2-m-tolylsulfanyl-phenylamine
The product of Example 48a was reduced with SnCl2 following the procedure of Example 1f to produce the title compound.
Example 48c
(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-mtholylsulfanyl-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (116 mg, 15%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 3 H) 7.78 (d, J = 8.82 Hz, 1 H) 8.37 (d, J = 6, 99 Hz, 1 H) 8.92 (d, J = 8.82 Hz, 1 H) 11.08 (wide s, 1 H) 14.45 (wide s, 1 H); MS (ESI +) m / z 372 (M + H) +.
Example 49
[2- (4-Fluoro-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 49a
1- (4-Fluoro-phenylsulfanyl) -4-methyl-2-nitro-benzene
The product of Example 4a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) instead of thiophenol following the procedure of Example 1e for 18 h to produce the compound of the crude title that was purified by silica gel column chromatography 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 SnCl2 following the procedure of Example 1f to produce the title compound.
Example 49c
[2- (4-Fluoro-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin4-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (224 mg, 49%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H) 8.41 (d, J = 6.99 Hz, 1 H) 8.95 (d, J = 8.46 Hz, 1 H) 11.04 (broad s., 1 H) 14.43 (wide s, 1 H); MS (ESI +) m / z 376 (M + H) +.
Example 50
[2- (4-Methoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 50a
1- (4-Methoxy-phenylsulfanyl) -4-methyl-2-nitro-benzene
The product of Example 4a (5.0 g, 175 mmol) was reacted with 4-methoxybenzenethiol (2.45 g, 175 mmol) for 18 h following the procedure of Example 4b to provide 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 SnCl2 following the procedure of Example 1f to produce 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (325mg, 70%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.11 (d, J = 7.72 Hz, 1 H) 7.26 (d, J = 8.82 Hz , 2 H) 7.31 (s, 1 H) 7.80 (d, J = 8.46 Hz, 1 H) 8.41 (d, J = 6.99 Hz, 1 H) 8.99 (d , J = 8.82 Hz, 1 H) 11.04 (s wide., 1 H) 14.32 (wide s., 1 H); MS ESI + m / z 388 (M + H) +.
Example 51
[2- (3,4-Dimethoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 51a
2- (3,4-Dimethoxy-phenylsulfanyl) -5-methyl-phenylamine
The product of Example 4a (11.25 g, 39.5 mmol) was reacted with 3,4-dimethoxybenzenethiol (6.71 g, 39.5 mmol) for 18 h following the procedure of Example 4b to provide the product as of a solid (7.75 g, 64%).
Example 51b
2- (3,4-Dimethoxy-phenylsulfanyl) -5-methyl-phenylamine
The product of Example 51a was reduced with SnCl2 following the procedure of Example 1f to produce the title compound.
Example 51c
[2- (3,4-Dimethoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
The product of Example 1d (277 mg, 1.56 mmol) was reacted with the product of Example 51b (430 mg, 1.56 mmol) for 5 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (628 mg, 79%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.35 (s, 3 H) 2.76 (s, 3 H) 3.56 (s, 3 H) 3.68 (s, 3 H) 6 , 24 (d, J = 6.99 Hz, 1 H) 6.82 (m, 3 H) 7.29 (m, 3 H) 7.79 (d, J = 8.46 Hz, 1 H) 8 , 38 (d, J = 6.99 Hz, 1 H) 8.97 (d, J = 8.46 Hz, 1 H) 10.97 (s, 1 H) 14.35 (s, 1 H); 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-nitrophenylsulfanyl) phenol (4.48 g, 35.6 mmol) for 18 h following the procedure of Example 4b providing 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 SnCl2 following the procedure of Example 1f to produce the title compound.
Example 52c
3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 1d (277 mg, 1.56 mmol) was reacted with the product of Example 52b (245 mg, 1.56 mmol) for 5 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (399 mg, 52%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H) 6.90 -7.08 (m, 1 H) 7.27 -7.47 (m, 3 H) 7.77 (d, J = 8.46 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H) 8.94 (d, J = 8.82 Hz, 1 H) 9.58 (s, 1 H) 10.96 (s, 1 H) 14.34 (s, 1 H); MS (ESI +) m / z 374 (M + H) +.
Example 53 (reference)
[3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanylphenyl] -methanol
Example 53a
4-Hydroxy-3-nitro-benzoic acid ethyl ester
A solution of 4-hydroxy-3-nitrobenzoic acid ethyl ester (15.0 g, 76.1 mmol) was reacted with trifluoromethanesulfonic anhydride (14.0 mL, 83.7 mmol) for 15 min following the procedure of Example 4a to give the title compound as an amber oil (22.26 g, 89%).
Example 53b
3-Nitro-4-phenylsulfanyl-benzoic acid ethyl ester
The product of Example 53a (22.6 g, 67.6 mmol) was reacted with sodium thiophenolate (7.54 g, 67.6 mmol) for 24 h following the procedure of Example 1e producing the title compound as of a solid (13.2 g, 67%).
Example 53c
3-Amino-4-phenylsulfanyl-benzoic acid ethyl ester
The product of Example 53b was reacted with SnCl2 following the procedure of Example 1f to produce the title compound as a solid.
Example 53c
3- (7-Methyl- [1,8] naphthyridine-4 -lamino) -4-phenylsulfanyl-benzoic acid ethyl ester
The product of Example 1d (2.06 g, 1.16 mmol) was reacted with the product of Example 53b (3.18 g, 1.16 mmol) for 5 h following the procedure of Example 1g producing the title compound crude which was purified by HPLC with TFA to provide the trifluoroacetic acid salt (3.61 g, 59%).
Example 53d
[3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanylphenyl] -methanol
The product of Example 53c (2.34 g, 5.54 mmol) in 60 mL of THF was reacted with LiAlH4, (420 mg, 11.0 mmol) for 18 h then quenched with diluted HCl. It was adjusted to pH 10 with NH4OH. It was extracted with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA to provide the trifluoroacetic acid salt (325mg, 70%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3 H) 3.99 (wide s, 1 H) 4.58 (s, 2 H) 6.31 (d, J = 7 , 35 Hz, 1 H) 7.25 (s, 5 H) 7.40 (m, 2 H) 7.46 (s, 1 H) 7.78 (d, J = 8.82 Hz, 1 H) 8.42 (d, J = 6.99 Hz, 1 H) 8.95 (d, J = 8.46 Hz, 1 H) 11.06 (wide s, 1 H) 14.44 (wide s, 1 HOUR); MS (ESI +) m / z 374 (M + H) +.
Example 54
[2- (4-Ethoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 54a
1- (4-Ethoxy-phenylsulfanyl) -4-methyl-2-nitro-benzene
The product of Example 4b (500 mg, 1.91 mmol) was reacted with NaH (0.048 g, 2.01 mmol) in 10 mL THF at 0 ° C for 2 h. It was warmed to room temperature and EtI (0.232 mL, 2.87 mmol) was added slowly then stirred at room temperature for 4 days. It was quenched with water, the layers were separated and dried over MgSO4, filtered and concentrated in vacuo to give the product as a solid (510 mg, 92%). It was reduced with SnCl2 following the procedure of Example 1f to produce 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (241 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.31 (t, J = 6.99 Hz, 3 H) 2.34 (s, 3 H) 2.76 (s, 3 H) 3.97 (c, J = 6.99 Hz, 2 H) 6.26 (d, J = 7.35 Hz, 1 H) 6.83 (d, J = 8.82 Hz, 2 H) 7.11 (d , J = 7.72 Hz, 1 H) 7.24 (d, J = 8.82 Hz, 2 H) 7.27 (s, 1 H) 7.30 (s, 1 H) 7.80 (d , J = 8.82 Hz, 1 H) 8.41 (d, J = 6.99 Hz, 1 H) 8.99 (d, J = 8.82 Hz, 1 H) 11.01 (s, 1 H) 14.38 (s, 1 H); MS (ESI +) m / z 402 (M + H) +.
Example 55
(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (4-propoxyphenylsulfanyl) -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 h. It was warmed to room temperature and EtI (0.232 mL, 2.87 mmol) was added slowly then stirred at 50 ° C for 7 days. The layers were quenched with water and dried over MgSO4, filtered and concentrated in vacuo to give the product as a solid (700 mg, 100%). It was reduced with SnCl2 following the procedure of Example 1f to produce the title compound.
Example 55b
(7-Methyl- [1,8] naphthyridin-yl) - [5-methyl-2- (4-propoxyphenylsulfanyl) -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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (187 mg, 23%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 6.27 (d, J = 6.99 Hz, 1 H) 6.84 (d. J = 8 , 82 Hz, 2 H) 7.11 (d, J = 7.72 Hz, 1 H) 7.24 (d, J = 8.46 Hz, 2 H) 7.29 (s, 1 H) 7, 80 (d, J = 8.46 Hz, 1 H) 8.42 (d, J = 6.99 Hz, 1 H) 8.99 (d, J = 8.46 Hz, 1 H) 11.01 ( s, 1 H) 14.39 (s, 1 H); MS (ESI +) m / z 416 (M + H) +.
Example 56
[2- (4-Isopropoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 56a
2- (4-Isopropoxy-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 h. It was warmed to room temperature and i-Pr-I (0.574 mL, 5.74 mmol) was added slowly then stirred at 50 ° C for 10 days. It was quenched with water, the layers were separated and dried over MgSO4, filtered and concentrated in vacuo to give the product as a solid (730 mg, 100%). It was reduced with SnCl2 following the procedure of Example 1f to produce the title compound.
Example 56b
[2- (4-Isopropoxy-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (185 mg, 23%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.23 (d, J = 6.25 Hz, 6 H) 2.34 (s, 3 H) 2.76 (s, 3 H) 4.48 -4.58 (m, 1 H) 6.27 (d, J = 6.99 Hz, 1 H) 6.81 (d, J = 8.82 Hz, 2 H) 7.14 (d, J = 8.09 Hz, 1 H) 7.22 (d, J = 8.82 Hz, 2 H) 7.27 (s. 1 H) 7.30 (s. 1 H) 7.79 (d, J = 8.82 Hz, 1 H) 8.41 (d, J = 6.99 Hz, 1 H) 8.99 (d, J = 8.46 Hz, 1 H) 10.99 (s, 1 H) 14 , 36 (s, 1 H); MS (ESI +) m / z 416 (M + H) +.
Example 57 (reference)
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-nitrobenzamide
A mixture of 4-bromoaniline (2.58 g 14.99 mmol) in dry CH2Cl2 (100 mL) was treated with 4-chloro-3-nitrobenzoyl chloride (3.60 g, 17.99 mmol) and N, N-diisopropylethylamine (3.14 mL, 17.99 mmol), and the resulting mixture was stirred at room temperature for 17 hours. The solvent was concentrated in vacuo to yield 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 in vacuo yielding the title compound as a tan solid (5.132 g, 14.45 mmol, 96%).
Example 57b
N- (4-Bromo-phenyl) -4- (4-hydroxy-phenylsulfanyl) -3-nitrobenzamide
A solution of the product of Example 57a (553 mg, 1,557 mmol) in anhydrous DMF (15 mL) was treated with 4mercaptophenol (196 mg, 1,557 mmol) and cesium carbonate (1,015 g, 3,114 mmol) at room temperature, then heated at 100 ° under nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the solvent was concentrated in vacuo yielding the title compound. The residue was taken up in H2O (30 mL) and the pH adjusted to 3 with 1N aqueous HCl. The aqueous layer was then extracted with ethyl acetate, and the combined organic extracts were washed with brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound. The residue was triturated with methylene chloride and purified by flash chromatography on silica gel with a gradient of 6% to 30% ethyl acetate / methylene chloride to give the title product as a yellow solid ( 517 mg, 1.16 mmol, 75%).
Example 57c
3-Amino-N- (4-bromo-phenyl) -4- (4-hydroxy-phenylsulfanyl) benzamide
The product of Example 57b was reduced with Fe and NH4Cl 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (30 mg, 20%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.99 (t, J = 7.35 Hz, 3 H) 1.69 -1.96 (m, 2 H) 3.02 (t; J = 7.3 Hz, 2 H) 6.42 (d, J = 6.99 Hz, 1 H) 6.87 (d, J = 8.46 Hz, 2 H) 7.02 (d, J = 8, 46 Hz, 1 H) 7.33 (d, J = 8.46 Hz, 2 H) 7.54 (d, J = 9.19 Hz, 2 H) 7.72 (d, J = 8.82 Hz , 2 H) 7.87 (d, J = 8.82 Hz, 1 H) 7.98 (dd, J = 8.46, 1.84 Hz, 1 H) 8.02 (d, J = 1, 84 Hz, 1 H) 8.52 (d, J = 6.62 Hz, 1 H) 9.09 (d, J = 8.46 Hz, 1 H) 10.09 (s, 1 H) 10.37 (s, 1 H) 11.14 (s, 1 H) 14.54 (s, 1 H); MS (ESI +) m / z 585/587 (M + H) +.
Example 58
5-Dimethylaminonaphthalene-1-sulfonic acid 4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
The product of Example 5 (167 mg, 0.94 mmol) was reacted with 5-dimethylaminonaphthalene-1sulfonyl chloride (245 mg, 0.94 mmol) in 10 mL of CH2Cl2 with N, N-diisopropylethylamine (0.530 mL, 410 mmoles) for 22 h. It was washed with water and dried over Na2SO4, filtered and concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA to provide the trifluoroacetic acid salt (35 mg, 40%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.16 (d, J = 8.82 Hz, 1 H) 7.34 (d, J = 7.72 Hz , 1 H) 7.53 -7.62 (m, 2 H) 7.69 -7.79 (m, 3 H) 7.97 (d, J = 7.35 Hz, 1 H) 8.22 ( d, J = 8.82 Hz, 1 H) 8.50 (d, J = 6.99 Hz, 1 H) 8.60 (d, J = 9.46 Hz, 1 H) 8.82 (d, J = 8.82 Hz, 1 H); MS 1 H) 8.50 (d, J = 6.99 Hz, 1 H) 8.60 (d, J = 8.46 Hz, 1 H) 8.82 (d, J = 8.82 Hz, 1 H); MS (DCI NH3 +) m / z 611 (M + H) +.
Example 59
Ethanesulfonic acid 4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
The product of Example 5 (100 mg, 0.24 mmol) was reacted with ethanesulfonyl chloride (31.0 mg, 0.24 mmol) for 18 h following the procedure of Example 58 yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (20 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 10.98 (s, 1 H) 8.89 (d, J = 8.46 Hz, 1 H) 8.39 (d, J = 6.99 Hz , 1 H) 7.76 (d, J = 8.82 Hz, 1 H) 7.45 -7.50 (m, 1 H) 7.36 -7.42 (m, 2 H) 7.25 ( d, 2 H) 7.17 (d, 2 H) 6.33 (d, J = 6.99 Hz, 1 H) 3.47 (c, J = 7.35 Hz, 2 H) 2.75 ( s, 3 H) 2.40 (s, 3 H) 1.34 (t, J = 7.35 Hz, 3 H); MS (DCI NH3 +) m / z 466 (M + H) +.
Example 60
Propane-2-sulfonic acid 4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
The product of Example 5 (80.0 mg, 0.195 mmol) was reacted with propane-2-sulfonyl chloride (27.8 mg, 0.195 mmol) for 18 h following the procedure of Example 58 yielding the crude title compound which purified by HPLC with TFA to provide the trifluoroacetic acid salt (20 mg, 21%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.90 (d, J = 8.46 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H) 7.76 (d , J = 8.82 Hz, 1 H) 7.43 -7.49 (m, 1 H) 7.35 -7.42 (m, 2 H) 7.24 -7.29 (m, 2 H) 7.12 7.19 (m, 2 H) 6.33 (d, J = 6.99 Hz, 1 H) 2.75 (s, 3 H) 3.66 (m, 1) 2.39 (s , 3 H) 1.40 (d, J = 6.99 Hz, 6 H); MS (DCI NH3 +) m / z 480 (M + H) +.
Example 61
Methanesulfonic acid 4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
The product of Example 5 (80 mg, 0.195 mmol) was reacted with methanesulfonyl chloride (22.3 mg, 0.195 mmol) for 18 h following the procedure of Example 58 yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (36 mg, 32%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.88 (d, J = 8.46 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H) 7.76 (d , J = 8.46 Hz, 1 H) 7.45 -7.51 (m, 1 H) 7.35 -7.42 (m, 2 H) 7.26 (d, 2 H) 7.19 ( d, 2 H) 6.33 (d, J = 6.99 Hz, 1 H) 3.34 (s, 3H) 2.75 (s, 3 H) 2.40 (s, 3 H); MS (DCI NH3 +) m / z 452 (M + H) +.
Example 62
Ethanesulfonic acid 4- [2- (7-ethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl ester
The product of Example 4 (20 mg, 0.47 mmol) was reacted with ethanesulfonyl chloride (72 mg, 0.56 mmol) for 22 h following the procedure of Example 58 yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (70 mg, 25%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.31 (d, 1 H) 7.73 (d, 1 H) 7.1 (d, 1 H) 6.85 (d, 1 H) 6 , 74 (s, 2 H) 6.64 (d, 2 H) 6.53 (d, 2 H) 5.75 (d, 1 H) 2.81 (c, 2 H) 2.42 (c, 2 H) 1.78 (s, 3 H) 0.76 (m, 6 H); MS (ESI +) m / z 484 (M + H) +.
Example 63
Phenyl methanesulfonic acid 4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
The product of Example 5 (120 mg, 0.294 mmol) was reacted with phenyl methanesulfonyl chloride (55 mg, 0.294 mmol) for 22 h following the procedure of Example 58 yielding the crude title compound that was purified by HPLC with TFA providing the trifluoroacetic acid salt (15 mg, 9%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.31 (d, 1 H) 7.73 (d, IH) 7.11 (d, 1 H) 6.85 (d, 1 H) 6, 74 (s, 2 H) 6.64 (d, 2 H) 6.53 (d, 2 H) 5.75 (d, 1 H) 2.81 (c, 2 H) 2.42 (c, 2 H) 1.78 (s, 3 H) 0.76 (m, 6 H); MS (ESI +) m / z 484 (M + H) +.
Example 64
{4- [4-Methyl-2- (7-methyl [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenoxy} -acetic acid ethyl ester
The substance of Example 5 (0.200 g, 0.536 mmol) was suspended in acetone, to which K2CO3 was added. This was treated with bromine-ethyl acetate (0.089 g, 0.536 mmol) at which time the reaction mixture was heated at reflux for 4 hrs. The reaction mixture was cooled to room temperature, the solid was filtered and concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (24 mg, 10%). . 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.22 (t, J = 6.99 Hz, 3 H), 2.34 (s, 3 H), 2.74 (s, 3 H), 4.20 (c, J = 6.99 Hz, 2 H), 5.47 (s, 2 H), 6.49 (d, J = 7.72 Hz, 1 H), 6.75 (d, J = 8.82 Hz, 2 H), 7.00 (d, J = 8.09 Hz, 1 H), 7.20 (d, J = 8.46 Hz, 2 H), 7.25 7, 40 (m, 2 H), 7.87 (d, J = 8.82 Hz, 1 H), 8.63 (d, J = 7.72 Hz, 1 H), 9.06 (d, J = 8.46 Hz, 1 H), 9.89 (s, 1 H); MS (ESI) m / z 460 (M + H) +, (ESI-) m / z 458 (MH) -.
Example 65
{4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenoxy} -acetic acid
The product of Example 64 (0.246 g, 0.535 mmol) was dissolved in 10 mL of 5% NaOH and 10 mL of EtOH and heated at 100 ° C for 2 hrs and then stirred at room temperature for 10 hrs. At this time all the solvent was removed in vacuo 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 by filtration and the solid was dried under vacuum overnight (150 mg, 64%) 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3 H), 2.75 ( s, 3 H), 5.42 (s, 2 H), 6.46 (d, J = 7.35 Hz, 1 H), 6.52 (s, 1 H), 6.75 (d, J = 8.46 Hz, 2 H), 6.99 (d, J = 8.46 Hz, 1 H), 7.15-7.40 (m, J = 8.46 Hz, 4 H), 7, 85 (s, 1 H), 8.62 (s, 1 H), 9.08 (d, J = 8.09 Hz, 1 H), 9.90 (s, 1 H); MS (ESI) m / z 432 (M + H) +, (ESI-) m / z 430 (MH) -.
Example 66
2,2-Dimethyl-N- {4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -propionamide
The product of Example 83 (0.50 g, 0.134 mmol) was dissolved in DMF and treated with 2,2-dimethylpropionyl chloride (0.016 g, 0.134 mmol) and stirred at room temperature for 1 h. The DMF was removed in 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-d6) δ ppm: 1.22 (s, 9 H), 2.35 (s, 3 H), 2.76 (s, 3 H), 6.33 (d, J = 6.99 Hz, 1 H), 7.15 (s, 1 H), 724 (d, J = 8.46 Hz, 3 H), 7.31 (s, 1 H), 7.61 (d , J = 8.82 Hz, 2 H), 7.80 (s, 1 H), 8.42 (s, 1 H), 8.96 (s, 1 H), 9.27 (s, 1 H ), 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 h. The DMF was removed in 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%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.91 (t, J = 7.35 Hz, 3 H), 1.54 1.65 (m, 2 H), 2.27 (t, J = 7.35 Hz, 2 H), 2.35 (s, 3 H), 2.76 (s, 3 H), 6.31 (d, J = 6.99 Hz, 1 H), 7.15 (d, J = 8.09 Hz, 1 H), 7.21 -7.32 (m, 4 H), 7.53 (d, J = 8.82 Hz, 2 H), 7.78 (d , J = 8.82 Hz, 1 H), 8.41 (d, J = 6.99 Hz, 1 H), 8.96 (d, J = 8.46 Hz, 1 H), 9.98 ( s, 1 H), 11.00 (s, 1 H); MS (ESI +) m / z 443 (M + H) +, (ESI-) m / z 441 (MH) -.
Example 68
{4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -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 hr. The DMF was removed in a stream of N2, and the crude residue was purified by HPLC with TFA to yield the title compound as a trifluoroacetic acid salt (25, mg, 40%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.80 (d, J = 6.25 Hz, 4 H), 1.71 -1.79 (m, 1 H), 2.35 (s, 3 H), 2.76 (s, 3 H), 6.31 (d, J = 7.35 Hz, 1 H), 7.16 (d, J = 7.72 Hz, 1 H), 7, 21 -7.32 (m, 4 H), 7.51 (d, J = 8.82 Hz, 2 H), 7.78 (d, J = 8.82 Hz, 1 H). 8.41 (d, J = 7.35 Hz, 1 H), 8.96 (d, J = 8.82 Hz, 1 H), 10.29 (s, 1 H), 10.99 (s, 1 HOUR); MS (ESI +) m / z 441 (M + H) +, (ESI-) m / z 439 (M = H) -.
Example 69
2- {4- [4-Methyl-2- (7-methyl [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] phenylcarbamoyl} -pyrrolidine-1-carboxylic acid benzyl ester
Carbbenzyloxy-proline (0.1110 g, 0.443 mmol) was dissolved in THF to which was added N-methylmorpholine (0.133 g, 0.443 mmol). Then pure isopropenyl chloroformate (0.053 g, 0.443 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. At this time the product of Example 83 (0.1250 g, 0.402 mmol) was added as a solution in THF, stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA to give the title compound as a salt of trifluoroacetic acid (118 mg, 48%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.82 -1.98 (m, 3 H), 2.22 (s, 2 H), 2.35 (s, 3 H), 2.75 (s, 3 H), 4.27-4.40 (m, 1 H); 4.89 -4.98 (m, 1 H), 5.00 -5.13 (m, 2 H), 6.35 (t, J = 6.80 Hz, 1 H), 7.06 -7 , 22 (m, 3 H), 7.24-7.39 (m, 6 H), 7.55 (d, J = 8.46 Hz, 2 H), 7.78 (d, J = 8, 82 Hz, 1 H), 8.44 (d, J = 6.99 Hz, 1 H), 8.96 (dd, J = 11.95, 8.64 Hz, 1 H), 10.20 (s , 1 H), 11.04 (s, 1 H), 14.39 (s, 1 H); 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-phenoxyphenylsulfanyl) -phenyl] -amine
Example 70a
5-Methyl-2- (4-phenoxy-phenylsulfanyl) -phenylamine
The product of Example 4c (0.500 g, 1.91 mmol) was dissolved in CH2Cl2 together with phenylboronic acid (0.701 g, 5.74 mmol), copper (II) acetate (0.659 g, 3.83 mmol), and triethylamine (0.387 g, 3.83 mmol). It was stirred at room temperature for 48 h, at which time 2 more equivalents of each reagent were added. It was stirred at room temperature for another 16 h at which time another 2eq of each reagent was added. It was stirred at room temperature for another 16h. The reaction was diluted with water and extracted with ethyl acetate. It was dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product that was purified by silica gel column chromatography eluting with 20% EtOAc / hexane (0.100 g, 15%). The product was reduced with SnCl2 following the procedure of Example 1f to give the title compound (90 mg, 98%).
Example 70b
(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (4-phenoxyphenylsulfanyl) -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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as a salt of trifluoroacetic acid (64 mg, 50%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.37 (s, 3 H), 2.73 -2.79 (m, 3 H), 6.30 (d, J = 6.99 Hz, 1 H), 6.78 -6.87 (m, 2 H), 6.97 (d, J = 7.72 Hz, 2 H), 7.17 7.24 (m, 1 H), 7, 24 -7.28 (m, 2 H), 7.32 -7.36 (m, 3 H), 7.37 -7.46 (m, 2 H), 7.79 (d, J = 8, 82 Hz, IH), 8.42 (d, J = 7.35 Hz, 1 H), 8.96 (d, J = 8.46 Hz, 1 H), 11.00 (s, 1 H); MS (ESI +) m / z 450 (M + H) +, (ESI-) m / z 448 (MH) -.
Example 71
N- {3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
Example 71a
3- (4-Methyl-2-nitro-phenylsulfanyl) -phenylamine
The product of Example 4a (1.00 g, 3.51 mmol) and 3-Amino-benzenethiol (658 mg, 5.26 mmol) were dissolved in DMF, to which was added K2CO3 (848 mg, 6.14 mmoles). The reaction mixture was then heated at 100 ° C for 16 hrs. 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. Stirring was allowed at room temperature for 1 h, at which time a solid was collected by filtration to provide 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) phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (100 mg, 0.599 mmol) was reacted with the product of Example 71c (152 mg, 0.599 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (45 mg, 18%) 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H), 7.06 (t, J = 8.09 Hz, 1 H), 7.25 (d, J = 8.09 Hz, 1 H), 7.33-7.41 (m, 2 H), 7.41-7.54 (m, 2 H), 7.74 (d, J = 8.82 Hz, 1 H), 8.33 (d, J = 6.99 Hz, 1 H), 8.89 (d, J = 8.82 Hz , 1 H), 9.81 (s, 1 H), 10.91 (s, 1 H); MS (ESI +) m / z 415 (M + H) +, (ESI-) m / z 413 (MH) -.
Example 72
{2- [4- (1-Imino-ethyl) -phenylsulfanyl] -5-methyl-phenyl} - (7methyl- [1,8] naphthyridin-4-yl) -amine
Example 72a
Thioacetimidic acid naphthalen-2-ylmethyl acid ester; HBr salt
The 2-bromomethyl-naphthalene (2.00 g, 9.05 mmol) and thioacetimide (680 mg, 9.05 mmol) were dissolved in CH3Cl and stirred at room temperature for 1hr. The product was collected by filtration to provide the title compound (1,500 g, 77%).
Example 72b
{2- [4- (1-Imino-ethyl) -phenylsulfanyl] -5-methyl-phenyl} - (7methyl- [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 h. The solvent was concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (118 mg, 70%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.32 (s, 3 H), 2.36 -2.43 (m, 3 H), 2.76 (s, 3 H), 6.38 (d, J = 6.99 Hz, 1 H), 7.19 -7.27 (m, 2 H), 7.32 -7.45 (m, 5 H), 7.79 (d, J = 8.82 Hz, 1 H), 8.44 (d, J = 6.99 Hz, 1 H), 8.57 (s, 1 H), 8.89-9.00 (m, 1 H), 9.55 (s, 1 H), 11.10 (s, 1 H); MS (ESI +) m / z 414 (M + H) +, (ESI-) m / z 412 (MH) -.
Example 73
1- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -ethanothione
The product of Example 18 (265 mg, 0.639 mmol) and Lawesson's reagent (517 mg, 1.28 mmol) were dissolved in 3 mL of toluene and heated at 80 ° C for 16h. The reaction mixture was cooled to room temperature, washed with water and extracted with EtOAc. It was dried over Na2SO4, filtered and concentrated in vacuo to yield the crude title compound that was purified by HPLC with TFA to provide the trifluoroacetic acid salt (14 mg, 5%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H), 7.06-7.21 (m, 3 H), 7.21-7, 27 (m, 2 H), 7.39 (d, J = 8.46 Hz, 1 H), 7.78 (d, J = 8.46 Hz, 2 H), 8.63 (d, J = 8.82 Hz, 1 H), 11.59 (s, 1 H); MS (ESI +) m / z 431 (M + H) +, (ESI-) m / z 429 (MH) -.
Example 74
N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2-phenylbutyramide
To a flask containing 3 equivalents of PS-DCC resin (N ', N', polymer-bound dicyclohexylcarbodiimide) 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 diethylisopropylamine (52 mg, 0.402 mmol). The reaction was heated at 55 ° C overnight, filtered and transferred to a vial containing 3 equivalents of MP-Carbonate resin (macroporous carbonate). The reaction vessel and PS-DCC resin were washed with MeOH and the combined filtrates were shaken on the MP-carbonate resin for 2 hours at room temperature. The MP-Carbonate resin was removed via filtration and the reactions were concentrated to dryness. They were purified by HPLC with TFA to provide the product as trifluoroacetic acid (2 mg, 4%). 1 H NMR (500 MHz, DMSO-D2O) δ ppm: 0.83-0.89 (m, 3 H), 1.66 -1.74 (m, J = 7.17, 6.90, 6.90 , 6.90, 6.90 Hz, 1 H), 2.00 -2.08 (m, 1 H), 2.32 -2.38 (m, 3 H), 2.72 -2.75 ( m, 3 H), 3.53-3.57 (m, 1 H), 6.37 (d, J = 7.02 Hz, 1 H), 7.14 -7.19 (m, 1 H) , 7.21 (d, J = 8.85 Hz, 2 H), 7.24 -7.31 (m, 3 H), 7.32 -7.39 (m, 4 H), 7.50 ( dd, J = 8.85, 1.53 Hz, 2 H), 7.69 (d, J = 8.85 Hz, 1 H), 8.39 (d, J = 7.02 Hz, 1 H) , 8.84 -8.88 (m, 1 H), 10.28 (s, 1 H); MS (ESI +) m / z 519; (ESI-) m / z 517, 631 (M + TFA-H) -.
Example 75
N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -4-phenyl-butyramide
The title compound was prepared using 4-phenyl-butyric acid (27 mg, 0.16 mmol) as acid following the procedure of Example 74, (1 mg, 2%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.85-1.92 (m, J = 7.55, 7.55, 7.55, 7.55 Hz, 2 H), 2.32 ( t, J = 7.32 Hz, 2 H), 2.36 (s, 3 H), 2.59 -2.64 (m, J = 7.63 Hz, 2 H), 2.74 (s, 3 H), 6.34 (d, J = 7.02 Hz, 1 H), 7.17 -7.23 (m, 6 H), 7.29 -7.35 (m, 4 H), 7 , 45 (d, J = 8.85 Hz, 2 H), 7.73 (d, J = 8.54 Hz, 1 H), 8.36 (d, J = 7.32 Hz, 1 H), 8.89 (d, J = 8.54 Hz, 1 H); 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-tolyloxyacetamide
The title compound was prepared using o-tolyloxy-acetic acid (26 mg, 0.16 mmol) as acid following the procedure of Example 74 (3 mg, 5%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H), 6.86 (d, J = 7.93 Hz, 1 H), 6.90 (t, J = 7.32 Hz, 1 H), 7.14 -7.20 (m, 2 H), 7.21 -7.26 (m, 3 H), 7.30 7.33 (m, 2 H), 7.48 (d , J = 8.54 Hz, 2 H), 7.73 (d, J = 8.85 Hz, 1 H), 8.36 (d, J = 7.02 Hz, 1 H), 8.88 ( d, J = 8.85 Hz, 1 H); MS (ESI +) m / z 521; (ESI-) m / z 519, 633 (M + TFA-H) -.
Example 77
N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2-p-tolyloxyacetamide
The title compound was prepared using p-tolyloxyacetic acid (26 mg, 0.16 mmol) as acid following the procedure of Example 74 (3 mg, 5%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H), 6.89 (d, J = 8.54 Hz, 2 H), 7.13 (d, J = 8.24 Hz, 2 H), 7.21 (d, J = 8.85 Hz, 2 H), 7.25 -7.29 (m, 1 H), 7.31 -7.33 (m, 2 H), 7 , 48 (d, J = 8.54 Hz, 2 H), 7.72 (d, J = 8.54 Hz, 1 H), 8.35 (d, J = 7.02 Hz, 1 H), 8.87 (d, J = 8.85 Hz, 1 H); 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 acid following the procedure of Example 74 (3 mg, 5%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H), 7.21 (d, J = 8.54 Hz, 3 H), 7.28-7.33 (m, 2 H ), 7.37 (d, J = 7.02 Hz, 1 H), 7.41 (t, J = 7.32 Hz, 2 H), 7.47 (d, J = 7.02 Hz, 2 H), 7.53-7.58 (m, 2 H), 7.69 (d, J = 8.85 Hz, 1 H), 8.38 (d, J = 7.02 Hz, 1 H) , 8.86 (d, J = 8.54 Hz, 1 H); 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 acid following the procedure of Example 74 (3 mg, 5%). 1 H NMR (300 MHz, DMSO-d6) δ 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 = 7.32 Hz, 1 H), 7.21 (d, J = 8.54 Hz, 3 H), 7.29-7.32 (m, 2 H) , 7.35 -7.38 (m, 1 H), 7.41 (t, J = 7.17 Hz, 2 H), 7.46 7.49 (m, 2 H), 7.54 -7 , 57 (m, 2 H), 7.69 (d, J = 8.54 Hz, 1 H), 8.38 (d, J = 7.02 Hz, 1 H), 8.86 (d, J = 8.54 Hz, 1 H); MS (ESI +) m / z 521; (ESI-) m / z 519, 633 (M + TFAH) -.
Example 80
({4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenylcarbamoyl} -methyl) -furan-3-carboxylic acid amide
The title compound was prepared using [(furan-2-carbonyl) -amino] -acetic acid (27 mg, 0.16 mmol) as acid following the procedure of Example 74 (1 mg, 2%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H), 7.16 (d, J = 3.05 Hz, 1 H), 7, 22 (t, J = 8.85 Hz, 3 H), 7.29-7.33 (m, 2 H), 7.46 (d, J = 8.85 Hz, 2 H), 7.74 ( d, J = 8.54 Hz, 1 H), 7.85 (s, 1 H), 8.37 (d, J = 7.32 Hz, 1 H), 8.87 (d, J = 8, 85 Hz, 1 H); 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-thiophene-3-yl-butyramide
The title compound was prepared using 4-thiophene-2-yl-butyric acid (27 mg, 0.16 mmol) as acid following the procedure of Example 74 (0.7 mg, 1%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.89 -1.96 (m, 2 H), 2.34 -2.39 (m, 5 H), 2.75 (s, 3 H) , 2.85 (t, J = 7.63 Hz, 2 H), 6.34 (d, J = 7.32 Hz, 1 H), 6.88 (d, J = 2.44 Hz, 1 H ), 6.96 (dd, J = 5.19, 3.36 Hz, 1 H), 7.18 -7.25 (m, 3 H), 7.29 -7.33 (m, 3 H) , 7.45 (d, J = 8.85 Hz, 2 H), 7.73 (d, J = 8.54 Hz, 1 H), 8.36 (d, J = 7.32 Hz, 1 H ), 8.89 (d, J = 8.54 Hz, 1 H); MS (ESI +) m / z 525; (ESI-) m / z 523, 637 (M + TFA-H) -.
Example 82
1-Acetylpiperidine-4-carboxylic acid {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -amidide
The title compound was prepared using 1-Acetyl-piperidino-4-carboxylic acid (27 mg, 0.16 mmol) as acid following the procedure of Example 74 (0.7 mg, 1%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H), 4 , 37 -4.43 (m, 1 H), 6.30 -6.36 (m, 1 H), 7.18 7.25 (m, 4 H), 7.29 -7.34 (m, 2 H), 7.41 -7.48 (m, 2 H), 7.72 -7.77 (m, 1 H), 8.34 -8.38 (m, 1 H), 8.87 8 , 91 (m, 1 H); 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 one hour. The solution was subsequently cooled in an ice bath and made alkaline with solid NaOH (2.64 g). The crude product was isolated by dichloromethane extraction and purified by HPLC with TFA to provide the title compound as the trifluoroacetic acid salt (96.1 mg, 37%). 1 H NMR (300 MHz, DMSO-d6) δ ppm; 2.31 (s, 3 H) 2.77 (s, 3 H) 6.30 (d, J = 6.99 Hz, 1 H) 6.57 (d, J = 8.46 Hz, 2 H) 6.90 (d, J = 7.72 Hz, 1 H) 7.07 (d, J = 8.46 Hz, 2 H) 7.23 (m, J = 7.72 Hz, 2 H) 7, 81 (d, J = 8.82 Hz, 1 H) 8.46 (d, J = 7.35 Hz, 1 H) 9.04 (d, J = 8.46 Hz, 1 H) 11.05 ( s, 1 H). MS (ESI +) m / z 373.1 (M + H) +; (ESI-) m / z 371.1 (MH) -.
Example 84
4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
Example 84a
4- (4-Methyl-2-nitro-phenylsulfanyl) -benzoic acid
The product of Example 4a (0.94 g, 3.31 mmol) was reacted with 4-mercapto-benzoic acid (0.51 g, 3.31 mmol) in aqueous ethanol at 80 ° C in nitrogen. The reaction mixture was poured into water and acidified with glacial acetic acid. The solid product was collected by filtration, washed with water and dried in vacuo to give the title compound (0.877 g, 91%) pure enough to use as isolated.
Example 84b
4- (4-Methyl-2-nitro-phenylsulfanyl) -benzamide
The product of Example 84a (0.3 g, 1.04 mmol) was dissolved in THF (15 mL) and treated with N-methylmorpholine (0.131 mL, 1.19 mmol) followed by cooling in an ice bath and addition of isobutyl chloroformate (0.148 mL, 1.14 mmol). The resulting mixture was allowed to warm to room temperature with stirring for thirty minutes. The subsequent cooling in an ice bath was followed by the addition of ammonia gas and heating at room temperature. The title compound was isolated by the addition of water and solid collection was used by vacuum filtration 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 a colored solid off-white (0.226 g, 88%).
Example 84d
4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
The product of Example 1d (0.156 g, 0.875 mmol) was reacted with the product of Example 84d (0.226 g, 0.875 mmol) for 24 hours following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of the trifluoroacetic acid salt (0.185 g, 38%). 1 H NMR (300 MHz, DMSOd6) δ ppm: 2.37 -2.46 (m, 3 H) 2.74 (s, 3 H) 6.36 (d, J = 6.99 Hz, 1 H) 7 , 19 (d, J = 8.46 Hz, 2 H) 7.31 -7.46 (m, 3 H) 7.47 -7.57 (m, 1 H) 7.68 (d, J = 8 , 46 Hz, 2 H) 7.75 (d, J = 8.46 Hz, 1 H) 7.90 (s, 1 H) 8.39 (d, J = 7.35 Hz, 1 H) 8, 90 (d, J = 8.46 Hz, 1 H) 11.02 (s, 1 H); MS (ESI +) m / z 401.0 (M + H) +; (ESI-) m / z 399.0 (MH-).
Example 85
N-Methyl-4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
Example 85a
N-Methyl-4- (4-nitro-phenylsulfanyl) -benzamide
The product of Example 84b (0.32 g, 1.11 mmol) was reacted as described in Example 84c by replacing N-methylamine in methanol with ammonia to give the title compound (0.32 g, 94%) .
Example 85b
4- (2-Amino-4-methyl-phenylsulfanyl) -N-methyl-benzamide
The product of Example 85a was reacted as described in Example 84d to give the title compound (0.28 g, 97%).
Example 85c
N-Methyl-4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
The product of Example 85b (0.277 g, 1.05 mmol) was reacted with the product of Example 1d (0.09 g, 0.504 mmol) for 41 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as the trifluoroacetic acid salt (0.078 g, 28%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.51 (d, 1 H) 7.64 (d, J = 8.46 Hz, 2 H) 7.75 (d, J = 8.82 Hz, 1 H) 8.33 -8.45 (m, 2 H) 8.90 (d, J = 8.82 Hz, 1 H) 11.03 (s, 1 H); MS (ESI +) m / z 415.0 (M + H) +; (ESI-) m / z 413.1 (MH) -.
Example 86
3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
Example 86a
3- (4-Methyl-2-nitro-phenylsulfanyl) -benzoic acid
The product of Example 84a (0.94 g, 3.29 mmol) was reacted with 3-mercapto-benzoic acid (0.51 g, 3.31 mmol) as described in Example 84b to give the compound of title (0.77 g, 80%).
Example 86b
3- (4-methyl-2-nitrophenylsulfanyl) -benzamide
The product of Example 86a (0.25 g, 0.86 mmol) was reacted as described in Example 84c to give the title compound (0.238 g, 95%).
Example 86c
3- (4-methyl-2-amino-phenylsulfanyl) -benzamide
The product of Example 86b was reacted as described in Example 84d to give the title compound (0.204 g, 96%).
Example 86d
3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
The product of Example 86c (0.204 g, 0.79 mmol) was reacted with the product of Example 1d (0.144 g, 0.79 mmol) for 24 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of the trifluoroacetic acid salt (0.159gm, 38%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 3 H) 7.90 (s, 1 H) 8.37 (d, J = 6.99 Hz, 1 H) 8.88 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 401.0 (M + H) +; (ESI-) m / z 399.0 (MH) -.
Example 87
N-Methyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
Example 87a
N-Methyl-3- (4-methyl-2-nitro-phenylsulfanyl) -benzamide
The product of Example 86a (0.25 g, 0.86 mmol) was reacted as described in Example 84c by replacing N-methylamine in methanol with ammonia to give the title compound (0.25 g, 96%) .
Example 87b
N-Methyl-3- (4-methyl-2-amino-phenylsulfanyl) -benzamide
The product of Example 87a was reacted as described in Example 84d to give the title compound (0.208 g, 92%).
Example 87c
N-Methyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide
The product of Example 87b (0.208 g, 0.76 mmol) was reacted with the product of Example 1d (0.136 g, 0.76 mmol) for 24 hours following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as the trifluoroacetic acid salt (0.204, 49%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 8.87 (d, J = 8.46 Hz, 1 H) 10.97 (s , 1 HOUR); MS (ESI +) m / z 415.0 (M + H) +; (ESI-) m / z 413.0 (MH) -.
Example 88
N, N-Dimethyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -benzamide
Example 88a
N, N-Dimethyl-3- (4-methyl-2-nitro-phenylsulfanyl) -benzamide
The product of Example 86a (0.25 g, 0.86 mmol) was reacted as described in Example 84c by replacing N, N-dimethylamine in methanol with 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of a trifluoroacetic acid salt (0.1552 g, 45%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2:40 (s, 3 H) 2.75 (s, 6 H) 2.92 (s, 3 H) 6.34 (d, J = 6, 99 Hz, 1 H) 7.11 -7.53 (m, 7 H) 7.76 (d, J = 8.82 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H ) 8.94 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 429.0 (M + H) +; (ESI-) m / z 427.0 (MH)
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-nitro-benzene
To the product of Example 4a (1.50 g, 5.3 mmol) and 2fluorobenzenethiol (0.56 mL, 5.3 mmol) in EtOH (15 mL) was added an aqueous solution of Na2CO3 (0.563 g, 5.3 mmoles) drop by drop at room temperature. The mixture was heated at reflux for 1 hour, and then evaporated. The residue was diluted with EtOAc, washed with H2O, 5% KOH and brine, dried over MgSO4, filtered and concentrated in vacuo yielding the title compound as yellow crystals, which was purified by washing with n - cold hexane to give the title product as yellow crystals (1.15 g, 83%).
Example 89b
2- (2-Fluoro-phenylsulfanyl) -5-methyl-phenylamine
The product of Example 89a was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 89c
[2- (2-Fluoro-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine

The product of Example 1d (200 mg, 1.12 mmol) was reacted with the product of Example 89b (260 mg, 1.12 mmol) for 72 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (180 mg, 43%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.32 (s, 3H), 2.62 (s, 3H), 6.11 (wide s, 1H), 6.95-7.45 (m , 8H), 8.26 (wide s, 1H), 8.55-8.70 (m, 1H), 9.08 (wide s, 1H); MS (ESI +) m / z 376 (M + H) +, (ESI-) m / z 374 (MH) -.
Example 90
[3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-benzyl] -carbamic acid tert-butyl ester
Example 90a
3-nitro-4- (phenylthio) benzonitrile
A solution of sodium thiophenolate (16.29 g, 123.3 mmol) in 150 mL of DMF was heated at 100 ° C with 4-chloro-3-nitrobenzonitrile (15.0 g, 82.2 mmol) with stirring for 24 hours. 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 yield the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc / hexane to yield a colored solid. yellow (4.0 g, 19%).
Example 90b
Tert-butyl 3-amino-4- (phenylthio) benzylcarbamate
A solution of the product of Example 90a (4.0 g, 15.6 mmol) and di-tert-butyl dicarbonate (1.70 g, 1.79 mmol) was catalytically reduced using Ra-Ni in MeOH to 4.22 kg / cm2 in an atmosphere of H2. Catalyst separation and concentration in vacuo afforded the title compound that was purified by silica gel column chromatography eluting with 10% EtOAc / hexane yielding 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 of Example 1d (557 mg, 3.12 mmol) was reacted with the product of Example 90b (1.032 mg, 3.12 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (310 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (s, 9 H) 2.76 (s, 3 H) 4.19 (d, J = 6.25 Hz, 2 H) 6.29 (d, J = 6.99 Hz, 1 H) 7.25 (s, 5 H) 7.31 (s, 1 H) 7.37 (d, J = 3.31 Hz, 2 H) 7.44 -7.56 (m, 1 H) 7.79 (d, J = 8.82 Hz, 1 H) 8.42 (d, J = 6.99 Hz, 1 H) 8.94 (d, J = 8.46 Hz, 1 H) 11.05 (s, 1 H) 14.43 (s, 1 H); MS (ESI +) m / z 473 (M + H) +.
Example 91 (reference)
[2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methyl-phenyl] - (7methyl- [1,8] naphthyridin-4-yl) -amine
Example 91A
2,5-Dimethyl-3- (4-methyl-2-nitro-phenylsulfanyl) -furan
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (2.00 g, 11.7 mmol), 2.5Dimethyl-furan-3-thiol (1.50 g, 11.7 mmol), and K2CO3 (3,233 g, 23.4 mmol) was heated in DMF at 100 ° C for 4 hrs. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. It was dried over Na2SO4, filtered and concentrated in vacuo yielding 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 SnCl2 following the procedure of Example 1f to give the title compound.
Example 91c
[2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methyl-phenyl] - (7methyl- [1,8] naphthyridin-4-yl) -amine
The product of Example 1d (50 mg, 0.217 mmol) was reacted with the product of Example 91b (51 mg, 0.217 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (2.6 mg, 3.2%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.15 (d, J = 15.08 Hz, 6 H), 2.33 (s, 3 H), 2.77 (s, 3 H), 5 , 98 (s, 1 H), 6.29 (d, J = 6.99 Hz, 1 H), 7.08 (d, J = 8.09 Hz, 1 H), 7.24-7.39 (m, 2 H), 7.83 (d, J = 8.46 Hz, 1 H), 8.47 (d, J = 6.62 Hz, 1 H), 9.03 (d, J = 8 , 46 Hz, 1 H), 11.04 (s, 1 H); MS (ESI +) m / z 378 (M + H-TFA) +; (ESI +) m / z 399 (M + Na-TFA) -; (ESI +) m / z 773 (2M + Na-TFA) -.
Example 92
(4- {2- [ethoxycarbonylmethyl- (7methyl- [1,8] naphthyridin-4-yl) -amino] -4-methylphenylsulfanyl} -phenoxy) -acetic acid ethyl ester
The product of Example 5 (200 mg, 0.536 mmol) was suspended in acetone to which K2CO3 (81 mg, 0.589 mmol), and ethyl bromoacetate (89 mg, 0.536 mmol) were added. The reaction mixture was then heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. It was purified by HPLC with TFA to provide the product as trifluoroacetic acid (15 mg, 6%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (td, J = 7.08, 2.39 Hz, 6 H), 2.35 (s, 3 H), 2.73 (s, 3 H), 4.18 (ddd, J = 14.16, 10.66, 7.17 Hz, 4 H), 4.76 (s, 2 H), 5.46 (s, 2 H), 6, 47 (d, J = 7.35 Hz, 1 H), 6.87 (d, J = 8.82 Hz, 2 H), 7.14 (d, J = 8.09 Hz, 1 H), 7 , 21 -7.42 (m, 4 H), 7.86 (d, J = 8.46 Hz, 1 H), 8.61 (d, J = 7.72 Hz, 1 H), 9.03 (d, J = 8.46 Hz, 1 H); MS (ESI +) m / z 546 (M + H-TFA) +.
Example 93
[3-Chloro-4- (4-chloro-phenoxy) -phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 93A
2-Chloro-1- (4-chloro-phenoxy) -4-nitro-benzene
A solution of 1,2-dichloro-4-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 in vacuo to give the title compound (13.5 g, 99%).
Example 93B
3-Chloro-4- (4-chloro-phenoxy) -phenylamine
A solution of the product of Example 93A (8.49 g, 30 mmol), iron powder (8.4 g, 150 mmol) and ammonium chloride (2.4 g, 45 mmol) in ethanol (180 mL), THF (210 mL), and water (60 mL) was heated at reflux for 16 hours. The resulting mixture was cooled and filtered through a bed of celite. The filtrate was partitioned with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel eluting with hexane 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 refluxed 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%). 1 H NMR (300 MHz, DMSO-D6) δ ppm 2.76 (s, 3 H) 6.94 (d, J = 7.35 Hz, 1 H) 7.10 (m, 2 H) 7.33 ( d, J = 8.46 Hz, 1 H) 7.49 (m, 3 H) 7.80 (m, 2 H) 8.53 (d, J = 6.99 Hz, 1 H) 9.18 ( d, J = 8.82 Hz, 1 H) 11.34 (s, 1 H) 14.49 (s, 1 H); (ESI-) m / z 394 (MH) -.
Example 94
[2- (4-Methoxy-phenylsulfanyl) -5-methyl-phenyl] - (7trifluoromethyl- [1,8] naphthyridin-4-yl) -amine
The product of Example 7d (50 mg, 0.215 mmol) was reacted with the product of Example 50b (53 mg, 0.215 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (28 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.35 (s, 3 H), 3.71 (s, 3 H), 6.38 (d, J = 6.99 Hz, 1 H), 6.78 -6.89 (m, 2 H), 7.11 -7.19 (m, 1 H), 7.23 -7.32 (m, 4 H), 8.41 (d, J = 8.46 Hz, 1 H), 8.58 (d, J = 6.99 Hz, 1 H), 9.43 (d, J = 8.46 Hz, 1 H); MS (ESI +) m / z 442 (M + H-TFA) +; (ESI-) m / z 440 (MH-TFA) -.
Example 95
4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -N-phenylbenzamide
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 at reflux for 22 h. The reaction mixture was poured into ice water (150 g) with stirring and stirred at 5 ° C for 30 minutes. The deposited crystals were collected by filtration, washed with H2O and n-hexane, and dried at 40 ° C under vacuum to give the title compound as pale brown crystals (4.85 g, 87%).
Example 95b
4-Methyl-2-nitro-N-phenyl-benzamide
The product of Example 95a (1.00 g, 5.5 mmol) and SOCl2 (4.03 mL, 55.0 mmol) were refluxed for 2 hours. The excess SOCl2 was removed under reduced pressure to give the corresponding acid chloride as a light yellow oil. To an acid chloride solution 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 35 days. The reaction mixture was evaporated. The residue was diluted with H2O, acidified to pH 3 with 10% HCl and then extracted with EtOAc. The extract was washed with 10% NaHCO3, dried over MgSO4, filtered and concentrated in vacuo yielding the title compound as pale brown crystals, which was purified by washing with n-hexane to give the desired product as of pale brown crystals (0.80 g, 57%).
Example 95c
2-Amino-4-methyl-N-phenyl-benzamide
The product of Example 95b was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 95d
4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -N-phenylbenzamide
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 h following the procedure of Example 1g yielding the crude title compound that was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH 50: 1 to give the title compound (210 mg, 68%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.40 (s, 3H), 2.68 (s, 3H), 6.62 (d, J = 6.9 Hz. 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.3 Hz, 2H), 7.36 (s, 1H), 7.38 (d, J = 8.3 Hz , 1H), 7.52 (d J = 7.3 Hz. 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H) , 8.40 (d, J = 6.9 Hz, 1H), 8.94 (d, J = 8.8 Hz. 1H); MS (BSI +) m / z 369 (M + H), ESI-m / z367 (MH).
Example 96 (reference)
N- [3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanylphenyl] -acetamide
Example 96a
3-Nitro-4-phenylsulfanyl-phenylamine
A mixture of 2-Nitro-4-chloroaniline (1.0 g, 5.79 mmol), sodium thiophenol (0.84 g, 6.4 mmol) in DMF (10 mL) was heated 2.5 h at 100 ° C . The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water, a 20% aqueous solution of potassium hydroxide and a 10% aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was concentrated in vacuo 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 to 80 ° C, 2 hr. The solvent was concentrated in vacuo leaving the title compound as a red oil that 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 and NH4Cl following the procedure of Example 237E to give the title compound.
Example 96d
N- [3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanylphenyl] -acetamide
The product of Example 1d (100 mg, 0.560 mmol) was reacted with the product of Example 96c (140 mg, 0.560 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (77 mg, 27%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.08 (s, 3 H) 2.75 (s, 3 H) 6.33 (d, J = 7.35 Hz, 1 H) 7.06 -7.26 (m, 4 H) 7.43 7.61 (m, 2 H) 7.77 (d, J = 8.46 Hz, 1 H) 7.97 (d, J = 1.84 Hz , IH) 8.39 (d, J = 6.99 Hz, 1 H) 8.89 (d, J = 8.82 Hz, IH) 10.36 (s, IH) 11.02 (s, IH) 14.36 (s, 1 H); MS (ESI +) m / z 401 (M + H) +, (ESI-) m / z 399 (M + H) -.
Example 97
[2- (4-Methoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-propyl [1,8] naphthyridin-4-yl) -amine
The product of Example 2g (275 mg, 1.33 mmol) was reacted with the product of Example 50b (326 mg, 1.33 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (392 mg, 56%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H) 1.85 (m, 2 H) 2.34 (s, 3 H) 3.00 (t, J = 7.54 Hz, 2 H) 3.72 (s, 3 H) 6.27 (d, J = 6.99 Hz, 1 H) 6.84 (d, J = 8.82 Hz , 2 H) 7.11 (d, J = 7.72 Hz, 1 H) 7.27 (m, 4 H) 7.83 (d, J = 8.82 Hz, 1 H) 8.41 (d , J = 6.99 Hz, 1 H) 9.02 (d, J = 8.46 Hz, 1 H) 11.06 (wide s, 1 H) 14.37 (wide s, 1 H); MS (ESI +) m / z 416 (M + H) +.
Example 98
3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 2g (275mg, 1.33 mmol) was reacted with the product of Example 52b (307 mg, 1.33 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (305 mg, 45%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.75 -1.94 (m, 2 H) 2.38 (s, 3 H ) 2.98 (t, J = 7.35 Hz, 2 H) 6.30 (d, J = 6.99 Hz, 1 H) 6.49 -6.66 (m, 3 H) 6.91 - 7.04 (m, 1 H) 7.29-7.44 (m, 3 H) 7.79 (d, J = 8.82 Hz, 1 H) 8.39 (d, J = 7.35 Hz , 1 H) 8.96 (d, J = 8.46 Hz, 1 H) 9.57 (s, 1 H) 10.95 (s, 1 H) 14.34 (s, 1 H); MS (ESI +) m / z 402 (M + H-TFA) +.
Example 99
Propane-2-sulfonic acid 4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
The product of Example 6 (120 mg, 0.274 mmol) was reacted with isopropylsulfonyl chloride (43 mg, 0.30 mmol), N, N-diisopropylethylamine (43 mg, 0.33 mmol), and catalytic DMAP in CH2Cl2 for 18 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (40 mg, 23%) .H1 NMR (300 MHz, DMSO-d6) δ ppm: 8.75 (d, J = 8.54 Hz, 1 H) 8.20 (d, J = 6.71 Hz, 1 H) 7.58 (d, J = 8.54 Hz, 1 H) 7.26 (d, J = 7, 93 Hz, 1 H) 7.17 -7.21 (m, 2 H) 7.08 (d, J = 9.16 Hz, 2 H) 6.95 (d, J = 8.54 Hz, 2 H ) 6.15 (d, J = 6.71 Hz, 1 H) 3, .43 -3.51 (m, J = 13.43, 1H) 2.79 (t, J = 7.63, 7, 63 Hz, 2 H) 2.20 (s, 3 H) 1.61 -1.67 (m, 2 H) 1.21 (d, J = 6.71 Hz, 6 H) 0.78 (t, J = 7.32 Hz, 3 H); MS (ESI +) m / z 508 (M + H) +.
Example 100
Methanesulfonic acid 4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
The product of Example 6 (100 mg, 0.228 mmol) was reacted with methanesulfonyl chloride (28 mg, 0.251 mmol), N, N-diisopropylethylamine (88.4 mg, 0.684 mmol), and catalytic DMAP in CH2Cl2 for 18 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (20 mg, 15%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.77 -1.90 (m, 2 H) 2.40 (s, 3 H ) 2.98 (t, J = 7.54 Hz, 2 H) 3.43 (s, 3H) 6.34 (d, J = 6.99 Hz, 1 H) 7.19 (d, 2 H) 7.27 (d, 2 H) 7.36-7.40 (m, 2 H) 7.48 (d, 1 H) 7.78 (d, J = 8.82 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H) 8.91 (d, J = 8.46 Hz, 1 H); MS (DCI NH3 +) 480 m / z (M + H) +.
Example 101
Ethanesulfonic acid 4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester
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 producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (30 mg, 22%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.34 (t, J = 7.17 Hz, 3 H) 1.79 -1 , 87 (m, 2 H) 2.40 (s, 3 H) 2.98 (t, J = 7.54 Hz, 2 H) 3.47 (c, J = 7.35 Hz, 2 H) 6 , 34 (d, J = 7.35 Hz, IH) 7.14 -7.19 (m, 2 H) 7.27 (d, 2 H) 7.39 (s, 2 H) 7.46 (d , 1 H) 7.78 (d, J = 8.46 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H) 8.92 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 494 (M + H) +.
Example 102
Propane-2-sulfonic acid 4- [2- (7-ethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl ester
The product of Example 4 (100 mg, 0.233 mmol) was reacted with isopropylsulfonyl chloride (40 mg, 0.280 mmol), N, N-diisopropylethylamine (90 mg, 0.70 mmol), and catalytic DMAP in dichloroethane for 18 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (12 mg, 12%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.93 (d, J = 8.46 Hz, 1 H) 8.40 (d, J = 7.35 Hz, 1 H) 7.79 (d , J = 8.82 Hz, 1 H) 7.46 (d, 1 H) 7.37 (s, 2 H) 7.27 (d, 2 H) 7.15 (d, J = 8.82 Hz , 2 H) 6.35 (d, J = 6.99 Hz, 1 H) 3.66 (m, J = 7.72 Hz, 1 H) 3.03 (c, J = 7.72 Hz, 2 H) 2.40 (s, 3 H) 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-methylphenylsulfanyl] -phenyl ester
The product of Example 4 (98 mg, 0.228 mmol) was reacted with benzylsulfonyl chloride (43 mg, 0.299 mmol), N, N-diisopropylethylamine (88 mg, 0.686 mmol), and catalytic DMAP in dichloroethane for 18 h yielding the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (35 mg, 23%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.35 (t, J = 7.54 Hz, 3 H) 2.39 (s, 3H) 3.03 (c, J = 7.72 Hz, 2H) 4.94 (s, 2 H) 6.33 (d, J = 6.99 Hz, 1 H) 7.07 (d, J = 8.82 Hz, 2 H) 7.25 (d, J = 8.82 Hz, 2 H) 7.38 -7.49 (m, 8 H) 7.79 (d, J = 8.82 Hz, 1 H) 8.39 (d, J = 6.99 Hz , 1 H) 8.91 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 542 (M + H) +.
Example 104
N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxymethyl] -phenyl} -acetamide
Example 104A
4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenol
The product of Example 1d (893 mg, 5 mmol) and 2Amino-4-methyl-phenol (616 mg, 5 mmol) in ethanol (20 mL) were refluxed for 4 hours. The mixture was cooled to room temperature and evaporated. The residue was triturated with hexane / ethyl acetate (3: 1) to give the title compound in quantitative yield as the hydrochloride salt.
Example 104B
(2-Hydroxy-5-methoxy-phenyl) (7-methyl- [1,8] naphthyridin-4-yl) -carbamic acid tert-butyl ester
To a mixture of Example 104A (1.51 g, 5 mmol) and di-tert-butyl dicarbonate (2.4 g, 11 mmol) in 20 mL anhydrous THF was added NaOH (40 mL, 1N, 40 mmol) . The solution was stirred at room temperature for 40 hours and poured into water, neutralized with citric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica eluting with 2% methanol in dichloromethane to give the title compound (1.70 g, 93%).
Example 104C
N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxymethyl] -phenyl} -acetamide
A solution of 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 iodide Tetrabutylammonium (0.001 g) in DMF (1 ml) was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo yielding the title compound. To the residue dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added 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, DMSO-d6) δ 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, 2 H) 7.25 (m, 3 H) 7.40 (d, J = 8.46 Hz, 2 H) 7.73 (d, J = 8.46 Hz, 1 H) 8.43 (d, J = 6.99 Hz, 1 H) 8.98 (d, J = 8.46 Hz, 1 H) 9.89 (s, 1 H) 10.65 (s, 1 H) 14.25 (s, 1 H); MS (ESI +) m / z 413 (M + H) +.
Example 105
2- {5- [2- (4-Acetylaminophenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} propionic acid ethyl ester
To a suspension of sodium hydride (95%, 0.025 g, 1.0 mmol) in 5 mL anhydrous THF at 0 ° C in an N2 atmosphere was added 2-methyl-malonic acid diethyl ester (0.174 g, 1 , 0 mmol) drop by drop. The mixture was stirred for 30 minutes at room temperature, treated with the product of Example 24a (0.047 g, 1.0 mmol), microwave at 120 ° C for 1 hour, cooled, partitioned between ethyl acetate and water and was neutralized with 1M HCl. The aqueous layer was extracted by ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo yielding 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%). 1 H NMR (300 MHz, DMSO-D6) δ ppm 1.14 (t, J = 7.17 Hz, 3 H) 1.52 (d, J = 7.35 Hz, 3 H) 2.04 (s, 3 H) 2.30 (s, 3 H) 4.10 (m, 3 H) 6.17 (s, br, 1 H) 7.04 (m, 3 H) 7.26 (d, J = 8 , 82 Hz, 2 H) 7.48 (d, J = 7.35 Hz, 1 H) 7.57 (d, J = 8.46 Hz, 2 H) 8.45 (d, J = 8.46 Hz, 1 H) 8.78 (d, J = 8.82 Hz, 1 H) 9.11 (s, 1 H) 10.05 (s, 1 H); (ESI +) m / z 501 (M + H) +.
Example 106
N- {4- [4-Bromo-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
Example 106a
N- [4- (4-Bromo-2-nitro-phenylsulfanyl) -phenyl] -acetamide
A mixture of 2-fluoro-4-bromonitrobenzene (0.875 g, 3.9 mmol), 4-Acetamidothiophenol (0.777 g, 4.29 mmol) and cesium carbonate (1.4 g, 4.29 mmol) in DMF ( 8 mL) was heated 2.5 h at 100 ° C. The mixture was cooled, poured onto ice and the resulting solid was collected by filtration and dried in vacuo leaving the title compound as a yellow solid (1.4 g, 100%).
Example 106b
N- [4- (2-Amino-4-bromo-phenylsulfanyl) -phenyl] -acetamide
A solution of the product of Example 106a (1.4 g, 3.9 mmol), iron powder (0.874 g, 15.6 mmol) and ammonium chloride (0.253 g, 4.68 mmol) in a methanol solution ( 6 mL), THF (6 mL), and water (2 mL) was heated at reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a bed of celite. The filtrate was concentrated in vacuo to a volume of 10 mL, the solution was diluted with water (50 mL) and extracted with ethyl acetate. The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound (1.2 g, 92%).
Example 106c
N- {4- [4-Bromo-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (106 mg, 0.59 mmol) was reacted in ethanol (2 mL) with the product of Example 106b (200 mg, 0.59 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (53 mg, 19%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3H) 2.77 (s, 3 H), 6.41 (d, J = .99 Hz, 1 H), 7.02 (d, J = 8.82 Hz, 1 H), 7.33 (d, J = 8.46 Hz, 2 H), 7.58 (d, J = 8.82 Hz, 2 H), 7, 65 (dd, J = 8.46, 2.21 Hz, 1 H) 7.77 (d, J = 2.21 Hz, 1 H), 7.81 (d, J = 8.82 Hz, 1 H ), 8.48 (d, J = 6.99 Hz, 1 H), 8.96 (d, J = 8.82 Hz, 1 H), 10.11 (s, 1 H), 11.06 ( s, 1 H), 14.53 (s, 1 H); MS (DCI / NH3) m / z 479 (M + H) +.
Example 107
N- {4- [2- (7-Hydrazino- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The title compound was prepared according to the procedure of Example 47 by replacing hydrazine hydrate (0.050 g, 1.0 mmol) with morpholine. The crude product was purified by HTP using HPLC with TFA to give the title compound as the trifluoroacetic acid salt (0.0125 g, 19%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H), 7.19-7.32 (m, 4 H), 7.57 (d, J = 8.82 Hz, 2 H), 8.10 (d, J = 6.99 Hz, 1 H), 8.62 (d, J = 9.56 Hz, 1 H), 10.09 (s , 1 H), 10.53 (s, 1 H), 13.64 (s, 1 H); MS (ESI +) m / z 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 replacing N, N-dimethyl ethanolamine (0.044 g, 0.5 mmol) with 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-d6) δ ppm: 2.04, (s, 3 H), 2.35 (s, 3 H), 2.92 (s, 6 H), 3.64 -3, 68 (m, 2 H), 4.73 -4.86 (m, 2 H), 6.31 (d, J = 6.99 Hz, 1 H), 7.14 (d, J = 8.82 Hz, 1 H), 7.24 (d, J = 8.46 Hz, 2 H), 7.27-7.32 (m, 2 H), 7.36 (d, J = 8.82 Hz, 1 H), 7.51 (d, J = 8.46 Hz, 2 H), 8.33 (d, J = 6.99 Hz, 1 H), 8.95 (d, J = 9.19 Hz , 1 H), 9.87 (s, 1 H), 10.07 (s, 1 H), 10.88 (s, 1 H), 14.23 (s, 1 H); 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 by 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%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.04 (s, 3 H), 2.33 (s, 3 H), 3.31 (s, 3 H), 3.56 (t, J = 4.96 Hz, 2 H), 3.60 -3.67 (m, 2 H), 6.05 (d, J = 6.99 Hz, IH), 6.95 (d, J = 9, 19 Hz, 1 H), 7.05 (d, J = 8.09 Hz, 1 H), 7.20 -7.3 (m, J = 7.91, 7.91 Hz, 4 H), 7 , 56 (d, J = 8.46 Hz, 2 H), 7.96 -8.11 (m, 1 H), 8.33 8.49 (m, 2 H), 10.07 (s, 1 H), 10.32 (s, 1 H), 13.42 (d, J = 5.88 Hz, 1 H); MS (ESI +) m / z 474 (M + H) +.
Example 110
(7-Isobutyl- [1,8] naphthyridin-4-yl) - [2- (4-methoxyphenylsulfanyl) -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 h yielding following the procedure of Example 1g the crude title compound that was triturated with ether / THF 3: 1 providing the title compound as a hydrochloride salt (121 mg, 96%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J = 6.62 Hz, 6 H) 2.24 (m, J = 6.62 Hz, 1 H) 2.34 (s , 3 H) 2.89 (d, J = 7.35 Hz, 2 H) 3.72 (s, 3 H) 6.27 (d, J = 6.99 Hz, 1 H) 6.84 (d , J = 8.46 Hz, 2 H) 7.10 (d, J = 8.09 Hz, 1 H) 7.23-7.32 (m, 4 H) 7.81 (d, J = 8, 46 Hz, 1 H) 8.41 (d, J = 6.99 Hz, 1 H) 9.07 (d, J = 8.46 Hz, 1 H) 11.09 (wide s, 1 H) 14, 40 (wide s, 1 H); MS (ESI +) m / z 430 (M-Cl) +; (ESI-) m / z 428 (M-HCl) -.
Example 111
{5- [2- (4-Amino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} -cyano-acetic acid ethyl ester
The product of Example 30 (19 mg, 0.037 mmol), 2 mL of ethanol and 1 M hydrochloric acid (1.5 mL) were combined and heated at 90 ° C for 3 h, cooled and concentrated in vacuo yielding the title compound. 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-d6) δ ppm: 1.28 (t, J = 6.99 Hz, 3 H), 2.28 (s, 3 H), 4.25 (c, J = 7, 11 Hz, 2 H), 6.14 (d, J = 5.88 Hz, 1 H). 6.67 (d, J = 8.46 Hz, 2 H), 6.86 (d, J = 7.72 Hz, 1 H), 6.98 -7.28 (m, 5 H), 8, 15 (d, J = 5.89 Hz, 1 H), 8.65 (d, J = 9.56 Hz, 1 H), 9.49 (s, 1 H), 13.14 (s, 1 H ); MS (ESI +) m / z 470 (M + H) +.
Example 112
N- {4- [2- (7-Isobutyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide
The product of Example 12d (50 mg, 0.226 mmol) was reacted with the product of Example 18b (62 mg, 0.226 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (35 mg, 33%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J = 6.62 Hz, 7 H), 2.03 (s, 3 H), 2.23 (s, 1 H), 2.35 (s, 3 H), 2.89 (d, J = 7.35 Hz, 2 H), 6.31 (d, J = 7.35 Hz, 1 H), 7.14 (d, J = 8.09 Hz, 1 H), 7.21 -7.33 (m, 4 H), 7.50 (d, J = 8.46 Hz, 2 H), 7.80 (d, J = 8.82 Hz, 1 H), 8.41 (d, J = 6.99 Hz, 1 H), 8.99 (d, J = 8.82 Hz, 1 H), 10.04 (s, 1 H); MS (ESI +) m / z 457 (M + H-TFA) +; (ESI-) m / z 455 (MH-TFA) -.
Example 113
N-Methyl-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -benzamide
The product of Example 85b (0.155 g, 0.57 mmol) was reacted with the product of Example 2g as a 3.15 M solution in ethanol (0.18 mL, 0.57 mmol) for 24 hours following the Procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.188 g, 56%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.72 -1.91 (m, 2 H) 2.41 (s, 3 H ) 2.75 (d, J = 4.41 Hz, 3 H) 2.97 (t, J = 7.35 Hz, 2 H) 6.36 (d, J = 6.99 Hz, 1 H) 7 , 20 (d, J = 8.46 Hz, 2 H) 7.33-7.47 (m, 2 H) 7.50 (d, 1 H) 7.63 (d, J = 8.46 Hz, 2 H) 7.77 (d, J = 8.82 Hz, 1 H) 8.30 -8.44 (m, J = 6.62, 6.62 Hz, 2 H) 8.91 (d, J = 8.82 Hz, 1 H) 10.86 -11.09 (s, 1 H); MS (ESI +) m / z 443.2 (M + H) +; (ESI-) m / z 441.2 (MH) -.
Example 114
N-Methyl-3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -benzamide
The product of Example 87b (0.155 g, 0.57 mmol) was reacted with the product of Example 2g as a 3.15 M solution in ethanol (0.18 mL, 0.57 mmol) for 24 hours following the Procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.042 g, 13%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H) 1.76 -1.91 (m, 2 H) 2.39 (s, 3 H ) 2.70 (d, J = 4.41 Hz, 3 H) 2.91 -3.04 (m, 2 H) 6.27 (d, J = 6.99 Hz, 1 H) 7.18 - 7.42 (m, 4 H) 7.42 -7.51 (m, 1 H) 7.55 -7.63 (m, 2 H) 7.76 (d, J = 8.82 Hz, 1 H ) 8.28 8.41 (m, J = 6.99 Hz, 2 H) 8.88 (d, J = 8.46 Hz, 1 H) 10.95 (s, 1 H); MS (ESI +) m / z 443.2 (M + H) +; (ESI-) m / z 441.2 (MH) -.
Example 115
{4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -methanol
Example 115a
[4- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -methanol
The product of Example 84b (0.5 g, 1.73 mmol) was dissolved in THF (15 mL) and cooled in an ice bath. To the cold nitrogen solution, diborane was added as a 1.0 M solution in THF (3.6 mL, 3.6 mmol) and the resulting mixture was allowed to warm to room temperature and stir overnight. The crude product was isolated by extractive processing (ether / water) and dried with MgSO4, filtered and concentrated in vacuo yielding the crude title compound. Purification by flash chromatography on silica gel produced the alcohol as a bright yellow solid (0.392 g, 82%).
Example 115b
[4- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -methanol
The product of Example 115a (0.389 g, 1.41 mmol) was reacted with stannous chloride (1.4 g, 7.05 mmol) as described in Example 1 to give the title compound with a quantitative yield in form of an orange oil.
Example 115c
{4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -methanol
The product of Example 2g in the form of 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 18.5h following the procedure of Example 1 g producing the crude title compound that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.0195 g, 14%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H) 1.75 -1.93 (m, 2 H) 2.31 -2.42 ( s, 3 H) 2.91 -3.08 (m, 2 H) 4.42 (s, 2 H) 6.30 (d, J = 6.99 Hz, 1 H) 7.11 -7.42 (m, 7 H) 7.81 (d, J = 8.46 Hz, 1 H) 8.39 (d, J = 6.99 Hz, 1 H) 8.98 (d, J = 8.82 Hz , 1 H) 11.01 (s, 1 H); MS (ESI +) m / z 416.2 (M + H) +, (ESI-) m / z 414.3 (MH) -.
Example 116 (reference)
4- [4- (4-Bromo-benzyloxy) -2- (7-methyl-pyrido [2,3d] 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 -nitrobenzene which was treated successively using the procedures of Example 237D and 237E to provide the title product.
Example 116B
4- [4- (4-Bromo-benzyloxy) -2- (7-methyl-pyrido [2,3d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 116A was reacted with the product of Example 237B using the procedure of Example 237F by replacing the product of Example 116A with the product of Example 237B to provide the crude title compound that was purified by HPLC with TFA to provide the compound of the title in the form of a trifluoroacetic acid salt (19 mg, 17%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3 H) 5.13 (s, 2 H) 6.63 (m, 2 H) 7.03 (dd, J = 8, 82, 2.57 Hz, 1 H) 7.10 (m, 2 H) 7.21 (d. J-8.46 Hz, 2 H) 7.40 (m, 2 H) 7.54 (d, J = 8.09 Hz, 1 H) 7.66 (s, 1 H) 7.73 (d, J = 8.46 Hz, 1 H) 8.72 (s, 1 H) 8.84 (d, J = 8.46 Hz, 1H) 9.69 (s, 1 H) 11.08 (m, 1 H); MS (ESI +) m / z 545, 547 (M + H) +.
Example 117
N- {4- [4-Hydroxy-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 2g (35 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product of Example 232B (46 mg, 0.17 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (15 mg, 20%), 1 H NMR (300 MHz, DMSO-d6) 5 ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.72 -1.92 (m 2 H) 2.01 (s, 3 H) 2.98 (t, J = 7.35 Hz, 2 H) 6.30 (d , J = 7.35 Hz, 1 H) 6.89 (d, J = 2.57 Hz, 1 H) 6.91 -6.98 (m, 1 H) 7.04 (s, 2 H) 7 , 38 (d, J = 8.82 Hz, 3 H) 7.78 (d, J = 8.82 Hz, 1 H) 8.34 (d, J = 6.99 Hz, 1 H) 8.93 (d, J = 8.82 Hz, 1 H) 9.94 (s, 1 H) 10.28 (s, 1 H) 10.94 (s, 1 H) 14.30 (s, 1 H); MS (ESI +) m / z 445 (M + H) +.
Example 118 (reference)
[2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methyl-phenyl] - (7isobutyl- [1,8] naphthyridin-4-yl) -amine
The product of Example 12d (80 mg 0.362 mmol) was reacted with the product of Example 91b (85 mg, 0.362 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (28 mg, 19%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J = 6.62 Hz, 6 H), 2.14 (d, J = 13.97 Hz, 6H), 2.19- 2-30 (m, 1 H), 2.33 (s, 3 H), 2.90 (d, J = 7.35 Hz, 2 H), 5.97 (s, 1 H), 6.28 (d, J = 7.35 Hz, 1 H), 7.08 (d, J = 8.09 Hz, 1 H), 7.21 7.35 (m, 2 H), 7.83 (d, J = 8.82 Hz, 1 H), 8.46 (d, J = 6.99 Hz 1 H), 9.05 (d, J = 8.82 Hz, 1 H), 11.02 (br. S., 1 H); MS (ESI +) m / z 418 (M + H-TFA) +.
Example 119
N- {4- [4 (2-Methyl-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4 -lamino) phenylsulfanyl] -phenyl} -acetamide
Example 119a N- {4- [2-Amino-4- (2-methyl-benzyloxy) -phenylsulfanyl] phenyl} -acetamide
A mixture of the product of Example 232b (28 mg, 0.085 mmol), 2-methylbenzyl bromide (13 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at temperature environment 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (32 mg, 100%).
Example 119b
N- {4- [4- (2-Methyl-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4 -lamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product of Example 119a (32 mg, 0.085 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound which It was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (23mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.69 -1.94 (m, 2 H) 2.02 (s, 3 H ) 2.32 (s, 3 H) 2.99 (t, J = 7.35 Hz, 2 H) 5.14 (s, 2 H) 6.32 (d, J = 6.99 Hz, 1 H ) 6.98 -7.30 (m, 7 H) 7.41 (dd, J = 11.40, 8.82 Hz, 4 H) 7.80 (d, J = 8.82 Hz, 1 H) 8.38 (d, J = 6.99 Hz, 1 H) 8.97 (d, J = 8.46 Hz, 1 H) 9.98 (s, 1 H) 11.02 (s, 1 H) 14.37 (s, 1 H); MS (ESI +) m / z 549 (M + H) +.
Example 120
N- {4- [4- (3-Methyl-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
Example 120a
N- {4- [2-Amino-4- (3-methyl-benzyloxy) -phenylsulfanyl] phenyl} -acetamide
A mixture of the product of Example 232b (28 mg, 0.085 mmol), 3-methylbenzyl bromide (13 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at temperature environment 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (32 mg, 100%).
Example 120b
N- {4- [4- (3-Methyl-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4 -lamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product of Example 120a (32 mg, 0.085 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound which It was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (14 mg, 26%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.62 -1.93 (m, 2 H) 2.02 (s, 3 H ) 2.31 (s, 3 H) 2.99 (t, J = 7.35 Hz, 2 H) 5.11 (s, 2 H) 6.30 (d, J = 6.99 Hz, 1 H ) 6.97 -7.33 (m, 8 H) 7.34 -7.50 (m, 3H) 7.80 (d, J = 8.82 Hz, 1 H) 8.36 (d, J = 6.99 Hz, 1 H) 8.97 (d, J = 8.82 Hz, 1 H) 9.97 (s, 1 H) 11.01 (s, 1 H) 14.36 (s, 1 H ); MS (ESI +) m / z 549 (M + H) +.
Example 121 (5-Bromo-2-phenylsulfanyl-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) -amine
Example 121a
5-Bromo-2-phenylsulfanyl-phenylamine
A solution of 4-bromo-2-nitrophenol (10.0 g, 45.9 mmol) and Et3N (14.0 mL, 137.6 mmol) in 100 mL of CH2Cl2 in an N2 atmosphere was treated with trifluoromatanesulfonic anhydride ( 8.5 mL, 50.5 mmol) at 0 ° C for 30 min. It was quenched by the addition of MeOH. It was washed successively with 10% citric acid, 0.5 M KOH and water. It was dried over MgSO4, filtered and concentrated in vacuo yielding the title compound that was purified by silica gel column chromatography eluting with CH2Cl2 yielding an amber oil (15.2 g, 95%).
Example 121b
(4-Bromo-2-nitrophenyl) (phenyl) sulfane
The product of Example 121a (15.2 g, 43.4 mmol) and benzenethiol (4.4 mL, 43.4 mmol) in 100 mL of EtOH was treated with Na2CO3 and heated overnight at reflux. It was cooled to room temperature and suffocated with water. It was extracted with EtOAc. It was dried over MgSO4, filtered and concentrated in vacuo yielding the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc / hexane to yield a yellow oil (13.3 g, 99 %).
Example 121c
5-Bromo-2- (phenylthio) bencenamine
The product of Example 121b (2.0 g, 6.45 mmol) was reduced with SnCl2 following the procedure of Example 1f to produce the title compound as a clear oil (1.8 g, 100%).
Example 121d
(5-Bromo-2-phenylsulfanyl-phenyl) - (7-methyl- [1,8] naphthyridin4-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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (129 mg, 15%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 6.43 (d, J = 6.99 Hz, 1 H) 7.20 (d, J = 8.46 Hz , 1 H) 7.34 (s, 5 H) 7.69 (dd, J = 8.82, 2.21 Hz, 1 H) 7.81 (m, 2 H) 8.47 (d, J = 6.99 Hz, 1 H) 8.95 (d, J = 8.46 Hz, IH); MS (ESI +) m / z 422 (M + H-TFA) +.
Example 122
4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] phenol
Example 122a
4- (4-methyl-2-nitrophenoxy) phenol
A solution of hydroquinone (3.2 g, 29.0 mmol) and K2CO3 (8.0 g, 54.0 mmol) in 40 mL of DMF was heated to 100 ° C with 1-fluoro-4-methyl-2- Nitrobenzene (3.0 g, 19.3 mmol) 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. It was filtered and concentrated in vacuo to yield the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc / hexane to yield an orange oil (1.89 g, 40%).
Example 122b
4- (2-amino-4-methylphenoxy) phenol
The product of Example 122a (1.89 g, 7.71 mmol) was reduced with SnCl2 following the procedure of Example 1f to yield the title compound as a white solid (1.42 g, 86%).
Example 122c
4- (4-methyl-2- (7-methyl-1,8-naphthyridin-4 -lamino) 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (226 mg, 31%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.34 (s, 3 H) 2.74 (s, 3 H) 6.56 (d, J = 6.99 Hz, 1 H) 6.64 -6.71 (m, 2 H) 6.75 -6.81 (m, 2 H) 6.89 (d, J = 8.46 Hz, IH) 7.26 (dd, J = 8.46, 1.84 Hz, 1 H) 7.31 (s, 1 H) 7.76 (d, J = 8.82 Hz, 1 H) 8.48 (d, J = 6.99 Hz, 1H) 8, 95 (d, J = 8.46 Hz, 1 H) 9.34 (s, 1 H) 10.91 (s, 1H) 14.36 (s, 1 H); MS (ESI +) m / z 358 (M + H-TFA) +.
Example 123
Bis- [3- (7-methyl [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-benzyl] carbamic acid tert-butyl ester
The product of Example 1d (556 mg, 3.12 mmol) was reacted with the product of Example 90c (1.032 g, 3.12 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (228 mg, 31%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.35 (s, 9 H) 2.76 (s, 6 H) 4.45 (s, 4 H) 6.28 (d, J = 6, 99 Hz, 2 H) 7.20 7.31 (m, 12 H) 7.34 (s, 4 H) 7.77 (d, J = 8.82 Hz, 2 H) 8.40 (d, J = 6.99 Hz, 2 H) 8.90 (d, J = 8.82 Hz, 2 H) 11.00 (s, 2 H) 14.40 (s, 2 H); MS (ESI +) m / z 829 (M + HTFA) +.
Example 124
(5-Bromo-2-phenoxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) amine
Example 124a
4-bromo-2-nitro-1-phenoxybenzene
A solution of phenol (2.35 g, 25.0 mmol) and K2CO3 (9.4 g, 68.1 mmol) in 40 mL of DMF was heated to 100 ° C with 4-bromo-1-fluoro-2- Nitrobenzene (5.0 g, 22.7 mmol) 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. It was filtered and concentrated in vacuo to yield the title compound, which was purified by silica gel column chromatography eluting with 15% EtOAc / hexane to yield a yellow oil (6.6 g, 99%).
Example 124b
5-Bromo-2-Phenoxybenzenamine
The product of Example 124a (6.6 g, 22.5 mmol) was reduced with SnCl2 following the procedure of Example 1f to produce the title compound as a brown oil (5.9 g, 100%).
Example 124c
N- (5-bromo-2-phenoxyphenyl) -7-propyl-1,8-naphthyridin-4-amine
The product of Example 2g (275 mg, 1.33 mmol) was reacted with the product of Example 124b (351 mg, 1.33 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (470 mg, 65%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J = 7.35 Hz, 3 H) 1.72 -1.93 (m, 2 H) 2.91 -3.02 ( m, 2 H) 6.70 (d, J = 6.99 Hz, 1 H) 6.97 (d, J = 7.72 Hz, 2 H) 7.10 (t, J = 8.27 Hz, 2 H) 7.27 -7.36 (m, 2 H) 7.68 (dd, J = 8.82, 2.57 Hz, 1 H) 7.78 (d, J = 8.46 Hz, 1 H) 7.82 (d, J = 2.57 Hz, 1 H) 8.52 (d, J = 6.99 Hz, 1 H) 8.89 (d, J = 8.82 Hz, 1 H) 10.90 (s, 1 H) 14.49 (s, 1 H); MS (ESI +) m / z 436 (M + H-TFA) +.
Example 125 (5-Bromo-2-phenoxy-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) amine
The product of Example 1d (278 mg, 1.56 mmol) was reacted with the product of Example 124b (412 mg, 1.56 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (206 mg, 25%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.68 (dd, J = 8.82, 2.57 Hz, 1 H) 7 , 75 (d, J = 8.46 Hz, 1 H) 7.82 (d, J = 2.21 Hz, 1 H) 8.52 (d, J = 6.99 Hz, 1 H) 8.86 (d, J = 8.82 Hz, 1 H) 10.93 (s, 1 H) 14.49 (s, 1 H); MS (ESI +) m / z 408 (M + H-TFA) +.
Example 126
4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] N- (2-methoxy-ethyl) -benzamide
Example 126a
4- (4-Chloro-2-nitrophenoxy) methyl benzoate
A mixture of 1,4-dichloro-2-nitrobenzene (20.0 g, 104.2 mmol) and methyl 4-hydroxybenzoate (15.85 g, 104.2 mmol) in 150 mL of EtOH was treated with Na2CO3 and It was heated overnight at reflux. It was cooled to room temperature and suffocated with water. It was extracted with EtOAc. It was dried over MgSO4, filtered and concentrated in vacuo to yield the title compound, which was purified by silica gel column chromatography eluting with 10% EtOAc / hexane to yield the title compound as a yellow solid. (29.6 g, 92%).
Example 126b
4- (4-Chloro-2-nitrophenoxy) benzoic acid
The compound of Example 126a (29.6 g, 96.2 mmol) in 200 mL of MeOH was treated with aqueous LiOH (1 M) and heated under reflux for 1 hour. It was cooled to room temperature and acidified with aqueous HCl (1 M). The precipitate was filtered, washed with H2O and air dried to yield the title compound as a yellow solid (28.2 g, 100%).
Example 126c
4- (4-Chloro-2-nitrophenoxy) benzoyl chloride
The product of Example 126b (4.0 g, 13.6 mmol) in 40 mL of CH2Cl2 was treated with oxalyl chloride (3.5 g, 27.2 mmol) and DMF (catalytic amount). The mixture was stirred for 12 hours. The mixture was concentrated in vacuo yielding the title compound as a yellow oil (4.2 g, 100%).
Example 126d
4- (4-Chloro-2-nitrophenoxy) -N- (2-methoxyethyl) benzamide
The compound of Example 126c (1.0g, 3.2 mmol) in CH2Cl2 was added to a mixture of 2-methoxyethanamine (722 mg, 9.61 mmol) in CH2Cl2. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo to yield the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc / hexane to yield 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 produce 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-methyloxyethyl) benzamide
The product of Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 126e (200 mg, 0.62 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (89.4 mg, 25%). 1 H NMR (300 MHz, DMSO-D6) δ 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, 2 H) 7.30 (d, J = 8.82 Hz, 1 H) 7.61 (dd, J = 8.82, 2.57 Hz, 1 M 7.70 -7.80 (m, 4 H) 8.42 (t, J = 5.15 Hz, 1 H) 8.53 (d, J = 6, 99 Hz, 1 H) 8.82 (d, J = 8.82 Hz, 1 H) 10.90 (s, 1 H) 14.54 (s, 1 H); 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 h following the procedure of Example 126d yielding 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 yielding 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (45.9 mg, 13%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 (t, J = 7.54 Hz, 3 H) 1.39 -1.60 (m, 2 H) 2.72 (s, 3 H ) 3.08 -3.26 (m, 2 H) 6.72 (d, J = 6.99 Hz, 1 H) 6.96 (d, J = 8.82 Hz, 2 H) 7.29 ( d, J = 8.82 Hz, 1 H) 7.61 (dd, J = 8.82, 2.57 Hz, 1 H) 7.69-7.80 (m, 4 H) 8.34 (t , J = 5.52 Hz, 1 H) 8.53 (d, J = 6.99 Hz, 1 H) 8.82 (d, J = 8.46 Hz, 1 H) 10.91 (s, 1 H) 14.55 (s, 1 H); MS (ESI +) m / z 447 (M + HTFA) +.
Example 128
4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] N-methoxy-N-methyl-benzamide
Example 128a
4- (4-Chloro-2-nitrophenoxy) -N-methoxy-N-methylbenzamide
The product of Example 126c (1.0 g, 3.20 mmol) was reacted with N-methoxymethanamine (391 mg, 6.41 mmol) for 12 h following the procedure of Example 126d yielding the title compound (1.03 g, 100%).
Example 128b
4- (2-amino-4-chlorophenoxy) -N-methoxy-N-methylbenzamide
The product of Example 128a (1.0, g, 2.97 mmol) was reduced with SnCl2 following the procedure of Example 1f yielding the title compound as a clear oil (911 mg, 100%).
Example 128c
4- (4-Chloro-2- (7-methyl-1,8-naphthyridin-4-ylamino) phenoxy) -Nmethoxy-N-methylbenzamide
The product of Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 128b (192 mg, 0.62 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (50.9 mg, 15%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.72 (s, 3 H) 3.19 (s, 3 H) 3.42 (s, 3 H) 6.71 (d, J = 6, 99 Hz, 1 H) 6.94 (d, J = 8.82 Hz, 2 H) 7.36 (d, J = 8.82 Hz, 1 H) 7.50 (d, J = 8.82 Hz , 2 H) 7.63 (dd, J = 8.82, 2.57 Hz, 1 H) 7.72 (d, J = 8.82 Hz, 1 H) 7.75 (d, J = 2, 57 Hz, 1 H) 8.53 (d, J = 6.99 Hz, 1 H) 8.81 (d, J = 8.46 Hz, 1 H) 10.88 (s, 1 H) 14.46 (s, 1 H); MS (ESI +) m / z 449 (M + H-TFA) +.
Example 129
4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] N, N-diethyl-benzamide
Example 129a
4- (4-Chloro-2-nitrophenoxy) -N, N-diethylbenzamide
The compound of Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of diethylamine (469 mg, 6.41 mmol) in CH2Cl2. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo to yield the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc / hexane to yield 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 yielding 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (49.2 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.22 (d, J = 8.82 Hz, 2 H ) 7.34 (d, J = 8.82 Hz, 1 H) 7.62 (dd, J-8.82, 2.57 Hz, 1 H) 7.73 (d, J = 6.25 Hz, 1 H) 7.75 (s, 1 H) 8.53 (d, J = 6.99 Hz, 1 H) 8.82 (d, J = 8.82 Hz, 1 H) 10.92 (s, 1 H) 14.55 (s, 1 H); MS (ESI +) m / z 461 (M + HTFA) +.
Example 130
4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-propyl-benzamide
The product of Example 2g (75 mg, 0.36 mmol) was reacted with the product of Example 127b (111 mg, 0.36 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (25.8 mg, 12%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 (t, J = 7.35 Hz, 3 H) 0.95 (t, J = 7.35 Hz, 3 H) 1.37 -1 , 56 (m, 2 H) 1.72 -1.88 (m, 2 H) 2.96 (t, J = 7.54 Hz, 2 H) 3.08 3.22 (m, 2 H) 6 , 72 (d, J = 6.99 Hz, 1 H) 6.97 (d, J = 8.82 Hz, 2 H) 7.29 (d, J = 8.82 Hz, 1 H) 7.61 (dd, J = 8.82, 2.57 Hz, 1 H) 7.75 (d, J = 8.82 Hz, 4 H) 8.34 (t, J = 5.70 Hz, 1 H) 8 , 52 (d, J = 6.99 Hz, 1 H) 8.85 (d, J = 8.82 Hz, 1 H) 10.90 (s, 1 H) 14.55 (s, 1 H); MS (ESI +) m / z 475 (M + H-TFA) +.
Example 131
4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N- (2-methoxy-ethyl) -benzamide
The product of Example 2g (75mg, 0.36 mmol) was reacted with the product of Example 126e (116 mg, 0.36 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (101.7 mg, 46%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J = 7.35 Hz, 3 H) 1.70 -1.90 (m, 2 H) 2.90 -3.01 ( m, 2 H) 3.24 (s, 3 H) 3.32 -3.47 (m, 4 H) 6.73 (d, J = 6.99 Hz, 1 H) 6.98 (d, J = 8.82 Hz, 2 H) 7.29 (d, J = 8.82 Hz, 1 H) 7.61 (dd, J = 8.82, 2.57 Hz, 1 H) 7.71 -7 , 81 (m, 4 H) 8.42 (t, J = 4.78 Hz, 1 H) 8.53 (d, J = 6.99 Hz, 1 H) 8.85 (d, J = 8, 82 Hz, 1 H) 10.92 (s, 1 H) 14.57 (s, 1 H); MS (ESI +) m / z 491 (M + H-TFA) +.
Example 132
4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-methoxy-N-methyl-benzamide
The product of Example 2g (75 mg, 0.36 mmol) was reacted with the product of Example 128b (111 mg, 0.36 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (76.3 mg, 36%). H1 NMR (300 MHz, DMSO-d6) δ ppm: 0.88 1.03 (m, 3 H) 1.70 -1.91 (m, 2 H) 2.88 -3.00 (m, 2 H) 3.18 (s, 3 H) 3.42 (s, 3 H) 6.71 (d, J = 7 , 35 Hz, 1 M 6.94 (d, J = 8.82 Hz, 2 H) 7.36 (d, J = 8.82 Hz, 1 H) 7.50 (d, J = 8.82 Hz , 2 H) 7.59 -7.66 (m, 1 H) 7.71 -7.79 (m, 2 H) 8.53 (d, J = 6.99 Hz, 1 H) 8.84 ( d, J = 8.82 Hz, 1 H) 10.89 (s, 1 H) 14.54 (s, 1 H); MS (ESI +)) m / z 477 (M + H-TFA) +.
Example 133
4- [4-Chloro-2 - ([1,8] naphthyridin-4-ylamino) -phenoxy] -N-ethylN-methyl-benzamide
Example 133a
4- (4-Chloro-2-nitrophenoxy) -N-ethyl-N-methylbenzamide
The compound of Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of N-methylethanamine (379 mg, 6.41 mmol) in CH2Cl2. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo to yield the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc / hexane to yield 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 yielding the title compound as a clear oil (751 mg, 83%).
Example 133c
4- (2- (1,8-Naphthyridin-4-ylamino) -4-chlorophenoxy) -N-ethyl-Nmethylbenzamide
The product of Example 16c (100mg, 0.61 mmol) was reacted with the product of Example 133b (185 mg, 0.61 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (141 mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 -1.18 (m, 3 H) 2.62 -2.92 (m, 5 H) 6.76 (d, J = 7.35 Hz, 1 H) 6.94 (d, J = 8.82 Hz, 2 H) 7.25 (d, J = 8.09 Hz, 2 H) 7.34 (d, J = 8.82 Hz, 1 H) 7.63 (dd, J = 8.82, 2.57 Hz, 1 H) 7.75 (d, J = 2.57 Hz, 1 H) 7.85 (dd, J = 8.46 , 4.41 Hz, 1 H) 8.61 (d, J = 6.99 Hz, 1 H) 8.96 (dd, J = 8.64.1.29 Hz, 1 H) 9.14 (dd , J = 4.23, 1.29 Hz, 1 H) 11.06 (s, 1 H) 14.74 (s, 1 H); MS (ESI +) m / z 433 (M + H-TFA) +.
Example 134
4- [4- (4-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 1d (100 mg, 0.599 mmol) was reacted with the product of Example 116A (224 mg, 0.599 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (129 mg, 61%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 5.12 (s, 2H) 6.26 (d, J = 6.99 Hz, 1H) 6.65 (d, J = 8.45 HZ, 2H) 7.07-7.25 (m, 5H) 7.39 (d, J = 8.45 Hz, 2H) 7.60 (d, J = 8.45 Hz, 2H ) 7.81 (d, J = 8.45 Hz, 1H) 8.39 (d, J = 7.35 Hz, 1H) 8.99 (d, J = 8.45 Hz, 1H) 9.78 ( s, 1H) 11.05 (wide s, 1H) 14.40 (wide s, 1H); MS (ESI +) m / z 544,546 (M + H-TFA) +; (ESI-) m / z 542, 544 (MH-TFA) -.
Example 135
4- [4- (3-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene using the conditions described in Example 237C to provide 4- (3-Bromo-benzyloxy) -1-chloro-2 -nitrobenzene which was treated successively using the procedures of Examples 237D and 237E to provide 4- [2-Amino-4- (3-bromo-benzyloxy) phenylsulfanyl] -phenol.
The product of Example 1d (57 mg, 0.319 mmol) was reacted with 4- [2-Amino-4- (3-bromo-benzyloxy) phenylsulfanyl] -phenol (128 mg, 0.319 mmol) for 28 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (118 mg, 56%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (3H) 5.15 (s, 2H) 6.25 (d, J = 6.99 Hz, 1H) 6.65 (d, J = 8.46 Hz, 2H) 7.06-7.68 (m, 8H) 7.80 (d, J = 8.46 Hz, 1H) 8.39 (d, J = 6.99 Hz, 1H) 8 , 99 (d, J = 8.45 Hz, 1H) 9.78 (s, 1H) 11.02 (wide s, 1H) 14.39 (wide s, 1H); MS (ESI +) m / z 544, 546 (M + H-TFA) +; (ESI-) m / z 542, 544 (MH-TFA) -.
Example 136
4- [4- (3-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 2g (62 mg, 0.30 mmol) was reacted with 4- [2-Amino-4- (3-bromo-benzyloxy) phenylsulfanyl] -phenol (120 mg, 0.30 mmol) for 48 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (86 mg, 41%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.73 Hz, 3 H) 1.85 (dt, J = 7.73 Hz, 2 H) 3.00 (dd , J = 7.72 Hz, 2 H) 5.15 (s, 2 H) 6.27 (d, J = 735 Hz, 1 H) 6.66 (d, J = 8.82 Hz, 2 H) 7.07-7.69 (m, 7 H) 7.65 (s, 1 H) 7.83 (d, J = 8.82 Hz, 1 H) 8.41 (d, J = 6.99 Hz , 1 H) 9.03 (d, J = 8.82 Hz, 1 H) 9.81 (s, 1 H) 11.05 (wide s, 1 H) 14.43 (wide s, 1 H); MS (ESI +) m / z572, 574 (M + H-TFA) +; (ESI-) m / z 570-572 (MH-TFA) -.
Example 137
4- [4- (4-Bromo-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 16c (50 mg, 0.30 mmol) was reacted with the product of Example 116A (120 mg, 0.30 mmol) for 26 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (95 mg, 49%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 5.12 (s, 2H) 6.30 (d, J = 7.35 Hz, 1H) 6.64 (d, J = 8.82 Hz, 2H ) 7.08-7.25 (m, 3H) 7.39 (d, J = 8.09 Hz, 2H) 7.60 (d, J = 8.09 Hz, 2H) 7.91 (dd, J = 4.42 Hz, 1H) 8.46 (d, J = 6.98 Hz, 1H) 9.12 (d, J = 8.46 Hz, 2H) 9.17 (d, J = 4.42 Hz , 1H) 9.78 (s, 1H) 11.10 (wide s, 1H) 14.49 (wide s, 1H); (ESI +) m / z 529, 531 (M + H-TFA) +; (ESI-) m / z 528, 530 (MH-TFA) -.
Example 138
4- [4- (3-Bromo-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 16c (50 mg, 0.30 mmol) was reacted with 4- [2-Amino-4- (3-bromo-benzyloxy) phenylsulfanyl] -phenol (120 mg, 0.30 mmol) for 40 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (87 mg, 45%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 5.15 (s, 2 H) 6.30 (d, J = 6.99 Hz, 1 H) 6.66 (d, J = 8.83 Hz , 2 H) 7.08-7.47 (m, 6 H) 7.56 (d, J = 7.72 Hz, 1 H) 7.65 (m, 1 H) 7.92 (dd, J = 4.41 Hz, J = 8.46 Hz, 1 H) 8.18 (d, J = 6.99 Hz, 1 H) 9.14 (dd, J = 8.83 Hz, 1 H) 9.17 (dd, J = 5.88 Hz, J = 1.84 Hz, 1 H) 9.80 (s, 1 H) 11.16 (wide s, 1 H) 14.53 (wide s, 1 H); MS (ESI +) m / z 529, 531 (M + H-TFA) =; (ESI-) m / z 528, 530 (M-HTFA) -.
Example 139
4- [4- (3-Fluoro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-3-fluorobenzene using the conditions described in Example 237C to provide 1-Chloro-4- (3-fluoro-benzyloxy) -2-nitrobenzene which was treated successively using the procedures of Examples 237D and 237E to provide 4- [2-amino-4- (3-fluoro-benzyloxy) phenylsulfanyl] -phenol.
The product of Example 1d (53 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 20 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (60 mg, 33%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3 H) 5.16 (s, 2 H) 6.27 (d, J = 6.99 Hz, 1 H) 6.64 (d, J = 8.46 Hz, 2 H) 7.03-7-36 (m, 7 H) 7.45 (m, J = 6.26 Hz, 1 H) 7.80 (d, J = 8.82 Hz, 1 H) 8.39 (d, J = 6.98 Hz, 1 H) 8.99 (d, J = 8.82 Hz, 1 H) 9.78 (s, 1 H) 11 , 02 (wide s, 1 H) 14.39 (wide s, 1 H); MS (ESI +) m / z, 484 (M + H-TFA) +; (ESI-) m / z, 482 (MH-TFA) -.
Example 140
4- [4- (4-Fluoro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-fluoro-benzene using the conditions described in Example 237C to provide 1-Chloro-4- (4-fluoro-benzyloxy) -2-nitrobenzene which was treated successively using the procedures of Examples 237D and 237E to provide 4- [2-amino-4- (4-fluoro-benzyloxy) phenylsulfanyl] -phenol.
The product of Example 1d (53 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (4-fluoro-benzyloxy) phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 18 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (115 mg, 64%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3 H) 5.11 (s, 2 H) 6.26 (d, J = 6.99 Hz, 1 H) 6.65 (d, J = 8.46 Hz, 2 H) 7.10 (d, J = 8.82 Hz, 2 H) 7.15 -7.27 (m, 4H) 7.49 (m, J = 5 , 88 Hz, 2 H) 7.81 (d, J = 8.46 Hz, 1 H) 8.40 (d, J = 6.98 Hz, 1 H) 8.98 (d, J = 8.46 Hz, 1 H) 9:78 (s, 1 H) 11.03 (wide s, 1 H) 14.36 (wide s, 1 H); MS (ESI +) m / z, 484 (M + H-TFA) +; (ESI-) m / z, 482 (MH-TFA) -.
Example 141
4- [4- (4-Fluoro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 16c (50 mg, 0.30 mmol) was reacted with the product of 4- [2-amino-4- (4-fluoro-benzyloxy) -phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 20 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (99 mg, 56%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 5.11 (s, 2 H) 6.31 (d, J = 6.99 Hz, 1 H) 6.64 (d, J = 8.45 Hz , 2 H) 7.08-7.27 (m, 6 H) 7.50 (m, J = 5.51 Hz, 2 H) 7.91 (d, J = 4.41 Hz, 1 H) 8 , 47 (d, J = 6.98 Hz, 1 H) 9.13 (dd, J = 1.47 Hz, J = 8.45 Hz, 1 H) 9.17 (dd, J = 1.47 Hz , J = 4.05 Hz, 1 H) 9.79 (s, 1 H) 11.14 (wide s, 1 H) 14.50 (wide s, 1 H); MS (ESI +) m / z, 470 (M + H-TFA) +; (ESI-) m / z, 468 (MH-TFA) -.
Example 142
4- [4- (3-Fluoro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 16c (50 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 22 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (75 mg, 43%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H) 7.44 (m, J = 6.61 Hz, 1 H) 7.93 (dd, J = 4.41 Hz, 1 H) 8.47 (d, J = 6.98 Hz, 1 H) 9.14 (dd, J = 1.47 Hz, J = 8.46 Hz, 1 H) 9.18 (dd, J = 1.47 Hz, J = 4.41 Hz, 1 H) 9.79 (s, 1 H) 11.16 (wide s, 1 H) 14.52 (wide s, 1 H); MS (ESI +) m / z, 470 (M + H-TFA) +; (ESI-) m / z, 468 (MH-TFA) -.
Example 143
4- [4- (4-Chloro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
Example 143a
4- [2-Amino-4- (4-chloro-benzyloxy) -phenylsulfanyl] -phenol
A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-4-bromomethylbenzene using the conditions described in Example 237C to provide 4- (4-chloro-benzyloxy) -1-chloro-2-nitrobenzene which was treated successively using the procedures of Examples 237D and 237E to provide the title compound.
Example 143b
4- [4- (4-Chloro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 2g (85 mg, 0.41 mmol) was reacted with the product of Example 143a (146 mg, 0.41 mmol) for 26 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (89 mg, 68%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H) 1.83 (sext, J = 7.35 Hz, 2 H) 3.00 (dd , J = 7.35 Hz, 2 H) 5.13 (s, 2 H) 6.27 (d, J = 6.99 Hz, 1 H) 6.64 (d, J = 8.82 Hz, 2 H) 7.05-7.25 (m, J = 8.45 Hz, 4H) 7.48 (m, 4 H) 7.83 (d, J = 8.45 Hz, 1 H) 8.40 ( d, J = 6.99 Hz, 1 H) 9.00 (d, J = 8.46 Hz, 1 H) 9.78 (s, 1 H) 11.03 (wide s, 1 H) 14.40 (s wide, 1 H); MS (ESI +) m / z, 528, 530 (M + HTFA) +; (ESI-) m / z, 526, 528 (MH-TFA) -.
Example 144
4- [4- (3-Chloro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
Example 144a 4- [2-Amino-4- (3-chloro-benzyloxy) -phenylsulfanyl] -phenol
A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-3-bromomethylbenzene using the conditions described in Example 237C to provide 4- (3-chloro-benzyloxy) -1-chloro-2-nitrobenzene which was treated successively using the procedures of Examples 237D and 237E to provide the title compound.
Example 144b
4- [2-Amino-4- (3-chloro-benzyloxy) -phenylsulfanyl] -phenol
The product of Example 2g (85 mg, 0.41 mmol) was reacted with the product of Example 144a (146 mg, 0.41 mmol) for 24 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (85 mg, 65%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.32 Hz, 3 H) 1.85 (sext, J = 7.35 Hz, 2 H) 3.00 (dd , J = 7.72 Hz, 2 H) 5.15 (s, 2 H) 6.26 (d, J = 6.99 Hz, 1 H) 6.65 (d, J = 8.83 Hz, 2 H) 7.07-7.25 (m, 5 H) 7.35-7.54 (m, 3 H) 7.83 (d, J = 8.46 Hz, 1 H) 8.40 (d, J = 7.36 Hz, 1 H) 9.02 (d, J = 8.46 Hz, 1 H) 9.79 (s, 1 H) 11.02 (wide s, 1 H) 14.39 (s width, 1 H); MS (ESI +) m / z, 528, 530 (M + H-TFA) +; (ESI-) m / z, 526, 528 (MH-TFA) -.
Example 145
4- [4- (3-Fluoro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 2g (85 mg, 0.41 mmol) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) phenylsulfanyl] -phenol (141 mg, 0.41 mmol) for 24 h following the procedure of Example 1g producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (95 mg, 37%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.36 Hz, 3 H) 1.85 (sext, J = 7.72 Hz, 2 H) 3.00 (dd , J = 7.36 Hz, 2 H) 5.16 (s, 2 H) 6.27 (d, J = 7.35 Hz, 1 H) 6.66 (d, J = 8.83 Hz, 2 H) 7.097.34 (m, 7 H) 7.43 (m, J = 6.25 Hz, 1 H) 7.83 (d, J = 8.83 Hz, 1 H) 8.40 (d, J = 6.99 Hz, 1 H) 9.03 (d, J = 8.83 Hz, 1 H) 9.80 (s, 1 H) 11.04 (wide s, 1 H) 14.45 (wide s ,1 HOUR); MS (ESI +) m / z, 512 (M + H-TFA) +; (ESI-) m / z, 510 (MH-TFA) -.
Example 146
4- [4- (3-Chloro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 16c (50 mg, 0.30 mmol) was reacted with the product of Example 144a (107 mg, 0.30 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (109 mg, 60%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 5 H) 7.38-7.53 (m, 3 H) 7.80 ( d, J = 8.45 Hz, 1 H) 8.40 (d, J = 6.99 Hz, 1 H) 8.99 (d, J = 8.83 HZ, 1 H) 9.79 (s, 1 H) 11.02 (wide s, 1 H) 14.38 (wide s, 1 H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (MH-TFA) -.
Example 147 4- [4- (4-Chloro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 16c (50 mg, 0.30 mmol) was reacted with the product of Example 143a (107 mg, 0.30 mmol) for 24 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (50 mg, 27%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 4 H) 7.46 (m, J = 5.52 Hz, 3 H) 7.93 (m, J = 4, 41 Hz, 1 H) 8.48 (d, J = 6.98 Hz, 1 H) 9.17 (m, J = 1.47 Hz, J = 5.88 Hz, 3 H) 9.79 (s , 1 H) 11.15 (wide s, 1 H) 14.54 (wide s, 1 H); MS (ESI +) m / z, 486 (M + H-TFA) +; (ESI-) m / z, 484 (MH-TFA) -.
Example 148
4- [4- (3-Chloro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 1d (71 mg, 0.40 mmol) was reacted with the product of Example 144a (143 mg, 0.41 mmol) for 24 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as trifluoroacetic acid (122 mg, 49%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 5 H) 7.38-7.53 (m, 3 H) 7.80 ( d, J = 8.45 Hz, 1 H) 8.40 (d, J = 6.99 Hz, 1 H) 8.99 (d, J = 8.83 HZ, 1 H) 9.79 (s, 1 H) 11.02 (wide s, 1 H) 14.38 (wide s, 1 H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (MH-TFA) -.
Example 149
4- [4-Benzyloxy-2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] phenol
A solution of 4-chloro-3-nitro-phenol was reacted with Bromomethyl-benzene using the conditions described in Example 237C to provide 4-benzyloxy-1-chloro-2-nitro-benzene which was treated successively using the methods of Examples 237D and 237E to provide 4- (2-amino-4-benzyloxy-phenylsulfanyl) -phenol.
The product of Example 16c (100 mg, 0.599 mmol) was reacted with 4- (2-amino-4-benzyloxyphenylsulfanyl) -phenol (224 mg, 0.599 mmol) for 18 h following the procedure of Example 1g yielding the title compound crude which was purified by HPLC with TFA to provide the product as trifluoroacetic acid (mg,%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 5 H), 7.92 (dd, J = 8.46, 4.41 Hz, 1 H), 8.47 (d, J = 6.99 Hz, 1 H), 9.10 -9.21 (m, 2 H), 9.77 (s, 1 H), 11.14 (s, 1 HOUR); MS (ESI +) m / z 452 (M + H-TFA) +; (ESI-) m / z 450 (M-HTFA) -.
Example 150
4- [4- (4-Chloro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 1d (100 mg, 0.599 mmol) was reacted with the product of Example 143a (224 mg, 0.599 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (mg,%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H), 5.16 (s, 2 H), 6.26 (d, J = 6.99 Hz, 1 H), 6.65 (d, J = 8.46 Hz, 2 H), 7.09-7.24 (m, 5 H), 7.37-7.44 (m, 3 H), 7.51 (s , 1 H), 7.81 (d, J = 8.82 Hz, 1 H), 8.40 (d, J = 6.99 Hz, 1 H), 8.99 (d, J = 8.82 Hz, 1 H), 9.80 (s, 1 H), 11.04 (s, 1 H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (M-HTFA) -.
Example 151
4- [4-Benzyloxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 1d (50 mg, 0.280 mmol) was reacted with 4- (2-amino-4-benzyloxyphenylsulfanyl) -phenol (91 mg, 0.280 mmol) for 18 h following the procedure of Example 1g yielding the title compound crude which was purified by HPLC with TFA to provide the product as trifluoroacetic acid (22 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 5 H), 7.32 -7.46 (m, 5 H), 7.80 (d , J = 8.46 Hz, 1 H), 8.39 (d, J = 6.99 Hz, 1 H), 8.99 (d, J = 8.46 Hz, 1 H), 9.78 ( s, 1 H), 11.01 (s, 1 H); MS (ESI +) m / z 466 (M + HTFA) +; (ESI-) m / z 464 (MH-TFA) -.
Example 152
4- [4-Benzyloxy-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 2g (50 mg, 0.241 mmol) was reacted with 4- (2-amino-4-benzyloxyphenylsulfanyl) -phenol (78 mg, 0.241 mmol) for 18 h following the procedure of Example 1g yielding the title compound crude which was purified by HPLC with TFA to provide the product as trifluoroacetic acid (2 mg, 2%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H), 1.78 -1.91 (m, J = 7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2 H), 3.00 (t, J = 7.54 Hz, 2 H), 5.13 (s, 2 H), 6.27 (d, J = 6.99 Hz, 1 H), 6.65 (d, J = 8.82 Hz, 2 H), 7.09-7.23 (m, 5 H), 7.32-7.46 ( m, 5 H), 7.82 (d, J = 8.82 Hz, 1 H), 8.39 (d, J = 6.99 Hz, 1 H), 9.02 (d, J = 8, 82 Hz, 1 H), 9.78 (s, 1 H), 11.00 (s, 1 H); MS (ESI +) m / z 494 (M + H-TFA) +; (ESI-) m / z 492 (MH-TFA) -.
Example 153
N- {4- [4- (3-Methoxy-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 of Example 232B (28 mg, 0.085 mmol), 3-methoxybenzyl bromide (19 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at temperature environment 15 h. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (33 mg, 100%).
Example 153b N- {4- [4- (3-Methoxy-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product of Example 153a (33 mg, 0.085 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound which It was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (14mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.69 -1.93 (m, 2 H) 2.02 (s, 3 H ) 2.99 (t, J = 6.99 Hz, 2 H) 3.75 (s, 3 H) 5.13 (s, 2 H) 6.29 (d, J = 7.35 Hz, 1 H ) 6.91 (dd, J = 8.09, 2.57 Hz, 1 H) 6.95 -7.05 (m, 2 H) 7.13 (d, J = 8.82 Hz, 2 H) 7.16 -7.24 (m, 2 H) 7.31 (t, J = 8.09 Hz, 1 H) 7.38 (d, J = 8.46 Hz, 1 H) 7.42 (d , J = 8.82 Hz, 2 H) 7.80 (d, J = 8.82 Hz, 1 H) 8.35 (d, J = 6.99 Hz, 1 H) 8.97 (d, J = 8.82 Hz, 1 H) 9.97 (s, 1 H) 11.00 (s, 1 H) 14.36 (s, 1H); MS (ESI +) m / z 565 (M + H) +.
Example 154
N- {4- [4- (3-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin4-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 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (37 mg, 100%).
Example 154b
N- {4- [4- (3-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4 -lamino) -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 h following the procedure of Example 1g yielding the crude title compound which It was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (15mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.65 -1.90 (m, 2 H) 2.02 (s, 3 H ) 2.99 (t, J = 7.54 Hz, 2 H) 5.17 (s, 2 H) 6.29 (d, J = 6.99 Hz, 1 H) 7.14 (d, J = 8.82 Hz, 2 H) 7.17 7.27 (m, 2 H) 7.28-7.40 (m, 3 H) 7.42 (d, J = 8.46 Hz, 2 H) 7 , 55 (d, J = 7.72 Hz, 1 H) 7.66 (s, 1 H) 7.80 (d, J = 8.46 Hz, 1 H) 8.37 (d, J = 6, 99 Hz, 1 H) 8.97 (d, J = 8.82 Hz, 1 H) 9.98 (s, 1 H) 11.00 (s, 1 H) 14.37 (s, 1 H); 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 temperature environment 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (34 mg, 100%).
Example 155b
N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4- (3-nitrobenzyloxy) -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 h following the procedure of Example 1 g yielding the crude title compound which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (13 mg, 29%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H) 1.72 -1.92 (m, 2 H) 2.02 (s, 3 H ) 2.99 (t, J = 7.54 Hz, 2 H) 5.32 (s, 2 H) 6.30 (d, J = 6.99 Hz, 1 H) 7.15 (d, J = 8.46 Hz, 2 H) 7.19 -7.25 (m, 1 H) 7.27 (d, J = 2.57 Hz, 1 H) 7.38 (d, J = 8.82 Hz, 1 H) 7.43 (d, J = 8.46 Hz, 2 H) 7.72 (t, J = 7.91 Hz, 1 H) 7.81 (d, J = 8.82 Hz, 1 H ) 7.91 (d, J = 7.72 Hz, 1 H) 8.22 (d, J = 8.82 Hz, 1 H) 8.32 (s, 1 H) 8.37 (d, J = 7.35 Hz, 1 H) 8.97 (d, J = 8.82 Hz, 1 H) 9.98 (s, 1 H) 11.01 (s, 1 H) 14.37 (s, 1 H ); MS (ESI +) m / z 580 (M + H) +.
Example 156
N- {4- [4- (4-Cyano-benzyloxy) -2- (7-propyl- [1,8] naphthyridin4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
Example 156a
N- {4- [2-Amino-4- (4-cyano-benzyloxy) -phenylsulfanyl] phenyl} -acetamide
A mixture of the product of Example 232B (28 mg, 0.085 mmol), 4-cyanobenzyl bromide (19 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at temperature environment 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (33 mg, 100%).
Example 156b
N- {4- [4- (4-Cyano-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4 -lamino) -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 h following the procedure of Example 1g yielding the crude title compound which It was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (12 mg, 21%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.69 -1.92 (m, 2 H) 2.02 (s, 3 H ) 2.99 (t, J = 7.54 Hz, 2 H) 5.27 (s, 2 H) 6.30 (d, J = 6.99 Hz, 1 H) 7.14 (d, J = 8.82 Hz, 2 H) 7.17 -7.27 (m, 2 H) 7.37 (d, J = 8.46 Hz, 1 H) 7.42 (d, J = 8.82 Hz, 2 H) 7.64 (d, J = 8.09 Hz, 2 H) 7.81 (d, J = 8.82 Hz, 1 H) 7.89 (d, J = 8.46 Hz, 2 H ) 8.38 (d, J = 6.99 Hz, 1 H) 8.97 (d, J = 8.82 Hz, 1 H) 9.98 (s, 1 H) 11.01 (s, 1 H ) 14.38 (s, 1 H); MS (ESI +) m / z 560 (M + H) +.
Example 157 N- {4- [4- (2-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
Example 157a
N- {4- [2-Amino-4- (2-bromo-benzyloxy) -phenylsulfanyl] phenyl} -acetamide
A mixture of the product of Example 232B (56 mg, 0.17 mmol), 2-bromobenzyl bromide (26 □ 1, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL ) stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (75 mg, 100%).
Example 157b
N- {4- [4- (2-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 2g (35 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product of Example 157a (75 mg, 0.17 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (18 mg, 29%). 1 H NMR (300 MHz, DMSO-d6), δ ppm: 0.97 (t, J = 7.35 Hz, 3 H), 1.72 -1.92 (m, 2 H) 2.02 (s, 3 H), 2.99 (t, J = 7.35 Hz, 2 H), 5.17 (s, 2 H), 6.33 (d, J = 6.99 Hz, 1 H), 7, 16 (d, J = 8.46 Hz, 2 H), 7.18 -7.28 (m, 2 H), 7.28 -7.51 (m, 5 H), 7.60 (dd, J = 7.54, 1.65 Hz, 1 H), 7.69 (d, J = 6.99 Hz, 1 H), 7.81 (d, J = 8.82 Hz, 1 H), 8, 39 (d, J = 6.99 Hz, 1 H), 8.97 (d, J = 8.82 Hz, 1 H), 9.99 (s, 1 H), 11.02 (s, 1 H ), 14.37 (s, 1 H): MS (ESI +) m / z 613M + H) +.
Example 158
N- {4- [4- (4-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
Example 158a
N- {4- [2-Amino-4- (4-bromo-benzyloxy) -phenylsulfanyl] phenyl} -acetamide
A mixture of the product of Example 232B (28 mg, 0.085 mmol), 4-bromobenzyl bromide (24 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at temperature environment 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (37 mg, 100%).
Example 158b
N- {4- [4- (4-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4 -lamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product of Example 158a (37 mg, 0.085 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound which purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (26 mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.67 -1: 92 (m, 2 H) 2.02 (s, 3 H ) 2.99 (t, J = 7.54 Hz, 2 H) 5.14 (s, 2 H) 6.30 (d, J = 6.99 Hz, 1 H) 7.14 (d, J = 8.46 Hz, 2 H) 7.16 -7.26 (m, 2 H) 7.31 -7.49 (m, 5 H) 7.53 -7.66 (m, 2 H) 7.80 (d, J = 8.46 Hz, 1 H) 8.37 (d, J = 6.99 Hz, 1 H) 8.97 (d, J = 8.82 Hz, 1 H) 9.97 (s , 1 H) 11.00 (s, 1 H) 14.37 (s, 1 H); MS (ESI +) m / z 615 (M + H) +.
Example 159
N- {4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -acetamide
Example 159A
N- [4- (4-Chloro-2-nitro-phenoxy) -phenyl] -acetamide
A mixture of 2-Fluoro-5-Chloro Nitrobenzene (0.5 g, 2.85 mmol), 4-Acetamidophenol (0.45 g, 3.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol ) in DMSO (5 mL) was heated 6 hr at 90 ° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water, a 20% aqueous solution of potassium hydroxide and a 10% aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was concentrated in vacuo 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 NH4Cl 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (25 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.92 -2.11 (m, 3 H) 2.74 (s, 3 H) 6.69 (d, J = 6.99 Hz, 1 H ) 6.87 -6.99 (m, 2 H) 7.07 (d, J = 9.19 Hz, 1 H) 7.45 -7.57 (m, 3 H) 7.69 (d, J = 2.57 Hz, 1 H) 7.77 (d, J = 8.82 Hz, 1 H) 8.52 (d, J = 6.99 Hz, 1 H) 8.91 (d, J = 8 , 46 Hz, 1 H) 9.93 (s, 1 H) 10.92 (s, 1 H) 14.50 (s, 1 H); MS (ESI +) m / z 419 (M + H) +, (ESI-) m / z 417 (MH) -.
Example 160
[2- (3,4-Dimethyl-phenylsulfanyl) -5-methyl-phenyl] - (7-propyl [1,8] naphthyridin-4-yl) -amine
The product of Example 2g (70 mg, 0.338 mmol) was reacted with the product of Example 4c by replacing 3,4-dimethylbencentiol with 4-mercaptophenol for 20h following the procedure of Example 1g yielding the crude title compound that was triturated with ether / THF 4: 1 providing the title compound as a hydrochloride salt (135 mg, 88%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.99 (t, J = 7.35 Hz, 3 H) 1.82 (m, J = 7.35 HZ, 2 H) 1.93 (s , 3 H) 2.05 (s, 3 H) 2.36 (s, 3 H) 2.99 (c, J = 7.35 Hz, 2 H) 6.20 (d, J = 6.99 Hz , 1 H) 6.94 (m, 3 H) 7.32 (m, 2 H) 7.34 (s, 1 H) 7.80 (d, J = 8.82 Hz, 1 H) 8.33 (d, J = 7.35 Hz, 1 H) 8.97 (d, J = 8.82 Hz, 1 H) 10.96 (wide s, 1 H) 14.29 (wide s, 1 H); MS (ESI +) m / z 414 (M-Cl) +; (ESI-) m / z 412 (M-HCl) -.
Example 161
(7-Ethyl- [1,8] naphthyridin-4-yl) - [2- (4-methoxyphenylsulfanyl) -5-methyl-phenyl] -amine
The product of Example 3f (79 mg, 0.41 mmol) was reacted with the product of Example 50b (88 mg, 0.41 mmol) for 23 h, producing following the procedure of Example 1g providing the crude title compound to be triturated with ether / THF 3: 1 to give the title compound (162 mg, 90%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J = 7.35 Hz, 3 H) 2.34 (s, 3 H) 3.05 (c, J = 7.35 Hz , 2 H) 3.72 (s, 3 H) 6.27 (d, J = 6.98 Hz, 1 H) 6.85 (m, J = 8.82 Hz, J = 2.20 Hz, 2 H) 7.10 (d, J = 8.09 Hz, 1 H) 7.23-7.32 (m, 4 H) 7.83 (d, J = 8.83 Hz, 1 H) 8.41 (d, J = 6.98 Hz, 1 H) 9.11 (d, J = 8.83 Hz, 1 H) 11.16 (wide s, 1 H) 14.39 (wide s, 1 H); MS (ESI +) m / z 402 (M-Cl) +; (ESI-) m / z 400 (M-HCl) -.
Example 162
4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-methyl-benzamide
Example 162a
4- (4-Chloro-2-nitro-phenoxy) -N-methyl-benzamide
The product of Example 126c (225 mg, 0.72 mmol) was reacted with methylamine (1.0 mL, 2.0 mmol) in THF (20 mL) at room temperature. THF was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with 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 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (100 mg, 55%).
Example 162c
4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-methyl-benzamide
The product of Example 2g (64 mg, 0.31 mmol) was reacted with Example 162b (85.0 mg, 0.31 mmol) in ethanol (5 mL) at 85 ° C in a sealed tube for 18 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (25 mg, 31%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.85 (d, J = 8.82 Hz, 1 H) 8.53 (d, J = 7.35 Hz, 1 H) 8.33 (d , J = 4.17 Hz, 1 H) 7.71 -7.78 (m, 4 H) 7.61 (dd, J = 8.82, 2.57 Hz, 1 H) 7.29 (d, 1 H) 6.97 (d, J = 8.82 Hz, 2 H) 6.73 (d, J = 6.99 Hz, 1 H) 2.93 3.00 (t, 2 H) 2.71 (d, 3 H) 1.76 -1.87 (m, 2 H) 0.95 (t, J = 7.35 Hz, 3 H); MS (ESI +) m / z 561 (M + H) +.
Example 163
1- {4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanone oxime
Example 163a
1- [4- (2-Amino-4-chloro-phenoxy) -phenyl] -ethanone
The product of Example 164a (1.0 g, 3.4 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.70 g, 78%).
Example 163b
1- [4- (2-amino-4-chloro-phenoxy) -phenyl] -ethanone oxime
To the product of Example 163a (150 mg, 0.57 mmol) in ethanol (15 mL) were 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 h. 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 in vacuo yielding 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 h yielding the crude title compound which was purified by HPLC with TFA to provide the product as trifluoroacetic acid (25 mg, 31%). 1 H NMR (500 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.32, 2.44 Hz, 3 H) 1.81 1.88 (m, 2 H) 2.09 (s , 3 H) 2.99 (t, 2H) 6.74 (d, J = 7.32 Hz, 1 H) 6.97 (d, J = 9.28 Hz, 2 H) 7.26 (d, J = 9.28 Hz, 1 H) 7.56 (d, J = 8.79 Hz, 2 H) 7.61 (dd, J = 9.03, 2.69 Hz, 1 H) 7.75 ( d, J = 2.44 Hz, 1 H) 7.77 7.79 (m, 1 H) 8.57 (d, J = 6.84 Hz, 1 H) 8.93 (d, J = 8, 30 Hz, 1 H); MS (ESI +) m / z 447 (M + H) +.
Example 164
1- {4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -ethanol
Example 164a
1- [4- (4-Chloro-2-nitro-phenoxy) -phenyl] -ethanone
1-Bromo-4-chloro-2-nitrobenzene (5 g, 21.2 mmol) was added to a solution of 4-hydroxyacetophenone (2.87 g, 21.1 mmol), and K2CO3 (7.28 g, 0.052 moles) in DMF (50 mL). The mixture was heated at 80 ° C for 15 h. 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 in vacuo yielding 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 164b
1- [4- (4-Chloro-2-nitro-phenoxy) -phenyl] -ethanol
The product of Example 164a (0.7 g, 2.4 mmol) was added to ethanol (30 mL) and sodium borohydride (115 g, 3.11 mmol) was added portionwise. The reaction was stirred for 1 h and then excess sodium borohydride was destroyed by dropwise addition of acetic acid. The reaction was poured onto ice / water and extracted with ethyl acetate. The organic phase was washed with water, brine, and dried over sodium sulfate, filtered and concentrated in vacuo yielding the title compound (0.634 g, 90%).
Example 164c
1- [4- (2-Amino-4-chloro-phenoxy) -phenyl] -ethanol
The product of Example 164b (0.58 g, 1.9 mmol) was reduced with SnCl2 as described in Example 1f to give the title compound (0.36 g, 70%).
Example 164d
Example 164 1- {4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanol
The product of Example 2g (125 mg, 0.60 mmol) was reacted with Example 164c (160 mg, 0.60 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (40 mg, 12%). 1 H NMR (300 MHz, DMSO-d6) S ppm: 8.91 (d, J = 8.82 Hz, 1 H) 8.52 (d, J = 6.99 Hz, 1 H) 7.78 (d , J = 8.82 Hz, 1 H) 7.70 (d, J = 2.57 Hz, 1 H) 7.56 (dd, J = 8.82, 2.57 Hz, 1 H) 7.23 (d, J = 8.46 Hz, 2 H) 7.12 (d, J = 8.82 Hz, 1 H) 6.87 -6.94 (m, 2 H) 6.69 (d, J = 6.99 Hz, 1 H) 4.63 (c, J = 6.25 Hz, 1 H) 2.97 (t, J = 7.54 Hz, 2 H) 1.75 -1.88 (m, J = 7.35, 7.35, 7.35, 7.35 Hz, 2 H) 1.19 (d, J = 6.25 Hz, 3 H) 0.95 (t, J = 7.35 Hz , 3 H); ); MS (ESI -) m / z 432 (MH) -.
Example 165
Propane-2-sulfonic acid 4- [4-chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl ester
Example 165a
4-Chloro-1- (4-methoxy-phenoxy) -2-nitro-benzene
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 4-methoxyphenol (5.3 g, 42.2 mmol), and K2CO3 (14.5 g, 105 mmol) in DMF (50 mL). The mixture was heated at 80 ° C for 16 h. 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 yielding the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (8.0 g, 67%).
Example 165b
4- (4-Chloro-2-nitro-phenoxy) -phenol
To Example 165a (0.98 g, 3.5 mmol) in CH2Cl2 (20 mL) was added boron tribromide (0.95 g, 3.90 mmol). The reaction was stirred for 18 h. Methanol was added to destroy excess boron tribromide. The reaction was poured into water and extracted with methylene chloride. The phases were separated. The organic phase was washed with water, brine, and dried over sodium sulfate, filtered and concentrated in vacuo yielding the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (0.57, 60%).
Example 165c
4- (2-Amino-4-chloro-phenoxy) -phenol
The product of Example 165b (1.0 g, 3.7 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.7 g, 78%).
Example 165d
4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] phenol
The product of Example 1d (80 mg, 4.5 mmol) was reacted with the product of Example 165c (106 mg, 4.5 mmol) in ethanol (15 mL) at 85 ° C in a sealed tube for 18 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (40 mg, 18%).
Example 165e
Propane-2-sulfonic acid 4- [4-chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl ester
The product of Example 165d (43 mg, 0.085 mmol) was reacted with isopropylsulfonyl chloride (14.5 mg, 0.102 mmol), N, N-diisopropylethylamine (33 mg, 0.255 mmol), and catalytic DMAP in CH2Cl2 for 18 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (16 mg, 31%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.38 (d, J = 6.99 Hz, 6 H) 2.73 (s, 3 H) 3.54-3.65 (m, 1 H ) 6.69 (d, J = 6.99 Hz, 1 H) 7.01 (d, J = 9.19 Hz, 2 H) 7.20 (d, J = 9.19 Hz, 2 H) 7 , 27 (d, J = 8.82 Hz, 1 H) 7.60 (dd, J = 8.82, 2.57 Hz, 1 H) 7.70 7.75 (m, 2 H) 8.51 (d, J = 6.99 Hz, 1 H) 8.81 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 484 (M + H) +.
Example 166
4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] N-methyl-benzamide
The product of Example 1d (100 mg, 0.562 mmol) was reacted with Example 162b (155.0 mg, 0.562 mmol) in ethanol (5 mL) at 85 ° C in a sealed tube for 18 h yielding the crude title compound which was purified by HPLC with TFA to provide the product as trifluoroacetic acid (40 mg, 13%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.82 (d, J = 8.46 Hz, IH) 8.53 (d, J = 6.99 Hz, 1 H) 8.33 (d, J = 4.41 Hz, 1 H) 7.71 -7.78 (m, 4 H) 7.61 (dd, J = 8.82, 2.57 Hz, 1 H) 7.30 (d, J = 8.82 Hz, 1 H) 6.96 (d, J = 8.82 Hz, 2 H) 6.72 (d, J = 6.99 Hz, 1 H) 2.71 -2.77 (m , 6 H); MS (ESI +) m / z 419 (M + H) +.
Example 167
[2- (4-Aminomethyl-phenoxy) -5-chloro-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 167a
4- (4-Chloro-2-nitro-phenoxy) -benzonitrile
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.3 mmol) was added to a solution of 4-cyanophenol (5.0 g, 42.3 mmol), and K2CO3 (14.6 g, 0 , 10 moles) 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 and the combined organic phases were washed with water, brine, and dried over sodium sulfate. The organic phase was filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with (hexanes / ethyl acetate 4: 1) to give the product (9.0 g, 77.8%).
Example 167b
4- (2-Amino-4-chloro-phenoxy) -benzonitrile
To the product of Example 116a (0.5 g, 1.8 mmol) in absolute ethanol (20 mL) was added BiCl3 (0.86 g, 27.3 mmol), and NaBH4 (0.55 g, 14.6 mmoles) while cooling in an ice / water bath. The mixture was stirred for 20 h. The reaction was filtered through celite to remove bismuth. The solution was concentrated under reduced pressure. The residue was treated with 5% HCl for 15 h and then made alkaline with ammonium hydroxide (pH = 10). The solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, and dried over sodium sulfate, filtered and concentrated in vacuo yielding the title compound as a solid (0.34 g, 77%).
Example 167c
4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] benzonitrile
The product of Example 1d (100 mg, 0.408 mmol) was reacted with Example 167b (100 mg, 0.408 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h yielding the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (125 mg, 44%).
Example 167d
[2- (4-Aminomethyl-phenoxy) -5-chloro-phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
The product of Example 167c (88 mg, 0.175 mmol) was reacted with lithium aluminum hydride (13.3 mg, 0.351 mmol) in THF (5 mL) at 60 ° C for 15 h yielding the crude title compound which purified by HPLC with TFA to provide the product as trifluoroacetic acid (15 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 11.04 (s, IH) 8.92 (d, J = 8.82 Hz, IH) 8.54 (d, J = 6.99 Hz, 1 H) 8.18 (s, 2 H) 7.72-7.80 (m, 2 H) 7.59 (dd, J = 9.01, 2.76 Hz, 1 H) 7.40 (d, J = 8.82 Hz, 2 H) 6.99 -7.12 (m, 3 H) 6.74 (d, J = 6.99 Hz, 1 H) 3.97 (c, J = 5.52 Hz, 2 H) 2.74 (s, 3 H); MS (ESI +) m / z 391 (M + H) +.
Example 168
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N, N-dimethyl-benzamide
Example 168a
3- (4-Chloro-2-nitro-phenoxy) -benzoic acid
To a solution of DMF (50 mL) was added 1-bromo2-nitro-4-chloro-benzene (10.0 g, 42.2 mmol), 3-hydroxybenzoic acid (5.8 g, 42.0 mmol), and K2CO3 (17.5 g, 0.13 mol). The solution was heated to 85 ° C and stirred overnight. The reaction was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over Na2SO4, filtered and concentrated in vacuo yielding a crude oil. This oil was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (90:10) to give the title compound (7.4 g, 60%).
Example 168b
3- (4-Chloro-2-nitro-phenoxy) -benzoyl chloride
The product of Example 168a (2.0 g. 6.8 mmol) was treated with oxalyl chloride (9.0 g, 13.6 mmol) and catalytic DMF at 60 ° C for 5 h. The excess oxalyl chloride was removed in vacuo. The residue was captured with benzene to give the desired product (2.2 g, 94%).
Example 168c
3- (4-Chloro-2-nitro-phenoxy) -N, N-dimethyl-benzamide
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 in vacuo yielding the title compound (1.9 g, 87%).
Example 168d
3- (2-Amino-4-chloro-phenoxy) -N, N-dimethyl-benzamide
The product of Example 168c (1.5 g, 4.6 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.91 g, 68%).
Example 168e
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N, N-dimethyl-benzamide
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 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (100 mg, 20.2%). 1 H NMR (500 MHz, DMSO-D6) δ ppm: 8.86 (d, J = 8.79 Hz, 1 H) 8.52 (d, J = 6.84 Hz, 1 H) 7.74 (d , 1 H) 7.72 (d, 1H) 7.60 (dd, J = 8.79, 2.93 Hz, 1 H) 7.28-7.33 (m, 1 H) 7.27 (d , 2H) 7.06 (d, J = 7.81 Hz, 1 H) 6.99 (dd, J = 8.06, 2.69 Hz, 1 H) 6.71 (d, J = 6.84 Hz, 1 H) 2.96 (t, 2 H) 2.91 (s, 3 H) 2.70 (s, 3 H) 1.79 -1.86 (m, 2 H) 0.96 (t , J = 7.49 Hz, 3 H); MS (ESI +) m / z 461 (M + H) +.
Example 169
3- [4-Chloro-2- (7-propyl [1,8] naphthyridin-4-ylamino) -phenoxy] -benzoic acid ethyl ester
Example 169a
3- (4-Chloro-2-nitro-phenoxy) benzoic acid ethyl ester
In the product of Example 168a (2.0 g, 6.8 mmol) in ethanol (50 mL) with cooling, HCl gas was bubbled for 10 h. The excess ethanol was removed in vacuo. The solid was collected in ethyl acetate. The organic layer was washed with saturated NaHCO3, water, brine, and dried over sodium sulfate, filtered and concentrated in vacuo yielding the title compound (2.0 g, 91%).
Example 169b
3- (2-Amino-4-chloro-phenoxy) benzoic acid ethyl ester
The product of Example 169a (1.5 g, 4.7 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (1.0 g, 73%).
Example 169c
3- [4-Chloro-2- (7-propyl [1,8] naphthyridin-4-ylamino) -phenoxy] -benzoic acid ethyl ester
The product of Example 2g (113 mg, 0.55 mmol) was reacted with Example 169b (160 mg, 0.55 mmol) in ethanol (5 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (200 mg, 63%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.76 (d, J = 8.46 Hz, 1 H) 8.54 (d, J = 6.99 Hz, 1 H) 7.74 (dd , J = 5.70, 3.13 Hz, 2 H) 7.58 7.65 (m, J = 5.70, 5.70, 2.57 Hz, 2 H) 7.29-7.43 ( m, 3 H) 7.20 (dd, J = 7.72, 2.21 Hz, 1 H) 6.68 (d, J = 6.99 Hz, 1 H) 4.23 (c, J = 6 , 99 Hz, 2 H) 2.96 (t, J = 7.54 Hz, 2 H) 1.77 -1.85 (m, 2 H) 1.29 (t, 3 H) 0.95 (t , J = 7.35 Hz, 3 H); MS (ESI +) m / z 461 (M + H) +.
Example 170
1- {3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -ethanol
Example 170a
1- [3- (4-Chloro-2-nitro-phenoxy) -phenyl] -ethanone
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 3-hydroxyacetophenone (5.5 g, 42.2 mmol), and K2CO3 (11.7g, 84 , 6 mmol) in DMF (50 mL). The mixture was heated at 80 ° C for 16 h. 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 in vacuo yielding 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%).
Example 170b
1- [3- (4-Chloro-2-nitro phenoxy) -phenyl] -ethanol
To the product of Example 170a (1.8 g, 6.2 mmol) in ethanol (50 mL) was added sodium borohydride (0.32 g, 8.64 mmol) in portions. The reaction was stirred at room temperature for 16 h. The excess sodium borohydride was destroyed by the addition of acetic acid. The reaction was poured onto ice / water and extracted with ethyl acetate. The organic phase was washed with water, brine, and dried over sodium sulfate, filtered and concentrated in vacuo yielding the title compound. The crude residue was purified by silica gel chromatography eluting with (hexanes / ethyl acetate / methanol (75: 15: 5) to give the desired product (0.98 g, 54%).
Example 170c
1- [3- (2-Amino-4-chloro-phenoxy) -phenyl] -ethanol
The product of Example 170b (0.98 g, 3.3 mmol) was reduced with SnCl2 as described in Example 1f to give the title compound (0.61 g, 70%).
Example 170d
1- {3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -ethanol
The product of Example 2g (140 mg, 0.68 mmol) was reacted with Example 170c (178 mg, 0.68 mmol) in ethanol (5 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (110 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1 H) 7.58 (dd, J = 8.82, 2.57 Hz, 1 H) 7.17 7.22 (d, 2 H) 7.01 (d, J = 7.72 Hz, 1 H) 6.87 (s, 1 H) 6.78 (dd, J = 7.54, 2.02 Hz , 1 H) 6.68 (d, J = 6.99 Hz, 1 H) 4.55 -4.62 (c, J = 6.62 Hz, 1 H) 2.96 (t, J = 7, 54 Hz, 2 H) 1.76 -1.86 (m, 2 H) 1.12 (d, J = 6.62 Hz, 3 H) 0.95 (t, J = 7.35 Hz, 3 H ); MS (ESI +) m / z 434 (M + H) +.
Example 171 3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -benzamide
Example 171 a
3- (4-Chloro-2-nitro-phenoxy) -benzamide
The product of Example 168b (1.8 g, 6.13 mmol) was added to cold NH4OH (15 mL) and stirred for 1 h. 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 in vacuo to yield the title compound (1.66 g, 92%).
Example 171b
3- (2-Amino-4-chloro-phenoxy) -benzamide
The product of Example 171a (0.56 g, 1.9 mmol) was reacted with SnCl2 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 h producing the crude title compound that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (110 mg, 30%). 1 H NMR (500 MHz, DMSO-d6) δ ppm: 8.81 (d, J = 8.54 Hz, 1 H) 8.45 (d, J = 7.32 Hz, 1 H) 6.76 -6 , 79 (m, 2 H) 6.64 (d, J = 8.54 Hz, 2 H) 6.44 (s, 1 H) 6.37 (t, J = 7.93 Hz, 1 H) 6 , 31 (d, J = 8.54 Hz, 1 H) 7.16 (dd, J = 7.93, 2.44 Hz, 1 H) 6.84 (d, J = 7.32 Hz, 1 H ) 2.95 (t, J = 7.32 Hz, 2 H) 1.80 (m, 2 H) 0.95 (t, J = 7.32 Hz, 3 H); MS (ESI +) m / z 433 (M + H) +.
Example 172
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-ethyl-benzamide
Example 172a
To the product of Example 168b (1.6 g, 5.1 mmol) in THF (25 mL) was added ethylamine (0.4 g, 8.0 mmol) and the reaction 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 in vacuo yielding the title compound (1.4 g, 85%).
Example 172b
3- (2-Amino-4-chloro-phenoxy) -N-ethyl-benzamide
The product of Example 172a (0.90 g, 2.8 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.65 g, 81%).
Example 172c
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-ethyl-benzamide
The product of Example 2g (128 mg, 0.62 mmol) was reacted with Example 172b (180 mg, 0.62 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (70 mg, 20%). 1 H NMR (500 MHz, DMSO-d6) δ ppm: 8.84 (d, J = 8.82 Hz, IH) 8.53 (d, J = 7.26 Hz, IH) 8.39 (t, J = 5.45 Hz, 1 H) 7.72 -7.76 (m, 2 H) 7.60 (dd, J = 8.82, 2.59 Hz, 1 H) 7.54 (d, J = 7.78 Hz, 1 H) 7.32 -7.36 (m, 2 H) 7.25 (d, J = 8.82 Hz, 1 H) 7.09 (dd, J = 7.78, 2 , 59 Hz, 1 H) 6.70 (d, J = 7.26 Hz, 1 H) 3.19 -3.25 (m, 2 H) 2.96 (t, J = 7.52 Hz, 2 H) 1.79 1.84 (m, 2 H) 1.08 (t, J = 7.00 Hz, 3 H) 0.95 (t, J = 7.52 Hz, 3 H); MS (ESI +) m / z 461 (M + H) +.
Example 173
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-phenyl-benzamide
Example 173a
To the product of Example 168b (0.81 g, 2.6 mmol) in THF (25 mL) was added benzylamine (0.25 g, 2.6 mmol), and N, N-diisopropylethylamine (0.67 g, 5 , 2 mmol). The reaction 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 in vacuo yielding the title compound (0.8 g, 85%).
Example 173b
3- (2-Amino-4-chloro-phenoxy) -N-phenyl-benzamide
The product of Example 173a (0.84 g, 2.3 mmol) was reacted with SnCl2 as described in Example 1f to give the desired product (0.60 g, 77%).
Example 173c
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-phenyl-benzamide
The product of Example 2g (131 mg, 0.63 mmol) was reacted with Example 173b (214 mg, 0.63 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (125 mg, 31%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 10.11 (s, 1 H) 8.80 (d, J = 8.82 Hz, 1 H) 8.53 (d, J = 6.99 Hz , 1 H) 7.67 -7.75 (m, 4 H) 7.58 7.67 (m, 2 H) 7.40 -7.46 (m, 2 H) 7.30 -7.37 ( m, 3 H) 7.08 -7.18 (m, 2 H) 6.70 (d, J = 7.35 Hz, 1 H) 2.92 (t, 2 H) 1.73 -1.82 (m, 2 H) 0.92 (t, J = 7.35 Hz, 3 H); MS (ESI +) m / z 509 (M + H) +.
Example 174
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N- (3-hydroxy-phenyl) -benzamide
Example 174a
N- [3- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (4-chloro-2-nitro-phenoxy) -benzamide
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 N , Ndiisopropylethylamine (0.67g, 5.2 mmol). 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 in vacuo yielding the title compound (1.3 g, 85%).
Example 174b
3- (4-Chloro-2-nitro-phenoxy) -N- (3-hydroxy-phenyl) -benzamide
To the product of Example 174a (1.5 g, 3.0 mmol) in THF (25 mL) was added tetrabutylammonium fluoride (0.94 g, 3.6 mmol). The reaction was stirred for 16 h. 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 in vacuo yielding the title compound (1.0 g, 86%).
Example 174c
3- (2-Amino-4-chloro-phenoxy) -N- (3-hydroxy-phenyl) -benzamide
The product of Example 174b (1.0 g, 2.6 mmol) was reacted with SnCl2 as described in Example 1f to 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 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (123 mg, 27%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.69 (d, 2 H) 7.61 (dd, 1 H) 7.43 (s, 2 H) 7 , 33 (s, 2 H) 7.17 (m, 1 H) 7.12 (s, 2 H) 6.71 (d, J = 6.99 Hz, 1 H) 6.52 (m, 1H) 2.93 (t, J = 7.54 Hz, 2 H) 1.72 -1.86 (m, 2 H) 0.93 (t, J = 7.35 Hz, 3 H); MS (ESI +) m / z 525 (M + H) +.
Example 175
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-propyl-benzamide
Example 175a
3- (4-Chloro-2-nitro-phenoxy) -N-propyl-benzamide
To Example 168b (1.0 g, 3.2 mmol) in THF (25 mL), n-propylamine (0.38 g, 6.4 mmol) was added 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 in vacuo yielding the title compound (0.88 g, 82%).
Example 175b
3- (2-Amino-4-chloro-phenoxy) -N-propyl-benzamide
The product of Example 175a (0.88 g, 2.6 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.61 g, 76%).
Example 175c
3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N-propyl-benzamide
The product of Example 2g (110 mg, 0.53 mmol) was reacted with Example 175b (162 mg, 0.53 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (50 mg, 16%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.85 (t, J = 7.54 Hz, 3 H) 0.95 (t, J = 7.35 Hz, 3 H) 1.42 -1 , 54 (m, 2 H) 1.75 -1.88 (m, 2 H) 2.96 (t, J = 7.54 Hz, 2 H) 3.15 (c, 2 H) 6.69 ( d, J = 6.99 Hz, 1 H) 7.09 (dd, J = 7.54, 2.39 Hz, 1 H) 7.26 (d, J = 8.82 Hz, 1 H) 7, 32 -7.36 (m, 2 H) 7.54 (d, J = 8.09 Hz, 1 H) 7.60 (dd, J = 8.82, 2.57 Hz, 1 H) 7.72 -7.77 (m, 2 H) 8.39 (t, J = 5.70 Hz, 1 H) 8.52 (d, J = 7.35 Hz, 1 H) 8.82 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 475 (M + H) +.
Example 176
{3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -methanol
Example 176a
3- (4-Chloro-2-nitro-phenoxy) -benzaldehyde
To a solution of DMF (50 mL) was added 1-bromo2-nitro-4-chloro-benzene (10.0 g, 42.2 mmol), 3-hydroxybenzaldehyde (5.2 g, 42.2 mmol), and K2CO3 (11.5 g, 84.6 mmol). The solution was heated to 85 ° C and stirred overnight. The reaction was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over Na2SO4, filtered and concentrated in vacuo yielding the crude title compound. This solid was purified by silica gel column chromatography eluting with hexanes / ethyl acetate (4: 1) to give the title compound (4.4 g, 41%).
Example 176b
[3- (4-Chloro-2-nitro-phenoxy) -phenyl] -methanol
To the product of Example 176a (2.0 g. 7.2 mmol) in ethanol (25 mL) was added sodium borohydride (0.32 g, 8.6 mmol). The reaction was stirred for 4 h. The excess sodium borohydride was destroyed by 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 in vacuo yielding the title compound (1.9 g, 94%).
Example 176c
[3- (2-Amino-4-chloro-phenoxy) -phenyl] -methanol
The product of Example 176b (1.9 g, 6.8 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (1.4 g, 83%).

Example 176d {3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -methanol
The product of Example 1d (110 mg, 0.62 mmol) was reacted with Example 176c (153 mg, 0.62 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h yielding the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (50 mg, 16%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.96 -9.00 (m, IH) 8.52 (d, J = 6.99 Hz, 1 H) 7.70 -7.74 (m , 2 H) 7.57 (dd, J = 9.01, 2.39 Hz, 1 H) 7.15 -7.25 (m, 2 H) 7.00 (d, J = 7.72 Hz, 1 H) 6.88 (s, 1 H) 6.82 (dd, 1 H) 6.68 (d, J = 6.99 Hz, 1 H) 4.37 (s, 2 H) 2.74 ( s, 3 H); MS (ESI +) m / z 392 (M + H) +.
Example 177
1- {3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -ethanol
The product of Example 1d (125 mg, 0.70 mmol) was reacted with Example 170c (184 mg, 0.70 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (59 mg, 16%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.15 (d, J = 6.25 Hz, 3 H) 2.62 (s, 3 H) 4.60 (c, J = 6.37 Hz , 1 H) 6.64 (d, J = 7.35 Hz, 1 H) 6.73 -6.79 (m, 1 H) 6.89 (s, 1 H) 7.01 (d, J = 7.72 Hz, 1 H) 7.16 (t, J = 8.09 Hz, 2 H) 7.56 (dd, J = 8.82, 2.57 Hz, 1 H) 7.68 -7, 72 (m, 2 H) 8.53 (d, J = 6.99 Hz, 1 H) 9.18 (d, J = 8.46 Hz, 1 H); MS (ESI +) m / z 406 (M + H) +.
Example 178 3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] N- (3-hydroxy-phenyl) -benzamide
The product of Example 1d (125 mg, 0.70 mmol) was reacted with Example 174c (237 mg, 0.70 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (120 mg, 28%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 10.00 (s, 1 H) 8.81 (d, J = 8.46 Hz, 1 H) 8.55 (d, J = 6.99 Hz , 1 H) 7.72 -7.75 (m, 2 H) 7.65 7.71 (m, 1 H) 7.62 (dd, J = 9.01, 2.76 Hz, 1 H) 7 , 42 (s, 2 H) 7.30 (d, J = 8.82 Hz, 1 H) 7.26 (s, 1 H) 7.16 (dd, J = 7.35, 2.57 Hz, 1 H) 7.10 (d, J = 5.52 Hz, 2 H) 6.71 (d, J = 6.99 Hz, 1 H) 6.48 -6.55 (m, 1 H) 2, 69 (s, 3 H); MS (ESI-) m / z 495 (MH) -.
Example 179
[5-Chloro-2- (4-isopropyl-phenoxy) -phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 179a
4-Chloro-1- (4-isopropyl-phenoxy) -2-nitro-benzene
1-Bromo-4-chloro-2-nitrobenzene (12 g, 50.7 mmol) was added to a solution of 4-isopropylphenol (8.3 g, 60.8 mmol), and K2CO3 (14.0 g, 101 mmol) in DMF (70 mL). The mixture was heated at 80 ° C for 16 h. 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 yielding the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (13.5 g, 92%).
Example 179b
5-Chloro-2- (4-isopropyl-phenoxy) -phenylamine
The product of Example 179a (13.7 g, 46.8 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (10.3 g, 84.4%).
Example 179
[5-Chloro-2- (4-isopropyl-phenoxy) -phenyl] - (7-methyl [1,8] naphthyridin-4-yl) -amine
The product of Example 1d (120 mg, 0.67 mmol) was reacted with Example 179b (175 mg, 0.67 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (60 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.86 (d, J = 8.46 Hz, 1 H) 8.51 (d, J = 7.35 Hz, 1 H) 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, 2 H) 6.67 (d, J = 6.98 Hz, 1 H) 2.79 (m, 1H) 2.73 (s, 3 H) 1.09 (d, J = 6.99 Hz, 6 H); MS (ESI +) m / z 404 (M + H) +.
Example 180
{2- [3 - (- Azido-ethyl) -phenoxy] -5-chloro-phenyl} - (7-propyl [1,8] naphthyridin-4-yl) -amine
Example 180a
2- [3- (1-Azido-ethyl) -phenoxy] -5-chloro-phenylamine
To the product of Example 170c in toluene (25 mL) was added diphenylphosphorylazide (1.72 g, 6.23 mmol), followed by 1,8-diazabicyclo [4,3,0] undec-7-ene (0.95 g, 6.2 mmol). The mixture was stirred at 25 ° C for 18 h. 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 in vacuo yielding 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%).
Example 180b
{2- [3- (1-Azido-ethyl) -phenoxy] -5-chloro-phenyl} - (7-propyl [1,8] naphthyridin-4-yl) -amine
The product of Example 2g (130 mg, 0.63 mmol) was reacted with Example 180a (181 mg, 0.63 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h to produce the compound of the crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (11 mg, 11%). 1 H NMR (500 MHz, DMSO-d6) δ ppm: 0.91 (t, J = 7.42 Hz, 3 H) 1.23 (d, J = 6.59 Hz, 3 H) 1.74 -1 , 81 (m, 2 H) 2.91 (t, J = 7.69 Hz, 2 H) 4.61 (c, J = 6.59 Hz, IH) 6.67 (d, J = 7.14 Hz, 1 H) 6.82 (s, 2 H) 6.99 (d, J = 7.14 Hz, 1 H) 7.21 (d, J = 8.79 Hz, 2 H) 7.52 ( dd, J = 8.79 Hz, 1 H) 7.64 (d, J = 2.75 Hz, 1 H) 7.65 (d, J = 8.79 Hz, 1 H) 8.48 (d, J = 6.04 Hz, 1 H) 8.81 (d, J = 8.79 Hz, 1 H); MS (ESI +) m / z 459 (M + H) +.
Example 181
3- [4-Fluoro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N, N-dimethyl-benzamide
Example 181a
3- (4-Fluoro-2-nitro-phenoxy) benzoic acid ethyl ester
2,5-Difluoronitrobenzene (5.0 g, 31.4 mmol), ethyl 3-hydroxybenzoate (5.2 g, 31.4 mmol), and K2CO3 (8.7 g, 62.8 mmol) were added to DMF (50 mL). The solution was heated to 85 ° C and stirred for 16 h. 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 yielding the crude title compound. The crude product was purified by silica gel column chromatography eluting with hexanes / ethyl acetate (90:10) to give the title compound (7.0 g, 73%).
Example 181b
3- (4-Fluoro-2-nitro-phenoxy) -benzoic acid
The product of Example 181a (3.0 g, 9.8 mmol) was added to a THF / H2O 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
h. 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 yielding the title compound (2.65 g, 97%).
Example 181 c
3- (4-Fluoro-2-nitro-phenoxy) -benzoyl chloride
The product of Example 181b (1.6 g, 5.6 mmol) was treated with oxalyl chloride (0.86 g, 6.7 mmol) and catalytic DMF at room temperature for 6 h. The excess oxalyl chloride was removed in vacuo. The residue was captured with benzene to give the title compound (1.66 g, 94%).
Example 181d
3- (4-Fluoro-2-nitro-phenoxy) -N, N-dimethylbenzamide
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). The reaction was stirred at room temperature for 16 h. The reaction was poured onto ice / water and extracted with ethyl acetate. The organic phase was washed with 5% HCl, water, brine, and dried over sodium sulfate, filtered and concentrated in vacuo yielding the title compound (0.90 g, 87%).
Example 181e
3- (2-Amino-4-fluoro-phenoxy) -N, N-dimethyl-benzamide
The product of Example 181d (1.1 g, 3.4 mmol) was reduced with SnCl2 as described in Example 1f to 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 h to produce the compound of crude title that was purified by HPLC with TFA to provide the product as trifluoroacetic acid (65 mg, 20%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J = 7.35 Hz, 3 H) 1.74 -1.87 (m, 2 H) 2.66 (s, 3 H ) 2.90 (s, 3 H) 2.96 (t, 2 H) 6.71 (d, J = 6.99 Hz, 1 H) 6.82 (s, 1 H) 6.91 (dd, J = 8.27, 1.65 Hz, 1 H) 7.01 (d, J = 7.72 Hz, 1 H) 7.27 (t, J = 7.91 Hz, 1 H) 7.36 - 7.45 (m, 2 H) 7.56 (dd, J = 8.82, 2.94 Hz, 1 H) 7.75 (d, J = 8.46 Hz, 1 H) 8.52 (d , J = 6.99 Hz, 1 H) 8.83 (d, J = 8.46 Hz, 1 H); MS (ESI +) m / z 445 (M + H) +.
Example 182
{2- [4- (1-Amino-ethyl) -phenoxy] -5-chloro-phenyl} - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 182a
1- [4- (1-Azido-ethyl) -phenoxy] -4-chloro-2-nitro-benzene
To the product of Example 164b (0.30 g, 1.0 mmol) in toluene (20 mL) was added diphenylphosphorylazide (0.36 g 6.26 mmol), followed by 1,8-diazabicyclo [4,3,0 ] undec-7eno (0.19 g, 1.3 mmol). The mixture was stirred at 25 ° C for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with 5% HCl, sat. NaCl. (1X), dried over sodium sulfate, filtered and concentrated in vacuo yielding the crude title compound. The crude product was purified by silica gel chromatography, eluting with hexanes / ethyl acetate / methanol.
(85: 15: 5) to provide the title compound (300 mg, 94%).
Example 182b
{1- [4- (4-Chloro-2-nitro-phenoxy) phenyl] -ethyl} -carbamic acid benzyl ester
To the product of Example 182a (1.3 g 4.1 mmol) in THF (20 mL) was added trimethylphosphine (4.7 g, 5.4 mmol). After stirring the mixture for 30 minutes at room temperature, the reaction mixture was treated with benzyl chloroformate (0.85 g, 5.0 mmol) and stirred 18 h. The reaction was poured into 0.1 M potassium phosphate buffer, pH = 7.0 and extracted with methylene chloride. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo yielding 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 182c
{1- [4- (2-Amino-4-chloro-phenoxy) phenyl] -ethyl} -carbamic acid benzyl ester
The product of Example 182b (1.0 g, 2.34 mmol) was reacted with SnCl2 as described in Example 237E to give the title compound (0.75 g, 80%).
Example 182d
{2- [4- (1-Amino-ethyl) -phenoxy] -5-chloro-phenyl} - (7-methyl [1,8] naphthyridin-4-yl) -amine
The product of Example 1d (120 mg, 0.67 mmol) was reacted with Example 182b (266 mg, 0.67 mmol) in ethanol (10 mL) at 85 ° C in a sealed tube for 18 h. The ethanol was then removed in vacuo. The crude compound was then treated with excess 48% HBr for 10 h. The excess HBr was removed in vacuo and the crude residue was purified by HPLC with TFA to provide the title compound as trifluoroacetic acid (15 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.38 (d, J = 6.62 Hz, 3 H) 2.74 (s, 3 H) 4.36 (c, 1 H) 6.72 (d, J = 6.99 Hz, 1 H) 7.03 (d, J = 8.82 Hz, 2 H) 7.13 (d, J = 8.82 Hz, 1 H) 7.39 (d , J = 8.82 Hz, 2 H) 7.59 (dd, J = 8.82, 2.57 Hz, 1 H) 7.72 -7.78 (m, 2 H) 8.24 (s, 2 H) 8.53 (d, J = 7.35 Hz, 1 H) 8.88 (d, J = 8.82 Hz, 1 H); MS (ESI-) m / z 403 (MH) -.
Example 183
N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4trifluoromethyl-phenylsulfanyl] -phenyl} -acetamide
Example 183a
N- [4- (2-Nitro-4-trifluoromethyl-phenylsulfanyl) -phenyl] acetamide
The title compound was prepared from 1-Chloro-2-nitro-4-trifluoromethyl-benzene (250 mg, 1.10 mmol), N- (4-Mercapto-phenyl) -acetamide (185 mg, 1.10 mmol) , and K2CO3 (268 mg, 1.94 mmol) heated in DMF at 100 ° C for 16 hrs. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate (350 mg, 88%).
Example 183B
N- [4- (2-Amino-4-trifluoromethyl-phenylsulfanyl) -phenyl] acetamide
The product of Example 183a (350 mg, 0.985 mmol), and Pt (IV) O2 (4 mg, 0.2 mmol) were placed in a 50 ml round bottom flask and dissolved in 1 ml of BtOH and 1 ml of THF. The reaction mixture was placed in vacuo and loaded with H2 using a balloon. The balloon was left overnight and the next day the reaction mixture was purged and charged with N2, filtered and concentrated in vacuo yielding the title compound (260 mg, 80%).
Example 183c
N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4trifluoromethyl-phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (50 mg, 0.280 mmol) was reacted with the product of Example 183b (91 mg, 0.280 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (18 mg, 16%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H), 7.68 (d, J = 8.46 Hz, 2 H), 7, 78 (dd, J = 8.64, 1.65 Hz, 1 H), 7.84 (d, J = 8.82 Hz, 1 H), 7.92 (d, J = 1.84 Hz, 1 H), 8.52 (d, J = 7.35 Hz, 1 H), 9.00 (d, J = 8.46 Hz, 1 H), 10.19 (s, 1 H), 11.12 (s, 1 H); MS (ESI +) m / z 469 (M + H-TFA) +; (ESI-) m / z 467 (M-HTFA) -.
Example 184 (reference)
[5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) phenyl] - (7propyl- [1,8] naphthyridin-4-yl) -amine
Example 184A
5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamine
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 1H [1,2,4] Triazol-3-thiol (1.94 g , 19.2 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100 ° C for 16 hrs. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound (1.1 g, 26%).
Example 184b
5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamine
The product of Example 184a was reduced with SnCl2 following the procedure of Example 1f to give the title compound.
Example 184c
[5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenyl] - (7propyl- [1,8] naphthyridin-4-yl) -amine
The product of Example 2g (60 mg, 0.290 mmol) was reacted with the product of Example 184b (60 mg, 0.290 mmol) for 18 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (17 mg, 16%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H), 1.78 -1.91 (m, 2 H), 2.38 (s, 3 H), 2.99 (t, 2 H), 6.33 (d, J = 6.99 Hz, 1 H), 7.29-7.39 (m, 2 H), 7.46 (d , J = 8.09 Hz, 1 H), 7.83 (d, J = 8.82 Hz, 1 H), 8.44 (d, J = 6.99 Hz, 1 H), 9.00 ( d, J = 8.46 Hz, 1 H), 11.07 (s, 1 H), 14.16-14.55 (m, 2 H); MS (ESI +) m / z 377 (M + HTFA) +; (ESI-) m / z 375 (MH-TFA) -.
Example 185
[2- (2-Amino-phenylsulfanyl) -5-methyl-phenyl] - (7-propyl [1,8] naphthyridin-4-yl) -amine
Example 185A
2- (4-Methyl-2-nitro-phenylsulfanyl) -phenylamine
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 2 Amino-benzenethiol (2.41 g, 19.23 mmol), and K2CO3 ( 4.22 g, 30.6 mmol) was heated in DMF at 100 ° C for 16 hrs. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. (0.990 g, 21%)
Example 185b
N- [2- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide
The substance of Example 185a (0.990 3.80 mmol) was dissolved in CH2Cl2 to which acetyl chloride (0.328 g, 4.183 mmol) was added. The reaction mixture was stirred at room temperature for 1 hr at which time the title compound was collected by filtration (910 mg, 79%).
Example 185c
N- [2- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -acetamide
The product of Example 185b was reduced with SnCl2 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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of 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 HCl: 50% H2O and heated at 100 ° C for 1hr. The reaction mixture was then cooled to room temperature, made alkaline with 2N NaOH, and extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo yielding the crude title compound. It was purified by HPLC with TFA to provide the product as trifluoroacetic acid (87 mg, 64%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H), 1.79 -1.92 (m, J = 7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2 H), 2.32 (s, 3 H), 3.00 (t, J = 7.54 Hz, 2 H), 6.34 (d, J = 6.99 Hz, 1 H), 6.49 (t, J = 7.54 Hz, 1 H), 6.68 (d, J = 6.99 Hz, IH), 6.92 (d, J = 8.09 Hz, 1 H), 7.05 -7.13 (m, 1 H), 7.15 -7.20 (m, 1 H), 7.24 (d, J = 8.46 Hz, 1 H), 7.28 (s, 1 H), 7.84 (d, J = 8.82 Hz, 1 H), 8.42 (d, J = 6.99 Hz, 1 H), 9.06 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 401 (M + H-TFA) +; (ESI-) m / z 399 (MH-TFA) -.
Examples 186
N- {3- [3-Methyl-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
Example 186A
3-Amino-benzenethiol-copper
3-Amino-benzenethiol (2.00 g, 15.98 mmol) was treated under the conditions described in 187a to provide the title compound (3.67 g, 100%).
Example 186b
3- (3-Methyl-5-nitro-phenylsulfanyl) -phenylamine
The title compound was prepared following the procedure of Example 187d using Example 187c (400 mg, 1.85 mmol), and Example 186a (348 mg, 1.85 mmol) to provide the title compound (300 mg, 62%).
Example 186c
N- [3- (3-Methyl-5-nitro-phenylsulfanyl) -phenyl] -acetamide
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
N- [3- (3-Amino-5-methyl-phenylsulfanyl) -phenyl] -acetamide
The title compound was obtained following the procedure of Example 183b using the product of Example 186c (130 mg, 0.430 mmol), and PtO2 (2 mg, 0.009 mmol) to provide (73 mg, 62%).
Example 186f
N- {3- [3-Methyl-5, (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 2g (70 mg, 0.338 mmol) was reacted with the product of Example 186d (73 mg, 0.338 mmol) for 16 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (14 mg, 10%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H), 6.85 (d, J = 7.35 Hz, 1 H), 7, 06 -7.14 (m, 2 H), 7.22 (s, 2 H), 7.35 (t, J = 7.91 Hz, 1 H), 7.47 (d, 1 H), 7 , 76 -7.82 (m, 2 H), 8.45 (d, J = 7.35 Hz, 1 H), 8.98 (d, J = 8.82 Hz, 1 H), 10.07 (s, 1 H), 10.97 (s, 1 H); MS (ESI +) m / z 443 (M + H TFA) +; (ESI-) m / z 441 (MH-TFA) -.
Example 187
N- {4- [3-Methyl-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
Example 187a
N- (4-Mercapto-phenyl) -acetamide-copper
The N- (4-Mercapto-phenyl) -acetamide (1.00 g, 5.98 mmol) and Cu2O (385 mg, 27.0 mmol) were dissolved in EtOH and heated under reflux for 24 hrs. At this time the reaction mixture was cooled to room temperature and the title compound was collected by filtration (1.374 g, 100%).
Example 187b
2-Bromo-4-methyl-6-nitro-phenylamine
The title compound was prepared by dissolving 4-methyl-2-nitro-phenylamine (20.0 g, 131 mmol) in 200 mL of HOAc. The reaction mixture was then heated to 100 ° C until the reaction mixture was homogeneous. At this time the reaction mixture was cooled to room temperature and Br2 (25.21 g, 157 mmol) was added dropwise in portions over the course of 10 minutes. An orange solid formed, and upon completion of the addition the reaction mixture was diluted with water and the title compound was collected by filtration (29 g, 96%).
Example 187c
1-Bromo-3-methyl-5-nitro-benzene
The title compound was prepared from Example 187b (10.0 g, 43.2 mmol) dissolved in 60 mL of MeOH and 8 mL of H2SO4 (conc). This mixture was heated to 85 ° C at which time NaNO2 (7.466 g, 108.2 mmol) was added portionwise so that the reaction mixture did not bubble. Once 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. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound (8.00 g, 85%).
Example 187d
N- [4- (3-Methyl-5-nitro-phenylsulfanyl) -phenyl] -acetamide
The title compound was prepared from Example 187c (400 mg, 1.85 mmol), Example 187a (425 mg, 1,852 mmol), 10 mL of quinoline, and 2 mL of pyridine was heated at 170 ° C for 22 hrs. At this time the reaction mixture was cooled to room temperature and quenched with 30% HCl and extracted with ether and dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound. It was purified by column chromatography on silica gel eluting with 30% ethyl acetate in hexanes (280 mg, 50%).
Example 187E
N- [4- (3-Amino-5-methyl-phenylsulfanyl) -phenyl] -acetamide
The title compound was achieved using the procedure of Example 183b using the product of Example 187d (280 mg, 0.926 mmol), and PtO2 (2 mg, 0.009 mmol) to provide the title compound (240 mg, 95%).
Example 187f
N- {4- [3-Methyl-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 2g (70 mg, 0.338 mmol) was reacted with the product of Example 187e (198 mg, 0.726 mmol) for 16 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (5 mg, 4%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H), 6.80 (d, J = 7.35 Hz, 1 H), 6, 95 (s, 1 H), 7.10 (d, J = 15.44 Hz, 2 H), 7.46 (d, J = 8.82 Hz, 2 H), 7.67 (d, J = 8.82 Hz, 2 H), 7.78 (d, J = 8.82 Hz, 1 H), 8.46 (d, J = 6.99 Hz, 1 H), 8.96 (d, J = 8.46 Hz, 1 H), 10.14 (s, 1 H), 10.90 (s, 1 H); MS (ESI +) m / z 443 (M + H-TFA) +; (ESI-) m / z 441 (MH-TFA) -.
Example 188
[3- (4-Amino-phenylsulfanyl) -5-methyl-phenyl] - (7-propyl [1,8] naphthyridin-4-yl) -amine
The product of Example 187 (60 mg, 0.136 mmol) was treated under the conditions of Example 185 to provide the title compound (10 mg, 18%). 1 H NMR (300 MHz, DMSO-d6) 8 ppm: 0.96 (t, J = 7.35 Hz, 3 H), 1.76 -1.89 (m, 2 H), 2.30 (s, 3 H), 2.97 (t, J = 7.54 Hz, 2 H), 6.65 (d, J = 8.46 Hz, 2 H), 6.74-6.83 (m, 2 H ), 6.94 (s, 1 H), 7.03 (s, 1H), 7.23 (d, J = 8.46 Hz, 2 H), 7.78 (d, J = 8.82 Hz , 1 H), 8.45 (d, J = 6.99 Hz, 1 H), 8.96 (d, J = 8.46 Hz, 1 H), 10.90 (s, 1 H); MS (ESI +) m / z 401 (M + H-TFA) +.
Example 189
(3-Benzyloxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) -amine
Example 189a
1-Benzyloxy-3-nitro-benzene
3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with benzyl bromide (1.352 g, 7.91 mmol), and K2CO3 (1.242 g, 8.986 mmol) in DMF. The reaction mixture was heated at 100 ° C for 1 hr 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 in vacuo yielding the title compound (1.6 g, 97%).
Example 189b
3-Benzyloxy-phenylamine
The title compound was obtained following the procedure of Example 183b using the product of Example 189a (1,600 g, 6.98 mmol), and PtO2 (15 mg, 0.070 mmol) to provide (1.00 g, 72%).
Example 189c
(3-Benzyloxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) -amine
The product of Example 2g (30 mg, 0.145 mmol) was reacted with the product of Example 189b (29 mg, 0.145 mmol) for 16 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (27 mg, 50%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H), 1.77 -1.90 (m, J = 7.35 Hz, 2 H) , 2.99 (t, J = 7.35 Hz, 2 H), 5.17 (s, 2 H), 6.80 (d, J = 6.99 Hz, 1 H), 7.06 (dd , J = 8.46, 1.10 Hz, 1 H), 7.09 -7.15 (m, J = 3.68 Hz, 2 H), 7.31-7.51 (m, 5 H) , 7.82 (d, J = 8.82 Hz, 1 H), 8.46 (d, J = 7.35 Hz, 1 H), 9.03 (d, J = 8.82 Hz, 1 H ), 11.00 (s, 1 H); MS (ESI +) m / z 370 (M + H-TFA) +; (ESI-) m / z 368 (MH-TFA) -.
Example 190
[3- (4-Bromo-benzyloxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4yl) -amine
Example 190A
1- (4-Bromo-benzyloxy) -3-nitro-benzene
3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with 4-bromo-benzyl bromide (1.976 g, 7.90 mmol) following the 189a procedure to provide the title compound (2.1 g, 97%)
Example 190B
3- (4-Bromo-benzyloxy) -phenylamine
The title compound was prepared by reduction of the product of Example 190a with SnCl2 following the procedure of Example 1f.
Example 190c
[3- (4-Bromo-benzyloxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4yl) -amine
The product of Example 1d (50 mg, 0.316 mmol) was reacted with the product of Example 190b (88 mg, 0.316 mmol) for 16 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (80 mg, 60%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H), 7.51 (t, J = 8.09 Hz, 1 H), 7, 62 (d, J = 8.46 Hz, 2 H), 7.79 (d, J = 8.82 Hz, 1 H), 8.47 (d, J = 6.99 Hz, 1 H), 9 , 00 (d, J = 8.46 Hz, 1 H), 10.98 (s, 1 H); MS (ESI +) m / z 422 (M + H-TFA) +; (ESI-) m / z 419 (MH-TFA) -.
Example 191
N- {4- [3-Fluoro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -acetamide
Example 191a
N- [4- (3-Fluoro-5-nitro-phenoxy) -phenyl] -acetamide
To a solution of N- (4-hydroxyphenyl) acetamide (1.00 g, 6.5 mmol) in DMSO (12 ml) was added a 1M solution of t-BuOK / THF (7.13 ml, 7.13 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 30 minutes in a stream of N2. 1,3-Difluoro-5-nitrobenzene (0.89 ml, 7.8 mmol) was added at room temperature, and then the mixture was stirred at room temperature for 2 hours and at 50 ° C for 2 hours in a stream of N2 . The reaction mixture was cooled to room temperature, diluted with H2O, and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound as a light brown solid, which was purified by washing with i-Pr2O to give the desired product in form of slightly brown crystals (1.73 g, 92%).
Example 191b
N- [4- (3-Amino-5-fluoro-phenoxy) -phenyl] -acetamide
The product of Example 191a was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 191c N- {4- [3-Fluoro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -acetamide
The product of Example 3f (150 mg, 0.84 mmol) was reacted with the product of Example 191b (190 mg, 0.84 mmol) for 6 h following the procedure of Example 1g yielding the crude title compound that was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH 50: 1 to give the title compound (210 mg, 68%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.40 (s, 3H), 2.68 (s, 3H), 6.62 (d, J = 6.9 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.3 Hz, 2H), 7.36 (s, 1H), 7.38 (d, J = 8.3 Hz , 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H ), 8.40 (d, J = 6.9 Hz, 1H), 8.94 (d, J = 8.8 Hz, 1H), MS (ESI +) m / z 369 (M + H) +, ( ESI-) m / z 367 (MH) -.
Example 192 (reference)
4- [3-Fluoro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N, N-dimethyl-benzamide
Example 192a
4- (3-Fluoro-5-nitro-phenoxy) benzoic acid methyl ester
To a solution of 4-hydroxybenzoic acid methyl ester (3.00 g, 19.5 mmol) in DMSO (30 ml) was added t-BuOK (2.56 g, 21.5 mmol) at room temperature and the mixture was stirred at room temperature for 30 minutes in a stream 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 in a stream of N2. The reaction mixture was cooled to room temperature, diluted with H2O, and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding the title compound as a dark brown oil, which was crystallized with i-Pr2O. The crystals were collected by filtration to give the desired product as pale yellow crystals (1.92 g, 40%). The filtrate provided additional product (1.46 g, 30%) as pale yellow crystals by silica gel column chromatography eluting with 4: 1 EtOAc / hexane.
Example 192b
4- (3-Fluoro-5-nitro-phenoxy) -benzoic acid
The product of Example 192a (3.30 g, 11.3 mmol) and 2N NaOH (11.3 ml, 22.7 mmol) in MeOH (33 ml) was refluxed for 30 minutes, and then evaporated. The residue was dissolved in H2O and acidified to pH 2 with 10% HCl with stirring. The precipitate was collected by filtration, washed with H2O, and dried under vacuum overnight to give the title compound as slightly yellow crystals (3.03 g, 96%).
Example 192c
4- (3-Fluoro-5-nitro-phenoxy) -N, N-dimethyl-benzamide
The product of Example 192b (1.00 g, 3.6 mmol) and SOCl2 (3.97 ml, 54.1 mmol) was refluxed for 1 hour. The excess SOCl2 was removed under reduced pressure to give the corresponding acid chloride as a pale brown oil. To a 2N solution of Me2NH / THF (18.0 ml, 36.1 mmol) was added a solution of the acid chloride obtained in THF (10 ml) dropwise at 5 ° C over 15 minutes. The mixture was stirred at 5 ° C for 1 hour and then evaporated. The residue was treated with H2O and the resulting solid was collected by filtration. The solid was washed with H2O and dried under vacuum to give the title compound as pale yellow crystals (1.09 g, 99%).
Example 192d
4- (3-Amino-5-fluoro-phenoxy) benzoic acid methyl ester
The product of Example 192c was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 192e
4- [3-Fluoro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -N, N-dimethyl-benzamide
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 h following the procedure of Example 1g yielding the crude title compound that was purified by trituration with EtOAc to provide the product (150 mg, 79%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H), 2.98 (wide s, 6H), 6.97-7.08 (m, 2H), 7.12 (d , J = 7.0 Hz, 1H), 7.18-7.25 (m, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8, 8 Hz, 2H), 7.79 (d, J = 8.5 Hz, 1H), 8.59 (d, J = 7.0 Hz, 1H), 9.00 (d, J = 8.5 Hz , 1 HOUR); MS (ESI +) m / z 417 (M + H) +, (ESI-) m / z 415 (MH) -.
Example 193
4- [3-Chloro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenol
Example 193a
1-Chloro-3,5-dinitro-benzene
To a mixture of t-BuONO (5.41 ml, 41.0 mmol) and CuCl2 (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 200 ml of EtOAc, washed with 20% HCl, 10% NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield the title compound that was purified by silica gel column chromatography eluting with 10: 1 EtOAc / hexane to give the title product as colored crystals. pale yellow (4.60 g, 83%).
Example 193b
4- (3-Chloro-5-nitro-phenoxy) -phenol
The product of Example 193a (1.00 g, 5.0 mmol), hydroquinone (0.50 g, 4.5 mmol) and K2CO3 (0.78 g, 5.6 mmol) in DMF (10 ml) was heated at 110 ° C for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding the title compound. The residue was treated with i-Pr2O and the insoluble matter was filtered off. The filtrate was evaporated and purified by silica gel column chromatography eluting with 5: 2 EtOAc / hexane to give the title product as a light yellow oil (0.51 g, 43%).
Example 193c
4- (3-Amino-5-chloro-phenoxy) -phenol
The product of Example 192c was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 193d
4- [3-Chloro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenol
The product of Example 2g (100 mg, 0.48 mmol) was reacted with the product of Example 134c (140 mg, 0.48 mmol) for 17 h following the procedure of Example 1g yielding the crude title compound that was purified by trituration with EtOAc to provide the title compound (140 mg, 71%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.4 Hz, 3H), 1.86 (sextet, J = 7.4 Hz, 2H), 3.00 (t , J = 7.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 1.8 Hz, 1H), 6.99-7.07 (m, 2H), 7.04 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.8 Hz , 1H), 8.57 (d, J = 7.0 Hz, 1H), 9.02 (d, J = 8.8 Hz, 1H); MS (ESI +) m / z 406, 408 (M + H) +, (ESI-) m / z 404, 406 (MH) -.
Example 194 N- {4- [3-Chloro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) phenoxy] -phenyl} -acetamide
Example 194a
N- [4- (3-Chloro-5-nitro-phenoxy) -phenyl] -acetamide
The product of Example 193a (1.06 g, 5.2 mmol), N- (4-hydroxyphenyl) acetamide (0.70 g, 4.5 mmol) and K2CO3 (0.79 g, 5.7 mmol) in DMF (14 ml) was heated at 110 ° C for 6 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to yield the crude title compound as pale brown crystals, which was purified by washing with i-Pr2O to give the desired product in form of pale brown crystals (1.28 g, 92%).
Example 194b
N- [4- (3-Amino-5-chloro-phenoxy) -phenyl] -acetamide
The product of Example 192c was reduced with Fe and NH4Cl 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 (100 mg, 0.48 mmol) was reacted with the product of Example 194bc (130 mg, 0.48 mmol) for 22 h following the procedure of Example 1g producing the crude title compound that was purified by trituration with EtOAc to provide the product (110 mg, 51%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.00 (t, J = 7.0 Hz, 3H), 1.87 (sextet, J = 7.0 Hz, 2H), 2.08 (s , 3H), 3.01 (t, J = 7.0 Hz, 2H), 7.01 (s, 1H), 7.07 (d, J = 7.0 Hz, 1H), 7.07 (s , 1H), 7.14 (d, J = 7.2 Hz, 2H), 7.30 (s, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.76 (d , J = 8.7 Hz, 1H), 8.55 (d, J = 7.0 Hz, 1H), 9.03 (d, J = 8.7 Hz, 1H); MS (ESI +) m / z 447, 449 (M + H) +, (ESI-) m / z445, 447 (MH) -.
Example 195
4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxymethyl] -N-methyl-benzamide
Example 195a
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 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The precipitate was collected by filtration and washed with H2O and i-Pr2O to give the title compound as pale brown crystals (2.54 g).
Example 195b
4- (3-Chloro-5-nitro-phenoxymethyl) -benzoic acid
The product of Example 195a (2.50 g, 13.5 mmol) and 2N NaOH (7.77 ml, 15.5 mmol) in MeOH (25 mL) was refluxed for 1 hour, and then evaporated. The residue was dissolved in H2O and acidified to pH 2 with 10% HCl with stirring. The precipitate was collected by filtration, washed with H2O, and dried in vacuo overnight to give the title compound as pale brown crystals (2.30 g, 62%).
Example 195c
4- (3-Chloro-5-nitro-phenoxymethyl) -N-methyl-benzamide
The product of Example 195b (0.70 g, 2.3 mmol) and SOCl2 (2.50 ml, 34.1 mmol) was refluxed for 1 hour. The excess SOCl2 was removed under reduced pressure to give the corresponding acid chloride as a brown solid. To a 2N solution of MeNH2 / THF (11.4 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 H2O, acidified to pH 2 with 10% HCl, and then the resulting solid was collected by filtration. The solid was washed with H2O and i-Pr2O, and dried in vacuo to give the title compound as pale brown crystals (0.69 g, 95%).
Example 195d
4- (3-Amino-5-chloro-phenoxymethyl) -N-methyl-benzamide
The product of Example 195c was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 195e
4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxymethyl] -N-methyl-benzamide
The product of Example 1d (100 mg, 0.56 mmol) was reacted with the product of Example 195d (160 mg, 0.56 mmol) for 15 h following the procedure of Example 1g yielding the crude title compound that was purified by trituration with EtOAc to provide the product (240 mg, 99%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3H), 2.79 (d, J = 4.4 Hz, 3H), 5.26 (s, 2H), 6.90 (d, J = 7.0 Hz, 1H), 7.14 (br-t, J = 1.9 Hz, 1H), 7.18 (br-t, J = 1.9 Hz, 1H), 7 , 20 (br-t, J = 1.9 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7 , 87 (d, J = 8.5 Hz, 2H), 8.47 (wide s, 1H), 8.50 (d, J = 7.0 Hz, 1H), 9.08 (d, J = 8 , 8 Hz, 1H), 11.08 (broad s, 1H); MS (ESI +) m / z 433, 435 (M + H) +, (ESI-) m / z 431, 433 (MH) -.
Example 196
[3- (4-Bromo-benzyloxy) -5-chloro-phenyl] - (7-propyl [1,8] naphthyridin-4-yl) -amine
Example 196a
1- (4-Bromo-benzyloxy) -3-chloro-5-nitro-benzene
The product of Example 193a (0.75 g, 3.7 mmol), 4-bromobenzyl alcohol (0.77 g, 4.1 mmol) and K2CO3 (0.64 g, 4.6 mmol) in DMF (15 ml ) was heated at 110 ° C for 23 hours. The reaction mixture was cooled to room temperature, diluted with H2O, acidified to pH 2 with 10% HCl, and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding the crude title compound. The residue was treated with 50 mL of a mixture of n-hexane and EtOAc (3: 1) and silica gel. After stirring at room temperature for 30 minutes, the mixture was filtered through celite. The filtrate was evaporated and the resulting solid was washed with i-Pr2O to give the title compound as pale yellow crystals (0.70 g).
Example 196b
3- (4-Bromo-benzyloxy) -5-chloro-phenylamine
The product of Example 196a was reduced with Fe and NH4Cl following the procedure of Example 237E to give the title compound.
Example 196c
[3- (4-Bromo-benzyloxy) -5-chloro-phenyl] - (7-propyl [1,8] naphthyridin-4-yl) -amine
The product of Example 2g (100 mg, 0.39 mmol) was reacted with the product of Example 196b (120 mg, 0.39 mmol) for 22 h following the procedure of Example 1g yielding the crude title compound that was purified by trituration with EtOAc to provide the title compound (1990 mg, 100%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.96 (t, J = 7.4 Hz, 3H), 1.83 (sextet, J = 7.4 Hz, 2H), 2.97 (t , J = 7.4 Hz, 2H), 5.18 (s, 2H), 6.91 (d, J = 6.7 Hz, 1H), 7.05-7.17 (m, 3H), 7 , 43 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.5 Hz, 1H), 8.51 (d, J = 6.7 Hz, 1H), 9.05 (d, J = 8.5 Hz, 1H); MS (ESI +) m / z 482, 484, 486 (M + H) +, (ESI-) m / z 480, 482, 484 (MH) -.
Example 197
N- {4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxymethyl] -phenyl} -acetamide
Example 197a
Acetic acid 4-acetylamino-benzyl ester
To a solution of 4-hydroxymethylaniline (2.00 g, 15.9 mmol) in pyridine (20 ml) was added Ac2O (3.76 mL, 39.8 mmol) dropwise over 5 minutes at temperature ambient and the mixture was allowed to stir for 1 hour and then evaporated. The residue was diluted with H2O (20 mL) and acidified to pH 3 with conc. HCl. at 5 ° C stirring. The resulting crystals were collected by filtration, washed with a small amount of cold H2O and dried at room temperature under vacuum overnight to give the title compound as pale brown crystals (2.90 g, 88% ).
Example 197b
N- (4-Hydroxymethyl-phenyl) -acetamide
To the product of Example 197a (4.00 g, 19.3 mmol) in THF (40 mL) was added an aqueous solution of LiOH (0.91 g, 21.2 mmol) dropwise at room temperature over 10 minutes The mixture was allowed to stir at room temperature for 27 hours and then evaporated. The aqueous residue was diluted with H2O, adjusted to pH 4 with 10% HCl, and then extracted with EtOAc. The extract was washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding the title compound that was purified by washing with cold EtOAc to give the title compound as colorless crystals (2.92 g, 92% ).
Example 197c
N- [4- (3-Chloro-5-nitro-phenoxymethyl) -phenyl] -acetamide
The product of Example 193a (1.00 g, 4.9 mmol), and the product of Example 197b (0.90 g, 5.4 mmol) and K2CO3 (0.86 g, 6.2 mmol) in DMF ( 20 mL) were heated at 100 ° C for 10 hours. The reaction mixture was cooled to room temperature, diluted with H2O. The resulting solid was collected by filtration, washed with H2O, and dried under vacuum to give brown crystals, which were purified by silica gel column chromatography eluting with 5: 2 EtOAc / hexane to give the title compound. in the form of dark orange crystals (0.47 g, 30%).
Example 197d
N- [4- (3-Amino-5-chloro-phenoxymethyl) -phenyl] -acetamide
The product of Example 196c was reduced with Fe and NH4Cl 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 1d (70 mg, 0.39 mmol) was reacted with the product of Example 197d (110 mg, 0.39 mmol) for 23 h following the procedure of Example 1g yielding the crude title compound that was purified by trituration with EtOAc to provide the title compound (140 mg, 82%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3H), 2.75 (s, 3H), 5.11 (s, 2H), 6.90 (d, J = 7, 0 Hz, 1H), 7.12 (wide s, 1H), 7.17 (wide 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 (wide s, 1H); MS (ESI +) m / z 433, 435 (M + H) +, (ESI-) m / z 431, 433 (MH) -.
Example 198
(5-Methyl-2-phenoxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) amine
The product of Example 2g (82 mg, 0.40 mmol) was reacted with the product of Example 42b (88 mg, 0.40 mmol) for 24 h following the procedure of Example 1g yielding the crude title compound that was triturated with ether / THF 3: 1 providing the title compound as a hydrochloride salt (159 mg, 93%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J = 7.73 Hz, 3 H) 1.82 (c, J = 7.72 Hz, 2 H) 2.97 (dd , J = 7.73 Hz, 2 H) 6.68 (d, J = 6.99 Hz, 1 H) 6.99 (d, J = 7.72 Hz, 2 H) 7.12 (dd, J = 8.82 Hz, 2 H) 7.30 (dd, J = 8.09 Hz, 2 H) 7.66 (dd, J = 8.82 Hz, J = 2.58 Hz, 1 H) 7, 71 (d, J = 2.2 Hz, 1 H) 7.77 (d, J = 8.82 Hz, 1 H) 8.52 (d, J = 6.98 Hz, 1 H) 9.07 ( d, J = 8.82 Hz, 1 H) 11.26 (wide s, 1 H) 14.45 (wide s, 1 H); MS (ESI +) m / z 390 (M-Cl) +; (ESI-) m / z 388 (M-HCl) -.
Example 199 2,2-Dimethyl-N- {3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -propionamide
Example 199a
3- (4-Methyl-2-nitro-phenylsulfanyl) -phenylamine
The title compound was prepared from 3-Amino-benzenethiol (5,034 g, 40.21 mmol), 1-Chloro-4-methyl-2-nitrobenzene (4,600 g, 26.81 mmol) and K2CO3 (6.484 g, 46, 92 mmol) dissolved in DMF and heated at 100 ° C for 16 hrs. At this time the reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. It was dried over Na2SO4, filtered and concentrated in vacuo yielding 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 hrs, at which time the title compound was collected by filtration (8.78 g, 92%).
Example 199c
N- [3- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -acetamide
The product of Example 199b was reduced with SnCl2 following the procedure of Example 14 to give the title compound.
Example 199d
N- {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The title compound was prepared from the product of Example 2g (750 mg, 3.63 mmol), and the product of Example 199c (988 mg, 3.63 mmol) combined in 10 mL of EtOH and heated to 80 ° C for 40 hrs. After cooling to room temperature the solvent was removed in vacuo yielding the title compound (1.2 g, 74%).
Example 199e
[2- (3-Amino-phenylsulfanyl) -5-methyl-phenyl] - (7-propyl [1,8] naphthyridin-4-yl) -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 hr. At this time the reaction mixture was cooled to room temperature and made alkaline with 2N NaOH. This was then extracted with CH2Cl2, which was then dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound (720 mg, 66%).
Example 199f
2,2-Dimethyl-N- {3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -propionamide
The title compound was prepared using 2,2-Dimethyl-propionic acid (26 mg, 0.16 mmol) as acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSOD2O) δ ppm: 0.97 (t, J = 7.48 Hz, 3 H), 1.16 (s, 9 H), 1.79 -1.86 (m, 2 H ), 2.39 (s, 3 H), 2.94 -3.00 (m, 2 H), 6.31 (d, J = 7.02 Hz, 1 H), 6.87 (d, J = 8.24 Hz, 1 H), 7.07 (t, J = 7.93 Hz, 1 H), 7.33-7.38 (m, 3 H), 7.43-7.49 (m , 1 H), 7.57-7.61 (m, 1 H), 7.72 (d, J = 8.85 Hz, 1 H), 8.28 (d, J = 7.02 Hz, 1 H), 8.86 (d, J = 8.85 Hz, 1 H), 9.10 (s, 1 H); MS (ESI +) m / z 485 (M + TFA + H) +; (ESI-) m / z 483 (M + TFA-H).
Example 200
2,5-Dimethyl-furan-3-carboxylic acid {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -amidide
The title compound was prepared using 2,5-Dimethyl-furan-3-carboxylic acid (26 mg, 0.16 mmol) as the acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSO-D2O) δ 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, 3 H), 2.82 -2.86 (m, 2 H), 6.27 (d, J = 7.02 Hz , 1 H), 6.53 (s, 1 H), 6.86 (d, J = 8.24 Hz, 1 H), 7.08 (t, J = 7.93 Hz, 1 H), 7 , 35 (s, 1 H), 7.38 (dt, J = 7.63, 2.14 Hz, 2 H), 7.54 (d, J = 7.93 Hz, 1 H), 7.61 (t, J = 2.14 Hz, 1 H), 7.66 (d, J = 8.54 Hz, 1 H), 8.26 (d, J = 7.02 Hz, 1 H), 8, 82 (d, J = 8.85 Hz, 1 H); MS (ESI +) m / z 523 (M + TFA + H) +; (ESI-) m / z 521 (M + TFA-H) -.
Example 201
Thiophene-2-carboxylic acid {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -amidide
The title compound was prepared using thiophene-2-carboxylic acid (26 mg, 0.16 mmol) as the acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSOD2O) 5 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, 1 H), 6.88 (d, J = 7.93 Hz, 1 H), 7.10 (t, J = 7.93 Hz, 1 H), 7.22-7.26 (m, 1 H), 7.36 (s, 1 H), 7.38-7.42 (m , 2 H), 7.57-7.60 (m, 2 H), 7.65 (d, J = 8.54 Hz, 1 H), 7.86 (dd, J = 5.03, 1, 07 Hz, 1 H), 7.90 (dd, J = 3.81, 1.07 Hz, 1 H), 8.25 (d, J = 7.02 Hz, 1 H), 8.81 (d , J = 8.54 Hz, 1 H); MS (ESI +) m / z 511 (M + TFA + H) +.
Example 202
6-Hydroxy-N- {3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -nicotinamide
The title compound was prepared using 6-hydroxy-nicotinic acid (26 mg, 0.16 mmol) as the acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSOD2O) δ ppm: 0.92 (t, J = 7.32 Hz, 3 H), 1.69 -1.77 (m, 2 H), 2.37 -2.42 ( m, 3 H), 2.82 -2.88 (m, 2 H), 6.24 (d, J = 7.02 Hz, 1 H), 6.46 (d, J = 9.46 Hz, 1 H), 6.87 (d, J = 8.54 Hz, 1 H), 7.09 (t, J = 8.09 Hz, 1 H), 7.32-7.37 (m, 2 H ), 7.39 (d, J = 7.93 Hz, 1 H), 7.55-7.60 (m, 2 H), 7.67 (d, J = 8.85 Hz, 1 H), 7.91 (dd, J = 9.76, 2.75 Hz, 1 H), 8.09 (d, J = 2.44 Hz, 1 H), 8.24 (d, J = 7.02 Hz , 1 H), 8.82 (d, J = 8.54 Hz, 1 H); MS (ESI +) m / z 522 (M + TFA + H) +; (ESI-) m / z 520 (M + TFA-H).
Example 203
2-Hydroxy-6-methyl-N- {3- [4-methyl-2- (7-propyl [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} nicotinamide
The title compound was prepared using 2-hydroxy-6-methyl-nicotinic acid (26 mg, 0.16 mmol) as the acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSO-D2O) δ 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, 3 H), 2.76 -2.81 (m, 3 H), 6.22 (d, J = 7.02 Hz, 1 H), 6.46 (d, J = 7.32 Hz, 1 H), 6.86 (d, J = 8.24 Hz, 1 H), 7, 10 (t, J = 7.93 Hz, 1 H), 7.14 -7.18 (m, 1 H), 7.35 (s, IH), 7.39 (d, J = 8.24 Hz , 1 H), 7.57 7.59 (m, 1 H), 7.62 (d, J = 8.54 Hz, 2 H), 8.21 (d, J = 7.32 Hz, IH) , 8.27 (d, J = 7.32 Hz, 1 H), 8.82 (d, J = 8.85 Hz, 1 H); MS (ESI +) m / z 536 (M + TFA + H) +.
Example 204
{3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -amino acid pyrazine-2-carboxylic acid
The title compound was prepared using pyrazino-2-carboxylic acid (26 mg, 0.16 mmol) as the acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSOD2O) δ ppm: 0.87 (t, J = 7.48 Hz, 3 H), 1.63 -1.70 (m, 2 H), 2.40 (s, 3 H ), 2.74-2.78 (m, 2 H), 6.28 (d, J = 7.02 Hz, 1 H), 6.94 (d, J = 8.54 Hz, 1 H), 7.13 (t, J = 7.93 Hz, 1 H), 7.36 (d, J = 1.22 Hz, 1 H), 7.40 (d, J = 7.93 Hz, 1 H) , 7.53 (dd, J = 7.63, 1.53 Hz, 1 H), 7.61 (d, J = 7.93 Hz, 1 H), 7.65 (d, J = 8.54 Hz, 1 H), 7.76 (t, J = 1.83 Hz, 1 H), 8.25 (d, J = 7.02 Hz, 1 H), 8.78 8.84 (m, 2 H), 8.94 (d, J = 2.44 Hz, IH); MS (ESI +) m / z 507 (M + TFA + H) +.
Example 205
({3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenylcarbamoyl} -methyl) -furan-2-carboxylic acid amide
The title compound was prepared using [(furan-2-carbonyl) -amino] -acetic acid (26 mg, 0.16 mmol) as acid in the procedure of Example 74 to provide the title compound (3 mg, 5%) . 1 H NMR (500 MHz, DMSO-D2O) δ ppm: 0.96 (t, J = 7.32 Hz, 3 H), 1.78 -1.86 (m, 2 H), 2.39 (s, 3 H), 2.94 -3.01 (m, 2 H), 6.34 (d, J = 7.02 Hz, 1 H), 6.62 -6.68 (m, 1 H), 6 , 87 (d, J = 7.63 Hz, 1 H), 7.02 -7.12 (m, 2 H), 7.14 7.22 (m, 2 H), 7.37 (d, J = 5.49 Hz, 2 H), 7.48 (d, J = 8.54 Hz, 1 H), 7.51 (s, 1 H), 7.72 (d, J = 8.85 Hz, 1 H), 7.81 -7.87 (m, 2 H), 8.33 (d, J = 7.02 Hz, 1 H), 8.86 (d, J = 8.54 Hz, 1 H ); MS (ESI +) m / z 552 (M + TFA + H) +.
Example 206
N- {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -4-thiophene-2-yl-butyramide
The title compound was prepared using 4-thiophene-2-yl-butyric acid (26 mg, 0.16 mmol) as the acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSOD2O) δ ppm: 0.96 (t, J = 7.32 Hz, 3 H), 1.79 -1.84 (m, 2 H), 1.85 -1.89 ( m, 2 H), 2.28 (t, J = 7.48 Hz, 2 H), 2.39 (s, 3 H), 2.79 -2.84 (m, 2 H), 2.92 -2.98 (m, 2 H), 6.29 (d, J = 7.02 Hz, 1 H), 6.82 -6.88 (m, 2 H), 6.96 (dd, J = 4.88, 3.36 Hz, 1 H), 7.05 (t, J = 7.93 Hz, 1 H), 7.22 (dd, J = 8.24, 1.22 Hz, 1 H) , 7.31 (dd, J = 5.03, 1.07 Hz, 1 H), 7.35 -7.38 (m, 2 H), 7.45 -7.51 (m, 2 H), 7.70 (d, J = 8.54 Hz, 1 H), 8.27 (d, J = 7.32 Hz, 1 H), 8.84 (d, J = 8.54 Hz, 1 H) ; MS (ESI +) m / z 553 (M + TFA + H) +.
Example 207
N- {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2- (3-phenoxyphenyl) -acetamide
The title compound was prepared using (3-phenoxy-phenyl) -acetic acid (26 mg, 0.16 mmol) as acid in the procedure of Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSOD2O) δ ppm: 0.96 (t, J = 7.32 Hz, 3 H), 1.77 -1.85 (m, 2 H), 2.39 (s, 3 H ), 2.92 -2.99 (m, 2 H), 3.55 (s, 2 H), 6.32 (d, J = 7.32 Hz, 1 H), 6.84 -6.90 (m, 2 H), 6.96 (s, 1 H), 7.00 (d, J = 7.63 Hz, 2 H), 7.07 (ddd, J = 7.78, 4.12, 3.97 Hz, 2 H), 7.16 (t, J = 7.48 Hz, 1 H), 7.23 (d, J = 9.15 Hz, 1 H), 7.33-7.42 (m, 5 H), 7.44 7.47 (m, 1 H), 7.49 (s, 1 H), 7.69 (d, J = 8.85 Hz, 1 H), 8.27 (d, J = 7.02 Hz, 1 H), 8.85 (d, J = 8.54 Hz, 1 H); MS (ESI +) m / z 611 (M + TFA + H) +.
Example 208
N-Alyl-3- [4-chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -benzamide
Example 208a
3- (4-Chloro-2-nitro-phenoxy) benzoic acid methyl ester
1-Bromo-4-chloro-2-nitro-benzene (7.00 g, 29.60 mmol) was dissolved in DMF to which K2CO3 (5.11 g, 37.01 mmol) and acid methyl ester were added 3-hydroxybenzoic acid (4.95 g, 32.57 mmol). The reaction mixture was then heated at 100 ° C for 2 h. The reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. The solvent was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound. (7.2 g, 79%)
Example 208b
3- (2-Amino-4-chloro-phenoxy) benzoic acid ethyl ester
The product of Example 208a (7.20 g, 23.40 mmol) was reduced with SnCl2 (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-ylamino) -phenoxy] -benzoic acid methyl ester
The product of Example 1d (175 mg, 0.979 mmol) and the product of Example 208b (272 mg, 0.979 mmol) were dissolved in 2 mL of EtOH abs. and heated at 80 ° C for 16 hrs. At this time the reaction mixture was cooled and the solvent removed by providing the title compound as a brown foam that was carried forward without purification (410 mg, 93%).
Example 208d
3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -benzoic acid
The product of Example 208c (447 mg, 1,065 mmol) was dissolved in 5 ml of a 1: 1 solution (THF: water). To this was added LiOH (51 mg, 2,129 mmol) and the reaction mixture was heated at 60 ° C for 2 h. The reaction mixture was then allowed to cool to room temperature and neutralized with HOAc. The product was extracted with ethyl acetate. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound (180 mg, 42%).
Example 208e
N-Alyl-3- [4-chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenoxy] -benzamide
The product of Example 208d (60 mg, 0.147 mmol) was dissolved in THF to which was added N-methylmorpholine (49 mg, 0.162 mmol), and isopropenyl chloroformate (36 mg, 0.295 mmol). This was stirred at room temperature for 1 hr, at which time allylamine (42 mg, 0.739 mmol) was added and the reaction mixture was stirred at room temperature for another hr. THF was then removed in a stream of N2 and then the crude oil was purified by HPLC with TFA to provide the product as trifluoroacetic acid. (8.0 mg, 9.5%). 1 H NMR (300 MHz, DMSOd6) δ 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, 1 H), 6.73 (d, J = 6.99 Hz, 1 H), 7.10 (dd, J = 7.72, 2.21 Hz, 1 H), 7.27-7.43 (m, 3 H), 7.51-7.65 (m, 2 H), 7.69-7.82 ( m, 2 H), 8.54 (d, J = 7.35 Hz, 1 H), 8.82 (d, J = 8.46 Hz, 1 H); 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
The 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 h with tributyl-phenyl -statane (0.185 mL, 0.564 mmol) in nitrogen in toluene at 75 ° C in the presence of 2 mol% of tetrakis (triphenylphosphine) palladium (0). Volatile substances were subsequently removed under reduced pressure to provide the crude product, which was purified by flash chromatography on silica gel to give the title compound (0.103 g, 88%).
Example 211b
6-Phenyl-pyridin-2-ylamine
The substituted pyridine described in Example 211a (0.289 g, 1.7 mmol) was reacted as described in Example 2c to give the title compound in quantitative yield.
Example 211c
5-Chloro-2-phenyl- [1,8] naphthyridine
The product of Example 211b was reacted following the procedures of Examples 2d, 2e, 2f and 2g to give the title compound.
Example 211d
(5-Chloro-2-phenoxy-phenyl) - (7-phenyl- [1,8] naphthyridin-4-yl) amine
The product of Example 211f (0.108 g, 0.45 mmol) was reacted with the product of Example 42b (0.100 g, 0.46 mmol) for 28 hours following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as the trifluoroacetic acid salt (0.144 g, 57%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 6.75 (d, J = 6.99 Hz, 1 H) 6.99 (d, J = 7.72 Hz, 2 H) 7.11 (t , J = 7.35 Hz, 1 H) 7.18 (d, J = 8.82 Hz, 1 H) 7.32 (t, J = 7.91 Hz, 2 H) 7.59 (dd, J = 8.82, 2.57 Hz, 1 H) 7.64 (m, 3 H) 7.75 (d, J = 2.57 Hz, 1 H) 8.36 (dd, J = 6.62, 2.94 Hz, 2 H) 8.51 (d, J = 9.19 Hz, 1 H) 8.61 (d, J = 6.99 Hz, 1 H) 9.10 (d, J = 8, 82 Hz, 1 H); MS (ESI +) m / z 423.9 (M + H) +; (ESI -) - m / z 422.0 (MH) -.
Example 212
2- (7-Methyl- [1,8] naphthyridine-4-ylamino) -biphenyl-4-carboxylic acid methyl ester
Example 212a
4-Bromo-3-nitro-benzoic acid methyl ester
Commercially available 4-bromo-3-nitro-benzoic acid (1.17 g, 4.76 mmol) was dissolved in methanol (5 mL) containing five drops of concentrated sulfuric acid. The mixture was heated in air at 90 ° C for six hours and more MeOH (7 mL) was added followed by concentrated sulfuric acid (0.6 mL). He continued heating another 24 hours. The extractive work up (ethyl acetate-water), followed by drying over MgSO4, was filtered and concentrated in vacuo yielding the title compound in quantitative yield.
Example 212b
2-Nitro-biphenyl-4-carboxylic acid methyl ester
The product of Example 212a (0.100 g, 0.384 mmol) was combined with iodobenzene (0.375 mL, 3.35 mmol) and copper powder (0.188 g, 2.96 mmol) and the mixture was heated in a sealed tube at 218 ° C for 90 minutes. The reaction mixture was subsequently diluted with dichloromethane and filtered through celite. The crude product, obtained by concentration in vacuo, was purified by flash chromatography on silica gel (ethyl acetate-hexanes) to give the title compound (0.0847 g, 86%).
Example 212c
2-Amino-biphenyl-4-carboxylic acid methyl ester
The product of Example 212b (0.0795 g, 0.309
mmol) was dissolved in ethanol (2mL) and Pt (IV) oxide (5.2 mg) was added to this solution. The reaction mixture was degassed under vacuum, then exposed to a hydrogen atmosphere for 3 h at room temperature. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give the title compound in quantitative yield.
Example 212d
2- (7-Methyl- [1,8] naphthyridine-4-ylamino) -biphenyl-4-carboxylic acid methyl ester
The product of Example 1d (0.0552 g, 0.309 mmol) was reacted with the product of Example 212c (0.070 g, 0.309 mmol) for 92h following the procedure of Example 1g yielding the crude title compound, which was purified by HPLC with AA. The resulting solid was triturated with 4N HCl in dioxane to generate the hydrochloride salt that was collected by vacuum filtration (0.0747 g, 55%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.72 (s, 3 H) 3.91 (s, 3 H) 6.27 (d, J = 6.99 Hz, 1 H) 7.30 (m, J = 6.99 Hz, 3 H) 7.52 (m, 2 H) 7.74 (d, J = 8.82 Hz, 1 H) 7.79 (d, J = 8.09 Hz , 1 H) 8.09 (d, J = 1.47 Hz, 1 H) 8.16 (dd, J = 7.91, 1.65 Hz, 1 H) 8.30 (d, J = 6, 99 Hz, 1 H) 9.15 (d, J = 8.82 Hz, 1 H) 11.54 (s, 1H); MS (ESI +) m / z 369.9 (M + H) +.
Example 213
(4-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine
Example 213a
4-Methyl-2-nitro-biphenyl
To a solution of commercially available 1-bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) in anhydrous toluene (3 mL) was added CsCO3 (0.305 g, 0.94 mmol) followed by phenylboronic acid (0.062 g, 0.49 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1 phosphobicyclo [3,3,3,] undecane in the form of a 0.1M solution in toluene (0.200 mL, 4 mol%). Nitrogen was bubbled through the resulting suspension for three 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 for 22 hours. Subsequent filtration through celite and removal of volatile substances in vacuo provided the crude product (0.105 g, 100%), which was pure enough to use as isolated.
Example 213b
4-Methyl-biphenyl-2-ylamine
The product of Example 213a was reacted as described in Example 212c to give the title amine (0.088 g, 100%).
Example 213c
(4-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine
The product of Example 2g (0.106 g, 0.49 mmol) was reacted with the product of Example 213b (0.088 g, 0.49 mmol) for 65 hours following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.122 g, 52%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.96 (t, J = 7.35 Hz, 3 H) 1.81 (d, J = 7.72 Hz, 2 H) 2.43 (s , 3 H) 2.89 -3.02 (m, 2 H) 6.31 (d, J = 6.99 Hz, 1 H) 7.14 7.58 (m, 8 H) 7.77 (d , J = 8.46 Hz, 1 H) 8.32 (d, J = 7.35 Hz, 1 H) 8.91 (d, J = 8.46 Hz, 1 H) 10.91 -11.08 (m, 1 H); MS (ESI +) m / z354.0 (M + H) +; (ESI-) m / z 351.9 (MH) -.
Example 214
(4-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine
Example 214a
4'-Methoxy-4-methyl-2-nitro-biphenyl
The 1-bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) was reacted as described in Example 213a by replacing 4-methoxyphenylboronic acid (0.074 g, 0.49 mmol) with Boronic acid to give the title biphenyl with a quantitative yield and sufficient purity for use in the next step as isolated.
Example 214b
4'-Methoxy-4-methyl-biphenyl-2-ylamine
The product of Example 214a was reacted as described in 212c to give the title amine (0.107 g, 100%).
Example 214
(4'-Methoxy-4-methyl-biphenyl-2-yl) - (7-methyl [1,8] naphthyridin-4-yl) -amine
The product of Example 1d (0.088 g, 0.49 mmol) was reacted with the product of Example 214b (107 mg, 0.49 mmol) for 65 hours following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.106 g, 45%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3 H) 2.72 (s, 3 H) 3.66 (s, 3 H) 6.29 (d, J = 6, 99 Hz, 1 H) 6.84 (d, J = 8.82 Hz, 2 H) 7.27 -7.53 (m, 5 H) 7.75 (d, J = 8.46 Hz, 1 H ) 8.32 (d, J = 6.99 Hz, 1 H) 8.90 (d, J = 8.46 Hz, 1 H) 10.88 -11.05 (m, 1 H); MS (ESI +) m / z 356.0 (M + H) +; (ESI-) m / z 354.1 (MH) -.
Example 215
N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) biphenyl-4-yl] -acetamide
Example 215a
N- (4'-Methyl-2'-nitro-biphenyl-4-yl) -acetamide
The 1-bromo-4-methyl-2-nitro-benzene (0.102 g, 0.49 mmol) was reacted as described in Example 213a replacing N- [4- (4,4,5,5-Tetramethyl [1,3,2] dioxaborolan-2-yl) -phenyl] -acetamide (0.1330 g, 0.49 mmol) by phenylboronic acid and heated for 18h at 100 ° C. The reaction mixture was filtered through celite and the volatiles were removed in vacuo and the crude product was purified by flash chromatography on silica gel eluting with EtOAchexanes to give the title biphenyl (0.051 mg, 38%).
Example 215b
N- (2'-Amino-4'-methyl-biphenyl-4-yl) -acetamide
The product of Example 215a (0.062 g, 0.23 mmol) was reacted as described in Example 212c to give the title amine in quantitative yield.
Example 215
N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) biphenyl-4-yl] -acetamide
The product of Example 1d (0.041 g, 0.23 mmol) was reacted with the product of Example 215b (0.062 g, 0.23 mmol) for 46 h at 100 ° C following the procedure of Example 1g yielding the crude title compound which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.073 g, 60%). 1 H NMR (300 MHz, DMSOd6) δ 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, 1 H) 8.33 (d, J = 7.35 Hz, 1 H) 8 , 94 (d, J = 8.82 Hz, IH) 9.95 (s, IH) 11.06 (s, 1 H); MS (ESI +) m / z 383.1 (M + H) +, (ESI-) m / z 381.1 (MH) -.
Example 216
N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) biphenyl-3-yl] -acetamide
Example 216a
N- (4'-Methyl-2'-nitro-biphenyl-3-yl) -acetamide
1-Bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) was reacted as described in Example 215a by replacing 3acetamidophenylboronic acid (0.086 g, 0.49 mmol) with phenylboronic acid , dicyclohexylamine (4 mol%) with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1 phosphobicyclo [3,3,3,] -decane and replacing the dioxane with toluene to give the title biphenyl (0.0552 g, 42%).
Example 216b
N- (2'-Amino-4'-methyl-biphenyl-3-yl) -acetamide
The product of Example 216a (0.070 g, 0.26 mmol) was reacted as described in 212c to give the title amine in quantitative yield.
Example 216
N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) biphenyl-3-yl] -acetamide
The product of Example 1g (0.046 g, 0.26 mmol) was reacted with the product of Example 216b (0.063 g, 0.26 mmol) for 47 hours at 100 ° C following the procedure of Example 1g producing the title compound crude which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.085 g, 64%). 1 H NMR (300 MHz, DMSOd6) δ ppm: 1.93 (s, 3 H) 2.43 (s, 3 H) 2.71 (s, 3 H) 6.34 (d, J = 6.99 Hz , 1 H) 7.04 (d, J = 7.35 Hz, 1 H) 7.17 (t, J = 7.72 Hz, 1 H) 7.22 -7.31 (m, 1 H) 7 , 36 (s, 1 H) 7.40 -7.54 (m, 2 H) 7.72 (d, J = 8.46 Hz, 1 H) 7.77 (s, 1 H) 8.36 ( s, 1 H) 8.88 (d, J = 8.82 Hz, 1 H) 9.88 (s, 1 H) 10.99 (s, 1 H); MS (ESI +) m / z 383.0 (M + H) +; (ESI-) m / z 381.1 (MH) -.
Example 217
(3'-Methoxy-4-methyl-biphenyl-2-yl) - (7-methyl [1,8] naphthyridin-4-yl) -amine
Example 217a
3'-Methoxy-4-methyl-2-nitro-biphenyl
1-Bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) was reacted as described in Example 216a by replacing 3-methoxyphenylboronic acid (0.074 g, 0.45 mmol) with acid 3-acetamidophenylboronic to give the title biphenyl (0.083 g, 76%).
Example 217b
3'-Methoxy-4-methyl-biphenyl-2-ylamine
The product of Example 217b (0.083 g, 0.34 mmol) was reacted as described in Example 212c to give the title amine in quantitative yield.
Example 217c
(3'-Methoxy-4-methyl-biphenyl-2-yl) - (7-methyl [1,8] naphthyridin-4-yl) -amine
The product of Example 1d (0.065 g, 0.36 mmol) was reacted with the product of Example 217b (0.072 g, 0.34 mmol) for 96h at 100 ° C following the procedure of Example 1g producing the crude title compound which was purified by HPLC with TFA to provide a trifluoroacetic acid salt (0.102 g, 64%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.43 (s, 3 H) 2.72 (s, 3 H) 3.62 (s, 3 H) 6.29 (d, J = 7, 35 Hz, 1 H) 6.77 (dd, J = 7.91, 2.02 Hz, 1 H) 6.87-7.00 (m, 2 H) 7.17 (t, J = 7.91 Hz, 1 H) 7.36 (s, 1 H) 7.41 -7.46 (m, 1 H) 7.51 -7.56 (m, 1 H) 7.75 (d, J = 8, 46 Hz, 1 H) 8.32 (d, J = 7.35 Hz, 1 H) 8.91 (d, J = 8.82 Hz, 1 H) 11.99 12.22 (s, 1 H) ; MS (ESI +) m / z 356.0 (M + H) +; (ESI-) m / z 354.0 (MH) -.
Example 218
(7-Propyl- [1,8] naphthyridin-4-yl) - (4-trifluoromethylbiphenyl-2-yl) -amine
Example 218a
2-Nitro-4-trifluoromethyl-biphenyl
Commercially available 1-bromo-2-nitro-4-trifluoromethyl-benzene (0.1330 g, 0.48 mmol) was reacted with phenylboronic acid (0.072 g, 0.59 mmol) as described in Example 213a replacing dioxane by toluene, bis (triphenylphosphine) -palladium (II) chloride by palladium acetate and omitting 2,8,9triisobutyl-2,5,8,9-tetraaza-1-phosphobicyclo [3,3,3,] undecano. The reaction was completed after hours and the title biphenyl was recovered in quantitative yield, pure enough to be used as isolated.
Example 218b
4-Trifluoromethyl-biphenyl-2-ylamine
The product of Example 218a was reacted as described in Example 212c replacing THF / EtOH
3: 1 (4 mL) per ethanol to give the title amine in quantitative yield.
Example 218c
(7-Propyl- [1,8] naphthyridin-4-yl) - (4-trifluoromethylbiphenyl-2-yl) -amine
The product of Example 2g in the form of a 3.15 M solution in ethanol (0.078 mL, 0.24 mmol) was reacted with the product of Example 218b (0.057 g, 0.24 mmol) for 64 h at 100 ° C following the procedure of Example 1g. Consumption of the starting substance required the periodic addition of the product of Example 2g (0.103 mL, 0.32 mmol) in total, and heating was continued at 100 ° C (70 hrs.). The crude title compound was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.0058 g, 5%). 1 H NMR (300 MHz, DMSOd6) δ ppm: 0.96 (t, J = 7.35 Hz, 3 H) 1.73 -1.92 (m, 2 H) 2.90 -3.02 (m, 2 H) 6.37 (d, J = 6.99 Hz, 1 H) 7.32 (d, J = 7.72 Hz, 3 H) 7.48 (dd, J = 7.91, 1.65 Hz, 2 H) 7.80 (d, J = 8.82 Hz, 1 H) 7.86 (d, J = 8.09 Hz, 1 H) 7.94 -8.03 (m, 2 H) 8.35 (d, J = 6.99 Hz, 1 H) 8.91 (d, J = 8.82 Hz, 1 H); MS (ESI +) m / z 408.1 (M + H) +; (ESI-) m / z 406.2 (MH) -.
Example 219
(5-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine
Example 219a
2-Bromo-4-methyl-1-nitro-benzene
In a flask containing 90% t-butyl nitrite (1.47 mL, 11.2 mmol) and copper (II) bromide (2.0 g, 8.95 mmol) in CH3CN (40 mL) at 70 A solution of commercially available 5-Methyl-2-nitrophenylamine (1.13 g, 7.46 mmol) in CH3CN (8mL) was added dropwise in nitrogen. After twenty minutes the reaction was quenched by pouring it into dilute HCl and the crude product was isolated by extraction with ether, drying with MgSO4 and concentrating in vacuo. Flash chromatography on silica gel produced the title compound (0.811 g, 50%).
Example 219b
5-Methyl-2-nitro-biphenyl
The product of Example 219a (0.20 g, 0.93 mmol) was reacted with phenylboronic acid (0.135 g, 1.11 mmol) for 19.5h at 80 ° C as described in Example 218a. The reaction mixture was cooled and filtered through celite, the filtrate was concentrated in vacuo to give the crude product that was purified by flash chromatography on silica gel to give the title biphenyl (0.187 g, 94%) in Shape of a yellow oil.
Example 219c
5-Methyl-biphenyl-2-ylamine
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 219c
(5-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine
The product of Example 2g in the form of a 4.1M 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 h at 100 ° C following the procedure of Example 1g. The consumption of the starting substance required a second addition of the product of Example 2g (0.03 mL, 0.12 mmol) and heating was continued at 100 ° C (19h). The crude title compound was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.060 g, 32%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J = 7.35 Hz, 3 H) 1.70 -1.89 (m, 2 H) 2.46 (s, 3 H ) 2.88 -3.00 (m, 2 H) 6.28 (d, J = 6.99 Hz, 1 H) 7.11 -7.53 (m, 8 H) 7.76 (d, J = 8.82 Hz, 1 H) 8.30 (d, J = 6.99 Hz, 1 H) 8.91 (d, J = 8.82 Hz, 1 H) 10.98 (s, IH); 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 produce the crude title compound that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt. 1 H NMR (500 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.25 Hz, 3 H) 1.80 -1.91 (m, 2 H) 2.31 (s, 3 H ) 2.96 -3.04 (m, 2 H) 6.31 (d, J = 6.96 Hz, 1 H) 6.57 (d, J = 8.69 Hz, 2 H) 6.91 ( d, J = 8.11 Hz, 1 H) 7.07 (d, J = 8.69 Hz, 2 H) 7.18 -7.29 (m, 2 H) 7.83 (d, J = 8 , 69 Hz, 1 H) 8.45 (d, J = 6.96 Hz, 1 H) 9.06 (d, J = 8.69 Hz, 1 H) 11.03 (s, 1 H); MS (ESI +) m / z 401.1 (M + H) +; (ESI-) m / z 399.1 (MH)
Example 221
4- [4-Phenoxymethyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
Example 221a
(4-Bromo-3-nitro-phenyl) -methanol
Commercially available 4-bromo-3-nitro-benzoic acid (5.95 g, 0.024 mole) was reacted as described in Example 115a to give the title compound with a quantitative crude yield pure enough to be used as used. isolated.
Example 221b
1-Bromo-2-nitro-4-phenoxymethyl-benzene
The product of Example 221a (0.5 g, 2.15 mmol) was combined with phenol (0.203 g, 2.15 mmol) and triphenylphosphine (0.735 g, 2.80 mmol) in anhydrous THF (7 mL) in nitrogen and The resulting solution was cooled in an ice bath. To the cold solution was added dropwise diisopropyl azodicarboxylate (0.467 mL, 2.37 mmol). Stirring was continued at 0 ° C for 15 min, then the cold bath was removed and the reaction mixture was allowed to warm to room temperature and 90 min later it was quenched and made by pouring it into dilute HCl and extracted with ether. The combined extracts were dried MgSO4, filtered and concentrated in vacuo yielding the crude title compound that was purified by flash chromatography on silica gel eluting with EtOAc-hexanes to give the title compound (0.162 g, 25%).
Example 221c
4- (2-Nitro-4-phenoxymethyl-phenylsulfanyl) -phenol
The product of Example 221b (0.16 g, 0.52 mmol) was reacted with 90% 4-mercapto-phenol (0.073 g, 0.52 mmol) in DMF at 80 ° C under nitrogen in the presence of potassium (0.126 g, 0.91 mmol). The reaction was quenched after 18h by pouring it into dilute HCl and extracted with ether. The combined extracts were dried over MgSO4, filtered and concentrated in vacuo yielding the crude title compound. The crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexanes to give the title compound (0.155 g, 84%).
Example 221d
4- (2-Amino-4-phenoxymethyl-phenylsulfanyl) -phenol
The product of Example 221c (0.154 g, 0.43 mmol) was reacted with 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-Phenoxymethyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol
The product of Example 2g in the form of 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 16.5h following the procedure of Example 1g. The consumption of the starting substance required a second addition of the product of Example 2g (0.025 mL, 0.102 mmol) and heating continued at 80 ° C (12h). The crude title compound was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.0269 g, 21.5%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.54 Hz, 3 H) 1.76 -1.99 (m, 2 H) 3.00 (t, J = 7.35 Hz, 2 H) 5.12 (s, 2 H) 6.31 (d, J = 6.99 Hz, 1 H) 6.79 (d, J = 8.82 Hz, 2 H) 6 , 91 -7.07 (m, 4 H) 7.17 -7.37 (m, 4 H) 7.43 7.55 (m, 2 H) 7.84 (d, J = 8.82 Hz, 1 H) 8.47 (d, J = 7.35 Hz, 1 H) 9.04 (d, J = 8.46 Hz, 1 H) 9.97 (s, 1 H); MS (ESI +) m / z 494.2 (M + H) +; (ESI-) m / z 492.2 (MH) -.
Example 222
4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenoxymethylphenylsulfanyl] -phenol
The product of Example 1d (0.037 g, 0.205 mmol) was reacted with the product of Example 221d (0.066 g, 0.205 mmol) for 16.5 hours following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of a trifluoroacetic acid salt (0.041 g, 34%). 1 H NMR (300 MHz, DMSOd6) δ ppm: 2.77 (s, 3 H) 5.13 (s, 2 H) 6.31 (d, J = 6.99Hz, 1 H) 6.79 (d, J = 8.46 Hz, 2 H) 6.88 -7.12 (m, 4 H) 7.20 -7.36 (m, 4 H) 7.46 -7.56 (m, 2 H) 7 , 81 (d, J = 8.82 Hz, 1 H) 8.48 (d, J = 6.99 Hz, 1 H) 9.02 (d, J = 8.46 Hz, 1 H) 10.01 (s, 1 H); MS (ESI +) m / z 466.3 (M + H) +; (ESI-) m / z 464.2 (MH) -.
Example 223
4- [4- (4-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
Example 223a
1-Bromo-4- (4-bromo-phenoxymethyl) -2-nitro-benzene
The product of Example 221a (0.5 g, 2.15 mmol) was reacted as described in Example 221b by replacing 4-bromo-phenol (0.372 g, 2.15 mmol) with phenol to give the title compound in the form of a white solid (0.238 g, 29%).
Example 223b
4- [4- (4-Bromo-phenoxymethyl) -2-nitro-phenylsulfanyl] -phenol
The product of Example 223a (0.236 g, 0.61 mmol) was reacted as described in Example 221c to give the title compound (0.188 g, 71%).
Example 223c
4- [2-Amino-4- (4-bromo-phenoxymethyl) -phenylsulfanyl] -phenol
The product of Example 223b (0.186 g, 0.43 mmol) was reacted as described in Example 221d to give the title compound (0.121 g, 70%).
Example 223
4- [4- (4-Bromo-phenoxymethyl) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 1d (0.03 g, 0.167 mmol) was reacted with the product of Example 223c (0.060 g, 0.15 mmol) for 17.5 h following the procedure of Example 1g. The consumption of the starting substance required a second addition of the product of Example 1d (0.016 g, 0.09 mmol) and continuous heating at 80 ° C (18h). The crude title compound was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.056 g, 55%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 5.12 (s, 2 H) 6.30 (d, J = 6.99 Hz, 1 H) 6.79 (d, J = 8.82 Hz, 2 H) 6.92 -7.08 (m, 3 H) 7.25 (d, J = 8.82 Hz, 2 H) 7.42 -7.54 ( m, 4 H) 7.81 (d, J = 8.82 Hz, 1 H) 8.47 (d, J = 6.99 Hz, 1 H) 9.01 (d, J = 8.46 Hz, 1 H) 9.98 (s, 1 H); MS (ESI +) m / z 546.0 (M + H) +.
Example 224
4- [4- (4-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
The product of Example 2g in the form of a 4.1M solution in ethanol (0.055 mL, 0.225 mmol) was reacted with the product of Example 223c (0.060 g, 0.15 mmol) for 17.5 h following the procedure of Example 1g The consumption of the starting substance required a second addition of the product of Example 2g (0.028 mL, 0.114 mmol) and heating continued at 80 ° C (18h). The crude title compound was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.044 g, 41%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H) 1.77 -1.96 (m, 2 H) 3.00 (t, J = 7.54 Hz, 2 H) 5.13 (s, 2 H) 6.31 (d, J = 6.99 Hz, 1 H) 6.79 (d, J = 8.82 Hz, 2 H) 6 , 91 -7.07 (m, 3 H) 7.26 (d, J = 8.46 Hz, 2 H) 7.40 7.56 (m, 4 H) 7.84 (d, J = 8, 82 Hz, 1 H) 8.47 (d, J = 6.99 Hz, 1 H) 9.04 (d, J = 8.82 Hz, 1 H) 9.98 (s, 1 H); MS (ESI +) m / z 573.9 (M + H) +; (ESI-) m / z 572.1 (MH) -.
Example 225
4- [4- (3-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol
Example 225a
1-Bromo-4- (3-bromo-phenoxymethyl) -2-nitro-benzene
The product of Example 221a (0.5 g, 2.15 mmol) was reacted as described in Example 221b by replacing 3-bromo-phenol (0.372 g, 2.15 mmol) with phenol to give the title compound (0.832 g, 56%).
Example 225b
4- [4- (3-Bromo-phenoxymethyl) -2-nitro-phenylsulfanyl] -phenol
The product of Example 225a (0.462 g, 1.19 mmol) was reacted as described in Example 221c to give the title compound (0.412 g, 80%).
Example 225c
4- [2-Amino-4- (3-bromo-phenoxymethyl) -phenylsulfanyl] -phenol
The product of Example 225b (0.412 g, 0.95 mmol) was reacted as described in Example 221d to give the title compound (0.310 g, 81%).
Example 225
4- [4- (3-Bromo-phenoxymethyl) -2- (7-methyl- [1,8] naphthyridine-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 substance required a second addition of the product of Example 1d (0.019 g, 0.109 mmol) and continuous heating at 80 ° C (18h). The crude title compound was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.041 g, 32%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.16 (d, 1 H) 7.20 -7.30 (m, 4 H) 7, 45 -7.55 (m, 2 H) 7.81 (d, J = 8.82 Hz, 1 H) 8.47 (d, J = 7.35 Hz, 1 H) 9.01 (d, J = 8.46 Hz, 1 H) 9.98 (s, 1 H); Ms (ESI +) m / z 546.0 (M + H) +; (ESI-) m / z 542.0.
Example 226 4- [4- (3-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4 -lamino) -phenylsulfanyl] -phenol
The product of Example 2g in the form of a 4.1M 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 h following the procedure of Example 1g. The consumption of the starting substance required a second addition of the product of Example 2g (0.028 mL, 0.114 mmol) and heating continued at 80 ° C (18h). The crude title compound was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.038 g, 28%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.35 Hz, 3 H) 1.85 (d, J = 7.35 Hz, 2 H) 3.00 (t , J = 7.54 Hz, 2 H) 5.16 (s, 2 H) 6.31 (d, J = 7.35 Hz, 1 H) 6.79 (d, J = 8.46 Hz, 2 H) 6.95 -7.09 (m, 2 H) 7.16 (d, 1 H) 7.18 7.34 (m, 4 H) 7.42 -7.58 (m, 2 H) 7 , 84 (d, J = 8.46 Hz, 1 H) 8.48 (d, J = 6.99 Hz, 1 H) 9.04 (d, J = 8.46 Hz, 1 H) 9.98 (s, 1 H) 10.99 -11.19 (m, 1 H); MS (ESI +) m / z 573.9 (M + H) +; (ESI-) m / z 572.3 (MH) -.
Example 227 (reference)
(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (pyridin-2-sulfanyl) -phenyl] -amine
Example 227a
2- (4-Methyl-2-nitro-phenylsulfanyl) -pyridine
The title compound was prepared from the reaction of trifluoro-methanesulfonic acid 4-methyl-2-nitro-phenyl ester (3.50 g, 12.27 mmol) by reacting it with pyridino-2-thiol (2,046 g, 18.41 mmol), and K2CO3 (2.968 g, 21.48 mmol) in DMF at 100 ° C for 16 h. The reaction mixture was then cooled to room temperature and diluted with water, extracted with EtOAc. It was dried over Na2SO4, filtered and concentrated in vacuo yielding the title compound (2.52 g, 78%).
Example 227b
5-Methyl-2- (pyridin-2-ylsulfanyl) -phenylamine
The product of Example 277a (2,250 g, 10.23 mmol) was reduced with SnCl2 (5.820 g, 30.70 mmol) 2 hrs. at 80 ° C following the procedure of Example 1f providing the title compound that was purified by silica gel column chromatography eluting with 30% EtOAc / hexanes (1.52 g, 70%).
Example 227c
(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (pyridin-2-sulfanyl) -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 h following the procedure of Example 1g yielding the crude title compound that was purified by HPLC with TFA providing the product in the form of trifluoroacetic acid (24 mg, 28%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.44 (s, 3 H), 2.73 (s, 3 H), 6.45 (d, J = 6.99 Hz, 1 H), 7.02 -7.12 (m, J = 7.72, 1.10 Hz, 2 H), 7.40 -7.49 (m, 2 H), 7.50 -7.58 (m, J = 1.84 Hz, 1H), 7.72 (dd, J = 8.46, 3.31 Hz, 2 H), 8.21 -8.27 (m, J = 2.94, 0.74 Hz , 1 H), 8.38 (d, J = 6.99 Hz, 1 H), 8.85 (d, J = 8.82 Hz, 1 H), 10.99 (s, 1H); MS (ESI +) m / z 359 (M + H-TFA) +; (ESI-) m / z 357 (MH-TFA) -.
Example 228
(5-Chloro-2-phenoxy-phenyl) - [1,6] naphthyridin-5-yl-amine
Example 228a
2-Trimethylsilaniletinyl-nicotinonitrile
In a pressure vessel of the appropriate size, commercially available 2-chloro-nicotinonitrile (1.5 g, 10.8 mmol) was combined with triphenylphosphine (0.228 g, 8 mol%) 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 five 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 h the pressure tube was cooled to room temperature and the contents filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel eluting with EtOAc / 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 by weight (8.74 g, 40.4 mmol) in methanol (5 mL) for two hours at 80 ° C. The crude product was isolated by ether extraction, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.46 g, 94%) pure enough to use as it was isolated.
Example 228c
2- (2,2-Dimethoxy-ethyl) -nicotinamide
The product of Example 228b (1.46 g, 7.6 mmol) was dissolved in methanol (20 mL) to which sodium carbonate in the form of a 3N solution (35 mL) was added at room temperature followed by hydrogen in the form of a 15% solution (35 mL). The reaction was allowed to stir for 4.5 hours after it was partitioned by the addition of ethyl acetate and solid sodium chloride. The aqueous phase was extracted several times with ethyl acetate and the combined organic extracts were stirred with solid sodium bisulfite followed by drying over MgSO4, filtered and concentrated in vacuo to give the title compound (1.36 g, 85% ) pure enough to use as isolated.
Example 228d
[1,6] Naftiridin-5-ol
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 at reflux for 23 h, then concentrated in vacuo to give the title compound in a quantitative yield sufficiently pure for use as isolated.
Example 228e
5-Chloro- [1,6] naphthyridine
The product of Example 228d (0.250 g, 1.71 mmol) was combined with phosphorus oxychloride (4mL) and heated under a nitrogen atmosphere at 80 ° C for 18.5 h followed by vacuum distillation to remove volatile substances. The residue was suspended with ice and made alkaline (pH 7-8) with concentrated ammonium hydroxide. The title compound was collected by vacuum filtration, washed with water and dried in vacuo to give a gray solid (0.245 g, 87%) sufficiently pure for use as isolated.
Example 228f
(5-Chloro-2-phenoxy-phenyl) - [1,6] naphthyridin-5-yl-amine
The product of Example 228e (0.040 g, 0.24 mmol) was reacted with the product of Example 42b (0.048 g, 0.24 mmol) for 48 h at 100 ° C following the procedure of Example 1g yielding the crude title compound which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (0.046 g, 40%). 1 H NMR (300 MHz, DMSOd6) δ ppm: 6.96 (d, J = 7.35 Hz, 2 H) 7.00 -7.10 (m, 2 H) 7.22 -7.39 (m, 4 H) 7.66 (dd, J = 8.46, 4.41 Hz, 1 H) 7.91 (d, J = 1.84 Hz, 1 H) 8.07 (d, J = 6.25 Hz, 1 H) 8.76 (d, J = 8.46 Hz, 1 H) 9.07 (d, J = 3.31 Hz, 1 H); MS (ESI +) m / z 348.0 (M + H) +; (ESI-) m / z 346.1 (MH) -.
Example 229
N- {4- [4-Methyl-2 - ([1,6] naphthyridin-5-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 228e (0.040 g, 0.24 mmol) was reacted with the product of Example 18b as a 1.5M solution in ethanol (0.162 mL, 0.24 mmol) for 17.5 h at 100 ° C following the procedure of Example 1g. Consumption of the starting substance required a second addition of the product of Example 228e (0.027 g, 0.16 mmol) and continuous heating at 100 ° C (24h) to produce the crude title compound that was purified by HPLC with TFA providing the product in the form of a salt of trifluoroacetic acid (0.038 g, 27%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.02 (s, 3 H) 2.36 (s, 3 H) 7.12-7.37 (m, 5 H) 7.38-7, 53 (m, 3 H) 7.73 -7.92 (m, J = 8.64, 4.60 Hz, 2 H) 8.94 (d, J = 8.46 Hz, 1 H) 9.18 (d, J = 4.04 Hz, 1 H) 9.99 (s, 1 H); MS (ESI +) m / z 401.3 (M + H) +; (ESI-) m / z 399.0 (MH) -.
Example 230
(5-Methyl-2-phenylsulfanyl-phenyl) - [1,8] naphthyridine-4-ylamine
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 22.5h following the procedure of Example 1g. Consumption of the starting substance required a second addition of the product of Example 16c (0.018 g, 0.113 mmol) and continuous heating at 80 ° C (22h) to yield the crude title compound that was purified by HPLC with ammonium acetate to provide the product in the form of the free base that was subsequently treated with trifluoroacetic acid to produce the corresponding trifluoroacetic acid salt (0.062 g, 43%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.38 (s, 3 H) 6.36 (d, J = 6.99 Hz, 1 H) 7.23 (s, 5 H) 730-7 , 42 (m, 3 H) 7.89 (dd, J = 8.46, 4.41Hz, 1 H) 8.46 (d, J = 6.99 Hz, 1 H) 9.03 -9.10 (m, 1 H) 9.15 (dd, J = 4.41, 1.47 Hz, IH) MS (ESI +) m / z 344.0 (M + H) +, (ESI-) m / z 342 , 0 (MH) -.
Example 231
N- {4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
Example 231a
N- [4- (5-Chloro-2-nitro-phenylsulfanyl) -phenyl] -acetamide
A mixture of 2,4-Dichloronitrobenzene (0.25 g, 1.3 mmol), 4-Acetamido thiophenol (0.26 g, 1.43 mmol) and cesium carbonate (0.466 g, 1.43 mmol) in DMF (3 mL) was heated 2.5 hr at 100 ° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and a 10% aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / methanol leaving the title compound as a yellow solid (0.25 g, 63%).
Example 231b
N- (4- (5-Chloro-2-nitrophenyl) phenyl) acetamide
A solution of the product of Example 231A (0.25 g, 0.77 mmol), iron powder (0.29 g, 5.2 mmol) and ammonium chloride (0.084 g, 1.6 mmol) in a solution of methanol (2 mL), tetrahydrofuran (2 mL), and water (0.7 mL) was heated at reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a bed of celite. The filtrate was concentrated in vacuo to a volume of 10 mL, the solution was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound (0.20 g, 87%).
Example 231c
N- {4- [5-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (48 mg, 0.27 mmol) was reacted in ethanol (2 ml) with the product of Example 231b (78 mg, 0.27 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt. (12 mg, 28%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 1H), 7.38 (d, J = 8.82 Hz, 2 H) 7.51 (s, 2H), 7.62 (d, J = 8, 82 Hz, 2 H), 7.81 (d, J = 8.82 Hz, 1 H), 8.47 (d, J = 7.35 Hz, 1H) 8.97 (d, J = 8.82 Hz, 1 H), 10.15 (s, 1 H), 11.01 (s, 1 H), 14.48 (s, 1 H); MS (DCI / NH3) m / z 435 (M + H) +.
Example 232
N- {4- [4-Cyanomethoxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
Example 232a N- [4- (4-Hydroxy-2-nitro-phenylsulfanyl) -phenyl] -acetamide
A mixture of 3-nitro-4-chloro phenol (1.59 g, 8.97 mmol), 4-acetamidothiophenol (2 g, 10.76 mmol) and cesium carbonate (7.0 g, 21.53 mmol) in DMF (20 mL) it was heated 2.5 h at 100 ° C. The mixture was cooled, poured onto ice and the resulting solid was collected by filtration and the title compound was dried in vacuo leaving a yellow solid (2.7 g, 100%).
Example 232b
N- [4- (2-Amino-4-hydroxy-phenylsulfanyl) -phenyl] -acetamide
A solution of the product of Example 232A (2.7 g, 8.97 mmol), iron powder (2.0 g, 35.9 mmol) and ammonium chloride (0.58 g, 10.76 mmol) in one methanol solution (6 mL), THF (6 mL), and water (2 mL) was heated at reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a bed of celite. The filtrate was concentrated in vacuo to a volume of 10 mL, the solution was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound (2.46 g, 77%).
Example 232c
N- [4- (2-Amino-4-cyanomethoxy-phenylsulfanyl) -phenyl] acetamide
A mixture of the product of Example 232b (56 mg, 0.17 mmol), 2-Bromoacetonitrile (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (53 mg, 100%).
Example 232d
N- {4- [4-Cyanomethoxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product of Example 232c (53 mg, 0.17 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (9 mg, 19%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 7.23 (dd, J = 8.82, 2.57 Hz, 1 H), 7.31 ( d, J = 2.57 Hz, 1 H), 7.38 (d, J = 8.82 Hz, 1 H) 7.45 (d, J = 8.82 Hz, 2 H), 7.80 ( d, J = 8.46 Hz, 1 H), 8.41 (d, J = 6.99 Hz, 1 H) 8.96 (d, J = 8.46 Hz, 1 H), 10.01 ( s, 1H), 11.04 (s, 1 H), 14.42 (s, 1 H); MS (ESI +) m / z 456 (M + H) +.
Example 233
N- {4- [4-Benzyloxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
Example 233a
N- [4- (2-Amino-4-benzyloxy-phenylsulfanyl) -phenyl] -acetamide
A mixture of the product of Example 232b (56 mg, 0.17 mmol), benzyl bromide (21 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (62 mg, 100%).
Example 233b
N- {4- [4-Benzyloxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product of Example 233a (62 mg, 0.17 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (24 mg, 47%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.02 (s, 3 H) 2.75 (s, 3 H) 5.15 (s, 2 H) 6.29 (d, J = 7, 35 Hz, 1 H) 7.12 (d, J = 8.82 Hz, 2 H) 7.16 -7.27 (m, 2 H) 7.29 -7.52 (m, 8 H) 7, 78 (d, J = 8.82 Hz, 1 H) 8.36 (d, J = 6.99 Hz, 1 H) 8.94 (d, J = 8.82 Hz, 1 H) 9.97 ( s, 1 H) 11.00 (s, 1 H) 14.34 (s, 1 H); MS (ESI +) m / z 507 (M + H) +.
Example 234
N- {4- [4- (2-Methyl-allyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
Example 234a
N- {4- [2-Amino-4- (2-methyl-allyloxy) -phenylsulfanyl] -phenyl} acetamide
A mixture of the product of Example 232b (56 mg, 0.17 mmol), 2 methyl-3-bromopropene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL ) stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (55 mg, 100%).
Example 234b
N- {4- [4- (2-Methyl-allyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product of Example 234a (55 mg, 0.17 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (12 mg, 25%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.76 (s, 3 H) 2.02 (s, 3 H), 2.75 (s, 3 H), 4.52 (s, 2H) , 4.98 (s, 1 H), 5.05 (s, 1 H), 6.30 (d, J = 7.35 Hz, 1H), 7.04 -7.19 (m, 4 H) , 7.36 (s, 1 H), 7.41 (d, J = 8.46 Hz, 2 H) 7.78 (d, J = 8.82 Hz, 1 H), 8.37 (d, J = 6.99 Hz, 1 H), 8.94 (d, J = 8.46 Hz, 1H) 9.97 (s, 1 H), 10.99 (s, 1H), 14.33 (s , 1 HOUR); MS (BSI +) m / z 471 (M + H) +.
Example 235
N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-propoxyphenylsulfanyl] -phenyl} -acetamide
Example 235a
N- [4- (2-Amino-4-propoxy-phenylsulfanyl) -phenyl] -acetamide
A mixture of the product of Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromopropene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (55 mg, 100%).
Example 235b
N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-propoxyphenylsulfanyl] -phenyl} -acetamide
The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product of Example 235a (55 mg, 0.17 mmol) for 18 h following the procedure of Example 1g producing the compound of the crude title that was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (14 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ 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, 2 H) 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, 3 H) 7.77 (d, J = 8.46 Hz, 1 H) 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, 1 H); MS (ESI +) m / z 459 (M + H) +.
Example 236 (reference) 4- [4- (4-Acetylamino-phenylsufanyl) -3- (7-propyl- [1,8] naphthyridine-4 -lamino) -phenoxymethyl] -benzoic acid methyl ester
Example 236a
4- [4- (4-Acetylaminophenylsulfanyl) -3-amino-phenoxymethyl] -benzoic acid methyl ester
A mixture of the product of Example 232b (28 mg, 0.085 mmol), 4-carbomethoxybenzyl bromide (22 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at temperature ambient for 15 hr. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to provide the title compound (35 mg, 100%).
Example 236b
4- [4- (4-Acetylaminophenylsulfanyl) -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 h following the procedure of Example 1g yielding the crude title compound which purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (22 mg, 37%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.75 -1.93 (m, 2 H), 2.02 (s, 3 H), 2.99 (t, J = 7.54 Hz, 2 H), 3.86 (s, 3H) 5.26 (s, 2 H) 630 (d, J = 6.99 Hz, 1 H ) 7.14 (d, J = 8.82 Hz, 2 H), 7.17-7.27 (m, 2 H), 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, 2 H), 8.36 (d, J = 7.35 Hz, 1 H), 8.97 (d, J = 8.46 Hz, 1 H) 9.98 (s , 1 H), 11.01 (s, 1 H). 14.38 (s, 1 H); MS (ESI +) m / z 593 (M + H) +.
Example 237 (reference)
4- [4- (4-Methoxy-benzyloxy) -2- (7-methyl-pyrido [2,3d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol
Example 237A
2-Amino-6-methyl-nicotinitrile
The 2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 moles) and liquid ammonia (250 mL) in 500 mL of ethanol were reacted in a sealed high pressure vessel at 130 ° C for 20 hours. The reaction mixture was concentrated in vacuo and the residue was washed with water (2 x 50 mL) then dried in a vacuum oven for 24 hours to provide the title compound as a light yellow solid (18 g , 82%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.30 (s, 3H), 6.52 (d, J = 7.7 Hz, 1H), 6.78 (s, 2H), 7.73 (d, J = 7.7 Hz, 1H).
Example 237B
N '- (3-Cyano-6-methyl-pyridin-2-yl) -N, N-dimethyl-formamidine
A solution of the product of Example 237A (10 g, 75.19 mmol) and Dimethylacetal N, N-dimethylformamide (11 mL, 82.71 mmol) in toluene (100 mL) was heated at reflux for 6 hours. After cooling to room temperature, the solution was concentrated in vacuo to give the title compound as a yellow solid (13.78 g, 98%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 6.87 (d, J = 7, 7 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 8.59 (s, 1H).
Example 237C
1-Chloro-4- (4-methoxy-benzyloxy) -2-nitro-benzene
A solution of 4-chloro-3-nitro-phenol (0.5 g, 2.88 mmol), 1-chloromethyl-4-methoxybenzene (0.496 g, 3.17 mmol), potassium carbonate (1.19 g, 8.64 mmol) and tetrabutylammonium iodide (0.005 g, 0.0135 mmol) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. After that, ice water (10 mL) was added to the solution and the resulting solid was collected by filtration and dried in a vacuum oven to provide the title compound (0.812 g, 96%).
Example 237D
4- [4- (4-Methoxy-benzyloxy) -2-nitro-phenylsulfanyl] -phenol
A solution of the product of Example 237C (0.812 g, 2.76 mmol), 4-hydroxythiophenol (0.419, 3.32 mmol) and cesium carbonate (2.16 g, 6.64 mmol) in N, N-dimethylformamide (5 mL ) was heated at 100 ° C for 16 hours. After cooling to room temperature the mixture was poured onto 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 in vacuo to provide the title compound (1.06 g, 100%).
Example 237E
4- [2-Amino-4- (4-methoxy-benzyloxy) -phenylsulfanyl] -phenol
A solution of the product of Example 237D (1.06 g, 2.76 mmol), iron powder (0.63 g, 11.04 mmol) and ammonium chloride (0.18 g, 3.31 mmol) in one methanol solution (18 mL), tetrahydrofuran (18 mL), and water (6 mL) was heated at reflux for 3 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a bed of celite. The filtrate was concentrated in vacuo to a volume of 10 mL, the solution was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound (0.99 g, 100%).
Example 237F
4- [4- (4-Methoxybenzyloxy) -2- (7-methyl-pyrido [2,3d] 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 130 ° preheated oil bath C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the resulting residue was triturated with methanol to give the title compound as a tan solid (26.5 mg, 35%). 1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.92 (s, 1 H), 9.63 (s, 1H), 8.70 (d, J = 8.09 Hz, 1H), 8, 55 (s, 1H), 7.52 (d, J = 8.46 Hz, 1H), 7.38 (d, J = 8.82 Hz, 2 H), 7.27 (s, 1H), 7 , 06-7.18 (m, 3 H), 6.94 (d, J = 8.46 Hz, 3 H), 6.61 -6.72 (m, 2 H), 5.02 (s, 2 H), 3.75 (s, 3H),
5.66 (s, 3 H); MS (ESI +) m / z 497.2 (M + H) +, (ESI-) m / z 495.3 (MH) -.

Biological Evaluation

The representative compounds of the invention were analyzed according to the analyzes described below.

The following 15 acronyms are used herein:

IC50

50% inhibitory concentration

TC50

50% toxic concentration

DMEM

Dulbecco® Modified Essential Medium

RNA

ribonucleic acid

RT-PCR

polymerase chain reaction with reverse transcriptase

SEAP

secreted alkaline phosphatase

The hepatitis C virus genome encodes a large polyprotein, which after maturation 20 produces the functional components necessary to synthesize the progeny RNA. Selectable cell lines that produce high and sustained levels of subgenomic HCV RNA (replicons) have been derived from human hepatoma cells (Huh7) as described by Ikeda et al., J. VIROLOGY, 76 (6): 2997-3006 ( 2002), and Blight et al., SCIENCE, 290: 1972-1974 (2000). Be

considers that the mechanism of RNA replication in these cell lines is identical to the replication of complete HCV RNA in infected hepatocytes. The compounds of this invention are inhibitors of HCV RNA replication in the replicon analysis systems described below.

Evaluation of HCV Inhibitors in HCV Replicons

Representative compounds of the invention were evaluated for their inhibitory effect on HCV genotype 1a and 1b replicons. They were also evaluated by MTT analysis for their cytotoxicity to host cells. Cell lines were maintained according to the methods described by Yi et al., VIROLOGY, 304 (2): 197-210 (2002).

A. RNA Analysis and SEAP Analysis

The purpose of these analyzes was to evaluate the efficacy of the compounds in inhibiting the replication of HCV genotype 1a and 1b replicons in vitro.

Cells with genotype 1a and / or 1b replicons were seeded at 3-5x103 cells per well in a 96-well plate in DMEM medium with 5% fetal bovine serum. The next day, the culture medium was removed and replaced by 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. The plates were incubated in a CO2 incubator at 37 ° C. On day 4, 100 µl of lysis buffer (RTL) (Qiagen) was added to each well after removal of the culture medium. The RNA was purified according to the manufacturer's recommendations (Qiagen RNAeasy) and eluted in 200 µl of water. The HCV RNA level was quantified from a portion (5 µl of 200 microliters) of the purified RNA by the real-time RT-PCR method. The primers and probe were derived from the specific sequence in the 5'Untranslated Region (5'UTR). The RT-PCR reaction was performed at 48 ° C for 30 min, 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 a compound according to the manufacturer's instructions. The percentage reduction of HCV or SEAP RNA in the presence of the compound was calculated and the 50% inhibitory concentration (IC50) was calculated by nonlinear 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 HCV replicon replication with IC50 values in the range of about 30 nM to about 100 µM.

B. Cytotoxicity analysis

The purpose of this analysis 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 analysis based on mitochondrial enzymes in cells with replicons. Briefly, cells with HCV replicons were plated at 3-5 x 103 cells per well in a 96-well plate in DMEM medium containing 5% FCS. On day 1, the culture medium was removed and replaced by means of a new contribution containing eight serial dilutions of compound. The untreated control culture was treated in an identical manner except that no inhibitor was added to the medium. The plates were incubated in a CO2 incubator at 37 ° C. On day 4, the starting solution of the tetrazolium salt, MTT (4 mg / ml in PBS, Sigma Cat. No. M2828) was added to each well at 25 µl per well. The plates were further incubated for 4 hours, treated with 20% SDS plus 0.02 N HCl at 50 µl per well to lyse the cells. After one night of incubation, the optical density was measured by reading the plates at wavelengths of 570/650 nm. The percentage of formazan blue color reduction formed relative to the control was calculated and the 50% toxicity concentration (CT50) was calculated by nonlinear regression analysis using the Prism program (version 4.0, GraphPad software, San Diego, CA ).

When the above method was tested, 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 characterizes pharmaceutical compositions comprising the compounds of the invention. By way of 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 II (a) or II (b). Preferably, each compound is independently selected from the Examples.

The present invention also characterizes pharmaceutical compositions comprising pharmaceutically acceptable salts or solvates of the compounds of this invention. Pharmaceutically acceptable salts may be zwitterions or acid derivatives.

or pharmaceutically acceptable inorganic or organic bases. Preferably, a pharmaceutically acceptable salt of a compound of the invention maintains the biological efficacy of the free acids or bases of the compound without undue toxicity, irritation or allergic reaction, has a reasonable benefit / risk ratio, and is effective for its intended use and It is not undesirable biologically or otherwise. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camforate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, phenoate, 3-phenoate, pamoate, phenoate, pamoate, phenoate, pamoate, phenoate, pamoate, phenoate, pamoate, phenoate, pamoate, phenoate, pamoate, phenoate, pamoate, phenoate, 3-phenoate, pamoate, phenoate, pamoate, phenoate, 3-phenoate, pamoate, phenoate, 3-phenoate , picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Alkaline nitrogen-containing groups can also be quaternized with agents such as lower alkyl halides (eg, chlorides, bromides or iodides of

methyl, ethyl, propyl or butyl), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl sulfates

or diamyl), long chain halides (for example, chlorides, bromides or iodides of decyl, lauryl, myristyl or stearyl), aralkyl halides (for example, benzyl or phenethyl bromides). Other salts that can be used in the present invention include salts with alkali 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, malic acid, succinic acid, citric acid, or other inorganic acids. or suitable organic.

The present invention further characterizes pharmaceutical compositions comprising a compound of the invention (or one of its salts or solvates) 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 or solvates), and 1, 2, 3 or more therapeutic agents. By way of illustration, not limitation, these other therapeutic agents can be selected from antiviral agents (for example, anti-HIV agents or other anti-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 (eg IFN alpha 2a or 2b), protease inhibitors; immunosuppressants; antibodies (for example, therapeutic or chimeric monoclonal antibodies); Antisense RNA 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); BILN2061 serine protease inhibitor (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel antiviral (Endo Pharmaceuticals Holdings Inc., Chadds Ford, Pennsylvania), IFN-alpha 2a Roferon-A (F. Hoffmann-La Roche Ltd, Basel, Switzerland); IFN-alpha 2a PEGylated Pegasys (F. Hoffmann-La Roche LTD, Basel, Switzerland); IFN-alpha 2a PEGylated / ribavirin Pegasys and ribavirin (F. Hoffmann-La Roche Ltd, Basel, Switzerland); Immunosuppressive IgG for HCV CellCept (F. Hoffmann-La Roche Ltd, Basel, Switzerland); IFN-alpha n1 lymphoblastoid Wellferon (Glaxo SmithKline plc, Uxbridge, United Kingdom); IFN alpha-2b-alpha albumin Albuferon (Human Genome Sciences Inc., Rockville, MD); ribavirin Levovirin (ICN Pharmaceuticals, from Costa Mesa, CA); caspase inhibitor IDN-6556 (Idun Pharmaceuticals Inc., San Diego, CA); IP-501 antifibrotic (Indevus Pharmaceuticals Inc., of Lexington, MA); INF-gamma Actimmune (InterMune Inc., Brisbane, CA); IFN alfacon-1 Infergen A (InterMune Pharmaceuticals Inc., Brisbane, CA); antisense ISIS 14803 (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmaceuticals Inc., New York, NY); RdRp inhibitor JTK-003 (Japan Tobacco Inc., Tokyo, Japan); PEGylated IFN-alpha 2a / immune modulator Pegasys and Ceplene (Maxim Pharmaceuticals Inc., San Diego, CA); Ceplene immune modulator (Maxim Pharmaceutical Inc., San Diego, CA); Immunosuppressive IgG of HCV Civacir (Nabi Biopharmaceuticals Inc., Boca Raton, FL); IFN-alpha 2b / Thymosin alpha 1 Intron A and Zadaxin (RegeneRx Biopharmiceuticals Inc., of Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); IMPDH Levovirin inhibitor (Ribapharm Inc., Costa Mesa, CA); viramidine IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA);

Ribozyme Heptazyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); IFN-alpha 2b Intron A (Schering-Plow Corporation, Kenilworth, NJ); IFN-alpha 2b PEGylated PEG-Intron (Schering-Plow Corporation, Kenilworth, NJ); 5 IFN-alpha 2b / ribavirin Rebetron (Schering-Plow Corporation, Kenilworth, NJ); Ribavirin (Schering-Plow Corporation, Kenilworth, NJ); PEGylated IFN-alpha 2b / ribavirin PEG-Intron / Ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Zadazim immune modulator 10 (SciClone Pharmaceuticals Inc., San Mateo, CA); IFN-beta 1a Rebif (Serono, Geneva, Switzerland); IFN-beta and EMZ701 IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); betatubulin T67 inhibitor (Tularik Inc., South San Francisco, CA); IMPDH inhibitor VX-497 (Vertex Pharmaceuticals Inc., Cambridge, MA); serine protease inhibitor VX950 / LY-570310 (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); IFN-alpha natural Omniferón (Viragen Inc., Plantation, FL);

20 monoclonal antibody XTL-002 (XTL Biopharmaceuticals);

image 1

(hereinafter, compound VX-950, Vertex Pharmaceuticals Inc.);

image 1

(hereinafter referred to as SCH503034, Schering-Plow Co.), and

image 1

(hereinafter Compound GS9137, Gilead Sciences, Inc., Foster City, CA). Any other or other desirable therapeutic agents 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 their salts or solvates), 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 their salts or solvates), and one or more other anti-HCV agents. In one example, each of the compounds of the present invention is independently selected from Formulas II (a) and II (b), or the Examples and each of the other anti-HCV agents is independently selected from RNA inhibitors. HCV RNA-dependent polymerase (for example, nucleoside or non-nucleoside type 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 their salts or solvates), and two or more other anti-HCV inhibitors. Preferably, each of the compounds of the present invention is independently selected from Formulas II (a) or II (b), or from the Examples. The other anti-HCV inhibitors may be selected from the same class of inhibitors (for example, all of them are selected from inhibitors of HCV RNA-dependent RNA polymerase, or among HCV protease inhibitors), or select between different classes of inhibitors (for example, one

or more are selected from the HCV RNA-dependent RNA polymerase inhibitor and the other or others are selected from the HCV protease inhibitors).

In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the prevention invention (or one of its salts or solvates), and at least one HCV RNA-dependent RNA polymerase inhibitor. Preferably, each compound of the present invention is independently selected from Formulas II (a) and II (b), or the examples.

In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or thereof), and at least one HCV protease inhibitor. Preferably, the compound of the present invention is selected from Formulas II (a) or II (b), or the Examples.

In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or one of its salts or solvates), at least one HCV RNA-dependent RNA polymerase inhibitor, and at least one inhibitor. of HCV protease. Preferably, the compound of the present invention is selected from Formulas II (a) and II (b), or the Examples.

In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or one of its salts or solvates), and two or more anti-HCV agents each independently selected from polymerase inhibitors. of HCV RNA-dependent RNAs or HCV protease inhibitors. Preferably, the compound of the present invention is selected from Formulas II (a) and II (b), or the examples.

In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or one of its salts or solvates), and three or more other anti-HCV agents each of which is independently selected from HCV RNA-dependent RNA polymerase inhibitors or HCV protease inhibitors. Preferably, the compound of the present invention is selected from Formulas II (a) and II (b), or the Examples.

Non-limiting examples of HCV RNA-dependent RNA polymerase inhibitors include those described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, BPI162196A1 and WO0204425. Non-limiting examples of HCV protease inhibitors are 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 one of its salts or solvates), and one or more other antiviral agents, such as anti-HBV or anti-HIN agents. Non-limiting examples of anti-HBV agents include adefovir, lamivudine and tenofovir. Non-limiting examples of HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abavirav, efavirav, efavirav , delavirdine, TMC-125, L-870812, S-1360, enfuvirtide. T1249, 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 will be 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 II (a) and II (b), or from the Examples, or one of its salts or solvates, and at least an anti-HBV agent. In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas II (a) and II (b), or from the Examples, or one of its salts

or solvates, and at least one anti-HIV agent. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas II (a) and II (b), or from the Examples, or one of its salts or solvates, and by at least one anti-hepatitis A, anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agent.

In another additional embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from the Formulas: II (a) and II (b), or from the Examples, or one of its salts or solvates, and at least one agent suitable for the treatment of inflammation of the liver.

A pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable 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 carboxymethyl cellulose , ethyl cellulose or cellulose acetate), oils (for example, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (for example, propylene glycol ), buffering agents (for example, magnesium hydroxide or aluminum hydroxide), agar, alginic acid, tragacanth powder, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, or a phosphate buffer solution. Lubricants, coloring agents, releasing agents, coating agents, sweeteners, flavoring or perfuming agents, preservatives, or antioxidants may also be included in a pharmaceutical composition of the present invention, as is appreciated by those of ordinary skill in the art.

A pharmaceutical composition of the present invention can be administered to a patient in need thereof through a variety of routes, for example orally, parenterally, sublingually, rectally, topically or as an inhalation spray. Topical administration may involve the use of transdermal administration for example in the form of transdermal patches or iontophoresis devices. Parenteral administration includes, but is 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 may be prepared in the form of a sterile aqueous or oleaginous injectable suspension using suitable dispersants or wetting agents 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 that are solid at ordinary temperature but liquid at rectal temperature and therefore will melt in the rectum and release the drugs. . Solid dosage forms for oral administration may be capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compounds may be mixed with at least one inert diluent such as sucrose, lactose or starch. 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 may also comprise buffering agents. Tablets and pills can be additionally 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. Liquid dosage forms may also comprise wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes, as described in United States Patent No.

6,703,403. The formulation of the drugs that are applicable to the present invention is generally discussed, for example, in Hoover, John E., REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, PA: 1975), and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker, New York, NY, 1980).

The methods described herein are methods for using the compounds of the present invention (or their salts or solvates) to inhibit HCV replication. In one embodiment, the methods comprise contracting the HCV virus with an effective amount of a compound of the present invention (or one of its salts or solvates), thereby inhibiting HCV virus replication. In another embodiment, the methods comprise contacting cells infected with the HCV virus with an effective amount of a compound of the present invention (or one of its salts or solvates), thereby inhibiting the replication of the HCV virus in the cells. In 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 their salts or solvates), thereby inhibiting the replication of the HCV virus. As used herein, "inhibit" means to significantly reduce, or suppress, the activity that is being inhibited (eg, viral replication). In many cases, representative compounds of the present invention can reduce the replication of the HCV virus (eg, analysis with HCV replicons 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 the HCV subtypes that may be the subject of the present invention include, but are not limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including HCV genotypes 1a, 1b, 2a, 2b, 2c or 3a. In one embodiment, a compound or compounds of the present invention (or their salts or solvates) are used to inhibit the replication of genotype 1a HCV. In another embodiment, a compound or compounds of the present invention (or their salts or solvates) are used to inhibit the replication of HCV of genotype 1b. In yet another embodiment, a compound or compounds of the present invention (or their salts or solvates) are used to inhibit HCV replication of both genotype 1a and 1b.

Methods of using the compounds of the present invention (or their salts) are described herein.

or solvates) to treat HCV infection. These methods typically comprise the administration of a therapeutically effective amount of a compound of the present invention (or one of its salts or solvates) to a patient with HCV, thereby reducing the viral level of HCV in the patient's blood or liver. As used herein, the term "treat" refers to reversing, relieving, inhibiting progress, or preventing the disorder or condition, or one or more symptoms.

of disorder or condition to which said term applies. The term "treatment" refers to the act of treating. In one embodiment, the methods comprise the administration of an effective therapeutic amount of two or more compounds of the present invention (or their salts or solvates) to a patient with HCV, thereby reducing the viral level of HCV in the blood or liver of the patient. Preferably, the compound or compounds employed in these methods have Formulas I (a), I (b) and II (a) and II (b), or are selected from the examples, or is

or they are one of their salts or solvates.

Methods of using a pharmaceutical composition of the present invention to treat HCV infection are described herein. Any pharmaceutical composition described herein can be used for this purpose. These methods typically comprise the administration of 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 another or other therapeutic agents, it can also treat other diseases, disorders or conditions in the patient.

In one embodiment, the pharmaceutical composition being administered comprises at least one compound of the present invention selected from Formulas II (a) and II (b), or from the Examples, or one of its salts or solvates, and at minus another anti-HCV agent selected from the HCV RNA-dependent RNA polymerase inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In another embodiment, the pharmaceutical composition being administered comprises at least one compound of the present invention selected from Formulas II (a) and II (b), or from the Examples, or one of its salts

or solvates, and at least two other anti-HCV agents each of which were independently selected from HCV RNA-dependent RNA polymerase inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In yet another embodiment, the pharmaceutical composition being administered comprises at least one compound of the present invention selected from Formulas II (a) and II (b), or from the Examples, or one of its salts

or solvates, and 1, 2 or more HCV RNA-dependent RNA polymerase inhibitors (for example, those described in WO0190121 (A2), US6348S87B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition being administered comprises at least one compound of the present invention selected from Formulas 1. II (a) or II (b), or from the Examples, or one of its salts or solvates , and 1, 2 or more HCV protease inhibitors (for example, BILN2061, VX-950, and SCH503034).

In a further embodiment, the pharmaceutical composition being administered comprises at least one compound of the present invention selected from Formulas II (a) and II (b), or from the Examples, or one of its salts or solvates, and at least one antiviral agent selected from anti-HIV agents, anti-HBV agents, anti-hepatitis A agents, anti-hepatitis D agents, anti-hepatitis E agents, or anti-hepatitis G agents.

Methods of using one or more compounds of the present invention and another or other therapeutic agents for treating HCV infection are described herein. The methods comprise the administration of an effective therapeutic amount of one

or various compounds of the present invention and other or other therapeutic agents to a patient with HCV, thereby reducing the viral level of HCV in the patient's blood or liver. Each compound of the present invention (or one of its salts, solvates or prodrugs) and the other or other therapeutic agents 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 or compounds of the present invention being administered include one or more compounds selected from Formulas II (a) and II (b), or from the Examples, or their salts or solvates, and the other or other therapeutic agents that are being administered include one

or more agents selected from HCV RNA-dependent RNA polymerase inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In another embodiment, the compound or compounds of the present invention being administered include one or more compounds selected from Formulas II (a) and II (b), or from the Examples, or their salts or solvates, and the Another or the other therapeutic agents being administered include two or more agents selected from HCV RNA-dependent RNA polymerase inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In other

embodiment, the compound or compounds of the present invention being administered include one or more compounds selected from Formulas II (a) and II (b), or from the Examples, or their salts or solvates, and the other or The other therapeutic agents being administered include one, two or more HCV RNA-dependent RNA polymerase inhibitors (for example, those described in WO0190121 (A2), US634S587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In another additional embodiment, the compound or compounds of the present invention being administered include one or more compounds selected from Formulas II (a) and II (b), or from the Examples, or their salts or solvates, and The other or other therapeutic agents being administered include one, two or more HCV protease inhibitors (eg, 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 D agents, anti-hepatitis agents. E, anti-hepatitis G agents, or other antiviral drugs.

A compound of the present invention (or one of its salts or solvates) can be administered to a patient in a single dose or in divided doses. A typical daily dose may vary, without limitation, from 0.1 to 200 mg / kg of body weight, for example from 0.25 to 100 mg / kg of body weight. Single dose compositions may contain these amounts or submultiples thereof until the daily dose is completed. Preferably, each dose contains a sufficient amount of a compound of the present invention that is effective in reducing the HCV viral load in the patient's blood or liver. 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 will be understood that the specific dosage 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, excretion rate, the combination of drugs and the severity of the specific disease undergoing therapy.

In yet another aspect, the compounds of Formulas II (a) and II (b) or their pharmaceutically acceptable salts, stereoisomers or tautomers, can be administered as the sole active pharmaceutical agent, or used in combination with one or more other agents, to treat infections or symptoms associated with other viruses that contain RNA.

Treatment or prevention of infection caused by viruses containing RNA can be provided by a combination therapy comprising a therapeutically effective amount of a first anti-viral agent provided by one or more compounds, or their salts, of Formulas II (a ) and II (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; an immune modulator of the host; an interferon derivative, such as interferon-alpha, PEGylated interferon-alpha, interferon-beta and interferongamma; a cytokine; a vaccine; a nucleoside analog; key enzyme inhibitors that lead to HCV dysfunction, examples of such enzymes being HCV metalloprotease, HCV serine protease, inosine monophosphate dehydrogenase (IMPDH), and HCV helicase, viral particle protein inhibitors such as protein HC4 HS4B, and HCV NS5a protein; and agents that inhibit HCV function, for example the entry of the HCV, the assembly of the HCV, and the output of the HCV. Also included are vaccines that

understand

antigens of the HCV or combinations from

adjuvant antigen

against he HCV Be include

further

the agents that interact with the

Host cellular components to block the synthesis of viral proteins by inhibiting the translation stage initiated at the internal ribosome entry site (IRES) of HCV viral replication or to block the maturation of viral particles and release them with agents directed towards the membrane proteins of the viroporin family such as, for example, HCV P7.

A method for treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of Formulas II (a) and II (b) is described herein. , or one of its pharmaceutically acceptable salts.

A method is described herein to treat or prevent infection caused by an RNA-containing virus that comprises co-administration to a patient in need of such treatment of one or more agents selected from the group consisting of an immune modulator of the host and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound of Formulas II (a) or II (b), or a pharmaceutically acceptable salt thereof.

A method for treating or preventing infection caused by an RNA-containing virus comprising co-administration to a patient in need of such treatment of one or more agents selected from the group consisting of interferon-alpha, interferon- is described herein. PEGylated alpha, interferonbeta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound of Formulas II (a) or II (b), or a pharmaceutically acceptable salt thereof.

It is described herein as a method to treat or prevent infection caused by an RNA-containing virus that comprises co-administration to a patient in need of such treatment of one or more agents selected from the group formed by a host immune modulator and a second antiviral agent that inhibits HCV replication by inhibiting host cellular functions associated with viral replication, or one of its combinations, with a therapeutically effective amount of a compound of Formulas II (a) and II (b), or a of its pharmaceutically acceptable salts.

A method for treating or preventing infection caused by an RNA-containing virus comprising co-administration to a patient in need of such agent treatment is described herein.

or combination of agents that treat or relieve the symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound of Formulas II (a) and II (b), or a pharmaceutically salts thereof acceptable.

It is described herein as a method to treat or prevent infection caused by an RNA-containing virus that comprises co-administration to a patient in need of such treatment of one or more agents that treat patients of hepatitis B disease. (HBV), with a therapeutically effective amount of a compound of formulas II (a) and II (b), or a pharmaceutically acceptable salt thereof.

It is described herein is a method to treat or prevent infection caused by an RNA-containing virus that comprises co-administration to a patient in need of such treatment of one or more agents to treat patients of the disease caused by the virus. human immunodeficiency (HIV), with a therapeutically effective amount of a compound of Formulas II (a) and II (b), or a pharmaceutically acceptable salt thereof.

The phrase "combination therapy" (or "co-therapy"), is intended to cover the administration of each agent sequentially in a regimen that will provide beneficial effects of the drug combination, and also aims to encompass the joint administration of these agents essentially simultaneously, for example by oral ingestion or a single capsule having a fixed ratio of these active agents or the ingestion of multiple capsules, separated for each agent. "Combined therapy" will also include simultaneous or sequential administration by oral, intravenous, intramuscular or other parenteral route to the body, including direct absorption through the tissues of the mucous membranes, as found in the breast ducts . Sequential administration also includes combinations of drugs where individual agents can be administered at different times and / or by different routes, but which act in combination to obtain a beneficial effect, for example, by the joint action of the pharmacokinetic or pharmacodynamic effects of Each agent

The present invention also characterizes the use of the compounds of the invention, or pharmaceutically acceptable salts, or solvates thereof, for the manufacture of medicaments for the treatment of HCV or other viral infections. In one embodiment, the present invention characterizes the use of a compound of the present invention selected from Formulas II (a) and II (b), or one of its salts or solvates, for the manufacture of a medicament for the treatment of the HCV infection In another embodiment, the present invention includes the use of two or more compounds of the present invention (or salts, or solvates thereof) for the manufacture of a medicament for the treatment of HCV infection, in which each of the two compounds is independently selected from Formulas II (a) and II (b).

In yet another embodiment, the present invention includes the use of at least one compound of the present invention (or a salt, or solvate thereof) and at least one additional therapeutic agent for the manufacture of a medicament for the treatment of infection. by HCV. Preferably, the compound or compounds of the present invention are selected from Formulas IX (a) or II (b), and the additional therapeutic agent or agents may be selected, by way of illustration, not limitation, from among antiviral agents (for example, anti-HIV agents or other anti-HCV agents), immunomodulators, anticancer or chemotherapeutic agents, and anti-inflammatory agents. Specific examples of additional therapeutic agents include, but are not limited to, ribavirin; interferons (eg IFN alpha 2a or 2b), protease inhibitors; immunosuppressants; antibodies (for example, therapeutic or chimeric monoclonal antibodies); Antisense RNA

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); BILN2061 serine protease inhibitor (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel antiviral (Endo Pharmaceuticals Holdings Inc., Chadds Ford, Pennsylvania), IFN-alpha 2a Roferon-A (F. Hoffmann-La Roche Ltd, Basel, Switzerland); IFN-alpha 2a PEGylated Pegasys (F. Hoffmann-La Roche LTD, Basel, Switzerland); IFN-alpha 2a PEGylated / ribavirin Pegasys and Ribavirin (F. Hoffmann-La Roche Ltd, Basel, Switzerland); Immunosuppressive IgG for HCV CellCept (F. Hoffmann-La Roche Ltd, Basel, Switzerland); IFN-alpha n1 lymphoblastoid Wellferon (Glaxo SmithKline plc, Uxbridge, United Kingdom); IFN alpha-2b-alpha albumin Albuferon (Human Genome Sciences Inc., Rockville, MD); ribavirin Levovirin (ICN Pharmaceuticals, from Costa Mesa, CA); caspase inhibitor IDN-6556 (Idun Pharmaceuticals Inc., San Diego, CA); IP-501 antifibrotic (Indevus Pharmaceuticals Inc., of Lexington, MA); INF-gamma Actimmune (InterMune Inc., Brisbane, CA); IFN alfacon-1 Infergen A (InterMune Pharmaceuticals Inc., Brisbane, CA); antisense ISIS 14803 (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmaceuticals Inc., New York, NY); RdRp inhibitor JTK-003 (Japan Tobacco Inc., Tokyo, Japan); PEGylated IFN-alpha 2a / immune modulator Pegasys and Ceplene (Maxim Pharmaceuticals Inc., San Diego, CA); Ceplene immune modulator (Maxim Pharmaceutical Inc., San Diego, CA); Immunosuppressive IgG of HCV Civacir (Nabi Biopharmaceuticals Inc., Boca Raton, FL); IFN-alpha 2b / Thymosin alpha 1 Intron A and Zadaxin (RegeneRx Biopharmiceuticals Inc., of Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); IMPDH Levovirin inhibitor (Ribapharm Inc., Costa Mesa, CA); viramidine IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Ribozyme Heptazyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); IFN-alpha 2b Intron A (Schering-Plow Corporation, Kenilworth, NJ); IFN-alpha 2b PEGylated PEG-Intron (Schering-Plow Corporation, Kenilworth, NJ); IFN-alpha 2b / ribavirin Rebetron (Schering-Plow Corporation, Kenilworth, NJ); Ribavirin (Schering-Plow Corporation, Kenilworth, NJ); PEGylated IFN-alpha 2b / ribavirin PEG-Intron / Ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Zadazim immune modulator (SciClone Pharmaceuticals Inc., San Mateo, CA); IFN-beta 1a Rebif (Serono, Geneva, Switzerland); IFN-beta and EMZ701 IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); betatubulin T67 inhibitor (Tularik Inc., South San Francisco, CA); IMPDH inhibitor VX-497 (Vertex Pharmaceuticals Inc., Cambridge, MA); serine protease inhibitor VX950 / LY-570310 (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); IFN-alpha natural Omniferón (Viragen Inc., Plantation, FL); monoclonal antibody XTL-002 (XTL Biopharmaceuticals); compound VX-950 (Vertex Pharmaceuticals Inc); compound SCH503034 (Schering-Plow Co.); and compound GS9137 (Gilead Sciences, Inc., Foster City, CA).

In another embodiment, the present invention includes the use of at least one compound of the present invention (or one of its salts or solvates) and at least one additional anti-viral agent for the manufacture of a medicament for the treatment of viral infection. . Preferably, the compound or compounds of the present invention are selected from Formulas II (a) and II (b), and the additional anti-viral agent or agents may be selected without limitation, among the anti-HCV or anti -HIV. In one example, the present invention includes the use of at least one compound of the present invention selected from Formulas II (a) and II (b) (or one of its salts or solvates), and at least one anti-HCV agent additional for the manufacture of a medicament for the treatment of HCV infection. Non-limiting examples of anti-HCV agents include HCV RNA-dependent RNA polymerase inhibitors (eg, nucleoside or non-nucleoside type polymerase inhibitors) or HCV protease inhibitors. In another example, the present invention characterizes the use of at least one compound of the present invention selected from Formulas II (a) and II (b) (or one of its salts or solvates, and at least two or more anti- agents Additional HCV for the manufacture of a medicament for the treatment of HCV infection Each of the additional anti-HCV agents can be independently selected from HCV RNA-dependent RNA polymerase inhibitors or HCV protease inhibitors .

In yet another embodiment, the present invention characterizes the use of at least one compound of the present invention selected from Formulas II (a) and II (b) (or one of its salts or solvates), and at least one anti-agent -HIV for the manufacture of a medicine

10 for the treatment of HIV or HCV. In another new embodiment, the present invention includes the use of at least one compound of the present invention selected from Formulas II (a) and II (b) (or one of its salts or solvates), and at least one anti- agent hepatitis A, anti

15 hepatitis B, anti-hepatitis D, anti-hepatitis E or antihepatitis G for the manufacture of a drug for the treatment of viral hepatitis. In a further embodiment, the present invention includes the use of at least one compound of the present invention selected

20 between Formulas II (a) and II (b) (or one of its salts or solvates), and at least one agent for the treatment of inflammation of the liver, for the manufacture of a medicament for the treatment of hepatitis C .

25

Claims (9)

1. A compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula II (a) or II (b), image 1 where: R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylaminocarbonyl; R4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; R7 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl amino, cyanoalkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, morpholino, hydrazino, Alkylaminoalkoxy, alkoxyalkylamino, and aryl; R9 is selected from the group consisting of arylalkylamino, N- [alkylamino (arylsulfanyl) arylalkyl] -N - [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarylalkoxy, nitroarylalkoxy, Cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkyl, arylalkoxy, alkylalkyl, haloalkylaminocarbonyl, alkylaminoarylaminocarbonyl, and arylalkoxy; R11 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R12 is selected from the group consisting of arylsulfanyl, arylsulfinyl, aryloxy, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; where R12 is optionally substituted with one or more substituents independently selected from R16; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl, alk ylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl; R13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylalkyl alkoxy, and alkylcarbonylaminoarylalkoxy. 2. The compound, tautomer, or salt of the claim 1, wherein: R12 is selected from the group consisting of image 1 10 n is an integer selected from the group that it consists of zero and one; R14 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, hydroxyarylaminocarbonyl, alkoxyalkyl, alkoxylaminocarbonyl, and azidoalkyl; 25 R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroaril-carbonylamino, heteroarilcarbonilaminoalquilcarbonil-amino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl , arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquil-carbonylamino, heteroarilcarbonilaminoalquilarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl , alkylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl. 3. The compound, tautomer, or salt of claim 1, wherein R2 and R3 are independently selected from the group consisting of hydrogen, ethoxycarbonyl, 3-N-methoxy-N-methylaminocarbonyl, and methyl; R4 is selected from the group consisting of hydrogen, tbutoxycarbonyl, 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-ethoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino, N, N-dimethylaminoethoxy, methoxyethylamino, and cyano-1-ethoxy- carbonylmethyl; R9 is selected from the group consisting of phenyl, phenylmethylamino, methyl [1,8] naphthyridin-4-ylamino- (2-phenylsulfanylphene-5-ylmethyl) amino- (Nt-butoxy-carbonyl-Nmethyl), methoxyphenylmethoxy, bromophenylmethoxy, nitrophenylmethoxy, cyanophenylmethoxy , phenoxymethyl, bromophenoxymethyl, phenylmethoxy, methylphenylmethoxy, methylphenylmethoxy, fluoro-3-methylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, N, N-dimethylaminophenylaminocarbonyl, fluorophenylmethyl, fluorophenyl; R11 is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy, and methyl; R12 is described as before in relation to Formulas II (a) and II (b); R11 is selected from the group consisting of hydrogen, chloro, methyl, methylcarbonylaminophenylsulfanyl, aminophenylsulfanyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethylaminophenoxy, hydroxyphenoxy, and methylaminocarbonylphenoxy; R14 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-methyl-6-methyl-6-methyl-6-yl ) carbonylamino, (3-pyrazinyl) carbonylamino, furanilcarbonilaminometilcarbonilamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) fenilmetilcarbonilamino, N-alilaminocarbonilo, ethoxycarbonyl, 1hidroxietilo, aminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, hidroxifenilaminocarbonilo, propylaminocarbonyl, hydroxyethyl, 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-dimetilaminonaft-1-ilsulfoniloxi, ethylsulfonyloxy, isopropylsulfonyloxy, methylsulfonyloxy, benzylsulfonyloxy, ethoxycarbonylmethoxy, hydroxycarbonylmethoxy, t-butylcarbonylamino, cyclopropylcarbonylamino, benzyloxycarbonylpyrrolidinylcarbonylamino, phenoxy, methylcarbonylamino, iminoethyl, tienoetilo, (S) -1fenilpropilcarbonilamino, metilfenoximetilcarbonilamino, (R) -1-phenyl-1metoximetilcarbonilamino, (S) -1-phenyl-1metoximetilcarbonilamino, furanilcarbonilaminometilcarbonilamino, tienilpropilcarbonilamino, metilcarbonilpiperidinilcarbonilamino, amino, aminocarbonyl, methylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy, phenylmethylsulfonyloxy, methylcarbonylamino, methylaminocarbonyl, hydroxymethyl, aminoethyl, metoxietilaminocarbonilo, propylaminocarbonyl, N-methoxy-N-methylaminocarbonyl, N, N-diethylaminocarbonyl, N- (2-methoxyethyl) aminocarbonyl, N-ethyl-methylaminocarbonyl, N-hydroxy -1-iminoethyl, hydroxyethyl, aminomethyl, N, N-dimethylaminocarbonyl, 2,6-dimethylfuranyl, 1H [1,2,4] triazolyl, and pyridinyl. 4. A pharmaceutical composition comprising a compound, tautomer or salt according to one of claims 1-3. 5. The use of a compound of formula II (a) or II (b), or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, for the manufacture of a medicament to inhibit the replication of the HCV virus, where : image 1 R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylaminocarbonyl; R4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; 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 [alkylarylamino (arylsulfanyl) arylalkyl] -N [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarylalkoxy nitroarylalkoxy, cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkyl, cyanoalkoxy, arylalkoxy, alkylarylalkoxy, haloalkylarylaminocarbonyl, alkylaminoarylaminocarbonyl, arylalkoxy, alkylalkyloxy, and alkoxycarbonyl; R11 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R12 is selected from the group consisting of hydrogen, arylsulfanyl, arylsulfinyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; where R12 is optionally substituted with one or more substituents independently selected from R16; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl, alk ylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl; R13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylalkyl alkoxy, and alkylcarbonylaminoarylalkoxy. image2 10 or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, for the manufacture of a medicament for the treatment of an HCV infection, where: R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylaminocarbonyl; R4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; 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 [alkylarylamino (arylsulfanyl) arylalkyl] -N [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarylalkoxy nitroarylalkoxy, cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkyl, cyanoalkoxy, arylalkoxy, alkylarylalkoxy, haloalkylarylaminocarbonyl, alkylaminoarylaminocarbonyl, arylalkoxy, alkylalkyloxy, and alkoxycarbonyl; R11 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R12 is selected from the group consisting of hydrogen, arylsulfanyl, arylsulfinyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; where R12 is optionally substituted with one or more substituents independently selected from R16; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl, Alkylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl; R13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylamino 10 arylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylarylalkoxy, and alkylcarbonylaminoarylalkoxy The use according to claim 5 or 6, where: R12 is selected from the group consisting of image 1 n is an integer selected from the group that 20 consists of zero and one; R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, Heteroarylcarbonylamino, hydroxyheteroarylcarbonylamino, hydroxyalkylheteroarylcarbonylamino, heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino, aryloxyarylalkylcarbonylamino, alkylaminocarbonyl, 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, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino, alkylcarbonylhetero cyclocarbonylamino, amino, aminocarbonyl, alkylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl. 8. The use according to claim 5 or 6, wherein R2 and R3 are independently selected from the group consisting of hydrogen, ethoxycarbonyl, 3, -N-methoxy-N-methylaminocarbonyl, and methyl; R4 is selected from the group consisting of hydrogen, tbutoxycarbonyl, 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-ethoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino, N, N-dimethylaminoethoxy, methoxyethylamino, and cyano-1-ethoxy- carbonylmethyl; R9 is selected from the group consisting of hydrogen, methyl, methoxy, phenyl, trifluoromethyl, phenylmethylamino, hydroxy, t-butoxycarbonylaminomethyl, carbonylamino, methylcarbonyl, amino, bromine, chlorine, fluoro, methyl [1,8] naphthyridine-4- ilamino- (2-fenilsulfanilfen-5-ylmethyl) amino- (Nt-butoxycarbonyl-N-methyl), methoxyphenylmethoxy, bromofenilmetoxi, nitrofenilmetoxi, cianofenilmetoxi, trifluoromethyl, phenoxymethyl, bromofenoximetilo, cyanomethoxy, phenylmethoxy, methylallyloxy, propoxy, metilfenilmetoxi, metilfenilmetoxi, fluoro -3-methylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, tnfluoromethylphenylaminocarbonyl, N, N-dimethylaminophenylaminocarbonyl, fluorophenylmethoxy, and chlorophenylmethoxy; R11 is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy, and methyl; R12 is described as before in relation to Formulas II (a) and II (b); R13 is selected from the group consisting of hydrogen, chloro, methyl, methylcarbonylaminophenylsulfanyl, aminophenylsulfanyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethylaminophenoxy, hydroxyphenoxy, and methylaminocarbonylphenoxy; R14 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-methyl-6-methyl-6-methyl-6-yl ) carbonylamino, (3-pyrazinyl) carbonylamino, furanilcarbonilaminometilcarbonilamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) fenilmetilcarbonilamino, N-alilaminocarbonilo, ethoxycarbonyl, 1hidroxietilo, aminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, hidroxifenilaminocarbonilo, 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-dimetilaminonaft-1-ilsulfoniloxi, ethylsulfonyloxy, isopropylsulfonyloxy, methylsulfonyloxy, benzylsulfonyloxy, ethoxycarbonylmethoxy, hydroxycarbonylmethoxy, tbutilcarbonilamino, cyclopropylcarbonylamino, benciloxicarbonilpirrolidinilcarbonilamino, phenoxy, methylcarbonylamino, iminoethyl, tienoetilo, (S) -1fenilpropilcarbonilamino, metilfenoximetilcarbonilamino, (R) -1-phenyl-1metoximetilcarbonilamino, (S) -1-phenyl-1metoximetilcarbonilamino, furanilcarbonilaminometilcarbonilamino, tienilpropilcarbonilamino, metilcarbonilpiperidinilcarbonilamino, amino, aminocarbonyl, Nmethylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy, phenylmethylsulfonyloxy, methylcarbonylamino, Nmethylaminocarbonyl, hydroxymethyl, aminoethyl, methoxylaminocarbonyl, propylaminocarbonyl. N-methoxyN-methylaminocarbonyl, N, N-diethylaminocarbonyl, N- (2-methoxyethyl) aminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-hydroxy-1-iminoethyl, hydroxyethyl, aminomethyl, N, N-dimethylaminocarbonyl, 2,6-dimethylfuranyl, 1H [1,2,4] triazolyl, and pyridinyl. 9. A compound of Formula II (a) or II (b), image 1 or a tautomer of the compound, or a pharmaceutically salt Acceptable compound or tautomer, for use in the treatment of an HCV infection, where: R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylaminocarbonyl; R4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; 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 [alkylarylamino (arylsulfanyl) arylalkyl] -N [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarylalkoxy nitroarylalkoxy, cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkyl, cyanoalkoxy, arylalkoxy, alkylarylalkoxy, haloalkylarylaminocarbonyl, alkylaminoarylaminocarbonyl, arylalkoxy, alkylalkyloxy, and alkoxycarbonyl; R11 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R12 is selected from the group consisting of hydrogen, arylsulfanyl, arylsulfinyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; where R12 is optionally substituted with one or more substituents independently selected from R16; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl, alk ylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, alkyl substituted heteroaryl, and heteroaryl; R13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonyl 5 arylalkoxy, and alkylcarbonylaminoarylalkoxy. 10. The compound for use in the treatment of an HCV infection according to claim 9, wherein: 10 R12 is selected from the group consisting of image 1 n is an integer selected from the group consisting of zero and one; R14 is selected from the group consisting of Hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, heteroarylcarbonylamino, hydroxyheteroarylcarbonylamino, hydroxyalkylheteroarylcarbonylamino, Heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino, aryloxyarylalkylcarbonylamino, allylaminocarbonyl, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hydroxyarylaminocarbonyl, alkoxyalkyl, alkoxyarylamino Carbonyl, and azidoalkyl; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroaxylcarbonylamino, 30 heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino , alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonilamino, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, amino, aminocarbonyl, alkylaminocarbonyl, hydroxyalkyl, aminoalkyl, alcoxialquilaminocarbonilo, hydroxyiminoalkyl, heteroaryl substituted with alkyl, and heteroaryl. 11. The compound for use in the treatment of an HCV infection 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; R4 is selected from the group consisting of hydrogen, tbutoxycarbonyl, 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-ethoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino, N, N-dimethylaminoethoxy, methoxyethylamino, and cyano-1-ethoxy- carbonylmethyl; R9 is selected from the group consisting of hydrogen, methyl, methoxy, phenyl, trifluoromethyl, phenylmethylamino, hydroxy, t-butoxycarbonylaminomethyl, carbonylamino, methylcarbonyl, amino, bromine, chlorine, fluoro, methyl [1,8] naphthyridine-4- ilamino- (2-fenilsulfanilfen-5-ylmethyl) amino- (Nt-butoxycarbonyl-N-methyl), methoxyphenylmethoxy, bromofenilmetoxi, nitrofenilmetoxi, cianofenilmetoxi, trifluoromethyl, phenoxymethyl, bromofenoximetilo, cyanomethoxy, phenylmethoxy, methylallyloxy, propoxy, metilfenilmetoxi, metilfenilmetoxi, fluoro -3-methylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, N, N-dimethylaminophenylaminocarbonyl, fluorophenylmethoxy, and chlorophenylmethoxy; R11 is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy, and methyl; R12 is described as before in relation to Formulas II (a) and II (b); R13 is selected from the group consisting of hydrogen, chloro, methyl, methylcarbonylaminophenylsulfanyl, aminophenylsulfanyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethylaminophenoxy, hydroxyphenoxy, and methylaminocarbonylphenoxy; R14 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-methyl-6-methyl-6-methyl-6-yl ) carbonylamino, (3-pyrazinyl) carbonylamino, furanilcarbonilaminometilcarbonilamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) fenilmetilcarbonilamino, N-alilaminocarbonilo, ethoxycarbonyl, 1hidroxietilo, aminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, hidroxifenilaminocarbonilo, 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 5 naphth-1-ylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy, methylsulfonyloxy, benzylsulfonyloxy, ethoxycarbonylmethoxy, hydroxycarbonylmethoxy, t-butylcarbonylamino, cyclopropylcarbonylamino, benzyloxycarbonylpyrrolidinylcarbonylaminocarbonylaminocarbonylamino 10 amino, iminoethyl, thienoethyl, (S) -1-phenylpropylcarbonylamino, methylphenoxymethylcarbonylamino, (R) -1-phenyl-1-methoxymethylcarbonylamino, (S) -1-phenyl-1methoxymethylcarbonylamino, furanylcarbonylaminomethylcarbonylamino, thienylpropylcarbonylamino, methylpropylcarbonylamino 15 piperidinylcarbonylamino, amino, aminocarbonyl, Nmethylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy, phenylmethylsulfonyloxy, methylcarbonylamino, Nmethylaminocarbonyl, hydroxymethyl, aminoethyl, Methoxyethylaminocarbonyl, propylaminocarbonyl, N-methoxyN-methylaminocarbonyl, N, N-diethylaminocarbonyl, N- (2-methoxyethyl) aminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-hydroxy-1-iminoethyl, hydroxyethyl, aminomethyl, N, N-dimethyl 6-dimethylfuranyl, 1H [1,2,4] triazolyl, and pyridinyl.