RU2441010C2 - Antiviral compound - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I)

B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R¹⁸, A represents phenyl which is optionally substituted by one or more R¹⁸; each W₁ and W₂ are independently selected from N or C(R³³); Z represents -NH-; each R¹⁰ and R³³ containing of hydrogen; X is selected from a group consisting of -L_s-O-, -L_s-S-; R²² means hydrogen or phenyl optionally substituted by one or more R²⁶ ; Y is selected from a group consisting of -L_s-O-, -L_s-S-_; -L_s-C(O)- and -L_s-NH(SO)₂-; R⁵⁰ represents -L¹-A¹, where L¹ represents a bond, and A¹ is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C₃-C₆carbocyclyl, banzimidazolyl and C₁-C₆alkyl optionally substituted by phenyl where A¹ is optionally substituted by one or more R³⁰ ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

Description

This application claims the priority of provisional application US No. 60/752473, filed December 21, 2005, cited in the present description by reference in full.

FIELD OF THE INVENTION

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

State of the art

HCV, a human pathogen, is an RNA virus belonging to the genus Hepacivirus of the family Flaviviridae. A distinctive feature of HCV, like all other viruses of the Flaviviridae family, are enveloped virions, which consist of an RNA genome of positive polarity that encodes all known virus-specific proteins with a single, uninterrupted open reading frame. An open reading frame contains approximately 9,500 nucleotides encoding a single large polypeptide consisting of approximately 3,000 amino acids. The polypeptide contains a capsid protein, envelope proteins E1 and E2, membrane-bound protein p7 and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. Cellular protease cleaves the viral protein at the junction of NS2-NS3, which allows the viral protease (NS3 protease) to mediate subsequent cleavages. Protein NS3 also has nucleoside triphosphatase and RNA helicase activity. NS2 and NS4A may also be associated with proteolytic activity. NS5A is a phosphoprotein involved in replication. NS5B is an RNA-dependent RNA polymerase. US Patent No. 2004/0265792, published December 30, 2004, states that inhibition of the above non-structural proteins can inhibit HCV replication.

HCV infection is associated with progressive liver disease, including cirrhosis and hepatic cell carcinoma. The final stage of the disease with HCV infection of the liver is the most common indication for liver transplantation in adults. In chronic hepatitis C, therapy may be an injection of peginterferon alfa once a week in combination with daily intake of ribavarin. Peginterferon-alpha is interferon-alpha attached to polyethylene glycol, which reduces the rate of excretion of the drug from the body. This increases the likelihood of a drug regimen and clinical antiviral activity compared to daily injections of interferon alfa. But significant limitations on effectiveness and tolerability remain, since a large number of patients have side effects, and a decrease in the amount of virus in the body is often insufficient.

Attempts have been made to create drugs that specifically inhibit the functions of the hepatitis C virus. In US Pat. No. 6,331,380 to Boehringer Ingelheim, tripeptide compounds are indicated as inhibitors of HCV serine proteases for the treatment of HCV infection.

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

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

For various biomedical applications, fused bicyclic heterocyclic compounds have been proposed. Examples of such heterocyclic compounds include naphthyridine, pyridopyrimidine, pyrimidopyrimidine, pyrazolopyrimidine and thiazolo / thienopyrimidine compounds.

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

Condensed bicyclic compounds of the pyridopyrimidine type have been investigated for use in the treatment of various diseases. For example, in Pfizer WO 98/05661, published February 12, 1998, as antagonists of corticoliberin (hormone) CRF (CRH) for the treatment of Alzheimer's disease and obesity, substituted pyridopyrimidine compounds such as [8- (1-ethylpropyl) -2 methyl 5,6,7,8-tetrahydropyrido (2,3-d) pyrimidin-4-yl] - (2,4,6-trimethylphenyl) amine. Pfizer WO 98/23613, published June 4, 1998, for the treatment of hyperproliferative diseases such as cancer, provides fused bicyclic pyrimidine compounds, including pyridopyrimidinylaminophenyl compounds such as (3-ethynylphenyl) pyrido [3,4-d] pyrimidine- 4-ylamine. In US patent No. 6169091, Glaxo Wellcome, published January 2, 2001, as tyrosine kinase inhibitors for the treatment of fibrosis, inflammation, diseases of the nervous system and cancer proposed bicyclic heteroaromatic compounds such as 4- (4-benzyloxyaniline) pyrido [2,3- d] pyrimidine. Eli Lilly document WO 01/32632, published May 10, 2001, discloses 4-substituted pyrimidine compounds including hydrochloride as antagonists of mGluR1 for the treatment of neurological disorders mediated by glutamate dysfunction such as cramps, migraine, psychosis, anxiety disorder and pain 2-trifluoromethyl-4- [2- (2- (2-chlorophenyl) ethylamino] pyrido [2,3-d] pyrimidine. In Abbott Laboratories, WO 01/57040, published August 9, 2001, as adenosine kinase inhibitors for for treating pain and inflammation, compounds 6,7-disubstituted-4-aminopyr are proposed ido [2,3-d] pyrimidine, such as 4-amino-6- (4-methylphenyl) -7- (4-bromophenyl) pyrido [2,3-d] pyrimidine. In Neurogen, WO 2004/055004, published July 1, 2004, pyridopyrimidinylaminophenyl compounds such as 2-methyl-2- {4- [2-methyl-7- (3-methylpyridin-2-yl) pyrido [2,3-d] are proposed as capsaicin receptor modulators pyrimidin-4-ylamino] phenyl} propionic acid US Pat. No. 6,395,733 to Pfizer, published May 28, 2002, for the treatment of a hyperproliferative disease such as cancer, fused ring heterocyclic pyrimidine compounds are provided E, such as 3-hlorfenilpirido [2,3-d] pyrimidin-4-ylamine.

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

Thienopyrimidine-type fused bicyclic compounds have been investigated for use in the treatment of various diseases. For example, in Warner-Lambert WO 95/19774, published July 27, 1995, fused heterocyclic pyrimidine compounds, including 4- (3-bromaniline) thieno, are proposed as tyrosine kinase inhibitors for treating cancer, vascular restenosis and psoriasis [2,3- d] pyrimidine. US Patent No. 6169091, Glaxo Wellcome, published January 2, 2001, proposes bicyclic heteroaromatic compounds such as 5-methyl-4- (4-phenoxyaniline) thieno hydrochloride as tyrosine kinase inhibitors for the treatment of fibrosis, inflammation, nervous system diseases and cancer. [2,3-d] pyrimidine. Eli Lilly document WO 01/32632, published May 10, 2001, discloses 4-substituted pyrimidine compounds as antagonists of mGluR1 for the treatment of neurological disorders associated with glutamate dysfunction such as cramps, migraine, psychosis, anxiety disorder and pain. as 6-methyl-4- [2,6-dichlorobenzylthio) ethylamino] thieno [2,3-d] pyrimidine hydrochloride.

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

Bristol-Myers Squibb document WO 2004/014313, published February 19, 2004, offers various types of combination therapies for treating viral diseases, including the anti-HCV compounds of iminothiazolidinone that inhibit the NS5A protein in combination with other agents that can affect HCV function .

SUMMARY OF THE INVENTION

The present invention relates to compounds of formulas I, II, III, IV, V, VI, VII or VIII, tautomers of these compounds and pharmaceutically acceptable salts of these compounds or tautomers. These compounds, tautomers or salts can be used, alone or in combination with other drugs or agents, to inhibit the replication of HCV or other viruses. These compounds, tautomers or salts can also be used, alone or in combination with other drugs or agents, to impair the functions of HCV or other viruses.

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

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

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

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

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

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

Other features, objects, and advantages of the present invention will be apparent from the following detailed description of the invention. However, it should be noted that a detailed description of the invention, which presents preferred embodiments of the invention, is given for illustrative purposes only and is not limited to them. Various variations and modifications without departing from the scope of the invention will be apparent to those skilled in the art from the detailed description.

DETAILED DESCRIPTION OF THE INVENTION

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

Connections

The present invention relates to compounds of formula I, their tautomers and pharmaceutically acceptable salts of the compounds or tautomers

I

where each A and B is independently selected from carbocyclyl or heterocyclyl and each is optionally substituted with one or more R ¹⁸ , where R ¹⁸ in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S ( O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _S', -L _S -C (= NR _S ) N (R _{S '} R _S'' ), -L _S -N (R _S' ) C (= NR _S ) R _{S ''} , -L _S -N (R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _S' , -L _S -SO ₂ N (R _S R _{S '} ) and -L _S -N ( R _S ) SO ₂ N (R _{S '} R _S'');

each W ₁ and W _{2 are} independently selected from N or C (R ³³ );

Z represents a bond, —CR ⁴¹ R ^{41 ′} - or —NR ⁴¹ -, where each R ⁴¹ and R ^{41 ′ is} independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

each R ¹⁰ and R ^{33 is} independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, - L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S - N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O ) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _S', -L _S -C (= NR _S ) N (R _{S '} R _S'' ), -L _S- N (R _{S '} ) C (= NR _S ) R _S'' , -L _S -N (R _S ) C (O) N (R _S' R _{S ''} ), -L _S -N (R _S ) SO ₂ R _{S '} , -L _S -SO ₂ N (R _S R _S' ), -L _S -N (R _S ) SO ₂ N (R _{S '} R _S'' ), -L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _E' - (M ₃ -M ₁₈ heterocyclyl);

X is selected from the group consisting of, -L _S -O-, -L _S -S-, -L _S -C (O) -, -L _S -N (R _S ) -, -L _S -N ( R _S ) C (O) -, -L _S -C (O) N (R _S ) -, -L _S -N (R _S ) C (O) O-, -L _S -OC (O) N ( R _S ) -, -L _S -N (R _S ) C (O) N (R _{S '} ) -, -L _S -C (= NR _S ) N (R _S' ) -, -L _S -N ( R _{S '} ) C (= NR _S ) -, -L _S -S (O) -, -L _S -SO ₂ -, -L _S -C (O) O- and -L _S -OC (O) - ;

R ²² is carbocyclyl or heterocyclyl and is optionally substituted with one or more R ²⁶ , where R ²⁶ in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl phosphate, azido, alkyl, alkenyl, alkynyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S (O) R _S , -L _S - SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _S' , -L _S -C (= NR _S ) N (R _{S '} R _S'' ), -L _S -N (R _S' ) C (= NR _S ) R _{S ''} , -L _S -N (R _S ) C (O) N (R _{S '} R _{S ''} ), -L _S -N = C (NR _S R _{S '} ) (NR _S R _S' ), -L _S -N (R _S ) SO ₂ R _{S '} , -L _S -SO ₂ N ( R _S R _{S '} ), -L _S -N (R _S ) SO ₂ N (R _S' R _{S ''} ), -L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and - L _E -QL _{E '} - (M ₃ -M ₁₈ heterocyclyl); or R ²² is alkyl, alkenyl or alkynyl and is optionally substituted with one or more R ²⁶ ; or R ²² represents hydrogen;

Y is selected from the group consisting of, -L _s -O-, -L _s -C (O) -, -L _s -S (O) ₂ -, -L _s -S (O) -, -L _s -OS (O) ₂ -, -L _s -OS (O) -, -L _s -C (O) O-, -L _s -OC (O) -, -L _s -OC (O) O-, -L _s -C (O) N (R ¹⁵ ) -, -L _s -N (R ¹⁵ ) C (O) -, -L _s -C (O) N (R ¹⁵ ) O-, -L _s - N (R ¹⁵ ) C (O) O-, -L _s -C (O) N (R ¹⁵ ) N (R ^{15 '} ) -, -L _s -S-, -L _s -C (S) -, -L _s -C (S) O-, -L _s -OC (S) -, - L _s -N (R ¹⁵ ) -, -L _s -C (S) N (R ¹⁵ ) -, -L _s -N (R ¹⁵ ) C (S) -, -L _s -N (R ¹⁵ ) S (O) -, -L _s -N (R ¹⁵ ) S (O) ₂ -, -L _s -S (O ) ₂ N (R ¹⁵ ) -, -L _s -S (O) N (R ¹⁵ ) -, -L _s -C (S) N (R ¹⁵ ) O- and -L _s -C (S) N ( R ¹⁵ ) N (R ^{15 '} ) -, where each R ¹⁵ and R ^15' in each case is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

R ⁵⁰ represents-L ¹ -A ¹ where A ^{1 is} selected from the group consisting of carbocyclyl, heterocyclyl, alkyl, alkenyl and alkynyl, and L ^{1 is} selected from the group consisting of bond, alkylene, alkenylene and alkynylene, where A ¹ optionally substituted with one or more R ³⁰ , and R ³⁰ in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl , -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S- N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _{S '} , -L _S -C (= NR _S ) N (R _S' R _{S ''} ), -L _S -N (R _{S '} ) C (= NR _S ) R _S'' , -L _S -N (R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _S' , -L _S -SO ₂ N (R _S R _{S '} ), - L _S -N (R _S ) SO ₂ N (R _{S '} R _S'' ), -L _E -QL _E' - (C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _{E '} - (M ₃ - M ₁₈ heterocyclyl), and where L ^{1 is} optionally substituted with one or more R ³⁸ , and R ³⁸ in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkoxy, thioalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylamino, alkoxycarbonylamino, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O ) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _{S '} , -L _S -C (= NR _S ) N (R _S' R _{S ''} ), -L _S -N (R _{S '} ) C (= NR _S ) R _S'' , -L _S - N (R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _S' , -L _S -SO ₂ N (R _S R _{S '} ), -L _S -N (R _S ) SO ₂ N (R _{S '} R _S'' ), carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, -L _E -QL _E' - (C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _{E '} - (M ₃ -M ₁₈ heterocyclyl);

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

each R _S , R _{S ′} and R _{S ″} in each case is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonyl, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino and alkoxycarbonylaminoalkyl;

each L _E and L _{E '} in each case is independently selected from the group consisting of bond, alkylene, alkenylene and alkynylene;

Q in each case is independently selected from the group consisting of bond, alkylene, alkenylene, alkynylene, -S-, -O-, -C (O) -, -N (R _S ) -, -N (R _S ) C ( O) -, -C (O) N (R _S ) -, -N (R _S ) C (O) O-, -OC (O) N (R _S ) -, -N (R _S ) C (O ) N (R _{S '} ) -, -C (= NR _S ) N (R _S' ) -, -N (R _{S '} ) C (= NR _S ) -, -S (O) -, -SO ₂ - , -O-SO ₂ -, -SO ₂ -O-, -OS (O) -, -S (O) -O-, -C (O) O- and -OC (O) -;

each R ¹⁰ , R ¹⁵ , R ^{15 '} , R ¹⁸ , R ²⁶ , R ³⁰ , R ³³ , R ³⁸ , R ⁴¹ and R ^41' in each case is optionally independently substituted with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate and azido; and

each C ₃ -C ₁₈ carbocyclyl and M ₃ -M ₁₈ heterocyclyl group in -L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _E' - (M ₃ -M ₁₈ heterocyclyl) in each case is optionally independently substituted by at least one substituent selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, alkoxy , thioalkoxy, alkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonylox alkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino and alkoxycarbonylaminoalkyl.

In one embodiment, the present invention relates to compounds of formula I, their tautomers and pharmaceutically acceptable salts of the compounds or tautomers, where

each A and B is independently selected from C ₄ -C ₁₁ carbocyclyl or M ₄ -M ₁₁ heterocyclyl and each independently optionally substituted with one or more R ¹⁸ , where R ^{18 is} independently selected in each case from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ carbocyclyl, M ₃ -M ₆ heterocyclyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _S' , -L _S -C (= NR _S ) N (R _{S '} R _S'' ), -L _S -N (R _{S '} ) C (= NR _S ) R _S'' , -L _S -N (R _S ) C (O) N (R _S' R _{S ''} ) , -L _S -N (R _S ) SO ₂ R _{S '} , -L _S -SO ₂ N (R _S R _S' ) and -L _S -N (R _S ) SO ₂ N (R _{S '} R _S'');

each W ₁ and W _{2 are} independently selected from N or C (R ³³ );

Z is a bond, —CR ⁴¹ R ^{41 ′} - or —NR ⁴¹ -, where each R ⁴¹ and R ^{41 ′ is} independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl;

each R ¹⁰ or R ^{33 is} independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ carbocyclyl, M ₃ -M ₆ heterocyclyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , - L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S-S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _{S '} , -L _S -C (= NR _S ) N (R _S' R _{S ''} ), -L _S -N (R _{S '} ) C (= NR _S ) R _S'' , -L _S -N ( R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _S' , -L _S -SO ₂ N (R _S R _{S '} ), -L _S- N (R _S ) SO ₂ N (R _{S '} R _S'' ), -L _E -QL _E' - (C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _{E '} - (M ₃ -M ₁₈ heterocyclyl);

X is selected from the group consisting of, -L _S -O-, -L _S -S-, -L _S -C (O) -, -L _S -N (R _S ) -, -L _S -N ( R _S ) C (O) -, -L _S -C (O) N (R _S ) -, -L _S -N (R _S ) C (O) O-, -L _S -OC (O) N ( R _S ) -, -L _S -N (R _S ) C (O) N (R _{S '} ) -, -L _S -C (= NR _S ) N (R _S' ) -, -L _S -N ( R _{S '} ) C (= NR _S ) -, -L _S -S (O) -, -L _S -SO ₂ -, -L _S -C (O) O- and -L _S -OC (O) - ;

R ²² is C ₄ -C ₁₁ carbocyclyl or M ₄ -M ₁₁ heterocyclyl and optionally substituted with one or more R ²⁶ , where R ²⁶ in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto , nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S - C (= NR _S ) R _{S '} , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _S' ), -L _S -N (R _S ) C (O) R _{S '} , -L _S -C (= NR _S ) N (R _S' R _{S ''} ), -L _S -N (R _{S '} ) C (= NR _S ) R _{S ''} , -L _S -N = C (NR _S R _{S '} ) (NR _S R _S' ), -L _S -N (R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _{S '} , -L _S -SO ₂ N (R _S R _S' ), -L _S -N (R _S ) SO ₂ N (R _{S '} R _{S ''} ), -L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and-L _E -QL _E' - (M ₃ -M ₁₈ heterocyclyl); or R ²² is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl or C ₁ -C ₆ alkynyl and optionally substituted with one or more R ²⁶ ; or R ²² represents hydrogen;

Y is selected from the group consisting of, -L _S -O-, -L _S -C (O) -, -L _S -S (O) ₂ -, -L _S -S (O) -, -L _S -OS (O) ₂ -, -L _S -OS (O) -, -L _S -C (O) O-, -L _S -OC (O) -, -L _S -OC (O) O-, -L _S -C (O) N (R ¹⁵ ) -, -L _S -N (R ¹⁵ ) C (O) -, -L _S -C (O) N (R ¹⁵ ) O-, -L _S - N (R ¹⁵ ) C (O) O-, -L _S -C (O) N (R ¹⁵ ) N (R ^{15 '} ) -, -L _S -S-, -L _S -C (S) -, -L _S -C (S) O-, -L _S -OC (S) -, -L _S -N (R ¹⁵ ) -, -L _S -C (S) N (R ¹⁵ ) -, -L _S -N (R ¹⁵ ) C (S) -, -L _S -N (R ¹⁵ ) S (O) -, -L _S -N (R ¹⁵ ) S (O) ₂ -, -L _S -S (O ) ₂ N (R ¹⁵ ) -, -L _S -S (O) N (R ¹⁵ ) -, -L _S -C (S) N (R ¹⁵ ) O- and -L _S -C (S) N ( R ¹⁵ ) N (R ^{15 ′} ) -, wherein each R ¹⁵ and R ^{15 ′ is} independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl;

R ⁵⁰ is —L ¹ -A ¹ , where A ^{1 is} selected from the group consisting of C ₄ -C ₁₁ carbocyclyl, M ₄ -M ₁₁ heterocyclyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl, and L ^{1 is} selected from the group consisting of a bond, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene and C ₂ -C ₆ alkynylene, where A ¹ is optionally substituted with one or more R ³⁰ , and R ³⁰ in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C ( O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _S' , -L _S -C (= NR _S ) N (R _{S '} R _S'' ), -L _S -N ( R _{S '} ) C (= NR _S ) R _S'' , -L _S -N (R _S ) C (O) N (R _S' R _{S ''} ), -L _S -N (R _S ) SO ₂ R _{S '} , -L _S -SO ₂ N (R _S R _S' ), -L _S -N (R _S ) SO ₂ N (R _{S '} R _S'' ), -L _E -QL _E' - ( C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _{E '} - (M ₃ -M ₁₈ heterocyclyl), and where L ^{1 is} optionally substituted with one or more R ³⁸ , and R ³⁸ in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyloxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxycarbonylamino, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O ) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _S' , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _{S '} ), -L _S -N (R _S ) C (O) R _S' , -L _S -C (= NR _S ) N (R _{S '} R _S`` ), -L _S -N (R _{S '} ) C (= NR _S ) R _S'' , -L _S -N (R _S ) C (O) N (R _S' R _{S ''} ) , -L _S -N (R _S ) SO ₂ R _{S '} , -L _S -SO ₂ N (R _S R _S' ), -L _S -N (R _S ) SO ₂ N (R _{S '} R _S'' ), carbocyclyl, heterocyclyl, carbocyclyl C ₁ -C ₆ alkyl, heterocyclyl C ₁ -C ₆ alkyl, -L _E -QL _E' - (C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _{E '} - (M ₃ - M ₁₈ heterocyclyl);

L _S in each case is independently selected from the group consisting of a bond, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene and C ₂ -C ₆ alkynylene;

each R _S , R _{S '} and R _S'' in each case is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ alkoxyC ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyC ₁ -C ₆ alkoxyC ₁ -C ₆ alkyl, C ₁ -C ₆ tioalkoksiC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyloxy, C ₁ -C ₆ alkilkarboniloksiC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkilaminoC ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonylamino and C ₁ -C ₆ alkoksikarbonilaminoC ₁ -C ₆ alkyl;

each L _E and L _{E '} in each case is independently selected from the group consisting of a bond, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene and C ₂ -C ₆ alkynylene;

Q in each case is independently selected from the group consisting of a bond, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, -S-, -O-, -C (O) -, - N (R _S ) -, -N (R _S ) C (O) -, -C (O) N (R _S ) -, -N (R _S ) C (O) O-, -OC (O) N (R _S ) -, -N (R _S ) C (O) N (R _{S '} ) -, -C (= NR _S ) N (R _S' ) -, -N (R _{S '} ) C (= NR _S ) -, -S (O) -, -SO ₂ -, -O-SO ₂ -, -SO ₂ -O-, -OS (O) -, -S (O) -O-, -C (O ) O- and -OC (O) -;

each R ¹⁰ , R ¹⁵ , R ^{15 '} , R ¹⁸ , R ²⁶ , R ³⁰ R ³³ , R ³⁸ , R ⁴¹ and R ^41' in each case is optionally independently substituted with at least one substituent selected from the group consisting of halogen oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate and azido; and

each C ₃ -C ₁₈ carbocyclyl and M ₃ -M ₁₈ heterocyclyl group in-L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and -L _E -QL _E' - (M ₃ -M ₁₈ heterocyclyl) in each case is optionally independently substituted by at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ thioalkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alk oksikarbonilC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyloxy, C ₁ -C ₆ alkilkarboniloksiC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkilaminoC ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonylamino; and C ₁ -C ₆ alkoxycarbonylamino C ₁ -C ₆ alkyl.

In one example of this embodiment, Y is —L _S —O—, —L _S —S— or —L _S —N (R ¹⁵ ) -, and R ⁵⁰ is —L ¹ —A ¹ , where L ¹ is a bond, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene and is optionally substituted with one or more R ³⁸ , and A ¹ is C ₄ -C ₁₁ carbocyclyl or M ₄ -M _{11 is} heterocyclyl and is optionally substituted with one or more R ³⁰ .

In another example of this embodiment, Y is a bond, and R ⁵⁰ is —L ¹ -A ¹ , where L ¹ is a bond, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene and is optionally substituted with one or more R ³⁸ , and A ¹ is C ₄ -C ₁₁ carbocyclyl or M ₄ -M ₁₁ heterocyclyl and is optionally substituted with one or more R ³⁰ .

In another further example of this embodiment, Y is a bond, and R ⁵⁰ is —L ¹ -A ¹ , where L ^{1 is} selected from the group consisting of a bond, C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, and C ₂ -C ₆ alkynylene and is optionally substituted with one or more R ³⁸ , and A ¹ represents hydrogen or R ¹⁸ .

In another example of this embodiment, Y is selected from the group consisting of -L _S -S (O) ₂ N (R ¹⁵ ) -, -L _S -OS (O) ₂ -, -L _S -OC (O) - , -L _S -C (O) O-, -L _S -C (O) - and -N (R ¹⁵ ) C (O) O-.

In yet another further example of this embodiment, each A and B is independently selected from C ₅ -C ₆ carbocyclyl or M ₅ -M ₆ heterocyclyl and each independently is optionally substituted with one or more R ¹⁸ .

In another further example of this embodiment, W ₁ and W ₂ are N and Z is —NR ⁴¹ -.

In yet another example of this embodiment, X is —O— or —S— and R ²² is C ₅ -C ₆ carbocyclyl or M ₅ -M ₆ heterocyclyl and is optionally substituted with one or more R ²⁶ .

In yet another example of this embodiment, a fragment

represents

where each W ₁ , W ₂ , W ₃ and W _{4 are} independently selected from N or C (R ³³ ); and

each R ¹⁰ , R ¹⁷ , R ³³ and R ^{35 is} independently selected in each case from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ carbocyclyl, M ₃ -M ₆ heterocyclyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _{S '} , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _S' ), -L _S -N ( R _S ) C (O) R _{S '} , -L _S -C (= NR _S ) N (R _S' R _{S ''} ), -L _S -N (R _{S '} ) C (= NR _S ) R _{S ''} , -L _S -N (R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _S' , -L _S -SO ₂ N ( R _S R _{S '} ), -L _S -N (R _S ) SO ₂ N (R _S' R _{S ''} ), -L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and -L _E - QL _{E '} - (M ₃ -M ₁₈ heterocyclyl).

In yet another example of this embodiment, a fragment

selected from the group consisting of

,

,

,

,

и

and

where Q represents N or C (R ³³ ); and

each R ¹⁰ , R ¹⁷ , R ³³ and R ^{35 is} independently selected in each case from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ carbocyclyl, M ₃ -M ₆ heterocyclyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _{S '} , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _S' ), -L _S -N ( R _S ) C (O) R _{S '} , -L _S -C (= NR _S ) N (R _S' R _{S ''} ), -L _S -N (R _{S '} ) C (= NR _S ) R _{S ''} , -L _S -N (R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _S' , -L _S -SO ₂ N ( R _S R _{S '} ), -L _S -N (R _S ) SO ₂ N (R _S' R _{S ''} ), -L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and -L _E - QL _{E '} - (M ₃ -M ₁₈ heterocyclyl).

In a further example of this embodiment, each A and B is independently selected from C ₅ -C ₆ carbocyclyl or M ₅ -M ₆ heterocyclyl and each independently is optionally substituted with one or more R ¹⁸ , where

W ₁ and W ₂ represent N;

Z represents —NR ⁴¹ -;

X represents —O— or —S—;

R ²² is C ₅ -C ₆ carbocyclyl or M ₅ -M ₆ heterocyclyl and is optionally substituted with one or more R ²⁶ ;

Y is a bond, —L _S —O—, —L _S —S— or —L _S —N (R ¹⁵ ) -; and

A ¹ represents C ₅ -C ₁₀ carbocyclyl or M ₅ -M ₁₀ heterocyclyl and is optionally substituted with one or more R ³⁰ .

In another example of this embodiment, each A and B is independently selected from C ₅ -C ₆ carbocyclyl or M ₅ -M ₆ heterocyclyl and each independently optionally substituted with one or more R ¹⁸ , where

W ₁ and W ₂ represent N;

Z represents —NR ⁴¹ -;

X represents —O— or —S—;

R ²² represents

,

или

,

or

where R ⁴⁸ represents hydroxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonylamino or C ₁ -C ₆ alkylcarbonyloxy and R ²² (for example, R ⁴⁸ or a phenyl ring in R ²² ) optionally substituted with one or more R ²⁶ ;

Y is a bond, —L _S —O—, —L _S —S— or —L _S —N (R ¹⁵ ) -; and

A ¹ represents C ₅ -C ₁₀ carbocyclyl or M ₅ -M ₁₀ heterocyclyl and is optionally substituted with one or more R ³⁰ .

In another further example of this embodiment, a fragment

selected from the group consisting of

,

,

,

,

и

and

where Q represents N or C (R ³³ );

each R ¹⁰ , R ¹⁷ , R ³³ and R ³⁵ in each case is independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ carbocyclyl, M ₃ -M ₆ heterocyclyl, -L _S -OR _S , -L _S -SR _S , -L _S -C (O) R _S , -L _S -OC (O) R _S , -L _S -C (O) OR _S , -L _S -N (R _S R _{S '} ), -L _S -C (= NR _S ) R _{S '} , -L _S -S (O) R _S , -L _S -SO ₂ R _S , -L _S -C (O) N (R _S R _S' ), -L _S -N ( R _S ) C (O) R _{S '} , -L _S -C (= NR _S ) N (R _S' R _{S ''} ), -L _S -N (R _{S '} ) C (= NR _S ) R _{S ''} , -L _S -N (R _S ) C (O) N (R _{S '} R _S'' ), -L _S -N (R _S ) SO ₂ R _S' , -L _S -SO ₂ N ( R _S R _{S '} ), -L _S -N (R _S ) SO ₂ N (R _S' R _{S ''} ), -L _E -QL _{E '} - (C ₃ -C ₁₈ carbocyclyl) and -L _E - QL _{E '} - (M ₃ -M ₁₈ heterocyclyl);

A represents C ₅ -C ₆ carbocyclyl or M ₅ -M ₆ heterocyclyl and is optionally substituted with one or more R ¹⁸ ;

Z represents —NR ⁴¹ -;

X represents —O— or —S—;

R ²² represents

,

или

где R⁴⁸ представляет собой гидрокси, амино, C₁-C₆алкиламино, C₁-C₆алкокси, C₁-C₆алкоксикарбониламино или C₁-C₆алкилкарбонилокси, и R²² (например, R⁴⁸ или фенильное кольцо в R²²) является необязательно замещенным одним или несколькими R²⁶;

,

or

where R ⁴⁸ represents hydroxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonylamino or C ₁ -C ₆ alkylcarbonyloxy, and R ²² (e.g., R ⁴⁸ or a phenyl ring in R ²² ) is optionally substituted with one or more R ²⁶ ;

Y is a bond, —L _S —O—, —L _S —S— or —L _S —N (R ¹⁵ ) -; and

A ¹ represents C ₅ -C ₁₀ carbocyclyl or M ₅ -M ₁₀ heterocyclyl and is optionally substituted with one or more R ³⁰ .

In another embodiment, the present invention relates to a family of compounds of pyridopyrimidinyl-aminophenyl ether, tautomers of these compounds or pharmaceutically acceptable salts of compounds or tautomers, where the compounds of this family correspond to the structure of formula II:

II

where R ⁶ selected from the group consisting of hydrogen and cyano;

R ^{8 is} selected from the group consisting of hydrogen and arylalkyl;

R ^{25 is} selected from the group consisting of hydrogen and alkyl;

R ³⁷ selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and cycloalkyl;

R ^{42 is} selected from the group consisting of arylsulfanyl, heteroarylsulfanyl and aryloxy; where R ^{42 is} optionally substituted with one or more substituents independently selected from R ⁴⁶ ;

R ⁴⁶ represents one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, dialkylamino and alkoxycarbonylamino;

R ^{70 is} selected from the group consisting of aryl and heterocyclo; where R ^{70 is} optionally substituted with R ⁷⁵ ;

R ⁷⁵ represents one or more substituents independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, alkyl, haloalkyl and aryl.

In the subfamily of this embodiment, in formula II, R ^{6 is} selected from the group consisting of hydrogen and cyano;

R ^{8 is} selected from the group consisting of hydrogen and phenylmethyl;

R ^{25 is} selected from the group consisting of hydrogen and methyl;

R ^{37 is} selected from the group consisting of hydrogen, methyl, ethyl, tert-butyl, isopropyl, hydroxymethylethyl and cyclohexyl;

R ^{42 is} selected from the group consisting of phenylsulfanyl, phenoxy and pyrimidinylsulfanyl;

R ^{46 is} selected from the group consisting of hydrogen, hydroxy, amino, N, N-dimethylamino and tert-butoxycarbonylamino;

R ^{70 is} selected from the group consisting of phenyl, thiazolyl, pyridinyl, tetrahydrofuranyl, naphthyl, quinolinyl and thienyl;

R ⁷⁵ represents one or more substituents selected from the group consisting of hydrogen, methyl, butyl, hydroxy, methoxy, bromo, chloro, fluoro, cyano, trifluoromethyl and phenyl.

In another embodiment, the present invention relates to a family of compounds of pyridopyrimidinyl-aminophenylalkyl ether, tautomers of these compounds or pharmaceutically acceptable salts of compounds or tautomers, where the compounds of this family correspond to the structure of formula III:

III

where R ^{80 is} selected from the group consisting of hydrogen, alkylcarbonyl and haloaryl.

In the subfamily of this embodiment in Formula III, R ^{80 is} selected from the group consisting of hydrogen, methylcarbonyl and bromophenyl.

In another embodiment, the present invention relates to a family of compounds of thiazolopyrimidinyl-aminophenyl and thienopyrimidinyl-aminophenyl, tautomers of these compounds or pharmaceutically acceptable salts of compounds or tautomers, where the compounds of this family correspond to the structure of formula IV:

IV

where Q is selected from the group consisting of N and CH;

R ¹ selected from the group consisting of alkylsulfanyl, cyanoalkylsulfanyl and alkyl;

R ^{19 is} selected from the group consisting of alkyl and haloarylalkoxy;

R ^{56 is} selected from the group consisting of hydrogen, hydroxy, alkyl, and alkylcarbonylamino.

In the subfamily of this embodiment in Formula IV, R ^{1 is} selected from the group consisting of methylsulfanyl, cyanomethylsulfanyl, propyl and butyl;

R ^{19 is} selected from the group consisting of methyl and bromophenylmethoxy;

R ^{56 is} selected from the group consisting of hydrogen, hydroxy, methyl and methylcarbonylamino.

In yet another embodiment, the present invention relates to a family of pyrimidopyrimidinyl-aminophenyl compounds, tautomers of these compounds, or pharmaceutically acceptable salts of the compounds or tautomers, where the compounds of this family correspond to the structure of formula V:

V

where R ⁵ selected from the group consisting of hydrogen and alkylsulfanyl;

R ^{29 is} selected from the group consisting of alkyl, arylalkoxy, halogen, and haloarylalkoxy;

R ^{47 is} selected from the group consisting of alkyl, haloalkyl, alkylsulfanyl, arylalkylsulfanyl and heterocyclo;

R ^{64 is} selected from the group consisting of hydrogen, alkoxy, and alkyl;

R ^{66 is} selected from the group consisting of hydrogen, hydroxy, aryloxy, alkylsulfonyloxy, alkylcarbonylaminoarylsulfonyloxy, halogenarylsulfonyloxy, cyano, arylalkoxy, alkylcarbonylamino, halogen and alkyl;

R ^{81 is} selected from the group consisting of hydrogen, alkoxy and carbonyl.

In the subfamily of this embodiment, in the formula, VR ^{5 is} selected from the group consisting of hydrogen and methylsulfanyl;

R ^{29 is} selected from the group consisting of methyl, ethyl, fluoro, phenylmethoxy and bromophenylmethoxy;

R ^{47 is} selected from the group consisting of hydrogen, propyl, isopropyl, ethylsulfanyl, piperidinyl, morpholinyl, heptaphthopropyl and phenylmethylsulfanyl;

R ^{64 is} selected from the group consisting of hydrogen, methoxy, hydroxy and methoxy;

R ^{66 is} selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, phenoxy, phenylmethoxy, phenylsulfanyloxy, isopropylsulfonyloxy, methylcarbonylaminophenylsulfonyloxy, bromophenylsulfanyloxy, cyano, methylcarbonylamino and fluorine;

R ^{81 is} selected from the group consisting of hydrogen, tert-butoxy and carbonyl.

In another embodiment, the present invention relates to a family of pyrazolopyrimidinyl-aminophenyl compounds, tautomers of compounds or pharmaceutically acceptable salts of compounds or tautomers, where the compounds of this family correspond to the structure of formula VI:

VI

where R ⁷³ represents alkyl;

R ^{76 is} selected from the group consisting of hydroxy, alkylaminocarbonyl and alkylcarbonylamino.

In the subfamily of this embodiment in Formula VI, R ^{73 is} selected from the group consisting of methyl and butyl;

R ^{76 is} selected from the group consisting of hydroxy, methylaminocarbonyl and methylcarbonylamino.

In yet another embodiment, the present invention relates to a family of pyridopyrimidinyl-aminophenyl compounds, tautomers of compounds or pharmaceutically acceptable salts of compounds or tautomers, where the compounds of this family correspond to the structure of formula VII:

VII

where A is selected from the group consisting of O and S;

R ^{21 is} selected from the group consisting of hydrogen and hydroxy;

or R ²¹ taken together with R ³⁹ forms a 5-12 membered heterocycle containing at least two heteroatoms selected from the group consisting of O, N and S; wherein the heterocycle is optionally substituted with aryl or halogen; or

R ³⁹ is selected from the group consisting of hydrogen, alkyl, arylalkenyl, dialkylamino, heteroaryl, galogengeteroarila, galogenarilaminosulfonila, arylsulfonyloxy, alkylcarbonyloxy, tsikloalkilaminokarbonila, arilalkoksikarbonilamino, galogengeteroarila, alkoxycarbonyl and NH-R ^99;

R ^{99 is} selected from the group consisting of hydrogen, arylalkyl, cycloalkylalkyl, aryl, heteroaryl, haloarylalkylamino, arylalkylamino and alkylheteroaryl;

R ^{67 is} selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylcycloalkyl;

R ^{96 is} selected from the group consisting of hydrogen, hydroxy, amino, alkoxy, arylsulfonyloxy, alkylcarbonylamino, alkoxy, halogen, alkoxycarbonyloxy, haloalkoxycarbonylamino and arylalkoxy.

In the subfamily of this embodiment in Formula VII, R ^{21 is} selected from the group consisting of hydrogen and hydroxy, or if R ^{21 is} taken together with R ³⁹ , it forms benzooxazolyl optionally substituted with phenyl or bromine; or

R ^{39 is} selected from the group consisting of hydrogen, methyl, phenylethenyl, N, N-dipropylamino, pyrrolyl, bromophenylaminosulfonyl, phenylsulfonyloxy, tert-butylcarbonyloxy, N-cyclohexylaminocarbonyl, N-cyclopentylaminocarbonylmethyl, benzylmethoxycarbonylbenamino,

R ^{67 is} selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl and methylcyclopropyl;

R ^{96 is} selected from the group consisting of hydrogen, hydroxy, amino, phenylsulfonyloxy, methylcarbonylamino, methoxy, fluorine, tert-butoxycarbonylamino, trichloroethoxycarbonylamino and phenylmethoxy;

R ^{99 is} selected from the group consisting of hydrogen, phenylmethyl, phenylethyl, cyclopentylmethyl, furanyl, thienyl, naphthale, bromophenylmethylamino, phenylmethylamino and methylpyrido [2,3-d] pyrimidinyl.

In yet another embodiment, the present invention relates to a family of pyridopyrimidinyl-aminophenyl compounds, tautomers of these compounds, or pharmaceutically acceptable salts of the compounds or tautomers, where the compounds of this family correspond to formula VIII:

VIII

where R ^{23 is} selected from the group consisting of hydrogen, alkoxyaryl, alkoxyarylsulfanyl, hydroxyarylsulfanyl, haloarylalkoxy, cyanoarylalkoxy and arylalkoxy;

R ^{31 is} selected from the group consisting of hydrogen and halogen;

R ^{49 is} selected from the group consisting of hydrogen, arylalkoxy, haloarylcarbonylamino, alkoxyarylcarbonylamino, arylalkenyl, arylalkyl, halogen, cyano, haloaryloxyalkyl, alkyl, alkoxyarylsulfanyl, haloheteroaryl and alkoxycarbonyl;

R ^{52 is} selected from the group consisting of hydrogen, halogen, alkyl, hydroxyaryloxy, aryloxy, hydroxyalkylaryloxy, alkoxyarylalkyl, alkoxyaryloxy, alkylarylalkoxyoxyrylamino, arylalkyl, heteroaryl and aminoaryloxy;

R ^{77 is} selected from the group consisting of hydrogen, alkyl and cycloalkyl.

In the subfamily of this embodiment in formula VIII, R ^{23 is} selected from the group consisting of hydrogen, methoxyphenyl, methoxyphenylsulfanyl, hydroxyphenylsulfanyl, fluorophenylmethoxy, difluorophenylmethoxy, cyanophenylmethoxy, phenylmethoxy, bromophenylmethoxy and methoxyphenylmethoxy;

R ³¹ selected from the group consisting of hydrogen, chlorine and fluorine;

R ^{49 is} selected from the group consisting of hydrogen, methyl, phenylmethoxy, bromophenylcarbonylamino, chlorophenylcarbonylamino, methoxyphenylcarbonylamino, fluorophenylcarbonylamino, phenylethhenyl, phenylethyl, chlorine, fluorine, bromine, cyano, bromophenoxymethyl and hydroxyphenylsulfanyl.

R ^{52 is} selected from the group consisting of hydrogen, fluorine, bromine, methyl, phenoxy, hydroxyphenoxy, hydroxyethylphenoxy, methoxyphenylethyl, methoxyphenoxy, N-methyl-N-4-phenylmethoxyphenylamino, phenylmethyl and thiazolylbenzimidazolyl;

R ^{77 is} selected from the group consisting of hydrogen, methyl and isopropyl.

Salts of the compounds of the present invention

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

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

Pharmaceutically acceptable addition salts of the compounds of the present invention may be prepared from inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carboxylic, sulfuric and phosphoric acids. Suitable organic acids typically include, for example, organic acids of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes. Specific examples of suitable organic acid salts include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoic acid, , mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylamino acid ximobutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentane propionate, dodecyl sulfate, glucoheptanoate, glycerophosphate, hemisulphate, heptanoate, hexanoate, nicotinate, nicotinate, nicotinate, nicotinate, nicotinate, 2-nicotinate , picrate, pivalate, thiocyanate, tosylate and undecanoate.

Pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts and organic salts. Preferred metal salts include, but are not limited to, alkali metal salts (group Ia), alkaline earth metal salts (group IIa) and other physiologically acceptable metal salts. Such salts can be obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Non-limiting examples of preferred organic salts can be obtained from tertiary amines and quaternary amine salts, for example tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Major nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (C ₁ -C ₆ ) (e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides) and others.

Solvates, Prodrugs, and Isomers

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

In one aspect of the compound, the tautomers or salts of the present invention may be in the form of prodrugs. Some aliphatic or aromatic esters are derived from the acid groups of the compounds of the present invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups of the compounds of the present invention. The present invention also relates to phosphate prodrugs of hydroxyl groups of the compounds of the present invention.

The compounds of the invention may contain asymmetrically substituted carbon atoms, known as chiral centers. These chiral centers are designated as “R” or “S” depending on the configuration of the substituents around the chiral carbon atom. As used herein, the terms “R” and “S” refer to configurations defined in “Nomenclature of Organic Chemistry”, Section E: Stereochemistry, Recommendations 1974, Pure Appl. Chem., 45: 11-30 (1976). The compounds of the present invention can exist, without limitation, as single stereoisomers (e.g., single enantiomers or single diastereomers), as mixtures of stereoisomers (e.g., any mixture of enantiomers or diastereomers), or as racemic mixtures. Any single stereoisomers, mixtures and racemates are included in the scope of the present invention. Compounds that are defined as single stereoisomers in the present description are understood to mean compounds that are in a form substantially free of other stereoisomers (e.g., other enantiomers or diastereomers). “Essentially free” means that at least 80% of the compound in the composition is in the form of the desired stereoisomer; preferably, at least 90% of the compound in the composition is in the form of the desired stereoisomer; and, more preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in the composition is in the form of the desired stereoisomer. If the stereochemistry of the chiral carbon (s) present in the chemical structure is not defined, then it is understood that the chemical structure includes compounds in any stereoisomeric form at each chiral center present in the chemical structure.

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

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

Separation of enantiomers can also be accomplished by converting enantiomers in a mixture into diastereomers by reaction with chiral auxiliary reagents. The resulting diastereomers can be separated by column chromatography or by crystallization / recrystallization. This technique can be used if the compounds intended for separation contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with a chiral auxiliary reagent. Non-limiting examples of suitable chiral auxiliary reagents include chiral pure amino acids, organic carboxylic acids, or organosulfonic acids. After separation of the diastereomers by chromatography, individual enantiomers can be reduced. Often, the chiral auxiliary reagent can be restored and used again.

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

Alternatively, the enantiomer salts in the mixture can be prepared by any method known in the art, including treating the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization / recrystallization of enantiomerically pure salts. Methods suitable for resolving a mixture of stereoisomers, including racemic mixtures, are presented in Enantiomers, Racemates, and Resolutions (Jacques et al ., 1981, John Wiley and Sons, New York, NY).

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

Some compounds of the invention may exist in various stable conformational forms, which may be separable. Torsion asymmetry, due to limited rotation around an asymmetric single bond, for example as a result of steric hindrance or ring tension, can produce various conformers. Compounds of the invention include each conformational isomer of these compounds and mixtures thereof.

Some compounds of the invention may also exist in a zwitterionic form, and each color-ionic form of these compounds and mixtures thereof are within the scope of the invention.

Definitions

The compounds of the present invention are mainly described herein using standard nomenclature. In the case of the listed compounds with asymmetric (s) center (s), it should be borne in mind that all stereoisomers of the compound and their mixtures are within the scope of the present invention, unless specifically indicated otherwise. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis transisomers. If the described compound exists in various tautomeric forms, then it is understood that the compound includes all tautomeric forms. Specific compounds are described herein using general formulas that contain variables (e.g., R ¹⁰ , A, L ¹ , X, or Y). Unless otherwise indicated, each variable in such a formula is defined independently of any other variable, and any variable that occurs more than once in the formula is defined independently in each case. If substituents are described as “independently selected from” groups, then each substituent is selected independently of the other. Each substituent, therefore, may be the same or different from the other (their) substituent (s).

The number of carbon atoms in a hydrocarbon substituent can be defined by the prefix “C _x -C _y ”, where x is the minimum number and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C ₁ -C ₆ alkyl” refers to an alkyl substituent containing 1-6 carbon atoms. As another example, C ₃ -C ₆ cycloalkyl denotes a saturated hydrocarbon ring containing 3-6 ring carbon atoms. The prefix of a multicomponent substituent refers only to the first component immediately following the prefix. For example, the term “alkylaryl” consists of two components: alkyl and aryl. Thus, for example, C ₁ -C ₆ alkylaryl refers to C ₁ -C ₆ alkyl attached to the main part of the molecule through an aryl group. Similarly, alkyl C ₆ -C ₁₀ aryl refers to an alkyl group attached to the main part of the molecule through a C ₆ -C ₁₀ aryl group. Similarly, the prefix “halogen” of haloalkoxyalkyl indicates that the alkoxy component is substituted with one or more halo radicals, while the prefix “halo” of alkoxyhaloalkyl indicates that the alkyl component is substituted with one or more halo radicals.

When describing a connection element of two other elements of the depicted chemical structure, the leftmost component of the connection element is a component that is attached to the left element of the depicted structure. For example, if the chemical structure is X-L-Y, and L is designated as methyl aryl ethyl, then the chemical compound will be X-methyl-aryl-ethyl-Y.

If the connection element in the depicted structure is a bond, then the left element in the depicted structure is directly connected to the right element of the depicted structure. For example, if the chemical structure is depicted as XLY and L is defined as a bond, then the chemical structure is XY. Another example, if the chemical group is depicted as -LX, and L is defined as a bond, then the chemical group is -X. Another example, if the chemical structure is depicted as XL ₁ -L ₂ -Y, XL ₁ -L ₂ -L ₃ -Y or XL ₁ -L ₂ -...- L _N -Y, and L ₁ , L ₂ , L ₃ , ... L _{N are} defined as a bond, then the chemical structure will be XY.

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

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

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

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

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

The term “alkenylene” (alone or in combination with other term (s)) refers to a divalent unsaturated hydrocarbon group, which may be linear or branched, and which has at least one carbon-carbon double bond. The alkenylene group usually contains 2-20 carbon atoms, more often 2-8 carbon atoms and even more often 2-6 carbon atoms. Non-limiting examples of alkenylene groups include —C (H) = C (H) -, —C (H) = C (H) —CH ₂ -, —C (H) = C (H) —CH ₂ —CH ₂ -, -CH ₂ -C (H) = C (H) -CH ₂ -, -C (H) = C (H) -CH (CH ₃ ) - and -CH ₂ -C (H) = C (H) - CH (CH ₂ CH ₃ ) -.

The term “alkoxy” (alone or in combination with other term (s)) refers to an alkyl group attached to the main part of the molecule via an oxy group (i.e., -O-alkyl). Non-limiting examples of such a substituent include methoxy (—O — CH ₃ ), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

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

The term “alkoxycarbonyl” (alone or in combination with other term (s)) refers to an alkoxy group attached to the main part of the molecule via a carbonyl group (ie ─C (O) ─ O─ alkyl). Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl

and tert-butoxycarbonyl.

The term “alkoxycarbonylamino” (alone or in combination with other term (s)) refers to N (R _A R _B ) -, where R _A is alkyl-OC (O) -, and R _B is alkyl-OC (O) - or hydrogen. R _A and R _B may be the same or different.

The term “alkoxycarbonylaminoalkyl” (alone or in combination with other term (s)) refers to N (R _A R _B ) -alkylene-, where R _A is alkyl-OC (O) - and R _B represents alkyl-OC (O) - or hydrogen. R _A and R _B may be the same or different.

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

The term “alkyl” (by itself or in combination with other term (s)) means a straight or branched chain saturated hydrocarbon substituent, usually containing 1-20 carbon atoms, more often 1-8 carbon atoms and even more often 1- 6 carbon atoms. Non-limiting examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and octyl.

The term “alkylamino” (alone or in combination with other term (s)) refers to —NR _A R _B , where R _A is alkyl and R _B is hydrogen or alkyl. R _A and R _B may be the same or different. For example, C ₁ -C ₆ alkylamino refers to ─NR _A R _B , where R _A is C ₁ -C ₆ alkyl and R _B is hydrogen or C ₁ -C ₆ alkyl.

The term “alkylaminoalkyl” (alone or in combination with other term (s)) refers to N (R _A R _B ) -alkylene-, where R _A is alkyl and R _B is hydrogen or alkyl. R _A and R _B may be the same or different. Thus, C ₁ -C ₆ alkilaminoC ₁ -C ₆ alkyl refers to N (R _A R _B) -C ₁ -C ₆ alkylene-, wherein R _A is C ₁ -C ₆ alkyl, and R _B represents hydrogen or C ₁ -C ₆ alkyl.

The term “alkylcarbonyl” (alone or in combination with other term (s)) refers to an alkyl group attached to the main part of the molecule via a carbonyl group (i.e., -C (O) -alkyl). Representative examples of alkylcarbonyl include, but are not limited to, acetyl, ethylcarbonyl

,

,

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

The term “alkylcarbonylalkyl” (alone or in combination with other term (s)) refers to an alkylcarbonyl group attached to the main part of the molecule via 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 other term (s)) refers to an alkylcarbonyl group attached to the main part of the molecule through an oxy group. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy.

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

The terms “alkylene” or “alkylenyl” (alone or in combination with other term (s)) denote a divalent group derived from a straight or branched saturated hydrocarbon chain, usually containing 1-20 carbon atoms, usually 1-8 carbon atoms and even more often 1-6 carbon atoms. Representative examples of alkylene include, but are not limited to, —CH ₂ -, —CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ CH ₂ -, and —CH ₂ CH (CH ₃ ) CH ₂ -.

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

The terms “alkynylene” (alone or in combination with other term (s)) refer to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon triple bond. Representative alkynylene groups include, for example, -C≡C-, -C≡C-CH ₂ -, -C≡C-CH ₂ -CH ₂ -, -CH ₂ -C≡C-CH ₂ -, -C≡C -CH (CH ₃ ) - and -CH ₂ -C≡C-CH (CH ₂ CH ₃ ) -.

The term “amino” (alone or in combination with another term (s)) means —NH ₂ . The term “monosubstituted amino” (alone or in combination with other term (s)) means an amino substituent in which one hydrogen radical is replaced by a non-hydrogen substituent. The term “disubstituted amino” (alone or in combination with other term (s)) means an amino substituent in which both hydrogen atoms are replaced by non-hydrogen substituents, which may be the same or different.

The term “aminocarbonyl” (alone or in combination with other term (s)) means —C (O) —NH ₂ , which may also be depicted as

The term “aminoalkyl” (alone or in combination with other term (s)) means -alkylene-NH ₂ .

The term “aminoalkylcarbonyl” (alone or in combination with other term (s)) means —C (O) -alkylene-NH ₂ . For example, “aminomethylcarbonyl” may be depicted as

The term “aminosulfonyl” (alone or in combination with other term (s)) means —S (O) ₂ —NH ₂ , which may also be depicted as

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

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

The term “arylalkylcarbonyl” (alone or in combination with other term (s)) refers to an arylalkyl group attached to the main part of the molecule via a carbonyl group (that is, arylalkyl─C (O) ─). Representative examples of arylalkylcarbonyl include, but are not limited to, 2-naphthylacetyl and phenylacetyl.

The term “arylalkoxy” (alone or in combination with other term (s)) refers to an arylalkyl group attached to the main part of the molecule through an oxy group (that is, 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 other term (s)) refers to an arylalkoxy group attached to the main part of the molecule via an alkylene group. Representative examples of arylalkoxyalkyl include, but are not limited to, benzyloxymethyl, 2- (benzyloxy) ethyl, and (2-phenylethoxy) methyl.

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

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

The term “aryloxy” (alone or in combination with other term (s)) refers to an aryl group attached to the main part of the molecule through an oxy group. Representative examples of substituted / unsubstituted aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.

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

The term “aryloxycarbonyl” (alone or in combination with other term (s)) refers to an aryloxy group attached to the main part of the molecule via a carbonyl group.

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

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

The term “arylthioalkoxy” (alone or in combination with other term (s)) refers to an arylthioalkyl group attached to the main part of the molecule through an oxy group.

The term “arylthioalkoxyalkyl” (alone or in combination with other term (s)) refers to an arylthioalkoxy group attached to the main part of the molecule via an alkylene group.

The terms “carbocycle” or “carbocyclic” or “carbocyclyl” (alone or in combination with other term (s)) refer to saturated (eg, “cycloalkyl”), partially saturated (eg, “cycloalkenyl” or “cycloalkynyl”) or a completely unsaturated (eg, “aryl”) ring system containing zero ring heteroatoms and usually 3-18 ring carbon atoms. “Ring atoms” or “ring members” are atoms bonded together to form a ring or rings of a cyclic substituent. A carbocyclic group may, without limitation, include a single ring, or two or more fused rings, or bridged rings, or a spiro ring. A carbocyclyl may contain 3-14 ring members (i.e., C ₃ -C ₁₄ carbocyclyl, such as C ₃ -C ₁₄ cycloalkyl), 3-10 ring members (i.e., C ₃ -C ₁₄ carbocyclyl, such as C ₃ -C ₁₀ cycloalkyl), 3-8 ring members (i.e., C ₃ -C ₈ carbocyclyl, such as C ₃ -C ₈ cycloalkyl), 3-6 ring members (i.e., C ₃ -C ₈ carbocyclyl, such as C ₃ -C ₆ cycloalkyl), 4-10 ring members (i.e. C ₄ -C ₁₀ carbocyclyl such as C ₄ -C ₁₀ cycloalkyl and C ₄ -C ₁₀ cycloalkenyl), 4-8 ring members (i.e. C ₄ -C ₈ carbocyclyl, such as C ₄ -C ₈ cycloalkyl and C ₄ -C ₈ cycloalkenyl), or 5-7 ring members (i.e., C ₅ -C ₇ carbocyclyl, such as C ₅ -C ₇ cycloalkyl, C ₅ -C ₇ cycloalkenyl and phenyl). Substituted carbocyclyl may have either cis or trans geometry. Representative examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydronaphthalenyl, octahydroindenyl, cyclohexenyl, phenyl, indo-naphthyl, 1,2 4-tetrahydronaphthyl, indenyl, isoindenyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl"), decalinyl and norpininil. A carbocyclyl group may be attached to the main part of the molecule through any substitutable carbon atom of the group.

The term “carbocyclylalkyl” (alone or in combination with other term (s)) refers to a carbocyclyl group attached to the main part of the molecule via an alkylene group. For example, C ₃ -C ₁₀ carbocyclyl C ₁ -C ₆ alkyl refers to a C ₃ -C ₁₀ carbocyclyl group attached to the main part of the molecule via C ₁ -C ₆ alkylene. Similarly, C ₅ -C ₇ carbocyclyl C ₁ -C ₆ alkyl refers to a C ₅ -C ₇ carbocyclyl group attached to the main part of the molecule via C ₁ -C ₆ alkylene.

The term “carbocyclylalkoxy” (alone or in combination with other term (s)), refers to a carbocyclylalkyl group attached to the main part of the molecule via an oxy group (i.e., carbocyclylalkylene-O-). For example, a C ₃ -C ₁₀ carbocyclyl C ₁ -C ₆ alkoxy refers to a C ₃ -C ₁₀ carbocyclyl C ₁ -C ₆ alkyl group attached to the main part of the molecule through an oxy group. Similarly, a C ₅ -C ₇ carbocyclyl C ₁ -C ₆ alkoxy group refers to a C ₅ -C ₇ carbocyclyl C ₁ -C ₆ alkyl group attached to the main part of the molecule through an oxy group.

The term “carbocyclylalkoxyalkyl” (alone or in combination with other term (s)) refers to a carbocyclylalkoxy group attached to the main part of the molecule via an alkylene group (i.e. carbocyclylalkylene-O-alkylene-). For example, C ₃ -C ₁₀ karbotsiklilC ₁ -C ₆ alkoxyC ₁ -C ₆ alkyl refers to a C ₃ -C ₁₀ karbotsiklilC ₁ -C ₆ alkoxy group attached to the parent molecular moiety through a C ₁ -C ₆ alkylene group.

The term “carbocyclylalkoxycarbonyl” (alone or in combination with other term (s)) refers to a carbocyclylalkoxy group attached to the main part of the molecule via a carbonyl group (i.e., -C (O) -O-alkylene carbocyclyl). For example, C ₃ -C ₁₀ carbocyclyl C ₁ -C ₆ alkoxycarbonyl refers to a C ₃ -C ₁₀ carbocyclyl C ₁ -C ₆ alkoxy group attached to the main part of the molecule via a carbonyl group. By way of non-limiting examples, “phenylethoxycarbonyl” may be depicted as

The term “carbocyclylalkylcarbonyl” (alone or in combination with other term (s)) refers to a carbocyclylalkyl group attached to the main part of the molecule via a carbonyl group (i.e., -C (O) -alkylene carbocyclyl). For example, “phenylethylcarbonyl” may be depicted as

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

.

.

The term “carbocyclyloxy” (alone or in combination with other term (s)) refers to a carbocyclyl group attached to the main part of the molecule through an oxy group (i.e., carbocyclyl-O-).

The term “carbocyclyloxyalkyl” (alone or in combination with other term (s)) refers to a carbocyclyloxy group attached to the main part of the molecule via an alkylene group (i.e. carbocyclylo-O-alkylene-).

The term “carbocyclyloxycarbonyl” (alone or in combination with other term (s)) refers to a carbocyclyloxy group attached to the main part of the molecule via a carbonyl group (i.e., -C (O) -O-carbocyclyl). For example, “phenyloxycarbonyl” may be depicted as

The term “carbocyclylthio” (alone or in combination with other term (s)) refers to a carbocyclyl group attached to the main part of the molecule through a sulfur atom (i.e. carbocyclyl-S-).

The term “carbocyclylthioalkoxy” (alone or in combination with other term (s)) refers to carbocyclylalkylene-S-.

The term “carbocyclylthioalkoxyalkyl” (alone or in combination with other term (s)) refers to carbocyclyl-alkylene-S-alkylene-.

The term “carbocyclylthioalkyl” (alone or in combination with other term (s)) refers to a carbocyclylthio group attached to the main part of the molecule via an alkylene group (i.e. carbocyclyl-S-alkylene-).

The term “carbocyclyl carbocyclyl” (alone or in combination with other term (s)) refers to a carbocyclyl group attached to the main part of the molecule through another carbocyclyl group (i.e. carbocyclyl-carbocyclyl-). For example, C ₃ -C ₁₀ carbocyclyl C ₅ -C ₇ carbocyclyl refers to a C ₃ -C ₁₀ carbocyclyl group attached to the main part of the molecule via a C ₅ -C ₇ carbocyclyl group (i.e. C ₃ -C ₁₀ carbocyclyl─C ₅ -C ₇ carbocyclyl─).

The term “carbocyclyl carbocyclylalkyl” (alone or in combination with other term (s)) refers to a carbocyclyl carbocyclyl group attached to the main part of the molecule via an alkylene group.

The term “carbocyclylalkoxycarbocyclylalkyl” (alone or in combination with other term (s)) refers to carbocyclyl-alkylene-O-carbocyclyl-alkylene-. For example, C ₃ -C ₁₀ carbocyclyl C ₁ -C ₆ alkoxyC ₅ -C ₇ carbocyclyl C ₃ -C ₄ alkyl refers to C ₃ -C ₁₀ carbocyclyl-C ₁ -C ₆ alkylene-OC ₅ -C ₇ carbocyclyl-C ₃ -C ₄ alkylene.

The term “(carbocyclylalkyl) carbocyclylalkyl” (alone or in combination with other term (s)) refers to carbocyclyl-alkylene-carbocyclyl-alkylene-. For example, C ₃ -C ₁₀ karbotsiklilC ₁ -C ₆ alkylC ₅ -C ₇ karbotsiklilC ₃ -C ₄ alkyl refers to a C ₃ -C ₁₀ karbotsiklilC ₁ -C ₆ alkylene-C ₅ -C ₇ -C karbotsiklilC _{3 4} alkylene.

The term “carbocyclylalkoxyheterocycloalkyl” (alone or in combination with other term (s)) refers to carbocyclyl-alkylene-O-heterocyclyl-alkylene-.

The term “carbocyclylcarbonylheterocycloalkyl” (alone or in combination with other term (s)) refers to carbocyclyl-C (O) -heterocyclyl-alkylene-.

The term “carbocyclyl heterocycloalkyl” (alone or in combination with other term (s)) refers to carbocyclyl heterocyclyl alkylene.

The term “carbocyclylcarbonylcarbocyclylalkyl” (alone or in combination with other term (s)) refers to carbocyclyl-C (O) -carbocyclyl-alkylene-. For example, C ₃ -C ₁₀ carbocyclylcarbonyl C ₄ -C ₈ carbocyclyl C ₁ -C ₆ alkyl refers to C ₃ -C ₁₀ carbocyclyl-C (O) -C ₄ -C ₈ carbocyclyl-C ₁ -C ₆ alkylene-.

The term “(carbocyclylalkyl) heterocycloalkyl” (alone or in combination with other term (s)) refers to carbocyclyl-alkylene-heterocyclyl-alkylene.

The term “carbonyl” (alone or in combination with other term (s)) refers to —C (O) -, which may also be depicted as

The term “carboxy” (alone or in combination with other term (s)) means —C (O) —OH, which may also be depicted as

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

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

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

The term “cycloalkyl” (alone or in combination with other term (s)) refers to a saturated carbocyclyl group containing zero ring heteroatoms and usually 3-18 carbon as ring members. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpininil.

The term “cycloalkylcarbonyl” (alone or in combination with other term (s)) refers to a cycloalkyl group attached to the main part of the molecule via a carbonyl group.

The term “cyano” (alone or in combination with other term (s)) means —CN, which can also be represented

as

The term “dialkylamino” (alone or in combination with other term (s)) refers to —NR _A R _B , where R _A and R _{B are} independently selected from alkyl groups.

The term “dialkylaminocarbonyl” (alone or in combination with other term (s)) refers to a dialkylamino group attached to the main part of the molecule via a carbonyl group (i.e. N (R _A R _B ) -C (O) -, where R _A and R _{B are} independently selected from alkyl groups).

The term “formyl” (alone or in combination with other term (s)) refers to the group —C (O) H.

The term “halogen” (alone or in combination with other term (s)) means a fluorine radical (which can be represented as -F), a chlorine radical (which can be represented as -Cl), a bromine radical (which can be depicted as -Br), or the radical iodine (which can be depicted as -I).

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

The prefix “perhalogen” indicates that each hydrogen radical on the substituent to which the prefix is attached is replaced by an independently selected halogen radical, that is, each hydrogen radical on the substituent is replaced by a halogen radical. If all halo radicals are the same, then the prefix usually defines the halo radical. Thus, for example, the term “perfluoro” means that each hydrogen radical of the substituent to which the prefix is attached is replaced by a fluorine radical. For example, the term “perfluoroalkyl” means an alkyl substituent in which each hydrogen radical is replaced with a fluorine radical. Non-limiting examples of perfluoroalkyl substituents include trifluoromethyl (—CF ₃ ), perfluoroisopropyl, perfluorobutyl, perfluorodecyl, and perfluorododecyl. Another example, the term “perfluoroalkoxy” means an alkoxy substituent in which each hydrogen radical is replaced by a fluorine radical. Non-limiting examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF ₃ ), perfluoroisopropoxy, perfluorobutoxy, perfluorodecoxy and perfluorododecoxy.

The terms “heterocycle” or “heterocyclo” or “heterocyclyl” (alone or in combination with other term (s)) refer to saturated (eg, “heterocycloalkyl”), partially unsaturated (eg, “heterocycloalkenyl” or “heterocycloalkynyl”) or a completely unsaturated (eg, “heteroaryl”) ring system, usually containing 3-18 ring atoms, in which at least one ring atom is a heteroatom (i.e. nitrogen, oxygen or sulfur), and the remaining atoms rings are independently selected from the group consisting of carbon genus, nitrogen, oxygen and sulfur. A heterocyclyl group may be attached to the main part of the molecule by any substitutable carbon or nitrogen atom in the group, provided that a stable molecule is formed.

Heterocyclyl may be, without limitation, a single ring, which typically contains 3-14 ring atoms (i.e., M ₃ -M ₁₄ heterocyclyl), 3-8 ring atoms (i.e., M ₃ -M ₈ heterocyclyl), 3-6 ring atoms (i.e., M ₃ -M ₆ heterocyclyl) or 5-6 ring atoms (i.e., M ₅ -M ₆ heterocyclyl). Non-limiting examples of single ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolynyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinolazolithiol azolithiol azole triol. , thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as azoximil), 1,2,5-oxadiazole sludge (also known as “furazanil”) and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2, 3-dioxazolyl, 1,2,4-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 1,2-diazinyl), pyrimidinyl (also known as 1,3-diazinyl) and pyrazinyl (also known as 1,4-diazinyl)), piperazinyl , triazinyl (including s-triazinyl (also known as “1,3,5-triazinyl”) , as-triazinyl (also known 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, thiepinyl and diazepinyl.

Heterocyclyl may also include, without limitation, two or more rings fused together, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl , pyridinyl, pyranopyrrolyl, 4H-quinolisinyl, purinyl, pyridopyridinyl (including pyrido [3,4-b] pyridinyl, pyrido [3,2-b] pyridinyl and pyrido [4,3-b] pyridinyl), pyridopyrimidine and pteridinyl. Other non-limiting examples of fused ring heterocyclyls include benzocondensed heterocyclyls such as indolyl, isoindolyl, indolinyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (including quinolinyl (also known as “1-benzazinyl) ) and isoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl, quinoxaline, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) and quinazolinyl (also known as “1,3-benzodiazinyl”)) benzopyr nyl (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”, “thionaphenyl” and “benzothiofuranyl”), isobenzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl” and “isobenzothiofuranyl”), benzothiazolyl, benzothiothiazole, iazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl and 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4 -benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl and acridinyl.

The term “two fused rings” heterocyclyl (alone or in combination with other term (s)) means a saturated, partially saturated or aromatic heterocyclyl containing two fused rings. Non-limiting examples of double-fused heterocyclyls include naphthyridinyl (including [1,8] naphthyridinyl and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinyl pyridinopyr pteridinyl, indolyl, isoindolyl, indolinyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxol nile, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzotriazolyl, benzoxazinyl, and tetrahydroisoquinolinyl benzoizoksazinil.

As members of the ring, heterocyclyl may contain one or more sulfur atoms; and in some cases, the sulfur atom (s) are oxidized (s) to SO or SO ₂ . The nitrogen heteroatom (s) in the heterocyclyl may be quaternized or not quaternized, and may be oxidized to N-oxide or not oxidized. In addition, nitrogen heteroatom (s) may be N-protected or not protected.

As used herein, the number of ring atoms in a heterocyclyl moiety can be determined using the prefix “M _x -M _y ”, where x is the minimum number and y is the maximum number of ring atoms in the heterocyclyl moiety.

The term “heterocycloalkoxy” (alone or in combination with other term (s)) refers to a heterocycloalkyl group attached to the main part of the molecule through an oxy group.

The term “heterocycloalkoxyalkyl” (alone or in combination with other term (s)) refers to a heterocycloalkoxy group attached to the main part of the molecule via an alkylene group (i.e., heterocyclyl-alkylene-O-alkylene-).

The term “heterocycloalkoxycarbonyl” (alone or in combination with other term (s)) refers to a heterocycloalkoxy group attached to the main part of the molecule through a carbonyl group (i.e., heterocyclyl-alkylene-O-C (O) -).

The term “heterocycloalkyl” (alone or in combination with other term (s)) refers to heterocyclyl attached to the main part of the molecule via an alkylene group (eg, heterocycloC ₁ -C ₆ alkyl).

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

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

The terms “heterocyclyloxy” or “(heterocyclo) oxy” (alone or in combination with other term (s)) refers to a heterocyclyl group attached to the main part of the molecule through an oxy group.

The term “(heterocyclo) oxyalkyl” (alone or in combination with other term (s)) refers to a heterocyclyloxy group attached to the main part of the molecule via an alkylene group (i.e., heterocyclyl-O-alkylene-).

The term “(heterocyclo) oxycarbonyl” (alone or in combination with other term (s)) refers to a (heterocyclo) oxy group attached to the main part of the molecule via a carbonyl group (i.e., heterocyclyl-OC (O) - )

The term “heterocyclotio” (alone or in combination with other term (s)) refers to heterocyclyl attached to the main part of the molecule via —S—.

The term “heterocyclothioalkoxy” (alone or in combination with other term (s)) refers to heterocyclyl-alkylene-S-.

The term “heterocyclothioalkoxyalkyl” (alone or in combination with other term (s)) refers to heterocyclyl-alkylene-S-alkylene-.

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

The term “heterocyclo-carbocyclyl” (alone or in combination with other term (s)) refers to heterocyclyl attached to the main part of the molecule via a carbocyclyl group (ie, heterocyclo-carbocyclyl-).

The term “heterocyclo-carbocyclylalkyl” (alone or in combination with other term (s)) refers to a heterocyclo-carbocyclyl group attached to the main part of the molecule via an alkylene group (ie, heterocyclyl-carbocyclyl-alkylene-).

The term “(heterocyclo) alkoxycarbocyclylalkyl” (alone or in combination with other term (s)) refers to heterocyclo-alkylene-O-carbocyclyl-alkylene-.

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

The term “(heterocyclo) heterocycloalkyl” (alone or in combination with other term (s)) refers to heterocyclo-heterocyclo-alkylene-.

The term “(heterocyclo) alkoxyheterocycloalkyl” (alone or in combination with other term (s)) refers to heterocyclo-alkylene-O-heterocyclo-alkylene-.

The term “(heterocyclo) carbonylheterocycloalkyl” (alone or in combination with other term (s)) refers to heterocyclo-C (O) -heterocycle-alkylene─.

The term “(heterocycloalkyl) carbocyclylalkyl” (alone or in combination with other term (s)) refers to heterocyclo-alkylene-carbocyclyl-alkylene-.

The term “(heterocycloalkyl) heterocycloalkyl” (alone or in combination with other term (s)) refers to heterocycloalkylene heterocycloalkylene. Thus, for example, (M ₃ -M ₁₀ heterocycloC ₁ -C ₆ alkyl) M ₅ -M ₆ heterocyclo C ₁ -C ₃ alkyl means M ₃ -M ₁₀ heterocyclo─C ₁ -C ₆ alkylene─M ₅ -M ₆ heterocyclo ─C ₁ -C ₃ alkylene.

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

The term “heteroarylalkoxy” (alone or in combination with other term (s)) refers to heteroarylalkyl attached to the main part of the molecule via an oxy group (i.e., heteroaryl-alkylene-O-). Representative examples of heteroarylalkoxy include, but are not limited to, 2-pyridin-3-yl-ethoxy, 1,3-thiazol-5-yl-methoxy, 3-quinolin-3-yl-propoxy and 5-pyridin-4-yl-pentyloxy.

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

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

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

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

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

The term “heteroaryloxy” (alone or in combination with other term (s)) refers to a heteroaryl group attached to the main part of the molecule through an oxy group. Representative examples of heteroaryloxy include, but are not limited to, pyridin-3-yloxy and quinolin-3-yloxy.

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

The term “heteroaryloxycarbonyl” (alone or in combination with other term (s)) refers to a heteroaryloxy group attached to the main part of the molecule via a carbonyl group (i.e., heteroaryl-O — C (O) -).

The term “heteroarylthio” (alone or in combination with other term (s)) refers to a heteroaryl group attached to the main part of the molecule via —S—.

The term “heteroarylthioalkoxy” (alone or in combination with other term (s)) refers to heteroaryl-alkylene-S-.

The term “heteroarylthioalkoxyalkyl” (alone or in combination with other term (s)) refers to heteroaryl-alkylene-S-alkylene-.

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

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

The term “hydroxy” (alone or in combination with other term (s)) refers to —OH.

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

The term “keto” (alone or in combination with other term (s)) means an oxo radical and can be depicted as = O.

, где H может быть необязательно замещен алкилом или гидрокси, и в этих случаях заместитель будет алкилиминоалкилом или гидроксииминоалкилом, соответственно.The term “iminoalkyl” (alone or in combination with other term (s)) refers to a radical of the formula

where H may be optionally substituted by alkyl or hydroxy, and in these cases, the substituent will be alkyliminoalkyl or hydroxyiminoalkyl, respectively.

The term “nitro” (alone or in combination with other term (s)) means ─ NO ₂ .

).The term “oxo” (alone or in combination with other term (s)) refers to the group = O (i.e.,

)

The term “hydroxy” (alone or in combination with other term (s)) means —O—.

The term “propargyl” (alone or in combination with other term (s)) means a monovalent radical depicted as —CH ₂ —CH≡CH.

The term “sulfonyl” (alone or in combination with other term (s)) means —S (O) ₂ -, which may also be depicted as

The term “sulfinyl” (alone or in combination with other term (s)) means —S (O) -, which may also be depicted as

The term “thio” or “thia” (alone or in combination with other term (s)) means —S—.

The term “thiol,” “mercapto” or “sulfhydryl” (alone or in combination with other term (s)) means a sulfhydryl substituent (i.e., —SH). Thus, for example, thiolalkyl is an alkyl substituent in which one or more hydrogen radicals are replaced by —SH, while alkylthio is alkyl-S—.

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

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

The term “thiocarbonyl” (alone or in combination with other term (s)) means carbonyl in which the oxygen atom is replaced by sulfur. Such a substituent may be depicted as -C (S) -, and may also be depicted as

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

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

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

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

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

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

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

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

The term “diastereomer” refers to stereoisomers that are not enantiomers or mirror images of each other.

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

The term “tautomer” refers to isomers that are interconverting. For example, enols and ketones are tautomers, since they turn into each other when treated with either acid or base.

, и [1,4] имидазол, изображенный как

, являются позиционными изомерами.The term “positional isomer” refers to any of two or more structural isomers that differ in the position of a particular substituent or group. Functional groups can be attached to structurally nonequivalent positions of the carbon skeleton. For example, [1,3] imidazole depicted as

, and [1,4] imidazole depicted as

are positional isomers.

The term “N-protecting group” or “N-protecting” refers to groups capable of protecting an amino group from undesired reactions. Commonly used N-protecting groups are described in Greene and Wuts, Protecting Groups in Chemical Synthesis ( 3 ^{rd ed., John Wiley & Sons} , NY ( 1999), disclosed herein by reference in its entirety. Non-limiting examples of N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, tert-butyl acetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzyl ; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such ac phenylsulfenyl (phenyl-S-) or triphenylmethylsulphenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S (O) -) or tert-butylsulfinyl (t-Bu-S (O) - ); carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxybenzyloxybenzylcarbonyl, 3,5-dimethoxybenzyloxybenzyloxybenzylcarbonyl, 3,5-dimethoxybenzyloxybenzylcarbonyl -methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trime oxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, phenoxycarbonyl, 2,2-methoxycarbonyl, ally nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl; p-methoxyphenyl; and silyl groups such as trimethylsilyl. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

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

AcOH = acetic acid

atm. = atmosphere

Boc = N-tert-butoxycarbonyl (protecting group)

CDI = 1,1'-carbonyldiimidazole

CH ₂ Cl ₂ = methylene chloride (dichloromethane)

CuI = copper iodide [copper (I) iodide]

DCE = 1,2-Dichloroethane

DEAD = diethyl azodicarboxylate

DMA = N-N-Dimethylacetamide

DMAP = 4-dimethylaminopyridine

DMF = N, N-dimethylformamide

DMSO = Dimethyl Sulfoxide

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

EMME = 2-ethoxymethylene malonic acid diethyl ester

Et ₃ N = triethylamine

Ether = diethyl ether

EtI = ethyl iodide

EtOAc = ethyl acetate

EtOH = Ethanol

Fe = iron

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

Chloride Fmoc = 9-fluorenylmethylchloroformate

HOBt = N-hydroxybenzotriazole

Hyunig base = N, N-diisopropylethylamine

IPA = isopropyl alcohol

K ₂ CO ₃ = potassium carbonate

KOH = potassium hydroxide

LDA = lithium diisopropylamine

MeOH = methanol

MsCl = methanesulfonyl chloride

NaH = sodium hydride

NH ₂ OH · HCl = hydroxylamine hydrochloride

NMP = 1-methyl-2-pyrrolidinone

Mg ₂ SO ₄ = magnesium sulfate

Na ₂ SO ₄ = sodium sulfate

NH ₃ = ammonium

NH ₄ Cl = ammonium chloride

NH ₄ OH = ammonium hydroxide

PG = protecting group such as Boc- or Troc-

POCl ₃ = phosphorus oxychloride

R-MgCl = Grignard reagent

R-I = alkyl iodide or substituted alkyl iodide

SnCl2 = Bivalent Tin Chloride (Tin (II) Chloride)

TFA = trifluoroacetic acid

THF (THF) = tetrahydrofuran

TLC = thin layer chromatography

triflate anhydride = trifluoromethanesulfonic acid anhydride

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

General synthesis methods and examples

The following synthesis methods and schemes illustrate the general methods by which the compounds of the present invention can be prepared. Starting materials may be obtained from commercial sources or obtained by methods well known to those skilled in the art. As an example, synthesis pathways similar to those shown below may be used together with synthesis methods known in the field of synthesis of organic compounds, or variants thereof obvious to one skilled in the art.

In the present invention are meant compounds obtained by any synthesis method or metabolic process. Metabolic processes include processes that occur in humans or animals ( in vivo ), or processes that occur in vitro .

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

Obtaining compounds of formulas I-VIII

с

Compounds of formula I can be synthesized by reaction

from

,

,

,

,

, или

с

,

,

,

,

,

или

where W ₁ , W ₂ , A, B, X, Y, R ¹⁰ , R ²² and R ⁵⁰ have the same meaning as indicated in the above embodiments or examples, and K is Cl or other halogen. Similarly, the compounds of formulas II-VIII can be obtained by interaction

,

,

,

,

, or

from

,

,

,

,

,

or

respectively.

The synthesis of compounds of formulas I-VIII is shown as examples in schemes 1-8. Typical compounds of formula I, where

represents

R ¹⁰ , R ¹⁷ and R ³⁵ such as defined above, and Z represents NR ⁴¹ can be obtained using the procedures presented in scheme 1.

Scheme 1

Amines of formula (2) in which R ⁴¹ is hydrogen can be treated with N, N-dimethylformamidine compounds of formula (1) in the presence of an acid, such as, but not limited to, acetic acid, at elevated temperatures (for example, from about 80ºC to about 150ºC), thus giving compounds of formula (3). Acetic acid may act as a solvent. Other suitable solvents may also be used in this reaction.

N-alkylation of compounds of formula (2) in which R ⁴¹ is hydrogen gives a compound of formula (2) or (3) in which R ⁴¹ is alkyl. This method can be accelerated with an alkylating agent of the formula R ⁴¹ X ¹ , where X ¹ is halogen, tosylate, triflate or mesylate, in the presence of a base such as, but not limited to, an organic base such as triethylamine or diisopropylamine, or an inorganic base, such as sodium, cesium or potassium carbonate, in a suitable solvent and at a temperature in the range of from about room temperature to about 100 ° C.

Scheme 2

The preparation of the compound N, N-dimethylformamidine of the formula (1) can be carried out by the method shown in Scheme 2. Ketones of the formula (4) and esters of the formula (5) in the presence of a base such as, but not limited to, sodium or potassium hydrate ( or sodium metal) at about 0 ° C. in a suitable solvent, such as, but not limited to, diethyl ether, giving a salt of formula (6), where M is potassium or sodium. The compound of formula (6) was treated with 2-cyanoacetamide in the presence of piperidine acetate at reflux to give the nitriles of formula (7a) and (7b). The regioisomers (7a) and (7b) can be separated at this point in time or later in the synthesis pathway using purification techniques known to those skilled in the art. Compounds of formula (7a) can either be converted to compounds of formula (8) in which X ² is Cl by treatment with phosphorus oxychloride or into compounds of formula (8) in which X ² is Br by treatment with tetrabutylammonium bromide and pentoxide phosphorus in a suitable solvent under reflux. A solution of the compounds of formula (8), where X ² is Cl or Br, and liquid ammonia were reacted in a sealed vessel at high pressure at elevated temperature, for example at about 130 ° C, to obtain compounds of formula (9). Compounds of formula (9) and N, N-dimethylformamide dimethylacetal in a solvent, such as, but not limited to, toluene, when refluxed, gave N, N-dimethylformamidine compounds of formula (1).

Scheme 3

Compounds of formula (2) in which R ⁴¹ is hydrogen and X is O or S can be prepared from compounds of formula (10) according to Scheme 3, where R ₁₀₁ is a leaving group, such as, but not limited to halogen, triflate or mesylate (the latter two can be obtained from the corresponding alcohol using methods known to one skilled in the art) by two-step synthesis, namely, by reduction of the nitro group followed by substitution of R ₁₀₁ or substitution of R ₁₀₁ followed by reduction the occurrence of a nitro group.

Substitution of R _{101 with a} group R ²² XH, in which X is O or S, can be accelerated in the presence of a suitable base, such as, but not limited to, potassium, cesium or sodium carbonate or bicarbonate, or sodium or potassium hydride and, optionally , in the presence of 18-crown-6, at elevated temperature. The reaction can usually be carried out in a solvent, such as, but not limited to, N, N-dimethylformamide or dimethyl sulfoxide, at a temperature of from about room temperature to about 180 ° C. The reaction can be carried out in a solvent, such as, but not limited to, N, N-dimethylformamide or dimethyl sulfoxide, at a temperature of from about room temperature to about 180 ° C. The reaction can also be carried out in a microwave. It is understood that compounds of formula (11) can also be prepared by reacting compounds of formula (10), where R ₁₀₁ is ─X─H, with compounds of formula R ²² X ³ , where X ³ is a leaving group, such as, but not limited to halogen, triflate or mesylate using the above reaction conditions. Replacement of the reaction groups can also be carried out in the presence of a metal catalyst, such as, but not limited to, metallic copper, CuI or palladium acetate, optionally in the presence of a ligand, such as, but not limited to, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl or tri-tert-butylphosphine and optionally in the presence of a base such as, but not limited to, pyridine, triethylamine, sodium tert-butoxide, cesium carbonate or sodium hydride. The reaction is usually carried out at a temperature of from about room temperature to about 180 ° C., in a solvent such as, but not limited to, toluene or N, N-dimethylformamide.

Reduction of the nitro group can be accomplished by treating the nitro compound with a condensing agent, such as, but not limited to, iron powder / ammonium chloride or tin (II) chloride, in a suitable solvent.

It is also understood that compounds of formula (10) can be converted into compounds of formula (2) by first reducing the functional nitro group and then replacing the functional group using the reaction conditions described above.

Obtaining aminophenyl-condensing agents (10, 11 and 12)

It is possible to use a wide variety of aminophenyl condensing agents. The agents in Scheme 3 are examples of this diversity.

In the usual preparation, the substituted 2-chloronitrobenzene compound in dimethylformamide (DMF) was treated with sodium thiophenolate at about 50 ° C for about 2 hours, cooled and diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give the substituted- 2-phenylsulfanylnitrobenzene. This nitrobenzene compound was then reduced with divalent tin chloride (SnCl ₂ ) or iron (Fe) in ethanol. The pH of the reaction mixture was adjusted to 12 with 1N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to give the substituted-2-phenylsulfanylaminobenzene compound 10 .

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

Similarly, any compound 10 in which R ⁹ is hydroxy or protected hydroxyl can be further modified by alkylation of the hydroxy group using substituted benzyl bromide to give the corresponding 5-substituted-phenoxy-2-substituted-phenylsulfanylaminobenzene compound 11 .

Scheme 4

R ^{9 is as} defined above;

X represents OH, NH ₂ , NHR, halogen, alkyl or alkoxy;

R represents alkyl, alkoxy, bromo, fluoro, chloro or cyano.

Preparation of 7-substituted-4-aminophenyl-substituted-pyrido [2,3-d] pyrimidine compounds

Representative preparation of 7-substituted-4-aminophenyl-substituted-pyrido [2,3-d] pyrimidine compounds (Scheme 6) involves condensing a substituted aminophenyl condensing agent (as described in Scheme 4) and a 6-substituted-2-amidino-3- compound cyanopyridine 9 (Scheme 5).

As described in Scheme 4, it is possible to use a wide variety of aminophenyl condensing agents.

The preparation of 7-substituted-4-aminophenyl-substituted-pyrido [2,3-d] pyrimidines can be accomplished by condensing the compound N, N-dimethylformamidino 9 with various condensing agents described in Scheme 4.

The preparation of N, N-dimethylformamidine 9 compounds can be carried out by the method shown in Scheme 5. Substituted alkyl methyl ketone and ethyl formate were added to a solution of sodium hydride diethyl ether (or sodium metal) at about 0 ° C. over about 2 hours. After addition, the reaction mixture was allowed to stir at room temperature overnight. Some more diethyl ether was added, and the precipitate was immediately isolated by vacuum filtration, dried in a vacuum desiccator. This substance was dissolved in water with 2-cyanoacetamide. A piperidine acetate solution was added and the resulting solution was heated under reflux for about 2 hours. The mixture was cooled to room temperature and the pH was adjusted to 4 with glacial acetic acid. The resulting solid was isolated by vacuum filtration, washed with water, dried and identified as 6-substituted-2-oxo-1,2-dihydropyridine-3-carbonitrile 24 . Compound 24 can either be converted to 2-chloropyridine using phosphorus oxychloride (as shown in Scheme 5), or to 2-bromopyridine. 2-Bromopyridine was obtained by treating a solution of toluene of compound 24 and reacting it with tetrabutylammonium bromide and phosphorus pentoxide while heating under reflux for about 5 hours. The reaction mixture was cooled, water was added and the mixture was stirred for about 2 hours at room temperature. The reaction mixture was diluted with toluene, the organic layer was separated, washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-bromopyridine. The ethanolic solution of either 2-chloropyridine or 2-bromopyridine and liquid ammonia were reacted in a sealed vessel under high pressure at about 130 ° C for about 20 hours. The reaction mixture was concentrated in vacuo, and the residue was washed with water and dried to give 6-substituted-2-amino-nicotinonitrile 25 . Compound 25 and N, N-dimethylformamide dimethyl acetal were dissolved in toluene and heated under reflux for about 3 hours. The resulting solution was cooled to room temperature and concentrated in vacuo to give 6-substituted-3-cyanopyridin-2-yl-N, N-dimethylformamidine 9 .

Scheme 5

R ^{7 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylalkylamino, cyanoalkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, morpholino, hydrazino, alkylaminoalkoxy, alkoxyalkylamino and aryl.

As described above, the preparation of 7-substituted-4-aminophenyl-substituted-pyrido [2,3-d] pyrimidines can be accomplished by condensation of a substituted 6-substituted-3-cyanopyridin-2-yl-N, N-dimethylformamidine 9 , as shown in Scheme 5, with various condensing agents, some of which are shown in Scheme 4. This condensation reaction is shown in Scheme 6.

In the usual preparation, compound 9 and an aminophenyl condensing agent similar to the agents shown in Scheme 4 were dissolved in acetic acid and stirred at about 130 ° C. for about 15 minutes. The mixture was cooled to room temperature, acetic acid was removed in vacuo, and the resulting precipitate was purified by reverse phase chromatography. At this time, any functional protecting group, such as Boc, Troc, or other groups, may be removed in any known manner to produce the final products.

Scheme 6

R ⁷ , R ⁹ , X and R are as defined above

Typical compounds of formula I, where ring B in

represents a five-membered ring heterocycle, and W ₁ represents CH, R ¹⁰ , R ¹⁷ and R ³⁵ , as defined above, and Z represents NR ⁴¹ , can be obtained using the procedure presented in scheme 7, and their preparation consists of the interaction of alkylamino substituted heterocycles, such as 13, with Meldrum acid and triethyl orthoformate and heating to about 100 ° C. The reaction mixture was concentrated and purified by chromatography to give aminomethylene malonic acid ester 14 . Compound 14 was then dissolved in diphenyl ether and the resulting solution was heated to 250 ° C for about 30 minutes to give 15 . A mixture of compound 15 was mixed with phosphorus oxychloride (POCl ₃ ) and heated to about 50 ° C with stirring for 6 hours, cooled and quenched by pouring onto ice. The mixture was then cooled, adjusted to pH 10 with concentrated ammonium hydroxide, and extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 16 . In the typical preparation, compound 16 and an aminophenyl condensing agent similar to those described in Scheme 4 were condensed with 2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3.3] undecane tris (dibenzylideneacetone) with dipalladium and sodium tert-butoxide in a solvent, usually toluene and the like, to give 21 .

Scheme 7

Typical compounds of formula I, where ring B in

represents a five-membered ring heterocycle, and W ₁ represents N, R ¹⁰ , R ¹⁷ and R ³⁵ , as defined above, and Z represents NR ⁴¹ , can be obtained using the procedure presented in scheme 8, and their preparation consists in the interaction of alkylamino substituted heterocycles, such as 17, with formamide when heated to reflux. The pyrimidine product 18 was then reacted with phosphorus oxychloride (POCl ₃ ) to give a condensing partner 19 . In the typical preparation of compound 19 and aminophenyl, a condensing agent similar to the agents described in Scheme 4 was dissolved in ethanol and heated under reflux for 12 hours to obtain 20 .

Scheme 8

Typical compounds of formula I, where ring B in

represents a five-membered ring heterocycle, and W1 represents N or CH, R10, R17 and R35, such as described above, and Z represents NR41, can be obtained

The optimal reaction conditions and the reaction time of each individual step may vary depending on the particular reagents and substituents used in the reagents used. Unless otherwise indicated, solvents, temperatures, and other reaction conditions can be easily selected by one of skill in the art. The reactions can be carried out by conventional methods, for example, removing the solvent from the precipitate and further purifying by methods commonly used in the art, such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography.

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

Example 1

4-amino-N- [2- (4-hydroxyphenylsulfanyl) -5-methylphenyl] -2- (2-methoxyethylamino) pyrimidine-5-carboxamidine

The product of Example 156 (42 mg, 0.1 mmol) in 2-methoxyethylamine (1 ml) was heated at 180 ° C. for 2 hours in a microwave. The solvent was evaporated and the residue was purified by TFA HPLC to give the title compound as the trifluoroacetic acid salt (15 mg, 28%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.31 (s, 3H), 3.28 (s, 3H), 3.49 (m, 4H), 6.86 (m, 3H) 7.28 (m, 4H), 8.17 (s, broad, 3H), 8.73 (s, broad, 1H), 9.75 (s, broad, 2H), 11.33 ( c, broad. 1H);

MS (ESI +) m / z 425 (M + H) +.

Example 2

4-amino-2-butylamino-N- [2- (4-hydroxyphenylsulfanyl) -5-methylphenyl] pyrimidine-5-carboxamidine

The product of Example 156 (42 mg, 0.1 mmol) in butylamine (1 ml) was heated at 180 ° C. for 2 hours in a microwave. The solvent was evaporated and the residue was purified by TFA HPLC to give the title compound as the trifluoroacetic acid salt (13 mg, 24%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 0.90 (t, J = 7.35 Hz, 3H), 1.29 (m, 2H), 1.51 (m, 2H), 2 30 (s, 3H), 3.32 (m, 2H), 6.85 (m, 3H), 7.27 (m, 4H), 8.15 (s, broad, 3H), 8.71 (s, broad, 1H), 9.55 (s, broad, 1H), 9.92 (s, broad, 1H), 11.23 (s, broad, 1H);

MS (ESI +) m / z 423 (M + H) +.

Example 3

N- {4- [4-Methyl-2- (6-propylthieno [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenyl} acetamide

Example 3a

Ethyl 2-amino-5-propylthiophene-3-carboxylate

A solution of equimolar amounts of ethyl cyanoacetate and sulfur in dimethylformamide was treated with triethylamine (0.5 equivalents) at ambient temperature, then valerian aldehyde (1 equivalent) was added dropwise when heated to 50 ° C. After 3 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to obtain the title compound.

Example 3b

6-propylthieno [2,3-d] pyrimidin-4-ol

The product of Example 3a was reacted with an excess of formamide by heating under reflux for 3 hours. The reaction was quenched with water and the resulting precipitate was collected by filtration and washed with water and dried in vacuo to give the title compound.

Example 3c

4-chloro-6-propylthieno [2,3-d] pyrimidine

The product of example 3b was reacted with an excess of POCl ₃ under reflux for 3 hours, then at room temperature for 16 hours. The reaction mixture was poured onto ice and partitioned between water and ethyl acetate. The organic layer was concentrated to obtain the title compound.

3d example

N- {4- [4-Methyl-2- (6-propylthieno [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenyl} acetamide

The product of example 3c was reacted with the product of example 7b in ethanol under reflux for 16 hours. The reaction mixture was concentrated to obtain the title compound.

Example 4

(6-Butylthieno [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

The title compound was prepared according to the methods described in Example 3 using hexanal instead of valerian aldehyde in Example 3a.

Example 5

(5-Methyl-2-phenylsulfanylphenyl) - (2-propylthiazolo [5,4-b] pyridin-7-yl) amine

Example 5A

Butyrylaminoacetic acid methyl ester

A suspension of glycine hydrochloride (1.00 g, 7.964 mmol) in methylene chloride (40 ml), cooled to 0 ° C under nitrogen atmosphere, was treated with triethylamine (4.44 ml, 31.86 mmol) and butyryl chloride (0.93 ml, 8, 76 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and saturated saline. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound. Purification by flash chromatography on silica gel with 25% ethyl acetate / methylene chloride gave the title compound as a colorless oil (0.776 g, 4.88 mmol, 61%).

Example 5B

Thiobutyrylaminoacetic acid methyl ester

A solution of the product of Example 5A (0.774 g, 4.862 mmol) in anhydrous THF (TGF) (50 ml) was treated with Lawesson's reagent (1.338 g, 3.209 mmol), then refluxed under nitrogen for 30 minutes. The reaction mixture was cooled to 0 ^{° C.} and saturated aqueous sodium bicarbonate (40 ml) was slowly added dropwise. The mixture was stirred at room temperature for 15 minutes and then extracted with ethyl acetate (100 ml) and the organic extract was washed with saturated aqueous sodium bicarbonate (50 ml), water (2 × 25 ml) and saturated saline. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound. Purification by flash chromatography on silica gel with 1% ethyl acetate / methylene chloride gave the title compound as a colorless oil (0.790 g, 4.508 mmol, 93%).

Example 5C

2-thiobutyrylaminoacetamide

A solution of the product of Example 5B (0.788 g, 4.496 mmol) in methanol (30 ml) was saturated with ammonia gas and the reaction mixture was stirred in a closed stopper vessel at room temperature for 17 hours. The solvent was concentrated in vacuo to give the title compound, and the solid was purified by flash chromatography on silica gel with 10% methanol / methylene chloride to give the title compound as a white solid (500 mg, 3.12 mmol, 69%).

Example 5D

2-propylthiazol-5-ylamine

A solution of the product of Example 5C (395 mg, 2.465 mmol) in anhydrous ethyl acetate (12 ml) was treated with phosphorus tribromide (0.189 ml, 1.972 mmol) in a nitrogen atmosphere and stirred at room temperature for 20 minutes. Additionally phosphorus tribromide (0.050 ml) was added and allowed to mix for 5 minutes. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (25 ml). The aqueous washes were extracted with ethyl acetate (2 × 50 ml) and the organic extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound. Purification by flash chromatography on silica gel with 3% methanol / methylene gave the title product (175 mg, 1.23 mmol, 50%).

Example 5E

2,2-Dimethyl-5 - [(2-propylthiazol-5-ylamino) methylene] - [1,3] dioxan-4,6-dione

A solution of the product of Example 5D (212.7 mg, 1.496 mmol) in anhydrous ethanol (5 ml) was treated with Meldrum acid (237 mg, 1.645 mmol) and triethyl orthofromate (0.25 ml, 1.496 mmol) at room temperature and the reaction mixture was preliminarily heated heated to 100ºС oil bath. After 15 minutes, the reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. Purification by flash chromatography on silica gel with a gradient of 10% -20% ethyl acetate / methylene chloride gave the title compound as a yellow-white solid (240 mg, 0.8099 mmol, 54%).

Example 5F

2-Propyl-4H-thiazolo [5,4-b] pyridin-7-one

To a refluxed diphenyl ether (5 ml) under nitrogen atmosphere was added the product of Example 5E (230 mg, 0.7781 mmol). After heating under reflux for 5 minutes, the solution was cooled in an ice bath and diluted with hexane (50 ml). The resulting golden solid was collected by vacuum filtration and washed thoroughly with hexane to give the title compound (125 mg, 0.644 mmol, 83%).

5G example

7-Chloro-2-propylthiazolo [5,4-b] pyridine

The product of Example 5F (123 mg, 0.6332 mmol) and phosphorus oxychloride (2 ml) were refluxed for 1 hour under nitrogen. The solution was cooled in an ice bath, treated with ice, and the pH was adjusted to 7 with 6N. an aqueous solution of sodium hydroxide. It was extracted with methylene chloride (3 × 50 ml) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a brown oil (120 mg, 0.564 mmol, 89%).

Example 5H

4-methyl-2-nitro-1-phenylsulfanylbenzene

A solution of sodium thiophenolate (3.96 g, 30 mmol) in 60 ml of DMF was heated at 50 ° C. with 4-chloro-3-nitrotoluene (2.65 ml, 20 mmol) with stirring for 2 days. Cooled to room temperature and diluted with CH ₂ Cl ₂ . Washed with water and the organic layer was dried over Na ₂ SO ₄ . Filtered and concentrated in vacuo to give the title compound (4.29 g, 87%).

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 2.36 (s, 3H), 6.76 (d, J = 8.09 Hz, 1H), 7.16 (d, J = 8.46 Hz , 1H), 7.45 (m, 3H), 7.58 (m, 2H), 8.03 (s, 1H).

Example 5I

5-methyl-2-phenylsulfanylphenylamine

A solution of the product of Example 5H (1.17 g, 7.0 mmol) in 25 ml of absolute EtOH and SnCl ₂ (3.58 g, 29.8 mmol) was stirred at room temperature for 16 hours. With the help of 1n. The NaOH pH was adjusted to 12 and extracted with EtOAc. Dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (835 mg, 82%).

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 2.30 (2, 3H), 6.62 (d, J = 8.83 Hz, 1H), 6.69 (s, 1H), 7.10 (m, 3H), 7.21 (m, 2H), 7.54 (d, J = 7.72 Hz, 2H).

Example 5J

(5-Methyl-2-phenylsulfanylphenyl) - (2-propylthiazolo [5,4-b] pyridin-7-yl) amine

2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3.3] undecane (38 mg, 0.111 mmol), tris (dibenzylideneacetone) dipalladium (25) were charged into a vessel purged with dry nitrogen. 4 mg, 0.0277 mmol) and sodium tert-butoxide (82.4 mg, 0.8322 mmol). Using a pipette, a solution of the product of Example 5G (118 mg, 0.5548 mmol) in anhydrous toluene (2 ml) and a solution of the product of Example 5I (107.5 mg, 0.4993 mmol) in toluene (3 ml) were added. The reaction mixture was refluxed in an oil bath preheated to 120 ^{° C.} for 18 hours, cooled to room temperature, treated with additional Tris (dibenzylideneacetone) dipalladium (25.4 mg), and refluxed for another 2.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator in vacuo. Purification by flash chromatography on silica gel with a gradient of 1-3% ethyl acetate / methylene chloride gave the title compound (29 mg, 0.074 mmol, 15%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.00 (t, J = 7.35 Hz, 3H), 1.71-1.90 (m, 2H), 2.38 (s, 3H ), 3.05 (t, J = 7.35 Hz, 2H), 6.87 (d, J = 5.52 Hz, 1H), 7.07 (dd, J = 7.91, 1.29 Hz) , 1H), 7.12-7.31 (m, 5H), 7.37-7.46 (m, 2H), 8.15 (d, J = 5.52 Hz, 1H), 8.52 ( s, 1H);

MS (DCI / NH ₃ ) m / z 392 (M + H) ⁺ .

Example 6

4- [4-Methyl-2- (2-propylthiazolo [5,4-b] pyridin-7-ylamino) phenylsulfanyl] phenol

Example 6a

Trifluoromethanesulfonic acid 4-methyl-2-nitrophenyl ester

A solution of 4-methyl-2-nitrophenol (6.0 g, 39.1 mmol) and Et ₃ N (16.38 ml, 117.5 mmol) in 100 ml of CH ₂ Cl ₂ in an atmosphere of N _{2 was} treated with trifluoromethanesulfonic anhydride (7 , 25 ml, 43.1 mmol) at 0ºC for 30 minutes. Quenched by the addition of MeOH. Sequentially washed with 10% citric acid, 0.5 M KOH and water. Dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound, which was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ , to give a yellow oil (11.22 g, 100%).

Example 6b

4- (4-Methyl-2-nitrophenylsulfanyl) phenol

The product of Example 6a (11.22 g, 39.3 mmol) and 4-mercaptophenol (4.96 g, 39.3 mmol) in 100 ml EtOH were treated with Na ₂ CO ₃ and heated overnight under reflux. Cooled to room temperature and quenched with water. Extracted with EtOAc. Dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound, which was purified by silica gel column chromatography, eluting with 25% EtOAc / hexane, to give a red oil (8.65 g, 85%).

Example 6c

4- (2-amino-4-methylphenylsulfanyl) phenol

The product of Example 6b (8.65 g, 31.3 mmol) was reduced with SnCl ₂ in accordance with the method described in Example 5I to give the title compound as a white solid (8.51 g, 100% )

Example 6d

4- (4-methyl-2- (2-propylthiazolo [5,4-b] pyridin-7-ylamino) phenylthio) phenol

2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3.3] undecane (40.4 mg, 0.118 mmol), tris (dibenzylideneacetone) dipalladium were loaded into a vessel purged with dry nitrogen (27 mg, 0.0295 mmol) and sodium tert-butoxide (87.7 mg, 0.885 mmol). Using a pipette, a solution of the product of example 5G (125.5 mg, 0.590 mmol) in anhydrous toluene (5 ml) was added, then the product of example 6c (136 mg, 0.590 mmol). The reaction mixture was refluxed in an oil bath preheated to 110 ° C for 14 hours, cooled to room temperature, and further treated with 2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3 , 3] undecane (40.4 mg) and tris (dibenzylideneacetone) dipalladium (27 mg) and heated under reflux for another 7 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator in vacuo. Purification by flash chromatography on silica gel with a gradient of 15-30% ethyl acetate / methylene chloride gave the crude material. Purification by flash chromatography on silica gel with a gradient of 1-2% methanol / methylene chloride gave the desired title compound as a light yellow solid (20 mg, 0.049 mmol, 8%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.03 (t, J = 7.35 Hz, 3H), 1.76-1.94 (m, 2H), 2.31 (s, 3H ), 3.10 (t, J = 7.35 Hz, 2H), 5.76 (s, 1H), 6.67-6.73 (m, 2H), 6.96-7.04 (m, 1H), 7.08-7.14 (m, 1H), 7.20 (d, J = 8.46 Hz, 2H), 7.29 (s, 1H), 8.14 (d, J = 5 52 Hz, 1H); 8.55 (s, 1H); 9.73 (s, 1H);

MS (DCI / NH ₃ ) m / z 408 (M + H) ⁺ .

Example 7

N- {4- [4-Methyl-2- (2-propylthiazolo [5,4-b] pyridin-7-ylamino) phenylsulfanyl] phenyl} acetamide

Example 7a

N- [4- (4-Methyl-2-nitrophenylsulfanyl) phenyl] acetamide

The product of example 6a (1 g, 3.51 mmol) was reacted with N- (4-mercaptophenyl) acetamide (0.65 g, 351 mmol) for 18 hours in accordance with the method described in example 6b, to obtain the specified in the title compound (1.04 g, 98%).

Example 7b

N- [4- (2-amino-4-methylphenylsulfanyl) phenyl] acetamide

The product of Example 7a (0.30 g, 1 mmol) was reacted with SnCl ₂ as described in Example 5I to give the title compound (0.27 g, 100%) as a yellow oil, which was used without further cleaning up.

Example 7c

N- (4- (4-methyl-2- (2-propylthiazolo [5,4-b] pyridin-7-ylamino) phenylthio) phenyl) acetamide

2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3.3] undecane (38.6 mg, 0.1128 mmol), tris (dibenzylideneacetone) were charged into a vessel purged with dry nitrogen ) dipalladium (25.8 mg, 0.0282 mmol) and sodium tert-butoxide (83.8 mg, 0.8463 mmol). Using a pipette, a solution of the product of Example 5G (120 mg, 0.5642 mmol) in anhydrous toluene (5 ml) was added, then the product of Example 7b (130 mg, 0.4773 mmol). The reaction mixture was heated in an oil bath preheated to 100ºC for 2.5 hours, cooled to room temperature, 2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo was further treated [3,3, 3] undecane (38.6 mg), tris (dibenzylideneacetone) dipalladium (25.8 mg) and the starting aniline (130 mg) and heated at 100 ° C for another 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator in vacuo. Purification by flash chromatography on silica gel with a gradient of 40 to 60% ethyl acetate / methylene chloride gave the desired title compound as a brown foam (26 mg, 10%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.01 (t, J = 7.35 Hz, 3H), 1.73-1.91 (m, 2H), 2.01 (s, 3H), 2.34 (s, 3H), 3.07 (t, J = 7.54 Hz, 2H), 6.78 (d, J = 5.52 Hz, 1H), 6.97-7, 09 (m, 1H), 7.16-7.30 (m, 3H), 7.36 (s, 1H), 7.51 (d, J = 8.82 Hz, 2H), 8.15 (d , J = 5.52 Hz, 1H), 8.53 (s, 1H), 9.99 (s, 1H);

MS (DCI / NH ₃ ) m / z 449 (M + H) ⁺ .

Example 8

N- {4- [4-Methyl-2- (2-methyl-2H-pyrazolo [3,4-b] pyridin-4-ylamino) phenylsulfanyl] phenyl} acetamide

Example 8a

2,2-Dimethyl-5 - [(1-methyl-1H-pyrazol-3-ylamino) methylene] - [1,3] dioxan-4,6-dione

A mixture of 1-methyl-1H-pyrazol-3-ylamine (1.05 g, 10.8 mmol), 2,2-dimethyl- [1,3] dioxan-4,6-dione (1.71 g, 11, 9 mmol) and triethylorthoformate (1.60 g, 10.8 mmol) in a 25 ml round bottom vessel were heated in an oil bath at 100 ° C for 15 minutes. The mixture was cooled to room temperature and EtOH (10 ml) was added. The reaction mixture was heated until all solids were dissolved and then cooled again to room temperature. The solid formed was isolated by filtration, washed with ethanol and dried to give the title compound (1.81 g, 66% yield).

Example 8b

2-Methyl-2,7-dihydropyrazolo [3,4-b] pyridin-4-one

A mixture of the product of Example 8a (1.50 g, 5.97 mmol) and diphenyl ether (25 ml) was heated under reflux for 1 hour to remove the resulting acetone by distillation. Then the solvent was decanted and the remaining solid residue was dissolved in dichloromethane (5 ml) and purified by silica gel chromatography eluting with a gradient of 0-10% MeOH / CH ₂ Cl ₂ to give the title compound (0.360 g, 40% yield).

Example 8c

4-Chloro-2-methyl-2H-pyrazolo [3,4-b] pyridine

A mixture of the product of example 8b (0.177 g, 1.19 mmol) and phosphorus oxychloride (3 ml) was heated under reflux for 30 minutes and then cooled to room temperature. The reaction mixture was poured onto ice, the pH was adjusted to 8 by the addition of 1N. aqueous sodium hydroxide solution and was extracted with dichloromethane (3 × 30 ml). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to obtain the title compound (0.170 g, 88% yield).

Example 8d

N- {4- [4-Methyl-2- (2-methyl-2H-pyrazolo [3,4-b] pyridin-4-ylamino) phenylsulfanyl] phenyl} acetamide

A mixture of the product of example 8c (47.3 mg, 0.282 mmol), the product of example 7b (84.6 mg, 0.310 mmol), Pd ₂ (dba) ₃ (12.9 mg, 0.0141 mmol), sodium tert-butoxide ( 67.8 mg, 0.706 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3.3] undecane (19.3 mg, 0.0564 mmol) a toluene (4 ml) was degassed, left under increased pressure in a nitrogen atmosphere, and heated under reflux for 2 hours. Additional amounts of Pd ₂ (dba) ₃ (4.0 mg, 0.0044 mmol) and PN3 (4.5 mg, 0.013 mmol) were added, the reaction mixture was heated under reflux for another 2 hours. The mixture was then cooled to room temperature and partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% MeOH / CH ₂ Cl ₂ to give the title compound (0.0195 g, 17% yield).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 4.11 (s, 3H), 5.97 (d, J = 5.15 Hz, 1H), 6.94-7.00 (m, 1H), 7.05 (dd, J = 8.09, 1.47 Hz, 1H), 7.19 (s, 1H), 7.26 (d, J = 8.82 Hz, 2H), 7.56 (d, J = 8.82 Hz, 2H), 8.09 (d, J = 5.15 Hz, 1H), 8, 20 (s, 1H); 8.80 (s, 1H); 10.04 (s, 1H);

MS (ESI ⁺ ) m / z 404.1 (M + H) ⁺ .

Example 9

4- [4-Methyl-2- (2-methyl-2H-pyrazolo [3,4-b] pyridin-4-ylamino) phenylsulfanyl] phenol

A mixture of the product of example 8c (62.1 mg, 0.371 mmol), the product of example 6c (85.7 mg, 0.371 mmol), Pd ₂ (dba) ₃ (16.9 mg, 0.0185 mmol), sodium tert-butoxide ( 89.0 mg, 0.926 mmol) and 2.8.9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3.3] undecane (25.4 mg, 0.0741 mmol) a toluene (3 ml) was degassed, left under increased pressure in a nitrogen atmosphere and heated under reflux for 2 hours. Additional amounts of Pd ₂ (dba) ₃ (7.0 mg, 0.0076 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraase-1-phosphabicyclo [3.3.3] undecane were added. (15 mg, 0.044 mmol), the reaction mixture was heated under reflux for another 2 hours. The mixture was then cooled to room temperature and partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 2-5% MeOH / CH ₂ Cl ₂ , to give the title compound (0.0279 g, 21% yield).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.27 (s, 3H), 4.11 (s, 3H), 5.92 (d, J = 5.15 Hz, 1H), 6 75-6.85 (m, 3H), 7.02 (dd, J = 8.27, 0.92 Hz, 1H), 7.14 (s, 1H), 7.18-7.27 (m , 2H), 8.09 (d, J = 5.15 Hz, 1H), 8.20 (s, 1H), 8.77 (s, 1H), 9.82 (s, 1H);

MS (ESI ⁺ ) m / z 363.0 (M + H) ⁺ (ESI ^- ) m / z 360.9 (MH) ^- .

Example 10

4- [4- (4-Methoxybenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 10A

2-amino-6-methylnicotinonitrile

2-Chloro-6-methylnicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 ml) in 500 ml of ethanol were reacted in a sealed pressure vessel at 130 ° C for 20 hours. The reaction mixture was concentrated in vacuo and the residue was washed with water (2 × 50 ml), then dried in a vacuum oven for 24 hours to obtain the title compound as a pale yellow solid (18 g, 82%).

¹ H NMR (300 MHz, DMSO-d ₆ ) 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 10B

N '- (3-Cyano-6-methylpyridin-2-yl) -N, N-dimethylformamidine

A solution of the product of Example 10A (10 g, 75.19 mmol) and N , N- dimethylformamide dimethyl acetal (11 ml, 82.71 mmol) in toluene (100 ml) was heated under 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-d ₆ ) 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 10C

1-Chloro-4- (4-methoxybenzyloxy) -2-nitrobenzene

Solution of 4-chloro-3-nitrophenol (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. Then, ice-water (10 ml) was added to the solution, and the obtained solid was collected by filtration and dried in a vacuum oven to obtain the title compound (0.812 g, 96%).

Example 10D

4- [4- (4-Methoxybenzyloxy) -2-nitrophenylsulfanyl] phenol

A solution of the product of Example 10C (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 up to 100ºC for 16 hours. After cooling to room temperature, the mixture was poured into ice water (20 ml), and the resulting solution was acidified with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 × 10 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (1.06 g, 100%).

Example 10E

4- [2-amino-4- (4-methoxybenzyloxy) phenylsulfanyl] phenol

A solution of the product of example 10D (1.06 g, 2.76 mmol), iron powder (0.63 g, 11.04 mmol) and ammonium chloride (0.18 g, 3.31 mmol) in a solution of methanol (18 ml) , tetrahydrofuran (18 ml) and water (6 ml) were heated under reflux for 3 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.99 g, 100%).

Example 10F

4- [4- (4-Methoxybenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of Example 10B (28.4 mg, 0.151 mmol) and the product of Example 10E (53.3 mg, 0.151 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the resulting residue was triturated in methanol to give the title compound as a light brown solid (26.5 mg, 35%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.92 (s, 1H), 9.63 (s, 1H), 8.70 (d, J = 8.09 Hz, 1H), 8 55 (s, 1H), 7.52 (d, J = 8.46 Hz, 1H), 7.38 (d, J = 8.82 Hz, 2H), 7.27 (s, 1H), 7 06-7.18 (m, 3H), 6.94 (d, J = 8.46 Hz, 3H), 6.61-6.72 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H); 2.66 (s, 3H);

MS (ESI +) m / z 497.2 (M + H) + (ESI-) m / z 495.3 (M-H) -.

Example 11

3- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

Example 11A

3- [3-amino-4- (4-hydroxyphenylsulfanyl) phenoxymethyl] benzonitrile

A solution of 4-chloro-3-nitrophenol was reacted with 3-bromomethylbenzonitrile using the conditions described in Example 10C to give 3- (4-chloro-3-nitrophenoxymethyl) benzonitrile, which was treated sequentially by the methods described in Examples 10D and 10E, to get the title product.

Example 11B

3- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 11A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 11A instead of the product of Example 10E to give the crude title compound that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm), using a gradient of a mixture of 10% to 100% acetonitrile / 0.1% trifluoroacetic acid in water, for 8 minutes (10 minutes transit time) at a flow rate of 40 ml / min to obtain the specified in the title compound as a salt of tr iforacetic acid (20 mg, 23%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 11.39 (s, 1H), 9.70 (s, 1H), 8.89 (d, J = 8.46 Hz, 1H), 8 77 (s, 1H), 7.92 (s, 1H), 7.75-7.86 (m, 3H), 7.62 (t, J = 7.72 Hz, 1H), 7.18- 7.29 (m, 2H), 7.03-7.14 (m, 3H), 6.55-6.69 (m, 2H), 5.18 (s, 2H), 2.74 (s, 3H);

MS (ESI +) m / z 492.1 (M + H) + (ESI-) m / z 490.2 (M-H) -.

Example 12

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (pyridin-2-ylmethoxy) phenylsulfanyl] phenol

Example 12A

4- [2-amino-4- (pyridin-2-ylmethoxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 2-bromomethylpyridine hydrobromide salt using the conditions described in Example 10C to give 2- (4-chloro-3-nitrophenoxymethyl) pyridine, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 12B

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (pyridin-2-ylmethoxy) phenylsulfanyl] phenol

The product of Example 12A was reacted with the product of Example 10B by the method described in Example 10F using the product of Example 12A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (15 mg, 17%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.76 (s, 3H), 5.19 (s, 2H), 6.63 (d, J = 8.82 Hz, 2H), 6, 98-7.17 (m, 3H), 7.20 (d, J = 2.57 Hz, 1H), 7.22-7.30 (m, 1H), 7.38 (dd, J = 6, 43, 4.96 Hz, 1H), 7.53 (d, J = 7.72 Hz, 1H), 7.71-7.94 (m, 2H), 8.58 (d, J = 4.04 Hz, 1H), 8.82 (s, 1H), 8.93 (d, J = 7.72 Hz, 1H), 9.71 (broad s, 1H), 11.66 (broad s, 1H );

MS (ESI +) m / z 468 (M + H) +.

Example 13

4- [4- (4-tert-butylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 13A

4- [2-amino-4- (4-tert-butylbenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromomethyl-4-tert-butylbenzene using the conditions described in Example 10C to give 4- (4-tert-butylbenzyloxy) -1-chloro-2-nitrobenzene, which processed sequentially by the methods described in examples 10D and 10E to obtain the title product.

Example 13B

4- [4- (4-tert-butylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 13A was reacted with the product of example 10B in the manner described in example 10F, using the product of example 13A instead of the product of example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as a trifluoroacetic salt acids (52 mg, 36%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.28 (s, 9H), 2.74 (s, 3H), 5.06 (s, 2H), 6.63 (d, J = 8 , 46 Hz, 2H), 7.00-7.12 (m, 3H), 7.15-7.27 (m, 2H), 7.30-7.47 (m, 5H), 7.79 ( d, J = 8.46 Hz, 1H), 8.77 (s, 1H), 8.89 (d, J = 8.46 Hz, 1H), 9.69 (s, 1H);

MS (ESI +) m / z 523 (M + H) +.

Example 14

4- [4- (2-Bromobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 14A

4- [2-amino-4- (2-bromobenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromo-2-bromomethylbenzene using the conditions described in Example 10C to give 4- (2-bromobenzyloxy) -1-chloro-2-nitrobenzene, which was treated sequentially with described in Examples 10D and 10E to give the title product.

Example 14B

4- [4- (2-Bromobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 14A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 14A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (42 mg, 39%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3H), 5.13 (s, 2H), 6.67 (m, 2H), 6.96 (d, J = 7 , 68 Hz, 1H), 7.14 (m, 3H), 7.30 (m, 2H), 7.44 (m, 1H), 7.59 (m, 2H), 7.68 (d, J = 7.68 Hz, 1H), 8.59 (s, 1H), 8.73 (d, J = 8.09 Hz, 1H), 9.66 (s, 1H), 10.27 (s, 1H );

MS (ESI +) m / z 545, 547 (M + H) +.

Example 15

4- [4- (3-Bromobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 15A

4- [2-amino-4- (3-bromobenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromo-3-bromomethylbenzene using the conditions described in Example 10C to give 4- (3-bromobenzyloxy) -1-chloro-2-nitrobenzene, which was treated sequentially with described in Examples 10D and 10E to give the title product.

Example 15B

4- [4- (3-Bromobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 15A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 15A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to afford the title compound as the trifluoroacetic salt acids (25 mg, 23%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3H), 5.13 (s, 2H), 6.65 (m, 2H), 7.11 (m, 5H), 7.40 (m, 2H), 7.54 (d, J = 7.72 Hz, 1H), 7.66 (s, 1H), 7.72 (d, J = 8.82 Hz, 1H), 8.71 (s, 1H), 8.84 (d, J = 8.09 Hz, 1H), 9.68 (s, 1H), 11.04 (m, 1H);

MS (ESI +) m / z 545, 547 (M + H) +.

Example 16

4- [4- (4-Bromobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 16A

4- [2-amino-4- (4-bromobenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromo-4-bromomethylbenzene using the conditions described in Example 10C to give 4- (4-bromobenzyloxy) -1-chloro-2-nitrobenzene, which was treated sequentially with described in Examples 10D and 10E to give the title product.

Example 16B

4- [4- (4-Bromobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 16A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 16A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (19 mg, 17%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3H), 5.13 (s, 2H), 6.63 (m, 2H), 7.03 (dd, J = 8 82, 2.57 Hz, 1H), 7.10 (m, 2H), 7.21 (d, J = 8.46 Hz, 2H), 7.40 (m, 2H), 7.54 (d , J = 8.09 Hz, 1H), 7.66 (s, 1H), 7.73 (d, J = 8.46 Hz, 1H), 8.72 (s, 1H), 8.84 (d , J = 8.46 Hz, 1H); 9.69 (s, 1H); 11.08 (m, 1H);

MS (ESI +) m / z 545, 547 (M + H) +.

Example 17

4- [4- (2-Methylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 17A

4- [2-amino-4- (2-methylbenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromomethyl-2-methylbenzene using the conditions described in Example 10C to obtain 1-chloro-4- (2-methylbenzyloxy) -2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 17B

4- [4- (2-Methylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 17A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 17A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (35 mg, 36%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.32 (s, 3H), 2.71 (s, 3H), 5.09 (s, 2H), 6.65 (m, 2H), 7.03 (dd, J = 8.82, 2.57 Hz, 1H), 7.11 (m, 2H), 7.24 (m, 5H), 7.41 (d, J = 6.99 Hz , 1H), 7.69 (d, J = 8.46 Hz, 1H), 8.69 (s, 1H), 8.82 (d, J = 8.82 Hz, 1H), 9.67 (s , 1H); 10.84 (s, 1H);

MS (ESI +) m / z 481 (M + H) +.

Example 18

4- [4- (3-Methylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 18A

4- [2-amino-4- (3-methylbenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromomethyl-3-methylbenzene using the conditions described in Example 10C to give 1-chloro-4- (3-methylbenzyloxy) -2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 18B

4- [4- (3-Methylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 18A was reacted with the product of Example 10B by the method described in Example 10F using the product of Example 18A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (37 mg, 39%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H), 2.73 (s, 3H), 5.07 (s, 2H), 6.64 (m, 2H), 7.16 (m, 9H), 7.75 (d, J = 8.46 Hz, 1H), 8.73 (s, 1H), 8.86 (d, J = 8.46 Hz, 1H), 9.69 (s, 1H); 11.16 (s, 1H);

MS (ESI +) m / z 481 (M + H) +.

Example 19

4- [4- (4-Methylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 19A

4- [2-amino-4- (4-methylbenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromomethyl-4-methylbenzene using the conditions described in Example 10C to obtain 1-chloro-4- (4-methylbenzyloxy) -2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 19B

4- [4- (4-Methylbenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 19A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 19A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (29 mg, 30%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H), 2.67 (s, 3H), 5.05 (s, 2H), 6.64 (m, 2H), 6.94 (d, J = 7.38 Hz, 1H), 7.17 (m, 6H), 7.33 (d, J = 8.09 Hz, 2H), 7.56 (d, J = 8 46 Hz, 1H), 8.57 (s, 1H), 8.72 (d, J = 8.09 Hz, 1H), 9.63 (s, 1H), 10.12 (s, 1H);

MS (ESI +) m / z 481 (M + H) +.

Example 20

2- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

Example 20A

2- [3-amino-4- (4-hydroxyphenylsulfanyl) phenoxymethyl] benzonitrile

A solution of 4-chloro-3-nitrophenol was reacted with 2-bromomethylbenzonitrile using the conditions described in Example 10C to give 2- (4-chloro-3-nitrophenoxymethyl) benzonitrile, which was treated sequentially by the methods described in Examples 10D and 10E, to get the title product.

Example 20B

2- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 20A was reacted with the product of Example 10B in the manner described in Example 10F, using the product of Example 20A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (21 mg, 16%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 9.93 (s, 1H), 9.63 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 8, 57 (s, 1H), 7.60 (d, J = 8.09 Hz, 1H), 7.38 (d, J = 8.46 Hz, 2H), 7.27 (s, 1H), 7, 05-7.19 (m, 3H), 6.85-7.00 (m, 3H), 6.67 (d, J = 8.82 Hz, 2H), 5.02 (s, 2H), 3 75 (s, 3H), 3.14-3.28 (m, 1H), 1.32 (d, J = 6.62 Hz, 6H);

MS (ESI +) m / z 492.2 (M + H) + (ESI-) m / z 490.2 (M-H) -.

Example 21

4- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

Example 21A

4- [3-amino-4- (4-hydroxyphenylsulfanyl) phenoxymethyl] benzonitrile

A solution of 4-chloro-3-nitrophenol was reacted with 4-bromomethylbenzonitrile using the conditions described in Example 10C to give 4- (4-chloro-3-nitrophenoxymethyl) benzonitrile, which was treated sequentially by the methods described in Examples 10D and 10E, to get the title product.

Example 21B

4- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 21A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 21A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to afford the title compound as the trifluoroacetic salt acids (15 mg, 14%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.69 (s, 1H), 9.72 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 8, 83 (s, 1H), 7.78-7.96 (m, 3H), 7.63 (d, J = 8.46 Hz, 2H), 7.22-7.27 (m, 1H), 7 18 (d, J = 2.57 Hz, 1H), 7.06-7.13 (m, 3H), 6.59-6.66 (m, 2H), 5.23 (s, 2H), 2.76 (s, 3H);

MS (ESI +) m / z 492.1 (M + H) + (ESI-) m / z 490.1 (M-H) -.

Example 22

4- [4- [1- (4-Bromophenyl) ethoxy] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 22A

1-bromo-4- (1-bromoethyl) benzene

A solution of 1- (4-bromophenyl) ethanol (4.21 g, 20.9 mmol) in 15 ml of CH ₂ Cl ₂ was reacted with 15 ml of 1.0M PBr ₃ in CH ₂ Cl ₂ at room temperature for 4 hours. Quenched by pouring onto ice, and the pH was adjusted to 9 with 5% aqueous NaHCO ₃ solution. It was extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (4.1 g, 75%).

Example 22B

4- [1- (4-Bromophenyl) ethoxy] -1-chloro-2-nitrobenzene

The product of Example 22A (995 mg, 3.77 mmol) was reacted with 4-chloro-3-nitrophenol (650 mg, 3.77 mmol) in 15 ml of DMF with K ₂ CO ₃ (10.4 g, 3.77 mmol) at 80ºC for 3 hours. Cooled to room temperature and diluted with water. It was extracted with CH ₂ Cl ₂ , washed with water four times. Dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (1.24 g, 92%).

Example 22C

4- {4- [1- (4-Bromophenyl) ethoxy] -2-nitrophenylsulfanyl} phenol

The product of Example 22B (1.15 g, 3.22 mmol) was reacted with 4-mercaptophenol (403 mg, 3.22 mmol) and K ₂ CO ₃ (890 mg, 6.44 mmol) in 25 ml of DMF at 80 ° C within 18 hours. Cooled to room temperature and poured into water. It was extracted with CH ₂ Cl ₂ and washed several times with water. Dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (980 mg, 68%).

Example 22D

4- [2-amino-4- (1-phenylethoxy) phenylsulfanyl] phenol

The product of Example 22C (560 mg, 1.25 mmol) was reacted with Fe (279 mg, 5.0 mmol) and NH ₄ Cl (76 mg, 1.40 mmol) in 5 ml MeOH / 5 ml THF / 2, 5 ml of water in accordance with the method described in Example 10E to give the title compound as a solid (439 mg, 84%).

Example 22E

4- [4- [1- (4-Bromophenyl) ethoxy] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 22D (204 mg, 0.49 mmol) was reacted with the product of Example 10B (93 mg, 0.49 mmol) in accordance with the method described in Example 10F to give the crude title compound that was purified with by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (38 mg, 12%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 11.24 (br s, 1H), 9.70 (s, 1H), 8.83 (d, J = 8.09 Hz, 1H) 8.74 (s, 1H), 7.76 (d, J = 8.45 Hz, 1H), 7.55 (d, J = 8.46 Hz, 2H), 7.37 (d, J = 8.46 Hz, 2H), 7.09 (m, 4H), 6.93 (dd, J = 6.62 Hz, J = 2.20 Hz, 1H), 6.63 (d, J = 8, 82 Hz, 2H), 5.51 (q, J = 6.25 Hz, 2H), 2.73 (s, 3H), 1.53 (d, J = 6.25 Hz, 3H);

MS (ESI +) m / z, 559, 561 (M + H-TFA) +; (ESI-) m / z, 557, 559 (M-H-TFA) -.

Example 23

4- [4- [1- (4-Fluorophenyl) ethoxy] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 23A

4- {2-amino-4- [1- (4-fluorophenyl) ethoxy] phenylsulfanyl} phenol

A solution of 1- (4-fluorophenyl) ethanol was converted to 1- (1-bromoethyl) -4-fluorobenzene using the conditions described in Example 22A, which was treated sequentially by the methods described in Examples 22B-22D to obtain the title product.

Example 23B

4- [4- [1- (4-Fluorophenyl) ethoxy] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 23A (207 mg, 0.584 mmol) was reacted with the product of example 10B (110 mg, 0.584 mmol) in accordance with the method described in example 10F, to obtain the crude specified in the title compound, which was purified using HPLC with TFA to give the title compound as a trifluoroacetic acid salt (30 mg, 35%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.54 (d, J = 6.25 Hz, 3H), 2.73 (s, 3H), 5.53 (q, J = 6 , 13 Hz, 1H), 6.63 (d, J = 8.82 Hz, 2H), 6.93 (dd, J = 8.82, 2.57 Hz, 1H), 7.05-7.14 (m, 4H), 7.18 (t, J = 9.01 Hz, 2H), 7.41-7.49 (m, 2H), 7.76 (d, J = 8.46 Hz, 1H) 8.73 (s, 1H); 8.84 (d, J = 8.46 Hz, 1H); 9.71 (s, 1H);

MS (ESI +) m / z 497 (MH) -.

Example 24

4- [4- [1- (3-Fluorophenyl) ethoxy] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 24A

4- {2-amino-4- [1- (3-fluorophenyl) ethoxy] phenylsulfanyl} phenol

A solution of 1- (3-fluorophenyl) ethanol was converted to 1- (1-bromoethyl) -3-fluorobenzene using the conditions described in example 22A, which was treated sequentially by the methods described in examples 22B-22D to obtain the title product.

Example 24B

4- [4- [1- (3-Fluorophenyl) ethoxy] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 24A (226 mg, 0.637 mmol) was reacted with the product of example 10B (120 mg, 0.637 mmol) in accordance with the method described in example 10F, to obtain the crude specified in the title compound, which was purified using HPLC with TFA to give the title compound as a trifluoroacetic acid salt (87 mg, 22%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.55 (d, J = 6.62 Hz, 3H), 2.72 (s, 3H), 5.54 (q, J = 6, 13 Hz, 1H), 6.64 (d, J = 8.46 Hz, 2H), 6.91 (dd, J = 8.82, 2.57 Hz, 1H), 7.06-7.15 ( m, 5H), 7.20-7.28 (m, 2H), 7.35-7.44 (m, 1H), 7.70 (d, J = 8.46 Hz, 1H), 8.68 (s, 1H), 8.81 (d, J = 8.46 Hz, 1H), 9.73 (s, 1H);

MS (ESI +) m / z 499 (M + H) +.

Example 25

4- [4- (2-Chlorothiazol-5-ylmethoxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 25A

4- [2-amino-4- (2-chlorothiazol-5-ylmethoxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 5-bromomethyl-2-chlorothiazole (prepared according to the method of Kim, H.-J., Liu, S., Keum, Y.-S., Qing, X. J Agric. Food Chem. 2003, 51 , 1823-1830) using the conditions described in Example 10C to give 2-chloro-5- (4-chloro-3-nitrophenoxymethyl) thiazole, which was treated sequentially by the methods described in the examples 10D and 10E to give the title product.

Example 25B

4- [4- (2-Chlorothiazol-5-ylmethoxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 25A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 25A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H), 5.34 (s, 2H), 6.66 (d, J = 8.46 Hz, 2H), 7, 01 (dd, J = 8.64, 2.02 Hz, 1H), 7.06-7.28 (m, 4H), 7.68 (d, J = 8.46 Hz, 1H), 7.80 (s, 1H), 8.67 (s, 1H), 8.82 (d, J = 8.46 Hz, 1H), 9.70 (s, 1H), 10.81 (br s, 1H) ;

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

Example 26

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-trifluoromethylbenzyloxy) phenylsulfanyl] phenol

Example 26A

4- [2-amino-4- (3-trifluoromethylbenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-chloromethyl-3-trifluoromethylbenzene using the conditions described in Example 10C to give 1-chloro-2-nitro-4- (3-trifluoromethylbenzyloxy) benzene, which was treated sequentially by methods described in Examples 10D and 10E to give the title product.

Example 26B

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-trifluoromethylbenzyloxy) phenylsulfanyl] phenol

The product of Example 26A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 26A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (9.9 mg, 9%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 5.22 (s, 2H), 6.64 (d, J = 8.46 Hz, 2H), 7, 10 (d, J = 8.82 Hz, 3H), 7.19-7.30 (m, 2H), 7.62-7.72 (m, J = 7.35 Hz, 2H), 7.72 -7.84 (m, 4H), 8.75 (s, 1H), 8.88 (d, J = 7.35 Hz, 1H), 9.69 (s, 1H);

MS ESI + m / z 535 (M + H) +, ESI m / z 533 (M-H) -.

Example 27

4- [4-Benzyloxy-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 27A

4- (2-amino-4-benzyloxyphenylsulfanyl) phenol

A solution of 4-chloro-3-nitrophenol was reacted with bromomethylbenzene using the conditions described in Example 10C to give 4-benzyloxy-1-chloro-2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to obtain the indicated in the product title.

Example 27B

4- [4-Benzyloxy-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 27A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 27A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (73 mg, 25%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.70 (s, 3H), 5.11 (s, 2H), 6.65 (d, J = 8.46 Hz, 2H), 6, 98 (d, J = 7.72 Hz, 1H), 7.10 (d, J = 8.46 Hz, 2H), 7.18 (d, J = 8.46 Hz, 1H), 7.24 ( s, 1H), 7.28-7.51 (m, 5H), 7.63 (d, J = 8.82 Hz, 1H), 8.64 (s, 1H), 8.78 (d, J = 8.82 Hz, 1H), 9.65 (s, 1H), 10.56 (br s, 1H);

MS (ESI +) m / z 467 (M + H) +.

Example 28

4- [4- (3-Fluorobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 28A

4- [2-amino-4- (3-fluorobenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromomethyl-3-fluorobenzene using the conditions described in Example 10C to obtain 1-chloro-4- (3-fluorobenzyloxy) -2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 28B

4- [4- (3-Fluorobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 28A was reacted with the product of Example 10B by the method described in Example 10F using the product of Example 28A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (41 mg, 42%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3H), 5.14 (s, 2H), 6.65 (m, 2H), 7.02 (dd, J = 8 64, 2.76 Hz, 1H), 7.10 (m, 2H), 7.23 (m, 5H), 7.44 (m, 1H), 7.71 (d, J = 8.46 Hz , 1H), 8.69 (s, 1H), 8.83 (d, J = 8.46 Hz, 1H), 9.69 (s, 1H), 10.96 (s, 1H);

MS (ESI +) m / z 485 (M + H) +.

Example 29

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (tetrahydrofuran-2-ylmethoxy) phenylsulfanyl] phenol

Example 29A

4- [2-amino-4- (tetrahydrofuran-2-ylmethoxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 2-bromomethyltetrahydrofuran using the conditions described in Example 10C to give 2- (4-chloro-3-nitrophenoxymethyl) tetrahydrofuran, which was treated sequentially by the methods described in Examples 10D and 10E, to get the title product.

Example 29B

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (tetrahydrofuran-2-ylmethoxy) phenylsulfanyl] phenol

The product of Example 29A was reacted with the product of Example 10B by the method described in Example 10F using the product of Example 29A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (29 mg, 17%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.55-1.84 (m, 1H), 1.84-2.07 (m, 1H), 2.67 (s, 3H), 3 59-3.71 (m, 2H), 3.73-3.83 (m, 1H), 3.85-4.02 (m, 2H), 4.15 (dd, J = 6.43, 4.23 Hz, 2H), 6.66 (d, J = 8.46 Hz, 2H), 6.87 (dd, J = 8.64, 2.76 Hz, 1H), 7.02-7, 15 (m, 2H), 7.12-7.24 (m, 2H), 7.53 (d, J = 8.46 Hz, 1H), 8.56 (s, 1H), 8.71 (d , J = 8.46 Hz, 1H); 9.62 (s, 1H); 9.92 (s, 1H);

MS (ESI +) m / z 461 (M + H) +.

Example 30

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (naphthalen-1-ylmethoxy) phenylsulfanyl] phenol

Example 30A

4- [2-amino-4- (naphthalen-1-ylmethoxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-chloromethylnaphthalene using the conditions described in Example 10C to give 1- (4-chloro-3-nitrophenoxymethyl) naphthalene, which was treated sequentially by the methods described in Examples 10D and 10E, to get the title product.

Example 30B

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (naphthalen-1-ylmethoxy) phenylsulfanyl] phenol

The product of Example 30A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 30A instead of the product of Example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (31 mg, 25%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3H), 5.56 (s, 2H), 6.67 (d, J = 8.82 Hz, 2H), 7, 01-7.16 (m, 3H), 7.16-7.24 (m, 1H), 7.35 (s, 1H), 7.45-7.64 (m, 4H), 7.69 ( d, J = 6.62 Hz, 1H), 7.87-8.02 (m, 2H), 8.05-8.14 (m, 1H), 8.59 (s, 1H), 8.74 (d, J = 8.46 Hz, 1H); 9.65 (s, 1H); 10.23 (s, 1H); MS (ESI +) 517 (M + H) +.

Example 31

4- [4- (3-Methoxybenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 31A

4- [2-amino-4- (3-methoxybenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-chloromethyl-3-methoxybenzene using the conditions described in Example 10C to obtain 1-chloro-4- (3-methoxybenzyloxy) -2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 31B

4- [4- (3-Methoxybenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 31A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 31A instead of the product of Example 10E to give a solid which was triturated in methanol to give the title compound (24 mg, 26%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 9.93 (s, 1H), 9.63 (s, 1H), 8.71 (d, J = 8.09 Hz, 1H), 8, 55 (s, 1H), 7.53 (d, J = 8.09 Hz, 1H), 7.26-7.35 (m, 2H), 7.15 (d, J = 8.46 Hz, 1H ), 7.07-7.13 (m, 2H), 6.98-7.04 (m, J = 5.15 Hz, 2H), 6.96 (s, 1H), 6.90 (dd, J = 8.09, 2.57 Hz, 1H), 6.62-6.71 (m, 2H), 5.08 (s, 2H), 3.75 (s, 3H), 2.67 (s , 3H);

MS (ESI +) m / z 497.2 (M + H) + (ESI-) m / z 495.2 (M-H) -.

Example 32

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (quinolin-2-ylmethoxy) phenylsulfanyl] phenol

Example 32A

4- [2-amino-4- (quinolin-2-ylmethoxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with the 2-chloromethylquinoline hydrochloride salt using the conditions described in Example 10C to give 2- (4-chloro-3-nitrophenoxymethyl) quinoline, which was sequentially treated by the methods described in Examples 10D and 10E to give the title product.

Example 32B

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (quinolin-2-ylmethoxy) phenylsulfanyl] phenol

The product of Example 32A was reacted with the product of Example 10B in the manner described in Example 10F, using the product of Example 32A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (13 mg, 27%).

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 2.75 (s, 3H), 5.39 (s, 2H), 6.62 (d, J = 8.54 Hz, 2H), 7, 09 (d, J = 8.54 Hz, 2H), 7.14 (dd, J = 8.54, 2.44 Hz, 1H), 7.22-7.28 (m, 2H), 7.63 (t, J = 7.93 Hz, 1H), 7.68 (d, J = 8.54 Hz, 1H), 7.74-7.81 (m, 1H), 7.83 (d, J = 8.54 Hz, 1H), 8.00 (t, J = 7.93 Hz, 2H), 8.44 (d, J = 8.54 Hz, 1H), 8.76 (s, 1H), 8 92 (d, J = 8.54 Hz, 1H); 9.68 (s, 1H); 11.64 (br s, 1H);

MS (ESI +) 518 (M + H) +.

Example 33

4- [4- (Biphenyl-4-ylmethoxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 16B (free acid form, 0.055 g, 0.1 mmol), phenylboric acid (0.017 g, 0.14 mmol), cesium carbonate (0.05 g, 0.15 mmol) and dichlorbis (triphenylphosphine) palladium (II ) (0.007 g, 0.01 mmol) were combined in N, N- dimethylformamide (1 ml) and heated to 100 ° C for 24 hours. After cooling to room temperature, the mixture was poured into ice water (20 ml) and the resulting solution was acidified with 1N. aqueous hydrochloric acid. Then the solution was extracted with ethyl acetate (3 × 10 ml), the combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (10 mg, 15%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3H), 5.16 (s, 2H), 6.60-6.72 (m, 2H), 6.98 (d , J = 8.09 Hz, 1H), 7.06-7.22 (m, 3H), 7.27-7.41 (m, 2H), 7.47 (t, J = 7.54 Hz, 2H), 7.54 (d, J = 8.46 Hz, 3H), 7.60-7.73 (m, 4H), 8.58 (s, 1H), 8.72 (d, J = 8 09 Hz, 1H); 9.64 (s, 1H); 10.08 (s, 1H);

MS (ESI +) m / z 543 (M + H +) +.

Example 34

4- [4- (5-Chlorothiophen-2-ylmethoxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 34A

4- [2-amino-4- (5-chlorothiophen-2-ylmethoxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 2-chloro-5-chloromethylthiophene using the conditions described in Example 10C to give 2-chloro-5- (4-chloro-3-nitrophenoxymethyl) thiophene, which was treated sequentially by methods described in Examples 10D and 10E to give the title product.

Example 34B

4- [4- (5-Chlorothiophen-2-ylmethoxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenolphenylsulfanyl] phenol

The product of example 34A was reacted with the product of example 10B in the manner described in example 10F, using the product of example 34A instead of the product of example 10E to give the crude title compound that was purified by HPLC with TFA to give the title compound as a trifluoroacetic salt acids (6.6 mg, 10%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3H), 5.25 (s, 2H), 6.65 (d, J = 8.46 Hz, 2H), 6, 97-7.14 (m, 4H), 7.19 (d, J = 8.46 Hz, 2H), 7.72 (d, J = 8.09 Hz, 1H), 8.71 (s, 1H ), 8.84 (d, J = 8.46 Hz, 1H), 9.69 (s, 1H), 11.01 (br s, 1H);

MS (ESI +) m / z 543 (M + H) +.

Example 35

4- [4- (4-Fluorobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 35A

4- [2-amino-4- (4-fluorobenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromomethyl-4-fluorobenzene using the conditions described in Example 10C to obtain 1-chloro-4- (4-fluorobenzyloxy) -2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 35B

4- [4- (4-Fluorobenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 35A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 35A instead of the product of Example 10E to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (40 mg, 41%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.69 (s, 3H), 5.09 (s, 2H), 6.65 (m, 2H), 6.97 (dd, J = 8 64, 2.39 Hz, 1H), 7.09 (m, 2H), 7.21 (m, 4H), 7.50 (m, 2H), 7.61 (d, J = 8.46 Hz , 1H), 8.61 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 9.65 (s, 1H), 10.41 (s, 1H);

MS (ESI +) m / z 485 (M + H) +.

Example 36

3- [4- (4-Hydroxyphenylsulfanyl) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

Example 36A

4-methyl-3-oxopental, sodium salt

A 100-milliliter vessel, dried in flame, equipped with a 25-milliliter additional funnel, was purged with nitrogen gas and anhydrous diethyl ether (40 ml) was charged, then sodium plates (1.65 g, 0.0725 mol) were added. The reaction mixture was cooled to a bath temperature with an ice / water mixture, and a solution of methyl isopropyl ketone (6.244 g, 0.0725 mol) and ethyl formate (5.481 g, 0.0725 mol) in anhydrous diethyl ether (5 ml) was slowly added dropwise over 1. 5 hours at 0ºC. After complete addition, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Then, additional ether (10 ml) was added to disperse the resulting precipitate, and the solid was rapidly isolated by vacuum filtration. The solid was washed with a small amount of ether and then dried in a vacuum desiccator for one hour to obtain the title product as an off-white solid (5.35 g, 54% yield). This material was used in the next step without further purification.

Example 36B

6-Isopropyl-2-oxo-1,2-dihydropyridin-3-carbonitrile

A solution of the product of example 36A (5.35 g, 0.0393 mol) and 2-cyanoacetamide (3.47 g, 0.0413 mol) in water (35 ml) was stirred at room temperature for 10 minutes. To this mixture was added 2.5 ml of the initial piperidine acetate solution (obtained from 9.8 ml of piperidine, 6 ml of acetic acid and 10 ml of water) and the solution was heated under reflux for 2 hours. The mixture was then cooled to room temperature and the pH was adjusted to 4 by the addition of glacial acetic acid. The resulting light yellow solid was isolated by vacuum filtration, washed with water (2 × 30 ml) and dried in vacuo to give the title product (4.36 g, 68%).

Example 36C

2-bromo-6-isopropylnicotinonitrile

A solution of the product of example 36B (4.35 g, 0.0269 mol), tetrabutylammonium bromide (10.4 g, 0.0323 mol) and phosphorus pentoxide (8.01 g, 1.05 mol) in toluene (80 ml) was heated under reflux for 5 hours. Then the reaction mixture was cooled to room temperature, water (80 ml) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with toluene (20 ml) and the organic layer was separated. The aqueous layer was washed with toluene (50 ml) and the combined organic layers were washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title product as a yellow oil (5.64 g, 93 %).

Example 36D

2-amino-6-isopropylnicotinonitrile

A solution of the product of Example 36C (21 g, 0.093 mol) and liquid ammonia (250 ml) in 500 ml of ethanol was reacted in a hermetically sealed pressure vessel at 130 ° C for 20 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with fine powder, then washed with water (2 × 50 ml) and dried in a vacuum oven for 24 hours to obtain the title compound as a beige solid (14 g, 93%).

Example 36E

N '- (3-Cyano-6-isopropylpyridin-2-yl) - N - N- dimethylformamidine

A solution of the product of Example 36D (7.1 g, 0.044 mol) and N , N- dimethylformamide dimethyl acetal (6.44 ml, 0.0484 mol) in toluene (100 ml) was heated under reflux for 3 hours. The resulting solution was cooled to room temperature and concentrated in vacuo to give the title compound (9.5 g, 100%) as a thick brown oil that solidified upon settling. Despite the fact that NMR showed the purity of this substance, it contains a small amount of brightly colored impurities. It can be purified by chromatography on silica gel (ethyl acetate / hexane gradient) to give a light yellow oil that solidifies upon settling (after chromatography, about 70% yield).

Example 36F

3- (4-Chloro-3-nitrophenoxymethyl) benzonitrile

The title compound was prepared according to the method described in Example 10C using 3-bromomethylbenzonitrile instead of 1-chloromethyl-4-methoxybenzene (0.813 g, 98%).

Example 36G

3- [4- (4-Hydroxyphenylsulfanyl) -3-nitrophenoxymethyl] benzonitrile

The title compound was prepared according to the method described in Example 10D using 3- (4-chloro-3-nitrophenoxymethyl) benzonitrile instead of 1-chloro-4- (4-methoxybenzyloxy) -2-nitrobenzene (1.07 g, one hundred%).

Example 36H

3- [3-amino-4- (4-hydroxyphenylsulfanyl) phenoxymethyl] benzonitrile

The title compound was prepared according to the method described in Example 10E using 3- [4- (4-hydroxyphenylsulfanyl) -3-nitrophenoxymethyl] benzonitrile instead of 4- [4- (4-methoxybenzyloxy) -2-nitrophenylsulfanyl] phenol ( 0.97 g, 98%).

Example 36I

3- [4- (4-Hydroxyphenylsulfanyl) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

A solution of the product of example 36E (47.4 mg, 0.219 mmol) and the product of example 36H (76.3 mg, 0.219 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 130 ° C for 15 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a mixture gradient of 10% to 100% acetonitrile / 0.1% trifluoroacetic acid in water for 8 minutes (passage time 10 minutes) at a flow rate of 40 ml / min to give the title compound as a trifluoroacetic acid salt (14 mg, 10%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.94 (s, 1H), 9.69 (s, 1H), 8.88 (d, J = 8.46 Hz, 1H), 8 70 (s, 1H), 7.92 (s, 1H), 7.72-7.87 (m, 3H), 7.62 (t, J = 7.72 Hz, 1H), 7.15- 7.28 (m, J = 8.82 Hz, 2H), 7.08-7.15 (m, 2H), 6.99-7.06 (m, 1H), 6.61-6.72 ( m, 2H), 5.18 (s, 2H), 3.19-3.30 (m, 1H), 1.34 (d, J = 6.99 Hz, 6H);

MS (ESI) m / z 520.3 (M + H) + (ESI-) m / z 518.3 (M-H) -.

Example 37

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (2-methoxybenzyloxy) phenylsulfanyl] phenol

Example 37A

4- [2-amino-4- (2-methoxybenzyloxy) phenylsulfanyl] phenol

A solution of 4-chloro-3-nitrophenol was reacted with 1-bromomethyl-2-methylbenzene using the conditions described in Example 10C to obtain 1-chloro-4- (2-methylbenzyloxy) -2-nitrobenzene, which was treated sequentially by the methods described in Examples 10D and 10E to give the title product.

Example 37B

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (2-methoxybenzyloxy) phenylsulfanyl] phenol

The product of example 37A was reacted with the product of example 36E by the method described in example 36I, using the product of example 37A instead of the product of example 36H to give a solid which was triturated in methanol to give the title compound (31 mg, 31%).

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 9.88 (s, 1H), 9.57 (s, 1H), 8.73 (d, J = 5.49 Hz, 1H), 8, 56 (s, 1H), 7.58 (d, J = 7.32 Hz, 1H), 7.40 (dd, J = 7.63, 1.53 Hz, 1H), 7.31-7.37 (m, 1H), 7.30 (s, 1H), 7.18 (d, J = 6.10 Hz, 1H), 7.11 (d, J = 8.54 Hz, 2H), 7.05 (d, J = 7.93 Hz, 1H), 6.97 (t, J = 7.32 Hz, 1H), 6.93 (s, 1H), 6.67 (d, J = 8.54 Hz , 2H), 5.06 (s, 2H), 3.80 (s, 3H), 3.16-3.25 (m, 1H), 1.33 (d, J = 6.71 Hz, 6H) ;

MS (ESI +) m / z 525.2 (M + H) + (ESI-) m / z 523.2 (M-H) -.

Example 38

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (4-methoxybenzyloxy) phenylsulfanyl] phenol

The product of Example 10E was reacted with the product of Example 36E in accordance with the method described in Example 36I, using the product of Example 10E instead of the product of Example 36H to give a solid which was triturated in methanol to give the title compound (43 mg, 49% )

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 9.93 (s, 1H), 9.63 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 8, 57 (s, 1H), 7.60 (d, J = 8.09 Hz, 1H), 7.38 (d, J = 8.46 Hz, 2H), 7.27 (s, 1H), 7, 05-7.19 (m, 3H), 6.85-7.00 (m, 3H), 6.67 (d, J = 8.82 Hz, 2H), 5.02 (s, 2H), 3 75 (s, 3H), 3.14-3.28 (m, 1H), 1.32 (d, J = 6.62 Hz, 6H);

MS (ESI +) m / z 525.3 (M + H) + (ESI-) m / z 523.3 (M-H) -.

Example 39

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (1-phenylethoxy) phenylsulfanyl] phenol

Example 39A

4- [2-amino-4- (1-phenylethoxy) phenylsulfanyl] phenol

A solution of 1- (3-fluorophenyl) ethanol was converted to 1- (1-bromoethyl) -3-fluorobenzene using the conditions described in example 22A, which was treated sequentially by the methods described in examples 22B-22D to obtain the title product.

Example 39B

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (1-phenylethoxy) phenylsulfanyl] phenol

The product of example 39A was reacted with the product of example 36E in accordance with the method described in example 36I, using the product of example 39A instead of the product of example 36H, to obtain the crude title compound, which was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 1.55 (d, J = 6.25 Hz, 3H), 3.14- 3.29 (m, 1H), 5.49 (q, J = 6.37 Hz, 1H), 6.63 (d, J = 8.82 Hz, 2H), 6.89 (dd, J = 8.82, 2.57 Hz, 1H), 7.09 (dd, J = 9.01, 2.76 Hz, 3H), 7.19-7.48 (m, 6H), 7.75 (d , J = 8.82 Hz, 1H), 8.67 (s, 1H), 8.83 (d, J = 8.46 Hz, 1H), 9.67 (s, 1H), 10.85 (s , 1H);

MS ESI + (m / z) 509, ESI- (m / z) 507.

Example 40

4- [4- [1- (4-Bromophenyl) ethoxy] -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 22D (211 mg, 0.506 mmol) was reacted with the product of Example 36E (109 mg, 0.506 mmol) in accordance with the method described in Example 36I, using the product of Example 22D instead of the product of Example 36H to give the crude title compound a compound that was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (150 mg, 42%).

¹ H NMR (300 MHz, DMSO d6) δ ppm: 10.87 (br s, 1H), 9.68 (s, 1H), 8.83 (d, J = 8.45 Hz, 1H), 8 67 (s, 1H), 7.75 (d, J = 7.72 Hz, 1H), 7.55 (d, J = 8.46 Hz, 2H), 7.37 (d, J = 8, 46 Hz, 2H), 7.09 (m, 4H), 6.89 (dd, J = 8.46 Hz, J = 2.20 Hz, 1H), 6.66 (d, J = 8.82 Hz , 2H), 5.50 (q, J = 6.25 Hz, 2H), 3.25 (sept., J = 6.99 Hz, 1H), 1.53 (d, J = 6.25 Hz , 3H), 1.34 (d, J = 6.99 Hz, 6H).

MS (ESI +) m / z 587, 589 (M + H-TFA) +; (ESI-) m / z 585, 587 (M-H-TFA) -.

Example 41

4- [4- [1- (3-Fluorophenyl) ethoxy] -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 24A (197 mg, 0.555 mmol) was reacted with the product of example 36E (120 mg, 0.555 mmol) in accordance with the method described in example 36I, using the product of example 24A instead of the product of example 36H to give the crude title compound a compound that was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (100 mg, 28%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 1.55 (d, J = 6.62 Hz, 3H), 3.19- 3.32 (m, J = 13.70, 6.94, 6.94 Hz, 1H), 5.53 (q, J = 6.62 Hz, 1H), 6.64 (d, J = 8 , 46 Hz, 2H), 6.91 (dd, J = 8.82, 2.57 Hz, 1H), 7.09 (d, J = 8.46 Hz, 5H), 7.19-7.29 (m, 2H), 7.39 (dd, J = 8.09, 5.88 Hz, 1H), 7.78 (d, J = 8.46 Hz, 1H), 8.68 (s, 1H) 8.85 (d, J = 8.46 Hz, 1H); 9.70 (s, 1H);

MS (ESI +) m / z 527 (M + H) +.

Example 42

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-trifluoromethylbenzyloxy) phenylsulfanyl] phenol

The product of example 26A was reacted with the product of example 36E in accordance with the method described in example 36I, using the product of example 26A instead of the product of example 36H to give the crude title compound, which was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid (22 mg, 21%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 5.22 (s, 2H), 6.65 (d, J = 8.46 Hz, 2H), 7.01-7.13 (m, 3H), 7.20 (d, J = 8.82 Hz, 2H), 7.66 (d, J = 7.35 Hz, 1H), 7.70-7.82 (m, 4H), 8.68 (s, 1H), 8.87 (d, J = 8.46 Hz, 1H), 9.68 (s, 1H);

MS ESI + m / z 563 (M + H) +, ESI m / z 561 (M-H) -.

Example 43

4- [4- (3-Fluorobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 57D was reacted with the product of Example 36E in accordance with the method described in Example 36I, using the product of Example 57D instead of the product of Example 36H, to obtain the crude title compound that was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid (26 mg, 51%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.28 (m, 1H), 5.14 (s, 2H), 6, 65 (m, 2H), 7.16 (m, 8H), 7.44 (m, 1H), 7.81 (d, J = 8.46 Hz, 1H), 8.73 (s, 1H), 8.90 (d, J = 8.46 Hz, 1H), 9.69 (s, 1H), 11.08 (s, 1H);

MS (ESI +) m / z 513 (M + H) +.

Example 44

4- [4- (4-Fluorobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 35A was reacted with the product of example 36E by the method described in example 36I, using the product of example 35A instead of the product of example 36H to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (23 mg, 45%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.26 (m, 1H), 5.09 (s, 2H), 6, 62 (m, 2H), 7.14 (m, 7H), 7.48 (m, 2H), 7.81 (d, J = 8.46 Hz, 1H), 8.73 (s, 1H), 8.90 (d, J = 8.46 Hz, 1H); 9.68 (s, 1H); 11.12 (s, 1H);

MS (ESI +) m / z 513 (M + H) +.

Example 45

4- [4- [1- (4-Fluorophenyl) ethoxy] -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 23A (180 mg, 0.510 mmol) was reacted with the product of example 36E (110 mg, 0.510 mmol) in accordance with the method described in example 36I using the product of example 23A instead of the product of example 36H to give the crude title compound a compound that was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (35 mg, 12%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 1.54 (d, J = 6.62 Hz, 3H), 3.23- 3.34 (m, 1H), 5.52 (q, J = 5.88 Hz, 1H), 6.63 (d, J = 8.82 Hz, 2H), 6.94 (dd, J = 8.82, 2.57 Hz, 1H), 7.08 (m, J = 8.82 Hz, 4H), 7.14 (d, J = 4.78 Hz, 1H), 7.17-7, 21 (m, 1H), 7.41-7.49 (m, 2H), 7.86 (d, J = 8.82 Hz, 1H), 8.76 (s, 1H), 8.91 (d , J = 8.46 Hz, 1H);

MS (ESI +) m / z 527 (M + H) +.

Example 46

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-methoxybenzyloxy) phenylsulfanyl] phenol

The product of example 31A was reacted with the product of example 36E by the method described in example 36I, using the product of example 31A instead of the product of example 36H, to obtain the crude title compound that was purified by HPLC with TFA to give the title compound as a trifluoroacetic salt acids (23 mg, 45%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.98 (s, 1H), 9.67 (s, 1H), 8.88 (d, J = 8.09 Hz, 1H), 8, 70 (s, 1H), 7.78 (d, J = 8.09 Hz, 1H), 7.31 (t, J = 8.09 Hz, 1H), 7.15-7.24 (m, J = 8.82 Hz, 2H), 7.06-7.15 (m, 2H), 6.95-7.05 (m, J = 6.62 Hz, 3H), 6.90 (dd, J = 7.72, 2.21 Hz, 1H), 6.54-6.73 (m, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 3.19-3.28 (m, 1H), 1.34 (d, J = 6.99 Hz, 6H);

MS (ESI +) m / z 525.2 (M + H) + (ESI-) m / z 523.2 (M-H) -.

Example 47

4- [4- (3-Bromobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 15A was reacted with the product of example 36E by the method described in example 36I, using the product of example 15A instead of the product of example 36H, to give the crude title compound that was purified by HPLC with TFA to give the title compound as trifluoroacetic salt acids (16 mg, 28%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.62 Hz, 6H), 3.21 (m, 1H), 5.13 (s, 2H), 6, 68 (d, J = 8.82 Hz, 2H), 6.95 (dd, J = 8.64, 2.76 Hz, 1H), 7.12 (m, 3H), 7.34 (m, 2H ), 7.50 (m, 2H), 7.60 (d, J = 8.82 Hz, 1H), (s, 1H), 8.57 (s, 1H), 8.76 (d, J = 8.46 Hz, 1H); 9.65 (s, 1H); 9.95 (s, 1H);

MS (ESI +) m / z 573.575 (M + H) +.

Example 48

4- [4- (4-Bromobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 16A was reacted with the product of example 36E in the manner described in example 36I, using the product of example 16A instead of the product of example 36H to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (28 mg, 49%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (d, J = 6.99 Hz, 6H), 3.22 (m, 1H), 5.10 (s, 2H), 6, 67 (d, J = 8.46 Hz, 2H), 6.94 (dd, J = 8.82, 2.57 Hz, 1H), 7.12 (m, 3H), 7.28 (d, J = 2.57 Hz, 1H), 7.41 (d, J = 8.46 Hz, 2H), 7.59 (m, 3H), 8.56 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 9.65 (s, 1H), 9.94 (s, 1H);

MS (ESI +) m / z 573.575 (M + H) +.

Example 49

4- [4- (4-Hydroxyphenylsulfanyl) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 21A was reacted with the product of Example 36E by the method described in Example 36I, using the product of Example 21A instead of the product of Example 36H, to obtain the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (32 mg, 26%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.91 (s, 1H), 9.69 (s, 1H), 8.87 (d, J = 9.19 Hz, 1H), 8, 69 (s, 1H), 7.88 (d, J = 8.09 Hz, 2H), 7.77 (d, J = 8.46 Hz, 1H), 7.64 (d, J = 8.46 Hz, 2H), 7.15-7.26 (m, J = 8.82 Hz, 2H), 7.08-7.15 (m, 2H), 7.01 (d, J = 8.82 Hz , 1H), 6.58-6.72 (m, 2H), 5.23 (s, 2H), 3.20-3.31 (m, 1H), 1.34 (d, J = 6.99 Hz, 6H);

MS (ESI +) m / z 520.2 (M + H) + (ESI-) m / z 518.2 (M-H) -.

Example 50

2- [4- (4-Hydroxyphenylsulfanyl) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 20A was reacted with the product of Example 36E in the manner described in Example 36I, using the product of Example 20A instead of the product of Example 36H to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (11 mg, 9%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.30 (s, 1H), 9.71 (s, 1H), 8.93 (d, J = 8.82 Hz, 1H), 8, 76 (s, 1H), 7.92 (d, J = 7.35 Hz, 1H), 7.84 (d, J = 8.82 Hz, 1H), 7.72-7.80 (m, 2H ), 7.59 (ddd, J = 7.72, 6.25, 2.58 Hz, 1H), 7.19-7.28 (m, 2H), 7.06-7.17 (m, 3H ), 6.64-6.69 (m, 2H), 5.25 (s, 2H), 3.22-3.33 (m, 1H), 1.35 (d, J = 6.99 Hz, 6H);

MS (ESI +) m / z 520.2 (M + H) + (ESI-) m / z 518.2 (M-H) -.

Example 51

4- [4-Benzyloxy-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 27A was reacted with the product of Example 36E by the method described in Example 36I, using the product of Example 27A instead of the product of Example 36H to give a solid which was triturated in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (d, J = 6.62 Hz, 6H), 3.10-3.30 (m, 1H), 5.11 (s, 2H ), 6.67 (d, J = 8.82 Hz, 2H), 6.90-6.99 (m, 1H), 7.07-7.19 (m, 1H), 7.11 (d, J = 8.82 Hz, 2H), 7.23-7.52 (m, 6H), 7.59 (d, J = 8.09 Hz, 1H), 8.56 (s, 1H), 8, 75 (d, J = 8.09 Hz, 1H), 9.64 (s, 1H), 9.95 (s, 1H);

MS (DCI / NH ₃ ) m / z 495 (M + H) +.

Example 52

3- [3- [7- (1-Hydroxy-1-methylethyl) pyrido [2,3-d] pyrimidin-4-ylamino] -4- (4-hydroxyphenylsulfanyl) phenoxymethyl] benzonitrile

The product of example 36E (45.9 mg, 0.212 mmol) and the product of example 36H (73.5 mg, 0.212 mmol) in acetic acid (1 ml) were gradually heated from room temperature to 130ºC in an oil bath for 15 minutes, then heated at 130ºC for another 1.5 hours. The mixture was then cooled to room temperature, concentrated in vacuo to give the crude title compound, which was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of the mixture from 10% to 100% acetonitrile / 0.1% trifluoroacetic acid in water, for 8 minutes (10 minutes transit time) at a flow rate of 40 ml / min, to give the title compound as a trifluoroacetic acid salt (22 mg, 20% )

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 11.76 (s, 1H), 9.72 (s, 1H), 9.06 (d, J = 8.09 Hz, 1H), 8 83 (s, 1H), 8.20 (d, J = 8.46 Hz, 1H), 7.92 (s, 1H), 7.75-7.88 (m, 2H), 7.63 ( t, J = 7.72 Hz, 1H), 7.21-7.26 (m, 1H), 7.19 (d, J = 2.57 Hz, 1H), 7.07-7.15 (m , 3H), 6.64 (d, J = 8.46 Hz, 2H), 5.18 (s, 2H), 1.56 (s, 6H);

MS (ESI) m / z 536.2 (M + H) +, (ESI-) m / z 534.2 (M-H) -.

Example 53

2- [3- [7- (1-Hydroxy-1-methylethyl) pyrido [2,3-d] pyrimidin-4-ylamino] -4- (4-hydroxyphenylsulfanyl) phenoxymethyl] benzonitrile

The product of Example 20A was reacted with the product of Example 36E in the manner described in Example 52, using the product of Example 20A instead of the product of Example 36H to give the crude title compound, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (11 mg, 11%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.73 (s, 1H), 9.75 (s, 1H), 9.05 (d, J = 8.46 Hz, 1H), 8, 84 (s, 1H), 8.20 (d, J = 8.82 Hz, 1H), 7.92 (d, J = 7.35 Hz, 1H), 7.69-7.84 (m, 2H ), 7.54-7.64 (m, 1H), 7.23-7.27 (m, 1H), 7.21 (d, J = 2.57 Hz, 1H), 7.10-7, 17 (m, 3H), 6.64-6.69 (m, 2H), 5.25 (s, 2H), 1.56 (s, 6H);

MS (ESI +) m / z 536.2 (M + H) + (ESI-) m / z 534.3 (M-H).

Example 54

4- [3- [7- (1-Hydroxy-1-methylethyl) pyrido [2,3-d] pyrimidin-4-ylamino] -4- (4-hydroxyphenylsulfanyl) phenoxymethyl] benzonitrile

The product of Example 21A was reacted with the product of Example 36E by the method described in Example 52, using the product of Example 21A instead of the product of Example 36H, to obtain the crude title compound which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (10 mg, 10%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.64 (s, 1H), 9.73 (s, 1H), 9.05 (s, 1H), 8.82 (s, 1H), 8.19 (d, J = 8.82 Hz, 1H), 7.88 (d, J = 8.09 Hz, 2H), 7.64 (d, J = 8.46 Hz, 2H), 7, 23 (d, J = 8.82 Hz, 1H), 7.18 (d, J = 2.57 Hz, 1H), 7.04-7.15 (m, 3H), 6.62-6.69 (m, 2H), 5.23 (s, 2H), 2.54 (s, 1H), 1.56 (s, 6H);

MS (ESI +) m / z 536.2 (M + H) + (ESI-) m / z 534.2 (M-H) -.

Example 55

4- [2- [7- (1-Hydroxy-1-methylethyl) pyrido [2,3-d] pyrimidin-4-ylamino] -4- (2-methoxybenzyloxy) phenylsulfanyl] phenol

The product of example 37A was reacted with the product of example 36E in the manner described in example 52, using the product of example 37A instead of the product of example 36H to give a solid which was triturated in methanol to give the title compound (8 mg, 8%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.81 (s, 1H), 9.40-9.95 (m, 1H), 9.06 (d, J = 8.46 Hz, 1H ), 8.85 (s, 1H), 8.21 (d, J = 8.46 Hz, 1H), 7.31-7.44 (m, 2H), 7.25 (d, J = 8, 46 Hz, 1H), 7.15 (d, J = 2.57 Hz, 1H), 7.02-7.14 (m, 4H), 6.97 (t, J = 7.54 Hz, 1H) 6.61-6.67 (m, 2H), 5.05 (s, 2H), 3.80 (s, 3H), 2.54 (s, 1H), 1.56 (s, 6H);

MS (ESI +) m / z 541.2 (M + H) + (ESI-) m / z 539.2 (M-H) -.

Example 56

4- {4- (4-Bromobenzyloxy) -2- [7- (1-hydroxy-1-methylethyl) pyrido [2,3-d] pyrimidin-4-ylamino] phenylsulfanyl} phenol

The product of example 16A was reacted with the product of example 36E in the manner described in example 52, using the product of example 16A instead of the product of example 36H to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (8 mg, 13%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.55 (s, 6H), 2.08 (s, 1H), 5.10 (s, 2H), 6.65 (d, J = 8 , 46 Hz, 2H), 7.13 (m, 5H), 7.41 (d, J = 8.46 Hz, 2H), 7.60 (d, J = 8.09 Hz, 2H), 8, 15 (d, J = 8.46 Hz, 1H), 8.77 (s, 1H), 9.00 (d, J = 8.46 Hz, 1H), 9.70 (s, 1H), 11, 43 (s, 1H);

MS (ESI +) m / z 589, 591 (M + H) +.

Example 57

4- [4- (3-Fluorobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 57A

N '- (3-Cyanopyridin-2-yl) -N, N-dimethylformamidine

A solution of 2-aminonicotinonitrile (5 g, 42 mmol) and N , N- dimethylformamide dimethyl acetal (6.13 ml, 46.2 mmol) in toluene (20 ml) was heated under reflux for 3 hours. After cooling to room temperature, the solution was concentrated in vacuo to give the title compound (7.3 g, 100%).

Example 57B

1-Chloro-4- (3-fluorobenzyloxy) -2-nitrobenzene

The title compound was prepared according to the method described in Example 10C using 1-bromomethyl-3-fluorobenzene instead of 1-chloromethyl-4-methoxybenzene (0.56 g, 100%).

Example 57C

4- [4- (3-Fluorobenzyloxy) -2-nitrophenylsulfanyl] phenol

The title compound was prepared according to the method described in Example 10D using 1-chloro-4- (3-fluorobenzyloxy) -2-nitrobenzene instead of 1-chloro-4- (4-methoxybenzyloxy) -2-nitrobenzene (0, 57 g, 77%).

Example 57D

4- [2-amino-4- (3-fluorobenzyloxy) phenylsulfanyl] phenol

The title compound was prepared according to the method described in Example 10E using 4- [4- (3-fluorobenzyloxy) -2-nitrophenylsulfanyl] phenol instead of 4- [4- (4-methoxybenzyloxy) -2-nitrophenylsulfanyl] phenol ( 0.501 g, 96%).

Example 57E

4- [4- (3-Fluorobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 57A (35 mg, 0.2 mmol) and the product of example 57D (68 mg, 0.2 mmol) in acetic acid (1 ml) was gradually heated from room temperature to 130 ^o C in an oil bath for 15 minutes, then heated at 130 ^o C for another 1.5 hours. The mixture was then cooled to room temperature, concentrated in vacuo to give the crude title compound, which was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100 % acetonitrile / 0.1% trifluoroacetic acid in water for 8 minutes (10 minutes transit time) at a flow rate of 40 ml / min to give the title compound as a trifluoroacetic acid salt (28 mg, 30%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 5.14 (s, 2H), 6.65 (m, 2H), 7.14 (m, 8H), 7.49 (m, 1H) , 7.66 (m, 1H), 8.61 (s, 1H), 8.88 (d, J = 7.47 Hz, 1H), 9.07 (s, 1H), 9.65 (s, 1H), 10.34 (s, 1H);

MS (ESI) m / z 471 (M + H) +.

Example 58

4- [4- (2-Methylbenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 17A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 17A instead of the product of Example 57D, to obtain the crude title compound which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (50 mg, 54%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H), 5.09 (s, 2H), 6.66 (m, 2H), 7.01 (m, 1H), 7.19 (m, 7 H), 7.42 (d, J = 6.99 Hz, 1H), 7.71 (dd, J = 7.91, 4.23 Hz, 1H), 8.63 ( s, 1H), 8.89 (d, J = 7.35 Hz, 1H), 9.09 (s, 1H), 9.66 (s, 1H), 10.50 (s, 1H);

MS (ESI +) m / z 467 (M + H) +.

Example 59

4- [4- (4-Methylbenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 19A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 19A instead of the product of Example 57D, to obtain the crude title compound which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (45 mg, 48%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H), 5.05 (s, 2H), 6.65 (m, 2H), 7.10 (m, 7H), 7.33 (d, J = 8.07 Hz, 2H), 7.69 (dd, J = 8.27, 4.23 Hz, 1H), 8.62 (s, 1H), 8.87 (d , J = 7.72 Hz, 1H), 9.07 (s, 1H), 9.64 (s, 1H), 10.42 (s, 1H);

MS (ESI +) m / z 467 (M + H) +.

Example 60

4- [4- (2-Bromobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 14A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 14A instead of the product of Example 57D, to give the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (40 mg, 38%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.13 (s, 2H), 6.66 (m, 2H), 6.99 (d, J = 8.43 Hz, 1H), 7, 15 (m, 3H), 7.35 (m, 3H), 7.64 (m, 3H), 8.60 (s, 1H), 8.85 (d, J = 7.32 Hz, 1H), 9.07 (s, 1H); 9.66 (s, 1H); 10.28 (s, 1H);

MS (ESI +) m / z 531, 533 (M + H) +.

Example 61

3- [4- (4-Hydroxyphenylsulfanyl) -3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 36H and the product of Example 57A were reacted according to the method described in Example 57E, using the product of Example 36H instead of the product of Example 57D, to obtain a solid which was triturated in methanol to give the title compound (44 mg, 44 %).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.08 (s, 1H), 9.65 (s, 1H), 9.06 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 7.92 (s, 1H), 7.77-7.86 (m, 2H), 7.54-7.70 (m, J = 7.72, 7.72 Hz, 2H), 7.28 (s, 1H), 7.07-7.19 (m, 3H), 6.97 (s, 1H), 6.63-6.72 (m, 2H), 5 18 (s, 2H);

MS (ESI +) m / z 478.2 (M + H) +, (ESI-) m / z 476.1 (M-H) -.

Example 62

4- [4- (3-Methylbenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 18A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 18A instead of the product of Example 57D, to obtain the crude title compound that was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (50 mg, 54%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H), 5.07 (s, 2H), 6.65 (m, 2H), 7.12 (m, 9H), 7.78 (dd, J = 8.10 Hz, 4.77 Hz, 1H), 8.72 (s, 1H), 8.94 (d, J = 7.47 Hz, 1H), 9.12 ( d, J = 3.15 Hz, 1H), 9.67 (s, 1H), 11.03 (s, 1H);

MS (ESI +) m / z 467 (M + H) +.

Example 63

4- [4- (4-Methoxybenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 10E and the product of Example 57A were reacted in accordance with the method described in Example 57E, using the product of Example 10E instead of the product of Example 57D to give a solid which was triturated in methanol to give the title compound (49 mg, 55 %).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.07 (s, 1H), 9.63 (s, 1H), 9.05 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 7.64 (s, 1H), 7.38 (d, J = 8.46 Hz, 2H), 7.20-7.29 (m, 1H), 7.12 -7.18 (m, 1H), 7.06-7.12 (m, 2H), 6.90-6.99 (m, 3H), 6.62-6.69 (m, 2H), 5 02 (s, 2H); 3.75 (s, 3H);

MS (ESI +) m / z 483.2 (M + H) +, (ESI-) m / z 481.2 (M-H) -.

Example 64

4- [4- (2-Methoxybenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 37A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 37A instead of the product of Example 57D to give a solid which was triturated in methanol to give the title compound (47 mg, 56%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.08 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.85 (d, J = 6 , 62 Hz, 1H), 8.59 (s, 1H), 7.64 (s, 1H), 7.41 (dd, J = 7.35, 1.47 Hz, 1H), 7.30-7 , 38 (m, 1H), 7.24 (s, 1H), 7.16 (d, J = 8.46 Hz, 1H), 7.08-7.14 (m, 2H), 7.05 ( d, J = 8.09 Hz, 1H), 6.89-7.01 (m, J = 7.54, 7.54 Hz, 2H), 6.61-6.71 (m, 2H), 5 05 (s, 2H); 3.80 (s, 3H);

MS (ESI +) m / z 483.2 (M + H) +, (ESI-) m / z 481.2 (M-H) -.

Example 65

4- [4- (4-Hydroxyphenylsulfanyl) -3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 21A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 21A instead of the product of Example 57D, to obtain the crude title compound which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (6 mg, 6%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.17 (s, 1H), 9.69 (s, 1H), 9.09-9.20 (m, J = 3.68 Hz, 1H ), 8.97 (d, J = 8.82 Hz, 1H), 8.74 (s, 1H), 7.78-7.96 (m, 3H), 7.64 (d, J = 8, 46 Hz, 2H), 7.20 (d, J = 8.46 Hz, 2H), 7.07-7.16 (m, 2H), 7.03 (d, J = 6.25 Hz, 1H) 6.57-6.70 (m, 2H); 5.23 (s, 2H);

MS (ESI +) m / z 478.2 (M + H) +, (ESI-) m / z 476.2 (M-H) -.

Example 66

4- [4- (3-Methoxybenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 31A and the product of example 57A were reacted in accordance with the method described in example 57E, using the product of example 31A instead of the product of example 57D, to obtain a solid which was triturated in methanol to give the title compound (38 mg, 45 %).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.07 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.86 (d, J = 7 , 72 Hz, 1H), 8.59 (s, 1H), 7.64 (s, 1H), 7.23-7.36 (m, 2H), 7.16 (dd, J = 8.64, 1.65 Hz, 1H), 7.07-7.13 (m, 2H), 6.93-7.05 (m, 3H), 6.89 (dd, J = 8.27, 2.02 Hz , 1H), 6.61-6.71 (m, 2H), 5.08 (s, 2H), 3.75 (s, 3H);

MS (ESI +) m / z 483.2 (M + H) +, (ESI-) m / z 481.2 (M-H) -.

Example 67

4- [4- (4-Bromobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 16A and the product of example 57A were reacted according to the method described in example 57E, using the product of example 16A instead of the product of example 57D, to give the crude title compound that was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid (11 mg, 16%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.09 (s, 2H), 6.66 (d, J = 8.46 Hz, 2H), 6.94 (s, 1H), 7, 11 (d, J = 8.46 Hz, 3H), 7.25 (s, 1H), 7.41 (d, J = 8.09 Hz, 2H), 7.57-7.69 (m, 3H ), 8.59 (s, 1H), 8.84 (s, 1H), 9.06 (s, 1H), 9.64 (s, 1H), 10.07 (s, 1H);

MS ESI + m / z 531 (M + H) +, ESI m / z 529 (M-H) -.

Example 68

4- [4- (3-Bromobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 15A and the product of example 57A were reacted in accordance with the method described in example 57E, using the product of example 15A instead of the product of example 57D, to obtain the crude title compound, which was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid (40 mg, 16%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.12 (s, 2H), 6.67 (d, J = 8.46 Hz, 2H), 6.94 (s, 1H), 7, 12 (d, J = 8.46 Hz, 3H), 7.26 (s, 1H), 7.36 (t, J = 7.72 Hz, 1H), 7.45 (s, 1H), 7, 54 (d, J = 6.62 Hz, 1H), 7.66 (s, 2H), 8.57 (s, 1H), 8.83 (s, 1H), 9.04 (s, 1H), 9.64 (s, 1H); 10.08 (s, 1H);

MS ESI + m / z 531 (M + H) +, ESI m / z 529 (M-H) -.

Example 69

4- [4-Benzyloxy-2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 27A and the product of example 57A were reacted in accordance with the method described in example 57E, using the product of example 27A instead of the product of example 57D, to give the title compound, which was isolated as the acetic acid salt (79 mg, 48% )

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 3H), 6.61-6.72 (m, 2H), 6.93 (d, J = 9.56 Hz, 1H ), 7.11 (d, J = 8.46 Hz, 4H), 7.24 (s, 1H), 7.32-7.47 (m, 5H), 7.59-7.68 (m, 1H), 8.54 (s, 1H), 8.83 (d, J = 9.56 Hz, 1H), 9.04 (s, 1H);

ESI + m / z 453 (M + H) +, ESI- m / z 451 (M-H) -.

Example 70

4- [4- [1- (4-Bromophenyl) ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 22D (153 mg, 0.367 mmol) was reacted with the product of example 57A (63 mg, 0.367 mmol) in accordance with the method described in example 57E, to obtain the crude specified in the title compound, which was purified using HPLC with TFA to give the title compound as a trifluoroacetic acid salt (97 mg, 40%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.60 (br s, 1H), 9.67 (s, 1H), 9.09 (s, 1H), 8.88 (d, J = 8.46 Hz, 1H), 8.64 (s, 1H), 7.73 (m, J = 3.31 Hz, 1H), 7.54 (d, J = 8.46 Hz, 2H) , 7.36 (d, J = 8.46 Hz, 2H), 7.11 (m, 4H), 6.86 (d, J = 9.19 Hz, 1H), 6.64 (d, J = 8.46 Hz, 2H), 5.51 (q, J = 6.62 Hz, 1H), 1.53 (d, J = 6.62 Hz, 3H);

MS (ESI +) m / z, 545, 547 (M + H-TFA) +; (ESI-) m / z, 543, 545 (M-H-TFA) -.

Example 71

4- [4- [1- (4-Fluorophenyl) ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 23A (180 mg, 0.803 mmol) was reacted with the product of example 57A (140 mg, 0.803 mmol) in accordance with the method described in example 57E, to obtain the crude specified in the title compound, which was purified using HPLC with TFA to give the title compound as a trifluoroacetic acid salt (60 mg, 12%).

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 1.53 (d, J = 6.35 Hz, 3H), 5.51 (q, 1H), 6.61 (d, J = 8, 79 Hz, 2H), 6.74-6.82 (m, 1H), 6.93 (dd, J = 8.79, 2.44 Hz, 1H), 7.06-7.09 (m, 3H ), 7.11-7.19 (m, 2H), 7.44 (dd, J = 8.54, 5.62 Hz, 2H), 7.83-7.86 (m, J = 8.54 , 5.13 Hz, 1H), 8.75 (s, 1H), 8.96 (d, J = 7.32 Hz, 1H), 9.14 (d, J = 2.93 Hz, 1H);

MS (ESI +) m / z 485.

Example 72

4- [4- [1- (3-Fluorophenyl) ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 24A (285 mg, 0.80 mmol) was reacted with the product of Example 57A (140 mg, 0.803 mmol) in accordance with the method described in Example 57E to obtain the crude title compound that was purified by HPLC. with TFA to give the title compound as a trifluoroacetic acid salt (150 mg, 31%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.55 (d, J = 6.25 Hz, 3H), 5.53 (q, J = 6.13 Hz, 1H), 6.65 (d, J = 8.46 Hz, 2H), 6.85 (d, J = 6.99 Hz, 1H), 7.03-7.18 (m, 4H), 7.21-7.29 ( m, 2H), 7.37-7.45 (m, 1H), 7.67 (dd, J = 8.09, 4.41 Hz, 1H), 8.57 (s, 1H), 8.81 (s, 1H); 9.06 (s, 1H); 9.66 (s, 1H);

MS (ESI +) m / z 485 (M + H) +.

Example 73

(5-Benzyloxy-4-chloro-2-fluorophenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 73A

2-Chloro-4-fluorophenyl ether ethyl carbonate

Ethyl chloroformate (0.9 ml) was added dropwise to a solution of 2-chloro-4-fluorophenol (0.8 ml, 7.64 mmol) and triethylamine (1.3 ml, 9.16 mmol) in dichloromethane (10 ml) at 0 ° C. 9.16 mmol). The ice bath was removed and the solution was allowed to warm to room temperature and was stirred for another 16 hours. Then dichloromethane (20 ml) was added to the mixture, the organic solution was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title product as an oil (1.65 g, 100%) .

Example 73B

2-Chloro-4-fluoro-5-nitrophenyl ether ethyl carbonate

A solution of the product of example 73A (0.88 g, 4.03 mmol) in concentrated sulfuric acid (2 ml) was cooled in an ice bath, fuming nitric acid (0.27 ml, 6.45 mmol) was slowly added to maintain the temperature at 0ºC . The mixture was stirred for another 2 hours, then ice-water (10 ml) was added to the solution, and the resulting solid was collected by filtration, washed with water and dried in a vacuum oven to obtain the title compound (0.87 g, 82%).

Example 73C

2-Chloro-4-fluoro-5-nitrophenol

To a solution of the product of Example 73B (0.87 g, 3.30 mmol) in methanol (20 ml) and water (1 ml) was added sodium bicarbonate (2.22 g, 26.4 mmol) and the mixture was stirred at room temperature in within 16 hours. Then, methanol was removed in vacuo, dichloromethane (20 ml) was added to the mixture, the organic solution was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title product (0.62 g, 98 %).

Example 73D

1-Benzyloxy-2-chloro-4-fluoro-5-nitrobenzene

The title compound was prepared according to the method described in Example 10C using benzyl bromide and the product of Example 73C instead of 1-chloromethyl-4-methoxybenzene and 4-chloro-3-nitrophenol (0.72 g, 79%).

Example 73E

5-benzyloxy-4-chloro-2-fluorophenylamine

The title compound was prepared according to the method described in Example 10D using the product of Example 73D instead of 1-chloro-4- (4-methoxybenzyloxy) -2-nitrobenzene (77 mg, 100%).

Example 73F

(5-Benzyloxy-4-chloro-2-fluorophenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of Example 10B (17 mg, 0.0927 mmol) and the product of Example 73E (28 mg, 0.111 mmol) in acetic acid (1 ml) was stirred in an oil bath pre-heated to 130 ° C for 15 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (8.1 mg, 17%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.72 (s, 3H), 5.19 (s, 2H), 7.28-7.53 (m, 6H), 7.66 ( d, J = 9.56 Hz, 1H), 7.70 (d, J = 8.82 Hz, 1H), 8.73 (s, 1H), 8.84 (d, J = 8.09 Hz, 1H), 10.85 (s, 1H);

MS (ESI) m / z 395 (M + H) +.

Example 74

(5-Benzyloxy-4-chloro-2-fluorophenyl) pyrido [2,3-d] pyrimidin-4-ylamine

The title compound was prepared according to the method described in Example 73F using the product of Example 57A instead of the product of Example 10B (7.9 mg, 19%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 5.19 (s, 2H), 7.20-7.54 (m, 6H), 7.65 (d, J = 9.56 Hz, 1H), 7.78 (dd, J = 8.27, 4.60 Hz, 1H), 8.73 (s, 1H), 8.95 (d, J = 8.09 Hz, 1H), 9, 12 (d, J = 3.31 Hz, 1H); 10.82 (s, 1H);

MS (ESI +) m / z 381 (M + H) +.

Example 75

(5-Benzyloxy-2,4-difluorophenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 75A

2,4-difluorophenyl ether ethyl carbonate

The title compound was prepared according to the method described in Example 73A using 2,4-difluorophenol instead of 2-chloro-4-fluorophenol (1.48 g, 96%).

Example 75B

2,4-Difluoro-5-nitrophenyl ether ethyl carbonate

The title compound was prepared according to the method described in Example 73B.

Example 75C

2,4-Difluoro-5-nitrophenol

The title compound was prepared according to the method described in Example 73C, using the product of Example 73B instead of 313B (0.59 g, 89%).

Example 75D

1-Benzyloxy-2,4-difluoro-5-nitrobenzene

The title compound was prepared according to the method described in Example 73D, using the product of Example 75C instead of 313C (0.56 g, 63%).

Example 75E

5-benzyloxy-2,4-difluorophenylamine

The title compound was prepared according to the method described in Example 73E using the product of Example 75D instead of the product 313D (89 mg, 100%).

Example 75F

(5-Benzyloxy-2,4-difluorophenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

The title compound was prepared according to the method described in Example 73F using the product of Example 75E instead of the product of Example 73E. The resulting residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (7.4 mg, 16%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.72 (s, 3H), 5.17 (s, 2H), 7.19-7.60 (m, 7H), 7.71 ( d, J = 8.46 Hz, 1H), 8.75 (s, 1H), 8.85 (d, J = 8.46 Hz, 1H), 10.84 (s, 1H);

MS (ESI) m / z 379 (M + H) +.

Example 76

(5-Benzyloxy-2,4-difluorophenyl) pyrido [2,3-d] pyrimidin-4-ylamine

A solution of the product of Example 57A (17 mg, 0.099 mmol) and the product of Example 73E (28 mg, 0.119 mmol) in acetic acid (1 ml) was stirred in an oil bath pre-heated to 130 ° C for 15 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as trifluoroacetic acid salt (21.4 mg, 45%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.17 (s, 2H), 7.19-7.61 (m, 7H), 7.80 (dd, J = 8.09, 4, 41 Hz, 1H), 8.77 (s, 1H), 8.97 (d, J = 7.35 Hz, 1H), 9.14 (d, J = 2.94 Hz, 1H), 10.88 (c, 1H);

MS (ESI +) m / z 365 (M + H) +.

Example 77

4- {2- [Benzyl- (7-methylpyrido [2,3-d] pyrimidin-4-yl) amino] -4-benzyloxyphenylsulfanyl} phenol

To a solution of the product of example 27 (26.3 mg, 0.062 mmol), benzyl bromide (0.0075 ml, 0.062 mmol) and potassium carbonate (8.6 mg, 0.062 mmol) in N, N- dimethylformamide (0.5 ml) was stirred at room temperature for 16 hours. Then the mixture was poured into ice water (10 ml) and the resulting solution was acidified with 1N. aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 × 10 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt ( 6.7 mg, 18%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 5.10 (s, 2H), 5.69 (s, 1H), 6.65 (d, J = 8 , 82 Hz, 2H), 7.02-7.18 (m, 2H), 7.14-7.26 (m, 1H), 7.26-7.58 (m, 12H), 7.86 ( s, 1H), 8.93 (s, 1H), 9.23 (s, 1H), 9.73 (s, 1H), 12.09 (s, 1H);

MS (ESI +) m / z 557 (M + H) +.

Example 78

(5-Benzyloxy-2-bromophenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 78A

5-benzyloxy-2-bromophenylamine

The title compound was prepared according to the method described in Boger, DL, Wysocki, RJ, Ishizaki, T. J. Am. Chem. Soc. 112, 1990, p. 5230-5240. The amount obtained was 4.58 g, 48%.

Example 78B

(5-Benzyloxy-2-bromophenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 78A (2.0 g, 7.19 mmol) and the product of example 10B (1.35 g, 7.19 mmol) in acetic acid (15 ml) were gradually heated from room temperature to 130ºC in an oil bath for 15 minutes, then heated at 130ºC for another 1.5 hours. The mixture was then cooled to room temperature, concentrated in vacuo to give the crude title compound (3.4 g of red sticky syrup, 100%), part of which was purified by HPLC with TFA to give the title compound as trifluoroacetic acid salt (81 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.74 (s, 3H), 5.14 (s, 2H), 7.06 (dd, J = 8.8, 2.9 Hz, 1H), 7.23 (m, 1H), 7.41 (m, 5H), 7.70 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 8.79 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 11.40 (br s, 1H);

MS (ESI +) m / z 421/423 (M + H) +.

Example 79

2-Chloro-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

Example 79A

N- (3-aminophenyl) -2-chlorobenzamide

The title compound was prepared according to the method described in Example 254A using 2-chlorobenzoyl chloride instead of 4-bromobenzoyl chloride, then the nitro group was reduced by the method described in Example 255B to give the title product.

Example 79B

2-Chloro-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

The product of example 79A was reacted with the product of example 57A by the method described in example 254C using the product of example 79A instead of the product of example 254B to give a crude product that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (18 mg, 22%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 7.45-7.54 (m, 4H), 7.56-7.62 (m, 3H), 7.83-7.90 (m, 1H), 8.25-8.29 (m, 1H), 8.93 (s, 1H), 9.12-9.18 (m, 2H), 10.70 (s, 1H), 11.23 (c, 1H);

MS ESI + m / z 376 (M + H) +, ESI m / z 374 (M-H) -.

Example 80

2-Bromo-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

Example 80A

N- (3-aminophenyl) -2-bromobenzamide

The title compound was prepared according to the method described in Example 254A using 2-bromobenzoyl chloride instead of 4-bromobenzoyl chloride, then the nitro group was reduced by the method described in Example 255B to give the title product.

Example 80B

2-Bromo-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

The product of example 80A was reacted with the product of example 57A by the method described in example 254C using the product of example 80A instead of the product of example 254B to give a crude product that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (18 mg, 22%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 7.44-7.54 (m, 4H), 7.56-7.60 (m, 2H), 7.74 (dd, J = 7, 91, 0.92 Hz, 1H), 7.82-7.89 (m, 1H), 8.27 (s, 1H), 8.92 (s, 1H), 9.11-9.19 (m , 2H); 10.68 (s, 1H); 11.20 (s, 1H);

MS ESI + m / z 420 (M + H) +, ESI- m / z 418 (M-H) -.

Example 81

2-Methoxy-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

Example 81A

N- (3-aminophenyl) -2-methoxybenzamide

The title compound was prepared according to the method described in Example 254A using 2-methoxybenzoyl chloride instead of 4-bromobenzoyl chloride, then the nitro group was reduced by the method described in Example 255B to give the title product.

Example 81B

2-Methoxy-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

The product of Example 81A was reacted with the product of Example 57A by the method described in Example 254C using the product of Example 81A instead of the product of Example 254B to give a crude product which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (26 mg, 33%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 3.90 (s, 3H), 7.08 (t, J = 6.99 Hz, 1H), 7.20 (d, J = 8.46 Hz, 1H), 7.41-7.56 (m, 4H), 7.62 (dd, J = 7.54, 1.65 Hz, 1H), 7.88 (dt, 1H), 8.28 (s, 1H), 8.94 (s, 1H), 9.12-9.19 (m, 2H), 10.30 (s, 1H), 11.30 (s, 1H);

MS ESI + m / z 372 (M + H) +, ESI m / z 370 (M-H) -.

Example 82

3-Methoxy-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

Example 82A

N- (3-aminophenyl) -3-methoxybenzamide

The title compound was prepared according to the method described in Example 254A using 3-methoxybenzoyl chloride instead of 4-bromobenzoyl chloride, then the nitro group was reduced by the method described in Example 255B to give the title product.

Example 82B

3-Methoxy-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

The product of Example 82A was reacted with the product of Example 57A by the method described in Example 254C using the product of Example 82A instead of the product of Example 254B to give a crude product which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (35 mg, 45%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 3.85 (s, 3H), 7.18 (dd, J = 7.54, 2.02 Hz, 1H), 7.42-7.51 (m, 3H), 7.53-7.61 (m, 3H), 7.82 (dd, J = 7.72, 5.15 Hz, 1H), 8.32 (t, J = 1.84 Hz, 1H), 8.89 (s, 1H), 9.09-9.17 (m, 2H), 10.38 (s, 1H), 10.99 (s, 1H);

MS ESI + m / z 372 (M + H) +, ESI m / z 370 (M + H) -.

Example 83

3-Fluoro-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

Example 83A

N- (3-aminophenyl) -3-fluorobenzamide

The title compound was prepared according to the method described in Example 254A using 3-fluorobenzoyl chloride instead of 4-bromobenzoyl chloride, then the nitro group was reduced by the method described in Example 255B to give the title product.

Example 83B

3-Fluoro-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

The product of Example 83A was reacted with the product of Example 57A by the method described in Example 254C using the product of Example 83A instead of the product of Example 254B to give a crude product which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (21 mg, 28%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 7.41-7.53 (m, 2H), 7.54-7.65 (m, 3H), 7.77-7.86 (m, 3H), 8.33 (s, 1H), 8.89 (s, 1H), 9.10-9.16 (m, 2H), 10.48 (s, 1H), 10.97 (s, 1H );

MS ESI + m / z 360 (M + H) +, ESI- m / z 358 (M-H) -.

Example 84

4- [4-Benzylamino-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 84A

4- (4-amino-2-nitrophenylsulfanyl) 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 dimethyl sulfoxide (10 ml) was heated at 100ºC for 16 hours. Then, 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 the solvent was removed in vacuo to give the title compound as a red solid (1.45 g, 92%).

Example 84B

4- (4-Benzylamino-2-nitrophenylsulfanyl) phenol

A solution of the product of example 84A (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 was quenched with water (20 ml) and the resulting solution was concentrated in vacuo to a yellow solid. The solid was dissolved in ethyl acetate (50 ml) and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to give a pale yellow oil. The oil was purified by silica gel chromatography eluting with 1% methanol in methylene chloride to give the title compound (0.63 g, 77%).

Example 84C

4- (4-amino-4-benzylaminophenylsulfanyl) phenol

A solution of the product of example 84B (0.5 g, 1.4 mmol), iron powder (0.49 g, 8.74 mmol) and ammonium chloride (0.50 g, 9.3 mmol) in a solution of methanol (10 ml) , tetrahydrofuran (10 ml) and water (5 ml) were heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.30 g, 66%).

Example 84D

4- [4-Benzylamino-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of Example 10B (30 mg, 0.159 mmol) and the product of Example 84C (56.5 mg, 0.17 mmol) in acetic acid (2 ml) were mixed in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as trifluoroacetic acid salt (12 mg, 10%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H), 4.50 (s, 2H), 6.60-6.69 (m, 2H), 6.73-6 85 (m, 2H), 7.04-7.29 (m, 6H), 7.31-7.40 (m, 2H), 7.46 (d, J = 7.35 Hz, 2H), 8.54 (s, 1H), 8.75 (s, 1H), 9.74 (s, 1H);

MS (ESI) m / z 466 (M + H) +, (ESI-) m / z 464 (M-H) -.

Example 85

N1-Benzyl-4- (4-benzyloxyphenylsulfanyl) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

Example 85A

4- (2-amino-4-nitrophenylsulfanyl) phenol

A solution of 2-chloro-5-nitroaniline (3 g, 17.4 mmol), 4-hydroxythiophenol (2.4 g, 19.0 mmol), cesium carbonate (12.35 g, 38 mmol) in dimethylformamide (35 ml) heated at 100ºC for 16 hours. Then, ice-water (200 ml) was added to the solution, and ethyl acetate (200 ml) was added to the resulting suspension. The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo to give a yellow oil. The oil was purified by silica gel chromatography, eluting with a methylene chloride / methanol mixture (97: 3), to give the title compound as a yellow solid (2.1 g, 46%).

Example 85B

2- (4-Benzyloxyphenylsulfanyl) -5-nitrophenylamine

A suspension containing the product of Example 85A (0.2 g, 0.763 mmol) and cesium carbonate (0.25 g, 0.763 mmol) in dimethylformamide (5 ml) was treated with benzyl bromide (0.091 ml, 0.763 mmol) and the resulting suspension was stirred for 18 hours at room temperature. Then, ice-water (50 ml) was added to the solution, and ethyl acetate (50 ml) was added to the resulting suspension. The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo to give the title compound as a yellow solid (0.24 g, 89%).

Example 85C

[2- (4-Benzyloxyphenylsulfanyl) -5-nitrophenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of Example 10B (62 mg, 0.331 mmol) and the product of Example 85B (120 mg, 0.331 mmol) in acetic acid (1 ml) were stirred in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo to give the title compound as a brown oil (0.15 g, 92%). The compound was used without purification in the next step.

Example 85D

4- (4-Benzyloxyphenylsulfanyl) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

A solution of the product of example 85C (0.150 g, 0.303 mmol), iron powder (0.10 g, 1.86 mmol) and ammonium chloride (0.10 g, 1.98 mmol) in a solution of methanol (2 ml), tetrahydrofuran ( 2 ml) and water (1 ml) were heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.06 g, 42%).

Example 85E

N1-Benzyl-4- (4-benzyloxyphenylsulfanyl) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

A mixture of the compound obtained in example 85D (0.06 g, 0.130 mmol), benzaldehyde (0.013 g, 0.130 mmol) and sodium cyanoborohydride (0.0081 g, 0.13 mmol) in methanol (1 ml) containing 1 drop of acetic acid, stirred for 18 hours at room temperature. The solvent was removed in vacuo and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (12 mg, 17%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.69 (s, 3H), 4.30 (s, 2H), 4.96 (s, 2H), 6.60 (dd, J = 8 46, 2.57 Hz, 1H), 6.72-6.89 (m, 3H), 6.94-7.09 (m, 2H), 7.19-7.29 (m, 1H), 7.29-7.46 (m, 11H), 7.63 (d, J = 8.46 Hz, 1H), 8.61 (s, 1H), 8.71 (d, J = 8.82 Hz , 1H), 10.69 (s, 1H).

Example 86

4- [4 - [(Furan-3-ylmethyl) amino] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 86A

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4-nitrophenylsulfanyl] phenol

A solution of the product of example 10B (340 mg, 1.80 mmol) and the product of example 85A (480 mg, 1.80 mmol) in acetic acid (10 ml) was stirred in an oil bath preheated to 130ºC for 30 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo to give the title compound as a brown oil (0.65 g, 89%).

Example 86B

4- [4-amino-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A suspension of the product of Example 86A (0.19 g, 0.469 mmol) and 10% Pd / C (0.025 g) in acetic acid (3 ml) was placed in a hydrogen atmosphere with stirring for 2 hours at room temperature. The suspension was filtered and the solvent was removed in vacuo to give a brown solid as the acetate salt of the title compound (0.21 g, 91%).

Example 86C

4- [4 - [(Furan-3-ylmethyl) amino] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of Example 86B (69.7 mg, 0.141 mmol), 3-furaldehyde (13.5 mg, 0.141 mmol) and sodium cyanoborohydride (8.7 mg, 0.141 mmol) in 2 ml of methanol was stirred for 18 hours at room temperature. The solvent was evaporated in vacuo and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (16 mg, 14%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.75 (s, 3H), 3.85 (s, 1H), 4.09 (s, 2H), 6.47 (s, 1H), 6.53 (d, J = 8.82 Hz, 2H), 6.62-6.75 (m, 2H), 6.94 (d, J = 8.46 Hz, 3H), 7.21-7 32 (m, 1H), 7.61 (s, 1H), 7.83 (d, J = 8.46 Hz, 1H), 8.77 (s, 1H), 8.88 (s, 1H) 9.51 (s, 1H); 11.68 (s, 1H).

Example 87

4- {2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4 - [(thiophen-3-ylmethyl) amino] phenylsulfanyl} phenol

The solution of the product of Example 86B and 3-thiophenecarboxaldehyde was reacted according to the method described in Example 86C using 3-thiophenecarboxaldehyde instead of 3-furaldehyde to give a crude product which was purified by HPLC with TFA to give the title compound as trifluoroacetic acid salt (26 mg, 37%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 3.74 (s, 1H), 4.26 (s, 2H), 6.52 (d, J = 8 , 82 Hz, 3H), 6.64-6.76 (m, 1H), 6.86-6.99 (m, 3H), 7.02-7.14 (m, 1H), 7.19- 7.34 (m, 1H), 7.42-7.54 (m, 1H), 7.82 (d, J = 8.09 Hz, 1H), 8.76 (s, 1H), 8.90 (s, 1H), 9.51 (s, 1H), 11.65 (s, 1H).

Example 88

4- {2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4 - [(naphthalen-1-ylmethyl) amino] phenylsulfanyl} phenol

The solution of the product of Example 86B and 1-naphthaldehyde was reacted according to the method described in Example 86C using 1-naphthaldehyde instead of 3-furaldehyde to give a crude product which was purified by HPLC with TFA to give the title compound as trifluoroacetic acid salt (18 mg, 12%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3H), 4.73 (s, 1H), 6.39 (s, 1H), 6.45-6.60 (m , 2H), 6.67-6.80 (m, 1H), 6.88-6.98 (m, 2H), 7.17-7.34 (m, 1H), 7.43-7.54 (m, 1H), 7.51-7.71 (m, 4H), 7.71-7.83 (m, 1H), 7.83 (d, J = 8.82 Hz, 1H), 7, 95-8.09 (m, 2H), 8.10-8.18 (m, 1H), 8.22 (d, J = 8.09 Hz, 1H), 8.76 (s, 1H), 8 82-8.89 (m, 1H); 9.51 (s, 1H); 11.64 (s, 1H).

Example 89

4- [4 - [(Furan-2-ylmethyl) amino] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The solution of the product of Example 86B and 2-furaldehyde was reacted according to the method described in Example 86C using 2-furaldehyde instead of 3-furaldehyde to give a crude product which was purified by HPLC with TFA to give the title compound as trifluoroacetic acid salt (18 mg, 16%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.69-2.81 (m, 3H), 4.26 (s, 2H), 6.27-6.44 (m, 1H), 6 , 45-6.59 (m, 2H), 6.46-6.60 (m, 3H), 6.68-6.78 (m, 2H), 6.89-7.00 (m, 2H) 7.20-7.33 (m, 1H), 7.59 (s, 1H), 7.84 (d, J = 8.09 Hz, 1H), 8.77 (s, 1H), 8, 89 (s, 1H); 11.73 (s, 1H).

Example 90

4- {2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4 - [(thiophen-2-ylmethyl) amino] phenylsulfanyl} phenol

The solution of the product of Example 86B and 2-thiophenecarboxaldehyde was reacted according to the method described in Example 86C using 2-thiophenecarboxaldehyde instead of 3-furaldehyde to give a crude product which was purified by HPLC with TFA to give the title compound as trifluoroacetic acid salt (11 mg, 16%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.64-2.86 (m, 3H), 4.47 (s, 2H), 6.46-6.57 (m, 2H), 6 64-6.78 (m, 3H), 6.87-7.00 (m, 3H), 7.02-7.13 (m, 2H), 7.19-7.31 (m, 2H) 7.32-7.48 (m, 1H), 7.82 (d, J = 8.82 Hz, 1H), 8.77 (s, 1H), 8.89 (s, 1H), 9, 50 (s, 1H); 11.68 (s, 1H).

Example 91

4- [4- (4-Bromobenzylamino) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 91A

4- [4- (4-Bromobenzylamino) -2-nitrophenylsulfanyl] phenol

The solution of the product of example 84A and 4-bromobenzaldehyde was reacted in accordance with the method described in example 84B using 4-bromobenzaldehyde instead of the product of example 84A to give a crude product which was purified by silica gel chromatography eluting with 2% methanol in methylene chloride, s obtaining the title compound as a yellow solid (0.11 g, 73%).

Example 91B

4- [2-amino-4- (4-bromobenzylamino) phenylsulfanyl] phenol

The product solution of Example 91A was reacted according to the method described in Example 84C to give the title compound (0.17 g, 76%).

Example 91C

4- [4- (4-Bromobenzylamino) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 10B (50 mg, 0.266 mmol) and the product of example 91B (110 mg, 0.266 mmol) in acetic acid (2 ml) was stirred in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (22 mg, 15%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3H), 4.26 (s, 2H), 6.53 (d, J = 8.46 Hz, 2H), 6, 54-6.69 (m, 2H), 6.85-7.03 (m, 2H), 7.23 (d, J = 8.46 Hz, 1H), 7.30 (d, J = 8, 46 Hz, 3H), 7.46-7.61 (m, 2H), 7.78 (d, J = 8.46 Hz, 1H), 8.73 (s, 1H), 8.89 (d, J = 19.12 Hz, 1H), 9.51 (s, 1H), 11.46 (s, 1H).

Example 92

N1-Benzyl-4- (4-methoxyphenylsulfanyl) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

4- (4-methoxyphenylsulfanyl) -3-nitrophenylamine

Example 92A

A solution of 4-chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-methoxythiophenol (0.84 g, 6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 ml) was heated at 100 ° C for 16 hours. Then, 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 the solvent was removed in vacuo to give the title compound as a red solid (1.5 g, 94%).

Example 92B

Benzyl- [4- (4-methoxyphenylsulfanyl) -3-nitrophenyl] amine

A solution of the product of example 92A (0.50 g, 1.81 mmol), benzaldehyde (0.19 g, 1.81 mmol) and sodium cyanoborohydride (0.11 g, 1.8 mmol) in methanol (10 ml) containing 1% acetic acid was stirred at room temperature for 16 hours. The reaction was quenched with water (20 ml) and the resulting solution was concentrated in vacuo to a yellow solid. The solid was dissolved in ethyl acetate (50 ml) and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to give a pale yellow oil. The oil was purified by silica gel chromatography eluting with 1% methanol in methylene chloride to give the title compound as a brown-red solid (0.62 g, 91%).

Example 92C

N1-Benzyl-4- (4-methoxyphenylsulfanyl) benzene-1,3-diamine

A solution of the product of example 92B was reacted in accordance with the method described in example 84C to give the title compound (0.49 g, 89%).

Example 92D

N1-Benzyl-4- (4-methoxyphenylsulfanyl) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

A solution of the product of Example 10B (27.8 mg, 0.148 mmol) and the product of Example 92C (49 mg, 0.148 mmol) in acetic acid (2 ml) was stirred in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as trifluoroacetic acid salt (15 mg, 14%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.64-2.81 (m, 3H), 3.56-3.71 (m, 3H), 4.29 (s, 2H), 6 , 61-6.75 (m, 3H), 6.95-7.07 (m, 2H), 7.16-7.45 (m, 8H), 7.76 (d, J = 8.46 Hz , 1H), 8.69 (s, 1H), 8.80 (d, 1H), 11.34 (s, 1H).

Example 93

N1-Benzyl-4- (4-methoxyphenoxy) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

Example 93A

4- (4-methoxyphenoxy) -3-nitrophenylamine

A solution of 4-chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-methoxyphenol (0.74 g, 6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 ml) was heated at 100 ^° C. for 16 hours. Then, 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 the solvent was removed in vacuo to give the title compound as a red solid (1.1 g, 73%).

Example 93B

N1-Benzyl-4- (4-methoxyphenoxy) benzene-1,3-diamine

The solution of the product of example 93A was subjected to interaction in accordance with the method described in example 92B, using the product of example 93A instead of the product of example 92A, which was restored in accordance with the method described in example 84C, to obtain the title compound (0.05 g, 12%).

Example 93C

N1-Benzyl-4- (4-methoxyphenoxy) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

A solution of the product of example 10B and the product of example 93B was reacted according to the method described in example 92D using the product of example 93B instead of the product of example 92C, which was purified by HPLC with TFA to afford the title compound as the trifluoroacetic acid salt (8 mg, 18%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.55-2.68 (m, 3H), 3.61 (s, 3H), 4.26 (d, J = 5.88 Hz, 2H ), 6.27 (t, J = 5.88 Hz, 1H), 6.50 (dd, J = 8.64, 2.76 Hz, 1H), 6.64-6.87 (m, 6H) 7.18-7.45 (m, 6H), 8.48 (s, 1H), 8.57 (d, J = 8.46 Hz, 1H), 9.59 (s, 1H).

Example 94

N1-Benzyl-4- (4-benzyloxyphenoxy) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

Example 94A

4- (4-Benzyloxyphenoxy) -3-nitrophenylamine

A solution of 4-chloro-3-nitroaniline (2.0 g, 11.16 mmol), 4-benzyloxyphenol (2.55 g, 12.76 mmol), powdered potassium hydroxide (0.94 g, 16.80 mmol) in dimethylformamide (15 ml) was heated at 120ºC for 20 hours. Then, 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 the solvent was removed in vacuo to give the title compound as a dark brown solid (2.07 g, 53%).

Example 94B

N1-Benzyl-4- (4-benzyloxyphenoxy) benzene-1,3-diamine

The solution of the product of example 94A was subjected to interaction in accordance with the method described in example 92B, using the product of example 94A instead of the product of example 92A, which was restored in accordance with the method described in example 84C, to obtain the title compound (0.6 g, 91%).

Example 94C

N1-Benzyl-4- (4-benzyloxyphenoxy) -N3- (7-methylpyrido [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

The solution of the product of Example 10B and the product of Example 94B were reacted according to the method described in Example 92D using the product of Example 94B instead of the product of Example 92C, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (12 mg, 10%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.70 (s, 3H), 4.27 (s, 2H), 4.94 (s, 2H), 4.99-5.12 (m , 1H), 6.64 (dd, J = 8.82, 2.94 Hz, 1H), 6.70-6.92 (m, 9H), 6.90-7.00 (m, 1H), 7.16-7.29 (m, 1H), 7.31-7.42 (m, 5H), 7.70 (d, J = 8.46 Hz, 1H), 8.67-8.86 ( m, 2H), 11.22 (s, 1H).

Example 95

4- [4-amino-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 95A

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-nitrophenylsulfanyl] phenol

A solution of the product of Example 10B (340 mg, 2.31 mmol) and the product of Example 85A (610 mg, 2.30 mmol) in acetic acid (10 ml) were mixed in an oil bath preheated to 130 ° C for 10 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo to give the title compound as a brown oil (0.92 g, 92%).

Example 95B

4- [4-amino-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A suspension of the compound obtained in Example 95A (0.7 g, 1.73 mmol) and 10% Pd / C (100 mg) in acetic acid (10 ml) and methanol (10 ml) was placed in a hydrogen atmosphere from a balloon with stirring for 20 hours at room temperature. The suspension was filtered and the solvent was removed in vacuo to give the title compound as an acetic acid salt (540 mg, 63%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 7.0 Hz, 6H), 1.91 (s, 6H), 3.27 (m, 1H), 6, 55 (d, J = 8.8 Hz, 2H), 6.62 (m, 1H), 6.69 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7, 20 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 8.75 (s, 1H), 8, 99 (m, 1H), 9.52 (s, 1H), 11.57 (br s, 1H);

MS (ESI +) m / z 404 (M + H) +.

Example 96

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-phenethylaminophenylsulfanyl] phenol

A solution containing the product of Example 95B (65 mg, 0.124 mmol), phenylacetaldehyde (15 mg, 0.124 mmol) and sodium cyanoborohydride (10 mg, 0.199 mmol) in 2 ml of methanol was stirred for 18 hours at room temperature. The solvent was evaporated in vacuo and the obtained residue was purified by TFA HPLC to give the title compound as the trifluoroacetic acid salt (25 mg, 32%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.28 (d, 6H), 2.31-2.48 (m, 1H), 2.78-2.93 (m, 2H), 3 , 16-3.35 (m, 2H), 4.17-4.36 (m, 2H), 4.73-4.91 (m, 1H), 6.47-6.59 (m, 2H) 6.61-6.74 (m, 1H), 6.86-7.01 (m, 2H), 7.10 (d, J = 6.99 Hz, 1H), 7.15-7.27 (m, 1H), 7.19-7.39 (m, 6H), 7.89 (d, J = 8.46 Hz, 1H), 8.77 (s, 1H), 8.96 (s, 1H), 9.50 (s, 1H), 11.61 (s, 1H).

Example 97

4- [4- (Cyclopentylmethylamino) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The solution containing the product of Example 95B was reacted with cyclopentanecarbaldehyde in accordance with the method described in Example 96 using cyclopentanecarbaldehyde instead of phenylacetaldehyde, which was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (11 mg, 9 %).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.26-1.43 (m, 6H), 1.53 (s, 4H), 1.75 (d, J = 3.31 Hz, 4H ), 2.01-2.19 (m, 1H), 2.92 (d, J = 6.99 Hz, 2H), 3.20-3.36 (m, 1H), 6.53 (d, J = 8.82 Hz, 2H), 6.58-6.73 (m, 1H), 6.87-7.00 (m, 2H), 6.98-7.13 (m, 1H), 7 , 17-7.36 (m, 1H), 7.89 (s, 1H), 8.15 (s, 1H), 8.77 (s, 1H), 8.95 (s, 1H), 9, 49 (s, 1H), 10.98 (s, 1H), 11.68 (s, 1H).

Example 98

N1-Benzyl-N3- (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) -4- (4-methoxyphenylsulfanyl) benzene-1,3-diamine

A solution of the product of Example 36E (40.4 mg, 0.187 mmol) and the product of Example 92C (62.8 mg, 0.187 mmol) in acetic acid (2 ml) was stirred in an oil bath preheated to 140 ° C for 45 minutes. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator and co-evaporated with methylene chloride / hexane (4 ×). The residue was dried under vacuum, then purified by flash chromatography on silica gel with a gradient of 15% to 20% ethyl acetate / methylene chloride as an eluent to give the title compound as a yellow solid (29.6 mg, 31%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J = 6.99 Hz, 6H), 3.11-3.26 (m, 1H), 3.64 (s, 3H ), 4.30 (d, J = 5.88 Hz, 2H), 6.53 (dd, J = 8.46, 2.57 Hz, 1H), 6.66-6.78 (m, 3H) 6.95 (d, J = 2.21 Hz, 1H), 7.03 (d, J = 8.82 Hz, 2H), 7.12-7.28 (m, 2H), 7.28- 7.44 (m, 4H), 7.54 (d, J = 8.46 Hz, 1H), 8.50 (s, 1H), 8.65 (d, J = 8.46 Hz, 1H), 9.75 (s, 1H);

MS (DCI / NH ₃ ) m / z 508 (M + H) ⁺ .

Example 99

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4-pyrrol-1-ylphenylsulfanyl] phenol

To a solution of the product of Example 86B (50 mg, 0.101 mmol) and succinic dialdehyde (40% solution in water) (0.065 ml, 0.303 mmol) in toluene (5 ml) and methanol (3 ml) were added 4Å molecular sieves (100 mg) . Then the mixture was heated to 60 ° C for 7 hours, cooled to room temperature, the solvent was removed in vacuo, 0.1 N was added. aqueous hydrochloric acid (20 ml) and the mixture was extracted with dichloromethane (2 × 25 ml) and dioxane (25 ml). The combined organic extracts were dried and concentrated in vacuo, then the resulting residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (14 mg, 26%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3H), 6.26 (m, 2H), 6.77 (d, J = 8.5 Hz, 2H), 7, 05 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.37 (m, 2H), 7.48 (dd, J = 8.6 , 2.4 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 2.6 Hz, 1H), 8.57 (s, 1H), 8.80 (d, J = 8.4 Hz, 1H); 9.81 (s, 1H); 10.11 (s, 1H);

MS (ESI +) m / z 426 (M + H) +.

Example 100

4- [2,4-Bis- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

To a solution of the product of example 86B (50 mg, 0.101 mmol) and the product of example 10B (19 mg, 0.101 mmol) in acetic acid (1 ml) was heated to 120 ° C for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and methanol (2 ml) was added. The resulting solid was collected and triturated in methanol to give the title compound as a light brown solid (12 mg, 23%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3H), 2.68 (m, 3H), 6.75 (d, J = 8.8 Hz, 2H), 6, 83 (m, 1H), 7.12 (m, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.34 (m, 1H), 7.58 (m, J = 8 8 Hz, 2H), 8.73 (s, 1H), 8.81 (m, 1H), 8.88 (m, 1H), 9.76 (s, 1H), 10.13 (s, 1H ), 11.95 (br s, 1H);

MS (ESI +) m / z 519 (M + H) +.

Example 101

4- [4- (4-Bromobenzylamino) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The solution containing the product of Example 95B was reacted with 4-bromobenzaldehyde in accordance with the method described in Example 96 using 4-bromobenzaldehyde instead of phenylacetaldehyde, which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt ( 7 mg, 3%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.6 Hz, 6H), 3.30 (m, 1H), 6.55 (d, J = 8.5 Hz, 2H), 6.68 (m, 1H), 6.76 (d, J = 8.8 Hz, 2H), 6.91 (m, 1H), 6.98 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.32 (m, 1H), 7.56 (m, 2H), 8.78 (s, 1H), 9, 53 (m, 1H);

MS (ESI +) m / z 574 (M + H) +.

Example 102

4- [4-Methyl-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

To a solution of the product of example 10B (100 mg, 0.575 mmol) and the product of example 6c (146 mg, 0.632 mmol) in acetic acid (1 ml) was heated at 130 ° C for 1 hour. The mixture was then allowed to cool to room temperature, then methanol (5 ml) was added to the solution, and the resulting solid was collected and washed with methanol to obtain the title compound (120 mg, 56%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.29 (s, 3H), 2.66 (s, 3H), 6.73 (d, J = 8.8 Hz, 2H), 6, 93 (m, 1H), 7.03 (m, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.26 (s, 1H), 7.53 (d, J = 8 5 Hz, 1H), 8.53 (s, 1H), 8.77 (m, 1H), 9.76 (br s, 1H), 9.96 (br s, 1H);

MS (ESI) + m / z 375 (M + H) +.

Example 103

(5-Methyl-2-phenylsulfanylphenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of example 10B (90 mg, 0.517 mmol) and the product of example 5I (122 mg, 0.569 mmol) in acetic acid (1 ml) was heated at 130 ° C for 1 hour. The mixture was then allowed to cool to room temperature, the resulting solid was collected and washed with methanol, then 50 mg of the substance was dissolved in dioxane (2 ml) and hydrochloric acid was added, then the solvent was removed in vacuo to give the title compound as the hydrochloride salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.37 (s, 3H), 2.74 (s, 3H), 7.18 (m, 5H), 7.24 (m, 1H), 7.37 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 8.80 (s, 1H), 8.99 (d, J = 8.5 Hz, 1H), 11.82 (br s, 1H); MS (ESI) + m / z 359 (M + H) +.

Example 104

[3- (3-Bromophenoxymethyl) phenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 104A

1-Nitro-3- (3-bromophenoxymethyl) benzene

A solution of 3-nitrobenzyl chloride (1.0 g, 5.83 mmol), 3-bromophenol (1.01 g, 5.83 mmol) and potassium carbonate (806 mg, 5.83 mmol) in acetone (25 ml) was heated with reflux for 23 hours. After cooling, the solid was filtered off and the filtrate was concentrated in vacuo to give a yellow residue, which was dissolved in ethyl acetate (50 ml) and washed with 1N. aqueous sodium hydroxide solution (25 ml) and water (25 ml), then dried and concentrated in vacuo to give the title compound as a white solid (1.64 g, 91%).

Example 104B

3- (3-Bromophenoxymethyl) phenylamine

A solution of the product of example 104A (1.64 g, 5.32 mmol), iron powder (1.49 g, 26.62 mmol) and ammonium chloride (430 mg, 7.98 mmol) in a mixture of tetrahydrofuran (20 ml), water (6 ml) and ethanol (20 ml) were heated under reflux for 3 hours. The mixture was cooled to room temperature, filtered through a pad of celite, which was washed with ethanol, and the resulting filtrate was concentrated in vacuo. The material was then dissolved in water (50 ml) and extracted with ethyl acetate (50 ml), the organic layer was dried and concentrated in vacuo to give the title compound as a yellow oil (1.43 g, 97%).

Example 104C

[3- (3-Bromophenoxymethyl) phenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

To a solution of the product of example 10C (50 mg, 0.266 mmol) and the product of example 104B (74 mg, 0.266 mol) in acetic acid (3 ml) was heated to 130 ° C for 30 minutes. After cooling to room temperature, the solution was concentrated in vacuo and purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (62 mg, 44%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H), 5.20 (s, 2H), 7.05 (m, 1H), 7.16 (m, 1H), 7.24 (m, 2H), 7.33 (m, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.79 (m, 1H), 7.84 (s, 1H), 8.83 (s, 1H), 8.96 (d, J = 8.4 Hz, 1H), 10.75 (br.s , 1H);

MS (ESI) + m / z 421/423 (M + H) +.

Example 105

(3'-Methoxy-5-methylbiphenyl-3-yl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 105A

3-bromo-5-methylphenylamine

The title compound was prepared from 3-bromo-5-nitrotoluene (1.08 g, 5.0 mmol) using the conditions described in Example 104B to give the title compound as an orange oil (0.8 g, 86%).

Example 105B

(3-Bromo-5-methylphenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 105A (0.8 g, 4.3 mmol) was reacted with the product of example 10C by the method described in example 104C using the product of example 105A instead of the product of example 104B to give a crude residue which was purified by silica gel chromatography , eluting with 99: 1 dichloromethane / methanol, to give the title compound as a yellow powder (1.1 g, 77%).

Example 105C

(3'-Methoxy-5-methylbiphenyl-3-yl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 105B (0.066 g, 0.2 mmol), 3-methoxy phenylboronic acid (0.043 g, 0.28 mmol), cesium carbonate (0.1 g, 0.3 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.014 g, 0.02 mmol) were combined in N, N- dimethylformamide (1 ml) and heated to 100 ^° C. for 24 hours. After cooling to room temperature, the mixture was poured into ice water (20 ml) and the resulting solution was acidified with 1N. aqueous hydrochloric acid. Then the solution was extracted with ethyl acetate (3 × 10 ml), the combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (12 mg, 13%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.45 (s, 3H), 2.75 (s, 3H), 3.83 (s, 3H), 6.98 (dd, J = 7 72, 2.21 Hz, 1H), 7.20 (d, J = 2.21 Hz, 1H), 7.25 (d, J = 8.09 Hz, 1H), 7.41 (t, J = 7.91 Hz, 1H), 7.48 (s, 1H), 7.56 (s, 1H), 7.82 (d, J = 5.15 Hz, 1H), 7.83 (d, J = 3.31 Hz, 1H), 8.96 (s, 1H), 9.03 (d, J = 8.46 Hz, 1H), 11.34 (s, 1H);

MS (ESI) + m / z 357 (M + H) +.

Example 106

{2-2- (4-Methoxyphenyl) ethyl] -5-methylphenyl} - (7-methylpyrido [2,3- d ] pyrimidin-4-yl) amine

Example 106A

1- [2- (4-Methoxyphenyl) vinyl] -4-methyl-2-nitrobenzene

A solution of 1-bromo-4-methyl-2-nitrobenzene (0.76 g, 3.5 mmol), 1-methoxy-4-vinylbenzene (0.59 g, 4.4 mmol), triethylamine (0.88 g, 8.8 mmol), tri- o- tolylphosphine (0.022 g) and palladium acetate (0.008 g) in N, N- dimethylformamide (7 ml) were placed in a pressure vessel and purged with nitrogen for 10 minutes. The vessel was sealed and heated at 120ºC for 16 hours. The mixture was partitioned between water and ethyl acetate, adjusting the pH to 3. The organic layer was washed with brine, dried (sodium sulfate) and filtered through a pad of silica gel. The filtrate was evaporated in vacuo and the residue was triturated with hexane / ethyl acetate (9: 1) to obtain the title compound (0.55 g, 58%).

Example 106B

2- [2- (4-Methoxyphenyl) ethyl] -5-methylphenylamine

A solution of the product of Example 106A (164 mg, 0.6 mmol) and 10% palladium-on-carbon (50 mg) in ethanol (20 ml) was hydrogenated with hydrogen from a balloon for three days. The solvent was filtered through celite, washed with ethanol and evaporated in vacuo to give the title compound (140 mg, 97%).

Example 106C

{2- [2- (4-Methoxyphenyl) ethyl] -5-methylphenyl} - (7-methylpyrido [2,3- d ] pyrimidin-4-yl) amine

The product of Example 106B was reacted with the product of Example 10C by the method described in Example 104C, using the product of Example 106B instead of the product of Example 104B to give a crude residue which was purified by silica gel chromatography, eluting with 99: 1 dichloromethane / methanol, s obtaining the title compound (53 mg, 69%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H), 2.69 (m, 7H), 3.64 (s, 3H), 6.69 (d, J = 8 8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 7, 22 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 8.50 (s, 1H), 8.79 (d, J = 8.5 Hz, 1H); 9.83 (s, 1H);

(ESI +) m / z 385 (M + H) +.

Example 107

4- [4-Methyl-2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 6c was reacted with the product of example 57A by the method described in example 10F using the product of example 6c instead of the product of example 10E and using the product of example 57A instead of the product of example 10B to give a crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H), 6.61-6.78 (m, 2H), 7.02 (d, J = 8.09 Hz, 1H ), 7.11-7.20 (m, 3H), 7.24 (s, 1H), 7.87 (dd, J = 8.46, 4.41 Hz, 1H), 8.79 (s, 1H), 9.03 (d, J = 8.46 Hz, 1H), 9.14-9.19 (m, 1H), 9.79 (s, 1H);

MS (ESI +) m / z 361 (M + H) +.

Example 108

(5-Methyl-2-phenylsulfanylphenyl) pyrido [2,3-d] pyrimidin-4-ylamine

The product of example 5I was reacted with the product of example 57A by the method described in example 10F, using the product of example 5I instead of the product of example 10E and using the product of example 57A instead of the product of example 10B, to obtain a crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.37 (s, 3H), 7.09-7.27 (m, 6H), 7.35 (d, J = 7.72 Hz, 2H ), 7.83 (dd, J = 8.09, 4.41 Hz, 1H), 8.75 (s, 1H), 8.96 (d, J = 7.72 Hz, 1H), 9.13 (d, J = 3.31 Hz, 1H);

MS (ESI +) m / z 345 (M + H) +.

Example 109

N- {4- [4-Methyl-2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenyl} acetamide

The product of example 7b was reacted with the product of example 57A by the method described in example 10F using the product of example 7b instead of the product of example 10E and using the product of example 57A instead of the product of example 10B to give a crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.02 (s, 3H), 2.34 (s, 3H), 7.13-7.35 (m, 5H), 7.46 (d , J = 8.46 Hz, 2H), 7.87 (dd, J = 8.09, 4.41 Hz, 1H), 8.80 (s, 1H), 9.01 (d, J = 8, 09 Hz, 1H), 9.15 (d, J = 3.31 Hz, 1H), 9.99 (s, 1H);

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

Example 110

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

The product of example 6c was reacted with the product of example 36E by the method described in example 36I using the product of example 6c instead of the product of example 36H to give a crude residue which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.62 Hz, 6H), 2.31 (s, 3H), 3.29 (t, J = 6.89 Hz, 1H), 6.70 (d, J = 8.82 Hz, 2H), 7.01 (d, J = 8.09 Hz, 1H), 7.17 (d, J = 8.82 Hz, 2H), 7.13-7.22 (m, 2H), 7.23 (s, 1H), 7.87 (d, J = 8.82 Hz, 1H), 8.79 (s, 1H), 8.97 (d, J = 8.82 Hz, 1H); 9.80 (s, 1H); 11.42 (s, 1H);

MS (ESI +) m / z 403 (M + H) +.

Example 111

2-Chloro-4- [2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

To a solution of the product of Example 110 (50 mg, 0.124 mmol) in acetic acid (1.5 ml) was added dropwise sulfuryl chloride (0.01 ml, 0.124 mmol) at room temperature. The mixture was stirred for another 30 minutes, then concentrated in vacuo and purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (19 mg, 28%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.6 Hz, 6H), 2.34 (s, 3H), 3.30 (m, 1H), 6, 82 (d, J = 8.5 Hz, 1H), 7.08 (dd, J = 8.5, 2.2 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 3H ), 8.74 (s, 1H), 8.94 (d, J = 8.5 Hz, 1H), 10.50 (s, 1H), 11.42 (br s, 1H);

MS (ESI +) m / z 437 (M + H) +.

Example 112

2,6-Dichloro-4- [2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

To a solution of the product of Example 110 (50 mg, 0.124 mmol) in acetic acid (1.5 ml) was added dropwise sulfuryl chloride (0.02 ml, 0.248 mmol) at room temperature. The mixture was stirred for another 30 minutes, then concentrated in vacuo and purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (17 mg, 23%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.6 Hz, 6H), 2.37 (s, 3H), 3.28 (m, 1H), 7, 12 (s, 1H), 7.28 (m, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 8, 70 (s, 1H), 8.88 (d, J = 8.8 Hz, 1H), 10.38 (s, 1H), 11.22 (br s, 1H);

MS (ESI +) m / z 472 (M + H) +.

Example 113

4- [4-Hydroxymethyl-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 113A

4- (4-Hydroxyphenylsulfanyl) -3-nitrobenzoic acid methyl ester

A solution of 4-chloro-3-nitrobenzoic acid methyl ester (4.0 g, 18.55 mmol) in anhydrous N, N-dimethylformamide (25 ml) was treated with 4-mercaptophenol (2.34 g, 18.55 mmol) and carbonate cesium (9.07 g, 27.83 mmol) at room temperature for 23 hours. Then the solvent was removed on a rotary evaporator under vacuum, the residue was treated in water (100 ml) and the pH was adjusted to 3 with 1N. an aqueous solution of HCl. The aqueous solution was extracted with ethyl acetate (2 × 100 ml) and the combined organic extracts were washed with saturated brine (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give the product as an orange oil with an admixture of N, N-dimethylformamide (7.28 g).

Example 113B

3-amino-4- (4-hydroxyphenylsulfanyl) benzoic acid methyl ester

A suspension of the product of example 113A (as a mono DMF adduct) (7.25 g, 19.23 mmol) of ammonium chloride (1.54 g, 28.8 mmol) and iron powder (5.37 g, 96.15 mmol) in tetrahydrofuran (75 ml), water (25 ml) and ethanol (75 ml) were heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and the mixture was filtered through a pad of celite, which was then washed with methanol and the filtrate was concentrated to a solid in vacuo. Then, the residue was dissolved in water (100 ml) and extracted with dichloromethane (2 × 50 ml). The combined organic extracts were washed with brine (25 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (4.2 g, 79%).

Example 113C

4- (2-amino-4-hydroxymethylphenylsulfanyl) phenol

To the product of Example 113B (500 mg, 1.82 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of lithium aluminum hydride (1.0 M in THF, 1.8 ml, 1.82 mmol) at room temperature, then the mixture was heated up to 70ºC for 4 hours. Then water (25 ml) was carefully added to the solution, and the organic layer was separated, dried and concentrated in vacuo to give the title compound (295 mg, 66%).

Example 113D

4- [4-Hydroxymethyl-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 113C was reacted with the product of example 36E by the method described in example 36I, using the product of example 113C instead of the product of example 36H to give a crude residue which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (30 mg, 31%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 7.0 Hz, 6H), 3.30 (m, 1H), 4.50 (s, 2H), 6, 72 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 7.27 ( m, 1H), 7.35 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 8.79 (s, 1H), 8.98 (m, 1H), 9, 82 (s, 1H); 11.43 (br s, 1H);

MS (ESI +) m / z 419 (M + H) +.

Example 114

4- (4-Hydroxyphenylsulfanyl) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) benzyl ester of acetic acid

The product of example 113C was reacted with the product of example 36E by the method described in example 36I, using the product of example 113C instead of the product of example 36H to give a crude residue which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (12 mg, 11%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.6 Hz, 6H), 2.05 (s, 3H), 3.30 (m, 1H), 5, 07 (s, 2H), 6.71 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 7.27 (m, 1H), 7.40 (m, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.89 (s, 1H), 9, 02 (d, J = 8.8 Hz, 1H), 9.75 (br s, 1H), 11.79 (br s, 1H);

MS (ESI +) m / z 461 (M + H) +.

Example 115

N- {4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The product of example 7b was reacted with the product of example 36E by the method described in example 36I using the product of example 7b instead of the product of example 36H to give a crude residue which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 2.02 (s, 3H), 2.33 (s, 3H), 3, 28 (t, J = 6.89 Hz, 1H), 7.18 (s, 1H), 7.20 (d, J = 8.46 Hz, 2H), 7.28 (s, 1H), 7, 46 (d, J = 8.46 Hz, 2H), 7.86 (d, J = 8.46 Hz, 1H,) 8.79 (s, 1H), 8.93 (d, J = 8.82 Hz, 1H), 9.99 (s, 1H), 11.46 (s, 1H);

MS (ESI +) m / z 444 (M + H) +.

Example 116

(7-Isopropylpyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxyphenoxy) -5-methylphenyl] amine

Example 116A

1- (4-Methoxyphenoxy) -4-methyl-2-nitrobenzene

4-Methoxyphenol was reacted with 1-fluoro-4-methyl-2-nitrobenzene in accordance with the method described in example 122a, using 4-methoxyphenol instead of hydroquinone, to give the title compound.

Example 116B

2- (4-Methoxyphenoxy) -5-methylphenylamine

The product of example 116A was restored in accordance with the method described in example 104B, using the product of example 116A instead of the product of example 104A, to obtain the title compound.

Example 116C

(7-Isopropylpyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxyphenoxy) -5-methylphenyl] amine

The product of Example 116B was reacted with the product of Example 36E by the method described in Example 36I, using the product of Example 116B instead of the product of Example 36H to give a crude residue which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.99 Hz, 6H), 2.33 (s, 3H), 3.26 (dt, J = 13.74 , 6.85 Hz, 1H), 3.67 (s, 3H), 6.77-6.96 (m, 5H), 7.18 (dd, J = 8.46, 2.21 Hz, 1H) , 7.33 (d, J = 1.84 Hz, 1H), 7.83 (d, J = 8.46 Hz, 1H), 8.84 (s, 1H), 8.91 (d, J = 8.82 Hz, 1H); 11.33 (s, 1H);

MS (ESI) + m / z 401 (M + H) +.

Example 117

4- [2- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenoxy] phenol

The product of example 122b was reacted with the product of example 36E by the method described in example 36I using the product of example 122b instead of the product of example 36H to give a crude residue which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.99 Hz, 6H), 2.32 (s, 3H), 3.27 (t, J = 6.89 Hz, 1H), 6.67 (m, 2H), 6.75-6.85 (m, 3H), 7.16 (dd, J = 8.46, 1.84 Hz, 1H), 7.31 (d, J = 1.47 Hz, 1H), 7.84 (d, J = 8.46 Hz, 1H), 8.85 (s, 1H), 8.94 (d, J = 8.46 Hz , 1H); 9.28 (s, 1H);

MS (ESI) + m / z 387 (M + H) +.

Example 118

(7-Isopropylpyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxyphenylsulfanyl) -5-methylphenyl] amine

The product of Example 6a (5.0 g, 175 mmol) was reacted with 4-methoxybenzenethiol (2.45 g, 175 mmol) for 18 hours in accordance with the method described in Example 6b to give 1- (4-methoxyphenylsulfanyl ) -4-methyl-2-nitrobenzene, which was reduced using SnCl ₂ in accordance with the method described in example 5I, to obtain 2- (4-methoxyphenylsulfanyl) -5-methylphenylamine.

2- (4-Methoxyphenylsulfanyl) -5-methylphenylamine was reacted with the product of Example 36E by the method described in Example 36I using 2- (4-methoxyphenylsulfanyl) -5-methylphenylamine instead of the product of Example 36H to give a crude residue that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.62 Hz, 6H), 2.33 (s, 3H), 3.28 (t, J = 6.89 Hz, 1H), 3.69 (s, 3H), 6.81 (d, J = 9.19 Hz, 2H), 7.06-7.20 (m, 2H), 7.23 (d, J = 8.82 Hz, 2H), 7.26 (s, 1H), 7.85 (d, J = 8.46 Hz, 1H), 8.76 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H); 11.36 (s, 1H); MS (ESI) + m / z 417 (M + H) +.

Example 119

(7-Cyclopropylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

Example 119A

N '- (3-Cyano-6-cyclopropylpyridin-2-yl) -N, N-dimethylformamidine

Cyclopropylmethyl ketone was reacted according to the methods described in Examples 36A-36E to give the title compound.

Example 119B

(7-Cyclopropylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

The product of example 5I was reacted with the product of example 119A by the method described in example 102, using the product of example 5I instead of the product of example 6c and using the product of example 119A instead of the product of example 10B, to obtain a crude residue, which was purified by trituration in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.05-1.19 (m, 4H), 2.22-2.41 (m, 1H), 2.35 (s, 3H), 7 05-7.31 (m, 7H), 7.37 (s, 1H), 7.58 (d, J = 8.46 Hz, 1H), 8.50 (s, 1H), 8.65 ( d, J = 8.46 Hz, 1H); 10.21 (s, 1H);

MS (ESI) + m / z 385 (M + H) +.

Example 120

4- [2- (7-Cyclopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

The product of example 6c was reacted with the product of example 119A by the method described in example 102 using the product of example 119A instead of the product of example 10B to give a crude residue which was purified by trituration in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.05-1.22 (m, J = 1.84 Hz, 4H), 2.24-2.39 (m, 1H), 2.29 (s, 3H), 6.73 (d, J = 8.82 Hz, 2H), 6.91 (d, J = 8.09 Hz, 1H), 7.04 (dd, J = 8.09, 1.47 Hz, 1H), 7.17 (d, J = 8.82 Hz, 2H), 7.25 (s, 1H), 7.57 (d, J = 8.82 Hz, 1H), 8 49 (s, 1H), 8.71 (d, J = 8.46 Hz, 1H), 9.74 (s, 1H), 9.92 (s, 1H);

MS (ESI) + m / z 401 (M + H) +.

Example 121

N- {4- [2- (7-Cyclopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The product of example 7b was reacted with the product of example 119A by the method described in example 102, using the product of example 7b instead of the product of example 6c and using the product of example 119A instead of the product of example 10B, to obtain a crude residue that was purified by trituration in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.13 (d, J = 6.25 Hz, 4H), 2.02 (s, 3H), 2.22-2.38 (m, 1H ), 2.31 (s, 3H), 7.07 (s, 2H), 7.20 (d, J = 8.82 Hz, 2H), 7.30 (s, 1H), 7.50 (d , J = 8.82 Hz, 2H), 7.56 (d, J = 8.46 Hz, 1H), 8.49 (s, 1H), 8.68 (d, J = 8.82 Hz, 1H ), 9.99 (s, 2H);

MS (ESI +) m / z 442 (M + H) +.

Example 122

4- [2- (7-Cyclopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenoxy] phenol

Example 122a

4- (4-Methyl-2-nitrophenoxy) phenol

A solution of hydroquinone (3.2 g, 29.0 mmol) and K ₂ CO ₃ (8.0 g, 54.0 mmol) in 40 ml of DMF was heated at 100 ° C with 1-fluoro-4-methyl-2-nitrobenzene (3 , 0 g, 19.3 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and the organic layer was dried over MgSO ₄ . It was filtered and concentrated in vacuo to give the title compound, which was purified by silica gel column chromatography, eluting with 5% EtOAc / hexane, to give an orange oil (1.89 g, 40%).

Example 122b

4- (2-amino-4-methylphenoxy) phenol

The product of Example 122a (1.89 g, 7.71 mmol) was reduced with SnCl ₂ in accordance with the method described in Example 5I to give the title compound as a white solid (1.42 g, 86% )

Example 122c

4- (2- (7-cyclopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenoxy) phenol

The product of example 122b was reacted with the product of example 119A by the method described in example 102, using the product of example 122b instead of the product of example 6c and using the product of example 119A instead of the product of example 10B, to obtain a crude residue that was purified by trituration in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.03-1.18 (m, J = 6.25 Hz, 4H), 2.20-2.35 (m, 1H), 2.30 (s, 3H), 6.57-6.85 (m, 5H), 7.03 (dd, J = 8.27, 1.65 Hz, 1H), 7.36 (d, J = 1.84 Hz, 1H), 7.52 (d, J = 8.46 Hz, 1H), 8.50 (s, 1H), 8.65 (d, J = 8.46 Hz, 1H), 9.18 ( s, 1H); 9.70 (s, 1H);

MS (ESI) + m / z 385 (M + H) +.

Example 123

(7-Cyclopropylpyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxyphenoxy) -5-methylphenyl] amine

The product of example 116B was reacted with the product of example 119A by the method described in example 102 using the product of example 116B instead of the product of example 6c and using the product of example 119A instead of the product of example 10B to give a crude residue that was purified by trituration in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.02-1.20 (m, J = 6.25 Hz, 4H), 2.21-2.37 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H), 6.75-6.92 (m, 5H), 7.06 (dd, J = 8.64, 0.92 Hz, 1H), 7, 37 (s, 1H), 7.51 (d, J = 8.46 Hz, 1H), 8.49 (s, 1H), 8.63 (d, J = 8.82 Hz, 1H), 9, 74 (s, 1H);

MS (ESI) + m / z 399 (M + H) +.

Example 124

(7-Cyclopropylpyrido [2,3-d] pyrimidin-4-yl) - [2- (4-fluorophenylsulfanyl) -5-methylphenyl] amine

The product of example 6a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) instead of thiophenol in accordance with the method described in example 5H for 18 hours to obtain 1- (4-fluorophenylsulfanyl) -4-methyl-2-nitrobenzene, which was purified by silica gel column chromatography, eluting with 5% EtOAc / hexane to give a solid (3.39 g, 74%). 1- (4-Fluorophenylsulfanyl) -4-methyl-2-nitrobenzene was reduced with SnCl ₂ in accordance with the method described in Example 5I to obtain 2- (4-fluorophenylsulfanyl) -5-methylphenylamine.

2- (4-Fluorophenylsulfanyl) -5-methylphenylamine was reacted with the product of Example 119A by the method described in Example 102 using 2- (4-fluorophenylsulfanyl) -5-methylphenylamine instead of the product of Example 6c and using the product of Example 119A instead of the product according to Example 10B, to obtain a crude residue which was purified by trituration in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.19 (m, J = 6.25 Hz, 4H), 2.22-2.42 (m, 1H), 2.33 (s, 3H), 7.02-7.28 (m, 6H), 7.33 (s, 1H), 7.56 (d, J = 8.46 Hz, 1H), 8.46 (s, 1H), 8.66 (d, J = 8.09 Hz, 1H), 10.03 (s, 1H);

MS (ESI) + m / z 403 (M + H) +.

Example 125

(7-Cyclopropylpyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxyphenylsulfanyl) -5-methylphenyl] amine

2- (4-Methoxyphenylsulfanyl) -5-methylphenylamine (Example 118) was reacted with the product of Example 119A by the method described in Example 102 using 2- (4-methoxyphenylsulfanyl) -5-methylphenylamine instead of the product of Example 6c and using the product of Example 119A instead of the product of Example 10B to give a crude residue, which was purified by trituration in methanol to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.30 (m, J = 5.52 Hz, 4H), 2.21-2.42 (m, 1H), 2.31 (s, 3H), 3.71 (s, 3H), 6.85 (d, J = 8.82 Hz, 2H), 6.99-7.12 (m, 2H), 7.24 (d, J = 8.82 Hz, 2H), 7.63 (d, J = 8.46 Hz, 1H), 8.53 (s, 1H), 8.72 (d, J = 8.46 Hz, 1H) 10.33 (s, 1H);

MS (ESI) + m / z 415 (M + H) +.

Example 126

[2- (4-Methoxyphenoxy) -5-methylphenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of Example 116B was reacted with the product of Example 10C by the method described in Example 104C, using the product of Example 116B instead of the product of Example 104B to give a crude residue which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.33 (s, 3H), 2.72 (s, 3H), 3.68 (s, 3H), 6.80-6.95 (m 5H), 7.18 (dd, J = 8.46, 2.21 Hz, 1H), 7.34 (d, J = 1.84 Hz, 1H), 7.76 (d, J = 8, 46 Hz, 1H), 8.85 (s, 2H), 11.32 (s, 1H).

Example 127

4- [2- (7-tert-Butylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

Example 127A

N '- (6-tert-butyl-3-cyanopyridin-2-yl) -N, N-dimethylformamidine

3,3-Dimethyl-2-butanone was reacted according to the methods described in Examples 36A-36E to give the title compound.

Example 127B

4- [2- (7-tert-Butylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

The product of example 6c was reacted with the product of example 127A by the method described in example 36I using the product of example 6c instead of the product of example 36H and using the product of example 127A instead of the product of example 276E to give a crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (40 mg, 29%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.44 (s, 9H), 2.31 (s, 3H), 6.71 (d, J = 8.5 Hz, 2H), 7, 00 (d, J = 8.1 Hz, 1H), 7.16 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.23 (s, 1H), 8, 01 (d, J = 7.6 Hz, 1H), 8.75 (s, 1H), 8.97 (d, J = 8.8 Hz, 1H), 9.79 (s, 1H), 11, 22 (br s, 1H);

MS (ESI) + m / z 417 (M + H) +.

Example 128

(5-Methyl-2-phenylsulfanylphenyl) - (7-propylpyrido [2,3-d] pyrimidin-4-yl) amine

The product was obtained by the method of Example 36A using 2-pentanone instead of methyl isopropyl ketone to give an intermediate, which was then reacted in accordance with the methods described in Examples 36A-36E.

Example 128A

N '- (3-Cyano-6-propylpyridin-2-yl) -N, N-dimethylformamidine

The product was obtained by the method of Example 36A using 2-pentanone instead of methyl isopropyl ketone to give an intermediate, which was then reacted in accordance with the methods described in Examples 36A-36E.

Example 128B

(5-Methyl-2-phenylsulfanylphenyl) - (7-propylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 5I (49 mg, 0.231 mmol) and the product of example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 ml) and heated to 130 ° C for 1.5 hours. After cooling to room temperature in a solvent, acetic acid, a solid formed which was collected by filtration to obtain the title compound as an acetic acid salt (68 mg, 62%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.94 (t, J = 7.4 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2, 35 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 7.18 (m, 5H), 7.23 (m, 2H), 7.37 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 8.48 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H);

MS (ESI) + m / z 387 (M + H) +.

Example 129

3- [4-Methyl-2- (7-propylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 6a (10.14 g, 35.6 mmol) was reacted with 3- (4-methyl-2-nitrophenylsulfanyl) phenol (4.48 g, 35.6 mmol) for 18 hours according to the method, described in example 6b, to obtain 3- (4-methyl-2-nitrophenylsulfanyl) phenol (7.88 g, 85%), which was restored using SnCl ₂ in accordance with the method described in example 5I, to obtain 3- ( 2-amino-4-methylphenylsulfanyl) phenol.

3- (2-amino-4-methylphenylsulfanyl) phenol (49 mg, 0.231 mmol) and the product of Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 ml) and heated to 130 ° C for 1.5 hours. After cooling to room temperature in a solvent, acetic acid, a solid formed which was collected by filtration to obtain the title compound as an acetic acid salt (78 mg, 68%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J = 7.3 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2, 40 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 6.57 (m, 3H), 7.00 (t, J = 7.7 Hz, 1H), 7, 13 (m, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 8, 50 (s, 1H); 8.70 (d, J = 8.5 Hz, 1H);

MS (ESI) + m / z 403 (M + H) +.

Example 130

N- {4- [4-Methyl-2- (7-propylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenyl} acetamide

The product of example 7b (49 mg, 0.231 mmol) and the product of example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 ml) and heated to 130 ° C for 1.5 hours. After cooling to room temperature and removing the solvent, acetic acid, in vacuo, methanol (3 ml) was added to the oil, resulting in the formation of a solid, which was triturated in methanol to give the title compound, 80 mg, 78%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J = 7.4 Hz, 3H), 1.89 (m, 2H), 2.02 (s, 3H), 2, 32 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 7.06 (s, 2H), 7.21 (t, J = 8.5 Hz, 2H), 7, 30 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.52 (m, 1H), 8.52 (s, 1H), 8.74 (d, J = 7 7 Hz, 1H); 10.00 (s, 1H);

MS (ESI) + m / z 444 (M + H) +.

Example 131

4- [4-Methyl-2- (7-propylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 6c (49 mg, 0.231 mmol) and the product of example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 ml) and heated to 130 ° C for 1.5 hours. After cooling to room temperature, in a solvent, acetic acid, a solid formed, which was collected by filtration to obtain the title compound as an acetic acid salt (77 mg, 68%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.96 (t, J = 7.4 Hz, 3H), 1.80 (m, 2H), 1.88 (s, 6H), 2, 40 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.1 Hz, 1H), 7.03 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.22 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 8.53 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H);

MS (ESI) + m / z 403 (M + H) +.

Example 132

N- {4- [5-Hydroxy-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] 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 for 2.5 hours at 100ºC. The mixture was cooled, diluted with ethyl acetate (100 ml) and the organic layer was washed with water and an aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo to give N- [4- (5-hydroxy-4-methyl-2-nitrophenylsulfanyl) phenyl] acetamide as a solid (2.5 g, 81%). Solution of N- [4- (5-hydroxy-4-methyl-2-nitrophenylsulfanyl) phenyl] acetamide (2.5 g, 6.45 mmol), iron powder (1.79 g, 32 mmol) and ammonium chloride (0.514 g, 9.6 mmol) in a solution of methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give N- [4- (2-amino-5-hydroxy-4-methylphenylsulfanyl) phenyl] acetamide (1.7 g, 91% )

N- [4- (2-amino-5-hydroxy-4-methylphenylsulfanyl) phenyl] acetamide was reacted with the product of example 36E by the method described in example 36I using N- [4- (2-amino-5-hydroxy- 4-methylphenylsulfanyl) phenyl] acetamide in place of the product of Example 36H to give a crude residue which was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 2.03 (s, 3H), 2.11 (s, 3H), 3, 27 (s, 1H), 6.63 (s, 1H), 7.12 (s, 1H), 7.25 (d, J = 8.82 Hz, 2H), 7.51 (d, J = 8 , 82 Hz, 2H), 7.85 (d, J = 8.46 Hz, 1H), 8.80 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 9, 75 (s, 1H), 10.02 (s, 1H), 11.36 (s, 1H);

MS (ESI) + m / z 460 (M + H) +.

Example 133

N ¹ - (4-benzyloxyphenyl) - N ² - (7-isopropylpyrido [2,3- d ] pyrimidin-4-yl) -4, N ¹ -dimethylbenzene-1,2-diamine

Example 133A

(4-Benzyloxyphenyl) - (4-methyl-2-nitrophenyl) amine

A mixture of 4-methyl-2-nitroaniline (1.006 g, 6.612 mmol), 4-benzyloxybromobenzene (5.794 g, 22.02 mmol), copper iodide (62.9 mg, 0.3306 mmol), potassium carbonate (0.914 g, 6.612 mmol) and anhydrous o-xylene (18 ml) were heated at 150 ° C for 24 hours. Additionally, copper iodide (30 mg) was added and heated for another 6 hours at 160 ° C. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. The residue was purified by flash chromatography on silica gel using a 1: 1 mixture of methylene chloride / hexane as the eluent to give the title compound as a red oil that slowly crystallized (1.23 g, 56%).

Example 133B

(4-Benzyloxyphenyl) methyl- (4-methyl-2-nitrophenyl) amine

To a suspension of sodium hydride (60% dispersion in mineral oil, 55 mg, 1.372 mmol) in N, N-dimethylformamide (3 ml) at room temperature in a nitrogen atmosphere was added a solution of the product of Example 133A (229.4 mg, 0.6861 mmol) ) in anhydrous N, N-dimethylformamide (3 ml). The reaction mixture was stirred at room temperature for 1 hour, then methyl iodide (0.171 ml, 2.744 mmol) was added and allowed to stir at room temperature for 2 hours. The solvent was removed on a rotary evaporator under vacuum. The residue was treated in water (30 ml) and extracted with methylene chloride (50 ml). The organic phase was washed with water (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator in vacuo to give the title compound as a dark red solid (239 mg, 100%).

Example 133C

(4-Benzyloxyphenyl) methyl- (4-methyl-2-aminophenyl) amine

A mixture of the product of Example 133B (129.4 mg, 0.3714 mmol), iron powder (128 mg, 2.284 mmol), ammonium chloride (130 mg, 2.433 mmol) in water (1 ml) and ethanol (2 ml) was heated at 70ºС in a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature and filtered under vacuum, the residue was washed with methanol. The filtrate was concentrated in vacuo and azeotropically distilled off with toluene (50 ml). The residue was purified by flash chromatography on silica gel using methylene chloride as eluent to afford the title compound as a waxy solid (85 mg, 72%).

Example 133D

N ¹ - (4-Benzyloxyphenyl) - N ² - (7-isopropylpyrido [2,3- d ] pyrimidin-4-yl) -4, N ¹ -dimethylbenzene-1,2-diamine

A solution of the product of example 36E (28 mg, 0.1297 mmol) and the product of example 133C (41.3 mg, 0.1297 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 140ºC for 1 hour . The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator in vacuo and evaporated together with methylene chloride / hexane (4 ×). The residue was dried, then purified by flash chromatography on silica gel using 20% ethyl acetate / methylene chloride as eluent to give the title compound as a yellow solid (35 mg, 55%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.27 (d, J = 6.62 Hz, 6H), 2.34 (s, 3H), 3.08 (s, 3H), 3, 06-3.22 (m, 1H), 4.79 (s, 2H), 6.50 (d, J = 9.19 Hz, 2H), 6.60 (d, J = 8.82 Hz, 2H ), 7.05-7.17 (m, 2H), 7.25-7.37 (m, 5H), 7.41 (d, J = 8.46 Hz, 1H), 7.47 (s, 1H), 8.42 (d, J = 8.46 Hz, 1H), 8.52 (s, 1H), 9.33 (s, 1H);

MS (DCI / NH ₃ ) m / z 490 (M + H) ⁺ .

Example 134

(2-Benzyl-5-methylphenyl) - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 134A

2-benzyl-5-methylphenylamine

A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 2.54 ml, 2.54 mmol) was pipetted into a vessel containing aluminum chloride (534 mg, 4.005 mmol) in a nitrogen atmosphere and cooled in a bath at 0 ° C. After allowing the mixture to cool for 5 minutes, a solution of 2-amino-4-methylbenzophenone (200 mg, 0.9467 mmol) in tetrahydrofuran (4 ml) was slowly added dropwise at 0 ° C. Then the reaction mixture was heated at 50 ° C for 30 minutes. The reaction mixture was cooled to room temperature and wet ethyl ether (5 ml) was added. The reaction mixture was carefully poured into water (20 ml) and extracted with ethyl ether (2 × 50 ml). The combined ether extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator in vacuo. Purification by flash chromatography on silica gel using a 40:60 hexane / methylene chloride mixture as the eluent gave the title compound as an oil (94 mg, 50%).

Example 134B

(2-Benzyl-5-methylphenyl) - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of example 36E (34.6 mg, 0.160 mmol) and the product of example 134A (31.6 mg, 0.160 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 140 ° C for 1 hour. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator in vacuo and evaporated together with methylene chloride / hexane (4 ×). The residue was dried, then purified by flash chromatography on silica gel using a 2% methanol / methylene chloride mixture as eluent to give the title compound as a light yellow solid (50 mg, 85%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (d, J = 6.99 Hz, 6H), 2.30 (s, 3H), 3.12-3.28 (m, 1H ), 3.87 (s, 2H), 6.95-7.20 (m, 8H), 7.57 (s, 1H), 8.47 (s, 1H), 8.74 (d, J = 8.46 Hz, 1H); 9.81 (s, 1H);

MS (DCI / NH ₃ ) m / z 369 (M + H) ⁺ .

Example 135

(7-Cyclohexylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

Example 135A

N '- (3-Cyano-6-cyclohexylpyridin-2-yl) -N, N-dimethylformamidine

1-Cyclohexylethanone was reacted according to the methods described in Examples 36A-36E to give the title compound.

Example 135B

(7-Cyclohexylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

To a solution of the product of example 135A (56.0 mg, 0.2322 mmol) in acetic acid (4 ml) was added the product of example 5I (50.0 mg, 0.2322 mmol) and the mixture was stirred in an oil bath preheated to 130ºC for 15 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (20 mg, 20%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.38-1.51 (m, 2H), 1.57-1.69 (m, 2H), 1.70-1.80 (m, 2H), 1.80-1.99 (m, 6H), 2.33-2.40 (m, 3H), 7.12-7.17 (m, 1H), 7.12-7.26 ( m, 3H), 7.30-7.33 (m, 1H), 7.33-7.38 (m, 2H), 8.68-8.75 (m, 1H), 8.82-8, 90 (m, 1H);

MS (DCI / NH ₃ ) m / z 427 (M + H) +.

Example 136

4- [2- (7-Cyclohexylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

The product of example 135A was reacted with the product of example 6c in accordance with the method described in example 135B, using the product of example 6c instead of the product of example 5I to give the title compound as the trifluoroacetic acid salt (20 mg, 20%) .

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.38-1.52 (m, 2H), 1.55-1.80 (m, 3H), 1.80-1.91 (m, 2H), 1.91-2.03 (m, 3H), 2.30 (s, 3H), 3.26-3.47 (m, 1H), 6.66-6.74 (m, 2H) 6.74-6.81 (m, 1H), 6.96-7.03 (m, 1H), 7.10-7.14 (m, 1H), 7.14-7.21 (m, 3H), 7.21-7.26 (m, 1H), 8.72-8.80 (m, 1H), 8.90-8.97 (m, 1H), 9.78 (s, 1H) ;

MS (DCI / NH ₃ ) m / z 443 (M + H) +.

Example 137

N- {4- [2- (7-Cyclohexylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The product of example 135A was reacted with the product of example 7b in accordance with the method described in example 135B, using the product of example 7b instead of the product of example 5I to give the title compound as the trifluoroacetic acid salt (21 mg, 25%) .

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.28-1.52 (m, 3H), 1.53-1.79 (m, 3H), 1.79-1.97 (m, 4H), 2.02 (s, 3H), 2.32 (s, 3H), 2.79-2.94 (m, 1H), 7.03-7.12 (m, 1H), 7.20 (d, J = 8.46 Hz, 2H), 7.31 (s, 1H), 7.50 (d, J = 8.82 Hz, 2H), 7.56 (d, J = 8.46 Hz , 1H), 8.54 (s, 1H), 8.76 (d, J = 8.82 Hz, 1H), 9.99 (s, 2H);

MS (DCI / NH ₃ ) m / z 484 (M + H) +.

Example 138

N- {4- [2- (7-Cyclobutylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

Example 138A

N '- (3-Cyano-6-cyclobutylpyridin-2-yl) -N, N-dimethylformamidine

1-Cyclobutylethanone was reacted according to the methods described in Examples 36A-36E to give the title compound.

Example 138B

N- {4- [2- (7-Cyclobutylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The product of example 138A was reacted with the product of example 7b in accordance with the method described in example 135B, using the product of example 7b instead of the product of example 5I and using the product of example 138A instead of the product of example 135A, to obtain the title compound in as a trifluoroacetic acid salt (30 mg, 36% yield).

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 0.86 (t, J = 7.02 Hz, 1H), 1.86-1.98 (m, 1H), 2.02 (s, 3H ), 2.06-2.18 (m, 1H), 2.34 (s, 3H), 2.37-2.47 (m, 4H), 3.80-4.02 (m, 1H), 7.13-7.25 (m, 4H), 7.29 (s, 1H), 7.45 (d, J = 8.54 Hz, 2H), 7.78 (d, J = 8.54 Hz , 1H), 8.80 (s, 1H), 8.92 (d, J = 8.54 Hz, 1H), 9.98 (s, 1H);

MS (DCI / NH ₄ ) m / z 456 (M + H) +.

Example 139

4- [2- (7-Cyclobutylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

The product of example 138A was reacted with the product of example 6c in accordance with the method described in example 135B, using the product of example 6c instead of the product of example 5I and using the product of example 138A instead of the product of example 135A, to give the title compound in as a trifluoroacetic acid salt (30 mg, 33%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.85-2.01 (m, 1H), 2.03-2.24 (m, 1H), 2.31 (s, 3H), 2 , 36-2.46 (m, 4H), 3.81-4.13 (m, 2H), 6.70 (d, J = 8.46 Hz, 2H), 7.02 (d, J = 8 , 09 Hz, 1H), 7.17 (d, J = 8.46 Hz, 3H), 7.24 (s, 1H), 7.82 (d, J = 8.46 Hz, 1H), 8, 82 (s, 1H), 8.97 (d, J = 8.46 Hz, 1H), 9.72-9.93 (m, 1H);

MS (DCI / NH ₄ ) m / z 415 (M + H) +.

Example 140

(7-sec-Butylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

Example 140A

N '- (6-sec-Butyl-3-cyanopyridin-2-yl) -N, N-dimethylformamidine

3-Methylpentan-2-one was reacted according to the methods described in Examples 36A-36E to give the title compound.

Example 140B

(7-sec-Butylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

The product of example 140A was reacted with the product of example 5I in accordance with the method described in example 135B, using the product of example 140A instead of the product of example 135A to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.83 (t, J = 7.35 Hz, 3H), 1.32 (d, J = 6.99 Hz, 3H), 1.59- 1.75 (m, 1H), 1.75-1.95 (m, 1H), 2.37 (s, 3H), 2.95-3.12 (m, 2H), 7.11-7, 22 (m, 5H), 7.25 (d, J = 6.62 Hz, 1H), 7.31-7.46 (m, 2H), 7.81 (d, J = 8.82 Hz, 1H ), 8.76 (s, 1H), 8.91 (d, J = 8.46 Hz, 1H);

MS (DCI / NH ₄ ) m / z 401 (M + H) +.

Example 141

N- {4- [2- (7-sec-Butylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The product of example 140A was reacted with the product of example 7b in accordance with the method described in example 135B, using the product of example 7b instead of the product of example 5I and using the product of example 140A instead of the product of example 135A, to obtain the title compound in as a trifluoroacetic acid salt (37 mg, 45%).

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 0.84 (t, J = 7.32 Hz, 3H), 1.33 (d, J = 6.71 Hz, 3H), 1.62- 1.76 (m, 1H), 1.77-1.91 (m, 1H), 2.34 (s, 3H), 2.49 (s, 3H), 2.96-3.14 (m, 1H), 7.11-7.25 (m, 4H), 7.28 (s, 1H), 7.46 (d, J = 9.16 Hz, 2H), 7.83 (d, J = 8 , 54 Hz, 1H), 8.79 (s, 1H), 8.94 (d, J = 7.93 Hz, 1H), 9.97 (s, 1H), 11.31-11.69 (m , 1H);

MS (DCI / NH ₄ ) m / z 458 (M + H) +.

Example 142

N- (4- {4-Methyl-2- [7- (1-methylcyclopropyl) pyrido [2,3-d] pyrimidin-4-ylamino] phenylsulfanyl} phenyl) acetamide

Example 142A

N '- [3-Cyano-6- (1-methylcyclopropyl) pyridin-2-yl] -N, N-dimethylformamidine

1- (1-Methylcyclopropyl) ethanone was reacted according to the methods described in Examples 36A-36E to give the title compound.

Example 142B

N- (4- {4-Methyl-2- [7- (1-methylcyclopropyl) pyrido [2,3-d] pyrimidin-4-ylamino] phenylsulfanyl} phenyl) acetamide

The product of example 142A was reacted with the product of example 7b in accordance with the method described in example 135B, using the product of example 7b instead of the product of example 5I and using the product of example 142A instead of the product of example 135A to give the title compound in as a trifluoroacetic acid salt (30 mg, 50%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.79-0.91 (m, 1H), 1.08-1.19 (m, 2H), 1.19-1.30 (m, 1H), 1.37-1.50 (m, 2H), 1.61 (s, 3H), 2.02 (s, 1H), 2.33 (s, 3H), 7.10-7.24 (m, 4H), 7.28 (s, 1H), 7.45 (d, J = 8.82 Hz, 2H), 7.85 (d, J = 8.46 Hz, 1H), 8.78 (s, 1H), 8.89 (d, J = 9.19 Hz, 1H), 9.99 (s, 1H);

MS (DCI / NH ₄ ) m / z 456 (M + H) +.

Example 143

4- {4-Methyl-2- [7- (1-methylcyclopropyl) pyrido [2,3-d] pyrimidin-4-ylamino] phenylsulfanyl} phenol

The product of example 142A was reacted with the product of example 6c in accordance with the method described in example 135B, using the product of example 6c instead of the product of example 5I and using the product of example 142A instead of the product of example 135A to give the title compound in as a trifluoroacetic acid salt (20 mg, 37%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.77-0.91 (m, 1H), 1.07-1.18 (m, 2H), 1.38-1.52 (m, 2H), 1.61 (s, 3H), 2.31 (s, 3H), 6.70 (d, J = 8.46 Hz, 2H), 7.02 (d, J = 8.09 Hz, 1H), 7.10-7.21 (m, J = 8.46 Hz, 3H), 7.23 (s, 1H), 7.86 (d, J = 8.82 Hz, 1H), 8, 78 (s, 1H), 8.93 (d, J = 8.82 Hz, 1H), 9.82 (s, 1H);

MS (DCI / NH ₄ ) m / z 415 (M + H) +.

Example 144

3- {4-Methyl-2- [7- (1-methylcyclopropyl) pyrido [2,3-d] pyrimidin-4-ylamino] phenylsulfanyl} phenol

The product of Example 142A was reacted with 3- (2-amino-4-methylphenylsulfanyl) phenol (Example 129) in accordance with the method described in Example 135B using 3- (2-amino-4-methylphenylsulfanyl) phenol instead of the product of Example 5I and using the product of Example 142A instead of the product of Example 135A to give the title compound as the trifluoroacetic acid salt (20 mg, 37%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.77-0.92 (m, 1H), 1.35-1.48 (m, 2H), 1.60 (s, 3H), 2 36 (s, 3H), 6.41-6.68 (m, 3H), 6.90-7.05 (m, 1H), 7.23 (d, J = 6.62 Hz, 1H), 7.29-7.42 (m, 2H), 7.77 (d, J = 9.56 Hz, 1H), 8.68 (s, 1H), 8.82 (d, J = 7.72 Hz , 1H); 9.52 (s, 1H);

MS (DCI / NH ₄ ) m / z 415 (M + H) +.

Example 145

(7-Ethylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

Example 145A

N '- (3-Cyano-6-ethylpyridin-2-yl) -N, N-dimethylformamidine

A solution of the product of Example 10B (0.942 g, 5.0 mmol) in anhydrous tetrahydrofuran (50 ml) was cooled to -78 ° C under a nitrogen atmosphere. A solution of lithium diisopropylamide (3.0 ml of a 2.0 M solution in toluene / hexane / heptane, 6.0 mmol, 1.2 eq.) Was slowly added dropwise to this solution. After complete addition, the reaction mixture was stirred at -78 ° C for 1 hour, and then methyl iodide (1.42 g, 10.0 mmol, 2.0 eq.) Was added dropwise. The reaction mixture was stirred for another 1.5 hours at -78 ° C, during which all solids were dissolved. Then the reaction vessel was removed from the cooling bath and a saturated aqueous solution of ammonium chloride (25 ml) and water (25 ml) were added. The reaction mixture was extracted with ethyl acetate (3 × 100 ml) and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with 3/2 hexane: ethyl acetate, to give the title compound (0.87 g, 86% yield).

Example 145B

(7-Ethylpyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

The product of Example 145A was reacted with the product of Example 5I in accordance with the method described in Example 135B, using the product of Example 145A instead of the product of Example 135A to give the title compound as the trifluoroacetic acid salt (20 mg, 33%) .

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 1.34 (t, J = 7.93 Hz, 3H), 2.35 (s, 3H), 3.01 (q, J = 7, 93 Hz, 2H), 7.09-7.29 (m, 6H), 7.36 (s, 1H), 7.78 (d, J = 8.54 Hz, 1H), 8.75 (s, 1H), 8.88 (d, J = 8.54 Hz, 1H);

MS (DCI / NH ₄ ) m / z 373 (M + H) +.

Example 146

N- {4- [2- (7-Ethylpyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The product of Example 145A was reacted with the product of Example 7b in accordance with the method described in Example 135B, using the product of Example 7b instead of the product of Example 5I and using the product of Example 145A instead of the product of Example 135A to give the title compound in as a trifluoroacetic acid salt (20 mg, 29%).

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 1.34 (m, 3H), 2.37 (s, 3H), 3.01 (q, J = 7.93 Hz, 2H), 7 , 12-7.28 (m, 5H), 7.35 (s, 1H), 7.36 (s, 1H), 7.78 (d, J = 8.54 Hz, 1H), 8.75 ( s, 1H); 8.88 (d, J = 8.54 Hz, 1H);

MS (DCI / NH ₄ ) m / z 430 (M + H) +.

Example 147

4- [4- (6-Bromo-1H-benzoimidazol-2-yl) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

Example 147A

4- (4-Benzyloxyphenoxy) -3-nitrobenzaldehyde

A mixture of 4-chloro-3-nitrobenzaldehyde (1.00 g, 5.389 mmol), 4- (benzyloxy) phenol (1.187 g, 5.928 mmol) and potassium carbonate (0.744 g, 5.389 mmol) in anhydrous pyridine (10 ml) was heated with reflux under nitrogen for 30 minutes. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. The residue was treated in ethyl acetate (100 ml) and washed with 1N. aqueous hydrochloric acid (2 × 50 ml), water (50 ml) and saturated saline (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methylene chloride as the eluent afforded the title compound as a yellow solid (1.625 g, 86%).

Example 147B

2- [4- (4-Benzyloxyphenoxy) -3-nitrophenyl] -6-bromo-1H-benzoimidazole

A solution of 4-bromo-1,2-benzenediamine (214 mg, 1.145 mmol) in N, N-dimethylformamide (12 ml) containing water (0.4 ml) was treated with the product of example 147A (400 mg, 1.145 mmol) and OXONE (458 mg, 0.7443 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Then water (40 ml) was added and the reaction mixture was stirred for 10 minutes. The mixture was filtered under vacuum and the solid was washed with water, then dried under vacuum. Purification by silica gel chromatography using a gradient of 3% to 4% ethyl acetate / methylene chloride as the eluent afforded the title compound as a yellow solid (305 mg, 51%).

Example 147C

2- (4-Benzyloxyphenoxy) -5- (6-bromo-1H-benzoimidazol-2-yl) phenylamine

The product of Example 147B (374 mg, 0.723 mmol), iron powder (248 mg, 4.45 mmol) and ammonium chloride (253 mg, 4.74 mmol) in water (5 ml) and ethanol (10 ml) were heated at 80 ° C. for 45 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with water (2 × 50 ml) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator in vacuo to give the title compound as a golden solid (327 mg, 93%).

Example 147D

[2- (4-Benzyloxyphenoxy) -5- (6-bromo-1H-benzoimidazol-2-yl) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of example 36E (26.7 mg, 0.123 mmol) and the product of example 147C (60 mg, 0.123 mmol) in acetic acid (2 ml) was stirred in an oil bath preheated to 140ºC for 30 minutes. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator in vacuo and evaporated together with methylene chloride / hexane (4 ×). The residue was dried under vacuum, then purified by silica gel chromatography using a 3% methanol / methylene chloride mixture as eluent to give the title compound as a yellow-white solid (59 mg, 73%).

Example 147E

4- [4- (6-Bromo-1H-benzoimidazol-2-yl) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

A solution of the product of Example 147D (38.8 mg, 0.059 mmol) and pentamethylbenzene (87 mg, 0.5901 mmol) in trifluoroacetic acid (5 ml) was stirred at room temperature for 2 hours. The solvent was removed on a rotary evaporator under vacuum and evaporated together with a mixture of methylene chloride / hexane (2 ×). The resulting solid was triturated in hexane (3 ×) and purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (22 mg, 47%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.99 Hz, 6H), 3.20-3.39 (m, 1H), 6.78 (d, J = 8.82 Hz, 2H), 6.95 (d, J = 9.19 Hz, 2H), 7.02 (d, J = 8.82 Hz, 1H), 7.36 (dd, J = 8 64, 2.02 Hz, 1H), 7.55 (d, J = 8.46 Hz, 1H), 7.78 (d, J = 1.47 Hz, 1H), 7.91 (d, J = 8.82 Hz, 1H), 8.11 (dd, J = 8.64, 2.02 Hz, 1H), 8.35 (d, J = 1.84 Hz, 1H), 8.94 (s , 1H), 9.03 (d, J = 8.82 Hz, 1H), 9.46 (br s, 1H), 11.63 (br s, 1H);

MS (APCI +) m / z 567/569 (M + H) ⁺ .

Example 148

4- [4- (6-Bromo-1H-benzoimidazol-2-yl) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

The product of Example 147C was reacted with the product of Example 10B by the method described in Example 147D, using the product of Example 10B instead of the product of Example 36E to give [2- (4-benzyloxyphenoxy) -5- (6-bromo-1H-benzoimidazole -2-yl) phenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine, which was subjected to debenzylation in accordance with the method described in example 147E, to obtain a crude product, which was purified using HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.77 (d, J = 9.19 Hz, 2H), 6.95 (d, J = 8.82 Hz, 2H), 7.01 (d, J = 8.82 Hz, 1H), 7.35 (dd, J = 8.46, 1.84 Hz, 1H), 7.54 (d, J = 8 , 82 Hz, 1H), 7.74-7.85 (m, 2H), 8.10 (dd, J = 8.82, 2.21 Hz, 1H), 8.36 (d, J = 2, 21 Hz, 1H), 8.90 (s, 1H), 8.95 (d, J = 8.46 Hz, 1H), 9.45 (broad s, 1H), 11.35 (broad s, 1H);

MS (ESI +) m / z 539/541 (M + H) +.

Example 149

4- (4-aminophenylsulfanyl) -N- (4-bromophenyl) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) benzenesulfonamide

Example 149A

N- (4-Bromophenyl) -4-chloro-3-nitrobenzenesulfonamide

A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.561 g, 10 mmol) in acetic acid (20 ml) was treated with 4-bromaniline (1.72 g, 10 mmol) and anhydrous sodium acetate (1.23 g, 15 mmol), then heated at 100 ^o for 30 minutes. The reaction mixture was cooled to room temperature and acetic acid was removed on a rotary evaporator under vacuum. The residue was taken up in ethyl acetate (100 ml) and washed with water (2 × 25 ml) and brine (25 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the oil was evaporated together with a methylene chloride / hexane mixture. Purification by silica gel chromatography using methylene chloride, then with 5% ethyl acetate / methylene chloride as an eluent, gave the title compound as a yellow solid (2.038 g, 52%).

Example 149B

4- (4-aminophenylsulfanyl) -N- (4-bromophenyl) -3-nitrobenzenesulfonamide

A mixture of the product of Example 149A (500 mg, 1.277 mmol), 4-aminothiophenol (240 mg, 1.915 mmol) and anhydrous sodium acetate (524 mg, 6.384 mmol) in anhydrous ethanol (9 ml) was heated under reflux in a nitrogen atmosphere for 1 hours. The reaction mixture was cooled to room temperature and ethanol was removed on a rotary evaporator under vacuum. The residue was taken up in ethyl acetate (100 ml) and washed with water (2 × 50 ml) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, coevaporation of the oil with methylene chloride / hexane gave the title compound as an orange foam (613 mg, 100%).

Example 149C

{4- [4- (4-bromophenylsulfamoyl) -2-nitrophenylsulfanyl] phenyl} carbamic acid tert-butyl ester

A solution of the product of example 149B (613 mg, 1.277 mmol) in anhydrous 1,4-dioxane (10 ml) was treated with di-tert-butyl dicarbonate (418 mg, 1.92 mmol) at room temperature, then the reaction mixture was heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, di-tert-butyl dicarbonate (500 mg) was additionally added, and the reaction mixture was heated under reflux for 17 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. Purification of the residue by silica gel chromatography using 3% ethyl acetate / methylene chloride as the eluent gave the title compound as a yellow solid (512 mg, 69%).

Example 149D

{4- [2-amino-4- (4-bromophenylsulfamoyl) phenylsulfanyl] phenyl} carbamic acid tert-butyl ester

The product of Example 149C (510 mg, 0.879 mmol), iron powder (302 mg, 5.40 mmol) and ammonium chloride (308 mg, 5.76 mmol) in water (4 ml) and ethanol (8 ml) were heated at 80 ° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with water (2 × 50 ml) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator in vacuo to give the title compound as a white foam (436 mg, 90%).

Example 149E

{4- [4- (4-bromophenylsulfamoyl) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenyl} carbamic acid tert-butyl ester

A solution of the product of example 36E (59 mg, 0.2725 mmol) and the product of example 149D (150 mg, 0.2725 mmol) in acetic acid (4 ml) was stirred in an oil bath preheated to 140 ° C for 25 minutes. The reaction mixture was cooled to room temperature, diluted with hexane (100 ml), concentrated on a rotary evaporator in vacuo and evaporated together with methylene chloride / hexane (4 ×). The residue was dried in vacuo, then purified by silica gel chromatography using 4% methanol / methylene chloride as the eluent, to give the title compound as a light brown solid (67 mg, 34%).

Example 149F

4- (4-aminophenylsulfanyl) -N- (4-bromophenyl) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) benzenesulfonamide

The product of Example 149E (44 mg, 0.061 mmol) was treated with trifluoroacetic acid (2 ml) in methylene chloride (2 ml) at room temperature for 30 minutes. The solvents were removed on a rotary evaporator under vacuum and the remaining oil was dried under high vacuum. Purification by silica gel chromatography using 5% methanol / methylene chloride as the eluent afforded the title compound as the trifluoroacetic acid salt (25 mg, 48%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.62 Hz, 6H), 3.13-3.38 (m, 1H), 6.63 (d, J = 8.46 Hz, 2H), 6.87 (d, J = 7.72 Hz, 1H), 7.01-7.09 (d, J = 8.82 Hz, 2H), 7.12 (d , J = 8.46 Hz, 2H), 7.44 (d, J = 8.82 Hz, 2H), 7.61 (dd, J = 7.72, 1.47 Hz, 1H), 7.71 (s, 1H), 7.81 (dd, J = 6.62, 1.47 Hz, 1H), 8.66-8.80 (m, 1H), 8.90 (d, J = 6.99 Hz, 1H); 10.55 (s, 1H);

MS (ESI +) m / z 621/623 (M + H) ⁺ .

Example 150

4- (4-aminophenylsulfanyl) -N- (4-bromophenyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) benzenesulfonamide

The product of example 149D was reacted with the product of example 10B by the method described in example 149E, using the product of example 10B instead of the product of example 36E, to obtain the tert-butyl ether {4- [4- (4-bromophenylsulfamoyl) -2- ( 7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenyl} carbamic acid, which was removed the protective group in accordance with the method described in example 149F, then chromatography on silica gel gave the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.64 (d, J = 8.46 Hz, 2H), 6.89 (d, J = 8.09 Hz, 1H), 7.05 (d, J = 9.19 Hz, 2H), 7.12 (d, J = 8.82 Hz, 2H), 7.44 (d, J = 8.82 Hz, 2H), 7.63 (dd, J = 7.72, 0.74 Hz, 1H), 7.74 (s, 1H), 7.79 (dd, J = 7.72, 1.10 Hz, 1H ), 8.70-8.83 (m, 1H), 8.88 (d, J = 8.09 Hz, 1H), 10.55 (s, 1H);

MS (ESI +) m / z 593/595 (M + H) +.

Example 151

4- [4-Chloro-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

Example 151A

4- (4-Chloro-2-nitrophenoxy) phenol

A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0159 mol) in anhydrous dimethyl sulfoxide (7 ml) was heated at 120 ° C for 30 minutes in a nitrogen atmosphere. A solution of 2,5-dichloronitrobenzene (1.90 g, 0.0099 mol) in dimethyl sulfoxide (3 ml) was added dropwise over 30 minutes at 120 ° C, then the reaction mixture was allowed to stir for 1 hour at the same temperature. Then the reaction mixture was cooled in an ice bath and poured into 30 ml of ice water. The mixture was acidified with concentrated hydrochloric acid to pH 1 and extracted with ethyl ether (2 × 50 ml). The combined ether extracts were washed with water (3 × 150 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator in vacuo. Purification of the residue by silica gel chromatography using methylene chloride as an eluent gave the product as a light brown solid (1.34 g, 51%).

Example 151B

4- (2-amino-4-chlorophenoxy) phenol

A mixture of the product of Example 151A (400 mg, 1.506 mmol) and iron powder (336 mg, 6.02 mmol) in acetic acid (10 ml) and ethanol (10 ml) was heated under reflux in a nitrogen atmosphere for 25 minutes. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and treated with solid sodium carbonate until the pH was 6. Extraction was performed with ethyl acetate (2 × 50 ml) and the organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator in vacuo. Coevaporation of the resulting oil with methylene chloride / hexane gave the title compound as a light brown solid (355 mg, 100%).

Example 151C

4- [4-Chloro-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

A solution of the product of example 36E (38 mg, 0.177 mmol) and the product of example 151B (42 mg, 0.177 mmol) in acetic acid (2 ml) were stirred in an oil bath preheated to 140ºC for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with hexane (100 ml), concentrated on a rotary evaporator in vacuo and evaporated together with methylene chloride / hexane (4 ×). The residue was dried under high vacuum, then purified by trituration with 40% ethyl acetate / methylene chloride to give the title compound as a beige solid (49 mg, 65%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J = 6.99 Hz, 6H), 3.10-3.29 (m, 1H), 6.70 (d, J = 8.82 Hz, 2H), 6.76-6.90 (m, 3H), 7.24 (dd, J = 8.64, 2.39 Hz, 1H), 7.55 (d, J = 8.82 Hz, 1H), 7.71 (broad s, 1H), 8.59 (broad s, 1H), 8.73 (d, J = 8.09 Hz, 1H), 9.31 ( broad s, 1H); 9.89 (broad s, 1H);

MS (DCI / NH ₃ ) m / z 407 (M + H) +.

Example 152

4- (4-Hydroxyphenoxy) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) benzonitrile

Example 152A

4- (4-hydroxyphenoxy) -3-nitrobenzonitrile

A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0159 mol) in anhydrous dimethyl sulfoxide (8 ml) was heated at 90 ° C. for 30 minutes under nitrogen. A solution of 4-chloro-3-nitrobenzonitrile (1.806 g, 0.0099 mol) in dimethyl sulfoxide (8 ml) was added dropwise over 30 minutes at 90 ° C, then the reaction mixture was allowed to stir for 1 hour at the same temperature. Then the reaction mixture was cooled in an ice bath and poured into 30 ml of ice water. The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with ethyl ether (3 × 100 ml). The combined ether extracts were washed with water (3 × 150 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator in vacuo. Purification by silica gel chromatography using 4% ethyl acetate / methylene chloride as the eluent gave the product as an orange solid (0.984 g, 39%).

Example 152B

3-amino-4- (4-hydroxyphenoxy) benzonitrile

The product of Example 152A (500 mg, 1.952 mmol) was hydrogenated in methanol (20 ml) with hydrogen (1 atmosphere, balloon) and 10% palladium-on-carbon (50 mg) for 30 minutes. The reaction mixture was filtered under vacuum through a 0.45 □ PTFE membrane and the catalyst was washed with methanol. The filtrate was concentrated on a rotary evaporator in vacuo to give the title compound as a pink-beige solid (437 mg, 99%).

Example 152C

4- (4-Hydroxyphenoxy) -3- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) benzonitrile

A solution of the product of example 36E (41 mg, 0.1896 mmol) and the product of example 152B (42.9 mg, 0.1896 mmol) in acetic acid (2 ml) was stirred in an oil bath preheated to 140 ° C for 1 5 hours. The reaction mixture was cooled to room temperature, diluted with hexane (100 ml), concentrated on a rotary evaporator in vacuo and evaporated together with methylene chloride / hexane (4 ×). The residue was dried under high vacuum. Purification by silica gel chromatography using 30% ethyl acetate / methylene chloride as the eluent afforded the title compound as a white solid (16 mg, 21%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J = 6.99 Hz, 6H), 3.11-3.28 (m, 1H), 6.77 (d, J = 8.82 Hz, 2H), 6.85 (d, J = 8.46 Hz, 1H), 6.93 (d, J = 8.46 Hz, 2H), 7.64 (dd, J = 17 28, 8.46 Hz, 2H), 8.12 (s, 1H), 8.66 (s, 1H), 8.81 (d, J = 8.09 Hz, 1H), 9.47 (s , 1H); 9.99 (s, 1H);

MS (DCI / NH ₃ ) m / z 398 (M + H) +.

Example 153

(5-Bromo-2-phenoxyphenyl) pyrido [2,3-d] pyrimidin-4-ylamine

5-Bromo-2-phenoxybenzolamine was reacted with the product of example 57A by the method described in example 57E, using 5-bromo-2-phenoxybenzolamine instead of the product of example 57D, to obtain a crude product which was purified by HPLC with TFA to obtain the specified in the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 6.94-7.03 (m, J = 8.09, 5.88 Hz, 3H), 7.07 (t, J = 7.35 Hz , 1H), 7.24-7.36 (m, 2H), 7.54 (dd, J = 8.82, 2.21 Hz, 1H), 7.77 (dd, J = 8.46, 4 , 41 Hz, 1H), 7.83 (d, J = 2.21 Hz, 1H), 8.82 (s, 1H), 8.89 (d, J = 7.35 Hz, 1H), 9, 10 (d, J = 2.57 Hz, 1H);

MS (ESI) + m / z 394 (M + 2) +.

Example 154

(5-Chloro-2-phenoxyphenyl) pyrido [2,3-d] pyrimidin-4-ylamine

5-Chloro-2-phenoxyphenylamine was reacted with the product of example 57A by the method described in example 57E using 5-chloro-2-phenoxyphenylamine instead of the product of example 57D to give a crude product that was purified by TFA HPLC to give the indicated in the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 6.97 (d, J = 7.72 Hz, 2H), 7.00-7.11 (m, 2H), 7.24-7.34 (m, J = 8.09, 8.09 Hz, 2H), 7.41 (dd, J = 8.82, 2.57 Hz, 1H), 7.69-7.77 (m, 2H), 8.77 (s, 1H), 8.85 (d, J = 8.46 Hz, 1H), 9.08 (d, J = 3.31 Hz, 1H);

MS (ESI) + m / z 349 (M + H) +.

Example 155

1- {3- [4-Chloro-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenyl} ethanol

1- [4- (2-amino-4-chlorophenoxy) phenyl] ethanol was reacted with the product of example 36E in accordance with the method described in example 152C using 1- [4- (2-amino-4-chlorophenoxy) phenyl ] ethanol instead of the product of Example 152B to give a crude product which was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.16 (d, J = 6.62 Hz, 3H), 1.31 (d, J = 6.99 Hz, 6H), 3.17- 3.28 (m, 1H), 4.60 (q, 1H), 6.81 (m, 1H), 6.94 (s, 1H), 7.01 (d, J = 7.72 Hz, 1H), 7.06 (d, J = 8.82 Hz, 1H), 7.23 (t, J = 7.91 Hz, 1H), 7.43 (dd, J = 8.82, 2.57 Hz, 1H), 7.72 (m, 1H), 7.76 (s, 1H), 8.79 (s, 1H), 8.82 (s, 1H);

MS (ESI-) m / z 433 (M-H) -.

Example 156

4- [2- (7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

Example 156A

4-amino-2-ethylsulfanylpyrimidine-5-carbonitrile

A solution of 2-ethyl-2-thiopseum urea hydrobromide (1.52 g, 8.19 mmol) (ethoxymethylene) malononitrile (1.0 g, 8.19 mmol) and N, N-diisopropylethylamine (3.57 ml, 20.05 mmol) in ethanol (20 ml) was stirred at room temperature for 3.5 hours. The resulting solid was collected, washed with ethanol and dried in vacuo to give the title compound as a pale yellow solid (580 mg, 39%).

Example 156B

N '- (5-Cyano-2-ethylsulfanylpyrimidin-4-yl) -N, N-dimethylformamidine

A solution of the product of Example 156A (200 mg, 1.11 mmol) and N, N-dimethylformamide dimethyl acetal (0.15 ml, 1.11 mmol) in toluene (10 ml) was heated under reflux for 2.5 hours. After cooling to room temperature, the solution was concentrated in vacuo to give the title compound as a colorless solid (260 mg, 100%).

Example 156C

4- [2- (7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

A solution of the product of example 6c (54 mg, 0.234 mmol) and the product of example 156B (50 mg, 0.213 mmol) in acetic acid (2 ml) was heated at 130 ° C for 1.5 hours. Then, the solution was allowed to cool to room temperature, acetic acid was removed in vacuo, and the resulting residue was purified by TFA HPLC to give the title compound as trifluoroacetic acid salt (51 mg, 45%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.38 (t, J = 7.4 Hz, 3H), 2.30 (s, 3H), 3.23 (q, J = 7 , 3 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.1 Hz, 1H), 7.10 (m, 1H), 7, 18 (d, J = 8.7 Hz, 2H), 7.21 (s, 1H), 8.62 (s, 1H), 9.70 (s, 1H), 9.78 (br s, 1H ), 10.85 (s, 1H);

MS (ESI) + m / z 422 (M + H) +.

Example 157

(7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [5-methyl-2- (4-phenoxyphenylsulfanyl) phenyl] amine

Example 157a

5-methyl-2- (4-phenoxyphenylsulfanyl) phenylamine

The product of Example 6c (0.500 g, 1.91 mmol) was dissolved in CH ₂ Cl ₂ 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 hours, during which time another 2 equivalents of each reagent was added. It was stirred at room temperature for another 16 hours, during which time another 2 equivalents of each reagent were added. Was stirred at room temperature for another 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography, eluting with 20% EtOAc / hexane (0.100 g, 15%). The product was reduced using SnCl ₂ in accordance with the method described in example 5I, to obtain the specified title compound (90 mg, 98%).

Example 157b

7- (Ethylthio) -N- (5-methyl-2- (4-phenoxyphenylthio) phenyl) pyrimido [4,5-d] pyrimidin-4-amine

A solution of the product of example 156B and the product of example 157a was reacted in accordance with the method described in example 156C, using the product of example 157a instead of the product of example 6c to give a crude product that was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid (16 mg, 21%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.37 (t, J = 7.35 Hz, 3H), 2.34 (s, 3H), 3.22 (q, J = 7, 35 Hz, 2H), 6.82 (m, 2H), 6.93 (m, 2H), 7.29 (m, 8H), 8.57 (s, 1H), 9.64 (s, 1H) 10.66 (s, 1H);

MS (ESI +) m / z 498 (M + H) +.

Example 158

4- [4-Methyl-2- (7-piperidin-1-ylpyrimido [4,5- d ] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 156C (42 mg, 0.1 mmol) in piperidine (1 ml) was heated in a microwave oven (CEM Discover microwave oven) at 180 ° C for 2 hours. The solution was concentrated in vacuo and the residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (17 mg, 38%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.64 (m, 6H), 2.30 (s, 3H), 3.96 (m, 4H), 6.72 (m, 2H), 7.01 (d, J = 7.72 Hz, 1H), 7.17 (m, 4H), 8.59 (s, 1H), 9.53 (s, 1H), 9.83 (s, 1H ), 11.43 (s, 1H);

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

Example 159

4- [2- (7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl ester of propan-2-sulfonic acid

The product of example 156C (0.042 g, 0.1 mmol), isopropylsulfonyl chloride (0.014 g, 0.105 mmol), 4-dimethylaminopyridine (0.002 g, 0.01 mmol) and diisopropylethylamine (0.04 g, 0.3 mmol) in 1 , 2-dichloroethane (2.0 ml) was stirred for 1 hour, poured into water (20 ml) and extracted with ethyl acetate (3 × 10 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (15 mg, 23%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.27-1.46 (m, 9H), 2.37 (s, 3H), 3.20 (q, J = 7.35 Hz, 2H), 3.56-3.70 (m, 1H), 7.09-7.20 (m, 2H), 7.19-7.29 (m, 3H), 7.34 (s, 1H) 7.39 (d, J = 8.09 Hz, 2H); 8.56 (s, 1H); 9.61 (s, 1H); 10.72 (s, 1H);

MS (ESI) + m / z 528 (M + H) +.

Example 160

4- [2- (7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] 4-acetylaminobenzenesulfonic acid phenyl ester

The product of Example 156C was reacted with 4-acetylaminobenzenesulfonyl chloride in accordance with the method described in Example 159 using 4-acetylaminobenzenesulfonyl chloride instead of isopropylsulfonyl chloride to give a crude product which was purified by HPLC with TFA to give the title compound as trisulfuric acid salt (31 mg, 50%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.10 (s, 3H), 2.35 (s, 3H), 3, 20 (q, J = 7.35 Hz, 2H), 6.85 (d, J = 8.82 Hz, 2H), 7.13 (d, J = 8.82 Hz, 2H), 7.26 (m, 3H), 7.71 (m, 2H), 7.81 (m, 2H), 8.52 (s, 1H), 9.59 (s, 1H), 10.48 (s, 1H) 10.71 (s, 1H);

MS (ESI +) m / z 619 (M + H) +.

Example 161

4- [4-Methyl-2- (7-morpholin-4-ylpyrimido [4,5-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 156C in morpholine (1 ml) was heated in a microwave oven (CEM Discover microwave oven) at 180 ° C for 2 hours. The solution was concentrated in vacuo and the residue was purified by TFA HPLC to give the title compound as the trifluoroacetic acid salt (29 mg, 65%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H), 3.73 (t, J = 4.41 Hz, 4H), 3.94 (br s, 4H), 6.72 (d, J = 8.82 Hz, 2H), 7.02 (d, J = 8.09 Hz, 1H), 7.18 (m, 4H), 8.61 (s, 1H), 9.57 (s, 1H); 9.85 (s, 1H); 11.47 (s, 1H);

MS (ESI +) m / z 447 (M + H) +.

Example 162

4- [2- (7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] benzenesulfonic acid phenyl ester

The product of Example 156C was reacted with benzenesulfonyl chloride in accordance with the method described in Example 159 using benzenesulfonyl chloride instead of isopropylsulfonyl chloride to give a crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (27 mg, 48 %).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.36 (s, 3H), 3.20 (q, J = 7, 35 Hz, 2H), 6.85 (m, 2H), 7.11 (m, 2H), 7.20 (d, J = 7.72 Hz, 1H), 7.35 (m, 2H), 7 65 (m, 2H); 7.86 (m, 3H); 8.51 (s, 1H); 9.58 (s, 1H); 10.65 (s, 1H);

MS (ESI +) 562 (M + H) +.

Example 163

4- [2- (7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] 4-bromobenzenesulfonic acid phenyl ester

The product of Example 156C was reacted with 4-bromobenzenesulfonyl chloride in accordance with the method described in Example 159 using 4-bromobenzenesulfonyl chloride instead of isopropylsulfonyl chloride to give a crude product which was purified by HPLC with TFA to give the title compound as a trifluorois salt .

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.37 (s, 3H), 3.20 (q, J = 7, 35 Hz, 2H), 6.87 (m, 2H), 7.12 (m, 2H), 7.19 (d, J = 7.05 Hz, 1H), 7.36 (m, 2H), 7 71 (m, 2H); 7.87 (m, 2H); 8.51 (s, 1H); 9.60 (s, 1H); 10.61 (s, 1H);

MS (ESI +) m / z 640/642 (M + H) +.

Example 164

(7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [2- (4-hydroxyphenylsulfanyl) -5-methylphenyl] carbamic acid tert-butyl ester

The product of Example 156C was reacted with di- tert- butyl dicarbonate and triethylamine in tetrahydrofuran at room temperature for 16 hours. The mixture was then poured into water (10 ml) and the resulting solution was extracted with ethyl acetate (3 × 10 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.52 (t, J = 7.35 Hz, 3H), 1.62 (s, 9H), 2.50 (s, 3H), 3, 35 (q, J = 7.35 Hz, 2H), 7.21 (d, J = 8.46 Hz, 2H), 7.41 (m, 5H), 8.71 (s, 1H), 9 80 (s, 1H); 10.72 (s, 1H);

MS (ESI +) m / z 522 (M + H) +.

Example 165

{4- [2- (7-Ethylsulfanylpyrimido [4,5- d ] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenoxy} acetonitrile

The product of example 164 (52 mg, 0.1 mmol), bromoacetonitrile (0.008 ml, 0.12 mmol), cesium carbonate (0.065 g, 0.2 mmol) and tetrabutylammonium iodide (0.001 g) in N, N- dimethylformamide ( 2 ml) was stirred at room temperature for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), filtered and evaporated in vacuo. Dichloromethane (2.5 ml) and trifluoroacetic acid (2.5 ml) were added to the residue, then stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was purified by TFA HPLC to give the title compound (9 mg, 20%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.42 (t, J = 7.35 Hz, 3H), 2.24 (s, 3H), 3.29 (q, J = 7, 35 Hz, 2H), 5.25 (s, 2H), 6.81 (m, 5H), 7.20 (d, J = 8.46 Hz, 2H), 8.34 (s, 1H), 9 25 (s, 1H); 9.75 (s, 1H);

MS (ESI +) m / z 461 (M + H) +.

Example 166

[2- (4-Benzyloxyphenylsulfanyl) -5-methylphenyl] - (7-ethylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) amine

The product of example 164 was reacted with benzyl bromide in accordance with the method described in example 165 using benzyl bromide instead of bromoacetonitrile to give a crude product which was purified by silica gel chromatography using 98/2 dichloromethane / methanol as the eluent to give the title the title compound (15 mg, 29%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.20 (t, J = 7.35 Hz, 3H), 2.27 (s, 3H), 3.08 (q, J = 7, 35 Hz, 2H), 5.44 (s, 2H), 6.74 (d, J = 8.46 Hz, 2H), 6.95 (m, 3H), 7.20 (d, J = 8, 46 Hz, 2H), 7.35 (m, 5H), 8.77 (s, 1H), 9.42 (s, 1H), 9.81 (s, 1H);

MS (ESI +) m / z 512 (M + H) +.

Example 167

4- [4- (3-Bromobenzyloxy) -2- (2-methylsulfanylthiazolo [4,5-d] pyrimidin-7-ylamino) phenylsulfanyl] phenol

Example 167A

N '- (5-Cyano-2-methylsulfanylthiazol-4-yl) -N, N-dimethylformamidine

The title compound was prepared by reacting 4-amino-2-methylsulfanylthiazole-5-carbonitrile with N, N-dimethylformamide dimethylacetal by the method described in Example 156B to give the title compound as a white foam (0.132 g, 99%) .

Example 167B

4- [4- (3-Bromobenzyloxy) -2- (2-methylsulfanylthiazolo [4,5-d] pyrimidin-7-ylamino) phenylsulfanyl] phenol

A solution of the product of example 167A (66.0 mg, 0.29 mmol) and the product of example 15A (118 mg, 0.29 mmol) in acetic acid (1 ml) were mixed in an oil bath preheated to 140 ° C for 20 minutes. The mixture was cooled and concentrated in vacuo. Then, the resulting residue was purified by TFA HPLC to give the title compound as the trifluoroacetic acid salt (34 mg, 17%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.75 (s, 3H), 5.12 (s, 2H), 6.70 (d, J = 8.82 Hz, 1H), 6, 96-7.05 (m, 2H), 7.07-7.16 (m, 3H), 7.33 (t, J = 7.72 Hz, 1H), 7.41-7.46 (m, 1H), 7.51 (d, J = 7.72 Hz, 1H), 7.63 (s, 1H), 8.47 (s, 1H), 9.73 (s, 2H);

MS (ESI) + m / z 583/585 (M + H) +.

Example 168

4- [4- (4-Bromobenzyloxy) -2- (2-methylsulfanylthiazolo [4,5-d] pyrimidin-7-ylamino) phenylsulfanyl] phenol

The solution of the product of example 167A and the product of example 16A were reacted in accordance with the method described in example 167B, using the product of example 16A instead of the product of example 15A, to obtain a crude substance which was purified by trituration in methanol to obtain the title compound in as a white solid (46 mg, 27%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.76 (s, 3H), 5.09 (s, 2H), 6.70 (d, J = 8.46 Hz, 2H), 6, 91-7.24 (m, 5H), 7.38 (d, J = 8.09 Hz, 2H), 7.56 (d, J = 8.09 Hz, 2H), 8.46 (s, 1H ), 9.71 (s, 2H);

MS (ESI) + m / z 583/585 (M + H) +.

Example 169

4- [4-Methyl-2- (2-methylsulfanylthiazolo [4,5-d] pyrimidin-7-ylamino) phenylsulfanyl] phenol

The solution of the product of example 167A and the product of example 6c were reacted in accordance with the method described in example 167B, using the product of example 6c instead of the product of example 15A, to obtain a crude material which was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid (17 mg, 11%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.27 (s, 3H), 2.76 (s, 3H), 6.76 (d, J = 8.46 Hz, 2H), 6, 82 (d, J = 8.09 Hz, 1H), 7.06-7.22 (m, 4H), 8.49 (s, 1H), 9.86 (s, 2H);

MS (ESI) + m / z 413 (M + H) +.

Example 170

N- {4- [4-Methyl-2- (2-methylsulfanylthiazolo [4,5-d] pyrimidin-7-ylamino) phenylsulfanyl] phenyl} acetamide

A solution of the product of example 167A and the product of example 7b was reacted in accordance with the method described in example 167B, using the product of example 7b instead of the product of example 15A, to obtain a crude substance, which was purified by trituration in methanol to obtain the title compound ( 110 mg, 83%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 2.76 (s, 3H), 6.96 (d, J = 8 , 09 Hz, 1H), 7.14 (d, J = 8.09 Hz, 1H), 7.18-7.26 (m, J = 8.82 Hz, 3H), 7.54 (d, J = 8.46 Hz, 2H), 8.45 (s, 1H), 9.74 (s, 1H), 10.04 (s, 1H);

MS (ESI) + m / z 454 (M + H) +.

Example 171

N- {4- [2- (1-tert-Butyl-1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

Example 171A

N '- (2-tert-butyl-4-cyano-2H-pyrazol-3-yl) -N, N-dimethylformamidine

The title compound was prepared by reacting 5-amino-1-tert-butyl-1H-pyrazole-4-carbonitrile with N, N-dimethylformamide dimethyl acetal by the method described in Example 156B to give the title compound.

Example 171B

N- {4- [2- (1-tert-butyl-1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The solution of the product of example 171A and the product of example 7b were reacted in accordance with the method described in example 167B, using the product of example 7b instead of the product of example 15A and using the product of example 171A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (54 mg, 32%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.74 (s, 9H), 2.03 (s, 3H), 2.41 (s, 3H), 7.13 (d, J = 8 , 82 Hz, 2H), 7.49 (m, 4H), 7.62 (s, 1H), 8.41 (s, 1H), 8.47 (s, 1H), 8.76 (s, 1H ), 10.06 (s, 1H), 10.39 (s, 1H);

MS (ESI +) m / z 447 (M + H) +.

Example 172

4- [2- (1-tert-Butyl-1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

The solution of the product of example 171A and the product of example 6c were reacted in accordance with the method described in example 167B, using the product of example 6c instead of the product of example 15A and using the product of example 171A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as trifluoroacetic acid salt (40 mg, 25%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.76 (s, 9H), 2.38 (s, 3H), 6.67 (d, J = 8.82 Hz, 2H), 7, 07 (d, J = 8.82 Hz, 2H), 7.34 (d, J = 8.09 Hz, 1H), 7.50 (d, J = 8.09 Hz, 1H), 7.58 ( s, 1H), 8.43 (s, 1H), 8.49 (s, 1H), 8.75 (s, 1H), 9.91 (s, 1H), 10.40 (s, 1H);

MS (ESI +) m / z 406 (M + H) +.

Example 173

4- [2- (7-Isopropylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

Example 173A

N '- (5-Cyano-2-isopropylpyrimidin-4-yl) -N, N-dimethylformamidine

The title compound was prepared by reacting 4-amino-2-isopropylpyrimidin-5-carbonitrile with N, N-dimethylformamide dimethylacetal by the method described in Example 156B to give the title compound.

Example 173B

4- [2- (7-Isopropylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

A solution of the product of example 173A and the product of example 6c was reacted in accordance with the method described in example 167B, using the product of example 6c instead of the product of example 15A and using the product of example 173A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (39 mg, 38%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.62 Hz, 6H), 2.30 (s, 3H), 3.29 (m, 1H), 6, 70 (d, J = 8.46 Hz, 2H), 6.98 (d, J = 8.09 Hz, 1H), 7.17 (m, 4H), 8.72 (s, 1H), 9, 76 (s, 1H), 9.90 (s, 1H), 11.13 (s, 1H);

MS (ESI +) m / z 404 (M + H) +.

Example 174

4- [4-Benzyloxy-2- (7-isopropylpyrimido [4,5-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 173A and the product of example 27A was reacted in accordance with the method described in example 167B, using the product of example 27A instead of the product of example 15A and using the product of example 173A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (10 mg, 20%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.27 (m, 1H), 5.11 (s, 2H), 6, 64 (d, J = 8.46 Hz, 2H), 7.06 (m, 5H), 7.40 (m, 5H), 8.64 (s, 1H), 9.65 (s, 1H), 9.84 (s, 1H); 10.88 (s, 1H);

MS (ESI +) m / z 496 (M + H) +.

Example 175

N- {4- [2- (7-Ethylsulfanyl-5-methylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

Example 175A

N '- (5-Cyano-2-ethylsulfanyl-6-methylsulfanylpyrimidin-4-yl) -N, N-dimethylformamidine

The title compound was prepared by reacting 4-amino-2-ethylsulfanyl-6-methylsulfanylpyrimidin-5-carbonitrile with N, N-dimethylformamide dimethylacetal by the method described in Example 156B to give the title compound.

Example 175B

N- {4- [2- (7-Ethylsulfanyl-5-methylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

The solution of the product of example 175A and the product of example 7b were reacted in accordance with the method described in example 167B, using the product of example 7b instead of the product of example 15A and using the product of example 175A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (23 mg, 35%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.03 (s, 3H), 2.24 (s, 3H), 2, 40 (s, 3H), 3.18 (q, J = 7.35 Hz, 2H), 6.84 (m, 3H), 7.19 (d, J = 8.46 Hz, 2H), 7 49 (d, J = 8.46 Hz, 2H), 7.82 (s, 1H), 9.97 (s, 1H), 12.25 (s, 1H);

MS (ESI +) m / z 509 (M + H) +.

Example 176

4- [2- (7-Ethylsulfanyl-5-methylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

A solution of the product of example 175A and the product of example 6c was reacted in accordance with the method described in example 167B, using the product of example 6c instead of the product of example 15A and using the product of example 175A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (19 mg, 31%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.21 (s, 3H), 2.44 (s, 3H), 3, 19 (q, J = 7.11 Hz, 2H), 6.70 (m, 5H), 7.18 (d, J = 8.46 Hz, 2H), 7.84 (s, 1H), 9 67 (s, 1H); 12.24 (s, 1H);

MS (ESI +) m / z 468 (M + H) +.

Example 177

N- {4- [2- (2-Cyanomethylsulfanylthiazolo [4,5-d] pyrimidin-7-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

Example 177A

N '- (5-Cyano-2-cyanomethylsulfanylthiazol-4-yl) -N, N-dimethylformamidine

The title compound was prepared by reacting 4-amino-2-cyanomethylsulfanylthiazole-5-carbonitrile with N, N-dimethylformamide dimethylacetal by the method described in Example 156B to give the title compound.

Example 177B

N- {4- [2- (2-Cyanomethylsulfanylthiazolo [4,5-d] pyrimidin-7-ylamino) -4-methylphenylsulfanyl] phenyl} acetamide

A solution of the product of example 177A and the product of example 7b was reacted in accordance with the method described in example 167B, using the product of example 7b instead of the product of example 15A and using the product of example 177A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (64 mg, 52%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.03 (s, 3H), 2.30 (s, 3H), 4.54 (s, 2H), 6.95 (d, J = 8 , 09 Hz, 1H), 7.15 (d, J = 8.09 Hz, 1H), 7.23 (m, 3H), 7.55 (d, J = 8.46 Hz, 2H), 8, 51 (s, 1H), 9.91 (s, 1H), 10.04 (s, 1H);

MS (ESI +) m / z 479 (M + H) +.

Example 178

{7- [2- (4-Hydroxyphenylsulfanyl) -5-methylphenylamino] thiazolo [4,5-d] pyrimidin-2-ylsulfanyl} acetonitrile

A solution of the product of example 177A and the product of example 6c was reacted in accordance with the method described in example 167B, using the product of example 6c instead of the product of example 15A and using the product of example 177A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (62 mg, 56%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.27 (s, 3H), 4.54 (s, 2H), 6.77 (m, 3H), 7.18 (m, 4H), 8.53 (s, 1H); 9.85 (s, 1H); 9.97 (s, 1H);

MS (ESI +) m / z 438 (M + H) +.

Example 179

4- [4-Benzyloxy-2- (7-heptafluoropropylpyrimido [4,5-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 179A

N '- (5-Cyano-2-heptafluoropropylpyrimidin-4-yl) -N, N-dimethylformamidine

The title compound was prepared by reacting 4-amino-2-heptafluoropropylpyrimidin-5-carbonitrile with N, N-dimethylformamide dimethyl acetal by the method described in Example 156B to give the title compound.

Example 179B

4- [4-Benzyloxy-2- (7-heptafluoropropylpyrimido [4,5-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 179A and the product of example 27A was reacted in accordance with the method described in example 167B, using the product of example 27A instead of the product of example 15A and using the product of example 179A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as the trifluoroacetic acid salt (24 mg, 39%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.11 (s, 2H), 6.61 (d, J = 8.46 Hz, 2H), 7.04 (dd, J = 8.82 , 2.57 Hz, 1H), 7.10 (d, J = 8.46 Hz, 2H), 7.17 (d, J = 2.57 Hz, 1H), 7.23 (d, J = 8 , 82 Hz, 1H), 7.40 (m, 5H), 8.79 (s, 1H), 9.63 (s, 1H), 10.12 (s, 1H), 11.01 (s, 1H) );

MS (ESI +) m / z 622 (M + H) +.

Example 180

(7-Isopropylpyrimido [4,5-d] pyrimidin-4-yl) - [5-methyl-2- (4-phenoxyphenylsulfanyl) phenyl] amine

A solution of the product of example 173A and the product of example 157a was reacted in accordance with the method described in example 167B, using the product of example 157a instead of the product of example 15A and using the product of example 173A instead of the product of example 167A, to obtain a crude substance that purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 2.34 (s, 3H), 3.24 (m, 1H), 6, 81 (d, J = 8.82 Hz, 2H), 6.94 (d, J = 7.72 Hz, 2H), 7.28 (m, 8H), 8.63 (s, 1H), 9, 83 (s, 1H); 10.78 (s, 1H);

MS (ESI +) m / z 480 (M + H) +.

Example 181

(7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [3- (4-methoxyphenylsulfanyl) -5-methylphenyl] amine

Example 181A

1- (4-Methoxyphenylsulfanyl) -3-methyl-5-nitrobenzene

Copper 4-Methoxy thiophenolate (0.94 g, 4.63 mmol), which was obtained by refluxing an excess of 4-methoxythiophenol with copper oxide in ethanol overnight and isolating the desired product by filtration, and 3-bromo-5- nitrotoluene (1.0 g, 4.63 mmol) obtained in the second stage from 3-nitro-4-aminotoluene, as described in J. Am. Chem. Soc . Vol. 78 , pp 1992, 1956, was heated to 165 ° C. in a mixture of quinoline (5 ml) and pyridine (1 ml) for 2 hours. After quenching with an aqueous HCl solution, the desired product was isolated by silica gel chromatography using ethyl acetate / hexane as an eluent to give the title compound (0.96 g, 75%).

Example 181B

3- (4-Methoxyphenylsulfanyl) -5-methylphenylamine

The product of example 181A was restored in accordance with the method described in example 147C, using the product of example 181A instead of the product of example 147B, to obtain the title compound.

Example 181C

(7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [3- (4-methoxyphenylsulfanyl) -5-methylphenyl] amine

The product of Example 181B was reacted with the product of Example 156B in accordance with the method described in Example 156C, using the product of Example 181B instead of the product of Example 6c, to obtain a crude product which was purified by HPLC with TFA to give the title compound in the form of a salt of trifluoroacetic acid.

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 1.37 (t, J = 7.32 Hz, 3H), 2.28 (s, 3H), 3.21 (q, J = 7, 32 Hz, 2H), 3.79 (s, 3H), 6.83 (s, 1H), 7.03 (d, J = 9.16 Hz, 2H), 7.42-7.53 (m, 4H), 8.71 (s, 1H), 9.72 (s, 1H), 10.39 (s, 1H);

MS (ESI +) m / z 436 (M + H) +.

Example 182

(7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [3- (3-methoxyphenylsulfanyl) -5-methylphenyl] amine

Example 182A

3- (3-Methoxyphenylsulfanyl) -5-methylphenylamine

Copper 3-Methoxy thiophenolate was reacted with 3-bromo-5-nitrotoluene in accordance with the method described in Example 181A using copper 3-methoxy thiophenolate instead of copper 4-methoxy thiophenolate to give 1- (3-methoxyphenylsulfanyl) -3- methyl 5-nitrobenzene, which was reduced in accordance with the method described in example 181B, to obtain the specified title compound.

Example 182B

(7-Ethylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [3- (3-methoxyphenylsulfanyl) -5-methylphenyl] amine

The product of example 182A was reacted with the product of example 156B in accordance with the method described in example 156C, using the product of example 182A instead of the product of example 6c, to obtain a crude product which was purified by HPLC with TFA to give the title compound in the form of a salt of trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.37 (t, J = 7.35 Hz, 3H), 2.33 (s, 3H), 3.21 (q, J = 7, 11 Hz, 2H), 3.74 (s, 3H), 6.84-6.96 (m, J = 1.10 Hz, 3H), 7.05 (s, 1H), 7.32 (dd, J = 9.01, 7.17 Hz, 1H), 7.60 (s, 1H), 7.65 (s, 1H), 8.74 (s, 1H), 9.74 (s, 1H), 10.47 (s, 1H);

MS (ESI +) m / z 436 (M + H) +.

Example 183

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - (5-ethyl-2-phenylsulfanylphenyl) amine

Example 183A

5-Ethyl-2-phenylsulfanylphenylamine

Sodium thiophenolate was reacted with 1-chloro-4-ethyl-2-nitrobenzene in accordance with the method described in Example 5H using 1-chloro-4-ethyl-2-nitrobenzene instead of 4-chloro-3-nitrotoluene, to give 4 ethyl-2-nitro-1-phenylsulfanylbenzene, which was reduced in accordance with the method described in example 5I, to obtain the specified title compound.

Example 183B

4-amino-2-benzylsulfanylpyrimidine-5-carbonitrile

Solution of 2-benzyl-2-thiopseum urea hydrochloride (5.0 g, 24.67 mmol) (ethoxymethylene) malononitrile (3.01 g, 24.67 mmol) and N, N-diisopropylethylamine (10.75 ml, 61.68 mmol) in ethanol (50 ml) was stirred at room temperature for 18 hours. The resulting solid was collected, washed with ethanol and dried in vacuo to give the title compound (2.69 g, 45%).

Example 183C

N '- (2-Benzylsulfanyl-5-cyanopyrimidin-4-yl) -N, N-dimethylformamidine

The solution of the product of Example 183B was reacted with N, N-dimethylformamide dimethyl acetal in accordance with the method described in Example 156B, using the product of Example 183B instead of the product of Example 156B to give the title compound.

Example 183D

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - (5-ethyl-2-phenylsulfanylphenyl) amine

The product of example 183A was reacted with the product of example 183C in accordance with the method described in example 156C, using the product of example 183A instead of the product of example 6c and using the product of example 183C instead of the product of example 156B, to obtain a crude product that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 482 (M + H) +.

Example 184

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [2- (4-methoxyphenylsulfanyl) -5-methylphenyl] amine

The product of Example 183C was reacted with 2- (4-methoxyphenylsulfanyl) -5-methylphenylamine (Example 118) in accordance with the method described in Example 156C using 2- (4-methoxyphenylsulfanyl) -5-methylphenylamine instead of the product of Example 6c and using the product of Example 183C instead of the product of Example 156B to give a crude product which was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 498 (M + H) +.

Example 185

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - (5-fluoro-2-phenylsulfanylphenyl) amine

Example 185A

5-fluoro-2-phenylsulfanylphenylamine

4-Fluoro-2-nitrophenol was reacted in accordance with methods similar to those described in examples 6a, 6b and 6c, using benzenethiol instead of 4-mercaptophenol and 4-fluoro-2-nitrophenol instead of 4-methyl-2-nitrophenol, to obtain the specified in the connection header.

Example 185B

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - (5-fluoro-2-phenylsulfanylphenyl) amine

The product of example 185A was reacted with the product of example 203A in accordance with the method described in example 156C, using the product of example 203A instead of the product of example 6c and using the product of example 185A instead of the product of example 156B, to obtain a crude product that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 472 (M + H) +.

Example 186

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [2- (4-fluorophenylsulfanyl) -5-methylphenyl] amine

The product of Example 183C was reacted with 2- (4-fluorophenylsulfanyl) -5-methylphenylamine (Example 124) in accordance with the method described in Example 156C using 2- (4-fluorophenylsulfanyl) -5-methylphenylamine instead of the product of Example 6c and using the product of Example 183C instead of the product of Example 156B to give a crude product which was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 486 (M + H) +.

Example 187

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - (5-methyl-2-m-tolylsulfanylphenyl) amine

The product of Example 183C was reacted with 5-methyl-2-m-tolylsulfanylphenylamine in accordance with the method described in Example 156C, using 5-methyl-2-m-tolylsulfanylphenylamine instead of the product of Example 6c and using the product of Example 183C instead of the product of Example 156B to afford a crude product which was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 482 (M + H) +.

Example 188

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanylphenyl) amine

The product of example 183C was reacted with the product of example 5I in accordance with the method described in example 156C, using the product of example 5I instead of the product of example 6c and using the product of example 183C instead of the product of example 156B, to obtain a crude product that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 468 (M + H) +.

Example 189

3- [2- (7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylphenylsulfanyl] phenol

The product of Example 183C was reacted with 3- (2-amino-4-methylphenylsulfanyl) phenol (Example 129) in accordance with the method described in Example 156C using 3- (2-amino-4-methylphenylsulfanyl) phenol instead of the product of Example 6c and using the product of Example 183C instead of the product of Example 156B to give a crude product which was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 484 (M + H) +.

Example 190

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [3- (3-methoxyphenylsulfanyl) -5-methylphenyl] amine

The product of example 183C was reacted with the product of example 182A in accordance with the method described in example 156C, using the product of example 182A instead of the product of example 6c and using the product of example 183C instead of the product of example 156B, to obtain a crude product that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.34 (s, 3H), 3.74 (s, 3H), 4.52 (s, 2H), 6.84-6.97 (m , J = 1.10 Hz, 3H), 7.05 (s, 1H), 7.21-7.39 (m, 4H), 7.46-7.53 (m, 2H), 7.61 ( s, 1H), 7.66 (s, 1H), 8.76 (s, 1H), 9.77 (s, 1H), 10.47 (s, 1H);

MS (ESI +) m / z = 498 (M + H) +.

Example 191

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [3- (4-methoxyphenylsulfanyl) -5-methylphenyl] amine

The product of example 183C was reacted with the product of example 181B in accordance with the method described in example 156C, using the product of example 181B instead of the product of example 6c and using the product of example 183C instead of the product of example 156B, to obtain a crude product that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.28 (s, 3H), 3.79 (s, 3H), 4.52 (s, 2H), 6.83 (s, 1H), 7.04 (d, J = 8.82 Hz, 2H), 7.19-7.38 (m, 2H), 7.41-7.55 (m, 5H), 8.74 (s, 1H) 9.75 (s, 1H); 10.42 (s, 1H);

MS (ESI +) m / z 497 (M + H) +.

Example 192

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - [2- (4-methoxyphenoxy) -5-methylphenyl] amine

The product of example 183C was reacted with the product of example 116B in accordance with the method described in example 156C, using the product of example 116B instead of the product of example 6c and using the product of example 183C instead of the product of example 156B, to obtain a crude product that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 482 (M + H) +.

Example 193

(7-Benzylsulfanylpyrimido [4,5-d] pyrimidin-4-yl) - (5-methyl-2-p-tolylsulfanylphenyl) amine

The product of Example 183C was reacted with 5-methyl-2-p-tolylsulfanylphenylamine in accordance with the method described in Example 156C, using 5-methyl-2-p-tolylsulfanylphenylamine instead of the product of Example 6c and using the product of Example 183C instead of the product of Example 156B to afford a crude product which was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt.

MS (ESI +) m / z 482 (M + H) +.

Example 194

4- [4- (3-Bromobenzyloxy) -2- (pyrimido [4,5-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 194A

N '- (5-Cyanopyrimidin-4-yl) -N, N-dimethylformamidine

The title compound was prepared by reacting 4-amino-5-pyrimidinecarbonitrile (Aldrich) with N, N-dimethylformamide dimethylacetal by the method described in Example 156B to obtain the title compound.

Example 194B

4- [4- (3-Bromobenzyloxy) -2- (pyrimido [4,5-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 194A was reacted with the product of example 15A in accordance with the method described in example 156C, using the product of example 15A instead of the product of example 6c and using the product of example 194A instead of the product of example 156B, to obtain a crude product that was purified by HPLC with NH ₄ OAc to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.12 (s, 2H), 6.64 (d, J = 8.82 Hz, 2H), 6.93-7.04 (m, 1H ), 7.10 (d, J = 8.82 Hz, 2H), 7.14-7.23 (m, 2H), 7.36 (t, J = 7.72 Hz, 1H), 7.43 -7.49 (m, 1H), 7.54 (dt, J = 7.81, 1.61 Hz, 1H), 7.65 (d, J = 1.47 Hz, 1H), 9.04 ( m, 1H); 9.63 (s, 1H); 10.29 (m, 1H);

MS (ESI-) m / z 531 (M-H) -.

Example 195

4- [4-Benzyloxy-2- (pyrimido [4,5-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 194A was reacted with the product of example 27A in accordance with the method described in example 156C, using the product of example 27A instead of the product of example 6c and using the product of example 194A instead of the product of example 156B, to obtain a crude product that was purified by HPLC with NH ₄ OAc to give the title compound.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 2H), 6.63 (d, J = 8.46 Hz, 2H), 6.94-7.05 (m, 1H ), 7.10 (d, J = 8.82 Hz, 2H), 7.18 (d, J = 7.72 Hz, 2H), 7.29-7.51 (m, 5H), 9.05 (m, 1H); 9.63 (s, 1H); 9.92 (s, 1H); 10.66 (s, 1H);

MS (ESI-) m / z 452 (M-H) -.

Example 196

(7-Isopropylpyrido [2,3-d] pyrimidin-4-yl) - [3- (4-methoxyphenylsulfanyl) -5-methylphenyl] amine

The product of example 181B was reacted with the product of example 36E by the method described in example 36I, using the product of example 181B instead of the product of example 36H to give a crude material that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.71 Hz, 6H), 2.29 (s, 3H), 3.25 (qs, J = 7.02, 6.90 Hz, 1H), 3.79 (s, 3H), 6.88 (s, 1H), 7.03 (d, J = 9.16 Hz, 2H), 7.42 ( d, J = 7.93 Hz, 2H), 7.45 (d, J = 8.54 Hz, 2H), 7.77 (d, J = 8.54 Hz, 1H), 8.81 (s, 1H), 8.95 (d, J = 8.54 Hz, 1H), 10.74 (s, 1H);

MS (ESI +) m / z 417 (M + H) +.

Example 197

4- [3- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -5-methylphenylsulfanyl] phenol

Example 197A

4- (3-amino-5-methylphenylsulfanyl) phenol

The product of Example 181B (0.5 g, 2.0 mmol) in dichloromethane was treated with boron tribromide (10 mmol) at room temperature for 1 hour. The solution was extracted with water, then the organic solution was dried and concentrated to obtain the title compound.

Example 197B

4- [3- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) -5-methylphenylsulfanyl] phenol

The product of example 197A was reacted with the product of example 36E by the method described in example 36I, using the product of example 197A instead of the product of example 36H, to obtain a crude material which was purified by HPLC with TFA to afford the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (s, 3H), 1.33 (s, 3H), 2.28 (s, 3H), 3.27 (sq. J = 6.86 Hz, 1H), 6.79-6.91 (m, 1H), 6.86 (d, J = 8.82 Hz, 2H), 7.30 (s, 1H), 7, 36 (d, J = 8.46 Hz, 2H), 7.35 (s, 1H), 7.83 (d, J = 8.46 Hz, 1H), 8.87 (s, 1H), 8, 98 (d, J = 8.82 Hz, 1H), 9.92 (s, 1H), 11.06 (s, 1H);

MS (ESI-) m / z 403 (M + H) +.

Example 198

4- [5- (3-Fluorobenzyloxy) -2- (4-hydroxyphenylsulfanyl) phenylamino] -7-methylpyrido [2,3-d] pyrimidine-6-carbonitrile

Example 198A

N '- (3,5-dicyano-6-methylpyridin-2-yl) -N, N-dimethylformamidine

A solution of 2-amino-6-methylpyridin-3,5-dicarbonitrile (0.158 g, 1.0 mmol) and N , N- dimethylformamide dimethyl acetal (0.119 g, 1.0 mmol) in toluene (10 ml) was heated under reflux for 6 o'clock. After cooling to room temperature, the solution was concentrated in vacuo to give the title compound as a brown solid (0.2 g, 94%).

Example 198B

4- [5- (3-Fluorobenzyloxy) -2- (4-hydroxyphenylsulfanyl) phenylamino] -7-methylpyrido [2,3-d] pyrimidine-6-carbonitrile

The product of Example 198A was reacted with the product of Example 10B by the method described in Example 10F, using the product of Example 198A instead of the product of Example 10E to give a crude material which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (18 mg, 29%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.82 (s, 3H), 5.13 (s, 2H), 6.64 (d, J = 8.46 Hz, 2H), 6, 99 (d, J = 9.56 Hz, 1H), 7.09 (d, J = 8.82 Hz, 2H), 7.12-7.21 (m, 3H), 7.29 (d, J = 7.72 Hz, 2H), 7.39-7.53 (m, 1H), 8.63 (s, 1H), 9.36 (s, 1H), 9.64 (s, 1H), 10 33 (s, 1H).

Example 199

[3- (3-Fluorobenzyloxy) phenyl] - (7-methylpyrido [2,3- d ] pyrimidin-4-yl) amine

Example 199A

(3-Fluorobenzyloxy) -3-nitrobenzene

A solution of 3-nitrophenol (0.278 g, 2.0 mmol), 1-bromomethyl-3-fluorobenzene (0.258 ml, 2.1 mmol), potassium carbonate (0.553 g, 4.0 mmol) and tetrabutylammonium iodide (0.001 g) N, N- dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Then, ice water (10 ml) was added to the solution, and the resulting solid was collected by filtration and dried in a vacuum oven to give the title compound in quantitative yield.

Example 199B

(3-Fluorobenzyloxy) -3-aminobenzene

To a solution of the product according to example 199A (0.494 g, 2.0 mmol), iron powder (0.56 g, 10.0 mmol) and ammonium chloride (0.54 g, 10.0 mmol) in a solution of methanol (20 ml) , tetrahydrofuran (20 ml) and water (10 ml) were heated under reflux for 2 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated. Ethyl acetate was then added, stirred for 30 minutes, filtered and concentrated in vacuo to give the title compound (0.405 g, 93%).

Example 199C

[3- (3-Fluorobenzyloxy) phenyl] - (7-methylpyrido [2,3- d ] pyrimidin-4-yl) amine

The product of example 199B was reacted with the product of example 10B in the manner described in example 10F using the product of example 199B instead of the product of example 10E to give a crude material which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (32 mg, 89%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 5.18 (s, 2H), 6.98 (m, 1H), 7.18 (m, 1H), 7.42 (m, 6H), 7.79 (d, J = 8.46 Hz, 1H), 8.92 (s, 1H), 9.00 (d, J = 8.82 Hz, 1H), 11.16 (s, 1H);

MS (ESI +) m / z 361 (M + H) +.

Example 200

[3- (3-Fluorobenzyloxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 199B was reacted with the product of example 36E by the method described in example 36I, using the product of example 199B instead of the product of example 36H to give a crude material that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 3.26 (m, 1H), 5.18 (s, 2H), 6, 93 (m, 1H), 7.17 (m, 1H), 7.42 (m, 6H), 7.79 (d, J = 8.46 Hz, 1H), 8.85 (s, 1H), 9.00 (d, J = 8.46 Hz, 1H); 10.76 (s, 1H);

MS (ESI +) m / z 389 (M + H) +.

Example 201

[3- (3-Fluorobenzyloxy) phenyl] pyrido [2,3-d] pyrimidin-4-ylamine

The product of example 199B was reacted with the product of example 57A by the method described in example 57E, using the product of example 199B instead of the product of example 57D, to give the crude title compound that was purified by HPLC with TFA to give the title compound as trifluoroacetic salt acids.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.18 (s, 2H), 6.98 (m, 1H), 7.18 (m, 1H), 7.42 (m, 6H), 7.87 (dd, J = 8.27, 4.60 Hz, 1H), 8.93 (s, 1H), 9.14 (m, 2H), 11.12 (s, 1H);

MS (ESI +) m / z 347 (M + H) +.

Example 202

[3- (4-Fluorobenzyloxy) phenyl] pyrido [2,3-d] pyrimidin-4-ylamine

Example 202A

3- (4-Fluorobenzyloxy) phenylamine

3-Nitrophenol was reacted with 1-bromomethyl-4-fluorobenzene in accordance with the method described in example 199A using 1-bromomethyl-4-fluorobenzene instead of 1-bromomethyl-3-fluorobenzene, then reduced in accordance with the method described in example 199B to give the title compound.

Example 202B

[3- (4-Fluorobenzyloxy) phenyl] pyrido [2,3-d] pyrimidin-4-ylamine

The product of Example 202A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 202A instead of the product of Example 57D, to obtain the crude title compound which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids (20 mg, 58%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.13 (s, 2H), 6.92 (m, 1H), 7.24 (m, 2H), 7.38 (m, 2H), 7.55 (m, 3H), 7.80 (dd, J = 8.27, 4.60 Hz, 1H), 8.87 (s, 1H), 9.07 (dd, J = 8.27, 1.65 Hz, 1H), 9.12 (dd, J = 4.41, 1.84 Hz, 1H), 10.69 (s, 1H);

MS (ESI +) m / z 347 (M + H) +.

Example 203

[3- (3,5-Difluorobenzyloxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 203A

3- (3,5-difluorobenzyloxy) phenylamine

3-Nitrophenol was reacted with 1-bromomethyl-3,5-difluorobenzene in accordance with the method described in Example 199A using 1-bromomethyl-3,5-difluorobenzene instead of 1-bromomethyl-3-fluorobenzene, then reduced according to the method described in Example 199B to obtain the title compound.

Example 203B

[3- (3,5-Difluorobenzyloxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 203A was reacted with the product of example 36E by the method described in example 36I, using the product of example 203A instead of the product of example 36H to give a crude material that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (26 mg, 67%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.26 (m, 1H), 5.19 (s, 2H), 6, 95 (m, 1H), 7.20 (m, 3H), 7.38 (m, 2H), 7.54 (s, 1H), 7.82 (d, J = 8.46 Hz, 1H), 8.86 (s, 1H), 9.02 (d, J = 8.46 Hz, 1H), 10.89 (s, 1H);

MS (ESI +) m / z 407 (M + H) +.

Example 204

[3- (3,5-Difluorobenzyloxy) phenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of Example 203A was reacted with the product of Example 10B by the method described in Example 10F using the product of Example 203A instead of the product of Example 10E to give a crude material which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3H), 5.19 (s, 2H), 6.95 (m, 1H), 7.21 (m, 3H), 7.38 (m, 2H), 7.55 (s, 1H), 7.75 (d, J = 8.46 Hz, 1H), 8.87 (s, 1H), 8.98 (d, J = 8.46 Hz, 1H); 10.90 (s, 1H);

MS (ESI +) m / z 379 (M + H) +.

Example 205

[3- (3,5-Difluorobenzyloxy) phenyl] pyrido [2,3-d] pyrimidin-4-ylamine

The product of Example 203A was reacted with the product of Example 57A by the method described in Example 57E, using the product of Example 203A instead of the product of Example 57D, to obtain the crude title compound which was purified by HPLC with TFA to give the title compound as the trifluoroacetic salt acids.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.19 (s, 2H), 6.94 (m, 1H), 7.21 (m, 3H), 7.39 (d, J = 5 , 15 Hz, 2H), 7.58 (s, 1H), 7.81 (dd, J = 8.09, 4.41 Hz, 1H), 8.87 (s, 1H), 9.10 (m , 2H), 10.79 (s, 1H);

MS (ESI +) m / z 365 (M + H) +.

Example 206

4- [3- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

Example 206A

4- (3-aminophenoxymethyl) benzonitrile

3-Nitrophenol was reacted with 4-bromomethylbenzonitrile in accordance with the method described in example 199A using 4-bromomethylbenzonitrile instead of 1-bromomethyl-3-fluorobenzene, then reduced in accordance with the method described in example 199B to obtain the title compound .

Example 206B

4- [3- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of Example 206A was reacted with the product of Example 10B by the method described in Example 10F using the product of Example 206A instead of the product of Example 10E to give a crude material which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H), 5.27 (s, 2H), 6.92 (m, 1H), 7.38 (m, 2H), 7.59 (s, 1H), 7.68 (m, 3H), 7.89 (d, J = 8.46 Hz, 2H), 8.83 (s, 1H), 8.95 (d, J = 8.82 Hz, 1H); 10.64 (s, 1H);

MS (ESI +) m / z 368 (M + H) +.

Example 207

4- [3- (Pyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of example 206A was reacted with the product of example 57A by the method described in example 57E, using the product of example 206A instead of the product of example 57D, to obtain the crude title compound that was purified by HPLC with TFA to give the title compound as a trifluoroacetate salt acids.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.27 (s, 2H), 6.93 (m, 1H), 7.38 (m, 2H), 7.60 (s, 1H), 7.67 (d, J = 8.46 Hz, 2H), 7.80 (dd, J = 8.46, 4.41 Hz, 1H), 7.90 (d, J = 8.46 Hz, 2H ), 8.86 (s, 1H), 9.07 (dd, J = 8.46, 1.65 Hz, 1H), 9.13 (dd, J = 4.41, 1.65 Hz, 1H) 10.72 (s, 1H);

MS (ESI +) m / z 354 (M + H) +.

Example 208

3- [3- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

Example 208A

3- (3-aminophenoxymethyl) benzonitrile

3-Nitrophenol was reacted with 3-bromomethylbenzonitrile according to the method described in example 199A using 3-bromomethylbenzonitrile instead of 1-bromomethyl-3-fluorobenzene, then reduced according to the method described in example 199B to give the title compound .

Example 208B

3- [3- (7-Isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of example 208A was reacted with the product of example 36E by the method described in example 36I, using the product of example 208A instead of the product of example 36H to give a crude material that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (22 mg, 56%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 3.26 (m, 1H), 5.22 (s, 2H), 6, 93 (m, 1H), 7.38 (m, 2H), 7.62 (m, 2H), 7.77 (d, J = 8.46 Hz, 1H), 7.84 (m, 2H), 7.95 (s, 1H), 8.83 (s, 1H), 8.99 (d, J = 8.46 Hz, 1H), 10.67 (s, 1H);

MS (ESI +) m / z 396 (M + H) +.

Example 209

2- [3- (Pyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

Example 209A

2- (3-aminophenoxymethyl) benzonitrile

3-Nitrophenol was reacted with 2-bromomethylbenzonitrile in accordance with the method described in example 199A using 2-bromomethylbenzonitrile instead of 1-bromomethyl-3-fluorobenzene, then reduced according to the method described in example 199B to obtain the title compound.

Example 209B

2- [3- (Pyrido [2,3-d] pyrimidin-4-ylamino) phenoxymethyl] benzonitrile

The product of example 209A was reacted with the product of example 36E by the method described in example 36I, using the product of example 209A instead of the product of example 36H, to obtain a crude material which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.30 (s, 2H), 7.02 (m, 1H), 7.42 (m, 2H), 7.59 (m, 2H), 7.78 (m, 2H), 7.85 (dd, J = 8.46, 4.41 Hz, 1H), 7.94 (d, J = 7.72 Hz, 1H), 8.92 (s , 1H); 9.14 (m, 2H); 11.03 (s, 1H);

MS (ESI +) m / z 354 (M + H) +.

Example 210

(3-Benzyloxyphenyl) - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 210A

3-benzyloxyphenylamine

3-Nitrophenol was reacted with bromomethylbenzene in accordance with the method described in Example 199A using bromomethylbenzene instead of 1-bromomethyl-3-fluorobenzene, then reduced in accordance with the method described in Example 199B to obtain the title compound.

Example 210B

(3-Benzyloxyphenyl) - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 210A was reacted with the product of example 36E by the method described in example 36I, using the product of example 210A instead of the product of example 36H to give a crude material that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (5 mg, 10%).

¹ H NMR (500 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.84 Hz, 6H), 3.25 (qt, J = 6.84 Hz, 1H), 5, 13 (s, 2H), 6.89-6.94 (m, J = 2.20, 2.20 Hz, 1H), 7.33-7.41 (m, 5H), 7.45-7, 48 (m, J = 7.32 Hz, 2H), 7.54-7.58 (m, J = 2.44, 2.44 Hz, 1H), 7.76 (d, J = 8.30 Hz , 1H), 8.84 (s, 1H), 9.02 (d, J = 8.30 Hz, 1H);

MS ESI + m / z 371 (M + H) +, ESI m / z 369 (M-H) -.

Example 211

[3- (3-Bromobenzyloxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 211A

3- (3-Bromobenzyloxy) phenylamine

3-Nitrophenol was reacted with 1-bromo-3-bromomethylbenzene in accordance with the method described in example 199A, using 1-bromo-3-bromomethylbenzene instead of 1-bromomethyl-3-fluorobenzene, then restored in accordance with the method described in example 199B to give the title compound.

Example 211B

[3- (3-Bromobenzyloxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 211A was reacted with the product of example 36E by the method described in example 36I, using the product of example 211A instead of the product of example 36H, to obtain a crude substance which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (1 mg, 1%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 5.16 (s, 2H), 6.94 (td, J = 4.50 , 2.39 Hz, 1H), 7.39 (td, J = 7.63, 3.86 Hz, 3H), 7.46-7.51 (m, 1H), 7.53-7.57 ( m, 2H), 7.69 (s, 1H), 7.80 (d, J = 8.46 Hz, 1H), 8.86 (s, 1H), 9.01 (d, J = 8.46 Hz, 1H); 10.84 (s, 1H);

MS ESI + m / z 451 (M + H) +, ESI m / z 449 (M-H) -.

Example 212

(7-Isopropylpyrido [2,3-d] pyrimidin-4-yl) - [3- (3-methoxybenzyloxy) phenyl] amine

Example 212A

3- (3-Methoxybenzyloxy) phenylamine

3-Nitrophenol was reacted with 1-bromomethyl-3-methoxybenzene in accordance with the method described in example 199A, using 1-bromomethyl-3-methoxybenzene instead of 1-bromomethyl-3-fluorobenzene, then restored in accordance with the method described in example 199B to give the title compound.

Example 212B

(7-Isopropylpyrido [2,3-d] pyrimidin-4-yl) - [3- (3-methoxybenzyloxy) phenyl] amine

The product of example 212A was reacted with the product of example 36E by the method described in example 36I, using the product of example 212A instead of the product of example 36H to give a crude material that was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid (8 mg, 9%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.76 (s, 3H), 5.12 (s, 2H), 6, 87-6.98 (m, 2H), 7.00-7.06 (m, 2H), 7.36 (dt, J = 19.85, 8.09 Hz, 3H), 7.52 (s, 1H), 7.82 (d, J = 8.82 Hz, 1H), 8.88 (s, 1H), 9.02 (d, J = 8.46 Hz, 1H), 10.94 (s, 1H);

MS ESI + m / z 401 (M + H) +, ESI m / z 399 (M-H) -.

Example 213

[3- (4-Bromobenzyloxy) phenyl] pyrido [2,3-d] pyrimidin-4-ylamine

Example 213A

3- (4-Bromobenzyloxy) phenylamine

3-Nitrophenol was reacted with 1-bromo-4-bromomethylbenzene in accordance with the method described in example 199A, using 1-bromo-4-bromomethylbenzene instead of 1-bromomethyl-3-fluorobenzene, then restored in accordance with the method described in example 199B to give the title compound.

Example 213B

[3- (4-Bromobenzyloxy) phenyl] pyrido [2,3-d] pyrimidin-4-ylamine

The product of example 213A was reacted with the product of example 36E by the method described in example 36I, using the product of example 213A instead of the product of example 36H, to obtain a crude substance which was purified by HPLC with TFA to give the title compound as a salt trifluoroacetic acid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 5.13 (s, 2H), 6.82 (dd, J = 8.09, 1.84 Hz, 1H), 7.32 (t, J = 8.09 Hz, 1H), 7.45 (d, J = 8.46 Hz, 3H), 7.61 (d, J = 8.46 Hz, 2H), 7.64-7.71 (m , 2H), 9.01 (dd, J = 8.46, 1.84 Hz, 1H), 9.08 (dd, J = 4.23, 1.65 Hz, 1H), 10.01 (s, 1H);

MS ESI + m / z 407 (M + H) +, ESI + m / z 429 (M + Na) +, ESI m / z 405 (M-H) -.

Example 214

[2- (4-Aminophenylsulfanyl) -5-benzyloxyphenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 214A

4-benzyloxy-1-chloro-2-nitrobenzene

A solution of 4-chloro-3-nitrophenol (2.0 g, 11.5 mmol), 1-bromomethylbenzene (2.01 g, 11.5 mmol), potassium carbonate (1.65 g, 12.0 mmol) and iodide tetrabutylammonium (0.005 g, 0.0135 mmol) in N, N- dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Then, ice-water (10 ml) was added to the solution, and the obtained solid was collected by filtration and dried in a vacuum oven to obtain the title compound (3.0 g, 99%).

Example 214B

4- (4-Benzyloxy-2-nitrophenylsulfanyl) phenylamine

A solution of the compound obtained in example 214A (1.0 g, 3.80 mmol), 4-aminothiophenol (0.5 g, 4.00 mmol), cesium carbonate (1.3 g, 4 mmol) in dimethylformamide (10 ml ) were heated at 40ºC for 16 hours. Then, 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 the solvent was removed in vacuo to give the title compound as an orange oil (1.1 g, 83%).

Example 214C

[4- (4-Benzyloxy-2-nitrophenylsulfanyl) phenyl] carbamic acid tert-butyl ester

A solution of the compound of Example 214B (1.1 g, 3.1 mmol) was treated with Boc anhydride (0.9 g, 4.00 mmol) in dioxane (15 ml) and heated under reflux for hours. The next day, the solvent was removed in vacuo to give the title compound as a pale brown oil (1.4 g, 100%).

Example 214D

[4- (2-amino-4-benzyloxyphenylsulfanyl) phenyl] carbamic acid tert-butyl ester

A solution of the product of example 214C (1.4 g, 3.09 mmol), iron powder (0.70 g, 12 mmol) and ammonium chloride (0.18 g, 3.41 mmol) in a solution of methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) were heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (1.1 g, 90%).

Example 214E

[2- (4-Aminophenylsulfanyl) -5-benzyloxyphenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of example 10B (67 mg, 0.355 mmol) and the product of example 214D (150 mg, 0.355 mmol) in acetic acid (1 ml) were mixed in an oil bath preheated to 130 ° C for 10 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the resulting residue was treated with 50% TFA in CH ₂ Cl ₂ (2 ml) for 30 minutes at room temperature. The solvent was evaporated in vacuo and the obtained residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (25 mg, 12%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.76 (s, 3H), 5.10 (s, 2H), 6.46-6.61 (m, 2H), 6.97-7 12 (m, 3H), 7.10-7.22 (m, 2H), 7.29-7.51 (m, 6H), 7.85 (d, J = 8.46 Hz, 1H), 8.80-8.90 (m, 2H), 8.95 (d, J = 8.46 Hz, 1H), 11.70 (s, 1H).

Example 215

[2- (4-Aminophenylsulfanyl) -5-benzyloxyphenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of example 36E (80 mg, 0.368 mmol) and the product of example 214D (160 mg, 0.368 mmol) in acetic acid (2 ml) was stirred in an oil bath preheated to 130ºC for 10 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the residue was treated with 50% TFA in CH ₂ Cl ₂ (2 ml) for 30 minutes at room temperature. The solvent was evaporated in vacuo and the obtained residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (22 mg, 10%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.62 Hz, 6H), 3.19-3.38 (m, 1H), 5.10 (s, 2H ), 6.41-6.61 (m, 2H), 6.92-7.18 (m, 5H), 7.27-7.52 (m, 6H), 7.91 (d, J = 8 46 Hz, 1H), 8.84 (s, 1H), 9.01 (s, 1H), 11.64 (s, 2H).

Example 216

[2- (4-Aminophenylsulfanyl) -5- (1-phenylethoxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 216A

1-Chloro-2-nitro-4- (1-phenylethoxy) benzene

A solution of 4-chloro-3-nitrophenol (2.0 g, 11.5 mmol), 1-bromoethylbenzene (3.2 g, 17.3 mmol), sodium carbonate (1.80 g, 17.0 mmol) in acetone (20 ml) was heated under reflux for 18 hours. The reaction mixture was cooled, the solids were filtered off, and the filtrate was concentrated to obtain a viscous syrup under vacuum. The residue was dissolved in ether (80 ml) and washed with water (20 ml) and a solution of 30% KOH (2 × 20 ml) and the solvent was concentrated in vacuo to give the title compound as an oily residue (3.01 g, 94%) .

Example 216B

4- [2-Nitro-4- (1-phenylethoxy) phenylsulfanyl] phenylamine

A solution of the compound of example 216A (1.86 g, 6.95 mmol), 4-aminothiophenol (0.88 g, 7.00 mmol), cesium carbonate (2.3 g, 7.00 mmol) in dimethylformamide (10 ml ) were heated at 40ºC for 16 hours. Then, 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 and dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo to give the title compound as an orange oil (2.35 g, 92%).

Example 216C

{4- [2-nitro-4- (1-phenylethoxy) phenylsulfanyl] phenyl} carbamic acid tert-butyl ester

A solution of the compound of Example 216B (2.35 g, 6.4 mmol) was treated with Boc anhydride (1.7 g, 7.70 mmol) in dioxane (20 ml) and heated under reflux for 18 hours. The next day, the solvent was removed in vacuo to give the title compound as a light brown oil (1.78 g, 60%).

Example 216D

{4- [2-amino-4- (1-phenylethoxy) phenylsulfanyl] phenyl} carbamic acid tert-butyl ester

A solution of the product of example 216C (1.78 g, 3.80 mmol), iron powder (0.85 g, 15.3 mmol) and ammonium chloride (0.25 g, 4.57 mmol) in methanol solution (10 ml ), tetrahydrofuran (10 ml) and water (5 ml) were heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.53 g, 32%).

Example 216E

[2- (4-Aminophenylsulfanyl) -5- (1-phenylethoxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of example 36E (57 mg, 0.265 mmol) and the product of example 216D (116 mg, 0.265 mmol) in acetic acid (2 ml) were mixed in an oil bath preheated to 130ºC for 10 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the residue was treated with 50% TFA in CH ₂ Cl ₂ (2 ml) for 30 minutes at room temperature. The solvent was evaporated in vacuo and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (18 mg, 11%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (m, 3H), 1.31 (d, 6H), 3.18-3.34 (m, 1H), 5.48 (s , 1H), 6.50 (s, 1H), 6.86-7.08 (m, 3H), 7.10 (d, J = 5.15 Hz, 2H), 7.22-7.50 ( m, 5H), 7.86 (s, 1H), 8.37 (s, 1H), 8.48 (s, 1H), 8.78 (s, 1H), 8.94 (s, 1H), 11.19 (s, 1H).

Example 217

[2- (2-amino-6-chloropyrimidin-4-ylsulfanyl) -5-benzyloxyphenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 217A

4-benzyloxy-2-nitrophenylamine

A solution containing 4-amino-3-nitrophenol (1.09 g, 7.07 mmol), benzyl bromide (1.28 g, 7.5 mmol and cesium carbonate (2.43 g, 7.5 mmol) was stirred for 4 days at room temperature After completion of the reaction, the reaction mixture was poured into ice water (500 ml), stirred for 1 hour and the resulting solid was filtered and dried under vacuum to obtain the title compound (1.1 g, 64%) .

Example 217B

4-Benzyloxy-2-nitrobenzenediazonium tetrafluoroborate

The product of Example 217A (0.5 g, 2.05 mmol) was dissolved in THF (10 ml) and added dropwise to a cooled (-20 ° C) solution containing boron trifluoride etherate (1.1 ml, 8.20 mmol) and tert-butyl nitrite (0.6 ml, 4.92 mmol) for 5 minutes. The resulting mixture was stirred for 10 minutes at -20ºC, then 2 hours at 10ºC. Then the reaction mixture was poured into hexane (100 ml) and the solid was filtered, washed with ether and dried under vacuum to obtain the title compound (0.61 g, 87%).

Example 217C

4- (4-Benzyloxy-2-nitrophenylsulfanyl) -6-chloropyrimidin-2-ylamine

To a solution containing potassium thioacetate (0.04 g, 0.350 mmol) in dimethyl sulfoxide (1 ml) was added dropwise a solution of the product of Example 217B (0.1 g, 0.290 mmol) in dimethyl sulfoxide (1 ml). The reaction mixture immediately began to sparge. After bubbling stopped, the mixture was stirred for 90 minutes at room temperature. The resulting dark green mixture was then treated with an aqueous 3M potassium hydroxide solution (0.1 ml) and stirred for an additional 80 minutes, after which solid 4,6-dichloro-2-aminopyrimidine was added and the mixture was stirred for another 60 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (20 ml), a solution of 10% sodium bicarbonate and 10% sodium chloride, dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the title compound as a brown solid (0.1 g, 88%).

Example 217D

4- (2-amino-4-benzyloxyphenylsulfanyl) -6-chloropyrimidin-2-ylamine

A solution of the product of example 217C (0.1 g, 0.257 mmol), iron powder (0.058 g, 1.03 mmol) and ammonium chloride (0.017 g, 0.310 mmol) in a solution of methanol (5 ml), tetrahydrofuran (5 ml) and water (2 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.04 g, 43%).

Example 217E

[2- (2-amino-6-chloropyrimidin-4-ylsulfanyl) -5-benzyloxyphenyl] - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

A solution of the product of example 10B (21 mg, 0.112 mmol) and the product of example 217D (40 mg, 0.112 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 130ºC for 10 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the resulting residue was treated with 50% TFA in CH ₂ Cl ₂ (2 ml) for 30 minutes at room temperature. The solvent was evaporated in vacuo and the obtained residue was purified by TFA HPLC to give the title compound as the trifluoroacetic acid salt (5 mg, 7%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 2.66 (s, J = 6.25 Hz, 3H), 5.21 (s, 2H), 6.53 (s, 1H), 7, 07 (s, 1H), 7.14 (dd, J = 8.64, 2.76 Hz, 1H), 7.25-7.61 (m, 6H), 7.62-7.72 (m, 1H), 8.52 (s, 1H), 8.66 (d, J = 8.82 Hz, 1H), 8.71 (s, 1H), 8.88 (d, J = 8.46 Hz, 1H), 10.05 (s, 1H).

Example 218

4- [4- (3-Bromobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

Example 218A

4- [4- (3-Bromobenzyloxy) -2-nitrophenoxy] phenol

A solution of hydroquinone (276.4 mg, 2.510 mmol) in anhydrous 3.64 mmol) and heated in a nitrogen atmosphere at 120 ° C for 30 minutes. A solution of 4- (3-bromobenzyloxy) -1-chloro-2-nitrobenzene (as in Example 15A) (774 mg, 2.259 mmol) in dimethyl sulfoxide (4 ml) was added dropwise using an additional funnel over 30 minutes at 120 ° C, then the mixture stirred at this temperature for 1 hour. The reaction mixture was cooled in an ice bath, then poured into ice water (20 ml) and the pH was adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl ether (3 × 100 ml), the combined ether extracts were washed with water (3 × 100 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator in vacuo. Purification of the residue by flash chromatography on silica gel using a 3% ethyl acetate / methylene chloride mixture as eluent afforded the title compound as a dark yellow solid (386 mg, 0.927 mmol, 41%).

Example 218B

4- [2-amino-4- (3-bromobenzyloxy) phenoxy] phenol

A mixture of the product of example 218A (384.6 mg, 0.924 mmol), iron powder (317.4 mg, 5.683 mmol) and ammonium chloride (323.7 mg, 6.052 mmol) in water (3 ml) and ethanol (6 ml) heated at 70 ° C in nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature and filtered under vacuum, the residue was washed with methanol. The filtrate was concentrated in vacuo and azeotropically distilled off with toluene (50 ml). The residue was purified by flash chromatography on silica gel using a gradient of 7% to 10% ethyl acetate / methylene chloride as the eluent to give the title compound as a beige solid (272 mg, 0.704 mmol, 76%).

Example 218C

4- [4- (3-Bromobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

A solution of the product of example 36E (25 mg, 0.116 mmol) and the product of example 218B (44.6 mg, 0.116 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 140 ° C for 1 hour. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator and co-evaporated with methylene chloride / hexane (4 ×). The residue was dried under high vacuum overnight, then purified by flash chromatography on silica gel using a 3% methanol / methylene chloride mixture as eluent to give the title compound as a light yellow solid (34 mg, 0.0613 mmol, 53%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (d, J = 6.62 Hz, 6H), 3.09-3.28 (m, 1H), 5.12 (s, 2H ), 6.62 (d, J = 9.20 Hz, 2H), 6.76 (d, J = 8.82 Hz, 2H), 6.82-6.97 (m, 2H), 7.32 -7.36 (m, 1H), 7.39 (d, J = 7.72 Hz, 1H), 7.45-7.58 (m, 3H), 7.68 (s, 1H), 8, 57 (s, 1H), 8.72 (d, J = 8.82 Hz, 1H), 9.14 (s, 1H), 9.75 (s, 1H);

MS (ESI +) m / z 557/559 (M + H) +.

Example 219

4- [4- (4-Bromobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

Example 219A

4- [2-amino-4- (4-bromobenzyloxy) phenoxy] phenol

4- (4-Bromobenzyloxy) -1-chloro-2-nitrobenzene (according to Example 16A) was reacted with hydroquinone in accordance with the method described in Example 39A, and reduced according to the method described in Example 39B to obtain product title.

Example 219B

4- [4- (4-Bromobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

The product of example 219A was reacted with the product of example 36E in accordance with the method described in example 39C, using the product of example 219A instead of the product of example 218B to give the title compound after chromatography on silica gel (38 mg, 59%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (d, J = 6.99 Hz, 6H), 3.10-3.27 (m, 1H), 5.09 (s, 2H ), 6.56-6.66 (m, 2H), 6.70-6.79 (m, 2H), 6.81-6.97 (m, 2H), 7.32 (d, J = 2 , 57 Hz, 1H), 7.43 (d, J = 8.46 Hz, 2H), 7.53 (d, J = 8.46 Hz, 1H), 7.60 (d, J = 8.46 Hz, 2H), 8.57 (s, 1H), 8.72 (d, J = 8.46 Hz, 1H), 9.14 (s, 1H), 9.74 (s, 1H);

MS (ESI +) m / z 557/559 (M + H) +.

Example 220

4- [4-Benzyloxy-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

Example 220A

4- (2-amino-4-benzyloxyphenoxy) phenol

4-Benzyloxy-1-chloro-2-nitrobenzene (as in Example 27A) was reacted with hydroquinone in accordance with the method described in Example 39A, and reduced in accordance with the method described in Example 39B to obtain the title product.

Example 220B

4- [4-Benzyloxy-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenoxy] phenol

The product of example 220A was reacted with the product of example 36E in accordance with the method described in example 39C, using the product of example 220A instead of the product of example 218B to give the title compound after chromatography on silica gel (58 mg, 65%) .

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (d, J = 6.99 Hz, 6H), 3.08-3.27 (m, 1H), 5.10 (s, 2H ), 6.62 (d, J = 9.2 Hz, 2H), 6.74 (d, J = 9.2 Hz, 2H), 6.81-6.98 (m, 2H), 7.26 -7.61 (m, 7H), 8.57 (s, 1H), 8.72 (d, J = 8.46 Hz, 1H), 9.13 (s, 1H), 9.75 (s, 1H);

MS (DCI / NH ₃ ) m / z 479 (M + H) +.

Example 221

4- [4-Benzyloxy-2- (7-ethylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 27A was reacted with the product of Example 145A by the method described in Example 10F, using the product of Example 27A instead of the product of Example 10E and using the product of Example 145A instead of the product of Example 10B to give the title product.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (t, J = 7.72 Hz, 3H), 2.95 (q, J = 7.72 Hz, 2H), 5.11 (s, 2H), 6.65 (d, J = 8.82 Hz, 2H), 6.91-7.05 (m, 1H), 7.10 (d, J = 8.46 Hz, 2H) 7.32-7.50 (m, 6H), 8.12 (d, J = 6.99 Hz, 1H), 8.66-8.77 (m, 1H), 9.04 (d, J = 8.82 Hz, 1H), 9.63 (s, 1H), 10.28 (s, 1H);

MS (APCI) m / z 481 (M + H) +.

Example 222

4- [4-Benzyloxy-2- (7-cyclohexylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 27A was reacted with the product of Example 135A by the method described in Example 10F, using the product of Example 27A instead of the product of Example 10E and using the product of Example 135A instead of the product of Example 10B to give the title product.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.23-1.51 (m, 4H), 1.53-1.79 (m, 4H), 1.80-2.00 (m, 2H), 2.77-3.02 (m, 1H), 5.10 (s, 2H), 6.67 (d, J = 8.46 Hz, 2H), 6.88-7.01 (m , 1H), 7.11 (d, J = 8.82 Hz, 2H), 7.22-7.31 (m, 1H), 7.32-7.49 (m, 6H), 7.56 ( d, J = 7.72 Hz, 1H), 8.55 (s, 1H), 8.73 (d, J = 8.09 Hz, 1H), 9.94 (s, 1H);

MS (APCI) m / z 535 (M + H) +.

Example 223

4- [4-Benzyloxy-2- (7-sec-butylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of Example 27A was reacted with the product of Example 140A by the method described in Example 10F, using the product of Example 27A instead of the product of Example 10E and using the product of Example 140A instead of the product of Example 10B to give the title product.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.82 (t, J = 7.35 Hz, 3H), 1.30 (d, J = 6.62 Hz, 3H), 1.58- 1.73 (m, 1H), 1.75-1.87 (m, 1H), 2.89-3.08 (m, 1H), 5.11 (s, 2H), 6.67 (d, J = 8.82 Hz, 2H), 6.85-7.03 (m, 1H), 7.11 (d, J = 8.46 Hz, 2H), 7.30-7.50 (m, 6H ), 7.56 (d, J = 8.82 Hz, 1H), 8.56 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 9.64 (s, 1H ), 9.95 (s, 1H);

MS (APCI) m / z

Example 224

4- [4- (2-Chlorothiazol-5-ylmethoxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 224A

4- [2-amino-4- (2-chlorothiazol-5-ylmethoxy) phenylsulfanyl] phenol

The title compound was prepared by the method described in Example 16A using benzyl bromide instead of 2-chloro-5-bromomethylthiazole to give the title compound (0.38 g, 64%).

Example 224b

4- [4- (2-Chlorothiazol-5-ylmethoxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 36E (40.4 mg, 0.187 mmol) and the product of example 224A (68 mg, 0.187 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 130 ° C for 10 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the resulting residue was purified by TFA HPLC to give the title compound as trifluoroacetic acid salt (31 mg, 30%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.17-3.36 (m, 1H), 5.35 (s, 2H), 6.55 (d, J = 7.72 Hz, 1H), 6.58-6.74 (m, 2H), 7.00-7.30 (m, 4H), 7.68-7 95 (m, 2H), 8.76 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 9.73 (s, 1H), 11.34 (s, 1H) ;

MS (ESI +) m / z 536 (M + H) + (ESI-) m / z 534 (M-H) -.

Example 225

4- [4- (6-Chloropyridin-2-ylmethoxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 225a

4- [2-amino-4- (6-chloropyridin-2-ylmethoxy) phenylsulfanyl] phenol

The title compound was prepared by the method described in Example 16A, replacing benzyl bromide with 2-chloro-5-bromomethylpyridine to give the title compound (0.63 g, 73%).

Example 225b

4- [4- (6-Chloropyridin-2-ylmethoxy) -2- (7-methylpyrido [2,3- d ] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 10B (37 mg, 0.197 mmol) and the product of example 225a (70.7 mg, 0.197 mmol) in acetic acid (2 ml) was stirred in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (20 mg, 20%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.70 (s, 3H), 5.18 (s, 2H), 6.65 (d, J = 8.82 Hz, 2H), 7 02 (d, J = 8.09 Hz, 1H), 7.11 (d, J = 8.82 Hz, 2H), 7.19 (d, J = 8.82 Hz, 1H), 7.25 (s, 1H), 7.52 (dd, J = 13.60, 7.72 Hz, 2H), 7.67 (d, J = 8.09 Hz, 1H), 7.93 (t, J = 7.72 Hz, 2H), 8.65 (s, 1H), 8.80 (d, J = 8.09 Hz, 1H), 9.68 (s, 1H);

MS (ESI +) m / z 502 (M + H) + (ESI-) m / z 500 (M-H) -.

Example 226

4- [4- (6-Chloropyridin-2-ylmethoxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 36E (36 mg, 0.168 mmol) and the product of example 225a (60 mg, 0.168 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 130 ° C for 10 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the resulting residue was purified by TFA HPLC to give the title compound as trifluoroacetic acid salt (31 mg, 30%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.16 (d, J = 6.99 Hz, 3H), 1.36 (d, J = 6.62 Hz, 3H), 3.20 -3.40 (m, 1H), 5.18 (s, 1H), 6.55 (d, J = 7.72 Hz, 1H), 6.64 (d, J = 8.82 Hz, 2H) 6.77 (s, 1H), 7.04-7.18 (m, 2H), 7.15-7.29 (m, 2H), 7.52 (dd, J = 10.48, 7, 91 Hz, 2H), 7.77 (d, J = 7.72 Hz, 1H), 7.93 (t, J = 7.72 Hz, 2H), 8.82 (s, 1H), 8.97 (s, 1H); 9.72 (s, 1H); 11.66 (s, 1H);

MS (ESI +) m / z 530 (M + H) + (ESI-) m / z 528 (M-H) -.

Example 227

4- [2- (7-Tert-butylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-fluorobenzyloxy) phenylsulfanyl] phenol

The product of example 127A (110 mg, 0.478 mmol) was reacted with the product of example 28A (164 mg, 0.48 mmol) in 1 ml of glacial acetic acid, heated at 120 ° C for 13 minutes. It was cooled to room temperature and acetic acid was removed in vacuo. The crude product was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (134 mg, 44%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.43 (s, 9H), 5.14 (s, 2H), 6.65 (d, J = 8.45 Hz, 2H), 7 , 17 (m, 4H), 7.29 (d, J = 8.45 Hz, 2H), 7.44 (d, J = 8.45 Hz, 2H), 7.99 (d, J = 7, 80 Hz, 1H), 8.72 (s, 1H), 8.93 (d, J = 8.45 Hz, 1H), 9.68 (s, 1H), 10.90 (br s, 1H) ;

MS (ESI +) m / z, 527 (M + H-TFA) +; (ESI-) m / z, 525 (M-H-TFA) -.

Example 228

4- [4- [1- (3-Bromophenyl) ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 228a

1- (1-bromoethyl) -4-fluorobenzene

To a solution of 1- (3-bromophenyl) ethanol (7.0 g, 34.0 mmol) in dichloromethane (40 ml) was added dropwise phosphorus tribromide (77 g, 34.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (7.8 g, 80%).

Example 228b

4- [1- (3-Bromophenyl) ethoxy] -1-chloro-2-nitrobenzene

To the product of Example 228a (7.8 g, 30 mmol) in DMF (50 ml) was added 4-chloro-3-nitrophenol (5.14 g, 30.0 mmol) and K ₂ CO ₃ (8.18 g, 60 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting (hexane / ethyl acetate 90:10) to obtain the title compound (7.0 g, 66%).

Example 228c

4- {4- [1- (3-Bromophenyl) ethoxy] -2-nitrophenylsulfanyl} phenol

To the product of Example 228b (5.0 g, 14.0 mmol) in DMF (50 ml) was added 4-mercaptophenol (1.7 g, 14.0 mmol) and K ₂ CO ₃ (3.8 g, 28 mmol) . The mixture was heated at 80 ° C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture (hexane / ethyl acetate / methanol 75: 15: 5) to obtain the title compound (5.2 g, 83%).

Example 228d

4- {2-amino-4- [1- (3-bromophenyl) ethoxy] phenylsulfanyl} phenol

The product of Example 228c (5.4 g, 12.2 mmol) was reacted with Fe and NH ₄ Cl as described in Example 10E to give the title compound (3.6 g, 76%).

Example 228e

4- [4- [1- (3-Bromophenyl) ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 57A (125 mg, 0.72 mmol) was reacted with the product of example 228d (298 mg, 0.72 mmol) in acetic acid (10 ml) at 125 ° C in a sealed vessel for 5 minutes to obtain the crude specified in the title compound which was purified by TFA HPLC to give the product as trifluoroacetic acid (120 mg, 31%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.54 (d, J = 6.25 Hz, 3H), 5.52 (q, J = 6.25 Hz, 1H), 6, 66 (d, J = 8.82 Hz, 2H), 6.85 (s, 1H), 7.07-7.12 (m, 3H), 7.19 (s, 1H), 7.32 (t , J = 7.72 Hz, 1H), 7.39-7.49 (m, 2H), 7.61 (s, 2H), 8.57 (s, 1H), 8.80 (s, 1H) 9.06 (s, 1H); 9.65 (s, 1H);

MS (ESI-) m / z 545 (M-H) -.

Example 229

4- [4- [1- (3-Bromophenyl) ethoxy] -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 10B (110 mg, 0.58 mmol) was reacted with the product of example 228d (243 mg, 0.58 mmol) in acetic acid (10 ml) at 125 ° C in a sealed vessel for 5 minutes to obtain the crude specified in the title compound which was purified by TFA HPLC to give the product as trifluoroacetic acid (100 mg, 30%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.33 (d, J = 6.25 Hz, 3H), 2.53 (s, 3H), 5.31 (q, J = 6 , 43 Hz, 1H), 6.44 (d, J = 8.82 Hz, 2H), 6.68 (dd, J = 8.82, 2.57 Hz, 1H), 6.85-6.92 (m, 3H), 6.95 (d, J = 2.57 Hz, 1H), 7.11 (t, J = 7.72 Hz, 1H), 7.19-7.27 (m, 2H) 7.40 (s, 1H), 7.44 (d, J = 8.46 Hz, 1H), 8.44 (s, 1H), 8.56 (d, J = 8.46 Hz, 1H) ; MS (ESI +) m / z 560 (M + H) +.

Example 230

4- [4- [1- (3-Bromophenyl) ethoxy] -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 36E (130 mg, 0.60 mmol) was reacted with the product of example 228d (250 mg, 0.60 mmol) in acetic acid (10 ml) at 125 ° C in a sealed vessel for 5 minutes to obtain the crude specified in the title of the compound, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (140 mg, 39%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 1.54 (d, J = 6.25 Hz, 3H), 3.26 (q, 1H), 5.52 (q, J = 6.62 Hz, 1H), 6.65 (d, J = 8.46 Hz, 2H), 6.92 (dd, J = 8, 82, 2.94 Hz, 1H), 7.10 (m, 4H), 7.32 (t, J = 7.72 Hz, 1H), 7.39-7.50 (m, 2H), 7, 60 (s, 1H), 7.79 (d, J = 8.46 Hz, 1H), 8.70 (s, 1H), 8.86 (d, J = 8.46 Hz, 1H), 9, 72 (s, 1H); MS (ESI +) m / z 588 (M + H) +.

Example 231

4- [4- (3-Bromobenzyloxy) -2- (7-tert-butylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 127A (147 mg, 0.63 mmol) and the product of example 15A (256 mg, 0.63 mmol) were heated in 2 ml of glacial acetic acid at 120 ° C for 15 minutes. It was cooled to room temperature and acetic acid was removed in vacuo. The crude product was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (45 mg, 10%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.43 (s, 9H), 5.13 9 (s, 2H), 6.66 (d, J = 8.83 Hz, 2H), 7.01 (d, J = 6.62 Hz, 1H), 7.11 (d, J = 8.83 Hz, 2H), 7.19 (m, 1H), 7.37 (m, 1H), 7.46 (d, J = 7.72 Hz, 1H), 7.54 (d, J = 6.62 Hz, 1H), 7.66 (s, 1H), 7.95 (d, J = 8 , 09 Hz, 1H), 8.69 (s, 1H), 8.88 (d, J = 8.83 Hz, 1H), 9.68 (s, 1H);

MS (ESI +) m / z 587, 589 (M + H-TFA) +; (ESI-) m / z 585, 587 (M-H-TFA) -.

Example 232

4- [4- (3-Bromophenoxymethyl) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 232A

4- [2-amino-4- (3-bromophenoxymethyl) phenylsulfanyl] phenol

A solution of 4- [4- (3-bromophenoxymethyl) -2-nitrophenylsulfanyl] phenol (325 mg, 0.752 mmol), sawdust (210 mg, 3.76 mmol) and ammonium chloride (60 mg, 1.13 mmol) in tetrahydrofuran (5 ml), water (1.5 ml) and ethanol (5 ml) were heated under reflux for 2.5 hours. After cooling to room temperature, the solution was filtered through a pad of celite, which was washed with methanol. The filtrate was then concentrated in vacuo, then dissolved in water (20 ml) and extracted with ethyl acetate (2 × 20 ml). The organic extracts were dried and concentrated in vacuo to give the title compound as a pale yellow solid (240 mg, 79%).

Example 232B

4- [4- (3-Bromophenoxymethyl) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 232A (85 mg, 0.211 mmol) and the product of example 36E (46 mg, 0.211 mmol) in acetic acid (3 ml) was heated at 130 ° C for 15 minutes. Then, the solution was allowed to cool to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (63 mg, 43%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.35 (d, J = 7.0 Hz, 6H), 3.25 (m, 1H), 5.13 (s, 2H), 6 77 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 7.15 (m, 1H), 7.23 (m, 4H), 7 36 (m, 1H), 7.46 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 8.76 (s, 1H), 8.95 (d, J = 8.8 Hz, 1H); 9.88 (s, 1H); 11.22 (br s, 1H);

MS (ESI) + m / z 573/575 (M + H) +.

Example 233

4- [4- (3-Bromophenoxymethyl) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A solution of the product of example 232A (60 mg, 0.149 mmol) and the product of example 10B (28 mg, 0.149 mmol) in acetic acid (3 ml) was heated at 130 ° C for 15 minutes. Then, the solution was allowed to cool to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (46 mg, 47%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 2.72 (s, 3H), 5.12 (s, 2H), 6.77 (d, J = 8.5 Hz, 2H), 7 02 (m, 2H), 7.16 (m, 1H), 7.23 (m, 4H), 7.36 (m, 1H), 7.47 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 8.70 (s, 1H), 8.86 (d, J = 8.5 Hz, 1H), 9.87 (s, 1H), 10.95 (br. s, 1H);

MS (ESI) + m / z 545/547 (M + H) +.

Example 234

4- [4- (2,5-Difluorobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 234a

2-bromomethyl-1,4-difluorobenzene

To a solution of (2,5-difluorophenyl) methanol (4.8 g, 33.6 mmol) in dichloromethane (40 ml) was added dropwise phosphorus tribromide (94 g, 33.6 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting (hexane / ethyl acetate 90:10) to obtain the title compound (3.5 g, 50%).

Example 234b

1-Chloro-4- (2,5-fluorobenzyloxy) -2-nitrobenzene

To the product of example 234a (2.2 g, 10.4 mmol) in DMF (50 ml) was added 4-chloro-3-nitrophenol (1.8 g, 10.4 mmol) and K ₂ CO ₃ (2.87 g 20.8 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting (hexane / ethyl acetate 90:10) to obtain the title compound (2.48 g, 66%).

Example 234c

4- [4- (2,5-Difluorobenzyloxy) -2-nitrophenylsulfanyl] phenol

To the product of Example 234b (2.5 g, 8.3 mmol) in DMF (50 ml) was added 4-mercaptophenol (1.0 g, 8.3 mmol) and K ₂ CO ₃ (2.3 g, 16.5 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with (hexane / ethyl acetate / methanol 75: 15: 5) to obtain the title compound (1.7 g, 52%).

Example 234d

4- [2-amino-4- (2,5-difluorobenzyloxy) phenylsulfanyl] phenol

The product of Example 234c (1.70 g, 4.2 mmol) was reacted with Fe and NH ₄ Cl by the method described in Example 10E to give the title compound (1.3 g, 84%).

Example 234e

4- [4- (2,5-Difluorobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 57A (100 mg, 0.57 mmol) was reacted with the product of example 234d (206 mg, 0.57 mmol) in acetic acid (10 ml) at 125 ° C in a sealed vessel for 5 minutes to obtain the crude specified in the title of the compound, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (140 mg, 39%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 5.13 (s, 2H), 6.67 (d, J = 8.46 Hz, 2H), 6.93-7.01 (m, 1H), 7.10-7.16 (m, 3H), 7.22-7.37 (m, 4H), 7.41-7.52 (m, J = 5.79, 5.79, 2 , 76 Hz, 1H), 7.64 (dd, J = 8.09, 4.41 Hz, 1H), 8.53 (s, 1H), 8.84 (d, J = 7.72 Hz, 1H ), 9.05 (s, 1H);

MS (ESI +) m / z 489 (M + H) +.

Example 235

4- [4- (2,5-Difluorobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 36E (100 mg, 0.46 mmol) was reacted with the product of example 234d (206 mg, 0.46 mmol) in acetic acid (10 ml) at 125 ° C in a sealed vessel for 5 minutes to obtain the crude specified in the title of the compound, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (140 mg, 39%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.34 (d, J = 6.62 Hz, 6H), 5.14 (s, 2H), 6.66 (d, J = 8, 46 Hz, 2H), 7.06 (d, J = 2.57 Hz, 1H), 7.12 (d, J = 8.46 Hz, 2H), 7.21-7.35 (m, 4H) , 7.44 (s, 1H), 7.77 (d, J = 8.46 Hz, 1H), 8.69 (s, 1H), 8.88 (d, J = 8.46 Hz, 1H) 9.70 (s, 1H);

MS (ESI +) m / z 531 (M + H) +.

Example 236

4- [4- (2-Chloro-5-fluorobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 236a

2-bromomethyl-1-chloro-4-fluorobenzene

To a solution of (2-chloro-5-fluorophenyl) methanol (5.0 g, 31.1 mmol) in dichloromethane (40 ml) was added dropwise phosphorus tribromide (87 g, 31.1 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (hexane / ethyl acetate 90:10) to obtain the title compound (5.75 g, 82.5%).

Example 236b

1-Chloro-4- (2-chloro-5-fluorobenzyloxy) -2-nitrobenzene

To the product of example 236a (5.7 g, 25.7 mmol) in DMF (50 ml) was added 4-chloro-3-nitrophenol (4.46 g, 25.7 mmol) and K ₂ CO ₃ (7.10 g 51.4 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / ethyl acetate 90:10 to obtain the title compound (7.0 g, 86%).

Example 236c

4- [4- (2-Chloro-5-fluorobenzyloxy) -2-nitrophenylsulfanyl] phenol

To the product of Example 236b (2.5 g, 8.3 mmol) in DMF (50 ml) was added 4-mercaptophenol (1.0 g, 8.3 mmol) and K ₂ CO ₃ (2.3 g, 16.5 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (hexane / ethyl acetate / methanol (70: 25: 5) to obtain the title compound (5.0 g, 78%).

Example 236d

4- [2-amino-4- (2-chloro-5-fluorobenzyloxy) phenylsulfanyl] phenol

The product of Example 236c (4.2 g, 10.2 mmol) was reacted with Fe and NH ₄ Cl by the method described in Example 10E to give the title compound (3.0 g, 77%).

Example 236e

4- [4- (2-Chloro-5-fluorobenzyloxy) -2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 36E (125 mg, 0.72 mmol) was reacted with the product of example 236d (298 mg, 0.72 mmol) in acetic acid (10 ml) at 125 ° C in a sealed vessel for 5 minutes to obtain the crude specified in the title of the compound, which was purified by adding ethyl ether to the residue to obtain the desired product as acetic acid (225 mg, 66%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 1.32 (d, J = 6.99 Hz, 6H), 3.21 (q, 1H), 5.15 (s, 2H), 6.69 (d, J = 8.46 Hz, 2H), 6.99 (dd, 1H), 7.13 (d, J = 8.46 Hz, 4H), 7.25-7.35 (m , 2H), 7.49 (dd, J = 9.38, 3.13 Hz, 1H), 7.54-7.62 (m, J = 8.82, 5.15 Hz, 3H), 8, 55 (1H, s), (1 8.74 (s, 1H), 9.66 (s, 1H), 9.98 (s, 1H);

MS (ESI-) m / z 547 (M + H) +.

Example 237

4- [5-Benzyloxy-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

Example 237A

4-benzyloxy-2-fluoro-1-nitrobenzene

A mixture of 3-fluoro-4-nitrophenol (0.30 g, 1.91 mmol), benzyl bromide (0.36 g, 2.10 mmol, 1.1 eq.), Potassium carbonate (0.792 g, 5.73 mmol, 3.0 equiv.) And tetrabutylammonium iodide (5.0 mg, 0.014 mmol, 0.007 equiv.) In dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Water (20 ml) was added to the reaction mixture, and the resulting solid precipitate was isolated by vacuum filtration and dried to obtain the title compound (0.455 g, 96%) as a yellow solid.

Example 237B

4- (5-Benzyloxy-2-nitrophenylsulfanyl) phenol

The product of example 237A (0.301 g, 1.22 mmol), 4-mercaptophenol (0.184 g, 1.46 mmol, 1.2 eq.) And cesium carbonate (0.952 g, 2.92 mmol, 2.4 eq.) dimethylformamide (10 ml) was heated in an oil bath at 100ºC for 3 hours and then cooled to room temperature. Water (20 ml) was added and the mixture was stirred at room temperature for 2 hours, and the obtained solid was isolated by vacuum filtration and dried to obtain the title compound (0.405 g, 94%) as a yellow solid.

Example 237C

4- (2-amino-5-benzyloxyphenylsulfanyl) phenol

The product of example 237B (0.390 g, 1.10 mmol), iron powder (0.248 g, 4.41 mmol, 4.0 eq.) And ammonium chloride (0.071 g, 1.32 mmol, 1.2 eq.) In tetrahydrofuran (6 ml), methanol (6 ml) and water (2 ml) were heated under reflux for 16 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with methanol, and the filtrate was evaporated under reduced pressure to obtain the title compound (0.340 g, 95%) as a gray powder, which was used in the following reactions without further purification.

Example 237D

4- [5-Benzyloxy-2- (7-isopropylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 237C (0.0908 g, 0.281 mmol) and the product of example 36E (0.0607 g, 0.281 mmol) in glacial acetic acid (2 ml) were heated in an oil bath at 140ºC for 10 minutes, cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 5% methanol / dichloromethane, to give the title compound (0.0368 g, 27%) as a brown solid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 9.88 (s, 2H), 8.82 (d, J = 8.46 Hz, 1H), 8.52 (s, 1H), 7, 58 (d, J = 8.46 Hz, 1H), 7.28-7.42 (m, 5H), 7.19-7.28 (m, 3H), 6.87 (dd, J = 8, 64, 2.76 Hz, 1H), 6.75-6.84 (m, 2H), 6.38 (d, J = 2.57 Hz, 1H), 4.99 (s, 2H), 3, 14-3.27 (m, 1H); 1.32 (d, J = 6.99 Hz, 6H);

MS (ESI ⁺ ) m / z 495.2 (M + H) ⁺ , (ESI ^- ) m / z 493.2 (MH) ^- .

Example 238

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4-styrylphenylsulfanyl] phenol

Example 238A

4- (4-Bromo-2-nitrophenylsulfanyl) phenol

A mixture of 4-bromo-1-fluoro-2-nitrobenzene (0.44 g, 2.0 mmol), 4-mercapthenol (0.303 g, 2.4 mmol) and cesium carbonate (1.56 g, 4.8 mmol, 2.4 equiv.) In dimethylformamide (10 ml) was heated in an oil bath heated to 100 ° C for 3 hours and then cooled to room temperature. The reaction mixture was poured into ice water (50 ml), the pH was adjusted to 3 by adding 1N. aqueous hydrochloric acid and extracted with ethyl acetate (3 × 100 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a yellow thick oil (0.70 g,> 100%), which was used without further purification.

Example 238B

4- (2-amino-4-bromophenylsulfanyl) phenol

A mixture of the product of Example 238A (0.302 g, 0.926 mmol), iron powder (0.208 g, 3.7 mmol, 4.0 eq.) And ammonium chloride (0.059 g, 1.11 mmol, 1.2 eq.) methanol (6 ml), tetrahydrofuran (6 ml) and water (2 ml) were heated under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered through celite and the filter layer was washed with methanol (25 ml). The filtrate was evaporated under reduced pressure to obtain a brown glassy solid (0.27 g, 99%), which was used without further purification.

Example 238C

4- [4-Bromo-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

A mixture of the product of example 238B (0.158 g, 0.533 mmol) and the product of example 10B (0.100 g, 0.533 mmol) in glacial acetic acid (2 ml) was heated in an oil bath heated to 130 ° C for 30 minutes. Additional product of Example 10B (0.060 g, 0.319 mmol) was added and the reaction mixture was heated for another 30 minutes at 130 ° C. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated in 2-propanol and the resulting solid was isolated by vacuum filtration and dried to give the title compound (0.083 g, 36% yield) as a beige solid.

Example 238D

4- [2- (7-Methylpyrido [2,3-d] pyrimidin-4-ylamino) -4-styrylphenylsulfanyl] phenol

The mixture of the product according to example 238C (0.0791 g, 0.180 mmol), styrene (0.176 g, 1.69 mmol, 9.4 equiv.), Palladium (II) acetate (6.2 mg, 0.0276 mmol, 0, 15 eq.), Tri-o-tolylphosphine (13.3 mg, 0.0437 mmol, 0.24 eq.) And diisopropyl ethylamine (0.697 g, 0.539 mmol, 3.0 eq.) In dimethylformamide (2 ml) was heated in an oil bath heated to 130ºC for 98 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (6.1 mg, 10% yield).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.27 (s, 1H), 9.89 (s, 1H), 8.93 (d, J = 8.09 Hz, 1H), 8, 79 (s, 1H), 7.78 (d, J = 8.82 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 7.35 Hz, 2H), 7, 52 (dd, J = 8.09, 1.47 Hz, 1H), 7.37 (t, J = 7.35 Hz, 2H), 7.19-7.31 (m, 5H), 7.00 (d, J = 8.09 Hz, 1H), 6.73-6.81 (m, 2H), 2.75 (s, 3H).

Example 239

(7-Methylpyrido [2,3-d] pyrimidin-4-yl) - (2-phenylsulfanyl-5-styrylphenyl) amine

Example 239A

(5-Bromo-2-phenylsulfanylphenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

5-Bromo-2- (phenylthio) benzeneamine was prepared according to methods similar to those described in Examples 6a, 6b and 6c, using benzene-thiol instead of 4-mercapthenol and 4-bromo-2-nitrophenol instead of 4-methyl-2-nitrophenol.

A mixture of the product of example 10B (0.188 g, 1.0 mmol) and 5-bromo-2- (phenylthio) benzeneamine (0.280 g, 1.0 mmol) in glacial acetic acid (2 ml) was heated in an oil bath heated to 130 ° C for 30 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated in methanol and the resulting solid was isolated by vacuum filtration and dried to give the title compound (0.276 g, 65% yield) as a beige solid.

Example 239B

(7-Methylpyrido [2,3-d] pyrimidin-4-yl) - (2-phenylsulfanyl-5-styrylphenyl) amine

The mixture of the product according to example 239A (0.127 g, 0.30 mmol), styrene (0.133 g, 1.27 mmol, 4.3 eq.), Palladium (II) acetate (5.3 mg, 0.0236 mmol, 0, 08 equiv.), Tri- o- tolylphosphine (17.7 mg, 0.058 mmol, 0.19 equiv.) And triethylamine (0.0913 g, 0.90 mmol, 3.0 equiv.) In dimethylformamide (3 ml) heated in an oil bath heated to 130ºC for 98 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (4.0 mg, 2.4%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.21 (s, 1H), 8.85 (d, J = 8.46 Hz, 1H), 8.74 (s, 1H), 7, 68-7.78 (m, 2H), 7.55-7.65 (m, J = 7.35 Hz, 3H), 7.19-7.46 (m, 11H), 2.72 (s, 3H);

MS (ESI ⁺ ) m / z 447.2 (M + H) ⁺ , (ESI ^- ) m / z 445.2 (MH) ^- .

Example 240

(7-Methylpyrido [2,3-d] pyrimidin-4-yl) - (3-styrylphenyl) amine

Example 240A

(3-Bromophenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

A mixture of the product of Example 10B (0.206 g, 1.09 mmol) and 3-bromaniline (0.188 g, 1.09 mmol) in glacial acetic acid (1 ml) was heated in an oil bath heated to 130 ° C for 15 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated in methanol and the resulting solid was isolated by vacuum filtration and dried to give the title compound (0.126 g, 37%) as a beige solid.

Example 240B

(7-Methylpyrido [2,3-d] pyrimidin-4-yl) - (3-styrylphenyl) amine

The mixture of the product according to example 240A (0.063 g, 0.20 mmol), styrene (0.0412 g, 0.40 mmol, 2.0 eq.), Palladium (II) acetate (0.9 mg, 0.004 mmol, 0, 02 equiv.), Tri- o- tolylphosphine (2.4 mg, 0.008 mmol, 0.04 equiv.) And triethylamine (0.0607 g, 0.60 mmol, 3.0 equiv.) In dimethylformamide (2 ml) heated in an oil bath at 120ºC for 4 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from methanol and dried to give the title compound as a yellow crystalline substance (11.8 mg, 17%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.01 (s, 1H), 8.89 (d, J = 8.46 Hz, 1H), 8.72 (s, 1H), 8, 03 (s, 1H), 7.72-7.85 (m, J = 6.07, 2.76 Hz, 1H), 7.64 (d, J = 6.99 Hz, 2H), 7.57 (d, J = 8.82 Hz, 1H), 7.35-7.49 (m, 4H), 7.24-7.35 (m, 3H), 2.63-2.74 (m, 3H );

MS (ESI ⁺ ) m / z 339.1 (M + H) ⁺ , (ESI ^- ) m / z 337.1 (MH) ^- .

Example 241

(2-Methyl-5-phenethylphenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 241A

1-Methyl-2-nitro-4-styrylbenzene

A mixture of 4-bromo-2-nitrotoluene (0.432 g, 2.0 mmol), styrene (0.250 g, 2.40 mmol, 1.2 eq.), Palladium (II) acetate (4.5 mg, 0.020 mmol, 0 , 01 equiv.), Tri- o- tolylphosphine (12.2 mg, 0.04 mmol, 0.02 equiv.) And triethylamine (0.405 g, 4.0 mmol, 2.0 equiv.) In dimethylformamide (2 ml ) were heated in an oil bath at 120ºC for 4 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography, eluting with a hexane / ethyl acetate gradient, to give the title compound as a yellow solid (166 mg, 35% yield).

Example 241B

2-methyl-5-phenethylphenylamine

A mixture of the product of Example 241A (0.166 g, 0.694 mmol) and 10% palladium-on-carbon (18.4 mg, 0.025 equiv.) In ethanol (10 ml) was stirred under a hydrogen atmosphere for 16 hours. Then the reaction mixture was filtered through celite and the solvent was evaporated under reduced pressure to obtain the title compound as a pale red oil (0.141 g, 96% yield).

Example 241C

(2-Methyl-5-phenethylphenyl) - (7-methylpyrido [2,3-d] pyrimidin-4-yl) amine

A mixture of the product of example 10B (0.041 g, 0.22 mmol) and the product of example 241B (0.046 g, 0.22 mmol) in glacial acetic acid (1 ml) was heated in an oil bath at 130 ° C for 15 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated in methanol and the resulting solid was isolated by vacuum filtration and dried to give the title compound (0.0121 g, 16% yield) as a pale orange solid.

¹ H NMR (300 MHz, CHCl ₃ -d) δ ppm: 8.84 (s, 1H), 8.23 (d, J = 8.46 Hz, 1H), 7.44 (s, 1H), 7 , 15-7.37 (m, 8H), 7.07 (dd, J = 7.72, 1.47 Hz, 1H), 2.93 (s, 4H), 2.78 (s, 3H), 2.28 (s, 3H);

MS (ESI ⁺ ) m / z 355.3 (M + H) ⁺ , (ESI ^- ) m / z 353.2 (MH) ^- .

Example 242

(7-Isopropylpyrido [2,3-d] pyrimidin-4-yl) - (2-methyl-5-phenethylphenyl) amine

A mixture of the product of example 241B (46.2 mg, 0.219 mmol) and the product of example 36E (47.3 mg, 0.219 mmol) in glacial acetic acid (1 ml) was heated in an oil bath at 130 ° C for 15 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (0.0131 g, 10%).

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 11.09 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 8.74 (s, 1H), 7, 82 (d, J = 8.46 Hz, 1H), 7.12-7.35 (m, 8H), 3.21-3.33 (m, 1H), 2.89 (s, 4H), 2 15 (s, 3H); 1.35 (d, J = 6.62 Hz, 6H);

MS (ESI ⁺ ) m / z 383.2 (M + H) ⁺ , (ESI ^- ) m / z 381.3 (MH) ^- .

Example 243

(5-Methyl-2-phenylsulfanylphenyl) - (7-propylpteridin-4-yl) amine

Example 243A

N '- (3-Cyano-6-propylpyrazin-2-yl) -N, N-dimethylformamidine

A mixture of 3-amino-5-propylpyrazine-2-carbonitrile (0.140 g, 0.863 mmol) (prepared according to the method of Taylor and LaMattina, JOC 1977, 47 , 1523) and dimethylformamide dimethylacetal (0.123 g, 1.04 mmol, 1, 2 eq.) In toluene (10 ml) was heated under reflux for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain the title compound (0.188 mg, 100%) as a thick oil.

Example 243B

(5-Methyl-2-phenylsulfanylphenyl) - (7-propylpteridin-4-yl) amine

A mixture of the product of example 243A (38.2 mg, 0.176 mmol) and the product of example 5I (41.6 mg, 0.193 mmol, 1.1 eq.) In acetic acid (1 ml) was heated under reflux for 1.5 hours . The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The resulting residue was triturated in methanol to give the title compound (19 mg, 28% yield) as a beige solid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.76-1.90 (m, 2H), 2.42 (s, 3H ), 2.94-3.05 (m, 2H), 7.08-7.28 (m, 6H), 7.55 (d, J = 8.09 Hz, 1H), 8.45 (s, 1H), 8.81 (s, 1H), 8.89 (s, 1H), 10.32 (s, 1H).

MS (ESI ⁺ ) m / z 388.1 (M + H) ⁺ (ESI ^- ) m / z 386.1 (MH) ^- .

Example 244

4- [4-Benzyloxy-2- (7-isopropylpteridin-4-ylamino) phenylsulfanyl] phenol

Example 244A

3-amino-5-isopropyl-4-hydroxypyrazine-2-carbonitrile

A mixture of 2-hydroxyimino-3-methylbutyraldehyde (1.93 g, 16.8 mmol) (prepared by Nakamura, Agric. Biol. Chem . 1961, 25 , 665-670) and 2-aminomalononitrile tosylate (4.25 g, 16 , 8 mmol) in i- propanol (40 ml) was stirred at room temperature for 18 hours. The resulting solid was isolated by vacuum filtration and washed with i- propanol and air dried to give the title compound (0.525 g, 18% yield) as a white solid.

Example 244B

3-amino-5-isopropylpyrazine-2-carbonitrile

A solution of the product of example 244A (0.525 g, 2.95 mmol) in tetrahydrofuran (30 ml) was stirred at a bath temperature with ice. Phosphorus trichloride (4.0 g, 2.6 ml, 29.5 mmol, 10 eq.) Was quickly added dropwise to this solution. The reaction mixture was stirred at room temperature for 16 hours, and then the solvent and excess reagent were evaporated. The resulting residue was partitioned between ethyl acetate and a half-saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3 × 100 ml) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound (0.370 g, 77% yield) as a light brown solid.

Example 244C

N '- (3-Cyano-6-isopropylpyrazin-2-yl) -N, N-dimethylformamidine

A mixture of the product of example 244B (0.37 g, 2.28 mmol) and dimethyl acetal dimethylformamide (0.30 g, 2.5 mmol, 1.1 eq.) In toluene (25 ml) was heated under reflux for 1, 75 hours. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure to obtain the title compound (0.50 g, 100%) as a red-brown thick oil, which was used in the following reactions without further purification.

Example 244D

4- [4-Benzyloxy-2- (7-isopropylpteridin-4-ylamino) phenylsulfanyl] phenol

A mixture of the product of example 244C (56.2 mg, 0.259 mmol) and the product of example 27A in acetic acid (1 ml) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The resulting residue was triturated in methanol to give the title compound (55.5 mg, 53% yield) as a beige solid.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 10.37 (s, 1H), 9.65 (s, 1H), 9.03 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 7.38 (d, J = 8.09 Hz, 1H), 7.21 (d, J = 8.82 Hz, 2H), 7.03 (dd, J = 8 09, 1.47 Hz, 1H), 6.68 (d, J = 8.82 Hz, 2H), 3.35-3.46 (m, 1H), 2.37 (s, 3H), 1 38 (d, J = 6.62 Hz, 6H).

MS (ESI ⁺ ) m / z 404.2 (M + H) ⁺ (ESI ^- ) m / z 402.3 (MH) ^- .

Example 245

[2- (4-Aminophenoxy) -5- (6-bromo-1H-benzoimidazol-2-yl) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 245A

[4- (4-Formyl-2-nitrophenoxy) phenyl] carbamic acid tert-butyl ester

A mixture of 4-chloro-3-nitrobenzaldehyde and (4-hydroxyphenyl) carbamic acid tert-butyl ester was reacted together in DMSO with the addition of KOH to give the title product.

Example 245B

{4- [2-amino-4- (6-bromo-1H-benzoimidazol-2-yl) phenoxy] phenyl} carbamic acid tert-butyl ester

The product of Example 245A was reacted in accordance with the methods described in Examples 147B and 147C to give the title product.

Example 245C

[2- (4-Aminophenoxy) -5- (6-bromo-1H-benzoimidazol-2-yl) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 245B was reacted with the product of example 36E in HOAc and placed in an oil bath preheated to 120 ° C. The solvent was removed in a stream of N ₂ . The product was removed the protective group by dissolving in 1: 1 a mixture of TFA in DCM and stirred at room temperature. The crude material was purified by TFA HPLC to give the title product as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.21-3.39 (m, 1H), 6.87-7.04 (m, 4H), 7.09 (d, J = 8.46 Hz, 1H), 7.36 (dd, J = 8.82, 1.84 Hz, 1H), 7.56 (d, J = 8.46 Hz, 1H), 7.78 (d, J = 1.47 Hz, 1H), 7.89 (d, J = 8.46 Hz, 1H), 8.14 (dd, J = 8, 82, 1.84 Hz, 1H), 8.37 (d, J = 1.84 Hz, 1H), 8.90 (s, 1H), 9.00 (d, J = 8.09 Hz, 1H) ;

MS (ESI +) m / z 568.2 (M + H) +.

Example 246

4- [4-Benzyloxy-2- (7-tert-butylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] phenol

The product of example 27A was heated at 130 ° C in acetic acid with the product of example 127A for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed and the residue was purified by silica gel column chromatography to obtain the title product.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.38 (s, 9H), 5.11 (s, 2H), 6.60-6.74 (m, 2H), 6.94 (d , J = 7.35 Hz, 1H), 7.06-7.19 (m, 3H), 7.27-7.50 (m, 6H), 7.78 (d, J = 8.09 Hz, 1H), 8.56 (s, 1H), 8.75 (s, 1H), 9.64 (s, 1H), 9.95 (s, 1H);

MS (ESI +) m / z 509 (M + H) +.

Example 247

2- (4-aminophenylsulfanyl) -5- (2-chlorothiazol-5-ylmethoxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 247A

{4- [2-amino-4- (2-chlorothiazol-5-ylmethoxy) phenylsulfanyl] phenyl} carbamic acid tert-butyl ester

2-Chloro-5- (4-chloro-3-nitrophenoxymethyl) thiazole (as described in Example 25A) was reacted with 4-aminothiophenol in anhydrous ethanol and under reflux in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and ethanol was removed on a rotary evaporator. The residue was treated in water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Trituration of the solid in 4% ethyl acetate / methylene chloride gave 4- (4 - ((2-chlorothiazol-5-yl) methoxy) -2-nitrophenylthio) aniline. A mixture of 4- (4 - ((2-chlorothiazol-5-yl) methoxy) -2-nitrophenylthio) aniline and di- tert- butyl dicarbonate in 1,4-dioxane was heated under reflux under nitrogen atmosphere and then Boc anhydride was added and the reaction mixture was allowed to reflux. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator in vacuo. The resulting solid was triturated with 2.5% ethyl acetate / methylene chloride to give tert-butyl 4- (4 - ((2-chlorothiazol-5-yl) methoxy) -2-nitrophenylthio) phenylcarbamate. A suspension of 4- (4 - ((2-chlorothiazol-5-yl) methoxy) -2-nitrophenylthio) phenylcarbamate, iron powder and ammonium chloride in water and ethanol was heated. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered and concentrated in vacuo to give the title compound.

Example 247B

[2- (4-Aminophenylsulfanyl) -5- (2-chlorothiazol-5-ylmethoxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 247A was heated at 130 ° C in acetic acid with the product of example 36E for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed in vacuo and dichloromethane / trifluoroacetic acid 1/1 was added, and then the residue was stirred at room temperature for 2 hours, then the solvent was removed in vacuo and the residue was purified by TFA HPLC to give the title product as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.99 Hz, 6H), 3.20-3.37 (m, 1H), 3.75 (s, 2H ), 5.33 (s, 2H), 6.53 (d, J = 8.46 Hz, 2H), 6.99-7.12 (m, 5H), 7.14 (s, 1H), 7 80 (s, 1H), 7.92 (d, J = 8.82 Hz, 1H), 8.83 (s, 1H), 9.01 (s, 1H), 11.62 (s, 1H) ;

MS (ESI +) m / z 535 (M + H) +.

Example 248

{4- [2- (7-tert-butylpyrido [2,3-d] pyrimidin-4-ylamino) -4- (2-chlorothiazol-5-ylmethoxy) phenylsulfanyl] phenyl} carbamic acid tert-butyl ester

The product of example 247A was heated at 130 ° C in acetic acid with the product of example 127A for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed and the residue was purified by HPLC with TFA to give the title product as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.43 (d, J = 11.40 Hz, 15H), 2.73 (s, 1H), 5.36 (s, 2H), 7, 00 (d, 1H), 7.13 (d, J = 8.46 Hz, 2H), 7.25 (d, 1H), 7.33 (d, J = 8.46 Hz, 3H), 7, 81 (s, 2H), 8.62 (s, 1H), 8.78 (s, 1H), 9.39 (s, 1H), 10.49 (br s, 1H); MS (ESI +) m / z 649 (M + H) +.

Example 249

[2- (4-Aminophenylsulfanyl) -5- (2-chlorothiazol-5-ylmethoxy) phenyl] - (7-tert-butylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of Example 248 was added to 1/1 dichloromethane / trifluoroacetic acid and the solution was stirred at room temperature for 2 hours, then the solvent was removed in vacuo and the resulting residue was purified by HPLC with TFA to give the title product as a trifluoroacetic acid salt .

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.44 (s, 6H), 2.51-2.59 (m, 1H), 3.72 (s, 2H), 5.33 (s , 2H), 6.24 (dd, J = 8.82, 2.94 Hz, 1H), 6.42 (d, J = 2.94 Hz, 1H), 6.53 (d, J = 8, 46 Hz, 2H), 6.98-7.12 (m, 3H), 7.14 (s, 1H), 7.74-7.85 (m, 1H), 8.09 (d, J = 8 46 Hz, 1H), 8.83 (s, 1H), 9.03 (s, 1H), 11.65 (s, 1H);

MS (ESI +) m / z 549 (M + H) +.

Example 250

[2- (4-Aminophenylsulfanyl) -5- (6-bromo-1H-benzoimidazol-2-yl) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 250A

[4- (4-Formyl-2-nitrophenylsulfanyl) phenyl] carbamic acid tert-butyl ester

A mixture of 4-chloro-3-nitrobenzaldehyde and 4-aminothiophenol was reacted together according to the method described in Example 216B using 4-chloro-3-nitrobenzaldehyde instead of the product of Example 216A, which was then subjected to the conditions described in Example 216C, with receipt specified in the product header.

Example 250B

[2- (4-Aminophenylsulfanyl) -5- (6-bromo-1H-benzoimidazol-2-yl) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of Example 250A was reacted according to the methods described in Examples 147B, 147C and 147C to give a crude residue which was purified by HPLC with TFA to give the title product as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.38 (d, J = 6.62 Hz, 6H), 3.26-3.40 (m, 1H), 6.64 (d, J = 8.46 Hz, 2H), 7.03 (d, J = 8.46 Hz, 1H), 7.17 (d, J = 8.46 Hz, 2H), 7.35 (dd, J = 8 46, 1.84 Hz, 1H), 7.54 (d, J = 8.82 Hz, 1H), 7.77 (d, J = 1.84 Hz, 1H), 7.94 (d, J = 8.46 Hz, 1H), 8.03 (dd, J = 8.46, 1.84 Hz, 1H), 8.18 (s, 1H), 8.89 (s, 1H), 9.05 (d, J = 8.82 Hz, 1H);

MS (ESI +) m / z 584 (M + H) +.

Example 251

[2- (4-Aminophenylsulfanyl) -5- (3-fluorobenzyloxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 251A

{4- [2-amino-4- (3-fluorobenzyloxy) phenylsulfanyl] phenyl} carbamic acid tert-butyl ester

The product of Example 57B was reacted with 4-aminothiophenol in accordance with the method described in Example 214B, then the reaction in accordance with the methods described in Examples 214C and 214D to obtain the title product.

Example 251B

[2- (4-Aminophenylsulfanyl) -5- (3-fluorobenzyloxy) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 251A was heated at 130 ° C in acetic acid with the product of example 36E for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed in vacuo and dichloromethane / trifluoroacetic acid 1/1 was added, and then the residue was stirred at room temperature for 2 hours, then the solvent was removed in vacuo and the residue was purified by silica gel column chromatography to obtain the title product.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.26-1.44 (d, 6H), 3.23-3.37 (m, 1H), 5.13 (s, 2H), 6 44-6.61 (m, 2H), 6.96-7.10 (m, 3H), 7.10-7.22 (m, 2H), 7.24-7.35 (m, 3H) , 7.35 (d, J = 6.25 Hz, 1H), 7.43 (dd, J = 7.91, 5.70 Hz, 2H), 7.92 (s, 1H), 8.18 ( d, J = 8.82 Hz, 1H), 8.83 (s, 1H), 9.03 (s, 1H);

MS (ESI +) m / z 512 (M + H) +.

Example 252

[2- (4-Aminophenylsulfanyl) -5- (3-fluorobenzyloxy) phenyl] - (7-tert-butylpyrido [2,3-d] pyrimidin-4-yl) amine

The product of example 251A was heated at 130 ° C in acetic acid with the product of example 127A for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed in vacuo and dichloromethane / trifluoroacetic acid 1/1 was added, and then the residue was stirred at room temperature for 2 hours, then the solvent was removed in vacuo and the residue was purified by TFA HPLC to give the title product as a trifluoroacetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.38-1.50 (m, 9H), 5.12 (s, 2H), 6.44-6.61 (m, 3H), 6 96-7.12 (m, 3H), 7.19 (s, 3H), 7.23-7.33 (m, 3H), 7.38-7.50 (m, 2H), 8.00 (s, 1H), 8.76 (s, 1H), 8.96 (s, 1H);

MS (ESI +) m / z 526 (M + H) +.

Example 253

[5-Benzyloxy-2- (4-dimethylaminophenylsulfanyl) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

Example 253A

5-benzyloxy-2- (4-dimethylaminophenylsulfanyl) phenylamine

The product of Example 214B (1.0 g, 0.284 mmol) was placed in a vessel together with formic acid (5 ml), dioxane (5 ml) and 37% aqueous formaldehyde solution (5 ml). The vessel was sealed and heated to 110ºC for 20 minutes. The mixture was cooled to room temperature, the solvent was removed, and the obtained residue was purified by silica gel column chromatography, then the nitro group was reduced in accordance with the method described in Example 214D to obtain the title product (411 mg, 43%).

Example 253B

[5-Benzyloxy-2- (4-dimethylaminophenylsulfanyl) phenyl] - (7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amine

A mixture of the product of example 253A and the product of example 36E in glacial acetic acid was heated in an oil bath preheated to 130 ° C for 20 minutes. Then, the reaction mixture was cooled to room temperature, and the solvent was evaporated in vacuo to give the title compound as an acetic acid salt.

¹ H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 7.0 Hz, 6H), 2.81 (s, 6H), 3.30 (m, 1H), 5, 10 (s, 2H), 6.45 (d, J = 9.2 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.12 (m, 2H), 7, 25 (d, J = 8.8 Hz, 1H), 7.40 (m, 5H), 7.94 (m, 1H), 8.78 (s, 1H), 8.99 (m, 1H), 11.70 (br s, 1H);

MS (ESI) m / z 522 (M + H) +.

Example 254

4-Bromo-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

Example 254A

4-bromo-N- (3-nitrophenyl) benzamide

The title compound was prepared according to the method described in Example 255A using 3-nitrophenylamine instead of 4-Fluoro-3-nitroaniline and using 4-bromobenzoyl chloride instead of 3-trifluoromethylbenzoyl chloride to give the title product (3.373 g, 90%) .

Example 254B

4-bromo-N- (3-aminophenyl) benzamide

The title compound was prepared according to the method described in Example 255B using the product of Example 254A instead of the product of Example 255A to give the title product (1.8 g, 80%).

Example 254C

4-Bromo-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) phenyl] benzamide

A solution of the product of Example 57A (40.0 mg, 0.212 mmol) and the product of Example 254B (61.0 mg, 0.212 mmol) in acetic acid (1 ml) were stirred in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (25.0 mg, 30%).

¹ H NMR (300 MHz, DMSO-D6 ) δ ppm: 7.45 (t, J = 8.09 Hz, 1H), 7.52-7.61 (m, 2H), 7.74-7.86 (m, 3H), 7.94 (d, J = 8.82 Hz, 2H), 8.33 (t, J = 1.84 Hz, 1H), 8.88 (s, 1H), 9.09 -9.17 (m, 2H); 10.48 (s, 1H); 10.94 (s, 1H);

MS (ESI +) m / z 420 (M + H) +, (ESI-) m / z 417 (M-H) -.

Example 255

N- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenyl] -3-trifluoromethylbenzamide

Example 255A

N- (4-Fluoro-3-nitrophenyl) -3-trifluoromethylbenzamide

A solution of 4-fluoro-3-nitroaniline (2.00 g, 12.8 mmol), 3-trifluoromethylbenzoyl chloride (1.895 ml, 12.8 mmol), Hunig base (4.463 ml, 25.6 mmol) in tetrahydrofuran (50 ml) stirred at room temperature for 1 hour. Then water (450 ml) was added to the solution, and the obtained solid was collected by filtration and dried in a vacuum oven to obtain the title compound (3.311 g, 97%).

Example 255B

N- [4- (4-Hydroxyphenylsulfanyl) -3-nitrophenyl] -3-trifluoromethylbenzamide

A solution of the product of example 255A (2.00 g, 5.80 mmol), 4-hydroxythiophenol (0.732 g, 5.80 mmol) and potassium carbonate (1.604 g, 11.6 mmol) in N, N- dimethylformamide (40 ml) heated to 80ºC for 2 hours. After cooling to room temperature, the mixture was poured into ice water (100 ml). The solution was then extracted with ethyl acetate (3 × 150 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (2.52 g, 100%).

Example 255C

N- [3-amino-4- (4-hydroxyphenylsulfanyl) phenyl] -3-trifluoromethylbenzamide

A solution of the product of example 255B (0.660 g, 1.52 mmol), iron powder (0.339 g, 6.07 mmol) and ammonium chloride (0.099 g, 1.82 mmol), a solution of tetrahydrofuran (18 ml) and water (6 ml) heated under reflux for 3 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was diluted with water (50 ml) and extracted with dichloromethane (2 × 100 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.60 g, 97%).

Example 255D

N- [4- (4-Hydroxyphenylsulfanyl) -3- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenyl] -3-trifluoromethylbenzamide

A solution of the product of Example 10B (40.0 mg, 0.212 mmol) and the product of Example 255C (86.0 mg, 0.212 mmol) in acetic acid (1 ml) was stirred in an oil bath preheated to 130 ° C for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo, and the obtained residue was purified by TFA HPLC to give the title compound as a trifluoroacetic acid salt (11 mg, 10%).

¹ H NMR (300 MHz, DMSO-D6 ) δ ppm: 2.74 (s, 3H), 6.70 (d, J = 8.82 Hz, 2H), 7.18 (d, J = 8.46 Hz, 3H), 7.64 (dd, J = 8.46, 2.21 Hz, 1H), 7.79 (t, J = 7.72 Hz, 2H), 7.93-8.07 (m , J = 6.62 Hz, 2H), 8.21-8.30 (m, 2H), 8.78 (s, 1H), 8.92 (d, J = 7.72 Hz, 1H), 9 79 (s, 1H); 10.67 (s, 1H); 11.17-11.50 (m, 1H);

MS (ESI +) m / z 548.2 (M + H) + (ESI-) m / z 546.2 (M-H) -.

Biological research

Representative compounds of the invention were analyzed in accordance with the procedures described below.

The following abbreviations were used:

IC ₅₀ Concentration leading to 50% inhibition TC ₅₀ Concentration leading to 50% toxicity DMEM Modified by the Dulbecco method Igla ™ medium RNA Ribonucleic acid RT-PCR Reverse transcription polymerase chain reaction Seap Secreted Alkaline Phosphatase

The genome of the hepatitis C virus encodes a large polypeptide, which after processing gives the necessary functional components for the synthesis of daughter RNAs. Breeding cell lines producing high and stable levels of HCV subgenomic RNA (replicons) were obtained from human hepatoma cells (Huh7) as described in Ikeda et al ., J. Virology, 76 (6): 2997-3006 (2002) and Blight et al ., Science, 290: 1972-1974 (2000). It is believed that the mechanism of RNA replication in these cell lines is the same as the replication of full-length HCV RNA in infected hepatocytes. The compounds of the present invention are inhibitors of HCV RNA replication in the replicon assays described below.

Assessment of HCV inhibitors in HCV replicon

The inhibitory effect of the representative compounds of the invention was evaluated for replicons of HCV genotype 1a and 1b. They were also evaluated using an MTT assay for cytotoxicity against host cells. Cell lines were maintained in accordance with the methods described by Yi et al ., Virology, 304 (2): 197-210 (2002).

A. RNA Analysis and SEAP Analysis

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

Cells with replicons of genotype 1a and / or 1b were placed in a 96-well plate containing DMEM medium with 5% fetal bovine serum, in the amount of 3-5 × 10 ³ cells per well. The next day, the culture medium was removed and replaced with fresh medium containing eight serial dilutions of the compound. The untreated control culture was treated in the same manner, but the inhibitor was not added to the medium. The plates were incubated in a CO ₂ 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. RNA was purified according to the manufacturer's instructions (Qiagen RNAeasy) and eluted in 200 μl of water. The quantitative level of HCV RNA in a portion (5 μl of 200 μl) of RNA purified by real-time RT-PCR was determined. Primers and probes were prepared based on the specific sequence of the 5'-untranslated region (5'UTR). The RT-PCR reaction was carried out at 48 ° C for 30 minutes, then 40 cycles, setting 95 ° C, 15 s; 54 ° C, 30 s; and 72 ° C, 40 s. Alternatively, the SEAP activity in each culture supernatant was measured after four days of incubation with the compound in accordance with the manufacturer's instructions. The percent reduction in HCV or SEAP RNA in the presence of the compound was calculated, and the concentration leading to 50% inhibition (IC ₅₀ ) was calculated using a nonlinear regression analysis using the Prism program (version 4.0, GraphPad, San Diego, CA).

When tested using the above method, representative compounds of the present invention inhibited HCV replicon replication at an IC ₅₀ value in the range of about 0.3 nM to about 100 μM.

B. Cytotoxic analysis

The purpose of this analysis was to demonstrate the toxicity of compounds to host cells carrying the virus in vitro .

The cytotoxicity of the compounds was measured using mitochondrial enzyme-based cell proliferation analysis / viability analysis in replicon cells. Briefly, cells with HCV replicon were placed in a 96-well plate containing DMEM medium with 5% FCS in an amount of 3-5 × 10 ³ cells per well. On day 1, the culture medium was removed and replaced with fresh medium containing eight serial dilutions of the compound. The untreated control culture was treated in the same manner, but the inhibitor was not added to the medium. The plates were incubated in a CO ₂ incubator at 37 ° C. On day 4, tetrazolium salt solution, MTT (4 mg / ml in PBS, Sigma cat. # M 2128) was added to each well in an amount of 25 μl per well. The plates were further incubated for 4 hours, treated with 20% SDS plus 0.02N HCl in an amount of 50 μl per well for cell lysis. After incubation overnight, the optical density was measured by reading the plates at a wavelength of 570/650 nm. The percentage recovery of the formazan blue dye relative to the control was calculated and the concentration resulting in 50% toxicity (TC ₅₀ ) was calculated using a nonlinear regression analysis using the Prism program (version 4.0, GraphPad, San Diego, CA software).

When tested using the above method, the TC ₅₀ value of the representative compounds of the present invention was greater than the corresponding IC ₅₀ values of these compounds.

Pharmaceutical Compositions and Use

The present invention relates to pharmaceutical compositions containing the compounds of the invention. As a non-limiting example, the pharmaceutical composition of the present invention contains one or more compounds of the present invention, where each compound is independently selected from formula I, II, III, IV, V, VI, VII, or VIII. Preferably, each compound is independently selected from Examples 1-255.

The present invention also relates to a pharmaceutical composition comprising pharmaceutically acceptable salts, solvates or prodrugs of the compounds of the present invention. Pharmaceutically acceptable salts may be zwitterions or may be derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, an acceptable salt of the compound of the invention preserves the biological effectiveness of the free acid or base of the compound without causing nonspecific toxicity, irritation or allergic reactions, has a suitable benefit / risk ratio and is effective for the intended use and is not undesirable from a biological or other point of view. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, the following salts: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, gulf sulfonate , heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Major nitrogen-containing groups can also be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl or butyl chlorides, bromides or iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl or diamyl sulfates), long alkyl alkyl halides chain (e.g. decyl, lauryl, myristyl or stearyl chlorides, bromides or iodides), aralkyl halides (e.g. benzyl or phenethyl bromides). Other salts that can be used in the present invention include alkali or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium, or organic bases. Examples of acids that can be used and form pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, citric acid, or other suitable inorganic or organic acids.

The present invention also relates to pharmaceutical compositions comprising a compound of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. In a non-limiting example, the pharmaceutical composition of the present invention includes 1, 2, 3 or more compounds of the invention (or their salts, solvates or prodrugs) and 1, 2, 3 or more other therapeutic agents. By way of non-limiting example, these other therapeutic agents can be selected from antiviral agents (e.g., anti-HIV agents or other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, or anti-inflammatory drugs. Specific examples of other therapeutic agents include, but are not limited to, ribavirin; interferons (e.g. IFN alpha 2a or 2b); protease inhibitors; immunosuppressive agents; antibodies (for example, therapeutic monoclonal or chimeric antibodies); antisense or siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); drugs for the treatment of cirrhosis and inflammation of the liver; IFN omega (BioMedicines Inc., Emeryville, CA); BILN-2061, a serine protease inhibitor (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel, an antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); roferon, A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis, PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis and ribavirin, PEGylated IFN-alpha 2a / ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); CellCept, IgG HCV immunosuppressant (F. Hoffmann-La Roche LTD, Basel, Switzerland); velferon, lymphoblastic IFN-alpha n1 (GlaxoSmithKline plc, Uxbridge, UK); albuferon alpha, albumin IFN alpha 2b (Human Genome Sciences Inc., Rockville, MD); levovirin, ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556, a caspase inhibitor (Idun Pharmaceuticals Inc., San Diego, CA); IP-501, an antifibrotic agent (Indevus Pharmaceuticals Inc., Lexington, MA); Aktimun, INF-gamma (InterMune Inc., Brisbane, CA); Infergen A, IFN Alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803, antisense oligonucleotides (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmaceuticals Inc., New York, NY); JTK-003, an RdRp inhibitor (Japan Tobacco Inc., Tokyo, Japan); pegasis and cling, PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals inc., San Diego, CA); cling, immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); civacir, HCV IgG immunosuppressant (Nabi Biopharmaceuticals Inc., Boca Raton, FL); intron A and zadaxine IFN-alpha 2b / alpha-1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); levovirin, an IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine, an IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); heptazim, ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); intron A, IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); PEG intron, PEGylated IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); rebetron, IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); ribavirin (Schering-Plow Corporation, Kenilworth, NJ); PEG intron / ribavirin; PEGylated IFN alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); preset immune modulator (SciClone Pharmaceuticals Inc., San Mateo, CA); rebif IFN-beta 1a (Serono, Geneva, Switzerland); IFN-beta and EMZ701, IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497, an IMPDH inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals);

(designated herein as compound VX-950,

Vertex Pharmaceuticals Inc.);

(designated herein as compound SCH503034, Schering-Plow Co.); and

(herein designated as compound GS9137, Gilead Sciences, Inc., Foster City, CA). Any other desirable therapeutic agents may also be included in the pharmaceutical composition of the present invention.

In one embodiment, the pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or their salts, solvates or prodrugs) and one or more other antiviral agents.

In another embodiment, the pharmaceutical composition of the present invention contains one or more compounds of the present invention (or their salts, solvates or prodrugs) and one or more other anti-HCV agents. In one example, each compound of the present invention is independently selected from formulas I, II, III, IV, V, VI, VII, or VIII, or Examples 1-255, and each other anti-HCV agent is independently selected from inhibitors of RNA-dependent RNA polymerase HCV (e.g., nucleoside or non-nucleoside type polymerase inhibitors), HCV protease inhibitors or HCV helicase inhibitors.

In another embodiment, the pharmaceutical composition of the present invention contains one or more compounds of the present invention (or their salts, solvates or prodrugs) and two or more other anti-HCV inhibitors. Preferably, each compound of the present invention is independently selected from formulas I, II, III, IV, V, VI, VII or VIII, or from examples 1-255. Other anti-HCV inhibitors can be selected from inhibitors of the same class (for example, all are selected from inhibitors of RNA-dependent RNA polymerase HCV, or HCV protease inhibitors), or selected from inhibitors of various classes (for example, one or more are selected from inhibitors of RNA-dependent RNA polymerase of HCV, and the other or others selected from inhibitors of HCV protease).

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one HCV RNA-dependent RNA polymerase inhibitor. Preferably, each compound of the present invention is independently selected from formulas I, II, III, IV, V, VI, VII or VIII, or examples 1-255.

In another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one HCV protease inhibitor. Preferably, the compound of the present invention is selected from formulas I, II, III, IV, V, VI, VII or VIII, or examples 1-255.

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof), at least one inhibitor of an RNA-dependent HCV RNA polymerase and at least one HCV protease inhibitor. Preferably, the compound of the present invention is selected from formulas I, II, III, IV, V, VI, VII or VIII, or examples 1-255.

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and two or more anti-HCV agents, each of which is independently selected from inhibitors of RNA-dependent HCV RNA polymerase or HCV protease inhibitors. Preferably, the compound of the present invention is selected from formulas I, II, III, IV, V, VI, VII or VIII, or examples 1-255.

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and three or more other anti-HCV agents, each of which is independently selected from an RNA-dependent RNA polymerase inhibitor HCV or HCV protease inhibitors. Preferably, the compound of the present invention is selected from formulas I, II, III, IV, V, VI, VII or VIII, or examples 1-255.

Non-limiting examples of inhibitors of the RNA-dependent HCV RNA polymerase include compounds described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425. Non-limiting examples of HCV protease inhibitors include BILN-2061, VX-950, and SCH503034.

In another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and one or more other antiviral agents, such as anti-HBV or HIV agents. Non-limiting examples of anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalvavirfin delavin, abac, delacinfin, abac, delacinfin, abac, delacinfin, -125, L-870812, S-1360, enfuvirtide, T-1249 and other protease inhibitors, reverse transcriptase, integrase or HIV fusion inhibitors. Other desirable antiviral agents may also be included in the pharmaceutical composition, which is obvious to a person skilled in the art.

In one embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt, solvate thereof or a prodrug, and at least one anti-HBV agent. In another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt, solvate or a prodrug, and at least one anti-HIV agent. In yet another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt, solvate thereof or a prodrug, and at least one agent against hepatitis A, hepatitis D, hepatitis E or hepatitis G.

In yet another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt, solvate thereof or a prodrug, and at least one agent suitable for treating liver inflammation.

The 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 ( e.g. peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g. propylene glycol), buffering agents (e.g. magnesium hydroxide and whether aluminum hydroxide), agar, alginic acid, tragacanth powder, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic solution, Ringer's solution, ethanol or phosphate buffer solutions. Lubricants, colorants, release agents, coating agents, sweeteners, flavors or perfumes, preservatives or antioxidants can also be included in the pharmaceutical composition of the present invention, which is obvious to a person skilled in this field.

The pharmaceutical composition of the present invention can be administered to a patient in various ways, such as oral, parenteral, sublingual, rectal, topical or by inhalation spray. Topical application may include the use of transdermal administration, such as transdermal patches or iontophoresis devices. Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intramuscular or intrasternal injection or infusion methods.

The pharmaceutical compositions of the present invention can be obtained depending on their methods of administration by methods well known in the art. For example, a sterile injectable preparation can be prepared as a sterile injectable aqueous or oily suspension using suitable dispersing or wetting agents and suspending agents. Suppositories for rectal administration can be prepared by mixing drugs with a suitable, non-irritating excipient, such as cocoa butter or polyethylene glycols, which retain their solid form at normal temperature but become liquid at rectal temperature and thus melt in the rectum and release 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 contain substances other than inert diluents, such as lubricants. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. Tablets and pills may additionally contain enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents commonly used in the art. Liquid dosage forms may also contain wetting, emulsifying, suspending, sweetening, flavoring or perfuming substances. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes, as described in US patent No. 6703403. The composition of drugs that can be used in the present invention, as described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975) and Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, NY, 1980).

The present invention also relates to methods of using the compounds of the present invention (or their salts, solvates or prodrugs) to inhibit HCV replication. In one embodiment, the methods comprise contacting the HCV virus with an effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), thereby inhibiting HCV virus replication. In another embodiment, the methods include contacting HCV virus infected cells with an effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), thereby inhibiting HCV virus replication in cells. In yet another embodiment, the methods comprise contacting the HCV virus or infected cells with an effective amount of two or more compounds of the present invention (or their salts, solvates or prodrugs), thereby inhibiting HCV virus replication. As used herein, the term “inhibition” means a significant decrease or decrease in inhibitory activity (eg, viral replication). In most cases, representative compounds of the present invention can reduce HCV virus replication (for example, in an HCV replicon assay as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

The compounds of the present invention can inhibit all subtypes of HCV. Examples of HCV subtypes that can be processed in accordance with 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, the compound or compounds of the present invention (or their salts, solvates or prodrugs) are used to inhibit the replication of the HCV 1a genotype. In another embodiment, the compound or compounds of the present invention (or their salts, solvates or prodrugs) are used to inhibit the replication of the HCV 1b genotype. In yet another embodiment, the compound or compounds of the present invention (or their salts, solvates or prodrugs) are used to inhibit the replication of both HCV genotypes 1a and 1b.

The present invention also relates to methods of using the compounds of the present invention (or their salts, solvates or prodrugs) for the treatment of HCV infection. These methods typically include administering a therapeutically effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof) to an HCV patient, thereby lowering the level of HCV virus in a patient’s blood or liver. As used herein, the term “treatment” refers to the treatment, reduction, inhibition of progress, or the prevention of a disease or condition, or one or more symptoms of such a disease or condition to which the term applies. The term “treatment” refers to the act of treatment. In one embodiment, the methods comprise administering a therapeutically effective amount of two or more compounds of the present invention (or their salts, solvates or prodrugs) to a patient suffering from HCV, thereby lowering the level of the HVC virus in the blood or liver of the patient. Preferably, the compound (s) used in these methods has the formula (s) I, II, III, IV, V, VI, VII or VIII, or is selected from the compounds of examples 1-255, or is (s) a salt, solvate or prodrug thereof.

In another aspect, the present invention relates to methods for using the pharmaceutical composition of the present invention to treat HCV infection. For this purpose, any pharmaceutical composition described herein can be used. These methods typically include administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a patient suffering from HCV, thereby lowering the level of HCV virus in the blood or liver of the patient. If the pharmaceutical composition comprises another (s) therapeutic (s) agent (s), then its action can also be directed to other diseases, disorders or conditions of the patient.

In one embodiment, the pharmaceutical composition that is administered contains at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt thereof, a solvate or prodrug, and at least one more anti-HCV agent selected from inhibitors of RNA-dependent RNA polymerase of HCV, inhibitors of HCV protease or inhibitors of HCV helicase. In another embodiment, the pharmaceutical composition that is administered contains at least one compound of the present invention selected from formula I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt, solvate thereof or a prodrug, and at least two other anti-HCV agents, each of which is independently selected from inhibitors of RNA-dependent HCV RNA polymerase, HCV protease inhibitors, or HCV helicase inhibitors. In yet another embodiment, the pharmaceutical composition that is administered contains at least one compound of the present invention selected from formula I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt thereof, a solvate or prodrug, and 1, 2 or more inhibitors of the RNA-dependent HCV RNA polymerase (e.g., the inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition that is administered contains at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII or examples 1-255, or a salt, solvate thereof or a prodrug, and 1, 2 or more HCV protease inhibitors (e.g., BILN-2061, VX-950, and SCH503034).

In yet another embodiment, the pharmaceutical composition that is administered contains at least one compound of the present invention selected from formula I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or a salt thereof, MES or prodrug, and at least one antiviral agent selected from anti-HIV agents, anti-HBV agents, anti-hepatitis A, hepatitis D, hepatitis E or hepatitis G.

In another aspect, the present invention relates to methods for using the compound (s) of the present invention and another (s) therapeutic (s) for the treatment of HCV infection. The methods include administering a therapeutically effective amount of the compound (s) of the present invention and other therapeutic agent (s) to a patient suffering from HCV, thereby lowering the level of the HVC virus in the blood or liver of the patient. Each compound of the present invention (or a salt, solvate or prodrug thereof) and other therapeutic agent (s) (s) can be combined into a general composition and administered to a patient at the same time. They can also be administered simultaneously in various compositions. In addition, they can be entered sequentially.

In one embodiment, the administration compound (s) of the present invention comprises (s) one or more compounds selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or their salts, solvates or prodrugs, and other therapeutic agent (s) administered (s) include (s) one or more agents selected from inhibitors of RNA-dependent HCV RNA polymerase, inhibitors of HCV protease or inhibitors HCV helicases. In another embodiment, the compound (s) administered (s) of the present invention comprise (s) one or more compounds selected from formulas I, II, III, IV, V, VI, VII or VIII or from Examples 1-255, or their salts, solvates or prodrugs, and other therapeutic agent (s) administered (s) include (s) two or more agents selected from inhibitors of RNA-dependent RNA polymerase HCV, inhibitors of HCV protease or inhibitors of HCV helicase. In yet another embodiment, the compound (s) to be administered according to the present invention include (s) one or more compounds selected from formulas I, II, III, IV, V, VI, VII or VIII or examples 1-255, or salts, solvates or prodrugs thereof, and other therapeutic agent (s) administered (s) include one, two or more inhibitors of the RNA-dependent HCV RNA polymerase (e.g., the inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the administered compound (s) of the present invention includes (are) one or more compounds selected from formula I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or their salts, solvates or prodrugs, and other administered therapeutic agent (s) include (s) one, two or more HCV protease inhibitors (e.g. BILN-2061, VX-950 and SCH503034) .

The compound of the present invention (or a salt, solvate or prodrug thereof) can also be administered in conjunction with other desirable drugs, such as anti-HIV drugs, anti-HBV drugs, anti-hepatitis A, hepatitis D, hepatitis E, hepatitis G, or others antiviral drugs.

The compound of the present invention (or a salt, solvate or prodrug thereof) may be administered to a patient in a single dose or in divided doses. A typical daily dose may range, without limitation, from 0.1 to 200 mg / kg body weight, for example from 0.25 to 100 mg / kg body weight. Unit dose formulations may contain these amounts or their fractional units to produce a daily dose. Preferably, each dose contains a sufficient amount of the compound of the present invention, which effectively reduces the level of HVC virus in the blood or liver of the patient. The amount of the active ingredient, or the active ingredients that are combined to form a single dosage form, may vary depending on the recipient and the particular route of administration. It is clear that the specific dose level for a particular patient will depend on various factors, including the activity of the particular compound used, age, body weight, general health, gender, diet, administration time, route of administration, rate of excretion, combination with other drugs, and severity the specific disease for which treatment is directed.

In yet another embodiment, the compounds of formulas I, II, III, IV, V, VI, VII or VIII, or their pharmaceutically acceptable salts, stereoisomers or tautomers, may be administered as an active pharmaceutical agent alone or used in combination with one or more others agents for treating infections or symptoms mediated by other RNA viruses.

Treatment or prevention of infection caused by RNA-containing viruses can be carried out by combination therapy containing a therapeutically effective amount of the first antiviral agent, provided that one or more compounds or their salts are compounds of formulas I, II, III, IV, V, VI , VII or VIII, together with a therapeutically effective amount of a second agent, provided that one or more compounds is selected from the group consisting of another antiviral agent; recipient immune modulator; an interferon derivative such as interferon-alpha, pegylated-interferon-alpha, interferon-beta and interferon-gamma; cytokine; vaccines; nucleoside analogue; inhibitors of major enzymes that lead to HCV dysfunction, examples of which are HCV metalloprotease enzymes, HCV serine protease, inosine monophosphate dehydroginase (IMPDH) and HCV helicase; viral particle protein inhibitors such as HCV NS4B protein and HCV NS5a protein; and agents that inhibit HCV function, such as penetration of HCV, assembly of HCV, and HCV release. Also included are vaccines containing HCV antigens, or combinations of antigens and adjuvants directed against HCV. In addition, these include agents that interact with the components of the host cells and block the synthesis of viral proteins by inhibiting the internal ribosome site of the virus (IRES), initiating the stage of translation of HCV virus replication, or blocking the maturation and release of viral particles, together with agents directed on membrane proteins of the viroporin family, such as, for example, HCV P7.

In one embodiment, the present invention relates to a method for treating or preventing an infection caused by an RNA-containing virus, comprising administering to a patient a therapeutically effective amount of a compound of Formulas I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a method for treating or preventing an infection caused by an RNA virus, comprising co-administering to a patient one or more agents selected from the group consisting of an immune modulator of a recipient and a second antiviral agent, or a combination thereof, and a therapeutically effective amounts of a compound of formulas I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention relates to a method for treating or preventing an infection caused by an RNA-containing virus, comprising co-administering to a patient one or more agents selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, cytokine, vaccine and vaccine containing antigen and adjuvant, and a second antiviral agent, or combinations thereof, with a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention relates to a method for treating or preventing an infection caused by an RNA-containing virus, comprising co-administering to a patient one or more agents selected from the group consisting of an immune modulator of a recipient and a second antiviral agent that inhibits HCV replication by inhibiting host cell functions associated with viral replication, or a combination thereof, with a therapeutically effective amount of a compound of formulas I, II, III, IV, V, VI, VII or VIII or e a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a method for treating or preventing an infection caused by an RNA virus, comprising co-administering to a patient an agent or combination of agents for treating or reducing symptoms of HCV infection, including cirrhosis and liver inflammation, with a therapeutically effective amount of a compound of formula I , II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a method for treating or preventing an infection caused by an RNA-containing virus, comprising co-administering to a patient one or more agents that are effective for treating a patient with a disease caused by hepatitis B virus (HBV), together with a therapeutically effective amount compounds of formulas I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention relates to a method for treating or preventing an infection caused by an RNA-containing virus, comprising co-administering to a patient one or more agents that are effective in treating a patient with a disease caused by human immunodeficiency virus (HIV), together with a therapeutically effective the amount of a compound of formulas I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.

The phrase “combination therapy” includes the introduction of each agent in a sequential manner in a mode that provides a satisfactory effect from the combination of drugs, and also includes the simultaneous administration of these drugs almost simultaneously, for example, by oral administration or with one capsule with a fixed ratio of these active agents, or taking many separate capsules of each agent. “Combination therapy” also includes co-administration or sequential administration by the oral, intravenous, intramuscular or other parenteral route into the body, including direct absorption through the mucous membrane, such as sinus sinuses. Sequential administration also includes combinations of drugs in which individual drugs can be administered at different times and / or in different ways, but which act in combination with achieving a beneficial effect, for example, by simultaneously affecting the pharmacokinetic or pharmacodynamic effects of each agent.

The present invention also relates to the use of the compounds of the invention or their pharmaceutically acceptable salts, solvates or prodrugs for the manufacture of medicaments for the treatment of HCV or other viral infections. In one embodiment, the present invention relates to the use of a compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII, or a salt, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of HCV infection . In another embodiment, the present invention relates to the use of two or more compounds of the present invention (or their salts, solvates or prodrugs) for the manufacture of a medicament for the treatment of HCV infection, where each of two or more compounds is independently selected from formulas I, II, III, IV, V, VI, VII or VIII.

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one additional therapeutic agent for the manufacture of a medicament for the treatment of HCV infection. Preferably, the compound (s) of the present invention is selected from compounds of formulas I, II, III, IV, V, VI, VII or VIII, and the additional therapeutic agent (s) may be selected, for example, but not limited to, from antiviral agents (e.g., anti-HIV agents or other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, and anti-inflammatory drugs. Specific examples of other therapeutic agents include, but are not limited to, ribavirin; interferons (e.g. IFN alpha 2a or 2b); protease inhibitors; immunosuppressive agents; antibodies (for example, therapeutic monoclonal or chimeric antibodies); antisense or siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); drugs for the treatment of cirrhosis and inflammation of the liver; IFN omega (BioMedicines Inc., Emeryville, CA); BILN-2061, a serine protease inhibitor (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel, an antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); roferon, A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis, PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis and ribavirin, PEGylated IFN-alpha 2a / ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); CellCept, IgG HCV immunosuppressant (F. Hoffmann-La Roche LTD, Basel, Switzerland); velferon, lymphoblastic IFN-alpha n1 (GlaxoSmithKline plc, Uxbridge, UK); albuferon alpha, albumin IFN alpha 2b (Human Genome Sciences Inc., Rockville, MD); levovirin, ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556, a caspase inhibitor (Idun Pharmaceuticals Inc., San Diego, CA); IP-501, an antifibrotic agent (Indevus Pharmaceuticals Inc., Lexington, MA); Aktimun, INF-gamma (InterMune Inc., Brisbane, CA); Infergen A, IFN Alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803, antisense oligonucleotides (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmaceuticals Inc., New York, NY); JTK-003, an RdRp inhibitor (Japan Tobacco Inc., Tokyo, Japan); pegasis and cling, PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals inc., San Diego, CA); cling, immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); civacir, HCV IgG immunosuppressant (Nabi Biopharmaceuticals Inc., Boca Raton, FL); intron A and zadaxine IFN-alpha 2b / alpha-1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); levovirin, an IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine, an IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); heptazim, ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); intron A, IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); PEG intron, PEGylated IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); rebetron, IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); ribavirin (Schering-Plow Corporation, Kenilworth, NJ); PEG intron / ribavirin; PEGylated IFN alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); preset immune modulator (SciClone Pharmaceuticals Inc., San Mateo, CA); rebif IFN-beta 1a (Serono, Geneva, Switzerland); IFN-beta and EMZ701, IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497, an IMPDH inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (Vertex Pharmaceuticals Inc.); compound SCH503034 (Schering-Plow Co.); and compound GS9137 (Gilead Sciences, Inc., Foster City, CA).

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one additional antiviral agent for the manufacture of a medicament for the treatment of a viral infection. Preferably, the compound (s) of the present invention is selected from compounds of formulas I, II, III, IV, V, VI, VII or VIII, and the additional antiviral agent (a) can be selected, without limitation, from anti-HCV or anti-HIV agents . In one example, the present invention relates to the use of at least one compound of the present invention selected from formula I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and at least one additional anti-HCV agent for the manufacture of a medicament for the treatment of HCV infection. Non-limiting examples of anti-HCV agents include inhibitors of RNA-dependent HCV RNA polymerase (e.g., nucleoside or non-nucleoside type polymerase inhibitors) or HCV protease inhibitors. In another example, the present invention relates to the use of at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and at least two or more additional anti-HCV agents for the manufacture of a medicament for the treatment of HCV infection. Each of the additional anti-HCV agents may be independently selected from inhibitors of RNA-dependent HCV RNA polymerase or HCV protease inhibitors.

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and at least at least one anti-HIV drug for the treatment of HIV or HCV infection. In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and at least at least one anti-hepatitis A, hepatitis B, hepatitis D, hepatitis E or hepatitis G drug for the manufacture of a medicament for the treatment of viral hepatitis. In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from formulas I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and at least at least one agent for treating inflammation of the liver, for a medicament for treating hepatitis C.

The above description of the present invention is given for illustration and description only and is not intended to be exhaustive or limiting in practice. Modifications and changes are possible in the light of the described information or can be detected in the practical implementation of the invention. Therefore, it should be noted that the scope of the invention is defined by the claims and equivalent objects.

Claims (17)

1. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula I

where B is a heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup, wherein B is optionally substituted with one or more R ¹⁸ ,
A represents phenyl, which is optionally substituted with one or more R ¹⁸ ,
R ^{18 is} independently selected in each case from the group consisting of halogen, hydroxy, C ₁ -C ₄ alkyl optionally substituted with halogen, C ₃ -C ₆ carbocyclyl optionally substituted with C ₁ -C ₄ alkyl, -L _s -OR _s , -L _s -SR _s and piperidine;
each W ₁ and W _{2 are} independently selected from N or C (R ³³ );
Z represents —NH—;
each R ¹⁰ and R ^{33 is} selected from the group consisting of hydrogen;
X is selected from the group consisting of -L _s -O-, -L _s -S-;
R ²² is hydrogen or phenyl optionally substituted with one or more R ²⁶ , where R ^{26 is} independently selected at each occurrence from the group consisting of halogen, hydroxy, amino, C ₁ -C ₄ alkyl, -L _s -OR _s , -L _E -QL _{E ′} - (carbocyclyl), where carbocyclyl means phenyl, and -L _E -QL _{E ′} - (heterocyclyl), where heterocyclyl is thiazole;
Y is selected from the group consisting of -L _s -O-, -L _s -S-, -L _s -C (O) - and -L _s -NH (SO) ₂ -;
R ⁵⁰ is —L ¹ -A ¹ , where L ¹ is a bond, and A ^{1 is} selected from the group consisting of carbocyclyl, where carbocyclyl is phenyl or C ₃ -C ₆ carbocyclyl, benzimidazolyl and C ₁ -C ₆ alkyl optionally substituted with phenyl, wherein A ^{1 is} optionally substituted with one or more R ³⁰ , and R ^{30 is} independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, amino, C ₁ -C ₄ alkyl, -L _s -N ( R _s R _{s ′} ), -L _s -C (O) N (R _s R _{s ′} ), -L _E -QL _{E ′} - (carbocyclyl), where carbocyclyl is selected from the group consisting of phenyl and naphthyl, and - L _E -QL _{E '-} (heterocyclyl), where g terotsiklil selected from the group consisting of thiophene, furan, quinoline, thiazole;
each R _s and R _{s ′ are} independently selected in each case from the group consisting of hydrogen and C ₁ -C ₄ alkyl, possibly substituted with cyano;
L _{s is} independently selected in each case from the group consisting of a bond, C ₁ -C ₄ alkylene and C ₁ -C ₄ alkenylene;
each L _E and L _{E ′ is} independently selected in each case from the group consisting of a bond, C ₁ -C ₄ alkylene and C ₁ -C ₄ alkenylene;
Q is independently selected in each case from the group consisting of, —O—, —N (R _s ) -, N (R _s ) C (O) -, —C (O) N (R _s ) -, —N (R _s ) C (O) O— and —C (O) O—;
each R ¹⁰ , R ¹⁸ , R ²⁶ , R ³⁰ and R ^{33 is} optionally independently substituted in each case with at least one substituent selected from the group consisting of halogen, hydroxy, cyano, amino and carboxy;
and
each carbocyclyl and heterocyclyl moiety in -L _E -QL _E - (carbocyclyl) and -L _E -QL _{E ′} - (heterocyclyl) is optionally independently substituted in each case with at least one substituent selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy. 2. The compound or pharmaceutically acceptable salt according to claim 1, where
And ^{1 is} selected from the group consisting of phenyl, C ₃ -C ₆ cycloalkyl and benzimidazolyl. 3. The compound or pharmaceutically acceptable salt of claim 2, wherein W ₁ and W ₂ are N. 4. The compound or pharmaceutically acceptable salt of claim 3, wherein X is —O— or —S—, and R ²² is phenyl. 5. The compound or pharmaceutically acceptable salt according to one of claims 2 to 4, where

selected from the group consisting of

and

and where R ¹⁰ represents hydrogen; and
each R ¹⁷ and R ^{35 is} independently selected in each case from the group consisting of C ₁ -C ₄ alkyl optionally substituted with halogen, C ₃ -C ₆ carbocyclyl optionally substituted with C ₁ -C ₄ alkyl, -L _s -SR _s and piperidine. 6. The compound or pharmaceutically acceptable salt according to claim 5, where R ²² represents

and optionally substituted with one or more R ²⁶ . 7. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula II:

Where
each R ⁶ and R ⁸ represents hydrogen;
R ^{25 is} selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;
R ^{37 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, and C ₃ -C ₆ cycloalkyl;
R ^{42 is} selected from the group consisting of phenoxy, naphthoxy, thiazolyloxy, phenylsulfanyl and pyrimidinylsulfanyl; where R ^{42 is} optionally substituted with one or more substituents independently selected from R ⁴⁶ ;
R ⁴⁶ represents one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, di-C ₁ -C ₄ alkylamino and C ₁ -C ₄ alkoxycarbonylamino;
R ^{70 is} selected from the group consisting of phenyl, thiazolyl, pyridinyl, tetrahydrofuranyl, benzimidazolyl, naphthyl, quinolinyl and thienyl; where R ⁷⁰ is an optionally substituted R ⁷⁵ ; and
R ⁷⁵ represents one or more substituents independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkoxy, cyano, C ₁ -C ₄ alkyl, halogen-C ₁ -C ₄ alkyl and phenyl. 8. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula III:

where R ^{80 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkylcarbonyl and halogen phenyl. 9. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula IV:

where Q is selected from the group consisting of N and CH;
R ¹ represents C ₁ -C ₄ alkyl;
R ^{19 is} selected from the group consisting of C ₁ -C ₄ alkyl and halo phenyl C ₁ -C ₄ alkoxy; and
R ^{56 is} selected from the group consisting of hydrogen, hydroxy and C ₁ -C ₄ alkyl. 10. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula V:

where R ^{5 is} selected from the group consisting of hydrogen and C ₁ -C ₄ alkylsulfanyl;
R ^{29 is} selected from the group consisting of C ₁ -C ₄ alkyl, phenylC ₁ -C ₄ alkoxy, halogen and halogenophenyl-C ₁ -C ₄ alkoxy;
R ^{47 is} selected from the group consisting of C ₁ -C ₄ alkyl, halogen-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylsulfanyl, phenyl-C ₁ -C ₄ alkylsulfanyl and piperidine;
R ⁶⁴ represents hydrogen;
R ^{66 is} selected from the group consisting of hydrogen, hydroxy, halogen and C ₁ -C ₄ alkyl; and
R ⁸¹ represents hydrogen. 11. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula VI:

where R ⁷³ represents a C ₁ -C ₄ alkyl; and
R ^{76 is} selected from the group consisting of hydroxy, C ₁ -C ₄ alkylaminocarbonyl and C ₁ -C ₄ alkylcarbonylamino. 12. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula VII:

where A is selected from the group consisting of O and S;
R ^{21 is} selected from the group consisting of hydrogen and hydroxy;
R ^{39 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, phenylalkenyl, C ₁ -C ₄ dialkylamino, heteroaryl, haloheteroaryl, halogen phenylaminosulfonyl, phenylsulfonyloxy, C ₁ -C ₄ alkylcarbonyloxy, C ₃ -C ₆ cycloalkylaminocarbonylcarbonyl, phenyl C ₁ -C ₄ alkoxycarbonyl and NH-R ⁹⁹ , wherein heteroaryl is selected from the group consisting of thiophenyl, quinolinyl, benzimidazolyl, pyrrolyl and thiazolyl;
R ^{99 is} selected from the group consisting of hydrogen, phenylC ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkylalkyl, phenyl, naphthyl, heteroaryl, halogen phenylalkylamino, phenylC ₁ -C ₄ alkylamino and C ₁ -C ₄ alkylheteroaryl, where heteroaryl is selected from a group consisting of thiophenyl, quinolinyl, furanyl, pyrrolyl pyridopyrimidinyl and thiazolyl;
R ^{67 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₄ alkyl-C ₃ -C ₆ cycloalkyl; and
R ^{96 is} selected from the group consisting of hydrogen, hydroxy, amino, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylcarbonylamino, halogen, and phenylalkoxy. 13. The compound or pharmaceutically acceptable salt of the compound, where the compound has the formula VIII:

where R ^{23 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkoxyphenyl, C ₁ -C ₄ alkoxyphenylsulfanyl, hydroxyphenylsulfanyl, halogenophenyl-C ₁ -C ₄ alkoxy, cyanophenyl-C ₁ -C ₄ alkoxy and phenylalkoxy;
R ^{31 is} selected from the group consisting of hydrogen and halogen;
R ^{49 is} selected from the group consisting of hydrogen, phenyl-C ₁ -C ₄ alkoxy, halogen phenylcarbonylamino, C ₁ -C ₄ alkoxyphenylcarbonylamino, phenyl-C ₁ -C ₄ alkenyl, phenyl-C ₁ -C ₄ alkyl, halogen, cyano, haloaryloxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyphenylsulfanyl and C ₁ -C ₄ alkoxycarbonyl;
R ^{52 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, hydroxyphenyloxy, phenyloxy, hydroxy C ₁ -C ₄ alkylphenyloxy, C ₁ -C ₄ alkoxyphenyl C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyphenyloxy, C ₁ -C ₄ alkylphenyl-C ₁ -C ₄ alkoxyphenylamino and aminophenyloxy; and
R ^{77 is} selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl. 14. A pharmaceutical composition having the properties of an inhibitor of HCV viral infection, containing a compound or pharmaceutically acceptable salt according to any one of claims 1 to 13 in an effective amount. 15. A method of inhibiting replication of HCV virus, comprising contacting the HCV virus with an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, thereby inhibiting the replication of said virus. 16. A method of treating HCV infection, comprising administering an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 13 to a patient suffering from HCV. 17. The use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of HCV infection or inhibition of HIV replication.