MX2008008161A - Anti-viral compounds - Google Patents

Abstract

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

Description

ANTI-VIRAL COMPOUNDS This application claims the benefit and incorporates here by reference all the content of the Provisional Application of E.U.A. No. 60 / 752,473, filed on December 21, 2005.

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

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

HCV infection is associated with progressive liver disease, including cirrhosis and hepatocellular carcinoma. End-stage liver disease associated with HCV is the most common indication for liver transplantation among adults. Chronic hepatitis C can be treated with an injection, once a week, of peginterferon-alpha in combination, daily, with ribavarin. Peginterferon-alpha is interferon-alpha linked to polyethylene glycol to reduce the elimination of the drug from the body. This results in improved attachment and anti-vira activity! clinically superior when compared to treatments of daily interferon-alpha injections. Substantial limitations remain in efficacy and tolerability since many users suffer from side effects and viral elimination from the body is usually inadequate. Attempts have been made to design drugs that specifically inhibit the functions of the hepatitis C virus. Boehringer Ingelheim, U.S. Pat. No. 6,323,180 mentions tri-peptide compounds as inhibitors of HCV serine protease proposed for the treatment of HCV infection. Another aspect is ISIS-14803 (Isis Pharmaceuticals), an antisense inhibitor complementary to a conserved sequence of the hepatitis C virus RNA. This molecule binds to the viral RNA and inhibits the expression of proteins required for replication. Inhibition of HCV translation, via yeast RNA that binds to cellular polypeptides and prevents their interaction with the viral internal ribosome entry site (IRES), is described in Das et al, J. VIROLOGY, 72 ( 7): 5638-5647 (1998). Heterocyclic, bicyclic, fused compounds have been proposed for various uses related to life-science. Examples of such heterocyclic compounds include naphthyridine, pyridopyrimidine, pyrimidopyrimidine, pyrazolopyrimidine and thiazolo / thienopyrimidine compounds. Fused bicyclic compounds of the naphthyridine type have been investigated for disease treatment uses. For example, Boots WO 93/13097, published on July 8, 1993, mentions [1, 8] naphthyridine compounds, such as ethyl 4- (4-methoxyanilino) -6-efoxy-7-methyl-1, 8-naphthyridine-3-carboxylate-hydrochloride, proposed for use as anti-rheumatic agents. Boots WO 95/00511, published January 5, 1995, mentions fused ring 4-aminopyridines, such as 3-ethoxy-5- (2-ethoxy-5-pyridylamino) -2-methyl-1,8-naphthyridine, proposals as anti-rheumatic agents. Zeneca WO 98/13350, published on April 2, 1998, mentions compounds [1, 8] n af tir id ina, such as 2-acetamido-5- (2-fluoro-5-hydroxy-4-methylanilino) hydrochloride -l, 8-naphthyridine, proposed as anti-angiogenic agents. Neurogen WO 2004/055004, published July 1, 2004, mentions naphthyridine compounds as capsaicin receptor modulators, the specific compounds being 5- (4-trifluoromethyl-phenylamino) -2- (3-trifluoromethyl-pyridin-2) acid -yl) - [1,6] naphthyridine-7-carboxylic acid, and 2-methoxymethyl-4- (4-trifluoromethyl-phenylamino) -7- (3-trifluoromethyl-pyridin-2-yl) - [1,8] naphthyridine-3-carboxylic acid. Fused bicyclic compounds of the pyridopyrimidine type have been investigated for various disease treatment uses. For example, Pfizer WO 98/05661, published on February 12, 1998, mentions substituted pyridopyrimidine compounds, such as 8- (1-ethyl-propyl) -2-methyl-5,6,7,8-tetrahydro-pyrido ( 2,3-d) pyrdin-4yl3- (2,4,6-trimethyl-phenyl) -amine, as CRF antagonists (hormone) (CRH) corticotrophin release factor proposed for the treatment of Alzheimer's Disease and obesity . Pfizer WO 98/23613, published on June 4, 1998, mentions compounds of bicyclic-fused pyrimidines, including pyridopyrimidinyl-aminophenyl compounds, such as (3-ethynyl-phenyl) -pyrido [3,4-d] pyrimidin-4-yl-amine, proposed for the treatment of proliferative diseases such as cancer. Glaxo Wellcome Patent of E.U.A. No. 6,169,091, issued January 2, 2001, mentions heteroaromatic bicyclic compounds, such as 4- (4-benzyloxyanilino) pyrido [2,3-d] -pyrimidine, as inhibitors of tyrosine kinase for the treatment of fibrosis, inflammation , diseases of the nervous system and cancer. Eli Lilly WO 01/32632, published May 10, 2001, mentions 4-substituted pyrimidine compounds, including 2-trifluoromethyl-4- [2- (2- (2-chlorophenyl) ethylamino] pyrido- [2] hydrochloride. 3-d] pyrimidine, as mGluRI antagonists proposed for the treatment of neurological disorders associated with glutamate dysfunction such as seizures, migraine, psychosis, anxiety and pain Abbott Laboratories WO 01/57040, published on August 9, 2001, mentions 6,7-disubstituted 4-aminopyrido [2,3-d] pyrimidine compounds, such as 4-amino-6- (4-methylphenyl) -7- (4-bromophenyl) pyrido [2,3-d] pyrimidine, as Adenosine kinase inhibitors proposed for the treatment of pain and inflammation Neurogen WO 2004/055004, published on July 1, 2004, mentions pyridopyrimidinyl-aminophenyl compounds, such as 2-methyl-2- { 4- [2 -methyl-7- (3-methyl-pyridin-2-yl) -pyrido [2,3-d] pyrimidin-4-ylamino] -phenyl} -propionic, as modulators of capsaicin receptor. nte of E.U.A. No. 6,395,733, issued on May 28, 2002, mentions compounds of heterocyclic ring fused pyrimidine, such as 3-chloro-phenyl-pyrido [2,3-d] pyrimidin-4-yl-amine, proposed for the treatment of hyperproliferative disease, such as cancer. Fused bicyclic compounds of the pyrimidopyrimidine type have been investigated both for pest control and for disease treatment uses. For example, Dow Elanco, Patent of E.U.A. No. 5,350,749, issued September 27, 1994, mentions proposed 4-substituted pyrimido [2,3-d] -pyrimidine compounds for use as fungicides, insecticides and miticides. Warner-Lambert WO 95/19774, published July 27, 1995, mentions pyrimidopyrimidine compounds, such as 4-benzylamino-7-methylaminopyrimido [4,5-d] pyrimidine, as tyrosine kinase inhibitors proposed for the treatment of Cancer, vascular restenosis and psoriasis. Fused bicyclic compounds of the thienopyrimidine type have been investigated for various uses in the treatment of diseases. For example, Warner-Lambert WO 95/19774, published July 27, 1995, mentions heterocyclic fused pyrimidine compounds, including 4- (3-bromoanilino) thieno [2,3-d] pyrimidine, as tyrosine kinase inhibitors. proposed for the treatment of cancer, vascular restenosis and psoriasis. Glaxo Wellcome, Patent of E.U.A. No. 6,169,091, issued January 2, 2001, mentions heteroaromatic bicyclic compounds, such as 5-methyl-4- (4-phenoxyanilino) thieno [2,3-d] pyrimidine hydrochloride as inhibitors of tyrosine kinase, proposed for he treatment of fibrosis, inflammation, diseases of the nervous system and cancer. Eli Lilly WO 01/32632, published May 10, 2001, mentions 4-substituted pyrimidine compounds, such as 6-methyl-4- [2,6-dichlorobenzylthio) ethylamino] -thieno [2,3-d] hydrochloride ] pyrimidine, as mGluRI antagonists for the treatment of neurological disorders associated with glutamate dysfunctions such as seizures, migraine, psychosis, anxiety and pain. Bristol-Myers Squibb WO 2004/014852, published on February 19, 2004, mentions iminothiazolidinones, including bicyclic fused derivatives of 2- (4-aminophenyl) -5H-thiazolo [2,3-6] quinazolin-3-one, as NS5A protein inhibitors proposed to prevent the replication of HCV. Bristol-Myers Squibb WO 2004/014313, published February 19, 2004, mentions combination therapies for the treatment of viral diseases, including iminothiazolidinone, anti-HCV compounds that inhibit NS5A protein in combination with other agents capable of interfering with function of HCV.

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

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

Compounds The present invention relates to compounds having the Formula I, tautomers thereof, and pharmaceutically acceptable salts of the compounds or tautomers, I wherein: A and B are each independently selected from carbocyclic or heterocyclyl, and each independently substituted with one or more of R18, wherein R18 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, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0 ) ORs, -LS-N (RSRS), -LS-C (= NRS) RS ', -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls -N (Rs) C (0) RS ', -LS-C (= NRS) N (RS.RS ||). -LS-N (RS.) C (= NRS) RS .., -Ls-N (Rs) C (0) N (Rs Rs ||). -Ls-N (Rs) S02RS ', -Ls-S02N (RsRs), and -Ls- N (Rs) S02N (Rs Rs); W, and W2, each is selected from N or C (R33); Z is a bond, -CR R41- or -NR41-, wherein R41 and R41 'are each independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; R10 and R33 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -Ls-O-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs'), -Ls-C (= NRs) Rs-, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs- , -Ls-C (= NRs) N (Rs RS '), -Ls- N (Rs) C (= N Rs) Rs'. -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs-, -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs ··). -LE-Q-LE. - (C3-Ci8 carbocyclyl) and -LE-Q-LE - (heterocyclyl of M3-18); X is selected from the group consisting of a bond, -Ls-0-, -Ls-S-, -Ls-C (O) -, -Ls-N (Rs) -, - Ls-N (Rs) C ( 0) -, -Ls-C (0) N (Rs) -, -Ls-N (Rs) C (0) 0-, -Ls-OC (0) N (Rs) -Ls-N (Rs) C (0) N (Rs -) -, -Ls-C (= NRS) N (RS) -, -LS-N (RS) C (= NRS) -, -Ls-S (0) -, -Ls- S02-, -Ls-C (0) 0-y-Ls-OC (O) -; R22 is carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R26, wherein R26 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl , phosphate, azido, alkyl, alkenyl, alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRS) RS ', -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRS'), -Ls -N (Rs) C (0) Rs-, -Ls-C (= NRs) N (Rs Rs ··) | -Ls-N (Rs.) C (= NRs) Rs ", -Ls-N (Rs) ) C (0) N (Rs-Rs-). -Ls-N = C (NRsRs <) (NRsRs '), -Ls-N (Rs) S02RS', -Ls-S02N (RSRs), -Ls- N (Rs) S02N (Rs.Rs ||), - LE-Q-LE- (carbocyclyl of C3 - and -LE-Q-LE - (heterocyclyl of M3-M18), or R22 is alkyl, alkenyl or alkynyl, and is optionally substituted with one or more of R26, or R22 is hydrogen, and Y is selected from the group consisting of a bond, -O-, -C (O) -, -S (0) 2-, -S (O ) -, -OS (0) 2-, - OS (O) -, -C (0) 0-, -OC (O) -, -OC (0) 0-, -C (0) N (R15) -, -N (R15) C (0), -C (O) N (R 15) O- , - N (R15) C (0) 0-, -C (0) N (R5) N (R15 '), -S-, -C (S) -, -C (S) 0-, -OC (S) -, -C (S) N (R15), -N (R15) -, -N (R15) C (S) -, -N (R15) S (0) -, -N (R15) S (0) 2-, -S (0) 2N (R15) -, S (0) N (R15), -C (S) N (R15) 0-, and -C (S) N (RS) N ( R15 ') -, wherein R15 and R5 > are independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl; R50 is -L1- A1, wherein A1 is selected from the group consisting of carbocyclyl, heterocyclyl, alkyl, alkenyl and alkynyl, and L1 is selected from the group consisting of a bond, alkylene, alkenylene and alkynylene, wherein A1 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl , -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRs) Rs-, -Ls-S (0) Rs, -Ls- S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs-, -LS-C (= NRS) N (RS RS | ·), -LS-N (RS) ) C (= NRS) RS ·, -Ls-N (RS) C (0) N (RS'-Rs), -LS-N (RS) S02RS'-, -LS-S02N (RsRs), -LS- N (RS) S02N (Rs RS "), -LE-Q-LE '- (carbocyclyl of C3-C18) and -LE-Q-LE - (heterocyclyl of M3-M | 8), and where L1 is optionally substituted with one or more of R38, and R38 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkoxy, thioalkoxy , alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylamino, alkoxycarbonylamino, -Ls-O-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -LS-OC (0) RSj -Ls-C (0) ORs , -Ls-N (Rs s'), -LS-C (= NRS) RS, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls- N (Rs) C (0) RS ', -Ls-C (= NRs) N (Rs Rs ||). -Ls-N (Rs.) C (= NRs) Rs -Ls-N (Rs) C ( 0) N (RS'Rs "), -Ls-N (Rs) S02RS ', -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs). carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, -LE-Q-LE - (C3-C18 carbocyclyl) and - LE-Q-LE - (heterocyclyl of M3-M 8); Ls is independently selected at each occurrence of the group consisting of a bond, alkylene, alkenylene and alkynylene; Rs, Rs' and Rs "are independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino and alkoxycarbonylaminoalkyl; LE and LE are independently selected at each occurrence from the group consisting of a bond, alkylene, alkenylene and alkynylene; Q is independently selected at each occurrence from the group consisting of a bond, alkylene, alkenylene, alkynylene , -S-, -O-, -C (O) -, -N (Rs) -, -N (Rs) C (0), -C (0) N (Rs) -, - N (Rs) C (0) 0-, -OC (0) N (Rs) -, -N (Rs) C (0) N (Rs) -, -C (= N Rs) N (Rs) -, -N (RS) C (= NRS) -, -S (O) -, -S02-, -O-SOz-, -S02-0-, -OS (O), -S (0) -0-, -C (0) 0- and -OC (O); R10, R5, R15, R18, R26, R30, R33, R35, R38, R41, and R41 'are independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate and azido; and each carbocyclyl portion of C3-C18 and heterocyclyl of M3-Mi8 in -LE-Q-LE '- (C3-C18 carbocyclyl) and -LE-Q-LE. - (heterocyclyl of M3-M18) is independently optionally substituted in each occurrence with at least one substituent selected from the group it consists of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino, and alkoxycarbonylaminoalkyl. In one embodiment, the present invention relates to compounds having Formula I, their tautomers, and pharmaceutically acceptable salts of the compounds or tautomers, wherein: A and B are independently selected from a C -C carbocyclyl or M4 heterocyclyl M14, and are optionally substituted with one or more of R 8, wherein R18 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate , azido, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocyclyl, heterocyclyl of M3-M6, -Ls-0-Rs, -Ls-S-Rs, -Ls- C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS '), -Ls-C (= NRS) RS', -Ls-S (0) ) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs-, -Ls-C (= NRs) N (Rs Rs), -LS -N (RS) C (= NRS) Rs-, -Ls-N (Rs) C (0) N (RS'Rs-). -Ls-N (Rs) S02RS ', -Ls-S02N (RsRs), and -Ls-N (Rs) S02N (Rs Rs); Wi and W2 each are selected from N or C (R33); Z is a bond, -CR 1R41- or -NR41-, wherein R41 and R41 'are each independently selected from the group consisting of hydrogen, C 1 -Ce alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl; R10 and R33 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C-C6 alkyl, C2 alkenyl -C6, C2-C6 alkynyl, C3-C6 carbocyclyl, heterocyclyl of M3-M6, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0 ) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRs) Rs-, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C ( 0) N (RsRs), -Ls-N (Rs) C (0) RS ', -LS-C (= NRS) N (RS.RS), -Ls- N (RS) C (= NRS) RS · , -Ls-N (Rs) C (O) N (Rs Rs, -Ls-N (Rs) S02Rs-, -Ls-SO2N (RsRs, -Ls-N (Rs) S02N (Rs-Rs "). LE-Q-LE - (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M 8); X is selected from the group consisting of a bond, -Ls-0-, -Ls -S-, -Ls-C (O) -, -Ls-N (Rs) -, - Ls-N (Rs) C (0) -, -Ls-C (0) N (Rs) -, -Ls -N (Rs) C (0) 0-, -Ls-OC (0) N (Rs) -Ls-N (Rs) C (0) N (Rs) -, -Ls-C (= NRS) N ( RS) -, -Ls-N (RS ') C (= NRs) -, -Ls-S (0) -, -Ls-S02-, -Ls-C (0) 0 -and -Ls-OC (O ) -; R22 is C4-C carbocyclyl or M4-Mn heterocyclyl, and is optionally is substituted with one or more of R26, wherein R26 is independently selected at each occurrence of the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, Ci alkyl -C6, C2-C6 alkenyl, C2-C6 alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs. -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -LS-C (= N RS) RS ', -Ls-S (0) Rs, -Ls-S02Rs, -l_s-C (0) N (RsRs), -Ls- N (RS) C (0) RS-, -Ls-C (= NRs) N (Rs Rs ||). -Ls-N (Rs) C (= NRs) Rs -Ls-N (Rs) C (0) N (Rs Rs | ·), -LS-N = C (NRSRS) (NRSRS |). -Ls-N (Rs) S02RS ', -Ls-S02N (RSRs), -Ls-N (Rs) S02N (Rs Rs). - LE-Q-LE- (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18); or R22 is C ^ -C6 alkyl, C2-C6 alkenyl, or C2-Ce alkynyl, and is optionally substituted with one or more of R26; or R22 is hydrogen; And it is selected from the group consisting of a bond, -Ls-0-, -Ls-C (O) -, -Ls-S (0) 2-, -Ls-S (O) -, -Ls-OS ( 0) 2-, -Ls-OS (0) -, -Ls-C (0) 0, -Ls-OC (O) -, -Ls-OC (0) 0-, -Ls-C (0) N (R15) -, -Ls-N (R15) C (0), -Ls-C (0) N (R15) 0-, -Ls-N (R5) C (0) 0-, -Ls-C (0) N (R15) N (R15 '), -Ls-S-, -Ls-C (S) -, -Ls-C (S) 0-, -Ls-OC (S) -, -LS- C (S) N (R15), -LS-N (R15) -, -LS-N (R15) C (S) -, -Ls-N (R15) S (0) -, -Ls-N (R 15) S (0) 2-, -Ls-S (0) 2N (R15) -, -Ls-S (0) N (R15), -Ls-C (S) N (R15) 0-, and - LS-C (S) N (R1S) N (R15 ') -, wherein R15 and R15 are independently selected at each occurrence from the group consisting of hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, and alkynyl of C2-C6; R50 is -L1-A1, wherein A1 is selected from the group consisting of C4-C carbocyclyl, M4- heterocyclyl, alkyl, alkenyl, and alkynyl, and L1 is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene, wherein A1 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, Ci-C6 alkyl, C2-C6 alkenyl, alkynyl of C2-C6, -Ls-O-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RSRs), -LS-C (= N RS) RS-, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls- N (Rs) C (0) Rs-, -LS-C (= NRS) N (RS Rs ||) | -Ls-N (Rs-) C (= NRs) Rs ", -Ls-N (RS) C (0) N (RS'-Rs-). -LS-N (RS) S02RS'-, -LS-S02N (RsRs), -LS-N (RS) S02N (Rs RS "), -LE-Q-LE - (carbocyclyl of C3-C18) and -LE-Q-LE- (heterocyclyl of M3-M, 8), and wherein L1 is optionally substituted with one or more of R38, and R38 is independently selected in each occurrence of the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, d-C6 alkoxy, d-C6 thioalkoxy, dd alkylcarbonyl, Ci-C6 alkoxycarbonyl, dd alkylcarbonyloxy , alkylamino of dd, alkoxycarbonylamino of dd, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -LS-C (= NRS) RS ', -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N ( Rs) C (0) Rs., -Ls-C (= NRs) N (RS'Rs "), -Ls-N (Rs) C (= N Rs) Rs |, -Ls-N (Rs) ) C (0) N (RS'Rs "). -Ls-N (Rs) S02RS ', -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs). carbocyclyl, heterocyclyl, carbocyclylalkyl of d-Ce, heterocyclylalkyl of d-Ce, -Le-Q-LE- (carbocyclyl of C3-C18) and -LE-Q-LE- (heterocyclyl of M3-M8); Ls is independently selected in each occurrence of the group consisting of a bond, alkylene of d-Ce, C2-C6 alkenylene and C2-C6 alkynylene; Rs, Rs 'and s' are independently selected in each occurrence of the group consisting of hydrogen, d-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, d-C6 alkoxy, thioalkoxy Ci-C6, Ci-C6 alkoxy dd alkyl, dd-C6 alkoxy dd alkyl, dd alkyl thioalkoxy dd alkyl, dd alkylcarbonyl, dd alkyl dd alkyl, alkoxycarbonyl dd, dd alkoxycarbonyl dd, dd alkylcarbonyloxy dd alkylcarbonyloxy ddC6 alkyl, dd alkylamino, dd alkylamino of dd, dd alkoxycarbonylamino and dd alkoxycarbonylamino of dd; LE and LE 'are independently selected in each occurrence of the group consisting of a bond, d-d alkylene, d-alkenylene and d-alkynylene; Q is independently selected at each occurrence from the group consisting of a bond, dd alkylene, dd alkenylene, dd alkynylene, -S-, -O-, -C (O) -, -N (RS) -, - N (Rs) C (0), -C (0) N (Rs) -, -N (Rs) C (0) 0-, -OC (0) N (Rs) -, -N (Rs) C ( 0) N (Rs) -, -C (= NRS) N (RS) -, -N (RS) C (= NRS) -, -S (O) -, -S02-, -0-S02-, - S02-0-, -OS (O), -S (0) -0-, -C (0) 0- and -OC (O); R10, R15, R15 ', R18, R26, R30, R33, R35, R38, R41, and R41' are independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate and azido; and each carbocyclyl portion of C3-C18 and heterocyclyl of M3-M8 in -LE-Q-LE- (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18) is independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, d-d alkyl. C2-C6 alkenyl, C2-C6 alkynyl, dd alkoxy, dd thioalkoxy, dd-C1-C6 alkyl alkoxy, dd alkyl dd alkyl, dd alkylcarbonyl, dd alkyl dd alkylcarbonyl, Ci-C6 alkoxycarbonyl, dd alkoxycarbonyl of dd, dd alkylcarbonyloxy, dd-C6 alkyl dicarboxyloxycarbonyl, dd alkylamino, dd alkylamino of C, -C6, dd alkoxycarbonylamino, and alkoxycarbonylamino of d-C6-dd alkyl- In one example of this embodiment, Y is -Ls-0-, -Ls-S- or LS-N (R15) -, and R50 month -L1-A1, wherein L1 is a bond, d-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene and is optionally substituted with one or more of R38, and A1 is dC carbocyclyl or MrM heterocyclyl and is optionally substituted with one or more of R30. In another example of this embodiment, Y is a bond, and R50 is -L1-A1, where L1 is a bond, dd alkylene, C2-C6 alkenylene or C2-C6 alkynylene and is optionally substituted with one or more of R38, and A1 is d-di or heterocyclyl carbocyclyl of M4-M and is optionally substituted with one or more of R30. In yet another example of this embodiment, Y is a bond, and R50 is -L1-A1, wherein L1 is selected from the group consisting of a bond, alkylene of d-d, C2-C6 alkenylene and alkynylene of C2-C6 and is optionally substituted with one or more of R38, and A1 is hydrogen or R18. In yet another example of this embodiment, Y is selected from the group consisting of -Ls-S (0) 2N (R15) -, -Ls-OS (0) 2-, -Ls-OC (0) -, Ls- C (0) 0-, -Ls-C (O) - and -N (R15) C (0) 0-. In yet another example of this embodiment, A and B are each independently selected from C5-C6 carbocyclyl or M5-M6 heterocyclyl and each independently are optionally substituted with one or more of R18. In yet another example of this embodiment, Wt and W2 are N, and Z is -NR41-. In still another example of this embodiment, X is -O- or -S-, and R22 is C5-C6 carbocyclyl or M5-M6 heterocyclyl and is optionally substituted with one or more of R24. In another additional example of this embodiment, the portion where: W1, W2, W3 and W4 are each independently selected from n or c (R33); and R10, R17, R33 and R35 each is independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl- C6, C2-C6 alkenyl, C2- alkynyl C6, C3-C6 carbocyclyl, heterocyclyl of M3-M6, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs, -Ls-C (= NRS) RS, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls - N (Rs) C (0) Rs-, -Ls-C (= NRs) N (RS'Rs "). -Ls-N (Rs.) C (= NRs) Rs | ·, -Ls-N ( Rs) C (0) N (Rs.Rs-), -Ls-N (Rs) S02RS ', -Ls-SO2N (RsRs, -Ls-N (Rs) S02N (Rs Rs | ·). -LE-Q -LE- (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18).

In another example of this modality, the portion is selected from the group consisting of wherein: Q is N or C (R33) and R 0, R17, R33 and R35 each is independently selected in each occurrence of the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino , carboxy, formyl, phosphate, azido, d-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocyclyl, heterocyclyl of M3-M6, -Ls-0-Rs, -Ls-S -Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS-). -Ls-C (= NRs) Rs', -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs-). -Ls-N (Rs) C (0) Rs-, -Ls-C (= NRs) N (Rs-RS "). -LS-N (RS) C (= NRS) RS ', -Ls-N ( Rs) C (0) N (Rs.RS "), -Ls-N (Rs) S02RS ', -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs'), -LE-Q -LE- (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18). In a further example of this embodiment, A and B are each independently selected from C5-C6 carbocyclyl or 5-M6 heterocyclyl and each independently is optionally substituted with one or more of R18, wherein: W, and W2 are N; Z is -NR41; X is -O- or -S-; R22 is C5-C6 carbocyclyl or 5-M6 heterocyclyl and is optionally substituted with one or more of R26; Y is a bond, -Ls-0-, -Ls-S-, or -LS-N (R15) - and A1 is C5-C10 carbocyclyl or M5-M10 heterocyclyl and is optionally substituted with one or more of R30 . In yet another example of this embodiment, A and B are each independently selected from C5-C6 carbocyclyl or M5-M6 heterocyclyl and each independently is optionally substituted with one or more of R18, wherein: W, and W2 are N; Z is -NR41; X is -O- or -S-; where R 48 is hydroxy, amino, C-C alkylamino, C-C6 alkoxy, Ci-C6 alkoxycarbonylamino or Ci-C6 alkylcarbonyloxy, and R22 (e.g., R48 or the phenyl ring in R22) is optionally substituted with one or more of R26; Y is a bond, -Ls-0-, -Ls-S-, or -LS-N (R15) - and A1 is C5-C10 carbocyclyl or heterocyclic of M5-M10 and is optionally substituted with one or more of R30. another example of this modality, the porció is selected from the group consisting of where: Q is N or C (R33); R10, R7, R33 and R35 each is independently selected in each occurrence of the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl of C! -Ce, C2-C6 alkenyl, C2 alkynyl C6, C3-C6 carbocyclyl, heterocyclyl of M3-M6, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRS) RS, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs'), -Ls-N (Rs) C (0) RS ', -LS-C (= NRS) N (RS RS |), -LS-N (RS) C (= NRS) RS ·, -Ls-N (Rs) ) C (0) N (Rs-s ") -Ls-N (Rs) S02Rs., -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs), -LE-Q-LE - (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M 8): A is C5-C6 carbocyclyl or heterocyclyl of M5-M6 and is optionally substituted with one or more of R18; Z is -NR41-; X is -O- or -S-; , 22 is where R 8 is hydroxy, amino, C-C alkylamino, C-C6 alkoxy or C-C6 alkoxy or Ci-C6 alkylcarbonyloxy, and R22 (e.g., R48 or the phenyl ring in R22) is optionally substituted with one or more of R26; Y is a bond, -Ls-0-, -Ls-S-, or -LS-N (R1S) - and A1 is C5-C10 carbocyclyl or M5-M10 heterocyclyl and is optionally substituted with one or more of R30 . In another embodiment, the present invention relates to a family of pyridopyrimidinyl aminophenyl ether compounds, tautomers of the compounds, or pharmaceutically acceptable salts of the compounds or tautomers, wherein the compounds of this family correspond in structure to the Formula p wherein: R6 is selected from the group consisting of hydrogen and cyano; R8 is selected from the group consisting of hydrogen and arylalkyl; R25 is selected from the group consisting of hydrogen and alkyl; R37 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and cycloalkyl; R42 is selected from the group consisting of arylsulfanyl, heteroarylsulfanyl and aryloxy; wherein R42 is optionally substituted with one or more substituents independently selected from R46; R46 is one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, dialkylamino, and alkoxycarbonylamino; R70 is selected from the group consisting of aryl, and heterocycle; wherein R70 is optionally substituted with R75; R 75 is one or more substituents independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, alkyl, haloalkyl and aryl. In a subgroup family of this embodiment within Formula II, R6 is selected from the group consisting of hydrogen and cyano; R8 is selected from the group consisting of hydrogen and phenylmethyl; R25 is selected from the group consisting of hydrogen and methyl; R37 is selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, isopropyl, hydroxymethylethyl and cyclohexyl; R42 is selected from the group consisting of phenylsulfanyl, phenoxy and pyrimidinylsulfanyl; R46 is selected from the group consisting of hydrogen, hydroxy, amino,?,? - dimethylamino, and t-butoxycarbonylamino; R70 is selected from the group consisting of phenyl, thiazolyl, pyridinyl, tetrahydrofuranyl, naphthyl, quinolinyl and thienyl; R 75 is one or more substituents selected from the group consisting of hydrogen, methyl, butyl, hydroxy, methoxy, bromo, chloro, fluoro, cyano, trifluoromethyl and phenyl. In still another embodiment, the present invention relates to a family of pyridopyrimidinyl-aminophenyl alkyl ether compounds, tautomers of the compounds, or pharmaceutically salts acceptable compounds or tautomers, wherein the compounds of this family correspond in structure to the Formula m wherein R is selected from the group consisting of hydrogen, alkylcarbonyl and haloaryl. In a subgroup family of this embodiment within Formula III, R80 is selected from the group consisting of hydrogen, methylcarbonyl and bromophenyl. In still another embodiment, the present invention relates to a family of thiazolopyrimidinyl-aminophenyl and thienopyrimidinyl-aminophenyl compounds, tautomers of the compounds, or pharmaceutically acceptable salts of the compounds or tautomers, wherein the compounds of this family correspond in structure to Formula IV: IV wherein: Q is selected from the group consisting of N and CH; R1 is selected from the group consisting of alkylsulfanyl, cyanoalkylsulfanyl and alkyl; R19 is selected from the group consisting of alkyl and haloarylalkoxy; R56 is selected from the group consisting of hydrogen, hydroxy, alkyl, and alkylcarbonylamino. In a subgroup family of this embodiment within Formula IV, R1 is selected from the group consisting of methylsulfanyl, cyanomethylsulfanyl, propyl and butyl; R 9 is selected from the group consisting of methyl and bromophenylmethoxy; R56 is selected from the group consisting of hydrogen, hydroxy, methyl, and methylcarbonylamino. In a further embodiment, the present invention relates to a family of pyrimidopyridinyl-aminophenyl compounds, tautomers of the compounds, or pharmaceutically acceptable salts of the compounds or tautomers, wherein the compounds of this family correspond in structure to Formula V: V wherein: R5 is selected from the group consisting of hydrogen and alkylsulfanyl; R29 is selected from the group consisting of alkyl, arylalkoxy, halogen, and haloarylalkoxy; R47 is selected from the group consisting of alkyl, haloalkyl, alkylsulfanyl, arylalkylsulfanyl, and heterocycle; R64 is selected from the group consisting of hydrogen, alkoxy and alkyl; R66 is selected from the group consisting of hydrogen, hydroxy, aryloxy, alkylsulfonyloxy, alkylcarbonylaminosulfonoyloxy, haloarylsulfonyloxy, cyano, arylaxy, alkylcarbonylamino, halogen and alkyl; R81 is selected from the group consisting of hydrogen, alkoxy and coal i 1 o. In a subgroup family of this embodiment within Formula V, R5 is selected from the group consisting of hydrogen and methylsulfanyl; R29 is selected from the group consisting of methyl, ethyl, fluoro, phenylmethoxy and bromophenylmethoxy; R47 is selected from the group consisting of hydrogen, propyl, isopropyl, ethylsulfanyl, piperidinyl, morpholinyl, heptafluoropropyl, and phenylmethylsulfanyl; R64 is selected from the group consisting of hydrogen, methoxy, hydroxy and methoxy; R66 is selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, phenoxy, phenylmethoxy, phenylsulfanyloxy, isopropylsulfonyloxy, methylcarbonylaminophenylsulfonyloxy, bromophenylsulfanyloxy, cyano, methylcarbonylamino and fluoro; R8 is selected from the group consisting of hydrogen, t-butoxy and carbonyl. In another embodiment, the present invention relates to a family of pyrazolopyrimidinyl aminophenyl compounds, tautomers of the compounds, or pharmaceutically acceptable salts of the compounds or tautomers, wherein the compounds of this family correspond in structure to Formula VI: SAW wherein: R73 is alkyl; R76 is selected from the group consisting of hydroxy, alkylaminocarbonyl and alkylcarbonylamino. In a subgroup family of this embodiment within Formula VI, R73 is selected from the group consisting of methyl and butyl; R76 is selected from the group consisting of hydroxy, methylaminocarbonyl and methylcarbonylamino. In another embodiment, the present invention relates to a family of pyridoprimidinyl-aminophenyl compounds, tautomers of the compounds, or pharmaceutically acceptable salts or tautomers, wherein the compounds of this family correspond in structure to Formula VII: ? p where: A is selected from the group consisting of O and S; R21 is selected from the group consisting of hydrogen and hydroxy; or R21 taken together with R39 form a heterocycle of 5-12 members containing at least two heterogeneous atoms selected from the group consisting of O, N, and S; wherein the heterocycle is optionally substituted aryl or halogen; R39 is selected from the group consisting of hydrogen, alkyl, arylalkenyl, dialkylamino, heteroaryl, haloheteroaryl, haloarylaminosulfonyl, arylsulfonyloxy, alkylcarbonyloxy; cycloalkylaminocarbonyl, arylalkoxycarbonylamino, haloheteroaryl, alkoxycarbonyl, and NH-R99; R99 is selected from the group consisting of hydrogen, arylalkyl, cycloalkylalkyl, aryl, heteroaryl, haloarylalkylamino, arylalkylamino, and alkyheteroaryl; R67 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylcycloalkyl; R96 is selected from the group consisting of hydrogen, hydroxy, amino, alkoxy, arylsulfonyloxy, alkylcarbonylamino, alkoxy, halogen, alkoxycarbonyloxy, haloalkoxycarbonylamino and arylalkoxy. In a subgroup family of this modality within the Formula VII, R21 is selected from the group consisting of hydrogen and hydroxy, or when taken together with R39 form benzoxazolyl optionally substituted with phenyl or bromine; or R39 is selected from the group consisting of hydrogen, methyl, phenylethenyl, N, N-dipropylamino, pyrrolyl, bromophenylaminosulfonyl, phenylsulfonyloxy, t-butylcarbonyloxy, N-cyclohexylaminocarbonyl, N-cyclopentylaminocarbonyl, phenylmethoxycarbonylamino, methoxycarbonylamino, methoxycarbonyl and bromobenzimidazolyl; R67 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl. T-butyl, sec-butyl, cyclopropyl, cyclobutyl and methylcyclopropyl; R96 is selected from the group consisting of hydrogen, hydroxy, amino, phenylsulfonyloxy, methylcarbonylamino, methoxy, fluoro, t-butoxycarbonylamino, trichloroethoxycarbonylamino and phenylmethoxy; R99 is selected from the group consisting of hydrogen, phenylmethyl, phenylethyl, cyclopentylmethyl, furanyl, thienyl, naphthyl, bromophenylmethylamino, phenylmethylamino and methylpyrido [2,3-d] pyrimidinyl.

In still another embodiment, the present invention relates to a family of pyridopyrimidinyl aminophenyl compounds, tautomers of the compounds, or pharmaceutically acceptable salts of the compounds or tautomers, wherein the compounds of this family correspond in structure to Formula VIII: Vffl wherein: R23 is selected from the group consisting of hydrogen, alkoxyaryl, alkoxyarylsulfanyl, hydroxyarylsulfanyl, haloarylalkoxy, cyanoarylalkoxy and arylalkoxy; R31 is selected from the group consisting of hydrogen and halogen; R49 is selected from the group consisting of hydrogen, arylalkoxy, haloarylcarbonylamino, alkoxyarylcarbonylamino, arylalkenyl, arylalkyl, halogen, cyano, haloaryloxyalkyl, alkyl, alkoxyarylsulfanyl, haloheteroaryl, and alkoxycarbonyl; R52 is selected from the group consisting of hydrogen, halogen, hydroxyaryloxy alkyl, aryloxy, hydroxyalkylaryloxy, alkoxyarylalkyl, alkoxyaryloxy, alkylarylalkoxyarylamino, arylalkyl, heteroaryl and aminoaryloxy; R77 is selected from the group consisting of hydrogen, alkyl and cycloalkyl. In a subgroup family of this embodiment within Formula VIII, R23 is selected from the group consisting of hydrogen, methoxyphenyl, methoxyphenylsulfanyl, hydroxyphenylsulfanyl, fluorophenylmethoxy, difluorophenylmethoxy, cyanophenylmethoxy, phenylmethoxy, bromophenylmethoxy and methoxyphenylmethoxy; R31 is selected from the group consisting of hydrogen, chlorine and fluoro; R49 is selected from the group consisting of hydrogen, methyl, phenylmethoxy, bromophenylcarbonylamino, chlorophenylcarbonylamino, methoxyphenylcarbonylamino, fluorophenylcarbonylamino, phenylethenyl, fe n i I et al, chloro, fluoro, bromo, cyano, bromophenoxymethyl, and hydroxyphenylsulfanyl. R52 is selected from the group consisting of hydrogen, fluoro, bromo, methyl, phenoxy, hydroxyphenoxy, hydroxyethylphenoxy, methoxyphenylethyl, methoxy phenoxy, N-methyl-N-4-phenylmethoxyphenylamino, phenylmethyl and thiazolylbenzimidazolyl; R77 is selected from the group consisting of hydrogen, methyl and isopropyl.

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

When it is intended to administer a salt to a patient, the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, salts commonly used to form alkali metal salts and / or to form addition salts of free acids or free bases. In general, these salts can typically be prepared through conventional means with a compound of this invention, for example, the appropriate acid or base with the compound. The pharmaceutically acceptable addition salts of the compounds of this invention can be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroonic acid, carbonic acid, sulfuric acid and phosphoric acid. Organic acids generally include, for example, the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxy, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, acid anthranilic, mesylate, stearate, sulfate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethane sulfonate, sufanilate, cyclohexylaminosulfonate, allenic acid, b-hydroxybutyric acid, galactarate , galacturonate, adipate, alginate, bisulfate, butyrate, camphorate camphor sulfonate, cyclopentanpropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate , thiocyanate, tosylate, and undecanoate.

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

Solvates, Prodrugs, and Isomers The compounds of the present invention, their tautomers, and their salts, may also exist in the form of solvates with water, for example, hydrates, or with organic solvents such as methanol, ethanol or acetonitrile to form, respectively, a methanolate., ethanolate or acetonitrilate. The compounds of the present invention can exist in each form of solvate or mixtures thereof. In one aspect, the compounds, tautomers or salts of the present invention may be in the form of prodrugs. Some are aliphatic or aromatic esters derived from acid groups in compounds of this invention. Other aliphatic or aromatic esters of hydroxyl or amino groups in the compounds of this invention. The present invention also modalizes phosphate prodrugs of hydroxyl groups in the compounds of this invention. The compounds of the invention may comprise asymmetrically substituted carbon atoms known as chiral centers. These chiral centers are designated as "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" used here are configurations as defined in Nomenclature of Organic Chemistry, Section E: Stereochemistry, Recommendations 1974, PURE APPL. CHEM., 45: 11-30 (1976). The compounds of this invention may exist, without limitation, as individual stereoisomers (e.g., single enantiomers or diastereomer), mixtures of stereoisomers (e.g., any mixture of enantiomers or diastereomers), or racemic mixtures. All of these individual stereoisomers, mixtures and racemates are encompassed within the scope of the invention. The compounds identified herein as individual stereoisomers are intended to describe compounds that are present in a form that is substantially free of other stereoisomers (e.g., other enantiomers or diastereomers). By "substantially free", it is meant that at least 80% of the compound in a composition is the desired stereoisomer; preferably, at least 90% of the compound in a composition is the desired stereoisomer; and most preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in a composition is the desired stereoisomer. When the stereochemistry of the chiral carbon (s) present in a chemical structure is not specified, the chemical structure is intended to encompass compounds that contain any stereoisomer of each chiral center present in the chemical structure. Individual stereoisomers of the compounds of this invention can be prepared using many methods known in the art. These compounds include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers, followed by chromatographic separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic resolution . Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or optionally pure, substantial materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at chiral centers. Mixtures of stereoisomers of compounds, including racemic mixtures, resulting from a synthetic reaction, can be prepared, for example, by chromatographic techniques as appreciated by those skilled in the art. Chromatographic resolution of enantiomers can be achieved in chiral chromatography resins, many of which are commercially available. In a non-limiting example, the racemate is placed in solution and charged to the column containing a chiral stationary phase. The enantiomers can then be separated through HPLC. Resolution of enantiomers can also be achieved by converting enantiomers into a mixture to diastereomers through reaction with chiral auxiliaries. The resulting diastereomers can be separated through chromatography of column or crystallization / re-crystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group which will form a salt or covalent bond with the chiral auxiliary. Non-limiting examples of suitable chiral auxiliaries include chirally pure amino acids, organic carboxylic acids or organosulfonic acids. Once the diastereomers are separated through chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be converted and used again. Enzymes, such as esterases, phosphatases or lipases, may be useful for the resolution of enantiomer derivatives in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be treated with an enzyme, which selectively hydrolyzes only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the non-hydrolyzed ester. Alternatively, salts of enantiomers can be prepared in a mixture, using any method known in the art, including treatment of the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization / re-crystallization of the enantiomerically salts pure Suitable methods for resolution / separation of a mixture of stereoisomers, including racemic mixtures, can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et al., 1981, John Wiley and Sons, New York, NY). A compound of this invention may possess one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as the cis (Z) and trans E isomers, and mixtures thereof, are intended to be encompassed within the scope of a disclosed compound unless otherwise specified. In addition, when a compound exists in various tautomeric forms, a described compound is not limited to any specific tautomer, but rather encompasses all tautomeric forms. Certain compounds of the invention may exist in different forms, which may be separable. Torsional asymmetry due to restricted rotations around an asymmetric individual link, for example, due to spherical impedance or ring tension, may allow the separation of different conformers. The compounds of the invention include each conformational isomer of these compounds and mixtures thereof. Certain compounds of the invention can also exist in zwitterionic form and the invention includes each zwitterionic form of these compounds and their mixtures.

Definitions The compounds of the present invention are generally described herein using standard nomenclature. For a described compound that has the asymmetric center (s), it should be understood that all stereoisomers of the compound and their mixtures are encompassed in the present invention, unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-transisomers. When a described compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms. Certain compounds are described herein using general formulas that include variables (e.g., R17, A1, L, X, Y, or Z). Unless otherwise specified, each variable within that formula is defined independently of any other variable, and any variable that occurs more than once in a formula is defined independently in each occurrence. If the substituents are described as being "independently selected" from a group, each substituent is independently selected from the other. Each substituent, therefore, may be identical to or different from the other substituent (s). The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix "Cx-Cy", where x is the minimum number and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-C6 alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. As illustrated below, C3-C6 cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon atoms in the ring. A prefix attached to a multi-component substituent only applies to the first component that immediately follows the prefix. To illustrate, the term "a I q u i i a r i I" contains two components: alkyl and aryl. Thus, for example, alkylaryl of C-i-C6 refers to a Ci-C6 alkyl attached to the molecular moiety of origin through an aryl group. Also, C6-C alkylaryl refers to an alkyl group attached to the molecular moiety through a C6-Ci0 aryl group. Similarly, the prefix "halo" in the haloalkoxyalkyl indicates that the alkoxy component is substituted with one or more halogen radicals, while the prefix "halo" in alkoxyhaloalkyl indicates that the alkyl component is substituted with one or more halogen radicals. When words are used to describe a linking element between two other elements of an illustrated chemical structure, the component described further to the left of the linking element is the compound that is attached to the left element in the illustrated structure. To show, if the chemical structure is X-L-Y and L is described as methylarylethyl, then the chemical could be X-methyl-aryl-ethyl-X. If a link element in a described structure is a link, then the left element in the illustrated structure is directly linked to the right element in the illustrated structure. For example, if a chemical structure is shown as X-L-Y and L is selected as a bond, then the chemical structure could be X-Y. For another example, if the chemical portion is represented as -L-X and L is selected as a link, then the chemical portion could be -X. for yet another example, if a chemical structure is described as X - - L2 - Y, X - L ^ - L2 - L3 - Y or X - Li - L2 --.... - LN - Y, and L (, L2 , L3, ... LN are selected as links, then the chemical structure could be XY When a chemical formula is used to describe a substituent, the hyphen on the right (or left) side of the formula indicates the portion of the substituent that has a valency (s) free If a substituent is described as being "substituted", a radical that is not hydrogen is in the place of one or more hydrogen radicals on a carbon, nitrogen or oxygen of the substituent. example, a substituted alkyl substituent is an alkyl substituent wherein at least one radical that is not hydrogen is in the place of a radical (s) hydrogen in the alkyl substituent.To illustrate, monofluoroalkyl is an alkyl substituted with a radical fluoro, and difluoroalkyl is alkyl subs It should be recognized that if there are two or more substitutions in a substituent, each of the radicals that are not hydrogen can be identical or different unless stated otherwise. A substituent is "capable of substitution" if it comprises at least one carbon, nitrogen or oxygen atom that is attached to one or more hydrogen atoms. If a substituent is described as being "optionally substituted", the substituent may be either substituted or unsubstituted. If a substituent is described as being optionally substituted with up to a particular number of radicals which are not hydrogen, that substituent may be either unsubstituted, or substituted up to a particular number of radicals which are not hydrogen or up to the maximum number of substitutable positions in the substituent, whichever is less. Thus, for example, if a substituent is described as an optionally substituted heteroaryl with up to three non-hydrogen radicals, then any heteroaryl with less than three substitutable positions could be optionally substituted with up to only as many non-hydrogen radicals as possible. possible since the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) could be optionally substituted with up to a radical that is not hydrogen. To further illustrate, if an amino-nitrogen is described as being optionally substituted with up to two non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to two non-hydrogen radicals, while a secondary amino nitrogen will be optionally substituted with only one radical that is not hydrogen. The term "alkenyl" (alone or in combination with another term (s)) means a straight or branched chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to 20 carbon atoms, more typically from 2 to 8 atoms of carbon, and still very typically from 2 to 6 carbon atoms. Each carbon-carbon double bond can have a geometry either cis or trans within the alkenyl portion, relative to substituted groups in the double bond carbons. Non-limiting examples of said substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentynyl, 1,4-butadienyl, 1-ynyl, 2-butenin and 3-butenyl. The term "alkenylene" (alone or in combination with another term (s)) refers to a divalent unsaturated hydrocarbyl group, which may be linear or branched and which has at least one carbon-carbon double bond. An alkenylene group typically contains from 2 to 20 carbon atoms, more typically from 2 to 8 carbon atoms, and still very typically from 2 to 6 carbon atoms. Non-limiting examples of alkenylene groups include-C (H) = C (H) -, -C (H) = C (H) -CH2 -, - C (H) = C (H) -CH2-CH2-, - CH2- C (H) = C (H) -CH2, _C (H) = C (H) - CH (CH3) -, and - CH2- C (H) = C (H) - CH (CH2CH3) -. The term "alkoxy" (alone or in combination with another term (s)) refers to an alkyl group attached to the molecular moiety through an oxy portion (i.e., -O-alkyl). Non-limiting examples of said substituent include methoxy (-0-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. The term "alkoxyalkyl" (alone or in combination with another term (s)) refers to an alkoxy group attached to the parent molecular moiety through an alkylene group. Non-limiting examples of alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl. The term "alkoxycarbonyl" (alone or in combination with another term (s)) refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group (ie, -C (O) -O-alkyl) . Representative examples of alkoxycarbonyl include, but are not limit to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl. The term "alkoxycarbonylamino" (alone or in combination with another term (s)) refers to N (RARB) -, where RA is alkyl-O-C (O), and RB is alkyl-O-C (O) - or hydrogen. RA and RB can be identical or different. The term "alkoxycarbonylaminoalkyl" (alone or in combination with another term (s)) refers to N (RARe) -alkylene-, where RA is alkyl-OC (O), and RB is alkyl-OC (O) - or hydrogen. RA and RB can be identical or different. The term "alkoxycarbonylalkyl" (alone or in combination with another term (s)) refers to an alkoxycarbonyl group attached to the parent molecular moiety through an alkylene group. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 2-methoxy-2-oxoethyl, 2-ethoxy-2-oxoethyl, 3-methoxy-3-oxopropyl, 3-ethoxy-3-oxopropyl, 4-ethoxy-2. (ethoxycarbonyl) -4-oxobutyl, 5-methoxy-5-oxopentyl, and 6-methoxy-6-oxohexyl. The term "alkyl" (alone or in combination with another term (s)) means a straight chain saturated hydrocarbyl substiuent or branched typically containing from 1 to 20 carbon atoms, more typically from 1 to 8 carbon atoms, and still very typically from 1 to 6 carbon atoms. Non-limiting examples of said substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, iso-amyl, hexyl and octyl. The term "alkylamino" (alone or in combination with another term (s)) refers to -NRARB-, where RA is alkyl, and RB is hydrogen or alkyl. RA and R8 can be identical or different. For example, C 1 -C 4 alkylamino refers to -NRARB, wherein RA is C 1 -C 6 alkyl, and RB is hydrogen or Ci-C 6 alkyl. The term "alkylaminoalkyl" (alone or in combination with another term (s)) refers to -N (RARB) -alkylene, where RA is alkyl, and RB is hydrogen or alkyl. RA and RB can be identical or different.

In this manner, Ci-C6 alkylamino Ci-C6 alkyl refers to N (RARB) -alkylene of C-C6, wherein RA is C1-C5 alkyl, and RB is hydrogen or C ^-C alquilo alkyl and; The term "alkylcarbonyl" (alone or in combination with another term (s)) refers to an alkyl group attached to the parent molecular moiety through a carbonyl group (ie, -C (O) -alkyl). Representative examples of alkylcarbonyl include, but are not limit acetyl, ethylcarbonyl 1 - . 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl. The term "alkylcarbonylalkyl" (alone or in combination with another term (s)) refers to an alkylcarbonyl group attached to the molecular portion of origin through an alkylene group. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl and 3-oxopentyl. The term "alkylcarbonyloxy" (alone or in combination with another term (s)) refers to an alkylcarbonyl group attached to the parent molecular moiety through an oxy portion. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The term "alkylcarbonyloxyalkyl" (alone or in combination with another term (s)) refers to an alkylcarbonyloxy group attached to the parent molecular moiety through an alkylene moiety. Representative examples of alkylcarbonyloxy include, but are not limited to, 2- (acetyloxy) ethyl, 3- (acetyloxy) propyl, and 3- (propionyloxy) propyl. The terms "alkylene" or "alkylenyl" (alone or in combination with another term (s)) denote a divalent group derived from a straight or branched chain saturated hydrocarbyl chain typically containing from 1 to 20 carbon atoms, more typically from 1 to 8 carbon atoms, and even more typically from 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH (CH3) CH2-, the term "alkynyl" (alone or in combination with another term (s)) means a straight or branched chain hydrocarbyl substituent containing one or more triple bonds and typically 2 at 20 carbon atoms, more typically at 2 to 8 carbon atoms, and still very typically at 2 to 6 carbon atoms. Non-limiting examples of said substituents include, ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The term "alkynylene" (alone or in combination with another term (s)) refers to a divalent unsaturated hydrocarbon group, which may be linear or branched and which has at least three carbon-carbon bonds. Representative alkynylene groups include, by way of example, -C = C-, -C = C-CH2-, -C = C-CH2-CH2-, -CH2-C = C-CH2-, -C = C -CH (CH3) -, and -CH2-C = C-CH (CH2CH3) -. The term "amino" (alone or in combination with another term (s)) means -NH2. The term "monosubstituted amino" (alone or in combination with another term (s)) means an amino substituent, wherein one of the hydrogen radicals is replaced by a substituent that is not hydrogen. The term "disubstituted amino" (alone or in combination with another term (s)) means an amino substituent, wherein both hydrogen atoms are replaced by substituents that are not hydrogen, which may be identical or different. The term "aminocarbonyl" (alone or in combination with another term (s)) means -C (0) -NH2, which may also be illustrated as: JL The term "aminoalkyl" (alone or in combination with another term (s)) means -alkylene-NH2. The term "aminoalkylcarbonyl" (alone or in combination with another term (s)) means -C (0) -alkylene-NH2. For example, "aminomethylcarbonyl" can be illustrated as: The term "aminosulfonyl" (alone or in combination with another term (s)) means -S (02) -NH2, which may also be illustrated as: The term "aryl" (alone or in combination with another term (s)) refers to an aromatic carbocyclyl containing from 6 to 14 carbon atoms in the ring. Non-limiting examples of aryls include phenyl, naphthalenyl, anthracenyl and indenyl. An aryl group can be connected to the molecular portion of origin through any substitutable carbon atom of the group. The term "a r i I to I q u i i o" (alone or in combination with another term (s)) refers to an aryl group attached to the parent molecular moiety through an alkylene group. Representative examples of a substituted or unsubstituted r i I to I q u i I include, but are not limited to, benzyl, 4- (benzyloxy) benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 3- (1, 3-benzodioxol-5-yl) -2-methylpropyl, 3- (phenoxy) benzyl, 3 (1,3-benzodioxol-5-yl) propyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthylmethyl , 3,5-di-tert-butyl-2-hydroxybenzyl, 3-methoxybenzyl, 3,4-dimethoxybenzyl, 4- (dimethylamino) benzyl, 4- [3- (dimethylamino) propoxy] benzyl, (6-methoxy) 2-naphthyl) methyl, and 2-naphth-2-ylethyl. The term "arylalkylcarbonyl" (alone or in combination with another term (s)) refers to an aryl group I to I which is attached to the parent molecular moiety through a carbonyl group (i.e., arylalkyl-C ( OR)-). Representative examples of arylalkylcarbonyl include, but are not limited to, 2-naphthylacetyl and phenylacetyl. The term "ari I a I coxi" (alone or in combination with another term (s)) refers to an ari I to I group that is linked to the molecular portion of origin through an oxy portion (i.e. arylalkyl-O-). Representative examples of arylalkylcarbonyl include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy. The term "arylalkoxyalkyl" (alone or in combination with another term (s)) refers to an arylalkoxy group attached to the parent molecular moiety through an alkylene group. Representative examples of arylalkoxyalkyl include, but are not limited to, benzyloxymethyl, 2- (benzyloxy) ethyl, and (2-phenylethoxy) methyl. The term "arylalkoxycarbonyl" (alone or in combination with another term (s)) refers to an arylalkoxy group attached to the parent molecular moiety through a carbonyl group. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphth-2-ylmethoxycarbonyl. The term "arylcarbonyl" (alone or in combination with another term (s)) refers to an aryl group attached to the parent molecular moiety through a carbonyl group. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl. The term "aryloxy" (alone or in combination with another term (s)) refers to an aryl group attached to the molecular portion of origin 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 another term (s)) refers to an aryloxy group attached to the parent molecular moiety through an alkylene group. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethylol, 3-naphth-2-yloxypropyl, and phenoxymethyl. The term "aryloxycarbonyl" (alone or in combination with another term (s)) refers to an aryloxy group attached to the parent molecular moiety through a carbonyl group. The term "arylthio" (alone or in combination with another term (s)) refers to an aryl group attached to the molecular portion of origin through a sulfur atom (ie, aryl-S-). Representative examples of arylthio include, but are not limited to, phenylthio, naphthalene-1 -thio, and naphthalene-2-ylthio. The term "arylthioalkyl" (alone or in combination with another term (s)) refers to aryio-S-alkylene. Representative examples of arylthioalkyl include, but are not limited to, (phenylthio) methyl, 2- (phenylthio) ethyl, and 3- (phenylthio) propyl. The term "arylthioalkoxy" (alone or in combination with another term (s)) refers to an arylthioalkyl group attached to the molecular portion of origin through an oxy group. The term "arylthioalkoxyalkyl" (alone or in combination with another term (s)) refers to an arylthioalkoxy group attached to the parent molecular moiety through an alkylene group. The terms "carbocyclyl" or "carbocyclic" (alone or in combination with another term (s)) refer to a partially saturated saturated (eg "cycloalkyl") ring system (eg, "cycloalkenyl" or "cycloalkynyl") ") or completely unsaturated (eg," aryl "), which contains zero ring atoms of heterogeneous atoms and typically 3 to 18 ring atoms. "Ring atoms" or "ring members" are atoms joined together to form the ring or rings of a cyclic substituent. A carbocycliy can be, without limitation, an individual ring, or two or more fused rings, or bridged or spiro rings. A carbocyclylium may contain from 3 to 14 ring members (ie, C3-C14 carbocyclyl, such as C3-C14 cycloalkyl), from 3 to 10 ring members (ie, C3-C10 carbocyclyl, such as cycloalkyl) of C3-C10), of 3 to 8 ring members (ie, C3-C8 carbocyclyl, such as C3-C8 cycloalkyl), of 3 to 6 ring members (ie, C3-C6 carbocyclyl, as C3-C6 cycloalkyl), from 4 to 10 ring members (ie, C4-C10 carbocyclyl, such as C-C10 cycloalkyl and C4-Ci0 cycloalkenyl), from 4 to 8 ring members (i.e. C4-C8 carbocyclyl, such as C-C8 cycloalkyl and C-C8 cycloalkenyl), or from 5 to 7 ring members (ie, C5-C7 carbocyclyl> such as C5-C7 cycloalkyl, cycloalkenyl C5-C7 and phenyl). A substituted carbocyclyl can have a geometry either cis or trans. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-napphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl , 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphtenyl (also known as "phenalenyl"), decalinyl, and norpinanil. A carbocyclyl group can be attached to the molecular moiety of origin through any substitutable carbon atom of the group. The term "carbocyclylalkyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the parent molecular moiety through an aikiene group. For example, C3-C10 carbocyclyl-Ci-C6 alkyl refers to a carbocyclyl group of C3-Ci0 attached to the molecular moiety of origin via an aikene Likewise, the C5-C7 carbocyclyl-Ci-C6 alkyl refers to a C5-C7 carbocyclyl group attached to the molecular moiety through a Ci-C6 aiquiieno.

The term "carbocyclylalkoxy" (alone or in combination with another term (s)) refers to a carbocyclylalkyl group attached to the parent molecular moiety through an oxy group (ie, carbocyclyl-alkylene-O-). For example, the C3-C-10-C6-C6-alkoxy carbocyclyl refers to a C3-C10 carbocyclyl group at which Ci-Ce is attached to the molecular portion of origin through a group oxy In the same manner, a C5-C7 carbocyclyl group of Ci-C6 alkoxy refers to a C5-C7 carbocyclyl group of Ci-C6 alkyl attached to the parent molecular moiety through an oxy group. The term "carbocyclylalkoxyalkyl" (alone or in combination with another term (s)) refers to a carbocyclylalkoxy group attached to the parent molecular moiety through an alkylene group (ie, carbocyclyl-alkylene-O-alkylene). For example, the C3-C10 carbocyclyl-C1-C6-alkoxy-C-Ce alkyl group refers to a C3-C10 carbocyclyl group-Ci-C6 alkoxy linked to the parent molecular moiety through a alkylene group of d-C6. The term "carbocyclylalcoxycarbonyl" (alone or in combination with another term (s)) refers to a carbocyclylalkoxy group attached to the parent molecular moiety through a carbonyl group (i.e., -C (O) -O-alkylene- carbocyclyl). For example, the C3-C 0 -alkoxycarbonyl carbocyclyl of C -, - C6 refers to a C3-C10 carbocyclyl-alkoxy group of bound to the molecular portion of origin through a carbonyl group. As a non-limiting example, "phenylethoxycarbonyl" can be illustrated as: The term "carbocyclylalkylcarbonyl" (alone or in combination with another term (s)) refers to a carbocyclylalkyl group attached to the parent molecular moiety through a carbonyl group (i.e., -C (O) -O-alkylene- carbocyclyl). For example, "phenylethylcarbonyl" can be illustrated as: The term "carbocyclylcarbonyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the parent molecular moiety through a carbonyl group (ie, carbocyclyl-C (O) -). For example, "phenylcarbonyl" can be illustrated as: The term "carbocyclyloxy" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the parent molecular moiety through an oxy (i.e., carbocyclyl-O-) moiety. The term "carbocyclyloxyalkyl" (alone or in combination with another term (s)) refers to a carbocyclyloxy group attached to the parent molecular moiety through an alkylene group (ie, carbocyclyl-O-alkylene). The term "carbocyclyloxycarbonyl" (alone or in combination with another term (s)) refers to a carbocyclyloxy group attached to the molecular portion of origin through a carbonyl group (ie, -C (O) -O-carbocyclyl). For example, "phenyloxycarbonyl" can be illustrated as: The term "carbocyclicthio" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the molecular moiety of origin through a sulfur atom (ie, carbocyclic i-S-). The term "carbocyclylthioalkoxy" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-S-. The term "carbocyclylthioalkoxyalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-S-alkylene. The term "carbocyclylthioalkyl" (alone or in combination with another term (s)) refers to a carbocyclicthio group attached to the parent molecular moiety through an alkylene group (ie, carbocyclyl-S-alkylene-). The term "carbocyclylcarbocyclyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the parent molecular moiety through another carbocyclyl group (ie, carbocyclyl-carbocyclyl-). For example, the C3-Ci0carbocyclyl carbocyclyl of C5-C7 refers to a C3-Ci0 carbocyclyl group attached to the parent molecular moiety through a C5-C7 carbocyclyl group (ie, C3- carbocyclyl). C 0-carbocyclyl of C5-C7). The term "carbocyclylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to a carbocyclylcarbocyclyl group attached to the parent molecular moiety through an alkylene group. The term "carbocyclylalcoxycarbocyclylalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-O-carbocyclyl-alkylene. For example, C3-C10 carbocyclyl-C5-C7-C7-C7-C7-C4-alkoxy-C3-C4-alkylcarbon refers to C3-Ci0-C3-C6-C6-C6-C6-C6-C7-C7-C6-C3-C3-C3-C3-C3-C3-C3-C3-cyclicyl. C3-C4 alkylene. The term "(carbocyclylalkyl) carbocyclylalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-carbocyclyl-alkylene. For example, C3-C10 carbocyclyl-Ci-C6-C5-C7-cyclic alkyl-C3-C4-alkyl refers to C3-C10-carbocyclyl-C6-C6-alkylene-C5-C7-alkylene carbocyclyl. of C3-C4-. The term "carbocyclylalkoxyheterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-O-heterocyclyl-alkylene-. The term "carbocyclylcarbonylheterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-C (O) -heterocyclyl-alkylene-. The term "carbocyclylheterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-heterocyclyl- alkylene-. The term "carbocyclylcarbonylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-C (O) -carbocyclyl-alkylene-. For example, C3-C10 carbocyclylcarbonyl-C4-C8 carbocyclyl-C6-alkyl- refers to C3-C10-C10-C (O) -carboxyclyl of C4-C8-alkylene of C ^ -Ce-- The term "(carbocyclylalkyl) heterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-heterocyclyl-alkylene. The term "carbonyl" (alone or in combination with another term (s)) refers to -C (O) -, which can also be illustrated as: The term "carboxy" (alone or in combination with another term (s)) refers to -C (0) -OH, which can also be illustrated as: The term "carboxyalkyl" (alone or in combination with another term (s)) refers to a carboxy group attached to the molecular portion of origin through an alkylene group. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.

The term "cyclic amino" (alone or in combination with another term (s)) means a heterocyclyl moiety comprising at least one nitrogen ring atom, the remaining ring atoms being carbon and optionally nitrogen or sulfur. Non-limiting examples of said portions include piperidinyl, piperazinyl and thiazine groups. The term "cycloalkenyl" (alone or in combination with another term (s)) refers to a non-aromatic, partially unsaturated carbocyclyl substituent having zero heterogeneous atom ring members and typically 4 to 18 carbon ring members. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl. The term "cycloalkyl" (alone or in combination with another term (s)) refers to a saturated carbocyclyl group containing zero heterogeneous atom ring members and typically 3 to 18 carbon ring members. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl. The term "cycloalkylcarbonyl" (alone or in combination with another term (s)) refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group. The term "cyano" (alone or in combination with another term (s)) means -CN, which can also be illustrated as: The term "dialkylamino" (alone or in combination with another term (s)) refers to -NRARB, wherein RA and RB are independently selected from alkyl groups. The term "dialkylaminocarbonyl" (alone or in combination with another term (s)) refers to a dialkylamino group attached to the parent molecular moiety through a carbonyl group (i.e., N (RARB) -C (0) -, wherein RA and B are independently selected from alkyl groups). The term "formyl" (alone or in combination with another term (s)) refers to a group -C (0) H. The term "halogen" or "halo" (alone or in combination with another term (s)) means a fluorine radical (which can be represented as -F), chloro radical (which can be represented as -Cl), radical bromine (which can be represented as -Br), or radical iodine (which can be represented as -I). The prefix "halo" indicates that the substitute to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, "haloalkyl" (alone or in combination with another term (s)) means an alkyl substituent, wherein at least one hydrogen radical is replaced with a halogen radical. Non-limiting examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. Further illustrated, "haloalkoxy" (alone or in combination with another term (s)) means an alkoxy substituent, wherein at least one hydrogen radical is replaced by a halogen radical. Non-limiting examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 1,1,1-trifluoroethoxy. It should be recognized that if a substituent is replaced by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated). The prefix "perhalo" indicates that each hydrogen radical in the substituent to which the prefix is attached is replaced with independently selected halogen radicals, ie, each hydrogen radical in the substituent is replaced with a halogen radical. If all halogen radicals are identical, the prefix will typically identify the halogen radical. Thus, for example, the term "perfluoro" means that each hydrogen radical in the substituent to which the prefix is attached is substituted with a fluoro radical. To illustrate, the term "perfluoroalkyl" means an alkyl substituent, wherein a fluoro radical is in place of each hydrogen radical. Non-limiting examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluoroisopropyl, perfluorobutyl, perfluorodecyl, and perfluorododecyl. To further illustrate, the term "perfluoroalkoxy" means an alkoxy substituent, wherein each hydrogen radical is replaced with a fluoro radical. Non-limiting examples of perfluoroalkoxy substituents include trifluoromethoxy (-0-CF3), perfluoroisopropoxy, perfluorobutoxy, perfluorodecoxy, and perfluorododekoxy.

The terms "heterocycle" or "heterocyclyl" (alone or in combination with another term (s)) refers to a saturated (eg, "heterocycloalkyl") ring system, partially unsaturated (eg, "heterocycloalkenyl" or "heterocycloalkynyl") ") or completely unsaturated (eg," heteroaryl ") typically containing from 3 to 18 ring atoms, wherein at least one of the ring atoms is a heterogeneous atom (i.e., nitrogen, oxygen or sulfur) ), the rest of the atoms in the ring independently being selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocyclyl group can be linked to the molecular portion of origin through any substitutable carbon or nitrogen atom in the group, provided that a stable molecule is present. A heterocyclyl can be, without limitation, an individual ring, which typically contains from 3 to 14 ring atoms (ie, heterocyclyl of M3-M14), of 3 to 8 ring atoms (ie, heterocyclyl of M3) -M8), from 2 to 6 ring atoms (i.e., heterocyclyl of M3-M6), or from 5 to 6 ring atoms (ie, heterocyclyl of M5-M6). Non-limiting examples of single ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl , isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,4-oxadiazolyl (also known as "azoximyl"), 1, 2,5-oxadiazolyl (also known as "furazanyl"), and 1,3,4-oxadiazolyl ), oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,4-dioxazolyl, 1,2,3) -dioxazolyl, and 1,4-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-diazinyl ")., 3,5-triazinyl "), as-triazinyl (also known as 1,2,4-triazinyl), and v-triazinyl (also known as" 1,2,3-triazinyl "), oxazinyl (including 1,2 , 3-oxazinyl, 1,2-oxazinyl, 1, 3,6-oxazinyl (also known as "pentoxazolyl"), 1, 2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl (including o- isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1, 2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2- oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl. A heterocyclyl can also include, without limitation, two or more rings fused together, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1, 6] naphthyridinyl), thiazolopyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H- quinolizinyl, purinyl, pyridopyridinyl (including pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl, and pyrido [4,3-b] -pyridinyl), pyridopyrimidine, and pteridinyl. Other non-limiting examples of fused ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as "pseudoindoil"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl (including quinolinyl (also known as " 1-benzazinyl ") and isoquinolinyl (also known as" 2-benzazinyl "), fta I azi or lo, quinoxalinyl, benzodiazinyl (including cinolinyl (also known as" 1,2-benzodiazinyl ") and quinazolinyl (also known as" 1,3-benzodiazinyl "), benzopyranyl (including" chromenyl "and" isocromenyl "), benzothiopyranyl (also known as" thiochromenyl "), benzoxazolyl, indoxazinyl (also known as" benzisoxazolyl "), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl , benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", "thionaphtenyl", and "benzothiofuranyl"), isobe nzothienyl (also known as "isobenzothiophenyl", "isothionaphtenyl", and "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,2-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 another term (s)) means a saturated, partially saturated, or aromatic heterocyclyl containing two fused rings. Non-limiting examples of fused two-ring heterocyclyls include naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolopyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl , pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinilo, ta I Azini I or, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl , benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzotriazolyl, benzoxazinyl, benzoisoxazinyl, and tetrahydroisoquinolinyl. A heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom (s) is oxidized to SO or S02. The heterogeneous atom (s) nitrogen in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to N-oxide. In addition, the heterogeneous atom (s) nitrogen may or may not be N-protected. As used herein, the number of atoms in the ring in a heterocyclyl portion can be identified by the prefix Mx-My ", where x is the minimum number and y is the maximum number of ring atoms in the heterocyclyl moiety.

The term "heterocycloalkoxy" (alone or in combination with another term (s)) refers to a heterocycloalkyl group attached to the parent molecular moiety through an oxy group. The term "heterocycloalkoxyalkyl" (alone or in combination with another term (s)) refers to a heterocycloalkoxy group attached to the parent molecular moiety through an alkylene group (ie, heterocyclyl-alkylene-O-alkylene-). The term "heterocycloalkoxycarbonyl" (alone or in combination with another term (s)) refers to a heterocycloalkoxy group attached to the parent molecular moiety through a carbonyl group (ie, heterocyclyl-alkylene-OC (O) -) . The term "heterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocyclyl linked to the molecular portion of origin through an alkylene group (e.g., heterocycle-CrC6 alkyl). The term "heterocycloalkylcarbonyl" (alone or in combination with another term (s)) refers to a heterocycloalkyl group attached to the parent molecular moiety through a carbonyl group (i.e., -C (O) -alkylene-heterocyclyl) . The term "heterocyclocarbonyl" (alone or in combination with another term (s)) refers to a heterocyclyl linked to the parent molecular moiety through a carbonyl group (ie, -C (O) -heterocyclyl). The terms "heterocyclyloxy" or "(heterocycle) oxy" (alone or in combination with another term (s)) refers to a heterocyclyl group bound to the molecular portion of origin through an oxy portion. The term "(heterocycle) oxyalkyl" (alone or in combination with another term (s)) refers to a heterocyclyloxy group attached to the parent molecular moiety through an alkylene group (ie, heterocyclyl-O-alkylene-) . The term "(heterocycle) oxycarbonyl" (alone or in combination with another term (s)) refers to a group (heterocycle) oxy linked to the molecular portion of origin through a carbonyl group (i.e., heterocyclyl- O-). C (O) -). The term "heterocyclic" (alone or in combination with another term (s)) refers to a heterocyclyl linked to the molecular portion of origin through-S-. The term "heterocyclothioalkoxy" (alone or in combination with another term (s)) refers to a heterocyclyl-alkylene-S-. The term "heterocyclothioalkoxyalkyl" (alone or in combination with another term (s)) refers to a heterocyclyl-alkylene-S-alkylene-. The term "heterocyclothioalkyl" (alone or in combination with another term (s)) refers to a heterocyclic group attached to the parent molecular moiety through an alkylene group (ie, heterocyclyl-S-alkylene-). The term "heterocyclocarbocyclyl" (alone or in combination with another term (s)) refers to a heterocyclyl linked to the parent molecular moiety through a carbocyclyl (i.e., heterocycle-carbocyclyl-) group.

The term "heterocyclocarbocyclylalkyl" (alone or in combination with another term (s)) refers to a heterocyclocarbocyclyl group attached to the parent molecular moiety through an alkylene group (ie, heterocyclyl-carbocyclyl-alkylene-). The term "(heterocycle) alkoxycarbicyclylalkyl" (alone or in combination with another term (s)) refers to a heterocyclic alkylene-O-carbocyclyl-alkylene- ester. The term "(heterocycle) carbonylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to a heterocyclic ester-C (O) -carbocyclyl-alkylene-. The term "(heterocycle) heterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycle-heteroaryl-alkylene-heterocycle. The term "(heterocycle) alkoxyheterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycle-alkylene-O-heterocycle-alkylene-. The term "(heterocycle) carbonylheterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycle-C (O) -heterocycle-alkylene-. The term "(heterocycloalkyl) carbocyclylalkyl" (alone or in combination with another term (s)) refers to a heterocycle-alkylene-carbocyclyl-alkylene-. The term "(heterocycloalkyl) heterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycle - alkylene-heterocycle-alkylene-. Thus, for example, (heterocycle of M3-10-C1-C6 alkyl) -heterocycle of M5-M6-C-1-C3 alkyl means heterocycle of M3-M10-alkylene of Ci-C6-heterocycle of M5 - 6-C-C3-alkylene. The term "heteroaryl" (alone or in combination with another term (s)) means an aromatic heterocyclyl which typically contains from 5 to 18 ring atoms. A heteroaryl can be an individual ring, or two or more fused rings. Non-limiting examples of five-membered heteroaryls include imidazolyl; furanyl; thiophenyl (or thienyl or thiofuranyl); pyrazolyl; oxazolyl; isoxazolyl; thiazolyl; 1,2,3-, 1,2,4-, 1,2,5-, and 1, 3,4-oxadiazolyl; and isothiazolyl. Non-limiting examples of six-membered heteroaryls include pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; and 1,3,5-, 1,2, 4-, and 1,2,3-triazinyl. Non-limiting examples of 6/5 membered fused ring heteroaryls include benzothiofuranyl; isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl. Non-limiting examples of 6/6 membered fused ring heteroaryls include quinolinyl; isoquinolinyl; and benzoxazinyl (including cinolinyl and quinazolinyl). The term "heteroarylalkoxy" (alone or in combination with another term (s)) refers to a heteroarylalkyl attached to the parent molecular moiety through an oxy group (ie, heteroaryl-alkylene-O-). Representative examples of heteroarylalkoxy include, but are not limited to, 2-pyridin-3-ylethoxy, 1,3-thiazol-5-ylmethoxy, 3-quinolin-3-ylpropoxy, and 5-pyridin-4-ylpentyloxy.

The term "heteroarylalkoxyalkyl" (alone or in combination with another term (s)) refers to a heteroarylalkoxy linked to the parent molecular moiety through an alkylene group (ie, heteroaryl-alkylene-O-alkylene). Representative examples of heteroarylalkoxyalkyl include, but are not limited to, (2-pyridin-3-ylethoxy) methyl, (3-quinolin-3-ylpropoxy) methyl, (1,3-thiazol-5-ylmethoxy) methyl, and 2- (5-pyridin-4-ylpentyloxy) ethyl. The term "heteroarylalkyl" (alone or in combination with another term (s)) refers to a heteroaryl attached to the parent molecular moiety through an alkylene group. Representative examples of heteroarylalkyl include, but are not limited to, 3-quinolinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 1H-imidazol-4-ylmethyl, 1H-pyrrol-2-ylmethyl, pyridin-3-ylmethyl, and -pyrimidin-2-ylpropyl. The term "heteroarylalkylcarbonyl" (alone or in combination with another term (s)) refers to a heteroarylalkyl group attached to the parent molecular moiety through a carbonyl group (ie, heteroaryl-alkylene-C (O) -) . The term "heteroarylcarbonyl" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the molecular portion of origin through a carbonyl group. Representative examples of heteroarylcarbonyl include, but are not limited to, pyridin-3-ylcarbonyl, (1,3-thiazol-5-yl) carbonyl, and quinolin-3-ylcarbonyl. The term "heteroaryloxy" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the molecular, origin through an oxy portion. Representative examples of heteroaryloxy include, but are not limited to, pyridin-3-yloxy, and quinolin-3-yloxy. The term "heteroaryloxyalkyl" (alone or in combination with another term (s)) refers to a heteroaryloxy group attached to the parent molecular moiety through an alkylene group (ie, heteroaryl-O-alkylene-). The term "heteroaryloxycarbonyl" (alone or in combination with another term (s)) refers to a heteroaryloxy group attached to the parent molecular moiety through a carbonyl group (ie, heteroaryl- O-C (O) -) . The term "heteroari Itio" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the molecular portion of origin through - S -. The term "heteroarylthioalkoxy" (alone or in combination with another term (s)) refers to heteroaryl-alkylene-S-. The term "heteroarylthioalkoxyalkyl" (alone or in combination with another term (s)) refers to heteroaryl-alkylene-S-alkylene-. The term "heteroarylthioalkyl" (alone or in combination with another term (s)) refers to a heteroarylthio group attached to the parent molecular moiety through an alkylene group (ie, heteroaryl-S-alkylene-). The term "hydrogen" (alone or in combination with another term (s)) refers to a hydrogen radical, and can be represented as -H.

The term "hydroxy" (alone or in combination with another term (s)) refers to -OH. The term "hydroxyalkyl" (alone or in combination with another term (s)) refers to an alkyl substituent, wherein one or more hydrogen radicals are replaced with -OH. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl. The term "keto" (alone or in combination with another term (s)) means an oxo radical, and can be represented as = 0. The term "iminoalkyl" (alone or in combination with another term (s)) refers to a radical of the formula wherein H may be optionally substituted with alkyl or hydroxy, in which case the substituent may be alkyliminoalkyl or hydroxyiminoalkimo, respectively. The term "nitro" (alone or in combination with another term (s)) means -N02. The term "oxo" (alone or in combination with another term (s)) is refers to a portion = 0 (that is, The term "oxy" (alone or in combination with another term (s)) means - O -. The term "propargyl" (alone or in combination with another term (s)) means the monovalent radical represented as: -CH2-CH- = CH. The term "sulfonyl" (alone or in combination with another term (s)) means -S (0) 2-, which may also be represented as: The term "sulfinyl" (alone or in combination with another term (s)) means -S (O) -, which may also be represented as: The term "uncle" or "aunt" (alone or in combination with another term (s)) means - S -. The term "thiol", "mercapto", or "sulfhydryl" (alone or in combination with another term (s)) means a sulfhydryl substituyeme (ie, - SH). Thus, for example, thioalkyl means an alkyl substituent, wherein one or more hydrogen radicals are replaced with -HS, while alkylthio means alkyl-S-. The term "thioalkoxy" (alone or in combination with another term (s)) refers to an alkyl group attached to the molecular portion of origin through-S-. Representative examples of thioalkoxy include, but are not limited to, methylthio, ethylthio, and butylthio. The term "thioalkoxyalkyl" (alone or in combination with another term (s)) refers to a thioalkoxy group attached to the parent molecular moiety through an alkylene group (i.e., alkyl-S-alkylene-). The term "thiocarbonyl" (alone or in combination with another term (s)) means a carbonyl, wherein the oxygen atom has been replaced with a sulfur. Said substituent can be represented as -C (S) -, and can also be represented as: The term "pharmaceutically acceptable" is used adjectivally to imply that the modified name is suitable for use as a pharmaceutical or as a part of a pharmaceutical product. The term "therapeutically effective amount" refers to a total amount of each active substance that is sufficient to show a significant benefit to the patient, for example, a reduction in viral load. The term "prodrug" refers to derivatives of the compounds of the invention, which have chemically or metabolically divisible groups and become, through solvolysis or under physiological conditions, the compounds of the invention that are pharmaceutically active in vivo. A prodrug of a compound can be formed in a conventional manner through the reaction of a functional group of the compound (such as an amino group, hydroxy or carboxy). The prodrug derivative form usually offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared through the reaction of the acidic compound of origin with a suitable alcohol, or amides prepared through the reaction of the acidic compound of origin with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated alcohol derivatives or amine functional groups within the compounds of the invention. The term "solvate" refers to the physical association of a compound of a compound of this invention with one or more solvent molecules, either organic or inorganic. This physical association usually includes a hydrogen bond. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice structure of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates and methanolates. The term "chiral" refers to molecules that do not have a plane of symmetry and, therefore, are not super-taxable in their mirror image. A chiral molecule can exist in two forms, one on the right and one on the left. The term "stereoisomer" refers to isomers that have their atoms connected in the same order but have different three-dimensional arrangements. The term stereoisomer includes, for example, enantiomers and diastereomers. The term "cis-trans isomer" refers to stereoisomers that differ in their stereochemistry over a double bond or ring. The cis-trans isomers are also called geometric isomers. The term "enantiomer" refers to stereoisomers of a chiral substance having a mirror image ratio. The term "diastereomer" refers to stereoisomers that are not enantiomers, or mirror images of each other. The term "racemic mixture" refers to a mixture consisting of enantiomers of equal parts (+) and (-) of a substantial chiral. Although the individual molecules are chiral, the racemic mixtures are optically inactive. The term "tautomer" refers to isomers that are inter-convertible. For example, enols and ketones are tautomers since they are inter-converted through treatment with either acid or base. The term "position isomer" refers to any of two or more constitutional isomers that differ in the position of a particular substituent or group. The functional groups can be joined in structurally non-equivalent positions on a skeleton or carbon structure. For example, [1,3] imidazole, r and [1,4] imidazole, represented as , are position isomers. The term "N-protecting group" or "N-protected" refers to those groups capable of protecting an amino group against undesirable reactions. The commonly used N-protecting groups are described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3rd ed., John Wiley &Sons, NY (1999), which is incorporated herein by reference in its entirety. N-protectors include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl, sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl, sulfenyl groups such as phenylisulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-), sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S (O)) -) or t-butyl its If ini I or (t-Bu-S (O) -): carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl , 3, 4-di methox benzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1- methylethoxycarbonyl, methylmethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl; p-methoxyphenyl; and silyl groups such as trimethylsilyl. Preferred N-protecting groups include formyl, acetyl, benzoyl, p i v a I o? I o, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The following abbreviations were used in the General Synthetic Methods and Examples described below: AcOH = acetic acid atm = atmospheres Boc = Nt-butoxycarbonyl (protecting group) CDI = 1,1 '-carbonyldiimidazole CH2Cl2 = methylene chloride (dichloromethane) Cul = cuprous iodide [copper iodide (I)] DCE = 1,2-dichloroethane DEAD = diethyl azodicarboxylate DMA = NN-dimethylacetamide DMAP = 4-dimethylaminopyridine DMF = N, N-dimethylformamide DMSO = dimethyl sulfoxide EDCI = (N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride EMME = 2-ethoxymethylene malonic acid diethyl ether Et3N = triethylamine Ether = diethyl ether Etl = ethyl iodide EtOAc = ethyl acetate ethyl EtOH = ethanol Fe = iron Fe (AcAc) 3 = iron acetylacetonate (III) Fmoc chloride = 9-fluorenylmethyl chloroformate HOBt = N-Hydroxybenzotriazole Hunig base =?,? - diisopropylethylamine IPA = isopropyl alcohol K2C03 = carbonate of potassium KOH = potassium hydroxide LDA = lithium diisopropylamine eOH = methanol MsCl = methanesulfonyl chloride NaH = sodium hydride NH2OH »HCl = hydroxylamine hydrochloride NMP = 1-methyl-2-pyrrolidinone Mg2S04 = magnesium sulfate Na2S04 = sodium sulfate NH3 = ammonia NH4Cl = ammonium chloride NH4OH = ammonium hydroxide PG = protective group such as Boc- or Troc- POCI3 = phosphorylated oxy-chloride R-MgCI = reactive of Grignard Rl = alkyl iodide or substituted alkyl iodide SnCl2 = stannous chloride (tin chloride (II)) TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography Triflic anhydride = trifluoromethanesulfonic anhydride Troc = 2,2,2-trichloroethoxycarbonyl- (protecting group).

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

Preparation of Compounds of Formulas I-VIII Compounds of Formula I can be synthesized making react wherein W ,, W2, A, B, X, Y, R10, R22 and R50 have the meanings established in the above embodiments or example, and K is Cl or another halogen. Also, the compounds of Formulas ll-VIII can be prepared by reacting: respectively. The synthesis of the compounds of Formulas I-VIII is illustrated in Schemes 1-8. Representative compounds of Formula I, wherein R10, R17 and R35 are as defined above, and Z is can be prepared using the procedure defined in Scheme 1.

SCHEME 1 (1) (2) (3) The amines of the formula (2) wherein R41 is hydrogen can be treated with?,? - dimethylformamidine compounds of the formula (1) in the presence of an acid such as, but not limited to, acetic acid, at elevated temperature ( for example, from about 80 ° C to about 150 ° C), thus producing compounds of the formula (3). Acetic acid can function as a solvent. Other solvents can also be used in the reaction. N-alkylation of the compounds of the formula (2), wherein R41 is hydrogen provides the formula (2) or (3), wherein R4 is alkyl. This process can be facilitated with an alkylation reagent of the formula R 1 X 1, wherein 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 which varies from about room temperature to about 100 ° C.

SCHEME 2 The preparation of the N, N-dimethylformamidine compounds of the formula (1) can be achieved as described in Scheme 2. The ketones of the formula (4) and the esters of the formula (5), in the presence of a base such as, but not limited to, sodium or potassium hydride (or sodium metal) at about 0 ° C in a suitable solvent such as, but not limited to, diethyl ether, provide a salt of the formula (6), where M is potassium or sodium. Treatment of the formula (6) with 2-cyanoacetamide in the presence of piperidine acetate, at about reflux provides the nitriles of the formula (7a) and (7b). The regioisomers (7a) and (7b) can be separated at this point O or later in the synthetic route, using purification techniques known to those skilled in the art. The compounds of the formula (7a) can be converted to either compounds of the formula (8), wherein X2 is Cl through treatment with phosphorus oxychloride or compounds of the formula (8), wherein X2 is Br through treatment with tetrabutylammonium bromide and phosphorus pentoxide in a suitable solvent, at reflux. A solution of compounds of the formula (8), wherein X 2 is Cl or Br and liquid ammonia are reacted in a sealed high pressure vessel at elevated temperature, for example, at about 130 ° C to provide the compounds of the formula (9) The compounds of the formula (9) and N, N-dimethylformamide dimethyl acetal in a solvent such as, but not limited to, toluene, under reflux produce the N, N-dimethylformamidine compounds of the formula (1).

SCHEME 3 (12) The compounds of the formula (2), wherein R41 is hydrogen and X is O or S, can be prepared from compounds of the formula (10) according to Scheme 3, wherein R10i is a leaving group such as , but not limited to, halogen, triflate or mesylate (the last two can be prepared from alcohol corresponding using methodologies known to a person skilled in the art), through a synthesis of two steps, mainly, reduction of the nitro group followed by displacement of R 101, or displacement of R101 followed by reduction of the nitro group. The displacement of R10i with R22XH, wherein X is O or S, may be facilitated in the presence of a suitable base such as, but not limited to, carbonate or bicarbonate of potassium, cesium or sodium, or sodium or potassium hydride, and optionally in the presence of 18-crown-6, at elevated temperature. The reaction in general can be carried out in a solvent such as, but not limited to, N, N-dimethylformamide or dimethyl sulfoxide, at a temperature from about room temperature to about 180 ° C. The reaction in general can be carried out in a solvent such as, but not limited to, N, N-dimethylformamide or dimethyl succinate, at a temperature from about room temperature to about 180 ° C. The reaction can also be conducted in a microwave oven. It is appreciated that the compounds of the formula (11) can be obtained from the reaction of the formula (10), wherein R10i is -XH with compounds of the formula R22X3, wherein X3 is a leaving group such as, but not limited to, halogen, triflate or mesylate, using the aforementioned reaction conditions. Displacement reactions can also be carried out in the presence of a metal catalyst such as, but not limited to, copper metal, Cul, or palladium acetate, optionally in the presence of a ligand such as, but not limited to, 2,2'-bis (diphenylphosphino) -1,1-biphenyl 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 generally carried out at a temperature from about room temperature to about 180 ° C, in a solvent such as, but not limited to, toluene or N, N-dimethylformamide. The reduction of the nitro group can be achieved through the treatment of the nitro compound with a reducing agent such as, but not limited to, iron powder / ammonium chloride or tin (II) chloride, in a suitable solvent. It should also be appreciated that the compounds of the formula (10) can be converted to compounds of the formula (2) by first reducing the nitro functionality, followed by the displacement reaction, using reaction conditions as described above.

Preparation of Aminophenyl Coupling Agents (10, 11 and 12) A wide variety of aminophenyl coupling agents are possible. The agents in Scheme 4 are illustrative for this variety. In a typical preparation, a substituted 2-chloro-nitrobenzene compound in dimethylformamide (DMF) was treated with a sodium thiophenolate at about 50 ° C for about 2 hours, cooled and diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to give the substituted 2-phenylsulfanyl-nitrobenzene compound. This nitrobenzene compound was then reduced with stannous chloride (SnCl2) or iron (Fe) in ethanol. The reaction mixture was adjusted to a pH of 12 with 1N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum to give the substituted 2-phenylsulfanyl-aminobenzene compound 10. Similarly, the corresponding substituted 2-hydroxy-nitrobenzene compound was dissolved in dimethylformamide which reacted with a sodium phenoxide solution., stirred and heated at 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 under vacuum to give the substituted 2-phenoxy-nitrobenzene compound. This nitrobenzene compound was then reduced with stannous chloride (SnCl2) and iron (Fe) in ethanol. The reaction mixture was adjusted to a pH of 12 with 1N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum to provide the substituted 2-phenoxy-aminobenzene compound 12. Similarly, any compound 10, wherein R9 is hydroxy or protected hydroxyl can be further modified by alkylating the hydroxy group using a substituted benzyl bromide to give the phenoxy-5-substituted-phenylsulfanyl-aminobenzene-2-compound. replaced 11 corresponding.

SCHEME 4 R was previously defined; X is OH, NH2, NHR, halogen, alkyl or alkoxy; R is alkyl, alkoxy, bromo, fluoro, chloro or cyano.

Preparation of 4-Aminophenyl-7-substituted Substituted pyrido [2,3-d] pyrimidine compounds A typical preparation of the 4-aminophenyl-7- compounds Substituted substituted pyrido [2,3-d] pyrimidine (Scheme 6) involves the coupling reaction of a substituted aminophenyl coupling agent (described in Scheme 4) with a 2-amidino-3-cyanopyridine compound. -substituted 9. (Scheme 5). As described in Scheme 4, a wide variety of aminophenyl coupling agents is possible. The preparation of substituted 4-aminophenyl-7-substituted-pyrido [2,3-substituted pyrimidines can be coupled by coupling a compound N, N-dimethylformamidino 9 with a variety of coupling agents, some of which are described in the Scheme 4. The preparation of the compounds N, N-dimethylformamidine 9 can be achieved as described in Scheme 5. A substituted alkyl methyl ketone and ethyl formate were added to a solution of diethyl ether of sodium hydride (or sodium metal) at about 0 ° C for about 2 hours. After the addition, the reaction was continued stirring at room temperature overnight. Additional diethyl ether was added and the precipitate was isolated rapidly by vacuum filtration, dried in a vacuum desiccator. This material was dissolved in water with 2-cyanoacetamide. A solution of piperidine acetate was added and the resulting solution was heated to 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, rinsed with water and dried and identified as 6-substituted 2-γ-1,2-dihydropyridine-3-carbonitrile.

Compound 24 was converted to both 2-chloro-pyridine with phosphorus oxychloride (as shown in Scheme 5) and 2-bromopyridine. 2-Bromopyridine was prepared by taking a toluene solution of compound 24 and reacting with tetrabutylammonium bromide and phosphorus pentoxide at 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 under vacuum to give 2-bromopyridine. An ethanol solution of either 2-chloropyridine or 2-bromopyridine and liquid ammonia were reacted in a sealed high pressure vessel at approximately 130 ° C for about 20 hours. The reaction mixture was concentrated under vacuum and the residue was washed with water and dried to give the 6-substituted 2-amino-nicotinonitrile 25. Compound 25 and N, N-dimethylformamide dimethyl acetal were dissolved in toluene and heated to reflux for about 3 hours. The resulting solution was cooled to room temperature and concentrated under vacuum to give 6-substituted 6-cyano-pyridin-2-yl-N, N-dimethylformamidine 9.

SCHEME 5 R7 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl amino, cyanoalkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, morpholino, hydrazino, alkylaminoalkoxy, alkoxyalkylamino, and aryl. As described above, the preparation of substituted 4-aminophenyl-7-substituted-pyrido [2,3-d] pirtmidines can be achieved by coupling 3-cyano-pyridin-2-yl-N, N-dimethylformamidine 6-substituted 9 as is shown in Scheme 5 with a variety of coupling agents, some of which are described in Scheme 4. This coupling reaction is described in Scheme 6. In a typical preparation, compound 9 and an aminophenyl coupling agent similar to that described in Scheme 4, they were dissolved in acetic acid and stirred at about 130 ° C for about 15 minutes. The mixture was cooled to At room temperature, the acetic acid was removed under vacuum and the resulting residue was purified by reverse phase chromatography. At this point, any functional protective group such as the Boc, Troc or other group can be removed by known methods to give the final products.

R7, R9, X and R are as defined above. Representative compounds of Formula I, wherein the B ring is a five-member heterocycle and W1 is CH, R10, R17 and R35 are as defined hereinabove, and Z is NR41, can be prepared using the procedure defined in Scheme 7 and consists of reacting a heterocycle Alkylamino-substituted such as 13 with Meldrum acid and triethylorotoformate and heat to about 100 ° C. The reaction mixture was concentrated and purified through chromatography to give the ester of aminomethylene malonic acid 14. Compound 14 was then dissolved in diphenyl ether and the resulting solution was heated at 250 ° C for about 30 minutes to give 15. A mixture of compound 15 was mixed with phosphorus oxychloride (POCI3) and heated to about 50 ° C with stirring for 6 hours, cooled and quenched by pouring on ice. It was cooled and adjusted to a pH of 10 with concentrated ammonium hydroxide and extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 16. In a typical preparation, the and an aminophenyl coupling agent similar to those described in Scheme 4, were coupled with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane tris (dibenzylideneacetone) -dipaladium, and sodium tert-butoxide in a solvent, typically toluene, and the like to provide 21.

SCHEME 7 Representative compounds of Formula I, wherein the B ring is a five-membered heterocycle and W, is N, R10, R7 and R35 are as defined herein above, and Z is NR41, can be prepared using the procedure defined in Scheme 8 and consists of reacting an alkylamino- substituted such as 17 with refluxing formamide. The pyrimidine product 18 was then reacted with phosphorus oxychloride (POCI3) to give the coupling standard 19. In a typical preparation, the compounds 19 and the aminophenyl coupling agent similar to those described in Scheme 4, were dissolved in ethanol and refluxed for 12 hours to give 20.

SCHEME 8 twenty Representative compounds of Formula I, wherein the is a five-member heterocycle and W1 is N or CH, R10, R17 and R35 are as defined herein above, and Z is NR41, can be prepared. The optimum reaction conditions and the reaction times for each individual step may vary depending on the particular reagents employed and substituents present in the reagents used. Unless otherwise specified, solvents, temperatures and other reaction conditions can be readily selected by one skilled in the art. The reactions can be processed in a conventional manner, for example, by removing the solvent from the residue and further purifying the according to the methodologies generally known in the art, such as, but not limited to, crystallization, distillation, extraction, titration and chromatography. It should be understood that the above-described embodiments and schemes and the following examples are provided by way of illustration, and not limitation. Various changes and modifications within the scope of the present invention will be apparent to those skilled in the art from the present disclosure.

Example 1 4-Amino-N-. { 2- (4-hydroxy-phenylsulfanyl) -5-methyl-phenyl] -2- (2-methoxy-ethylamino) -pyrimidine-5-carboxamidine The product of Example 156 (42 mg, 0.1 mmol) in 2-methoxy-ethylamine (1 mL) was heated at 180 ° C for 2 hours in a microwave reactor. The solvent was evaporated and the residue was purified by HPLC with the TFA method to give the title compound as a trifluoroacetic acid salt (15 mg, 28%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.31 (s, 3 H) 3.28 (s, 3 H) 3.49 (m, 4 H) 6.86 (m, 3 H) 7.28 (m, 4 H) 8.17 (s, br, 3 H 8.73 (s, br, 1H) 9.75 (s, br, 2H) 11.33 (s, br, 1H); S (ESI +) m / z 425 (M + H) +.

Example 2 4-Amino-2-butylamino-N- [2- (4-hydroxy-phenylsulfanyl) -5-methyl-phenyl] -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 reactor. The solvent was evaporated and the residue was purified by HPLC with the TFA method to give the title compound as the trifluoroacetic acid salt (13 mg, 24%). 1 H NMR (300 MHz, DMSO-de) d 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, br, 3H) 8.71 (s, br, 1H) 9.55 (s, br, 1H) 9.92 (s, br, 1H) 11.23 (s, br, 1H); MS (ESI +) m / z 423 (M + H) +.

Example 3 N-. { 4- [4-Methyl-2- (6-propyl-thieno [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 at room temperature was treated with triethylamine (0.5 equivalents) then heated to 50 ° C, valeraldehyde (1 equivalent) was added dropwise. After 3 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to provide 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 at reflux for 3 hours. The reaction mixture was quenched with water and the resulting precipitate was collected through filtration and washed with water and dried under vacuum to provide the title compound.

Example 3c 4-chloro-6-propylthieno [2,3-d] pyrimidine The product of Example 3b was reacted with an excess of POCI3 at reflux for 3 hours, then at room temperature for 16 hours. The reaction was emptied on ice and partitioned between water and ethyl acetate. The organic layer was concentrated to provide the title compound. 3d Illustration N-. { 4- [4-Methyl-2- (6-propyl-thieno [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide The product of Example 3c was reacted with the product of Example 7b, reacted in ethanol at reflux for 16 hours. The reaction was concentrated to yield the title compound.

Example 4 (6-Butyl-thieno [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine The title compound was prepared according to the procedures of Example 3 substituting hexanal for valeraldehyde in Example 3a.

Example 5 (5-Methyl-2-phenylsulfanyl-phenyl) - (2-pyrrol-thiazolo [5,4-b] pyridin-7-yl) -amine Example 5A Butyrylaminoacetic acid methyl ester A suspension of glycine hydrochloride (1.00 g, 7.964 mmoles) in methylene chloride (40 ml), cooled to 0 ° under a nitrogen atmosphere, 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. environment for 2.5 hours. The reaction was washed with saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound. Purification via 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 (50 mL) was treated with Lawesson's reagent (1338 g, 3,209 mmol), then heated to reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to 0 ° and a solution of 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 x 25 ml), and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound. Purification via flash chromatography on silica gel with 1% ethyl acetate / methylene chloride afforded the title compound as a colorless oil (0.790 g, 4508 mmol, 93%).

Example 5C 2-Thiobutyrylamino-acetamide A solution of the product from Example 5B (0.788 g, 4.496 mmol) in methanol (30 mL) was saturated with ammonia gas and the reaction was stirred in a stoppered flask at room temperature for 17 hours. The solvent was concentrated in vacuo to give the title compound and the solid was purified via flash chromatography on silica gel with 10% methanol / methylene chloride to give the title compound as a white solid (500 mg, 3.12. mmoles, 69%).

Example 5D 2-Propyl-thiazole-5-ylamine A solution of the product of Example 5C (395 mg, 2465 mmol) in anhydrous ethyl acetate (12 mL) was treated with phosphorus tribromide (0.189 mL, 1.972 mmol) under a nitrogen atmosphere and stirred at room temperature for 20 minutes. . Added additional phosphorus tribromide (0.050 ml) and allowed to stir for 5 minutes. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (25 ml). The aqueous wash was extracted with ethyl acetate (2 x 50 mL), and the organic extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound. Purification through flash chromatography of silica gel with 3% methanol / methylene gave the title product (175 mg, 1.23 mmol, 50%).

Example 5E 2,2-Dimethyl-5 - [(2-propyl-thiazol-5-ylamino) -methylene] - [1,3] dioxan-4,6-dione A solution of the product of Example 5D (212.7 mg, 1496 mmol) in anhydrous ethanol (5 mL) was treated with Meldrum's Acid (237 mg, 1645 mmol) and triethyl orthoformate (0.25 mL, 1496 mmol) at room temperature, and the reaction it was heated in an oil bath preheated to 100 °. After 15 minutes, the reaction was cooled to room temperature and the solvent was removed by rotary evaporation under vacuum. Purification through flash chromatography of silica gel with a gradient of 10% to 20% ethyl acetate / methylene chloride afforded the title compound as an off-white solid (240 mg, 0.8099 mmol, 54%) Example 5F 2-Propyl-H-thiazolo [5,4-b] pyridin-7-one The product of Example 5E (230 mg, 0.7781 mmol) was added to refluxing biphenyl ether (S mi) under a nitrogen atmosphere. After refluxing for 5 minutes, the solution was cooled in an ice bath and diluted with hexanes (50 ml). The resulting brown solid was collected by vacuum filtration and washed thoroughly with hexanes to give the title compound (125 mg, 0.644 mmol, 83%).

Example 5G 7-Chloro-2-propyl-thiazolo [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 a nitrogen atmosphere. The solution was cooled in an ice bath, treated with ice, and the pH was adjusted to 7 with 6N aqueous sodium hydroxide. It was extracted with methylene chloride (3 x 50 mL) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound as a brown oil (120 mg, 0.564 mmol, 89% ).

Example 5H: methyl-2-nitro-1-phenylsulfan-1-benzene A solution of thiophenolate sodium (3.96 g, 30 mmol) in 60 ml of DMF was heated at 50 ° C with 4-chloro-3-nitrotoluene (2.65 ml, 20 mmol) with stirring for 2 days. It was cooled to room temperature and diluted with CH2Cl2. It was washed with water and the organic layer was dried over Na2SO4. Filtered and concentrated in vacuo to give the title compound (4.29 g, 87%) 1 H NMR (300 MHz, CDCl 3) d ppm: 2.36 (s, 3 H) 6.76 (d, J = 8.09 Hz, 1 H) 7.16 (d , J = 8.46 Hz, 1H) 7.45 (m, 3H) 7.58 (m, 2H) 8.03 (s, 1H).

Example 51 5-Met l-2-phenylsulfanyl-phenylamine 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. The pH was adjusted to 12 with 1N NaOH and extracted with EtOAc. Dry over Na 2 SO 1, filter and concentrate in vacuo to give the title compound (835 mg, 82%) 1 H NMR (300 MHz, CDCl 3) d ppm: 2.30 (2, 3 H) 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-Met l-2-phenylsulfanyl-phenyl) - (2-propyl-thiazolo [5,4-b] pyridin-7-yl) -amine A flask purged with nitrogen was charged with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane (38 mg, 0.111 mmol), tris (dibenzylideneacetone) - dipalladium (25.4 mg, 0.0277 mmol), and sodium tert-butoxide (82.4 mg, 0.8322 mmol). 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 51 (107.5 mg, 0.4993 mmol) in toluene (3 mL) were added via syringe. The reaction was heated to reflux in an oil bath preheated to 120 ° for 18 hours, cooled to room temperature, treated with additional tris (dibenzylidene ketone) dipalladium (25.4 mg), and heated to reflux for a further 2.5 hours. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation in vacuo. Purification through flash chromatography of silica gel with a gradient of 1% to 3% ethyl acetate / methylene chloride afforded the title compound (29 mg, 0.074 mmol, 15%). 1H NMR (300 MHz, DMSO-D6) d 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); S (DCI / NH3) m / z 392 (M + H) +.

Example 6 4- [4-Methyl-2- (2-propyl-thiazolo [5,4-b] pyridin-7-ylami) -phenylsulfanyl] -phenol Example 6a Trifluoro-methanesulfonic acid 4-methyl-2-nitro-phenyl 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 under an N 2 atmosphere was treated with trifluoromethanesulfonic anhydride (7.25 mL, 43.1 mmol) at 0 ° C for 30 minutes. It was quenched through the addition of MeOH. It was washed sequentially with 10% citric acid, 0.5 m KOH and water. Dried over MgSO4, filtered and concentrated in vacuo to give the title compound, which was purified through silica gel column chromatography eluting with CH2Cl2 to give an amber oil (11.22 g, 100%).

Example 6b 4- (4-ethyl-2-nitro-phenylsulfanyl) -phenol The product of Example 6a (11.22 g, 39.3 mmol) and 4-mercaptophenol (4.96 g, 39.3 mmol) in 100 mL of EtOH was treated with Na 2 CO 3 and heated overnight under efflux. It was cooled to room temperature and extinguished with water. It was extracted with EtOAc. It was dried over MgSO, filtered and concentrated under vacuum giving the compound of the title, which was purified through silica gel column chromatography eluting with 25% EtOAc / hexane to give a red oil (8.65 g, 85%).

Example 6c 4- (2-Amino-4-methyl-phenylsulfanyl) -phenol The product of Example 6b (8.65 g, 31.3 mmol) was reduced with SnCl 2 following the procedure of Example 51 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) phenylphiol) phenol A flask purged with dry nitrogen was charged with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane (40.4 mg, 0.118 mmol), tris (dibenzylidenacetone) -dipaladium (27 mg, 0.0295 mmoles), and sodium tert-butoxide (87.7 mg, 0.885 mmoles). A solution of the product of Example 5G (125.5 mg, 0.590 mmol) in anhydrous toluene (5 mL) was added via syringe, followed by the product of Example 6c (136 mg, 0.590 mmol). The reaction was heated to reflux in an oil bath pre-heated to 110 ° for 14 hours, cooled to room temperature, treated with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1. -phospha-bicyclo [3.3.3] additional undecane (40.4 mg) and tris (dibenzylideneacetone) dipalladium (27 mg), and heated to reflux for 7 more hours. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation in vacuo. Purification through flash chromatography of silica gel with a gradient of 15% to 30% ethyl acetate / methylene chloride provided an impure material. Purification through flash chromatography of silica gel with a gradient of 1% to 2% methanol / methylene chloride gave the desired title compound as a light yellow solid (20 mg, 0.049 mmol, 8%). 1H NMR (300 MHz, DMSO-D6) d 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, 1 H) 6.67-6.73 (m, 2 H) 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 / NH3) m / z 408 (M + H) +.

Example 7 ÍM-. { 4- [4-Wietl-2- (2-propyl-thiazolo [5,4-b] pyridin-7-ylamino) -phenylsulfanyl] -phenyl} -acetamide Example 7a N- [4- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide The product of Example 6a (1 g, 3.51 mmol) was reacted with N- (4-mercapto-phenyl) -acetamide (0.65 g, 351 mmol) for 18 hours following the procedure of Example 6b to give the compound of the title (1.04 g, 98%).

Example 7b N- [4- (2-Amino-4-met yl-phenylsulfanyl) phenyl] -acetamide The product of Example 7a (0.30 gm, 1 mmol) was reacted with SnCl2 as described in Example 51 to give the title compound (0.27 gm, 100%) as an amber oil which was used without further purification.

Example 7c N- (4- (4-methyl-2- (2-propylthiazolo [5,4-b] pyridin-7-ylamino) phenylthio) phenyl) acetamide A flask purged with dry nitrogen was charged with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane (38.6 mg, 0.1128 mmol), tris (dibenzylidenacetone) -dipaladium (25.8 mg, 0.0282 mmoles), and sodium tert -butoxide (83.8 mg, 0.8463 mmoles). A solution of the product of Example 5G (120 mg, 0.5642 mmol) in anhydrous toluene (5 mL) was added via syringe, followed by the product of Example 7b (130 mg, 0.4773 mmol). The reaction was heated in a preheated oil bath at 100 ° C for 2.5 hours, cooled to room temperature, treated with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1- phosphabicyclo [additional 3.3.31undecano (38.6 mg), tris (dibenzylideneacetone) dipalladium (25.8 mg) and starting with aniline (130 mg), and heated at 100 ° C for an additional 18 hours. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation in vacuo. Purification via flash chromatography on silica gel with a gradient of 40% to 60% ethyl acetate / methylene chloride gave the desired title compound as a tan foam (26 mg, 10%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.01 (t, J = 7.35 Hz, 3 H) 1.73-1.91 (m, 2 H) 2.01 (s, 3 H) 2.34 (s, 3 H) 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 / NH3) 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-ylammon) -methylene] - [1, 3] dioxan-4,6-dione A mixture of 1-methyl-1 H-pyrazol-3-ylamine (1.05 g, 10.8 mmol), 2,2-dimethyl- [, 3] dioxan-4,6-dione (1.71 g, 11.9 mmol), and triethyl orthoformate (1.60 g, 10.8 mmol,) in a 25 ml round bottom flask was heated in an oil bath at 100 ° C for 15 minutes. The mixture was cooled to room temperature and EtOH (10 ml) added. The reaction mixture was heated to dissolve all solids and then cooled to room temperature. The solid that formed was cooled through filtration, rinsed with ethanol, and dried to provide the title compound (1.81 g, 66% yield).

Example 8b 2-Methyl-2,7-dihydro-pyrazolo [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, with the removal of the resulting acetone through distillation. The solvent was then decanted, and the remaining solid residue was dissolved in dichloromethane (5 ml) and purified by chromatography on silica gel 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 emptied on ice, brought to a pH of 8 through the addition of a 1N aqueous sodium hydroxide solution, and extracted with dichloromethane (3 x 30 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to provide 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} -acet amide 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), Pd2 (dba) 3 (12.9 mg, 0.0141 mmol), sodium t-butoxide (67.8 mg, 0.706 mmoles), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3, 3, 3] undecane (193 mg, 0.0564 mmol) in toluene (4 mL) was degassed, it was left under a positive nitrogen pressure, and heated under reflux for 2 hours. Additional amounts of Pd2 (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 a further 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 chromatography on silica gel, eluting with 5% MeOH / CH2C12, to give the title compound (0.0195 g, 17% performance). H NMR (300 MHz, DMSO-d6) d 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-Mephyl-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), Pd2 (dba) 3 (16.9 mg, 0.0185 mmol), sodium t-butoxide (89.0 mg, 0.926 mmol), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicycl [3, 3, 3] undecane (25.4 mg, 0.0741 mmol) in toluene (3 mL) was degassed, it was left under a positive nitrogen pressure, and heated under reflux for 2 hours. Additional amounts of Pd2 (dba) 3 (7.0 mg, 0.0076 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicycl [3,3,3] undecane (15 mg , 0.044 mmole), the reaction mixture was heated under reflux for a further 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 through chromatography on silica gel, eluting with a 2-5% MeOH / CH2Cl2 gradient, to give the title compound (0.0279 g, 21% yield). 1 H NMR (300 MHz, D SO-d 6) d ppm: 2.27 (s, 3 H), 4.11 (s, 3 H), 5.92 (d, J = 5.15 Hz, 1 H), 6.75-6.85 (m, 3 H), 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 (M-H) -.

Example 10 4- [4- (4-Methoxy-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 10A 2-Amino-6-methyl-nicotinonitrile 2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 ml) were reacted in 500 ml of ethanol in a high-pressure vessel sealed at 130 ° C for 20 hours. The reaction mixture was concentrated under vacuum and the residue was washed with water (2 x 50 mL) then dried in a vacuum oven for 24 hours to give the title compound as a light yellow solid (18 g, 82%). . 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.30 (s, 3 H), 6.52 (d, J = 7.7 Hz, 1 H), 6.78 (s, 2 H), 7.73 (d, J = 7.7 Hz, 1 H) .

Example 1 OB N '- (3-Cyano-6-methyl pyridin-2-yl) -N, N-dimethyl-formamidine A solution of the product of Example 10A (10 g, 75.19 mmol) and?,? - Dimethylformamide dimethyl acetal (11 mL, 82.71 mmol) in toluene (100 mL) was heated to reflux for 6 hours. After room temperature was cooled, the solution was concentrated under vacuum to provide the title compound as a yellow solid (13.78 g, 98%). 1H NR (300 Hz, DMSO-d6) d 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-methoxy-benzyloxy) -2-nitro-benzene A solution of 4-chloro-3-nitro-phenol (0.5 g, 2.88 mmol), 1-chloromethyl-4-methoxy-benzene (0.496 g, 3.17 mmol), potassium carbonate (1.19 g, 8.64 mmol) and iodide tetrabutylammonium (0.005 g, 0.0135 mmol) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. Ice-water (10 ml) was then added to the solution and the resulting solid was collected through filtration and dried in a vacuum oven to provide the title compound (0.812 g, 96%).

Example 1 OD 4- [4- (4-Methoxy-benzyloxy) -2-nitro-f-enyl-sulfonyl-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 to 100 ° C. C for 16 hours. After cooling to room temperature, the mixture was poured into ice-water (20 ml) and the resulting solution was acidified with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 x 10 mL), the combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.06 g, 100%).

Example 10E 4- [2-Amino-4- (4-methoxy-benzyloxy) -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 methanol (18 mL), tetrahydrofuran (18 mL), and a solution of water (6 ml) was heated to reflux for 3 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.99 g, 100%).

Example 10F 4-. { 4- (4-Wietoxy-benzyl KÍ) -2- (7-methyl-pyrido [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 a pre-heated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was titrated with methanol to give the title compound as a tan solid (26.5 mg, 35%). 1 H NMR (300 MHz, D SO-d 6) d ppm: 9.92 (s, 1 H), 9.63 (s, 1 H), 8.70 (d, J = 8.09 Hz, 1 H), 8.55 (s, 1 H) , 7.52 (d, J = 8.46 Hz, 1 H), 7.38 (d, J = 8.82 Hz, 2H), 7.27 (s, 1 H), 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); S (ESI +) m / z 497.2 (M + H) +, (ESI-) m / z 495.3 (M-H) -.

Example 11 3- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] -benzonitrile Example 11 A 3- [3-Amino-4- (4-hydroxy-phenylsulfanM) -phenoxymethyl] -benzonitrile A solution of 4-chloro-3-nitro-phenol was reacted with 3-bromomethyl-benzonitrile using the conditions described in Example 10C to provide 3- (4-chloro-3-nitro-phenoxymethyl) -benzonitrile, which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 11 B 3- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-mephyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] -benzonitrile The product of Example 11 A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 11A for the product of Example 10E to provide the crude title compound which was purified through HPLC preparation reverse phase on a Waters Symmetry C8 column (25mm x 100mm, 7 m particle size) using a gradient of 10% to 100% acetonitrile / 0.1% trifluoroacetic acid in water for 8 minutes (10 minutes run time) at a rate of flow 40ml / min to provide the title compound as a trifluoroacetic acid salt (20 mg, 23%). 1H NR (300 MHz, DMSO-d6) d 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-Methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (pyridin-2-ylmethoxy) phenylsulfanyl] -phenol Example 12 A 4- [2-Amino-4- (pyridin-2-ylmethoxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with the hydrobromide salt of 2-bromomethyl-pyridine using the conditions described in Example 10C to provide 2- (4-chloro-3-nitrophenoxymethyl) -pyridine which it was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 12B 4- [2- (7-Methyl-pyrido [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 using the procedure of Example 10 F substituting the product of Example 12A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA for provide the compound of the title as a trifluoroacetic acid salt (15 mg, 17%). 1 H NMR (300 MHz, DMSO-D 6) d ppm 2.76 (s, 3 H) 5.19 (s, 2 H) 6.63 (d, J = 8.82 Hz, 2 H) 6.98-7.17 (m, 3 H) 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 (br s, 1H) 11.66 (br s, 1H); MS (ESI +) m / z 468 (M + H) +.

Example 13 4- [4- (4-tert-Butyl-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 13A 4- [2-Amino-4- (4-tert-butyl-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-4-tert-butyl-benzene using the conditions described in Example 10C to provide 4- (4-tert-Butyl-benzyloxy) -1 -chloro-2-nitro-benzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 13B 4- [4- (4-tert-Butyl-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 13A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 13A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to give the title compound as a trifluoroacetic acid salt ( 52 mg, 36%). 1H NMR (300 MHz, DMSO-D6) d 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-Bromo-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-lamino) -phenylsulfanyl) -phenol Example 14A 4- [2-Amino-4- (2-bromo-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-2-bromomethyl-benzene using the conditions described in Example 10C to provide 4- (2-Bromo-benzyloxy) -1-chloro-2 -nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 14B 4-. { 4- (2-Bromo-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 14A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 14A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (42 mg, 39%). H NMR (300 Hz; DMSO-D6) d 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-Bromo-benzyloxy) -2- (7-methyl-pyrid [2,3-d] pyrimidin-4-ylamino) -phenylsulf-indol] -phenol Example 15A 4- [2-Amino-4- (3-bromo-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene using the conditions described in Example 10C to provide 4- (3-bromo-benzyloxy) -1-chloro-2 - nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 15B 4- [4- (3-Bromobenzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 15A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 15A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (25 mg, 23%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.72 (s, 3 H) 5.13 (s, 2 H) 6.65 (m, 2 H) 7.11 (m, 5 H) 7.40 (m, 2 H) 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-Bromo-benzmoxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -fe nylsulfanyl] -phenol Example 16A 4- [2-Amino-4- (4-bromobenzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-4-bromomethyl-benzene using the conditions described in Example 10C to provide 4- (4-bromo-benzyloxy) -1-chloro-2 -nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 16B 4- [4- (4-Bromo-benzyloxy) -2- (7-methyl-pyrid [2,3-d] pyrimidn-4-ylamino) -phenylsulfanyl] - phenol The product of Example 16A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 16A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (19 mg, 17%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.72 (s, 3 H) 5.13 (s, 2 H) 6.63 (m, 2 H) 7.03 (dd, J = 8.82, 2.57 Hz, 1 H) 7.10 (m, 2 H) 7.21 (d, J = 8.46 Hz, 2H) 7.40 (m, 2H) 7.54 (d, J = 8.09 Hz, 1 H) 7.66 (s, 1 H) 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, 1 H); MS (ESI +) m / z 545, 547 (M + H) +.

Example 17 4- [4- (2-ftphlethyl-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 17A 4- [2-Amino-4- (2-methy1-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-2-methyl-benzene using the conditions described in Example 10C to provide 1-chloro-4- (2-methyl-benzyloxy) -2 -nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 17B 4-. { 4- (2-Methyl benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 17A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 17A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (35 mg, 36%). 1H NMR (300 MHz, DMSO-D6) d 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-ftphlethyl-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 18A 4- [2-Amino-4- (3-methyl-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-3-methyl-benzene using the conditions described in Example 10C to provide -Chloro-4- (3-methyl-benzyloxy) -2- nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 18B 4- [4- (3-Methyl-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol The product of Example 18A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 18A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to give the title compound as a trifluoroacetic acid salt (37 mg, 39%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.31 (s, 3 H) 2.73 (s, 3 H) 5.07 (s, 2 H) 6.64 (m, 2 H) 7.16 (m, 9 H) 7.75 (d, J = 8.46 Hz, 1 H) 8.73 (s, 1 H) 8.86 (d, J = 8.46 Hz, 1 H) 9.69 (s, 1 H) 11.16 (s, 1 H); MS (ESI +) m / z 481 (M + H) +.

Example 19 4- [4- (4-Methyl-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylisulfanyl] -phenol Example 19A 4- [2-Amino-4- (4-methyl-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-4-methyl-benzene using the conditions described in Example 10C to provide 1-chloro-4- (4-methyl-benzyloxy) -2 -nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 19B 4- [4- (4-Wlethyl-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidine-4-mamino) -phenylsulfanyl] -phenol The product of Example 19A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 19A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (29 mg, 30%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.30 (s, 3 H) 2.67 (s, 3 H) 5.05 (s, 2 H) 6.64 (m, 2 H) 6.94 (d, J = 7.38 Hz, 1 H) 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-Hydroxy-phenylsulfanyl) -3- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] -benzonitrile EXAMPLE 20A 2- [3-Amino-4- (4-hydroxy-phenylsulfanyl) -phenoxymethyl] -benzonitrile A solution of 4-chloro-3-nitro-phenol was reacted with 2-bromomethyl-benzonitrile using the conditions described in Example 10C to provide 2- (4-chloro-3-nitro-phenoxymethyl) - benzonitrile which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 20B 2- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-meityl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] -benzonitrile The product of Example 20A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 20A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (21 mg, 16%). 1H NR (300 MHz, DMSO-D6) d 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-Hydroxy-phenylsulfanyl) -3- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl-benzonitrile Example 21A 4- [3-Amino-4- (4-hydroxy-phenylsulfanyl) -phenoxymethyl] -benzonitrile A solution of 4-chloro-3-nitro-phenol was reacted with 4-bromomethyl-benzonitrile using the conditions described in Example 10C to provide 4- (4-chloro-3-nitro-phenoxymethyl) -benzonitrile which was sequentially treated using the procedures of Examples 10D and 10E to provide the title product.

Example 21 B 4- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl-benzonitrile The product of Example 21A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 21A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (15 mg, 14%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 11.69 (s, 1 H), 9.72 (s, 1 H), 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-Bromo-phenyl) -ethoxy] -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 22A 1-Bromo-4- (1-bromo-ethyl) -benzene A solution of 1- (4-bromo-phenyl) -ethanol (4.21 g, 20.9 mmol) in 15 ml of CH 2 Cl 2 was reacted with 15 ml of 1.0 PBr 3 in CH 2 Cl 2 at room temperature for 4 hours. It was quenched by flushing in ice and the pH was adjusted to 9 with 5% aqueous NaHCO 3. Extract with CH2Cl2 and dry over Na2SO4a, filter and concentrate in vacuo to give the title compound (4.1 g, 75%).

Example 22B 4- [1- (4-Bromo-phenyl) -ethoxy] -1-chloro-2-nitro-benzene The product of Example 22A (995 mg, 3.77 mmol) was reacted with 4-chloro-3-nitro-phenol (650 mg, 3.77 mmol) in 15 mL of DMF with C2CO3 (10.4 g, 3.77 mmol) at 80 ° C. during 3 hours. HE cooled to room temperature and diluted with water. Extract with CH2Cl2, wash four times with water. Dry over Na2SO4, filter and concentrate in vacuo to give the title compound (1.24 g, 92%).

Example 22C 4-. { 4- [1- (4-Bromo-phenyl) -ethoxy] -2-nitro-phenylsulfanyl} -phenol The product of Example 22B (1.15 g, 3.22 mmol) was reacted with 4-mercapto-phenol (403 mg, 3.22 mmol) and K2CO3 (890 mg, 6.44 mmol) in 25 ml of DMF at 80 ° C for 18 hours. It was cooled to room temperature and emptied in water. It was extracted with CH2Cl2 and washed several times with water. Dry over Na2SO4, filter and concentrate in vacuo to give the title compound (980 mg, 68%).

Example 22D 4- [2-Amino-4- (1-phenyl-ethoxy) -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 water following the procedure of Example 10E giving the title compound as a solid (439 mg, 84%).

Example 22E 4- [4- [1- (4-Bromo phenyl) -ethoxy] -2- (7-methyl-pyrido [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) following the procedure of Example 10F to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (38 mg, 12%). H NMR (300 MHz, DMSO-d6) d 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-Fluoro-phenyl) -ethoxy] -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 23A 4-. { 2-Amino-4- [1 - (4-fluoro-phenyl) -ethoxy] -phenylsulfanyl} -phenol A solution of 1- (4-f luoro-phenyl) -ethanol was converted to 1- (1- bromo-ethyl) -4-fluoro-benzene using the conditions described in Example 22A which was treated sequentially using the procedures of Examples 22B-22D to provide the title product.

Example 23B 4- [4- [1- (4-Fluoro-phenyl) -ethoxy] -2- (7-methyl-pyrido [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) following the procedure of Example 10F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (30 mg, 35%). 1H NMR (300 Hz, DMSO-d6) d 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-Fluoro-phenyl) -ethoxy] -2- (7-methyl-pyrido [2,3-] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 24A 4-. { 2-Amino-4- [1 - (3-f luoro-phenyl) -ethoxy] -phenylsulfanyl} -phenol A solution of 1- (3-fluoro-phenyl) -ethanol was converted to 1- (1-bromo-ethyl) -3-fluoro-benzene using the conditions described in Example 22A which was treated sequentially using the procedures of the Examples 22B-22D to provide the title product.

Example 24B 4- [4- [1- (3-Fluoro-phenyl) -ethoxy] -2- (7-methyl-pyrido [2,3-] 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) following the procedure of Example 10F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (87 mg, 22%). 1H NMR (300 MHz, DMSO-D6) d 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) .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 ); S (ESI +) m / z 499 (M + H) +.

Example 25 - [4- (2-Chloro-thiazol-5-ylmethoxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 25A 4- [2-Amino-4- (2-chloro-thiazol-5-ylmethoxy) -phenylsulfanyl] phenol A solution of 4-chloro-3-nitro-phenol was reacted with 5-bromomethyl-2-chloro-thiazole (prepared according to the method of Kim, H.-J., Liu, S., Keum, Y. -S., Qing, XJ Agrie, Food Chem. 2003, 51, 1823-1830) using the conditions described in Example 10C to provide 2-chloro-5- (4-chloro-3-nitro-phenoxymethyl) -thiazole which it was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 25B 4- [4- (2-Chloro-thiazol-5-ylmethoxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 25A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 25A for the product of Example 10E to provide the crude title compound which was purified via HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1 H NMR (300 MHz, D SO-D6) d 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 (bs, 1H); MS (ESI +) m / z 508 (M + H) +.

Example 26 - [2- (7-Methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-trifluoromethyl-benzyloxy) -phenylsulfanyl] -phenol Example 26A 4- [2-Amino-4- (3-trifluoromethyl-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloromethyl-3-trif luoromethyl-1-benzene using the conditions described in Example 10C to provide 1-chloro-2-nitro-4- (3 -trifluoromethyl-benzyloxy) -benzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 26B 4- [2 - (7-Methyl-pyrido [2,3-d] pyrimidin -lamino) -4- (3-trifluor-rom and -I-benzyloxy) -phenylsulfanyl] -phenol The product of Example 26A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 26A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (9.9 mg, 9%). 1H NMR (300 MHz, DMSO-D6) d 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-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanylj-phenol Example 27A 4- (2-Amino-4-benzyloxy-phenylsulfanyl) -phenol A solution of 4-chloro-3-nitro-phenol was reacted with bromomethyl-benzene using the conditions described in Example 10C to provide 4-benzyloxy-1-chloro-2-nitro-benzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 27B 4- [4-Benzyloxy-2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -f-phenylsulfanyl] -phenol The product of Example 27A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 27A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (73 mg, 25%). 1 H NMR (300 MHz, D SO-D 6) d ppm: 2.70 (s, 3 H) 5.11 (s, 2 H) 6.65 (d, J = 8.46 Hz, 2 H) 6.98 (d, J = 7.72 Hz, 1 H) 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, 1 H) 9.65 (s, 1H) 10.56 (br s, 1 H); MS (ESI +) m / z 467 (M + H) +.

Example 28 4- (4- (3-Fluoro-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 28A 4- [2-Amino-4- (3-fluoro-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-3-fluoro-benzene using the conditions described in Example 10C to provide 1-chloro-4- (3-fluoro-benzyloxy) -2 -nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 28B 4- [4- (3-Fluoro-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 28A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 28A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (41 mg, 42%). 1H NMR (300 Hz, D SO-D6) d 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-Meityl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (teirahydro-furan-2-ylmethoxy) -phenylsulfanyl] -phenol Example 29A 4- [2-Amino-4- (tetrahydro-furan-2-ylmethoxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 2-bromomethyl-tetrahydrofuran using the conditions described in Example 10C to provide 2- (4-chloro-3-nitro-phenoxymethyl) -tetrahydrofuran which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 29B 4- [2- (7-Methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (tetrahydro-furan-2-ylmethoxy) -phenylsulfanyl] -phenol The product of Example 29A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 29A for the product of Example 10E to provide the crude title compound which was purified via HPLC with TFA to give the title compound as a trifluoroacetic acid salt (29 mg, 17%). 1H NMR (300 MHz, DMSO-D6) d 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, 1 HOUR); MS (ESI +) m / z 461 (M + H) +.

EXAMPLE 30 4- [2- (7-Methyl-pyrido [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-nitro-phenol was reacted with 1-chloromethyl-naphthalene using the conditions described in Example 10C to provide 1- (4-chloro-3-nitro-phenoxymethyl) -naphthalene which was sequentially treated using the procedures of Examples 10D and 10E to provide the title product.

Example 30B 4- [2- (7-Methyl-pyrido [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 using the procedure of Example 10F substituting the product of Example 30A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (31 mg, 25%). H NMR (300 MHz, DMSO-D6) d 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-Methoxy-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 31 A 4- [2-Amino-4- (3-methoxy-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloromethyl-3-methoxy-benzene using the conditions described in Example 10C to provide 1-chloro-4- (3-methoxybenzyloxy) -2-nitro-benzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 31 B 4- [4- (3-Methoxy-benzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 31A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 31A for the product of Example 10E to provide a solid, which was titrated with methanol to provide the title compound ( 24 mg, 26%). 1 H NMR (300 MHz, DMSO-D 6) d ppm 9.93 (s, 1 H), 9.63 (s, 1 H), 8.71 (d, J = 8.09 Hz, 1 H), 8.55 (s, 1 H), 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-Met.l-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (quinolin-2-ylmeyoxy) -phenylsulfanyl] -phenol Example 32A 4-. { 2-Amino-4- (quinolin-2-ylmethoxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 2-chloromethyl-quinoline hydrochloride salt using the conditions described in Example 10C to provide 2- (4-chloro-3-nitro-phenoxymethyl) -quinoline which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 32B 4- [2- (7-Meilyyl-pyrido [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 using the procedure of Example 10F substituting the product of Example 32A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as an acid salt. trifluoroacetic (13 mg, 27%). 1H NMR (500 MHz, DMSO-D6) d 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, 1 H) 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, 1 H); MS (ESI +) 518 (M + H) +.

Example 33 4- [4- (Biphenyl-4-ylmethoxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 16B (free salt form, 0.055 g, 0.1 mmol), phenylboronic acid (0.017 g, 0.14 mmol), cesium carbonate (0.05 g, 0.15 mmol) and dichlorobis (triphenylphosphine) palladium (ll) (0.007 g , 0.01 mmole) were combined in N, N-dimethylformamide (1 ml) and heated at 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. The solution was then extracted with ethyl acetate (3 x 10 mL), the combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (10 mg, 15%). 1H NMR (300 MHz, DMSO-D6) d 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-Chloro-thiophen-2-ylmethoxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) amino) -phenylsulfanyl] -phenol Example 34A 4- [2-Amino-4- (5-chloro-thiophen-2-ylmethoxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 2-chloro-5-chloromethyl-thiophene using the conditions described in Example 10C to provide 2-chloro-5- (4-chloro-3-nitrophenoxymethyl) -thiophene that was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

EXAMPLE 34B 4- [4- (5-Chloro-thiophen-2-ylmethoxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol-enylsulfanyl] - phenol The product of Example 34A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 34A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (6.6 mg, 10%). 1 HOUR NMR (300 MHz, DMSO-D6) d 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-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol Example 35A 4- [2-Amino-4- (4-fluorobenzyloxy) phenylsulfanylj-phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-4-fluoro-benzene using the conditions described in Example 10C to provide 1-chloro-4- (4-f luoro-benzyloxy) - 2-nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the title product.

Example 35B 4- [4- (4-Fluoro-benzyloxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 35A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 35A for the product of Example 10E to provide the crude title compound which was purified through HPLC with TFA to give the title compound as a trifluoroacetic acid salt (40 mg, 41%). 1H NMR (300 MHz, DMSO-D6) d 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) , 1 HOUR); MS (ESI +) m / z 485 (M + H) +.

Example 36 3- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] benzonitrile Example 36A 4-ftphlethyl-3-oxo-pentanal, sodium salt A 100 ml flask dried with flames equipped with a 25-ml addition funnel was purged with nitrogen gas and charged with anhydrous diethyl ether (40 ml) followed by the addition of sodium strips (1.65 g, 0.0725 mol). The reaction mixture was cooled to an ice / water bath temperature and a solution of methyl isopropyl ketone (6.244 g, 0.0725 mol) and ethyl formate (5.481 g, 0.0725 mol) in ether was slowly added dropwise. Anhydrous diethyl ether (5 ml) for 1.5 hours at 0 ° C. After the addition was complete, the cooling bath was stirred and the reaction mixture was stirred at room temperature overnight. Then additional ether (10 ml) was added to break up the resulting precipitate, and the solid was rapidly isolated by vacuum filtration. The solid was rinsed with small amounts of ether and then dried in a vacuum desiccator for 1 hour to give 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-lsopropyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile To 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 a solution of piperidine acetate (prepared 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 brought to a pH of 4 through the addition of glacial acetic acid. The pale yellow solid was asylated by vacuum filtration, rinsed with water (2 x 30 mL), and dried under vacuum to provide the title product (4.36 g, 68%).

Example 36C 2-Bromo-6-isopropyl-nicotinonitrile 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. The reaction mixture was then 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 brine (50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as an oil. yellow (5.64 g, 93%).

Example 36D 2-Amino-6-isopropyl-nicotinonitrile A solution of the product of Example 36C (21 g, 0.093 mol) liquid ammonia (250 ml) in 500 ml of ethanol was reacted in a sealed high pressure vessel at 130 ° C for 20 hours. The reaction mixture was concentrated under vacuum and the residue was ground to a fine powder, then washed with water (2 x 50 mL) and dried in a vacuum oven for 24 hours to provide the title compound. title as a beige solid (14 g, 93%).

Example 36E N '- (3-Cyano-6-isopropyl-pyridin-2-yl) -N-N dimethyl-formamidine A solution of the product from Example 36D (7.1 g, 0.044 mol) and?,? - Dimethylformamide dimethyl acetal (6.44 ml, 0.0484 mol) in toluene (100 ml) was heated to reflux for 3 hours. The resulting solution was cooled to room temperature and concentrated under vacuum to provide the title compound (9.5 g, 100%) as a thick brown oil which solidified upon standing. Although this material appeared to be pure through NMR, it contained small amounts of highly colored impurities. Chromatography on silica gel (gradient ethyl acetate / hexane) to give a slightly yellow oil, which solidified after standing (about 70% recovery from chromatography).

Example 36F 3- (4-Chloro-3-nitro-phenoxymethyl) -benzonitrile The title compound was prepared according to the procedure of Example 10C substituting 3-bromomethyl-benzonitrile for 1-chloromethyl-4-methoxy-benzene (0.813 g, 98%).

Example 36G 3- [4- (4-Hydroxy-phenylsulfanyl) -3-nitro-phenoxymethyl] -benzonitrile The title compound was prepared according to the procedure of Example 10D by substituting 3- (4-chloro-3-nitro-phenoxymethyl) -benzonitrile for 1-chloro-4- (4-methoxy-benzylloxy) -2-ni tro-benzene (1.07 g, 100%).

Example 36H 3- [3-Amino-4- (4-hydroxy-phenylsulfanyl) -phenoxymethyl] -benzonitrile The title compound was prepared according to the procedure of Example 10E substituting 3- [4- (4-hydroxy-phenylsulfanyl) -3-nitro-phenoxymethyl-benzonitrile for 4- [4- (4-methoxy-benzyloxy) -2- Nitro-phenylsulfanyl] -phenol (0.97 g, 98%).

Example 361 3- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-isopropyl-pyrido [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 a preheated oil bath at 130 ° C for 15 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the The resulting residue was purified through reverse phase preparation HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7pm particle size) using a gradient of 10% to 100% acetonitrile / 0.1% trifluoroacetic acid in water for 8 minutes. (10 minutes run time) at a flow rate of 40ml / min to provide the title compound as a trifluoroacetic acid salt (14 mg, 10%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 10.94 (s, 1 H), 9.69 (s, 1 H), 8.88 (d, J = 8.46 Hz, 1 H), 8.70 (s, 1 H), 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-lsopropyl-pyrido [2,3-dipyrimidin-4-ylamino) -4- (2-methoxy-benzyloxy) -phenylsulfanyl] -phenol Example 37A 4- [2-Amino-4- (2-methoxybenzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-2-methyl-benzene using the conditions described in Example 10C to provide 1-chloro-4- (2-methyl-benzyloxy) -2 -nitrobenzene which was treated sequentially using the procedures of Examples 10D and 10E to provide the product of the title.

Example 37B 4- [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (2-methoxy-benzyloxy) -phenylsulfanyl] -phenol The product of Example 37A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 37A for the product of Example 36H to provide a solid, which was titrated with methanol to provide the title compound ( 31 mg, 31%). 1H NR (500 MHz, DMSO-D6) d 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-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (4-methoxy-benzyloxy) -phenylsulfanyl] -phenol The product of Example 10E was reacted with the product of Example 36E following the procedure of Example 36I substituting the product of Example 10E for the product of Example 36H to provide a solid, which was titrated with methanol to provide the title compound (43 mg, 49%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 9.93 (s, 1 H), 9.63 (s, 1 H), 8.75 (d, J = 8.46 Hz, 1 H), 8.57 (s, 1 H), 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 (MH) -.

Example 39 4- [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (1-phenyl-ethoxy) -phenylsulfanyl] -phenol Example 39A 4- [2-Amino-4- (1-phenyl-ethoxy) -phenylsulfanyl] -phenol A solution of 1- (3-f luoro-phenyl) -ethanol was converted to 1- (1-Bromo-ethyl) -3-fluoro-benzene using the conditions described in Example 22A which was treated sequentially using the procedures of the Examples 22B-22D to provide the title product.

Example 39B 4- [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (1-phenyl-ethoxy) -phenylsulfanyl] -phenol The product of Example 39A was reacted with the product of Example 36E following the procedure of Example 36I substituting the product of Example 39A for the product of Example 36H to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 IVIHz, DMSO-D6) d 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-. { miz) 507.

Example 40 4- [4- [1- (4-Bromo-phenyl) -ethoxy] -2- (7-isopropyl-pyrido [2,3- d] pyrimidin-4-ylamino) -phenylsulfanyl-1-phenol The product of Example 22D (211 mg, 0.506 mmol) was reacted with the product of Example 36E (109 mg, 0.506 mmol) following the procedure of Example 36I substituting the product of Example 22D for the product of Example 36H to provide the compound of the crude title that was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (150 mg, 42%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 10.87 (br s, 1 H) 9.68 (s, 1 H) 8.83 (d, J = 8.45 Hz, 1 H) 8.67 (s, 1 H) 7.75 (d, J = 7.72 Hz, 1H) 7.55d, 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-Fluoro-phenyl) -ethoxy] -2- (7-isopropyl-pyrido [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) following the procedure of Example 36I substituting the product of Example 24A for the product of Example 36H to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (100 mg, 28%). 1H NMR (300 MHz, DMSO-D6) d 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, ./ = 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-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-trifluoromethyl-yl-phenyloxy) -phenylsulfanyl] -phenol The product of Example 26A was reacted with the product of Example 36E following the procedure of Example 361 substituting the product of Example 26A for the product of Example 36H to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (22 mg, 21%). 1H NMR (300 MHz, DMSO-D6) d 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-Fluoro-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 57D was reacted with the product of Example 36E following the procedure of Example 36I substituting the product of Example 57D for the product of Example 36H to provide the crude title compound which was purified via HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (26 mg, 51%). 1H NMR (300 MHz, DMSO-D6) d 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-Fluoro-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d-pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 35A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 35A for the product of Example 36H to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (23 mg, 45%). 1H NMR (300 MHz, DMSO-D6) d ppm: 1.35 (d, J = 6.99 Hz, 6H) 3.26 (m, 1H) 5.09 (s, 2H) 6.62 (m, 2H) 7.14 (m, 7 H) 7.48 (m, 2 H) 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-Fluoro-phenyl) -ethoxy] -2- (7-isopropyl-pyrido [2,3-d] -pyrimidin-4-yl-amino) -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) following the procedure of Example 36I substituting the product of Example 23A for the product of Example 36H to provide the compound of crude title which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (35 mg, 12%). H NMR (300 MHz, DMSO-D6) d 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); S (ESI +) m / z 527 (M + H) +.

Example 46 4- [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-methoxy-benzyloxy) -phenylsulfanyl] -phenol The product of Example 31A was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 31A for the product of Example 36H to provide the crude title compound that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (23 mg, 45%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 10.98 (s, 1 H), 9.67 (s, 1 H), 8.88 (d, J = 8.09 Hz, 1 H), 8.70 (s, 1 H), 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 (+ H) + (ESI-) m / z 523.2 (-H) -.

Example 47 4- [4- (3-Bromo-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d3-pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 15A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 15A for the product of Example 36H to provide the crude title compound that was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (16 mg, 28%). 1H NMR (300 MHz, DMSO-D6) d 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-Bromo-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 16A was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 16A for the product of Example 36H to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (28 mg, 49%). 1H NMR (300 MHz, DMSO-D6) d 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 (+ H) +.

Example 49 4- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] -benzontromyl The product of Example 21A was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 21A for the product of Example 36H to provide the crude title compound that was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (32 mg, 26%). 1 H NMR (300 Hz, DMSO-D 6) d ppm: 10.91 (s, 1 H), 9.69 (s, 1 H), 8.87 (d, J = 9.19 Hz, 1 H), 8.69 (s, 1 H), 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 (+ H) + (ESI-) m / z 518.2 (M-H) -.

Example SO 2- [4- (4-Hydroxy-phenylsulfanyl) -3- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] -benzonitrile The product of Example 20A was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 20A for the product of Example 36H to provide the crude title compound that was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (11 mg, 9%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 11.30 (s, 1 H), 9.71 (s, 1 H), 8.93 (d, J = 8.82 Hz, 1 H), 8.76 (s, 1 H), 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-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 27A was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 27A for the product of Example 36H to provide a solid, which was titrated with methanol to provide the title compound. HNR (300 MHz, DMSO-D6) d 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, 1 H) 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 / NH3) m / z 495 (M + H) +.

Example 52 3- [3- [7- (1-Hydroxy-1-methyl-ethyl) -pyrido [2,3-d] pyrimidin-4-ylamino] -4- (4-hydroxy-phenylsulfanyl) -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 130 ° C in an oil bath for a period of time. 15 minutes, followed by heating at 130 ° C for 1.5 hours more. The mixture was then cooled to room temperature, concentrated under vacuum to provide the crude title compound that was purified through reverse phase preparation HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7m particle size) using a gradient of 10% to 100% acetonitrile / 0.1% acid trif luoroacetic in water for 8 minutes (10 minutes run time) at a flow rate of 40 ml / min to provide the title compound as the trifluoroacetic acid salt (22 mg, 20%). H NMR (300 MHz, DMSO-de) d 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); S (ESI) m / z 536.2 (M + H) +, (ESI-) m / z 534.2 (M-H) -.

Example 53 2- [3- [7- (1-Hydroxy-1-methyl-ethyl) -pyrido [2,3-d] pyrimidin-4-ylam (4-hydroxy-phenylsulfanyl) -phenoxymethyl] benzonitrile The product of Example 20A was reacted with the product of Example 36E using the procedure of Example 52 substituting the product of Example 20A for the product of Example 36H to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (11 mg, 11%). H NMR (300 MHz, DMSO-D6) d ppm: 11.73 (s, 1H), 9.75 (s, 1H), 9.05 (d, J = 8.46 Hz, 1H), 8.84 (s, 1H), 8.20 (d, 5 = 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-methyl-ethyl) -pyrido [2,3-d] pyrimidin-4-ylamino] -4- (4-idroxy-phenylsulfanyl) -phenoxymethyl] - benzonitri! The product of Example 21A was reacted with the product of Example 36E using the procedure of Example 52 substituting the product of Example 21A for the product of Example 36H to provide the crude title compound that was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (10 mg, 10%). 1H NR (300 MHz, DMSO-D6) d 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), 723 (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-methyl-ethyl) -pyrido [2,3-d] pyrimidin-4-ylamino] -4- (2-methoxy-benzyloxy) -phenylsulfanyl] -phenol The product of Example 37A was reacted with the product of Example 36E using the procedure of Example 52 substituting the product of Example 37A for the product of Example 36H to provide a solid, which was titrated with methanol to provide the title compound ( 8 mg, 8%). H NMR (300 MHz, D SO-D6) d 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) ); S (ESI +) m / z 541.2 (M + H) + (ESI-) m / z 539.2 (M-H) -.

Example 56 4-. { 4- (4-Bromo-benzyloxy) -2- [7- (1-hydroxy-1-methyl-ethyl) -pyrido [2,3-d] -pyrimidin-4-ylamino] -phenylsulfanyl) -phenol The product of Example 16A was reacted with the product of Example 36E using the procedure of Example 52 substituting the product of Example 16A for the product of Example 36H to provide the crude title compound that was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (8 mg, 13%). 1H NMR (300 Hz, DMSO-D6) d 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, IH) 9.70 ( s, 1H) 11.43 (s, 1H); MS (ESI +) m / z 589, 591 (+ H) +.

Example 57 4- [4- (3-Fluoro-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyljphenol Example S7A N '- (3-Cyano-pyridin-2-yl) -N, N-dimethyl-formamidine A solution of 2-amino-nicotinonitrile (5 g, 42 mmol) and N, N-dimethylformamide dimethyl acetal (6.13 mL, 46.2 mmol) in toluene (20 mL) was refluxed for 3 hours. After it was cooled to room temperature, the solution was concentrated under vacuum to provide the title compound (7.3 g, 100%).

Example 57B 1-Chloro-4- (3-fluorobenzyloxy) -2-nitro-benzene The title compound was prepared according to the procedure of Example 10C substituting 1-bromomethyl-3-f luoro-benzene for 1-chloromethyl-4-r-methoxy-benzene (0.56 g, 100%).

Example 57C [4- (3 Fluoro-benzyloxy) -2-nitro-phenylsulfanyl] -phenol The title compound was prepared according to the procedure of Example 10D substituting 1-chloro-4- (3-f luoro-benzyloxy) -2-nitro-benzene for 1-chloro-4- (4-methoxy-benzyloxy) - 2-nitrobenzene (0.57 g, 77%).

Example 57D 4- [2-Amino-4- (3-fluoro-benzyloxy) -phenylsulfanyl} -phenol The title compound was prepared according to the procedure of Example 10E substituting 4-. { 4- (3-Fluoro-benzyloxy) -2-nitro-phenylsuif anil] -phenol for 4- [4- (4-methoxy-benzyloxy) -2-nitrophenylsulfanyl} -phenol (0.501 g, 96%).

Example 57E 4- [4- (3-Fluorobenzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanylj-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 ° C in an oil bath during a period of 15 minutes, followed by heating at 130 ° C for 1.5 hours more. The mixture is then cooled to room temperature, concentrated in vacuo to provide the crude title compound which was purified through reverse phase preparation HPLC on a Waters Symmetry C8 column (25mm x 100mm, 71.tm particle size) using a gradient of 10% to 100% acetonitrile / 0.1% trifluoroacetic acid in water for 8 minutes (10 minutes run time) at a flow rate of 40 ml / min to provide the title compound as the trifluoroacetic acid salt (28 mg, 30 mg). %). 1 H NMR (300 Hz, DMSO-de) d ppm: 5.14 (s, 2 H) 6.65 (m, 2 H) 7.14 (m, 8 H) 7.49 (m, 1 H) 7.66 (m, 1 H) 8.61 (s, 1 H) 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 Í- (2-Methyl-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol The product of Example 17A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 17A for the product of Example 57D to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (50 mg, 54%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.31 (s, 3 H) 5.09 (s, 2 H) 6.66 (m, 2 H) 7.01 (m, 1 H) 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-Methyl-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) -f-phenylsulfonyl] -f-enol The product of Example 19A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 19A for the product of Example 57D to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (45 mg, 48%). H NMR (300 MHz, DMSO-D6) d 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, 1 H) 9.07 (s, 1H) 9.64 (s, 1H) 10.42 (s, 1H); MS (ESI +) m / z 467 (M + H) +.

Example 60 4- [4- (2-Bromo-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-yl) amino) -phenylsulfanyl] -phenol The product of Example 14A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 14A for the product of Example 57D to provide the crude title compound that was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (40 mg, 38%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 5.13 (s, 2 H) 6.66 (m, 2 H) 6.99 (d, J = 8.43 Hz, 1 H) 7.15 (m, 3 H) 7.35 (m, 3 H) 7.64 (m, 3H) 8.60 (s, 1H) 8.85 (d, J = 7.32 Hz, 1 H) 9.07 (s, 1 H) 9.66 (s, 1 H) 10.28 (s, 1 H); MS (ESI +) m / z 531, 533 (M + H) +.

Example 61 3- [4- (4-Hydroxy-phenylsulfanyl) -3- (pyrido [2,3-d] pyrimidin-4-ylammon) -phenoxymethyl] -benzonitrile The product of Example 3611 and the product of Example 57A were reacted according to the procedure in Example 57E by substituting the product of Example 36H for the product of Example 57D to provide a solid, which was titrated with methanol to provide the compound of the title (44 mg, 44%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 10.08 (s, 1 H), 9.65 (s, 1 H), 9.06 (s, 1 H), 8.86 (s, 1 H), 8.58 (s, 1 H), 7.92 (s, 1 H), 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 (+ H) +, (ESI-) m / z 476.1 (M-H) -.

Example 62 4- [4- (3-Efil-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol The product of Example 18A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 18A for the product of Example 57D to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (50 mg, 54%). 1 H NMR (300 MHz, D SO-D 6) d ppm: 2.31 (s, 3 H) 5.07 (s, 2 H) 6.65 (m, 2 H) 7.12 (m, 9 H) 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-Methoxy-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanylj-phenol The product of Example 10E and the product of Example 57A were reacted according to the procedure in Example 57E by substituting the product of Example 10E for the product of Example 57D to provide a solid, which was titrated with methanol to provide the compound of the title (49 mg, 55%). 1H NMR (300 MHz, DMSO-D6) d 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); S (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] pyrimtdin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 37A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 37A for the product of Example 57D to provide a solid, which was titrated with methanol to provide the title compound ( 47 mg, 56%). 1H NMR (300 MHz, DMSO-D6) d 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, r = 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-Hydroxy-phenylsulfanyl) -3- (pyrid [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl-benzonitrile The product of Example 21A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 21A for the product of Example 57D to provide the crude title compound which was purified through HPLC with TFA to give the title compound as a trifluoroacetic acid salt ( 6 mg, 6%). 1H NR (300 MHz, DMSO-D6) d 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-Methoxy-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 31A and the product of Example 57A were reacted according to the procedure in Example 57E by substituting the product of Example 31A for the product of Example 57D to provide a solid, which was titrated with methanol to provide the compound of the title (38 mg, 45%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 10.07 (s, 1 H), 9.63 (s, 1 H), 9.07 (s, 1 H), 8.86 (d, J = 7.72 Hz, 1 H), 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-Bromo-benzyloxy) -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 procedure in Example 57E substituting the product of Example 16A for the product of Example 57D to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (11 mg, 16%). 1H NMR (300 MHz, D SO-D6) d 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 (+ 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 according to the procedure in Example 57E by replacing the product of Example 15A for the product of Example 57D to provide the crude title compound which was purified via HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (40 mg, 16%). 1H NMR (300 MHz, DMSO-D6) d 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 according to the procedure in Example 57E by substituting the product of Example 27A for the product of Example 57D to provide the title compound, which was isolated as the salt of acetic acid (79 mg, 48%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 5.10 (s, 3 H), 6.61-6.72 (m, 2 H), 6.93 (d, J = 9.56 Hz, 1 H), 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) , 1 HOUR); ESI + m / z 453 (M + H) +, ESI-m / z 451 (M-H) -.

Example 70 4- [4- [1- (4-Bromo-phenyl) -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) following the procedure of Example 57E to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (97 mg, 40%). H NMR (300 MHz, DMSO-d6) d ppm: 10.60 (br s, 1 H) 9.67 (s, 1 H) 9.09 (s, 1 H) 8.88 (d, J = 8.46 Hz, 1H) 8.64 (s, 1 H) 7.73 (m, J = 3.31 Hz, 1 H) 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, 1 H) 6.64 (d, J = 8.46 Hz, 2H) 5.51 (q, J = 6.62 Hz, 1 H) 1.53 (d, J = 6.62 Ha, 3H); MS (ESI +) m / z, 545, 547 (M + H-TFA) +; (ESI-) m / z, 543, 545 (M-H-TFA) -.

Example 71 4- [4- [1- (4-Fluoro-phenyl) -ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylammon) -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) following the procedure of Example 57E to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as an acid salt trifluoroacetic (60 mg, 12%). H NMR. (500 MHz, DMSO-D6) d 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, 1 H); MS (ESI +) m / z 485.

Example 72 4- [4- [1- (3-Fluoro-phenyl) -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) following the procedure of Example 57E to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (150 mg, 31%). H NMR (300 MHz, DMSO-D6) d 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-fluoro-phenyl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 73A Ethyl ester-2-chloro-4-f luoro-phenyl carbonic acid ester To a solution of 2-chloro-4-phlorophenol (0.8 mL, 7.64 mmol) and triethylamine (1.3 mL, 9.16 mmol) in dichloromethane (10 mL) at 0 ° C was added ethyl chloroformate (0.9 mL, 9.16 mmol). drop by drop. The ice bath was stirred and the solution allowed to warm to room temperature and stirred for a further 16 hours. Then dichloromethane (20 ml) was added to the mixture, the organic solution was washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as an oil ( 1.65 g, 100%).

Example 73 B Ethyl ester-2-chloro-4-fluoro-5-nitro-phenyl ester of carbonic acid A solution of the product of Example 73A (0.88 g, 4.03 mmol) in concentrated sulfuric acid (2 ml) cooled in an ice bath was added fuming nitric acid (0.27 ml, 6.45 mmol) slowly to maintain the temperature at 0 ° C. The mixture was stirred for a further 2 hours, then ice-water (10 ml) was added to the solution and the resulting solid was collected through filtration, washed with water and dried in a vacuum oven to provide the title compound (0.87 g, 82%).

Example 73C 2-Chloro-4-fluoro-5-nitro-phenol 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 for 16 hours. . The methanol was then removed under vacuum, dichloromethane (20 ml) was added to the mixture, the organic solution was washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the product of the title (0.62 g, 98%).

Example 73D 1-Benzyloxy-2-chloro-4-fluoro-5-nitro-benzene The title compound was prepared according to the procedure of Example 10C substituting benzyl bromide and the product of Example 73C for 1-chloromethyl-4-methoxy-benzene and 4-chloro-3-nitro-phenol (0.72 g, 79% ).

Example 73E 5-Benzyloxy-4-chloro-2-f luoro-phenylam The title compound was prepared according to the procedure of Example 10D substituting the product of Example 73D for 1-Chloro-4- (4-methoxy-benzyloxy) -2-nitro-benzene (77 mg, 100%).

Example 73F (5-Benzyloxy-4-chloro-2-fluoro-phenyl) - (7-methyl-pyrido [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 a preheated oil bath at 130 ° C for 15 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (8.1 mg, 17%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.72 (s, 3 H), 5.19 (s, 2 H), 7.28-7.53 (m, 6 H), 7.66 (d, J = 9.56 Hz, 1 H), 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-fluoro-phenyl) -pyrido [2,3-d] pyrimidin-4-ylamine The title compound was prepared according to the procedure of Example 73F substituting the product of Example 57A for the product of Example 10B (7.9 mg, 19%). 1H NMR (300 MHz, DMSO-d6) d 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); S (ESI +) m / z 381 (M + H) +.

Example 75 (5-Benzyloxy-2,4-difluoro-phenyl) - (7-meityl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 75A Ethyl ester-2,4-difluorophenyl ester of carbonic acid The title compound was prepared according to the procedure of Example 73A by substituting 2,4-Difluoro-phenol for 2-chloro-4-fluoro-phenol (1.48 g, 96%).

EXAMPLE 75B 2,4-Difluoro-5-nitro-phenyl Ester Ethyl ico-ester of carbonic acid The title compound was prepared according to the procedure of Example 73B.

Example 75C 2,4-Difluoro-5-nitro-phenol The title compound was prepared according to the procedure of Example 73C substituting the product of Example 73B for the product of 313B (0.59 g, 89%).

Example 75D 1-Benzyloxy-2,4-difluoro-5-nitro-benzene The title compound was prepared according to the procedure of Example 73D substituting the product of Example 75C for the product of 313C (0.56 g, 63%).

Example 75E 5-Benzyloxy-2,4-difluoro-phenyl amine compound of the title was prepared in accordance with procedure of Example 73E substituting the product of Example 75D for the product of 313D (89 mg, 100%).

Example 75F (5-Benzyloxy-2,4-difluoro-phenyl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amine The title compound was prepared according to the procedure of Example 73F substituting the product of Example 75E for the product of Example 73E. The resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (7.4 mg, 16%). 1 H NMR (300 Hz, D SO-d 6) d ppm: 2.72 (s, 3 H), 5.17 (s, 2 H), 7.19-7.60 (m, 7 H), 7.71 (d, J = 8.46 Hz, 1 H), 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-difluoro-phenyl) -pyrido [2,3-d] pyrimidin-4-yl-amine 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 a preheated oil bath at 130 ° C for 15 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA provide the title compound as a trifluoroacetic acid salt (21.4 mg, 45%). 1H NR (300 MHz, DMSO-D6) d ppm: 5.17 (s, 2H) 7.19-7.61 (m, 7H) 7.80 (dd, J = 8.09, 4.41 Hz, 1 H) 8.77 (s, 1H) 8.97 (d , J = 7.35 Hz, 1 H) 9.14 (d, J = 2.94 Hz, 1 H) 10.88 (s, 1 H); MS (ESI +) m / z 365 (M + H) +.

Example 77 4-. { 2- [Benzyl- (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amino] -4-benzyloxy-phenylsulfanyl} -phenol 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?,? - dimethylformamide (0.5 mL) was stirred at room temperature. environment for 16 hours. Then, the mixture was poured into ice water (10 ml) and the resulting solution was acidified with 1 N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 x 10 mL), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the crude title compound which was purified through HPLC with TFA for provide the title compound as a trifluoroacetic acid salt (6.7 mg, 18%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.74 (s, 3 H) 5.10 (s, 2 H) 5.69 (s, 1 H) 6.65 (d, J = 8.82 Hz, 2 H) 7.02-7.18 (m, 2 H) 7.14-7.26 (m, 1 H) 7.26-7.58 (m, 12H) 7.86 (s, 1 H) 8.93 (s, 1 H) 9.23 (s, 1 H) 9.73 (s, 1H) 12.09 (s, 1 H) ); MS (ESI +) m / z 557 (M + H) +.

Example 78 (5-Benzyloxy-2-bromo-phenyl) - (7-methyl-pyrido [2,3-d] pinmidin-4-yl) -amine Example 78A 5-Benzyloxy-2-bromo-phenylamine The title compound was made according to the method of: Boger, D.L., Wysocki, RJ., Ishizaki, T.J. Am. Chem. Soc, 112, 1990, p. 5230-5240. The amount obtained was 4.58g, 48%.

Example 78B (5-Benzyloxy-2-bromo-phenyl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) - am i na 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) was gradually heated from room temperature to 130 ° C in an oil bath for a period of time. 15 minutes, followed by heating at 130 ° C for 1.5 hours more. The mixture was then cooled to room temperature, concentrated under vacuum to provide the crude title compound (3.4 g of a thick, 100% red syrup) a portion of which was purified through HPLC with TFA to provide the title compound as the trifluoroacetic acid salt (81 mg). H NMR (300 MHz, DMSO-d6) d 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 (bs, 1H); MS (ESI +) m / z 421/423 (M + H) +.

Example 79 2-Chloro N- [3- (pyrido [2,3-d] pyrimidin-4-lamino) -fe n i I] - nzamide Example 79A N- (3-Amino-phenyl) -2-chloro-benzamide The title compound was prepared according to the procedure of Example 254A by substituting 2-chloro-benzoyl chloride for 4-bromo-benzoyl chloride followed by reduction of the nitro group using the procedure of Example 255B to provide 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 using the procedure of Example 254C substituting the product of Example 79A for the product of Example 254B to provide the crude product which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (18 mg, 22%). 1 H NMR (300 MHz, D SO-D 6) d ppm: 7.45-7.54 (m, 4 H), 7.56-7.62 (m, 3 H), 7.83-7.90 (m, 1 H), 8.25-8.29 (m, 1 H), 8.93 (s, 1H), 9.12-9.18 (m, 2H), 1.0.70 (s, 1H), 11.23 (s, 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-Amino-phenyl) -2-bromo-benzamide The title compound was prepared according to the procedure of Example 254A by substituting 2-bromo-benzoyl chloride for 4-bromo-benzoyl chloride followed by reduction of the nitro group using the procedure of Example 255B to provide 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 using the procedure of Example 254C substituting the product of Example 80A for the product of Example 254B to provide the crude product that was purified to HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (18 mg, 22%). HNR (300 MHz, DMSO-D6) d 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- (pyridyl [2,3-d] pyrimidin-4-ylamino) -phenyl] -benzamide Example 81 A N- (3-Amino-phenyl) -2-methoxy benzamide The title compound was prepared according to the procedure of Example 254A by substituting 2-methoxy-benzoyl chloride for 4-bromo-benzoyl chloride followed by reduction of the nitro group using the procedure of Example 255B to provide the title product.

Example 81 B 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 using the procedure of Example 254C substituting the product of Example 81A for the product of Example 254B to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (26 mg, 33%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 3.90 (s, 3 H), 7.08 (t, J = 6.99 Hz, 1 H), 7.20 (d, J = 8.46 Hz, 1 H), 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-Amino-phenyl) -3-methoxy-benzamide The title compound was prepared according to the procedure of Example 254A by substituting 3-methoxy-benzoyl chloride for 4-bromo-benzoyl chloride followed by reduction of the nitro group using the procedure of Example 255B to provide 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 using the procedure of Example 254C substituting the product of Example 82A for the product of Example 254B to provide the crude product that was purified through HPLC with TFA to provide it! compound of the title as a trifluoroacetic acid salt (35 mg, 45%). 1H NMR (300 MHz, DMSO-D6) 8 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-Amino-phenyl) -3-fluoro-benzamide The title compound was prepared according to the procedure of Example 254A by substituting 3-fluoro-benzoyl chloride for 4-bromo-benzoyl chloride followed by reduction of the nitro group using the procedure of Example 255B to provide 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 using the procedure of Example 254C substituting the product of Example 83A for the product of Example 254B to provide the crude product which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (21 mg, 28%). 1H NMR (300 MHz, DMSO-D6) d 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 (+ H) +, ESI-m / z 358 (M-H) -.

Example 84 4- [4-Benzylamino-2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 84A 4- (4-Amino-2-nitro-phenylsulfanyl) -phenol A solution of 4-chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-hydroxythiophenol (0.75 g, 6.00 mmol), cesium carbonate (3.9 g, 12 mmol) in dimethyl sulfoxide (10 mL) was heated to 100 ° C for 16 hours. Then ice-water (50 ml) was added to the solution and the resulting slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound, g, 92%).

Example 84B 4- (4-Benzylamino-2-nitro-phenylsulfanyl) -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 mixture was quenched with water (20 ml) and the resulting solution was concentrated under vacuum 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 under vacuum leaving a light yellow oil. The oil was purified through silica gel chromatography eluting with 1% methanol in methylene chloride to give the title compound (0.63 g, 77%).

Example 84C 4- (2-Amino-4-benzylamino-phenylsulfanyl) -phenol A solution of the product of Example 848 (0.5 g, 1.4 mmol), iron powder (0.49 g, 8.74 mmol) and ammonium chloride (0.50 g, 9.3 mmol) in methanol (10 mL), tetrahydrofuran (10 mL), and solution of water (5 ml) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water - (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.30 g, 66%).

Example 84D 4- [4-Benzylamino-2- (7-methyl-pyrido [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) was stirred in a pre-heated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (12 mg, 10%). H NMR (300 MHz, DMSO-D6) d 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 N 1-Benzyl-4- (4-benzyloxy-phenylsulfanyl) -N 3 - (7-methyl-pyridyl [2,3-d] -pyrimidin-4-yl) -benzene-1,3-diamine Example 85A 4- (2-Amino-4-nitro-phenylsulfanyl) -phenol A solution of 2-Chloro-5-nitroaniline (3 g, 17.4 mmol), 4-idroxythiophenol (2.4 g, 19.0 mmol), cesium carbonate (12.35 g, 38 mmol) in dimethylformamide (35 mL) was heated to 100 °. C for 16 hours. Then ice-water (200 ml) was added to the solution and ethyl acetate (200 ml) was added to the resulting slurry. 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 solvent was removed under vacuum leaving a yellow oil. The oil was purified through silica gel chromatography eluting with methylene chloride / methanol (97: 3), to give a yellow solid as the title compound (2.1g, 46%).

Example 8SB 2- (4-Benzyloxy-phenylsulfanyl) -5-nitro-phenylamine A slurry containing the product of Example 85A (0.2 g, 0.763 mmole) and cesium carbonate (0.25 g, 0.763 mmole) in dimethylformamide (5 mL) was treated with benzyl bromide (0.091 mL, 0.763 mmol) and the resulting slurry was stirred 18 hours at room temperature. Ice-water (50 ml) was then added to the solution and ethyl acetate (50 ml) was added to the resulting slurry. 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 under vacuum leaving a yellow solid as the title compound (0.24 g, 89%).

Example 85C [2- (4-Benzyloxy-phenylsulfanyl) -5-nitro-phenyl] - (7-methy1-pyrido [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) was stirred in a pre-heated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum leaving a brown oil as the title compound (0.15 g, 92%). The compound was used without purification in the next step.

Example 85D 4- (4-Benzyloxy-phenylsulfanyl) -N3- (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -benzene-1,3-diamine A solution of the product of Example 85C (0.150 g, 0.303 mmole), iron powder (0.10 g, 1.86 mmole) and ammonium chloride (0.10 g), 1.98 mmol) in methanol (2 mL), tetrahydrofuran (2 mL), and a water solution (1 mL) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.06 g, 42%).

Example 85E 1-Benzyl-4- (4-benzyloxy-phenylsulfanyl) -N 3 - (7-methy1-pyridyl [2,3-d] -pyrimidin-4-yl) -benzene-1,3-diamine A mixture of the compound prepared 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 was stirred 18 hours at room temperature. The solvent was removed under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (12 mg, 17%). 1H NR (300 MHz, DMSO-D6) d 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-methylmethyl) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 86A 4- [2- (7-ethyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-nitrophenylsulfanylj-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 a pre-heated oil bath at 130 ° C for 30 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum leaving a brown oil as the title compound (0.65 g, 89%).

Example 86B 4- [4-Amino-2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanylj-phenol A slurry 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 under a hydrogen atmosphere with stirring for 2 hours at room temperature. The slurry was filtered and the solvent was removed under vacuum leaving a brown solid as an acetate salt of the title compound (0.21 g, 91%).

EXAMPLE 86C 4- [4 - [(Furan-3-ylmethyl) -amino} -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol A solution of the product from 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 methanol was stirred 18 hours at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (16 mg, 14%). 1H N MR (300 MHz, DMSO-D6) d 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, 5 = 8.46 Hz, 1H), 8.77 (s, 1H), 8.88 (s, 1H), 9.51 (s, 1H), 11. 68 (s, 1 H).

Example 87 4-. { 2- (7-Methyl-pyrido [2 &g; 3-d] pyrimidin-4-ylamino) -4 - [(thiophen-3-ylmethyl) -amino] -phenylsulfanyl} -phenol A solution of the product of Example 86B and 3-thiophene carboxaldehyde were reacted according to the procedure of Example 86C by substituting 3-thiophene carboxaldehyde for 3furaldehyde to give the crude product which was purified via HPLC with TFA to give the title compound as a trifluoroacetic acid salt (26 mg, 37%). 1H NMR (300 MHz, DMSO-D6) d 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, 5 = 8.09 Hz, 1H), 8.76 (s, 1H), 8.90 (s, 1H), 9.51 (s, 1H), 11.65 (s, 1 H).

Example 88 4-. { 2- (7-Methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4 - [(naphthalen-1-ylmethyl) -amino] -f-enylsulfanyl} -f enol A solution of the product of Example 86B and -naphthalaldehyde were reacted according to the procedure of Example 86C substituting 1-naphthalimide for 3-furaldehyde to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (18 mg, 12%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.73 (s, 3 H), 4.73 (s, 1 H), 6.39 (s, 1 H), 6.45-6.60 (m, 2 H), 6.67-6.80 (m, 1 H) ), 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 , 5 = 8.82 Hz, 1H), 7.95-8.09 (m, 2H), 8.10-8.18 (m, 1H), 8.22 (d, 5 = 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-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol A solution of the product of Example 86B and 2-furaldehyde were reacted according to the procedure of Example 86C substituting 2-furaldehyde for 3-furaldehyde to give the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (18 mg, 16%). 1H NMR (300 MHz, DMSO-D6) d 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-Methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4 - [(thiophen-2-ylmethyl) -amino] -phenylsulfanyl} -phenol A solution of the product of Example 86B and 2-thiophene carboxaldehyde were reacted according to the procedure of Example 86C substituting 2-thiophene carboxaldehyde for 3-furaldehyde to give the crude product which was purified by HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (11 mg, 16%). 1H NMR (300 MHz, DMSO-D6) d 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-Bromo-benzylamino) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 91 A 4-. { 4- (4-Bromo-benzylamino) -2-nitro-phenylsulfanyl] -phenol A solution of the product of Example 84A and 4-bromobenzaldehyde were reacted according to procedure of Example 84B substituting 4-bromobenzaldehyde for the product of Example 84A to afford the crude product which was purified through silica gel chromatography eluting with 2% methanol in methylene chloride to provide the title compound as a yellow solid ( 0.11 g, 73%).

Example 91 B 4- [2-Amino-4- (4-bromo-benzylamino) -phenylsulfanyl] -phenol A solution of the product of Example 91A was reacted according to the procedure of Example 84C to give the title compound (0.17 g, 76%).

Example 91C 4- [4- (4-Bromo-benzylamino) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol A solution of the product of Example 1013 (50 mg, 0.266 mmol), and the product of Example 91B (110 mg, 0.266 mmol) in acetic acid (2 mL) was stirred in a preheated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (22 mg, 15%). 1 H NMR (300 MHz, DMSO-D6) d 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-methoxy phenylsulfanyl) -N3- (7-methyl-pyrido [2,3- d] pyrimidin-4-yl) -benzene-1,3-diamine Example 92A 4- (4-Methoxy-phenylsulfanyl) -3-nitro-phenylamine 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 to 100 ° C for 16 hours. Then ice-water (50 ml) was added to the solution and the resulting slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound (1.5 g, 94%).

Example 92B Bencil-. { 4- (4-methoxyphenylsulfanyl) -3-nifro-phenyl] -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 mixture was quenched with water (20 mL) and the resulting solution was concentrated under vacuum 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 solvent was removed under vacuum leaving a light yellow oil. The oil was purified through silica gel chromatography eluting with 1% methanol in methylene chloride to provide the title compound as a brick red solid (0.62 g, 91%).

Example 92C N1-Benzyl-4- (4-methoxy-phenylsulfa ni l) -benzene-1,3-d-amine A solution of the product of Example 928 was reacted according to the procedure of Example 84C to give the title compound (0.49 g, 89%).

Example 92D N 1-Benzyl-4- (4-methoxy-phenylsulfanyl) -N 3 - (7-methyl-pyrido [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 a pre-heated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (15 mg, 14%). NMR (300 MHz, DMSO-D6) d 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, 1 H), 8.80 (d, 1 H), 11.34 (s, 1 H).

Example 93 N1-Benzyl-4- (4-methoxy-phenoxy) -N3- (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -benzene-1,3-diamine Example 93A 4- (4-ethoxy-phenoxy) -3-nitro-phenylamino A solution of 4-chloro-3-nitroaniline (1.0 g, 5.79 mmole), 4-methoxyphenol (0.74 g, 6.00 mmole), cesium carbonate (1.95 g, 6.00 mmoles) 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 slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound (1.1 g, 73%).

Example 93B N1-Benzyl-4- (4-methoxy-phenoxy) -benzene-1,3-diamine A solution of the product of Example 93A was reacted according to the procedure of Example 92B by substituting the product of Example 93A for the product of Example 92A which was reduced according to the procedure of Example 84C to provide the title compound (0.05 g , 12%).

Example 93C N 1-Benzyl-4- (4-methoxy-phenoxy) -N 3 - (7-methyl-pyrido [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 procedure of Example 92D substituting the product of Example 93B for the product of Example 92C which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (8 mg, 18%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.55-2.68 (m, 3 H), 3.61 (s, 3 H), 4.26 (d, J = 5.88 Hz, 2 H), 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, 1 H).

Example 94 N 1 -Benzyl-4- (4-benzyloxy-phenoxy) -N 3 - (7-methy1-pyrido [2,3- d] pyrimidin-4-yl) -benzene-1,3-d! amine Example 94A 4- (4-Benzyloxy-phenoxy) -3-nitro-phenylamine A solution of 4-chloro-3-nitroaniline (2.0 g, 11.16 mmol), 4-benzyloxyphenol (2.55 g, 12.76 mmol), potassium hydroxide powder (0.94 g, 16.80 mmol) in dimethylformamide (15 mL) was heated to 120 ° C for 20 hours. Then ice-water (50 ml) was added to the solution and the resulting slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a dark red solid as the title compound, (2.07 g, 53%).

Example 94B N1-Benzyl-4- (4-benzyloxy-phenoxy) -benzene -1,3-diamine A solution of the product of Example 94A was reacted according to the procedure of Example 92B by substituting the product of Example 94A for the product of Example 92A, which was reduced according to the procedure of Example 84C to provide the title compound (0.6 g, 91%).

Example 94C-Benzyl-4- (4-benzyloxy-phenoxy) N 3 - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -benzene-1,3-diamine A solution of the product of Example 10B and the product of Example 94B was reacted according to the procedure of Example 92D substituting the product of Example 94B for the product of Example 92C which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (12 mg, 10%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.70 (s, 3 H), 4.27 (s, 2 H), 4.94 (s, 2 H), 4.99-5.12 (m, 1 H), 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-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanylj-phenol Example 95A - [2- (7-lsopropyl-pyrido [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) was stirred in a pre-heated oil bath at 130 ° C for 10 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum to give a brown oil as the title compound (0.92 g, 92%).

Example 95 B 4- [4-Amino-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -f-phenylsulfanyl] -phenol A slurry of the compound prepared 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 under a hydrogen balloon atmosphere with stirring for 20 hours at room temperature. The slurry was filtered and the solvent was removed under vacuum to provide the compound of the title as a salt of acetic acid (540 mg, 63%). 1H NMR (300 MHz, DMSO-D6) d 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 (bs, 1H); MS (ESI +) m / z 404 (M + H) +.

Example 96 4- [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-phenethylamino-phenylsulfanylj-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 18 hours at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (25 mg, 32%). 1H NMR (300 MHz, DMSO-D6) d 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- (Cyclopentylmethyl-amino) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol A solution containing the product of Example 95B was reacted with cyclopentancarbaldehyde according to the procedure of Example 96 substituting cyclopentancarbaldehyde for phenylacetaldehyde which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (11 mg, 9%). H NMR (300 MHz, DMSO-D6) d 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 1-Benzyl-3- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -4- (4-methoxy-phenylsulfanyl) -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 a pre-heated oil bath at 140 ° C for 45 minutes. minutes The reaction was cooled to room temperature, diluted with hexanes (50 mL), concentrated through rotary evaporation, and co-evaporated with methylene chloride / hexanes (4x). The residue was dried under vacuum, then purified by flash chromatography on silica gel with a gradient from 15% to 20% ethyl acetate / methylene chloride as eluent to give the title compound as a yellow solid ( 29.6 mg, 31%). 1H NMR (300 MHz, DMSO-D6) S ppm: L31 (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, 1 H) 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, 1 H) 8.50 (s, 1H) 8.65 (d, J = 8.46 Hz, 1H) 9.75 (s, 1H); MS (DCI / NH3) m / z 508 (M + H) +.

Example 99 4- [2- (7-ftphlethyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-pyrrol-1-yl-phenylsulfanyl] -phenol To a solution of the product of Example 86B (50 mg, 0.101 mmol) and succinic dialdehyde (40% in water solution) (0.065 mL, 0.303 mmol) in toluene (5 mL) and methanol (3 mL) was added 4A molecular sieves. (100 mg). The mixture was then heated at 60 ° C for 7 hours, cooled to room temperature, the solvent was removed under vacuum, a solution of 0.1 N aqueous hydrochloric acid (20 ml) was added and the mixture was extracted with dichloromethane (2 × 25). mi) and dioxane (25 ml). The combined organic extracts were dried and concentrated under vacuum, then the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (14 mg, 26%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.68 (s, 3 H), 6.26 (m, 2 H), 6.77 (d, J = 8.5 Hz, 2 H), 7.05 (d, J = 8.5 Hz, 1 H) , 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 (+ H) +.

Example 100 4- [2,4-Bis- (7-meityl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] phenol 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 at 120 ° C for 2 hours. After cooling to room temperature, the solvent was removed under vacuum and methanol (2 ml) was added. The resulting solid was collected and titrated with methanol to give the title compound as a light brown solid (12 mg, 23%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.67 (s, 3 H), 2.68 (m, 3 H), 6.75 (d, J = 8.8 Hz, 2 H), 6.83 (m, 1 H), 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 (bs, 1H); MS (ESI +) m / z 519 (M + H) +.

Example 101 [4- (4-Bromo-benzylamino) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin- -i lam i no) -phenylsulf-indol] -phenol A solution containing the product of Example 95B was reacted with 4-Bromo-benzaldehyde according to the procedure of Example 96 substituting 4-Bromo-benzaldehyde for phenylacetaldehyde which was purified by HPLC with TFA to provide the title compound as a salt of trifluoroacetic acid (7 mg, 3%). 1H NMR (300 MHz, DMSO-D6) d 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); S (ESI +) m / z 574 (M + H) +.

Example 102 4- [4-Methyl-2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyljphenol 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 provide the title compound (120 mg, 56%). 1 H NMR (300 MHz, DMSO-D 6) ppm: 2.29 (s, 3 H), 2.66 (s, 3 H), .73 (d, J = 8.8 Hz, 2 H), 6.93 (m, 1 H), 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 (bs, 1H), 9.96 (bs, 1H); MS (ESI) + m / z 375 (M + H) +.

Example 103 (5-Methyl-2-phenylsulfanyl-phenyl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) - am i na A solution of the product of Example 10B (90 mg, 0.517 mmol) and the product of Example 51 (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 material was dissolved in dioxane (2 mL) and hydrochloric acid was added followed by removal of the solvent under vacuum to provide the compound of the title as a hydrochloride salt. H NMR (300 MHz, DMSO-D6) 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 (bs, 1H); MS (ESI) + m / z 359 (M + H) +.

EXAMPLE 104 [3- (3-Bromo-phenoxythylene) -phenyl] - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 104A 1-Nitro-3- (3-bromo-phenoxymethyl) -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 to reflux for 23 hours . After cooling, the solid was filtered and the filtrate was concentrated under vacuum to a yellow residue, which was dissolved in ethyl acetate (50 ml) and washed with a solution of 1N aqueous sodium hydroxide (25 ml) and water (25 ml) was then dried and concentrated in vacuo to the title compound as a white solid (1.64 g, 91%).

Example 104B 3- (3-Bromo-phenoxymethyl) -fen lamina 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) was heated to reflux for 3 hours. The mixture was cooled to room temperature, filtered through a Celite pad, which was washed with ethanol and the resulting filtrate was concentrated under vacuum. The material was then dissolved in water (50 ml) and extracted with ethyl acetate (50 ml), the organic layer was dried and concentrated under vacuum to provide the title compound as a yellow oil (1.43 g, 97%). .

Example 104C [3- (3-Bromo-phenoxymethyl) -phenyl] - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -nane 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 at 130 ° C for 30 minutes. After cooling to room temperature, the solution was concentrated under vacuum and purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (62 mg, 44%). 1H N MR (300 MHz, DMSO-D6) d 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 (bs, 1H); MS (ESI) + m / z 421/423 (M + H) +.

Example 105 (3, -Metoxy-5-methyl-biphenyl-3-yl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) - am i na Example 105A 3-Bromo-5-methyl-phenylamine The title compound was prepared from 3-Bromo-5-nitrotoluene (1.08 g, 5.0 mmol) using the conditions of Example 104B to give the title compound as an orange oil (0.8 g, 86%).

Example 105B (3-Bromo-5-methyl-phenyl) - (7-methyl-pyrido [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 using the procedure of Example 104C substituting the product of Example 105A for the product of Example 104B to provide the crude residue that was purified through chromatography on silica eluting with 99: 1 dichloromethane / methanol to give the title compound as a yellow powder (1.1 g, 77%).

Example 105C (3, -Metoxy-5-methyl-biphenyl-3-yl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) - am i na The product of Example 105B (0066 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 (l I) (0.014 g, 0.02 mmol) were combined in N, N-dimethylformamide (1 ml) and heated at 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. The solution was then extracted with ethyl acetate (3 x 10 mL), the combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (12 mg, 13%). 1H NMR (300 MHz, DMSO-D6) d 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-Methoxy-phenyl) -ethyl] -5-methyl-phenyl} - (7-methyl-pyrid [2,3-d] -pyrimidin-4-yl) amine Example 106A 1- [2- (4-Methoxy-phenyl) -vinyl-4-methyl-2-nitrobenzene A solution of 1-bromo-4-methyl-2-nitro-benzene (0.76 g, 3.5 mmol), 1-methoxy-4-vinyl-benzene (0.59 g, 4.4 mmol), triethylamine (0.88 g, 8.8 mmol), tri-o -to I i I fo sf (0.022 g) and palladium acetate (0.008 g) in N, N-dimethylformamide (7 ml) was placed in a high pressure tube and purged with nitrogen for 10 minutes. The tube was sealed and heated at 120 ° C for 16 hours. The mixture was partitioned with water and ethyl acetate by adjusting the pH to 3. The organic layer was washed with brine, dried (sodium sulfate) and filtered through a plug of silica. The filtrate was evaporated under vacuum and the residue was titrated with hexane / ethyl acetate (9: 1) to give the title compound (0.55 g, 58%).

Example 106B 2- [2- (4-Methoxy-phenyl) -ethyl] -5-methyl-phenylamine A solution of the product of Example 106A (164 mg, 0.6 mmol) and 10% palladium on charcoal (50 mg) in ethanol (20 ml) was hydrogenated with a hydrogen balloon for three days. The solvent it was filtered through celite, washed with ethanol and evaporated under vacuum to provide the title compound (140 mg, 97%).

Example 106C. { 2-2- (4-Methoxy-phenyl) -ethyl] -5-methylene-phenol} - (7-methyl-pyridyl [2,3-d] - pyrimidin-4-yl) amine The product of Example 106B was reacted with the product of Example 10C using the procedure of Example 104C substituting the product of Example 106B for the product of Example 104B to provide the crude residue which was purified through chromatography on silica eluting with 99: 1 dichloromethane / methanol to provide the title compound (53 mg, 69%). HN MR (300 MHz, DMSO-D6) d 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-Mephyl-2- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 6c was reacted with the product of Example 57A using the procedure of Example 10F substituting the product of Example 6c for the product of Example 10E and substituting the product of Example 57A for the product of Example 10B to provide the 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-D 6) d ppm: 2.31 (s, 3 H), 6.61-6.78 (m, 2 H), 7.02 (d, J = 8.09 Hz, 1 H), 7.11-7.20 (m, 3 H), 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 (+ H) +.

Example 108 (5-Methyl-2-phenylsulfanyl-phenyl) -pyrido [2,3-d] pyrimidin-4-yl-amine The product of Example SI was reacted with the product of Example 57A using the procedure of Example 10F substituting the product of Example 51 for the product of Example 10E and substituting the product of Example 57A for the product of Example 10B to provide the crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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- (pyridot-2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] phenyl} Acetamide The product of Example 7b was reacted with the product of Example 57A using the procedure of Example 10F substituting the product of Example 7b for the product of Example 10E and substituting the product of Example 57A for the product of Example 10B to provide the crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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); S (ESI +) m / z 402 (M + H) +.

Example 110 4- [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyljphenol The product of Example 6c was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 6c for the product of Example 36H to provide the crude residue which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D6) d 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-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol To a solution of the product of Example 110 (50 mg, 0.124 mmol) in acetic acid (1.5 ml) was added sulfuryl chloride (0.01 ml, 0.124 mmol) dropwise at room temperature. The mixture was stirred for a further 30 minutes, then concentrated in vacuo and purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (19 mg, 28%). 1H NMR (300 MHz, DMSO-D6) d 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 (bs, 1H); MS (ESI +) m / z 437 (M + H) +.

Example 112 2,6-Dichloro-4- [2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol To a solution of the product of Example 110 ( 50 mg, 0.124 mmoles) in acetic acid (1.5 ml) was added sulfuryl chloride (0.02 ml, 0.248 mmol) dropwise at room temperature. The mixture was stirred for a further 30 minutes, then concentrated under vacuum and purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (17 mg, 23%). 1 H NMR (300 MHz, DMSO-D 6) d 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 (bs, 1H); MS (ESI +) m / z 472 (+ H) +.

Example 113 4- [4-Hydroxymethyl-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -f-phenylsulfanyl] -phenol Example 13A 4- (4-Hydroxy-phenylsulfanyl) -3-nitro-benzoic acid methyl ester A solution of 4-chloro-3-nitro-benzoic acid methyl ester (4.0 g, 18.55 mmol) in anhydrous N-dimethylformamide (25 mL) was treated with 4-mercaptophenol (2.34 g, 18.55 mmol) and cesium carbonate. (9.07 g, 27.83 mmol) at room temperature for 23 hours. The solvent was then removed by rotary evaporation under vacuum, the residue was taken up in water (100 ml) and the pH was adjusted to 3 with aqueous 1N HCl. The aqueous solution was extracted with ethyl acetate (2 x 100 mL), and the combined organic extracts they were washed with brine (50 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to give the product as an orange oil contaminated with N, N-dimethylformamide (7.28 g).

Example 113B 3-Amino-4- (4-hydroxy-phenylsulfanyl) -benzoic acid methyl ester A suspension of the product of Example 113A (as a mono-D F adduct) (7.25 g, 19.23 mmole), ammonium chloride (1.54 g, 28.8 mmole) and iron powder (5.37 g, 96.15 mmole) in tetrahydrofuran (75 ml. ), water (25 ml) and ethanol (75 ml) was heated to reflux for 3 hours. The reaction 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 under vacuum. The residue was then dissolved in water (100 ml) and extracted with dichloromethane (2 x 50 ml). The combined organic extracts were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title compound as a white solid (4.2 g, 79%).

Example 113C 4- (2-Amino-4-hydroxymethyl phenylsulfanyl) -phenol To the product of Example 113B (500 mg, 1.82 mmol) in tetrahydrofuran (50 mL) was added a solution of lithium-aluminum hydride (1.0M in THF, 1.8 mL, 1.82 mmol) dropwise at room temperature followed by heating Mix at 70 ° C for 4 hours. Then water (25 ml) was carefully added to the solution and the organic layer was separated, dried and concentrated under vacuum to provide the title compound (295 mg, 66%).

Example 113D 4- [4-Hydroxymethyl-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 113C was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 113C for the product of Example 36H to provide the crude residue which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (30 mg, 31%). 1H NMR (300 MHz, DMSO-D6) d ppm: 1.36 (d, J = 7.0 Hz, 6H), 3.30 (m, 1 H), 4.50 (s, 2H), 6.72 (d, J = 8.5 Hz, 2H ), 7.05 (d, J = 8.1 Hz, 1 H), 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, 1 H), 9.82 (s, 1 H), 11.43 (bs, 1 H); MS (ESI +) m / z 419 (M + H) +.

EXAMPLE 11 Ester 4- (4-hydroxy-phenyl) -3- (7-isopropyl-pyrido [2,3-d] -pyrimidin-4-ylamino) -benzyl acetic acid ester The product of Example 113C was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 113C for the product of Example 36H to provide the crude residue which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (12 mg, 11%). H NMR (300 MHz, DMSO-D6) d 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 (bs, 1H), 11.79 (bs, 1H); MS (ESI +) m / z 461 (M + H) +.

Example 115 N-. { 4- [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide The product of Example 7b was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 7b for the product of Example 3611 to provide the crude residue that was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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, 1 H ,) 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-lsopropyl-pyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxy-phenoxy) -5-methyl-pheny] -amine Example 116A 1- (4-Methoxy-phenoxy) -4-methyl-2-nitro-benzene 4-methoxy-phenol was reacted with 1-f-luoro-4-methyl-2-nitrobenzene according to the procedure of Example 122a substituting 4-methoxy-phenol for hydroquinone to provide the title compound.

Example 116B 2- (4-Wleto i-phenoxy) -5-methyl-f eni sheet The product of Example 116A was reduced according to the procedure of Example 104B substituting the product of Example 116A for the product of Example 104A to provide the title compound.

Example 116C (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxy-phenoxy) -5-methyl-phenyl] -amine The product of Example 116B was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 116b for the product of Example 36H to provide the crude residue which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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 [2- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenoxy] -phenol The product of Example 122b was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 122b for the product of Example 36H to provide the crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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 (+ H) +.

Example 118 (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxy-phenylsulfa-5-methyl-phenyl] -amine The product of Example 6a (5.0 g, 175 mmol) was reacted with 4-methoxy-benzenethiol (2.45 g, 175 mmol) for 18 hours following the procedure of Example 6b to give 1- (4-methoxy-phenylsulfanyl) -4- methyl-2-nitro-benzen, which was reduced with SnCl 2 following the procedure of Example 51 to provide 2- (4-methoxy-phenylsulfanyl) -5-methyl-phenylamine. 2- (4-methoxy-phenylsulfanyl) -5-methyl-phenylamine was reacted with the product of Example 36E using the procedure of Example 36I substituting 2- (4-methoxy-f-phenylsulfanyl) -5-methyl-phenylamine for the product of Example 36H to provide the crude residue that was purified through HPLC with TFA to provide the title compound as an acid salt trifluoroacetic. 1H NMR (300 MHz, DMSO-D6) d 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), 836 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 11.36 (s, 1H); MS (ESI) + m / z 417 (M + H) +.

Example 119 (7-Cyclopropyl-pyrido [2,3-d) pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine Example 119A N '- (3-Cyano-6-cyclopropyl pyridin-2-yl) -N, N-dimethyl-formamidine Cyclopropyl methyl ketone was reacted according to the procedures described in Examples 36A-36E to provide the title compound.

Example 119B (7-Cyclopropyl-pyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine The product of Example 51 was reacted with the product of Example 119A using the procedure of Example 102 substituting the product of Example 51 for the product of Example 6c and substituting the product of Example 119A for the Product of Example 10B to provide the crude residue which was purified through titration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) d 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-Cyclopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol The product of Example 6c was reacted with the product of Example 119A using the procedure of Example 102 substituting the product of Example 119A for the product of Example 10B to provide the crude residue which was purified through titration with methanol to provide the compound of the title. 1H NMR (300 MHz, DMSO-D6) d 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-Cyclopropyl-pyrido [23-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide The product of Example 7b was reacted with the product of Example 119A using the procedure of Example 102 by substituting the product of Example 7b for the product of Example 6c and substituting the product of Example 119A for the product of Example 10B to provide the crude residue. which was purified through methane titration! to provide the title compound. 1H NMR (300 Hz, DMSO-D6) d 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, 1 0) , 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-Cyclopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenoxy] -phenol Example 122a 4- (4-methyl-2-nitro-fe-noxy) phenol A solution of hydroquinone (3.2 g, 29.0 mmol) and K2C03 (8.0 g, 54.0 mmol) in 40 ml of DMF was heated to 100 ° C with 1- f luoro-4-methyl-2-nitrobenzene (3.0 g, 19.3 mmol) with stirring for 24 hours. It was cooled to room temperature and diluted with EtOAc. It was washed with water and the organic layer was dried over MgSO4. Filtered and concentrated in vacuo to give the title compound, which was purified through silica gel column chromatography eluting with 5% EtOAc / hexane to give an orange oil (1.89 g, 40%).

Example 122b 4- (2-amino-4-methylphenoxy) phenol The product from Example 122a (1.89 g, 7.71 mmol) was reduced with SnCl 2 following the procedure of Example 51 to give the title compound as a white solid (1.42 g, 86%).

Example 122c 4- (2- (7-Cyclopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methylphenoxy) -phenol The product of Example 122b was reacted with the product of Example 119A using the procedure of Example 102 substituting the product of Example 122b for the product of Example 6c and substituting the product of Example 119A for the product of Example 10B to provide the crude residue which was purified through titration with methanol to provide the composed of the title. 1 H NMR (300 MHz, DMSO-D 6) d 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-Cyclopropyl-pyrido [2,3-d] pyrimidin-4-yl) 42- (4-methoxy-phenoxy) -5-methyl-phenyl] -amine The product of Example 116B was reacted with the product of Example 119A using the procedure of Example 102 by substituting the product of Example 116B for the product of Example 6c and substituting the product of Example 119A for the product of Example 10B to provide the crude residue. which was purified by titration with methanol to provide the title compound. 1 H NMR (300 MHz, DMSO-D 6) d 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-Cyclopro-pyrido [2,3-d] pyrimidin-4-yl) - [2- (4-fluoro-phenylsulfanyl) -5-methyl-phe nor I] -amine The product of Example 6a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) in place of thiophenol following the procedure of Example 5H for 18 hours to give 1- (4-Fluoro-phenylsulfanyl) - 4-methyl-2-nitro-benzene, which was purified through silica gel column chromatography eluting with 5% EtOAc / hexane to give a solid (3.39 g, 74%). 1 - (4-Fluoro-phenylsulfanyl) -4-methyl-2-nitro-benzene was reduced with SnCl 2 following the procedure of Example SI to give 2- (4-Fluoro-phenylsulfanyl) -5-methyl-phenylamine. 2- (4-Fluoro-phenylsulfanyl) -5-methyl-phenylamine was reacted with the product of Example 119A using the procedure of Example 102 substituting 2- (4-f luoro-phenylsulfanyl) -5-methyl-phenylamine for the product of Example 6c and substituting the product of Example 119A for the product of Example 10B to provide the crude residue which was purified through titration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) d 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-Cyclopropyl-pyrido [2,3-d] pyrimidin-4-yl) - [2- (4-methoxy-phenylsulfanyl) -5-methyl-phenyl] -amine Reacted 2- (4-methoxy-phenylsulfanyl) -5-methyl-phenylamine (Example 118) with the product of Example 119A using the procedure of Example 102 substituting 2- (4-methoxy-phenylsulfanyl) -5-methyl-phenylamine for the product of Example 6c and substituting the product of Example 119A for the product of Example 10B to provide the crude residue that was purified through titration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) d 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-fV) ethoxy-phenoxy) -5-methy1-phenyl] - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amine The product of Example 116B was reacted with the product of Example 10C using the procedure of Example 104C substituting the product of Example 116B for the product of Example 104B to provide the crude residue that was purified HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D 6) 6 ppm: 2.33 (s, 3 H), 2.72 (s, 3 H), 3.68 (s, 3 H), 6.80-6.95 (m, 5 H), 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-Butyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol Example 127A N '- (6-tert-Butyl-3-cyano-pyridin-2-yl) -N, N-dimethyl-formamidine 3, 3-Dimethyl-2-butanone was reacted according to the procedures described in Examples 36A-36E to provide the title compound.

Example 127B 4- [2- (7-tert-Buyl-pyrid [2,3-d] pyrimidin-4-ylamino) -4-meityl-phenylsulfanyl] -phenol The product of Example 6c was reacted with the product of Example 127A using the procedure of Example 361 substituting the product of Example 6c for the product of Example 36H and substituting the product of Example 127A for the 276E product to provide the 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-D 6) d ppm: 1.44 (s, 9 H), 2.31 (s, 3 H), 6.71 (d, J = 8.5 Hz, 2 H), 7.00 (d, J = 8.1 Hz, 1 H) , 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 (bs, 1H); MS (ESI) + m / z 417 (M + H) +.

Example 128 (5-Methyl-2-phenylsulfanyl-phenyl) - (7-propyl-pyrido [2,3-d] pyrimidin-4-yl) - am i na The product was prepared using the procedure of Example 36A substituting 2-pentanone for methyl isopropyl ketone to give the intermediate which was reacted after according to the sequential procedures of Examples 36A-36E.

Example 128A N '- (3-Cyano-6-propyl pyridin-2-yl) -N, N-dimethyl-formamidine The product was prepared using the procedure of Example 36A substituting 2-pentanone for methyl isopropyl ketone to give the intermediate which was reacted after according to the sequential procedures of Examples 36A-36E.

Example 128B (5-Wletyl-2-phenylsulfanyl-phenyl) - (7-propyl-pyrid [2,3-d] pyrimidin-4-yl) - am i na The product of Example 51 (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 at 130 ° C for 1.5 hours. After cooling to room temperature, a solid appeared in the acetic acid solvent, which was collected through filtration to give the title compound as an acetic acid salt (68 mg, 62%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 0.94 (t, J = 7.4 Hz, 3 H), 1.79 (m, 2 H), 1.88 (s, 6 H), 2.35 (s, 3 H), 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 3 3- [4-Methyl-2- (7-propyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product from Example 6a (10.14 g, 35.6 mmol) was reacted with 3- (4-methyl-2-nitro-phenylsulfanyl) -phenol (4.48 g, 35.6 mmol) for 18 hours following the procedure of Example 6b to give 3- (4-Methyl-2-nitro-phenylsulfanyl) -phenol (7.88 g, 85%), which was reduced with SnCl 2 following the procedure of Example 51 to give 3- (2-amino-4-methyl-phenylsulfanyl) -phenol. 3- (2-Amino-4-methyl-phenylsulfanyl) -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, a solid appeared in the acetic acid solvent, which was collected through filtration to provide the title compound as an acetic acid salt (78 mg, 68%). 1H NR (300 MHz, DMSO-D6) d ppm: 0.95 (t, J = 73 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 (+ H) +.

Example 130 N-. { 4- [4-Methyl-2- (7-propyl-pyrido [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 at 130 ° C for 1.5 hours. After cooling to room temperature and removal of the acetic acid solvent under vacuum, methanol (3 mL) was added to the oil, which caused a solid to form, which was titrated with methanol to provide the title compound 80 mg , 78%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 0.95 (t, J = 7.4 Hz, 3 H), 1.89 (m, 2 H), 2.02 (s, 3 H), 2.32 (s, 3 H), 2.89 (t, J = 7.5 Hz, 2H), 7.06 (s, 2H), 7.21 (t, J = 8.5 Hz, 2H), 7.30 (s, 1 H), 7.50 (d, J = 8.8 Hz, 2H), 7.52 (m, 1 H), 8.52 (s, 1H) 8.74 (d, J = 7.7 Hz, 1 H), 10.00 (s, 1 H); MS (ESI) + m / z 444 (M + H) +.

Example 131 4- [4-Methyl-2- (7-propyl-pyrido [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 at 130 ° C for 1.5 hours. After cooling to room temperature, a solid appeared in the acetic acid solvent, which was collected through filtration to provide the title compound as an acetic acid salt (77 mg, 68%). 1H NR (300 MHz, DMSO-D6) d 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, 1 H), 7.03 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.22 (s, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 8.53 (s, 1 H), 8.78 (d, J = 8.5 Hz, 1 H); MS (EST) + m / z 403 (M + H) +.

Example 132 N-. { 4- [5-Hydroxy-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide A mixture of 2-methyl-4-nitro-5-chloro-phenol (1.5 g, 8.0 mmol), 4-acetamido thiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74) g, 17.6 mmol) in D F (10 mL) was heated 2.5 hours at 100 ° C. The mixture was cooled, diluted with ethyl acetate (100 ml) and the organic layer was washed with water and a 10% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed under vacuum leaving N- [4- (5-hydroxy-4-methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide as a solid (2.5 g, 81%). A solution of N- [4- (5-hydroxy-4-methyl-2-nitro-phenylsulfanyl) -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 methanol (10 mL), tetrahydrofurane (10 mL), and water solution (5 mL) was heated at reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide N- [4- (2-amino-5-hydroxy-4-methyl-phenylsulfanyl) -phenyl] -acetamide (1.7g, 91%). N- [4- (2-amino-5-hydroxy-4-methyl-phenylsulfanyl) -phenyl] -acetamide was reacted with the product of Example 36E using the procedure of Example 36I substituting N- [4- (2-amino 5-hydroxy-4-methyl-phenylsulfanyl) -phenyl] -acetamide for the product of Example 36H to provide the crude residue which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMS0-D6) d 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 '- (4-Benzyloxy-phenyl) -N 2 - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -4- N 1 -dimethyl-benzene-1,2-diamine Example 133A (4-Benzyloxy-phenyl) - (4-methyl-2-nitro-phenyl) -amine A mixture of 4-methyl-2-nitroaniline (1,006 g, 6,612 mmol), 4-benzyloxybromobenzene (5,794 g, 22.02 mmol), cuprous iodide (62.9 mg, 0.3306 mmol), potassium carbonate (0.914 g, 6.612 mmol) and O-xylene anhydrous (18 mL) was heated at 150 ° for 24 hours. Additional cuprous iodide (30 mg) was added and heated an additional 6 hours at 160 °. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation under vacuum. The residue was purified by flash chromatography on silica gel using 1: 1 methylene chloride / hexanes as eluent to give the title compound as a red oil, which crystallized slowly (1.23 g, 56%).

Example 133B (4-Benzyloxy-phenyl) -methyl- (4-methyl-2-nitro-phenyl) -amine A solution of the product of Example 133A (229.4 mg, 0.6861 mmol) in anhydrous N, N-dimethylformamide (3 mL) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 55 mg, 1372 mmol) in N , N-dimethylformamide (3 ml) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 hour, then methyl iodide (0.171 ml, 2.744 mmol) was added and it was allowed to stir at room temperature for 2 hours. The solvent was removed by rotary evaporation under vacuum. The residue was taken up 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 by rotary evaporation under vacuum to give the title compound as a brown solid (239 mg, 100 mg). %).

Example 133C (4-Benzyloxy-phenyl) -methyl- (4-methyl-2-amino-phenyl) -amine A mixture of the product of Example 133B (129.4 mg, 0.3714 mmol), iron powder (128 mg, 2284 mmol), ammonium chloride (130 mg, 2.433 mmol) in water (1 mL) and ethanol (2 mL) was heated at 70 ° under a nitrogen atmosphere for 1 hour. The reaction cooled to room temperature and filtered under vacuum, washing the residue with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified by flash chromatography on silica gel using methylene chloride as eluent to give the title compound as a waxy solid (85 mg, 72%).

Example 133D l-Benzyloxy-phenyl) -N2- (7-isopropyl-pyrido [2,3-djpyrimidin-4- 4, N 1 -dimethyl-benzene-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 a preheated oil bath at 140 ° C for 1 hour. hour. The reaction was cooled to room temperature, diluted with hexanes (50 ml), concentrated by rotary evaporation under vacuum, and co-evaporated with methylene chloride / hexanes (4x). 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%). H NMR (300 MHz, DMSO-D6) d 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 / NH3) m / z 490 (M + H) +.

Example 134 (2-Benzyl-5-methyl-phenyl) - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 134A 2-Benzyl-5-methyl-phen laminate A solution of lithium-aluminum hydride in tetrahydrofuran (1.0 M, 2.54 ml, 2.54 mmol) was added through a syringe to a flask containing aluminum chloride (534 mg, 4.005 mmol) under a nitrogen atmosphere and cooled in a 0 ° bath. 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 °. The reaction was then heated at 50 ° for 30 minutes. The reaction was cooled to room temperature and wet ethyl ether (5 ml) was added. The reaction was carefully poured into water (20 ml) and extracted with ethyl ether (2 x 50 ml). The combined ether extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification through flash chromatography on silica gel using 40:60 hexanes / methylene chloride as eluent afforded the title compound as a oil (94 mg, 50%) Example 134B (2-Benzyl-5-methyl-phenyl) - (7-isopropyl-pyrido [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 a pre-heated oil bath at 140 ° C for 1 hour. hour. The reaction was cooled to room temperature, diluted with hexanes (50 ml), concentrated by rotary evaporation under vacuum, and co-evaporated with methylene chloride / hexanes (4x). The residue was dried, then purified by flash chromatography on silica gel using 2% methanol / methylene chloride as eluent to give the title compound as a light yellow solid (50 mg, 85%). ? NMR (300 MHz, DMSO-D6) d 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 / NH3) m / z 369 (M + H) +.

Example 135 (7-Cyclohexyl-pyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine Example 135A N '- (3-Cyano-6-cyclohexyl-pyridin-2-yl) -N, N-dimethyl-formamidine 1-Cyclohexyl-ethanone was reacted according to the procedures described in Examples 36A 36E to provide the title compound.

Example 135B (7-Cyclohexyl-pyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl phenyl) -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 51 (50.0 mg, 0.2322 mmol) and the mixture was stirred in a preheated oil bath to a 130 ° C for 15 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (20 mg, 20%). 1H NMR (300 MHz, DMSOD6) d 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 / NH3) m / z 427 (M + H) +.

Example 136 4- [2- (7-Cyclohexyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol The product of Example 135A was reacted with the product of Example 6c according to the procedure of Example 135B substituting the product of Example 6c for the product of Example SI to provide the title compound as a trifluoroacetic acid salt (20 mg, twenty%). HNR (300 MHz, D SO-D6) d 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 / NH3) m / z 443 (M + H) +.

Example 137 N-. { 4- [2- (7-Cyclohexyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide The product of Example 135A was reacted with the product of Example 7b according to the procedure of Example 135B substituting the product of Example 7b for the Product of Example 51 to provide the title compound as a trifluoroacetic acid salt (21 mg, 25%). 1H NR (300 MHz, DMSO-D6) d 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 / NH3) m / z 484 (M + H) +.

Example pio 138 N-. { 4- [2- (7-Cyclobutyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide Example 138A N '- (3-Cyano-6-cyclobutyl-pyridin-2-yl) -N, N-dimethyl-formamidine 1-Cyclobutyl-ethanone was reacted according to the procedures described in Examples 36A-36E to provide the title compound.

Example 138B N-. { 4- [2- (7-Cyclobuyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methy1-phenylsulfanyl] -phenyl} -acetamide The product of Example 138A was reacted with the product of Example 7b according to the procedure of Example 135B replacing the product of Example 7b for the product of Example 51 and substituting the product of Example 138A for the product of Example 135A to provide the title compound as a trifluoroacetic acid salt (30 mg, 36% yield). 1H NMR (500 MHz, DMSO-D6) d 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 / NH4) m / z 456 (M + H) +.

Example 139 4- (2- (7-Cyclobutyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol The product of Example 138A was reacted with the product of Example 6c according to the procedure of Example 135B by replacing the product of Example 6c for the product of Example 51 and substituting the product of Example 138A for the product of Example 135A to provide the compound of the title as a trifluoroacetic acid salt (30 mg, 33%). 1H NMR (300 MHz, DMSO-D6) d 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, = 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,) m / z 415 (M + H) + Example 140 (7-sec-Butyl-pyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine Example 140A N '- (6-sec-Butyl-3-cyano-pyridin-2-yl) -N, N-dimethyl-formamidine 3-Methyl-pentan-2-one was reacted according to the procedures described in Examples 36A-36E to provide the title compound.

Example 140B (7-sec-Butyl-pyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine The product of Example 140A was reacted with the product of Example 51 according to the procedure of Example 135B substituting the product of Example 140A for the product of Example 135A to give the title compound as a trifluoroacetic acid salt. 1H NR (300 MHz, DMSO-D6) d 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); S (DCI / N H4) M / Z 401 (M + H) +.

Example 141 N-. { 4- [2- (7-sec-Butyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide The product of Example 140A was reacted with the product of Example 7b according to the procedure of Example 135B by replacing the product of Example 7b for the product of Example 51 and substituting the product of Example 140A for the product of Example 135A to provide the compound of the title as a trifluoroacetic acid salt (37 mg, 45%). 1H NMR (500 MHz, DMSO-D6) d 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, 1 HOUR); MS (DCI / NH4) m / z 458 (M + H) +.

Example 142 N- (4-. {4-Wlethyl-2- [7- (1-methyl-cyclopropyl) -pyrid [2,3-d] pyrimidin-4-ylamino] -phenylsulfanyl}-phenyl) -acetamide Example 142A N '- [3-Cyano-6- (1-methyl-cyclopropyl) -pyridin-2-yl] -N, N-dimethyl-formamidine 1- (1-methyl-cyclopropyl) -ethanone was reacted according to the procedures described in Examples 36A-36E to provide the title compound.

EXAMPLE 142B N- (4- (4-Methyl-2- [7- (1-methyl-1-cyclopropi I) -pi [2, 3-d] p-rim id i n-4-lamino] - nilsulfanil.}.-phenyl) -acetamida The product of Example 142A was reacted with the product of Example 7b according to the procedure of Example 135B by replacing the product of Example 7b for the product of Example 51 and substituting the product of Example 142A for the product of Example 135A to provide the compound of the title as a trifluoroacetic acid salt (30 mg, fifty%). 1H NMR (300 Hz, DMSO-D6) d 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 (s) d, J = 8.46 Hz, 1H), 8.78 (s, 1H), 8.89 (d, J = 9.19 Hz, 1H), 9.99 (s, 1H); MS (DCI / NH4) m / z 456 (M + H) +.

Example 143 4- (4-Methyl-2- [7- (1-methyl-cyclopropyl) -pyrido [2,3-d] pyrimidin-4-ylamino] phenylsulfanyl} - phenol The product of Example 142A was reacted with the product of Example 6c according to the procedure of Example 135B by replacing the product of Example 6c for the product of Example 51 and substituting the product of Example 142A for the product of Example 135A to provide the compound of the title as a trifluoroacetic acid salt (20 mg, 37%). 1H NMR (300 MHz, DMSO-D6) d 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) m / z 415 (M + H) +.

Example 144 3-. { 4-Methyl-2- [7- (1-meityl-cyclopropyl) -pyrido [2,3-d] pyrimidin-4-ylamino] -f-enylsulfanyl} -phenol The product of Example 142A was reacted with 3- (2-amino-4-methyl-phenylsulfanyl) -phenol (Example 129) according to the procedure of Example 135B substituting 3- (2-amino-4-methyl-phenylsulfanyl) -phenol for the product of Example 51 and substituting the product of Example 142A for the product of Example 135A for provide the title compound as a trifluoroacetic acid salt (20 mg, 37%). 1H NMR (300 MHz, DMSO-D6) d 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 / NH4) m / z 415 (M + H) +.

Example 145 (7-Ethyl-pyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) amine Example 145A N '- (3-Cyano-6-ethyl-pyridin-2-yl) -N, N-d-methyl-formamidine 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. To this solution was slowly added dropwise a solution of lithium diisopropylamide (3.0 ml of a 2.0 M solution in toluene / hexane / heptane, 6.0 mmole, 1.2 eq). After the addition was complete, 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 an additional 1.5 hours at -78 ° C, during which time, all the solids were dissolved. The reaction flask was then removed from the cooling bath and chloride was added saturated aqueous ammonium (25 ml) and water (25 ml). The reaction mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The residue was purified by chromatography on silica gel, eluting with 3/2 hexane: ethyl acetate to give the title compound (0.87 g, 86% yield).

Example 145B (7-Ethyl-pyrido [2,3-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) - amine The product of Example 145A was reacted with the product of Example 51 according to the procedure of Example 135B substituting the product of Example 145A for the product of Example 135A to give the title compound as a trifluoroacetic acid salt (20 mg, 33%). 1H NMR (500 Hz, DMSO-D6) d 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 / NH4) m / z 373 (+ H) +.

Example 146 N-. { 4- (2- (7-Ethyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl] -acetamide The product of Example 145A was reacted with he product of Example 7b according to the procedure of Example 135B substituting the product of Example 7b for the product of Example 51 and substituting the product of Example 145A for the product of Example 135A to provide the title compound as a trifluoroacetic acid salt (20 mg, 29%). 1H NMR (500 MHz, DMSO-D6) d 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 / NhU) m / z 430 (M + H) +.

Example 147 4- [4- (6-Bromo-1H-benzoimidazol-2-yl) -2- (7-isopropyl-pyrido [2,3-d] -pyrimidin-4-ylamino) -phenoxy] -phenol Example 147A 4- (4-Benzyloxy-phenoxy) -3-nitro-benzaldehyde A mixture of 4-chloro-3-nitrobenzaldehyde (1.00 g, 5.389 mmole), 4- (benzyloxy) phenol (1187 g, 5.928 mmole), and potassium carbonate (0.744 g, 5.389 mmole) in anhydrous pyridine (10 ml) it was heated to reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 ml) and washed with 1N aqueous hydrochloric acid (2 x 50 ml), water (50 ml), and brine (50 ml). The Organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification through flash chromatography of silica gel using methylene chloride as eluent afforded the title compound as a yellow solid (1.625 g, 86%).

Example 147B 2- [4- (4-Benzyloxy-phenoxy) -3-nitro-phenyl} -6-bromo-1H-benzoimidazole A solution of 4-bromo-1,2-benzenediamine (214 mg, 1145 mmol) in N, N-dimethylformamide (12 mL) containing water (0.4 mL) was treated with the product of Example 147A (400 mg, 1145 mmol) and OXONE (458 mg, 0.7443 mmol), and the reaction was stirred at room temperature for 30 minutes. Then water (40 ml) was added and the reaction was stirred for 10 minutes. The mixture was filtered under vacuum and the solid was washed with water, then dried under vacuum. Purification through silica gel chromatography using a gradient of 3% to 4% ethyl acetate / methylene chloride as eluent afforded the title compound as a yellow solid (305 mg, 51%).

Example 147C 2- (4-Benzyloxy-phenoxy) -5- (6-bromo-1H-benzoimidazol-2-yl) -phenylamine The product of Example 147B (374 mg, 0.723 mmol), powder of iron (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 ° for 45 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml), and washed with water (2 x 50 ml) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide the title compound as a golden solid (327 mg, 93%).

Example 147D [2- (4-Benzyloxy-phenoxy) -5- (6-bromo-1H-benzoimidazol-2-yl) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-) il) -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 a preheated oil bath at 140 ° C for 30 minutes. minutes The reaction was cooled to room temperature, diluted with hexanes (50 ml), concentrated by rotary evaporation under vacuum, and co-evaporated with methylene chloride / hexanes (4x). The residue was dried under vacuum, then purified through silica gel chromatography using 3% methanol / methylene chloride as eluent to give the title compound as an off-white solid (59 mg, 73%).

Example 147E 4- [4- (6-Bromo-1H-benzoimidazol-2-yl) -2- (7-isopropyl-pyrido [2,3-d] -pyrimidin-4-ylamino) -phenoxy] -phenol A solution of the product from 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 by rotary evaporation under vacuum and co-evaporated with methylene chloride / hexanes (2x). The resulting solid was titrated with hexanes (3x) and purified by HPLC with TFA to give the title compound as a trifluoroacetic acid s(22 mg, 47%). H NMR (300 MHz, DMSO-D6) d 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-methyl-pyrido [2,3-d] -pyrimidin-4-ylamino) -phenoxy] -phenol The product of Example 147C was reacted with the product of Example 10B using the procedure described in Example 147D substituting the product of Example 10B for the product of Example 36E to provide [2- (4-Benzyloxy-phenoxy) -5- (6-bromo-1H-benzoimidazol-2yl) -phenyl] - (7-methyl-pyrido [ 2,3-d] -pyrimidin-4-yl) -amine, which was debenzylated according to the procedure described in Example 147E to provide the crude product which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt. ? NMR (300 MHz, DMSO-D6) d 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 (bs, 1H), 11.35 (bs, 1H); MS (ESI +) m / z 539/541 (M + H) +.

Example 149 4- (4-Amino-phenylsulfanyl) -N- (4-bromo-phenyl) -3- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -benzenesulfonamide Example 149A N- (4-Bromo-phenyl) -4-chloro-3-nitro-benzenesulfonamide A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.561 g, 10 mmol) in acetic acid (20 mL) was treated with 4-bromoaniline (1.72 g, 10 mmol) and anhydrous sodium acetate (1.23 g, 15 mmol). ), then heated at 100 ° for 30 minutes. The The reaction was cooled to room temperature and the acetic acid was removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 ml) and washed with water (2 x 25 ml) and brine (25 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum, co-evaporating the oil with methylene chloride / hexanes. Purification through silica gel chromatography using methylene chloride followed by 5% ethyl acetate / methylene chloride as eluent afforded the title compound as a yellow solid (2.038 g, 52%).

Example 149B 4- (4-Amino-phenylsulfanyl) -N- (4-bromo-phenyl) -3-nitrobenzenesulfonamide A mixture of the product of Example 149A (500 mg, 1277 mmol), 4-aminothiophenol (240 mg, 1915 mmol) and anhydrous sodium acetate (524 mg, 6.384 mmol) in anhydrous ethanol (9 ml) was heated to reflux under a Nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and the ethanol was removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 ml) and washed with water (2 x 50 ml) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, co-evaporating the oil with methylene chloride / hexanes to obtain the title compound as a orange foam (613 mg, 100%).

EXAMPLE 149C Tert-butyl acid ester. { 4- [4- (4-bromo-phenylsulfamoyl) -2-nitro-phenylsulfanyl] -phenyl} -carbamic A solution of the product from Example 149B (613 mg, 1277 mmol) in anhydrous 1,4-dioxane (10 mL) was treated with di-tert-butyl carbonate (418 mg, 1.92 mmol) at room temperature, then the reaction was heated to reflux under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, additional di-tert-butyl carbonate (500 mg) was added, and the reaction was brought to reflux for 17 hours. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation under vacuum. Purification of the residue through silica gel chromatography using 3% ethyl acetate / methylene chloride as eluent afforded the title compound as a yellow solid (512 mg, 69%).

Example 149D Tert-butyl acid ester. { 4- [2-am i non-4- (4-bromo-phenylsulfamoyl) -phenylsulfanyl] -phenyl} -carbamic The product of Example 149C (510 mg, 0.879 mmol), iron powder (302 mg, 5.40 mmol), and ammonium chloride (308 mg, 5.76 g. mmoies) in water (4 ml) and ethanol (8 ml) were heated at 80 ° for 40 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (2 x 50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide the title compound as a white foam (436 mg, 90%).

Example 149E Tert-butyl acid ester. { 4- [4- (4-bromo-phenylsulfamoyl) -2- (7- isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenyl} - carbamic A solution of the product of Example 36E (59 mg, 0.2725 mmoies) and the product of Example 149D (150 mg, 0.2725 mmoies) in acetic acid (4 ml) was stirred in a pre-heated oil bath at 140 ° C for 25 minutes. minutes The reaction was cooled to room temperature, diluted with hexanes (100 mL), concentrated by rotary evaporation under vacuum, and co-evaporated with methylene chloride / hexanes (4x). The residue was dried under vacuum, then purified through silica gel chromatography using 4% methanol / methylene chloride as eluent to give the title compound as a tan solid (67 mg, 34%).

Example 149F [4-Amino-phenylsulfanyl) -N- (4-bromo-phenyl) -3- (7-isopropy pyrido [2,3-d] pyrimidin-4-ylamino) -benzenesulonamide 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 by rotary evaporation under vacuum and the residual oil was dried under high vacuum. Purification through silica gel chromatography using 5% methanol / methylene chloride as eluent afforded the title compound as a trifluoroacetic acid salt (25 mg, 48%). 1H NMR. (300 MHz, DMSO-D6) d ppm: 1.35 (d, J = 6.62 Hz, 6H), 3.13-3.38 (m, 1H), 6.63 (d, J = 8.46, .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-Amino-phenylsulfanyl) -N- (4-bromo-phenyl) -3- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -benzenesulfonamide The product of Example 149D was reacted with the product of Example 10B using the procedure described in Example 149E replacing the product of Example 10B for the product of Example 36E to provide tert-butyl acid ester. { 4- [4- (4-bromo-phenylsulfamoyl) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenyl} Carbamic, which was deprotected according to the procedure described in Example 149F, followed by silica gel chromatography afforded the title compound as a trifluoroacetic acid salt. 1 H NMR (300 MHz, D SO-D 6) d ppm: 2.74 (s, 3 H), 6.64 (d, J = 8.46 Hz, 2 H), 6.89 (d, J = 8.09 Hz, 1 H), 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-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxy] -phenol Example 151 A 4- (4-Chloro-2-nitro-phenoxy) -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 ° for 30 minutes under a nitrogen atmosphere. A solution of 2,5-dichloronitrobenzene (1.90 g, 0.0099 mol) in dimethyl sulfoxide (3%) was added dropwise. mi) for a period of 30 minutes at 120 °, then the reaction was allowed to stir for 1 hour at the same temperature. The reaction was then cooled in an ice bath and evacuated to 30 ml of ice-water. The mixture was acidified with concentrated hydrochloric acid to a pH of 1 and extracted with ethyl ether (2 x 50 mL). The combined ether extracts were washed with water (3 x 150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification of the residue through silica gel chromatography using methylene chloride as eluent afforded the product as a tan solid (1.34 g, 51%).

Example 151 B 4- (2-Amino-4-chloro-phenoxy) -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 to reflux under a nitrogen atmosphere for 25 minutes. . The reaction was cooled to room temperature, diluted with water (50 ml), and treated with solid sodium carbonate until the pH was 6. It was extracted with ethyl acetate (2 x 50 ml) and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Co-evaporation of the resulting oil with methylene chloride / hexanes provided the compound of the title as a tan solid (355 mg, 100%).

Example 151 C 4- [4-Chloro-2- (7-isopropyl-pyridyl [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) was stirred in a pre-heated oil bath at 140 ° C for 1.5 hour. The reaction was cooled to room temperature, diluted with hexanes (100 mL), concentrated by rotary evaporation under vacuum, and co-evaporated with methylene chloride / hexanes (4x). The residue was dried under high vacuum, then purified by titration with 40% ethyl acetate / methylene chloride to give the title compound as a beige solid (49 mg, 65%). 1H NMR (300 MHz, DMSO-D6) d 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 (bs, 1H), 8.59 (bs, 1H), 8.73 (d, J = 8.09 Hz, 1H), 9.31 (bs, 1H), 9.89 (bs, 1H); MS (DCI / NH3) m / z 407 (M + H) +.

Example 152 4- (4-Hydroxy-phenoxy) -3- (7-isopropyl-pyridyl [2,3-d] pyrimidin-4-ylamino) -benzonitrile EXAMPLE 152A 4- (4-Hydro-i-phenoxy) -3-nitro-benzoniiryl 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 a nitrogen atmosphere. A solution of 4-chloro-3-nitrobenzonitrile (1,806 g, 0.0099 mol) in dimethyl sulfoxide (8 ml) was added dropwise over a period of 30 minutes at 90 °, then the reaction was allowed to stir for 1 hour at the same temperature. The reaction was then cooled in an ice bath and evacuated to 30 ml of ice-water. The mixture was acidified with concentrated hydrochloric acid to a pH of 3 and extracted with ethyl ether (3 x 100 mL). The combined ether extracts were washed with water (3 x 150 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification through silica gel chromatography using 4% ethyl acetate / methylene chloride as eluent afforded the product as an orange solid (0.984 g, 39%).

Example 152B 3-Amino-4- (4-hydroxy-phenoxy) -benzonitrile The product of Example 152A (500 mg, 1952 mmol) was hydrogenated in methanol (20 mL) with hydrogen (1 atmosphere, balloon) and 10% palladium on charcoal (50 mg) for 30 minutes. The reaction was vacuum filtered through a 0.450 PTFE membrane and the catalyst was washed with methanol. The filtrate was concentrated by rotary evaporation under vacuum to provide the title compound as a pinkish-beige solid (437 mg, 99%).

Example 152C 4- (4-Hydroxy-phenoxy) -3- (7-isopropyl-pyrido [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 a preheated oil bath at 140 ° C for 1.5 hour. The reaction was cooled to room temperature, diluted with hexanes (100 mL), concentrated by rotary evaporation under vacuum, and co-evaporated with methylene chloride / hexanes (4x). The residue was dried under high vacuum. Purification through silica gel chromatography using 30% ethyl acetate / methylene chloride as eluent afforded the title compound as a white solid (16 mg, 21%). 1H N R (300 MHz, DMSO-D6) d 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 / NH3) m / z 398 (M + H) +.

Example 153 (5-Bromo-2-phenoxy-phenyl) -pyrido [2,3-d] pyrimidin-4-yl-amine -Bromo-2-phenoxybenzenamine was reacted with the product of Example 57A using the procedure described in Example 57E substituting 5-bromo-2-phenoxybenzenamine for the product of Example 57D to provide the crude product which was purified by HPLC. with TFA to provide the title compound as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d 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-phenoxy-phenyl) -pyrido [2,3-d] pyrimidin-4-yl-amine -Chloro-2-phenoxy-phenylamine was reacted with the product of Example 57A using the procedure described in Example 57E replacing 5-chloro-2-phenoxy-phenylamine for the product of Example 57D to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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 , 1 HOUR); MS (ESI) + m / z 349 (M + H) +.

Example 155 1-. { 3- [4-Chloro-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxy] -phenyl} -ethanol 1 - [4- (2-Amino-4-chloro-phenoxy) -phenyl] -ethanol was reacted with the product of Example 36E according to the procedure of Example 152C substituting 1 - [4- (2-amino-4 -chloro-phenoxy) -phenyl] -ethanol for the product of Example 152B to give the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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-Ethylsulfanyl-pyrimido [4,5 -d-pyrimidin--lamino) -4-meityl-phenylsulfanyl] -phenol Example 156A 4-Amino-2-ethylsulfanyl-pyrimidine-5-carbonitrile A solution of 2-ethyl-2-thiophosedourea hydrobromide (1.52 g, 8.19 mmol), (Ethoxymethylene) malononitrile (1.0 g, 8.19 mmol) and?,? - diisopropylethylamine (3.57 ml, 20.05 mmol) in ethanol (20 ml) it was stirred at room temperature for 3.5 hours. The resulting solid was collected, washed with ethanol, and dried under vacuum to provide the title compound as a light yellow solid (580 mg, 39%).

Example 156B N '- (5-Cyano-2-ethylsulfanyl-pyrimidin-4-yl) -N, N-dimethyl-formamidine 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 refluxed for 2.5 hours. After cooling to room temperature the solution was concentrated under vacuum to provide the title compound as a colorless solid (260 mg, 100%).

Example 156C 4- [2- (7-Etysulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl) -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. The solution was then allowed to cool to room temperature, the acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (51 mg, 45%). 1 H NMR (300 MHz, DMSO-de) d ppm: 1.38 (t, J = 7.4 Hz, 3 H), 2.30 (s, 3 H), 3.23 (q, J = 7.3 Hz, 2 H), 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 (bs, 1H), 10.85 (s, 1H); MS (ESI) + m / z 422 (M + H) +.

Example 157 (7-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [5-methyl-2- (4-phenoxy-phenylsulfanyl) -phenyl] -amine Example 157A 5-Methyl-2- (4-phenoxy-phenylsulfanyl) -phenol The product of Example 6c (0.500 g, 1.91 mmol) was dissolved in CH2Cl2 together with phenyl boronic acid (0.701 g, 5.74 mmol), copper (II) acetate (0.659 g, 3.83 mmol), and triethylamine (0.387 g, 3.83 mmol). It was stirred at room temperature for 48 hours, at which time 2 more equivalents of each reagent were added. It was stirred at room temperature for another 16 hours, at which time another 2 eq. Of each reagent. It was stirred at room temperature for another 16 hours. The reaction was diluted with water and extracted with ethyl acetate. It was dried over Na2SO4, filtered and concentrated under vacuum to give the crude product, which was purified through silica gel column chromatography eluting with 20% EtOAc / hexane (0.100 g, 15%). The product was reduced with SnCl 2 following the procedure of Example 51 to give the title compound (90 mg, 98%).

Example 157B 7- (ethylthio) -N- (5-methyl-2- (4-phenoxyphenyl) phenyl) pyrimido [4,5-d] pyrimidin-4-amine A solution of the product of Example 156B and the product of Example 157a was reacted according to the procedure of Example 156C substituting the product of Example 157a for the product of Example 6c to provide the crude product which was purified through HPLC with TFA for provide the title compound as a trifluoroacetic acid salt (16 mg, 21%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 1.37 (t, J = 7.35 Hz, 3 H), 2.34 (s, 3 H), 3.22 (q, J = 7.35 Hz, 2 H), 6.82 (m, 2 H) , 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-yl-pyrimido [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 microwave applied (CEM Discover microwave) at 180 ° C for 2 hours. The solution was concentrated under vacuum and the residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (17 mg, 38%). 1 H NMR (300 MHz, DMSO-D6) d ppm: I.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), I.43 (s, 1H); (ESI +) m / z 445 (+ H) +.

EXAMPLE 159 Ester 4- [2- (7-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl-phenyl-2-propan-2-sulfonic acid The product of Example 156C (0.042 g, 0.1 mmol), isopropyl sulfonyl 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 mi) were shaken for 1 hour, emptied to water (20 ml) and extracted with ethyl acetate (3 x 10 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (15 mg, 23%). 1H NR (300 MHz, DMSO-D6) d 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-Acetylamino-benzenesulfonic acid 4- [2- (7-ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl ester The product of Example 156C was reacted with 4-acetylamino-benzenesulfonyl chloride according to the procedure of Example 159 substituting 4-acetylamino-benzenesulfonyl chloride for isopropyl sulfonyl chloride to give the crude product which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (31 mg, 50%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 1.36 (t, J = 7.35 Hz, 3 H), 2.10 (s, 3 H), 2.35 (s, 3 H), 3.20 (q, J = 7.35 Hz, 2 H) , 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 - M e t I - 2 - (7 - m o r f o I i n - 4 - i I - p i r i m i d o [4, 5 - d] p i r i m i d i n - 4 - i a m i n o) - phenylsulfanyl] -phenol A solution of the product of Example 156C in morpholine (1 ml) was microwave applied (CEM Discover microwave) at 180 ° C for 2 hours. The solution was concentrated under vacuum and the residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (29 mg, 65%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.30 (s, 3 H), 3.73 (t, J = 4.41 Hz, 4 H), 3.94 (bs, 4 H), 6.72 (d, J = 8.82 Hz, 2 H) , 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-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl ester of benzenesulfonic acid The product of Example 156C was reacted with benzenesulfonyl chloride according to the procedure of Example 159 substituting benzenesulfonyl chloride for isopropyl sulfonyl chloride to provide the crude product which was purified through HPLC with TFA to give the title compound as a salt of trifluoroacetic acid (27 mg, 48%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 1.36 (t, J = 7.35 Hz, 3 H), 2.36 (s, 3 H), 3.20 (q, J = 7.35 Hz, 2 H), 6.85 (m, 2 H) , 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 (+ H) +.

Example 163 4-Bromo-benzenesulfonic acid 4- [2- (7-ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl ester The product of Example 156C was reacted with 4-bromo-benzenesulfonyl chloride according to the procedure of Example 159 by substituting 4-bromo-benzenesulfonyl chloride for isopropyl sulfonyl chloride to give the crude product which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D 6) d ppm: 1.36 (t, J = 7.35 Hz, 3 H), 2.37 (s, 3 H), 3.20 (q, J = 7.35 Hz, 2 H), 6.87 (m, 2 H) , 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 Ester-butyl ester of (7-ethylsulfanyl-pyrimido [4,5- d] pyrimidin-4-yl) - [2- (4-hydroxy-phenylsul anyl) -5-mephyl-phenyl } -carbám¡co The product of Example 156C was reacted with Carbonate of d i-te r-butyl and triethylamine in tetrahydrofuran at room temperature for 16 hours. Then, the mixture was poured into water (10 mL) and the resulting solution was extracted with ethyl acetate (3 x 10 mL), the combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the compound of the title. 1 H NMR (300 MHz, D SO-D 6) d ppm: 1.52 (t, J = 735 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 p. 165 { 4- [2- (7-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenoxy} -acetonitrile The product of Example 164 (52 mg, 0.1 mmol), bromo-acetonitrile (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 mg). mi) was stirred at room temperature for 2 hours. The mixture was partitioned between water and ethyl acetate. The layer organic was washed with brine, dried (sodium sulfate), filtered and evaporated under vacuum. To the residue was added dichloromethane (2.5 ml) and trifluoroacetic acid (2.5 ml), then stirred at room temperature for 1 hour. The solvent was evaporated under vacuum and the residue was purified by HPLC with TFA to give the title compound (9 mg, 20%). 1H NMR (300 MHz, DMSO-D6) d 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-Benzyloxy-phenylsulfanyl) -5-methylene-phenyl] - (7-ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) -amine The product of Example 164 was reacted with benzyl bromide according to the procedure of Example 165 substituting benzyl bromide for bromo-acetonitrile to give the crude product which was purified through silica gel chromatography using 98/2 dichloromethane / methanol as eluent to provide the title compound (15 mg, 29%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 1.20 (t, J = 7.35 Hz, 3 H), 2.27 (s, 3 H), 3.08 (q, J = 7.35 Hz, 2 H), 5.44 (s, 2 H) , 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- (3-Bromo-benzyloxy) -2- (2-methylsulfanyl-thiazolo [4,5-d] pyrimycin-7-ylamino) -phenylsulfanyl] phenol Example 167A N '- (5-Cyano-2-mephilesulfanyl-thiazol-4-yl) -N, N-dimethyl-formamidine The title compound was prepared from the reaction of 4-amino-2-methylsulfanyl-thiazole-5-carbonitrile with N, N-dimethylformamide dimethyl acetal using the procedure of Example 156B to give the title compound as a foam white (0.132, g, 99%).

Example 167B 4- (4- (3-Bromo-benzyloxy) -2- (2-methylsulfanyl-thiazolo [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) was stirred in a pre-heated oil bath at 140 ° C for 20 minutes. minutes The mixture was cooled and concentrated in v. The resulting residue was then purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (34 mg, 17%). H N R (300 MHz, DMSO-D6) d 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-Bromo-benzyloxy) -2- (2-methylsulfanyl-thiazolo [4,5-d] pyrimidin-7-ylamino) -phenylsulfanyl] -phenol A solution of the product of Example 167A and the product of Example 16A were reacted according to the procedure of Example 167B by substituting the product of Example 16A for the product of Example 15A to provide the crude material that was purified through methanol titration. to provide the title compound as a white solid (46 mg, 27%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.76 (s, 3 H), 5.09 (s, 2 H), 6.70 (d, J = 8.46 Hz, 2 H), 6.91-7.24 (m, 5 H), 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-Meityl-2- (2-methylsulfanyl-thiazolo [4,5-d] pyrimidin-7-ylammon) phenylsulfanyl] -phenol A solution of the product of Example 167A and the product of Example 6c were reacted according to the procedure of Example 167B substituting the product of Example 6c for the product of Example 15A to provide the crude material which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (17 mg, 11%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.27 (s, 3 H), 2.76 (s, 3 H), 6.76 (d, J = 8.46 Hz, 2 H), 6.82 (d, J = 8.09 Hz, 1 H) , 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-Wiethyl-2- (2-methylsulfanyl-thiazolo [4,5-d] pyrimidin-7-ylamino) -phenylsulfanyl] -phenyl} -acetamide A solution of the product of Example 167A and the product of Example 7b were reacted according to the procedure of Example 167B by substituting the product of Example 7b for the product of Example 15A to provide the crude material that was purified through methanol titration. ! to provide the title compound (110 mg, 83%). 1 H NMR (300 MHz, DMSO-D6) d 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-pi) ra [3, 4-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acefamide Example 171 A N '- (2-tert-Butyl-4-cyano-2H-pyrazol-3-yl) -N, N-dimethyl-formamidine The title compound was prepared from the reaction of 5-amino-1-tert-butyl-1H-pyrazole-4-carbonitrile with N, N-dimethylformamide dimethyl acetal using the procedure of Example 156B to provide the title compound.

Example 171 B N-. { 4- [2- (1-tert-Butyl-1 H -pyrazolo [3,4-d] pyrimidin-4-ylammonyl) -4-methylphenylsulfanyl) -phenyl} -acetamide A solution of the product of Example 171A and the product of Example 7b were reacted according to the procedure of Example 167B by substituting the product of Example 7b for the product of Example 15A and substituting the product of Example 171A for the product of Example 167A for provide the crude material which was purified via HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (54 mg, 32%). 1H NR (300 Hz, DMSO-D6) d 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-pyrazolot-3,4-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol A solution of the product of Example 171A and the product of Example 6c were reacted according to the procedure of Example 167B by substituting the product of Example 6c for the product of Example 15A and substituting the product of Example 171A for the product of Example 167A for provide the crude material which was purified via HPLC with TFA to give the title compound as a trifluoroacetic acid salt (40 mg, 25%). 1H NMR (300 MHz, D SO-D6) d 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-lsopropyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol emplo 173A N '- (5-Cyano-2-isopropyl-pyrimidin-4-yl) -N, N-dimethyl-formamidine The title compound was prepared from the reaction of 4-amino-2-isopropyl-pyrimidine-5-carbonitrile with N, N-dimethylformamide dimethyl acetal using the procedure of Example 156B to provide the title compound.

Example 173B 4- [2- (7-lsopropyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methylsulfanyl] -phenol A solution of the product of Example 173A and the product of Example 6c were reacted according to the procedure of Example 167B by substituting the product of Example 6c for the product of Example 15A and substituting the product of Example 173A for the product of Example 167A for provide the crude material which was purified via HPLC with TFA to give the title compound as a trifluoroacetic acid salt (39 mg, 38%). 1 H NMR (300 MHz, DMSO-D 6) d 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, 11-1), 9.76 (s, 1H), 9.90 (s, 1H), 11.13 (s, 1H); MS (ESI +) m / z 404 (M + H) +.

Example 4 4- [4-Benzyloxy-2- (7-isopropyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol A solution of the product of Example 173A and the product, Example 27A were reacted according to the procedure of Example 167B by replacing the product of Example 27A for the product of Example 15A and substituting the product of Example 173A for the product of Example 167A to provide the crude material that was purified by HPLC. with TFA to provide the title compound as a trifluoroacetic acid salt (10 mg, 20%). ?? NMR (300 Hz, DMSOD6) d 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 p. 175 N-. { 4- [2- (7-Ephysulfanyl-5-methylsulfanyl-pyrimido [4,5-d.] Pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide Example 175A N '- (5-Cyano-2-ethylsulfanyl-6-methylsulfanyl-1-methyl-4-yl) -N, N-dimethyl-formamidine The title compound was prepared from the reaction of 4- amino-2-ethylsulfanyl-6-methylsulfanyl-pyrimidine-5-carbonitrile with?,? - dimethylformamide dimethyl acetal using the procedure of Example 156B to provide the title compound.

Example 175B N-. { 4- [2- (7-Ethylsulfanyl-5-methylsulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide A solution of the product of Example 175A and the product of Example 7b was reacted according to the procedure of Example 167B by substituting the product of Example 7b for the product of Example 15A and substituting the product of Example 175A for the product of Example 167A for provide the raw material that was purified through. HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (23 mg, 35%). 1H NMR (300 MHz, DMSO-D6) d 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 4 4- [2- (7-Ethyl sulphonyl-5-methylsulfonyl-pyrimido [4,5-d] pyrimidin-4-ylammon) -4-methyl phenylsulfanyl] phenol A solution of the product of Example 175A and the product of Example 6c were reacted according to the procedure of Example 167B by substituting the product of Example 6c for the product of Example 15A and substituting the product of Example 175A for the product of Example 167A to provide the crude material that was purified by HPLC. with TFA to provide the title compound as a trifluoroacetic acid salt (19 mg, 31%). H NMR (300 MHz, DMSO-D6) d 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 pio 177 N-. { 4- [2- (2-Cyanomethylsulfanyl-thiazolo [4,5-d] pyrimidi n-7-ylamino) -4-meityl-phenylsulfanyl] -phenyl} -acetamide Example 177A N '- (5-Cyano-2-cyanomethylsulfanyl-thiazol-4-yl) -N, N-dimethyl-formamidine The title compound was prepared from the reaction of 4-amino-2-cyanomethylsulfanyl-thiazole-5-carbonitrile with N, N-dimethylformamide dimethyl acetal using the procedure of Example 156B to provide the title compound.

Example 177B N-. { 4- [2- (2-Cyanomethylsulfanyl-thiazolo [4,5-d] pyrimidin-7-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide A solution of the product of Example 177A and the product of Example 7b were reacted according to the procedure of Example 167B by replacing the product of Example 7b for the product of Example 5A and substituting the product of Example 177A for the product of Example 167A to provide the raw material which was purified by HPLC. with TFA to provide the title compound as a trifluoroacetic acid salt (64 mg, 52%). 1H NMR (300 MHz, DMSO-D6) d ppm: 2.03 (s, 3H), 2.30 (s, 3H), 4.54 (s, 2H), 6.95 (d, J = 8.09 Hz, 113), 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); S (ESI +) m / z 479 (+ H) +.

Example 178 { 7- { 2- (4-Hydroxy-phenylsulfanyl) -5-methyl-phenylamino] -thiazolo [4,5- d] pyrimidin-2-ylsulfanyl} -acetonitrile A solution of the product of Example 177A and the product of Example 6c were reacted according to the procedure of Example 167B by substituting the product of Example 6c for the product of Example 15A and substituting the product of Example 177A for the product of Example 167A for provide the crude material which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (62 mg, 56%). H NMR (300 MHz, D SO-D6) d 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-heptafluoropropyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 179A N, - (5-Cyano-2-heptafluoropropyl-pyrimidin-4-yl) -N, N-dimethyl-formamidine The title compound was prepared from the reaction of 4-amino-2-heptafluoropropyl-pyrimidine-5-carbonitrile with N, N-dimethylformamide dimethyl acetal using the procedure of Example 156B to provide the title compound.

Example 179B 4- [4-Benzyloxy-2- (7-heptafluoropropyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol A solution of the product of Example 179A and the product of Example 27A were reacted according to the procedure of Example 167B substituting the product of Example 27 for the product of Example 15A and substituting the product of Example 179A for the product of Example 167A to provide the crude material that was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (24 mg, 39%). H NMR (300 MHz, DMSOD6) d 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-lsopropyl-pyrimido [4,5-d] pyrimidin-4-yl) - [5-methyl-2- (4-phenoxy-phenylsulfanyl) -phenyl] -amine A solution of the product of Example 173A and the product of Example 157a were reacted according to the procedure of Example 167B by replacing the product of Example 157a for the product of Example 15A and substituting the product of Example 173A for the product of Example 167A for provide the crude material which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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, 1 HOUR); MS (ESI +) m / z 480 (M + H) +. 181 (7-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [3- (4-methoxy-phenylsulfanyl) -5-methyl-phenyl] -amine emplo 181 A 1 - (4-Methoxy-phenylsulfanyl) -3-methyl-5-nitrobenzene 4-Metoxy thiophenolate cuprous (0.94 g, 4.63 mmol), which was prepared by refluxing an excess of 4-methoxythiophenol with copper oxide in ethyl alcohol overnight and isolating the desired product through filtration, and -bromo-5-nitrotoluene (1.0 g, 4.63 mmol), prepared in two steps from 3-nitro-4-aminotoluene as described in J. Am. Chem. Soc. Vol. 78, pp. 1992, 1956, they were heated at 165 ° C in a mixture of quinoline (5 ml) and pyridine (1 ml) for 2 hours. After quenching with aqueous HCl, the desired product was isolated through chromatography on silica using ethyl acetate / hexane as eluent to give the title compound (0.96 g, 75%).

Example 181 B 3- (4-Methoxy-phenylsulfanyl) -5-methyl-phenylamine The product of Example 181A was reduced according to procedure of Example 147C substituting the product of Example 181A for the product of Example 147B to provide the title compound.

Example 181 C (7-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [3- (4-methoxy-phenylsulfanyl) -5-methyl-phenyl] -amine The product of Example 181B was reacted with the product of Example 156B according to the procedure of Example 156C substituting the product of Example 181B for the product of Example 6c to provide the crude product which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1 H NMR (500 MHz, DMSO-D 6) d ppm: 1.37 (t, J = 7.32 Hz, 3 H), 2.28 (s, 3 H), 3.21 (q, J = 7.32 Hz, 2 H), 3.79 (s, 3 H) , 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-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [3- (3-methoxy-phenylsulfanyl) -5-methyl-phenyl] -amine EXAMPLE 182A 3- (3-Methoxy-phenylsulfanyl) -5-methyl-phenylamine Cuprous 3-methoxy thiophenolate was reacted with 3-bromo-5-nitrotoluene according to the procedure of Example 181A substituting cuprous 3-methoxy thiophenolate for cuprous 4-methoxy thiophenolate to provide 1- (3-methoxy-phenylsulfanyl) -3- methyl-5-nitro-benzene, which was reduced according to the procedure of Example 181B to provide the title compound.

Example 182B (7-Ethylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) -. { 3- (3-methoxy-phenylsulfanyl) -5-methyl-phenyl] -amine The product of Example 182A was reacted with the product of Example 156B according to the procedure of Example 156C substituting the product of Example 182A for the product of Example 6c to provide the crude product which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, D SO-D6) d ppm: 1.37 (t, J = 7.35 Hz, 3H), 2.33 (s, 3H), 3.21 (q, J = 7. 1 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-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - (5-ethyl-2-phenylsulfanyl-phenyl) -amine Example 183A 5-Ethyl-2-phenylsulfanyl-phenylamine Sodium thiophenolate was reacted with 1-chloro-4-ethyl-2-nitro-benzene according to the procedure of Example 5H substituting 1-chloro-4-ethyl-2-nitro-benzene for 4-chloro-3-nitrotoluene to provide 4-ethyl-2-n-nitro-1-phenylsulfanyl-benzene, which was reduced according to the procedure of Example 51 to provide the title compound.

Example 183B 4-Amino-2-benzyl sulfanyl-pyrimidine-5-carbonitrile A solution of 2-benzyl-2-thiopsuedourea hydrochloride (5.0 g, 24.67 mmol), (Etoxymethylene) malononitrile (3.01 g, 24.67 mmol) and N, N-diisopropylethylamine (10.75 ml, 61.68 mmol) in ethanol (50 ml) it was stirred at room temperature for 18 hours. The resulting solid was collected, washed with ethanol, and dried under vacuum to provide the title compound (2.69 g, 45%).

Example 183C N '- (2-Benzylsulfanyl-5-cyano-pyrimidin-4-yl) -N, N-dimethyl-formamidine A solution of the product of Example 183B was reacted with?,? - dimethylformamide dimethyl acetal according to the procedure of Example 156B substituting the product of Example 183B for the product of Example 156B to provide the title compound.

Example 183D (7-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - (5-ethyl-2-phenylsulfanyl-phenyl) -amine The product of Example 183A was reacted with the product of Example 183C according to the procedure of Example 156C by substituting the product of Example 183A for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which 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-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [2- (4-methoxy-phenylsulfanyl) -5-methyl-phenyl] -amine The product of Example 183C was reacted with 2- (4-ethoxy-phenylsulfanyl) -5-methyl-phenylamine (Example 118) according to the procedure of Example 156C substituting 2- (4-methoxy-phenylsulfanyl) -5-methyl phenylamine for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. MS (ESI +) m / z 498 (M + H) +.

Example 185 (7-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - (5-fluoro-2-phenylsulfanyl-phenyl) -amine Example 185A 5-Fluoro-2-phenylsulfanyl-phenylamines 4-Fluoro-2-nitrophenol was reacted according to procedures similar to those described in Examples 6a, 6b, and 6c substituting benzenethiol for 4-mercaptophenol and 4-fluoro-2-nitrophenol for 4-methyl-2-nitro phenol to provide the title compound.

Example 185B (7-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - (5-fluoro-2-phenylsulfanyl phenyl) -amine The product of Example 185A was reacted with the product of Example 203A according to the procedure of Example 156C substituting the product of Example 203A for the product of Example 6c and substituting the product of Example 185A for the product of Example 156B to provide the crude product which 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-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [2- (4-fluoro-phenylsulfanyl) -5-methyl-phenyl] -amine The product of Example 183C was reacted with 2- (4-fluoro-phenylsulfanyl) -5-methyl-phenylamine (Example 124) according to the procedure of Example 156C substituting 2- (4-fluoro-phenylsulfanyl) -5-methyl-phenylamine for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. MS (ESI +) m / z 486 (M + H) +.

Example 187 (7-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - (5-methyl-2-m-tolylsulfanyl-phenyl) -amine The product of Example 183C was reacted with 5-methyl-2-m-tolylsulfanyl-phenylamine according to the procedure of Example 156C substituting 5-methyl-2-m-tolylsulfanyl-phenyl amine for the product of Example 6c and substituting the Product of Example 183C for the product of Example 156B to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. MS (ESI +) m / z 482 (M + H) +.

Example 188 (7-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine The product of Example 183C was reacted with the product of Example 51 according to the procedure of Example 156C substituting the product of Example 51 for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which 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-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-ylamino) -4-meitylphenylsulfanylj-phenol The product of Example 183C was reacted with 3- (2-amino-4-methyl-phenylsulfanyl) -phenol (Example 129) according to the procedure of Example 156C substituting 3 (2-am ino-4-methyl-phenylsulfanyl) phenol for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to give the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. MS (ESI +) m / z 484 (M + H) +.

Example 190 (7-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [3- (3-meioxy-phenylsulfanyl) -5-methyl-phenyl] -amine The product of Example 183C was reacted with the product of Example 182A according to the procedure of Example 156C substituting the product of Example 182A for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [3- (4-methoxy-phenylsulfanyl) -5-methyl-phenyl] -amine The product of Example 183C was reacted with the product of Example 181B according to the procedure of Example 156C substituting the product of Example 181B for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.28 (s, 3 H), 3.79 (s, 3 H), 4.52 (s, 2 H), 6.83 (s, 1 H), 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-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - [2- (4-methoxy-phenoxy) -5-methyl-phenyl] -amine product of Example 183C was reacted with product of Example 116B according to the procedure of Example 156C substituting the product of Example 116B for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. MS (ESI +) m / z 482 (M + H) +.

Example 193 (7-Benzylsulfanyl-pyrimido [4,5-d] pyrimidin-4-yl) - (5-methyl-2-p-tolylsulfanyl-phenyl) -amine The product of Example 183C was reacted with 5-methyl-2-p-tolylsulfanyl-phenylamine according to the procedure of Example 156C substituting 5-methyl-2-p-tolylsulfanylphenylamine for the product of Example 6c and substituting the product of Example 183C for the product of Example 156B to provide the crude product which was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt. MS (ESI +) m / z 482 (M + H) +.

Example 194 4- [4- (3-Bromo-benzylKi) -2- (pyrimido [4,5-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 194A N '- (5-Cyano-pyridin-4-yl) -N, N-dimethyl-formamidine The title compound was prepared from the reaction of 4-amino-5-pyrimidinecarbonitrile (Aldrich) with N, N-dimethylformamide dimethyl acetal using the procedure of Example 156B to provide the title compound.

Example 194B 444 { 3-Bromo-benzyloxy) -2- (pyrimido [4,5-d] pyrimidin-4-ylamino) - phenylsulfanylj-phenol The product of Example 194A was reacted with the product of Example 15A according to the procedure of Example 156C by substituting the product of Example 15A for the product of Example 6c and substituting the product of Example 194A for the product of Example 156B to provide the crude product which was purified by HPLC with NH4OAc to provide the title compound. 1 H NMR (300 MHz, DMSO-D 6) d ppm: 5.12 (s, 2 H), 6.64 (d, J = 8.82 Hz, 2 H), 6.93-7.04 (m, 1 H), 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 , 1 HOUR); 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 according to the procedure of Example 156C substituting the product of Example 27A for the product of Example 6c and substituting the product of Example 194A for the product of Example 156B to provide the crude product which was purified by HPLC with NH4OAc to provide the title compound. 1 H NMR (300 MHz, DMSO-D 6) d ppm: 5.10 (s, 2 H), 6.63 (d, J = 8.46 Hz, 2 H), 6.94-7.05 (m, 1 H), 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, 113), 9.92 (s, 1H), 10.66 (s, 113 ); MS (ESI-) m / z 452 (M-H) -.

Example 196 (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-yl) - [3- (4-meioxy-phenylsulfanyl) -5-methyl-phenyl] -amine The product of Example 181B was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 181B for the product of Example 36H to provide the crude material which was purified through HPLC with TFA to give the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, DMSO-D6) d ppm: 1.33 (d, J = 6.71 Hz, 6H), 2.29 (s, 3H) 3.25 (qq, 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, 213), 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-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -5-methyl-phenylsulfanyl] -phenol Example 197A 4- (3-Amino-5-methyl-phenylsulfanyl) -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 provide the title compound.

Example 197B 4- [3- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -5-methyl-phenylsulfanylj-phenol The product of Example 197A was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 197A for the product of Example 36H to provide the crude material that was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d ppm: 1.35 (s, 3H), 1.33 (s, 3H), 2.28 (s, 3H), 3.27 (qq, 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-Fluoro-benzyloxy) -2- (4-hydroxy-phenylsulfanyl) -phenylamino] -7-methyl-pyrido [2,3-d] pyrimidine-6-carbonitrile Example 198A N '- (3,5-Dithiane-6-methyl-pyridin-2-yl) -N, N-dimethyl-formamidine A solution of 2-Amino-6-methyl-pyridine-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 to reflux for 6 hours. After cooling to room temperature, the solution was concentrated under vacuum to provide the title compound as a brown solid (0.2 g, 94%).

Example 198B 4- [5- (3-Fluoro-benzyloxy) -2- (4-hydroxy-phenylsulfanyl) -phenylamino] -7-methyl-pyrido [2,3-d] pyrimidine-6-carbonitrile The product of Example 198A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 198A for the product of Example 10E to provide the crude material which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (18 mg, 29%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.82 (s, 3 H), 5.13 (s, 2 H), 6.64 (d, J = 8.46 Hz, 2 H), 6.99 (d, J = 9.56 Hz, 1 H) , 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-Fluoro-benzyloxy) -phenyl] - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) - am i na Example 199A (3-Fluoro-benzyloxy) -3-nitro-benzene A solution of 3-nitro-phenol (0.278 g, 2.0 mmol), 1-bromomethyl-3-fluoro-benzene (0.258 mL, 2.1 mmol), potassium carbonate (0.553 g, 4.0 mmol) and tetrabutylammonium iodide (0.001 g) ) 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 resulting solid was collected through filtration and dried in a vacuum oven to provide the title compound in a quantitative yield.

Example 199B (3-Fluoro-benzyloxy) -3-amino-benzene A solution of the product of 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 methanol (20 mL), tetrahydrofuran (20 mL), and Water solution (10 mL) was heated to reflux for 2 hours. The resulting mixture was filtered through a pad of celite, and the filtrate was concentrated. After ethyl acetate was added, stirred for 30 minutes, it was filtered and concentrated under vacuum to provide the title compound (0.405 g, 93%).

Example 199C [3- (3-Fluoro-benzyloxy) -phenyl] - (7-methyl-pyrido [2,3-d] pyrimidin-4-amine The product of Example 199B was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 199B for the product of Example 10E to provide the crude material which was purified by HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (32 mg, 89%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.74 (s, 3 H), 5.18 (s, 2 H), 6.98 (m, 1 H), 7.18 (m, 1 H), 7.42 (m, 6 H), 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-Fluoro-benzyloxy) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -amine The product of Example 199B was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 199B for the product of Example 36H to provide the crude material that was purified to HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d 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), 8.8 (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-Fluoro-benzyloxy) -phenyl] -pyrido [2,3-d] pyrimidin-4-yl-amine The product of Example 199B was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 199B for the product of Example 57D to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d 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-Fluoro-benzyloxy) -phenyl] -pyrido [2,3-d] pyrimidin-4-yl-amine Example 202A 3- (4-Fluoro-benzyloxy) -phenylamine 3-Nitro-phenol was reacted with 1-bromomethyl-4-f luoro- Benzene according to the procedure of Example 199A substituting 1-bromomethyl-4-fluoro-benzene for 1-bromomethyl-3-f luoro-benzene was then reduced according to the procedure of Example 199B to provide the title compound.

Example 202B [3- (4-Fluoro-benzyloxy) -phenyl] -pyrido [2,3-d] pyrimidin-4-yl-amine The product of Example 202A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 202A for the product of Example 57D to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (20 mg, 58%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 5.13 (s, 2 H), 6.92 (m, 1 H), 7.24 (m, 2 H), 7.38 (m, 2 H), 7.55 (m, 3 H), 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) , 1 HOUR); MS (ESI +) m / z 347 (M + H) +.

Example 203 [3- (3,5-Difluoro-benzyloxy) -phenyl] - (7-isopropyl-pyrido [2,3-d] -pyrimidin-4-yl) -amine Example 203A 3- (3,5-Difluoro-benzyloxy) -phenylamine 3-n -itrophenol was reacted with 1-bromomethyl-3,5-difluoro-benzene according to the procedure of Example 199A substituting 1-bromomethyl-3,5-difluoro-benzene for 1-bromomethyl-3-fluorobenzene after was reduced according to the procedure of Example 199B to provide the title compound.

Example 203B [3- (3,5-Difluoro-benzyloxy) -phenyl] - (7-isopropyl-pyrido [2,3-d] -pyrimidin-4-yl) -amine The product of Example 203A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 203A for the product of Example 36H to provide the crude material that was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (26 mg, 67%). 1 H NMR (300 MHz, DMSO-D 6) d 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, 1 H); MS (ESI +) m / z 407 (M + H) +.

Example 204 [3- (3,5-Difluoro-benzyl i) -phenyl] - (7-methyl-pyrido [2,3-d] pyrimidn-4-yl) -na na The product of Example 203A was reacted with the product of Example 1013 using the procedure of Example 10F substituting the product of Example 203A for the product of Example 10E to provide the crude material which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d 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, S = 8.46 Hz, 1H), 8.87 (s, 1H), 8.98 (d, S = 8.46 Hz, 1H), 10.90 (s, 1H); MS (ESI +) m / z 379 (M + H) +.

Example 205 [3- (3,5-Difluoro-benzyloxy) -phenyl] -pyrido [2,3-d] pyrimidin-4-yl-amine The product of Example 203A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 203A for the product of Example 57D to provide the crude title compound which was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d ppm: 5.19 (s, 2H), 6.94 (m, 1H), 7.21 (m, 3H), 7.39 (d, 5 = 5.15 Hz, 2H), 7.58 (s, 1H), 7.81 (dd, S = 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-Methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxymethyl] -benzonitrile Example 206A 4- (3-Amino-phenoxymethyl) -benzonitrile 3-Nitro-phenol was reacted with 4-bromomethyl-benzonitrile according to the procedure of Example 199A substituting 4-bromomethyl-benzonitrile for 1-bromomethyl-3-fluorobenzene then reduced according to the procedure of Example 199B to provide the composed of the title.

Example 206B 4- [3- (7-Methyl-pyrido [2,3-d] pirlmidin-4-ylamino) -phenoxymethyl] -benzonitrile The product of Example 206A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 206A for the product of Example 10E to provide the crude material which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.71 (s, 3 H), 5.27 (s, 2 H), 6.92 (m, 1 H), 7.38 (m, 2 H), 7.59 (s, 1 H), 7.68 ( m, 3H), 7.89 (d, S = 8.46 Hz, 2H), 8.83 (s, 1H), 8.95 (d, J = 8.82 Hz, 1 H), 10.64 (s, 1 H); S (ESI +) m / z 368 (+ 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 using the procedure of Example 57E substituting the product of Example 206A for the product of Example 57D to provide the crude title compound that was purified through HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D 6) d ppm: 5.27 (s, 2 H), 6.93 (m, 1 H), 7.38 (m, 2 H) 7.60 (s, 1 H), 7.67 (d, J = 8.46 Hz , 2H), 7.80 (dd, J = 8.46, 4.41 Hz, 1 H), 7.90 (d, J = 8.46 Hz, 2H), 8.86 (s, 1 H), 9.07 (dd, J = 8.46, 1.65 Hz, 1 H), 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-lsopropyl-pyrido [2,3-d] pyrimidin-4-amino) -phenoxymethyl] -benzonitrile Example 208A 3- (3-Amino-phenoxymethyl) -benzonitrile 3-Nitro-phenol was reacted with 3-bromomethyl-benzonitrile according to the procedure of Example 199A substituting 3- Bromomethyl-benzonitrile for 1-bromomethyl-3-fluorobenzene was then reduced according to the procedure of Example 199B to provide the title compound.

Example 208B 3- [3- (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-ylammon) -phenoxymethyl) -benzonitrile The product of Example 208A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 208A for the product of Example 3611 to provide the crude material that was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (22 mg, 56%). 1H NMR (300 MHz, DMSO-D6) d 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-amino) -phenoxymethyl] -benzonitrile Example 209A 2- (3-Amino-phenoxymethyl) -benzonitrile 3-Nitro-phenol was reacted with 2-bromomethyl-benzonitrile according to the procedure of Example 199A substituting 2-bromomethyl-benzonitrile for 1-bromomethyl-3-fluorobenzene was then reduced according to the procedure of Example 199B to provide 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 using the procedure of Example 361 substituting the product of Example 209A for the product of Example 36H to provide the crude material which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d ppm: 5.30 (s, 2H), 7.02 (m, 1H), 7.42 (m, 2H), 7.59 (m, 2H), 7.78 (m, 2H), 7.85 (m, 1H), 7.42 (m, 2H), 7.85 (m, 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-Benzyl) -phenyl] - (7-isopropyl-pyrid [2,3-d] pyrimidin-4-yl) -amine Example 210A 3-Benzyloxy-phenylamine 3-Nitro-phenol was reacted with bromomethyl-benzene according to the procedure of Example 199A substituting bromomethyl-benzene for 1-bromomethyl-3-fluoro-benzene was then reduced according to the procedure of Example 199B to provide the title compound.

Example 21 OB (3-Benzyloxy-phenyl) - (7-isopropyl-pyrid [2,3-d] pyrimidin-4-yl) -amine The product of Example 210A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 210A for the product of Example 36H to provide the crude material which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (5 mg, 10%). 1 H NMR (500 MHz, DMSO-D 6) d 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-Bromo-benzyloxy) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 211 A 3- (3-B romo-be nc i loxi) -fen i lamina 3-Nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene according to the procedure of Example 199A substituting 1-bromo-3-bromomethyl-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure of Example 199B to provide the title compound.

Example 211 B [3- (3-Bromo-benzyloxy) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -amine The product of Example 211A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 211A for the product of Example 36H to provide the crude material which was purified through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (1 mg, 1%). H NMR (300 Hz, DMSO-D6) d 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, 1 H), 7.80 (d, J = 8.46 Hz, 1 H), 8.86 (s, 1 H), 9.01 (d, J = 8.46 Hz, 1 H), 10.84 (s, 1 H); MS ESI + m / z 451 (M + H) +, EST-m / z 449 (M-H) -.

Example 212 (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-yl) - [3- (3-methoxy-benzyloxy) -phenyl] -amine EXAMPLE 212A 3- (3-Methoxy-benzyloxy) -phenylamine 3-Nitro-phenol was reacted with 1-bromomethyl-3-methoxy-benzene according to the procedure of Example 199A substituting 1-bromomethyl-3-methoxy-benzene for 1-bromomethyl-3-f luoro-benzene then reduced according to the procedure of Example 199B to provide the title compound.

Example 212B (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) - [3- (3-methoxy-benzyloxy) -phenyl] -amine The product of Example 212A was reacted with the product of Example 36E using the procedure of Example 36I substituting the product of Example 212A for the product of Example 36H to provide the crude material which was puri through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt (8 mg, 9%). 1H NMR (300 MHz, DMSO-D6) d 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-Bromo-benzyloxy) phenyl] pyrido [2,3-d] pyrimidin-4-yl-amine Example 213A 3- (4-Bromo-benzyloxy) -phenylamine 3-Nitro-phenol was reacted with 1-bromo-4-bromomethyl-benzene according to the procedure of Example 199A substituting 1-bromo-4-bromomethyl-benzene for 1-bromomethyl-3-f luoro-benzene then reduced according to the procedure of Example 199B to provide the title compound.

Example 213B [3- (4-Bromo-benzyloxy) -phenyl] -pyrido [2,3-d] pyrimidin-4-yl-amine The product of Example 213A was reacted with the product of Example 36E using the procedure of Example 361 substituting the product of Example 213A for the product of Example 36H to provide the crude material that was puri through HPLC with TFA to provide the compound of the title as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D6) d ppm: 5.13 (s, 2H), 6.82 (dd, J = 8.09, 1.84 Hz, 1H), 7.32 (t, J = 8.09 Hz, 1 H), 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, 1 H), 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 21 [2- (4-Amino-phenylsulfanyl) -5-benzyloxy-phenyl] - (7-methyl-pyrido [2,3-d] -pyrimidin-4-yl) -amine Example 214A 4-Benzyloxy-1-chloro-2-nitro-benzene A solution of 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromomethyl-benzene (2.01 g, 11.5 mmol), potassium carbonate (1.65 g, 12.0 mmol) and tetrabutylammonium iodide (0.005 g) , 0.0135 mmole) 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 resulting solid was collected through filtration and dried in a vacuum oven to provide the title compound (3.0 g, 99%).

Example 214B 4- (4-Benzyloxy-2-nitro-phenylsulfanyl) -phenylamine A solution of the compound prepared 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) was heated at 40 ° C for 16 hours. Then, ice water (50 ml) was added to the solution and the resulting slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (1.1 g, 83%).

Example 214C [4- (4-Benzyloxy-2-nitro-phenylsulfanyl) -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 to reflux for hours. The next day, the solvent was removed under vacuum leaving the title compound as a light tan colored oil (1.4 g, 100%).

Example 214D [4- (2-Amino-4-benzyloxy-phenylsulfanyl) -phenyl-carbamic acid tert-butyl ester] A solution of the product of Example 214C (1.4 g, 3.09 mmoles), iron powder (0.70 g, 12 mmol) and ammonium chloride (0.18 g, 3.41 mmol) in methanol (10 ml), tetrahydrofuran (10 mL), and water solution (5 mL) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.1 g, 90%).

Example 214E [2- (4-Amino-phenylsulfanyl) -5-benzyloxy-phenyl] - (7-methyl-pyrido [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) was stirred in a preheated oil bath at 130 ° C for 10 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, 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 under vacuum and the resulting 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) d 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-Amino-phenylsulfanyl) -5-benzyloxy-phene] - (7-isopropyl-pyrido [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 a pre-heated oil bath at 130 ° C for 10 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum 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 under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (22 mg, 10%). 1H NMR (300 MHz, DMSO-D6) d 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, 1 H), 11.64 (s, 2H) ).

Example 216 [2- (4-Amino-phenylsulfanyl) -5- (1-phenyl-ethoxy) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 216A 1-Chloro-2-nitro-4- (1-phenyl-ethoxy) -benzene A solution of 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromoethyl-benzene (3.2 g, 17.3 mmol), sodium carbonate (1.80 g, 17.0 mmol) in acetone (20 mL) was added. heated to reflux for 18 hours. The reaction mixture was cooled, the solids were filtered and the filtrate was concentrated to a thick syrup under vacuum. The residue was dissolved in ether (80 mL) and washed with water (20 mL) and a solution of 30% KOH (2 X 20 mL) and the solvent was concentrated under vacuum leaving an oily residue as the title compound (3.01 g, 94%).

Example 216B 4 - [2-Ithro-4- (1-phenyl-ethoxy) -phenylsulfanyl] -pheni sheet 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) was heated at 40 ° C for 16 h. hours. Then ice-water (50 ml) was added to the solution and the resulting slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (2.35 g, 92%).

Example 216C Tert-butyl ester of acid. { 4-. { 2-N itro-4- (1-phenyl-ethoxy) -phenylsulfanyl] -phenyl} -carbamic 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 to reflux for 18 hours. The next day, the solvent was removed under vacuum leaving the title compound as a light tan colored oil (1.78 g, 60%).

Example 216D Ter-butyl acid ester. { 4-. { 2-amino-4- (1-phenyl] -ethoxy) -phenylsulfanyl] -phenyl} -carbamic 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 (10 mL), tetrahydrofuran (10 mL), and The water solution (5 ml) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a ml volume, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.53 g, 32%).

Example 216E [2- (4-Amino-phenylsulfanyl) -5- (1-phenyl-ethoxy) -phenyl] - (7-isopropyl-pyrid [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) was stirred in a pre-heated oil bath at 130 ° C for 10 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum 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 under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (18 mg, 11%). H NMR (300 MHz, DMSO-D6) d 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, 31), 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., 'Hi), 8.94 (s, 1H), 11.19 (s, 1H).

Example 217 [2- (2-Amino-6-chloro-pyrimidin-4-ylsulfanyl) -5-benzyloxy-phenyl] - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 217A 4-Benzyloxy-2-nitro-phen i lamina A solution containing 4-amino-3-nitro phenol (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. The reaction was complete, the reaction mixture was poured into ice-water (500 ml), stirred 1 hour, and the resulting solid was filtered and dried under vacuum to provide the title compound (1.1 9, 64%).

Example 217B 4-Benzyloxy-2-nitrobenzene-diazonium tetrafluoroborate The product of Example 217A (0.5 g, 2.05 mmol) was dissolved in THF (10 mL) and added dropwise to a cold solution (-20 ° C) containing boron trifluoride etherate (1.1 mL, 8.20 mmol), and tert-butyl nitrite (0.6 ml, 4.92 mmol) over a period of 5 minutes. The resulting mixture was stirred for 10 minutes at -20 ° C, then 2 hours at 10 ° C. The reaction mixture was then poured into hexane (100 ml) and the solid was filtered, washed with ether and dried under vacuum to provide the title compound (0.61 g, 87%).

Example 217C 4- (4-Benzyloxy-2-nitro-phenylsulfanyl) -6-chloro-pyrimidin-2-i lamina A solution of the product from Example 217B (0.1 g, 0.290 mmol) in dimethyl sulfoxide (1 mL) was added dropwise to a solution containing potassium thioacetate (0.04 g, 0.350 mmol) in dimethyl sulfoxide (1 mL). The reaction mixture immediately began to bubble. The mixture was stirred 90 minutes at room temperature when the bubbling stopped. The resulting dark green mixture was then treated with a solution of 3M aqueous potassium hydroxide (0.1 ml) and stirred an additional 80 minutes, then solid 4,6-dichloro-2-aminopyrimidine was added and the mixture was stirred an additional 60 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL), 10% sodium bicarbonate and 10% sodium chloride, dried over sodium sulfate, filtered and the solvent removed. under vacuum to provide a tan solid as the title compound (0.1 g, 88%).

Example 217D 4- (2-Amino-4-benzyloxy-phenylsulfanyl) -6-chloro-pyrimidin-2-ylamine A solution of the product of Example 217C (0.1 g, 0.257 mmole), iron powder (0.058 g, 1.03 mmole) and ammonium chloride (0.017 g, 0.310 mmol) in methanol (5 mL), tetrahydrofuran (5 mL), and water solution (2 mL) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.04 g, 43%).

Example 217E [2- (2-Amino-6-chloro-pyrimidin-4-ylsulfanyl) -5-benzyloxy-phenyl] - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) )-amine A solution of the prt of Example 10B (21 mg, 0.112 mmol), and the prt of Example 217D (40 mg, 0.112 mmol) in acetic acid (1 mL) was stirred in a pre-heated oil bath at 130 ° C for 10 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, 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 under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (5 mg, 7%). 1H NMR (300 MHz, DMSO-D6) d 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-Bromo-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxy] -phenol Example 218A 4- [4- (3-Bromo-benzyloxy) -2-nitro-phenoxy] -phenol A solution of hydroquinone (276.4 mg, 2.510 mmol) in anhydrous (3.64 mmol) was heated under a nitrogen atmosphere at 120 ° for 30 minutes. A solution of 4- (3-bromo-benzyloxy) -1-chloro-2-nitro-benzene (from Example 15A) (774 mg, 2259 mmol) in dimethyl sulfoxide (4 mL) was added dropwise from an addition funnel over a period of 30 minutes at 120 °, the mixture was then stirred at this temperature for 1 hour. The reaction was cooled in an ice bath, then emptied into ice-water (20 mL) and the pH was adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl ether (3 x 100 mL), the combined ether extracts were washed with water (3 x 100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated through of rotary evaporation under vacuum. The purification of the residue through vaporization chromatography Flash silica gel using 3% ethyl acetate / methylene chloride as eluent afforded the title compound as a dark yellow solid (386 mg, 0.927 mmol, 41%).

Example 218B 4- [2-Amino-4- (3-bromo-benzyloxy) -phenoxy] -phenol A mixture of the prt 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) were added. heated to 70 ° under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and filtered under vacuum, washing the residue with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified via flash chromatography on silica gel using a gradient of 7% to 10% ethyl acetate / methylene chloride as eluent to give the title compound as a beige solid (272 mg, 0.704 mmol, 76%).

Example 218C 4- [4- (3-Bromo-benzyl) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxy] -phenol A solution of the prt of Example 36E (25 mg, 0.116 mmoles) and the prt of Example 218B (44.6 mg, 0.116 mmol) in acetic acid (1 ml) was stirred in a preheated oil bath at 140 ° C for 1 hour. The reaction was cooled to room temperature, diluted with hexanes (50 mL), concentrated through rotary evaporation, and co-evaporated with methylene chloride / hexanes (4x). The residue was dried under high vacuum overnight, then purified through flash chromatography on silica gel using 3% methanol / methylene chloride as eluent to give the title compound as a light yellow solid (34 mg, 0.0613 mmoles, 53%). 1 H NMR (300 MHz, DMSO-D 6) d 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-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenoxy] -phenol Example 219A 4- [2-Amino-4- (4-bromo-benzyloxy) -phenoxy] -phenol 4- (4-Bromo-benzyloxy) -1-chloro-2-nitro-benzene (from Example 16A) was reacted with hydroquinone in accordance with procedure of Example 39A and reduced according to the procedure of Example 39B to provide the title product.

Example 219B 4- [4- (4-Bromo-benzyloxy) -2- (7-isopropyl-pyrid [2,3-d] pyrimidin-4-ylamino) phenoxy] -phenol The product of Example 219A was reacted with the product of Example 36E according to the procedure of Example 39C substituting the product of Example 219A for the product of Example 218B to provide the title compound followed by silica gel chromatography (38 mg, 59%). 1 H NMR (300 MHz, DMSO-D6) d ppm: 1.30 (d, J = 6.99 Hz, 6H), 3.10-3.27 (m, 1 H), 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, 1 H), 7.43 (d, J = 8.46 Hz, 2H), 7.53 (d, J) = 8.46 Hz, 1 H), 7.60 (d, J = 8.46 Hz, 2H), 8.57 (s, 1 H), 8.72 (d, J = 8.46 Hz, 1 H), 9.14 (s, 1 H), 9.74 (s, 1 H); MS (ESI +) m / z 557/559 (M + H) +.

Example 220 4- [4-Benzyloxy-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylammon) -phenoxy-phenol emplo 220A 4- (2-Amino-4-benzyloxy-phenoxy) -phenol 4-Benzyloxy-1-chloro-2-nitro-benzene (from Example 27A) was reacted with hydroquinone according to the procedure of Example 39A and reduced according to the procedure of Example 39B to provide the title product.

Example 220B 4- [4-Benzyloxy-2- (7-isopropyl-pyrid [2,3-d] pyrimid-4-amino) phenoxy] -phenol The product of Example 220A was reacted with the product of Example 36E according to the procedure of Example 39C substituting the product of Example 220A for the product of Example 218B to provide the title compound followed by silica gel chromatography (58 mg, 65%). 1 H NMR (300 MHz, DMSO-D 6) d 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 / NH3) m / z 479 (M + H) +.

Example 221 4- [4-Benzyloxy-2- (7-ethyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 27A was reacted with the product of Example 145A using the procedure of Example 10F substituting the product of Example 27A for the product of Example 10E and substituting the product of Example 145A for the product of Example 10B to provide the title product. 1H NMR (300 MHz, D SO-D6) d ppm: 1.32 (t, = 1.12 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, 1 H), 7.10 (d, J = 8.46 Hz, 2H), 7.32-7.50 (m, 6H), 8.12 (d, J = 6.99 Hz, 1 H) , 8.66-8.77 (m, 1 H), 9.04 (d, J = 8.82 Hz, 1 H), 9.63 (s, 1H), 10.28 (s, 1H); MS (APCI) m / z 481 (M + H) +.

Example 222 4- [4-Benzyloxy-2- (7-cyclohexyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 27A was reacted with the product of Example 135A using the procedure of Example 10F substituting the product of Example 27A for the product of Example 10E and substituting the product of Example 135A for the product of Example 10B to provide the product of Title. H NMR (300 MHz, DMSO-D6) d ppm: 1.23-1.51 (m, 4H), 1.53-1.79 (m, 4H), 1.80-2.00 (m, 2H), 2.77-3.02 (m, 1 H), 5.10 (s, 2H), 6.67 (d, J = 8.46 Hz, 2H), 6.88-7.01 (m, 1 H), 7.11 (d, J = 8.82 Hz, 2H), 7.22-7.31 (m, 1 H) , 7.32-7.49 (m, 6H), 7.56 (d, J = 7.72 Hz, 1H), 8.55 (s, 1 H), 8.73 (d, J = 8.09 Hz, 1H), 9.94 (s, 1 H); MS (APCI) m / z 535 (M + H) +.

Example 223 4-. { 4-Benzyloxy-2- (7-sec-butyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 27A was reacted with the product of Example 140A using the procedure of Example 10F by substituting the product of Example 27A for the product of Example 10E and substituting the product of Example 140A for the product of Example 10B to provide the product of Title. 1H NMR (300 MHz, DMSO-D6) d 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, 1 H) , 2.89-3.08 (m, .1 H), 5.11 (s, 2H), 6.67 (d, J = 8.82 Hz, 2H), 6.85-7.03 (m, 1 H), 7.11 (d, J = 8.46 Hz, 2H), 7.30-7.50 (m, 6H), 7.56 (d, J = 8.82 Hz, 1 H), 8.56 (s, 1 H), 8.75 (d, J = 8.46 Hz, 1 H), 9.64 (s, 1 H), 9.95 (s, 1 H); MS (APCI) m / z Example 224 4- [4- (2-Chloro-thiazol-5-ylmethoxy) -2- (7-isopropyl-pyrido [2,3-d] -pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 224A 4- [2-Amino-4- (2-chloro-thiazol-5-ylmethoxy) -phenylsulfanyl] -phenol The title compound was prepared as described in Example 16A by replacing benzyl bromide with 2-chloro-5- bromomethyl thiazole to provide the title compound (0.38 g, 64%).

Example 224b 4- [4- (2-Chloro-thiazol-5-ylmethoxy) -2- (7-isopropyl-pyrido [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 a pre-heated oil bath at 130 ° C to 10 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (31 mg, 30%). H NMR (300 MHz, DMSO-d6) d 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, 1 HOUR); MS (ESI +) m / z 536 (M + H) +, (ESI-) m / z 534 (M-H) -.

Example 225 4- [4- (6-Chloro-pyridin-2-ylmethoxy) -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol 225a emplo 4- [2-Amino-4- (6-chloro-pyridin-2-ylmethoxy) -phenylsulfanyl] -phenol The title compound was prepared as described in Example 16A by substituting benzyl bromide with 2-chloro-5-bromomethyl-pyridine to give the title compound (0.63 g, 73%).

Example 225b 4- [4- (6-Chloro-pyridin-2-ylmethoxy) -2- (7-methyl-pyrido [2,3-d] pyrimid-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 a pre-heated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (20 mg, 20%). 1 H NMR (300 Hz, DMSO-d 6) d ppm: 2.70 (s, 3 H) 5.18 (s, 2 H) 6.65 (d, J = 8.82 Hz, 2 H) 7.02 (d, J = 8.09 Hz, 1 H) 7.11 (d , J = 8.82 Hz, 2H) 7.19 (d, J = 8.82 Hz, 1H) 7.25 (s, 1 H) 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-Chloro-pyridin-2-ylmethoxy) -2- (7-isopropyl-pyrido [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 a preheated oil bath at 130 ° C for 10 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (31 mg, 30%). 1 H NMR (300 Hz, DMSO-d 6) d ppm: 1.16 (d, J = 6.99 Hz, 3 H) 1.36 (d, J = 6.62 Hz, 3 H) 3.20-3.40 (m, 1 H) 5.18 (s, 1 H) 6.55 (d, J = 7.72 Hz, 1 H) 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, 1 H) 7.93 (t, J = 7.72 Hz, 2H) 8.82 (s, 1 H) 8.97 (s, 1 H) 9.72 (s, 1 H) 11.66 (s, 1 H); MS (ESI +) m / z 530 (M + H) +, (ESI-) m / z 528 (M-H) -.

Example 227 4- [2- (7-tert-Butyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4- (3-fluoro-benzyloxy) -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 the glacial acetic acid was heated at 120 ° C for 13 minutes. It was cooled to room temperature and the acetic acid was removed under vacuum. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (134 mg, 44%). H NMR (300 MHz, D SO-d6) d 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) +; (EST-) m / z, 525 (M-H-TFA) -.

Example 228 4- [4- [1- (3-Bromo-phenyl) -ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 228a 1 - (1 -B rom o -eti I) -4-f I or gold-benzene To a solution of 1- (3-bromo-phenyl) -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 was emptied to 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 under vacuum to give the title compound (7.8 g, 80%).

Example 228b 4- [1- (3-Bromo-phenyl) -ethoxy] -1-chloro-2-nitro-benzene To Example 228a (7.8 g, 30 mmol) in DMF (50 mL) was added 4-chloro-3-nitro-phenol (5.14 g, 30.0 mmol), and K2CO3 (8.18 g, 60 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2x) and the combined phases were washed with water, brine, and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified through silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (7.0 g, 66%).

Example 228c 4-. { 4- [1 - (3-Bromo-phenyl) -ethoxy] -2-nitro-phenylsulfanyl} -phenol To Example 228b (5.0 g, 14.0 mmol) in DMF (50 mL) was added 4-mercaptophenol (1.7 g, 14.0 mmol), and K2CO3 (3.8 g, 28 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2x) and the combined phases were washed with water, brine, and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified through silica gel chromatography eluting with (hexanes / ethyl acetate / methanol 75: 15: 5) to give the title compound (5.2 g, 83%).

EXAMPLE 228d 4- (2-Amino-4- [1-bromo-phenyl-n-yl] -ethoxy] -phenesulfanyl} -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-Bromo-phenyl) -ethoxy] -2- (pyrido [2,3-d] pyrimidin-4-ylamino) f-phenylsulfanyl] -phenol The product of Example 57A (125 mg, 0.72 mmol) was reacted with Example 228d (298 mg, 0.72 mmol) in acetic acid (10 mL) at 125 ° C in a sealed tube for 5 minutes to give the crude title compound which was purified by HPLC with TFA to afford the product as trifluoroacetic acid (120 mg, 31%). 1H NMR (300 MHz, DMSO-d6) d ppm: 1.54 (d, J = 6.25 Hz, 3H) 5.52 (q, J = 6.25 Hz, 1 H) 6.66 (d, J = 8.82 Hz, 2H) 6.85 (s) , 1 H) 7.07-7.12 (m, 3H) 7.19 (s, 1 H) 7.32 (t, J = 7.72 Hz, 1 H) 7.39-7.49 (m, 2H) 7.61 (s, 2H) 8.57 (s, 1H) 8.80 (s, 1 H) 9.06 (s, 1 H) 9.65 (s, 1 H); MS (ESI.-) m / z 545 (-H) -.

Example 229 4- [4- [1- (3-Bromo-phenyl) -ethoxy] -2- (7-methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product from Example 10B (110 mg, 0.58 mmol) was reacted with Example 228d (243 mg, 0.58 mmol) in acetic acid (10 mL) at 125 ° C in a sealed tube for 5 minutes to give the crude title compound that it was purified by HPLC with TFA to give the product as trifluoroacetic acid (100 mg, 30%). H NMR (300 MHz, DMSO-d6) d ppm: 1.33 (d, J = 6.25 Hz, 3H) 2.53 (s, 3H) 5.31 (q, J = 6.43 Hz, 1 H) 6.44 (d, J = 8.82 Hz , 2H) 6.68 (dd, J = 8.82, 2.57 Hz, 1 H) 6.85-6.92 (m, 3H) 6.95 (d, J = 2.57 Hz, 1 H) 7.11 (t, J = 7.72 Hz, 1 H) 7.19 -7.27 (m, 2H) 7.40 (s, 1 H) 7.44 (d, J = 8.46 Hz, 1 H) 8.44 (s, 1 H) 8.56 (d, J = 8.46 Hz, 1 H); MS (ESI +) m / z 560 (M + H) +.

Example 230 4- [4- [1- (3-Bromo-phenyl) -ethoxy] -2- (7-isopropyl-pyrido [2,3- d] pyrimidin-4-ylamino) -phenylsulfanyl] - phenol The product of Example 36E (130 mg, 0.60 mmol) was reacted with Example 228d (250 mg, 0.60 mmol) in acetic acid (10 mL) at 125 ° C in a sealed tube for 5 minutes to give the crude title compound. which was purified by HPLC with TFA affording the product as trifluoroacetic acid (140 mg, 39%). 1H NMR (300 MHz, DMSO-d6) d 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-Bromo-benzyloxy) -2- (7-tert-butyl-pyrido [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 the acetic acid was removed under vacuum. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt 45 mg, 10%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.43 (s, 9 H) 5.13 9 (s, 2 H) 6.66 (d, J = 8.83 Hz, 2 H) 7.01 (d, J = 6.62 Hz, 1 H) 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 (ES +) m / z, 587, 589 (M + H-TFA) +; (ESI-) m / z, 585, 587 (M-H-TFA) -.

Example 232 4- [4- (3-Bromo-phenoxymethyl) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 232A 4- [2-Amino-4- (3-bromo-phenoxymethyl) -phenylsulfanyl] -phenol A solution of 4-. { 4- (3-bromo-phenoxymethyl) -2-nitro-phenylsulfanyl] -phenol (325 mg, 0.752 mmol), iron powder (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) was heated to 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 under vacuum, then dissolved in water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The organic extracts were dried and concentrated under vacuum to provide the title compound as a light yellow solid (240 mg, 79%).

Example 232B 4- [4- (3-Bromo-phenoxymethyl) -2- (7-isopropyl-pyrido [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. The solution was then allowed to cool to room temperature, the acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (63 mg, 43%). 1H NMR (300 MHz, DMSO-d6) d 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 (bs, 1H); MS (ESI +) + m / z 573/575 (M + H) +.

Example 233 4- [4- (3-Bromo-phenoxymethyl) -2- (7-methyl-pyrido [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. The solution was then allowed to cool to room temperature, the acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (46 mg, 47%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.72 (s, 3 H), 5.12 (s, 2 H), 6.77 (d, J = 8.5 Hz, 2 H), 7.02 (m, 2 H), 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 , 1 HOUR), .87 (s, 1H), 10.95 (bs, 1H); MS (ESJ) + m / z 545/547 (M + H) +.

Example 234 4- [4- (2,5-Difluoro-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 234A 2-Bromomethyl-1,4-difluoro-benzene To a solution of (2,5-difluoro-phenyl) -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 was emptied to 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 through silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (3.5g, 50%).

Example 234B 1-Chloro-4- (2,5-fluoro-benzyloxy) -2-n-tro-benzene To Example 234a (2.2 g, 10.4 mmol) in DMF (50 mL) was added 4-chloro-3-nitro-phenol (1.8 g, 10.4 mmol), and K2C03 (2.87 g, 20.8 mmol). The mixture was heated at 80 ° C for 16 hours. The The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2x) and the combined phases were washed with water, brine, and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified through silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (2.48 g, 66%).

Example 234C 4- [4- (2,5-D-fluoro-benzyloxy) -2-nitro-phenylsulfanyl] -phenol To Example 234b (2.5 g, 8.3 mmol) in DMF (50 mL) was added 4-mercaptophenol (1.0 g, 8.3 mmol), and K2CO3 (2.3 g, 16.5 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2X) and the combined phases were washed with water, brine, and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with (hexanes / ethyl acetate / methanol 75: 15: 5) to give the title compound (1.7 g, 52%).

Example 234D 4- [2-Amino-4- (2,5-difluoro-benzyloxy) -phenylsulfanyl] -phenol The product of Example 234c (1.70 g, 4.2 mmol) was reacted with Fe and NH 4 Cl as described in Example 10E for give the title compound (1.3 g, 84%).

Example 234E 4- [4- (2,5-Difluoro-benzyloxy) -2- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 57A (100 mg, 0.57 mmol) was reacted with Example 234d (206 mg, 0.57 mmol) in acetic acid (10 mL) at 125 ° C in a sealed tube for 5 minutes to give the crude title compound that it was purified by HPLC with TFA to give the product as trifluoroacetic acid (140 mg, 39%). H NMR (300 MHz, DMSO-d6) d ppm: 5.13 (s, 2H) 6.67 (d, J = 8.46 Hz, 2H) 6.93-7.01 (m, 1 H) 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-Difiuoro-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylami) -fe or Isulf-indigo] -phenol The product of Example 36E (100 mg, 0.46 mmol) was reacted with Example 234d (206 mg, 0.46 mmol) in acetic acid (10 mL) at 125 ° C in a sealed tube for 5 minutes to give the crude title compound that it was purified by HPLC with TFA providing the product as trifluoroacetic acid (140 mg, 39%). 1H NMR (300 MHz, DMSO-d6) d ppm: 1.34 (d, J = 6.62 Hz, 6H) 5.14 (s, 2H) 6.66 (d, J = 8.46 Hz, 2H) 7.06 (d, J2.57 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-fluoro-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d] - pi rim-din-4-ylamino) -phenylsulfanyl] phenol Example 236A 2-B romomethyl-1-chloro-4-fluoro-benzene To a solution of (2-chloro-5-f luoro-phenyl) -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 was emptied to 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 through silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (5.75 g, 82.5%).

Example 236B 1-Chloro-4- (2-chloro-5-flouro-benzyloxy) -2-nitro-benzene To Example 236a (5.7 g, 25.7 mmol) in DMF (50 mL) was added 4-chloro-3-nitro-phenol (4.46 g, 25.7 mmol), and K2C03 (7.10 g, 51.4 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2x) and the combined phases were washed with water, brine, and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified through silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (7.0 g, 86%).

Example 236C 4- [4- (2-Chloro-5-fluoro-benzyloxy) -2-nitro-phenylsulfanyl] -phenol To Example 236b (2.5 g, 83 mmol) in DMF (50 mL) was added 4-mercaptophenol (1.0 g, 8.3 mmol), and K2C03 (2.3 g, 16.5 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2X) and the combined phases were washed with water, brine, and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified through silica gel chromatography eluting with (hexanes / ethyl acetate / methanol (70: 25: 5) to give the title compound (5.0 g, 78%).

Example 236D 4- [2-Amino-4- (2-chloro-5-fluoro-benzyloxy) -phenylsulfanyl] -phenol The product of Example 236c (4.2g, 10.2 mmol) was reacted with Fe and NH 4 Cl as described in Example 10E to give the title compound (3.0 g, 77%).

Example 236E 4- [4- (2-Chloro-5-fluoro-benzyloxy) -2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) amino) -phenylsulfanyl] -phenol The product from Example 36E (125 mg, 0.72 mmol) was reacted with Example 236d (298 mg, 0.72 mmol) in acetic acid (10 mL) at 125 ° C in a sealed tube for 5 minutes to give the crude title compound that it was purified through the addition of ethyl ether to the residue to give the desired product as acetic acid (225 mg, 66%). H NMR (300 MHz, DMSO-d6) d 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, J8.46 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 (1 H, s) (1 8.74 (s, 1H) 9.66 (s, 1H) 9.98 (s, 1H); S (ESI-) m / z 547 (+ H) +.

Example 237 4- [5-Benzyloxy-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) -phenylsulfanyl] -phenol Example 237A 4-Benzyloxy-2-fluoro-1-nitro-benzene 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 eq) and tetrabutylammonium iodide ( 5.0 mg, 0.014 mmol, 0.007 eq) 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 give the title compound (0.455 g, 96%) as a yellow solid.

Example 237B 4- (5-Benzyloxy-2-nitro-phenylsulfanyl) -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) in dimethylformamide (10 mL) was heated in a oil bath at 100 ° C 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 solid The resulting product was isolated by vacuum filtration and dried to provide the title compound (0.405 g, 94%) as a yellow solid.

Example 237C 4- (2-Amino-5-benzyloxy-phenylsulfanyl) -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, 12 eq) in tetrahydrofuran (6 mL), methanol (6 mL). mi) and water (2 ml) were heated under reflux for 16 hours and then cooled to room temperature. The reaction mixture was filtered through celite, rinsing with methanol, and the filtrate was evaporated under reduced pressure to provide the title compound (0.340 g, 95%) as a gray powder which was used in subsequent reactions without further purification.

Example 237D 4- [5-Benzyloxy-2- (7-isopropyl-pyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol The product of Example 237C (0.0908 g, 0.281 mmole) and the product of Example 36E (0.0607 g, 0.281 mmole) in glacial acetic acid (2 ml) was heated in an oil bath at 140 ° C for 10 minutes, cooled at room temperature, and evaporated under pressure reduced. The residue was purified by column chromatography on silica gel eluting with 5% methanol / dichloromethane to give the title compound (0.0368 g, 27%) as a tan solid. H NMR (300 MHz, DMSO-D6) d 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 (M-H) -.

Example 238 4- [2- (7-Methyl-pyrido [2,3-d] pyrimidin-4-ylamino) -4-styryl-phenylsulfanyl] -phenol EXAMPLE 238A 4 - (4- Bromo -2-N-tro-phenylsulfonyl) -phenol A mixture of 4-bromo-1-fluoro-2-nitrobenzene (0.44 g, 2.0 mmol), 4-mercaptophenol (0.303 g, 2.4 mmol), and cesium carbonate (1.56 g, 4.8 mmol, 2.4 eq) in dimethylformamide (10 mg). mi) was heated in an oil bath at 100 ° C for 3 hours and then cooled to room temperature. The reaction mixture was poured into ice-water (50 ml), the pH adjusted to 3 through the addition of 1N aqueous hydrochloric acid, and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over sodium sulfate Anhydrous magnesium was filtered and evaporated to give the title compound as a thick yellow oil (0.70 g,> 100%) which was used without further purification.

Example 238B 4- (2-Amino-4-bromo-phenylsulfanyl) -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) in a methanol mixture (6 ml) ), tetrahydrofuran (6. ml), and water (2 ml.) was heated under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered through celite and the filter pad was rinsed with methanol (25 ml). The filtrate was evaporated under reduced pressure to leave a brown vitreous solid (0.27 g, 99%) which was used without further purification.

Example 238C 4- [4-Bromo-2- (7-methyl-pyrido [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 at 130 ° C oil bath for 30 minutes. An additional quantity of the product was added of Example 10B (0.060 g, 0.319 mmol) and the reaction mixture was heated for an additional 30 minutes at 130 ° C. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was titrated with 2-propanol, and the resulting solid was isolated by vacuum filtration and dried to provide the title compound (0.083 g, 36% yield) as a beige solid.

EXAMPLE 238D 4- [2- (7-phenyl-pyridyl [2,3-d] pyrimidin-4-ylamino) -4-styryl phenylsulfanyl] -phenol A mixture of the product of Example 238C (0.0791 g, 0.180 mmole), styrene (0.176 g, 1.69 mmole, 9.4 eq), palladium acetate (A) (6.2 mg, 0.0276 mmole, 0.15 eq), tri-o-tolylphosphine ( 13.3 mg, 0.0437 mmol, 0.24 eq), and di-isopropylethylamine (0.697 g, 0.539 mmol, 3.0 eq) in dimethylformamide (2 mL) was heated in an oil bath at 130 ° C for 98 hours. The mixture was then cooled to room temperature and the solvent was evaporated under 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 HPLC with TFA to give the title compound as a trifluoroacetic acid salt (6.1 mg, 10% yield). 1H NMR (300 MHz, DMS0-D6) d 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, J7.35 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-Methyl-pyrido [2,3-d] pyrimidin-4-yl) - (2-phenylsulfanyl-5-styryl-phenyl) -amine Example 239A (5-Bromo-2-phenylsulfanyl-phenyl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amine -Bromo-2- (phenylthio) benzenamine was prepared according to procedures similar to those described in Examples 6a, 6b, and 6c substituting benzenethiol for 4-mercaptophenol and 4-bromo-2-nitrophenol for 4-methyl-2 -nitro phenol. A mixture of the product of Example 10B (0.188 g, 1.0 mmol) and 5-bromo-2- (phenylthio) benzenamine (0.280 g, 1.0 mmol) in glacial acetic acid (2 mL) was heated in a 130 ° oil bath. C for 30 minutes. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was titrated with methanol, and the resulting solid was isolated through vacuum filtration and dried to provide the compound of the title (0.276 g, 65% yield) as a beige solid.

Example 239B (7-Methyl-pyrido [2,3-d] pyrimid-4-yl) - (2-phenylsulfanyl-5-styryl-phenyl) -amine A mixture of the product of Example 239A (0.127 g, 0.30 mmole), styrene (0.133 g, 1.27 mmole, 4.3 eq), palladium acetate (H) (5.3 mg, 0.0236 mmole, 0.08 eq), tri-o-tolylphosphine ( 17.7 mg, 0.058 mmol, 0.19 eq), and triethylamine (0.0913 g, 0.90 mmol, 3.0 eq) in dimethylformamide (3 mL) was heated in an oil bath at 130 ° C for 98 hours. The mixture was then cooled to room temperature and the solvent was evaporated under 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 HPLC with TFA to give the title compound as a trifluoroacetic acid salt (4.0 mg, 2.4%). 1H NR (300 Hz, DMSO-D6) d 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 = 735 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 (M-H) -.

Example 240 (7-Methyl-pyrido [2,3-d] pyrimidin-4-yl) - (3-styryl-phenyl) -amine Example 240A (3-Bromo-phenyl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) -amine A mixture of the product of Example 10B (0.206 g, 1.09 mmol) and 3-bromoamylin (0.188 g, 1.09 mmol) in glacial acetic acid (1 mL) was heated in an oil bath at 130 ° C for 15 minutes. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was titrated with 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- ethyl-pyrido [2,3-d] pyrimidin-4-yl) - (3-styryl-phenyl) -amine A mixture of the product of 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 eq), tri-o-tolylphosphine ( 2.4 mg, 0.008 mmole, 0.04 eq), and triethylamine (0.0607 g, 0.60 mmole, 3.0 eq) in dimethylformamide (2 ml) was heated in an oil bath at 120 ° C for 4 hours. The mixture was then cooled to room temperature and the solvent was evaporated under a gas stream nitrogen. 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 yellow crystals (11.8 mg, 17%). 1H NMR (300 MHz, DMSO-D6) d 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 (M-H) -.

Example 241 (2-ethyl-5-phenethyl-phenyl) - (7-methyl-pyrido [2,3-d] pyrimidin-4-yl) - am i na Example 241A 1-Meityl-2-nitro-4-styryl-benzene 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 eq), tri-o tolylf osf ina (12.2 mg, 0.04 mmol, 0.02 eq), and triethylamine (0.405 g, 4.0 mmol, 2.0 eq) in dimetuf ormamide (2 ml) was heated in an oil bath at 120 ° C for 4 hours. The mixture was then cooled to room temperature and the solvent was evaporated under a gas stream nitrogen. 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 chromatography on silica gel, eluting with hexane / ethyl acetate gradient to give the title compound as a yellow solid (166 mg, 35% yield).

Example 241 B 2-Methyl-5-phenethyl-phenylamine A mixture of the product of Example 241A (0.166 g, 0.694 mmol) and 10% palladium on charcoal (18.4 mg, 0.025 eq) in ethanol (10 mL) was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was then filtered through celite and the solvent was evaporated under reduced pressure to give the title compound as a slightly red oil (0.141 g, 96% yield).

Example 241 C (2-Methyl-5-phenethyl-phenyl] - (7-methyl-pyrido [2,3-d.] Pyrimidin-4-yl) -amine A mixture of the product of Example 10B (0.041 g, 0.22 mmole) and the product of Example 241B (0.046 g, 0.22 mmole) in Glacial acetic acid (1 mL) was heated in an oil bath at 130 ° C for 15 minutes. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was titrated with methanol, and the resulting solid was isolated by vacuum filtration and dried to provide the title compound (0.0121 g, 16% yield) as a light orange solid. 1 H NMR (300 MHz, CHCl 3 -d) d ppm: 8.84 (s, 1 H), 8.23 (d, J = 8.46 Hz, 1 H), 7.44 (s, 1 H), 7.15-7.37 (m, 8 H), 7.07 ( dd, J = 7.72, 1.47 Hz, 1H), 2.93 (s, 413), 2.78 (s, 3H), 2.28 (s, 3H); MS (ESI +) m / z 355.3 (M + H) +, (ESI-) m / z 353.2 (M-H) -.

Example 242 (7-lsopropyl-pyrido [2,3-d] pyrimidin-4-yl) - (2-methyl-5-phenethyl-phenyl) -amino 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. The reaction mixture was then 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-D 6) d ppm: 11.09 (s, 1 H), 8.94 (d, J = 8.46 Hz, 1 H), 8.74 (s, 1 H), 7.82 (d, J = 8.46 Hz, 1 H) , 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 (M-H) -.

Example 243 (5-Methyl-2-phenylsulfanyl-phenyl) - (7-propyl-pteridin-4-yl) -amine Example 243A N '- (3-Cyano-6-propylpyrazin-2-yl)?,? - dimethylformamidine A mixture of 3-amino-5-propylpyrazine-2-carbonitrile (0.140 g, 0. 863 mmole) (prepared according to the method of Taylor and LaMattina, JOC 1977, 47, 1523) and dimethylformamide di metí lacetal (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 give the title compound (0.188 mg, 100%) as a thick oil.

Example 243B (5-Methyl-2-phenylsulfanyl-phenyl) - (7-propyl-pteridin-4-yl) -amine A mixture of the product of Example 243A (38.2 mg, 0.176 mmol) and the product of Example 51 (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 titrated with methanol to provide the title compound (19 mg, 28% yield) as a beige solid. ?? NMR (300 MHz, DMSO-D6) d ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.761.90 (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 (M-H) -.

Example 244 4- [4-Benzyloxy-2- (7-isopropyl-pteridin-4-ylamino) -phenylsulfanyl] -phenol Example 244A 3-Amino-5-isopropyl-4-oxy-pyrazine-2-carbonitrile A mixture of 2-hydroxyimino-3-methylbutyraldehyde (1.93 g, 16. 8 mmol) (prepared through the procedure of Nakamura, Agrie, 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 1.8 hours. The resulting solid was isolated by vacuum filtration and rinsed with i-propanol and air dried to provide the title compound (0.525 g, 18% yield) as a white solid.

Example 244B 3-Amino-5-isopropyl-pyrazine-2-carbonyltryl A solution of the product of Example 244A (0.525 g, 2.95 mmol) in tetrahydrofuran (30 mL) was stirred at ice-water bath temperature. Phosphorus trichloride (4.0 g, 2.6 ml, 29.5 mmol, 10 eq) was added dropwise to this solution. The reaction mixture was stirred at room temperature for 16 hours and then the solvent and an excess of reagent were evaporated. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (3 x 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 solid light coffee.

Example 244C N '- (3-Cyano-6-isopropyl-prazrazin-2-yl) -N, N-dimethyl-formamidine A mixture of the product from Example 244B (0.37 g, 2.28 mmol) and dimethylformamide dimethylacetal (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 provide the title compound (0.50 g, 100%) as a red / thick brown oil. which was used in subsequent reactions without further purification Example 244D 4- [4-Benzyloxy-2- (7-isopropyl-pteridin-4-amino) -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 titrated with methanol to provide the title compound (55.5 mg, 53% yield) as a beige solid. 1 H NMR (300 MHz, DMSO-D 6) d ppm: 10.37 (s, 1 H), 9.65 (s, 1 H), 9.03 (s, 1 H), 8.80 (s, 1 H), 8.31 (s, 1 H), 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 (M-H) -.

Example 245 [2- (4-Amino-phenoxy) -5- (6-bromo-1 H -benzoimidazol-2-yl) -phenyl] - (7-isopropyl-pyrido [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 tert-butyl ester of (4-hydroxy-phenyl) -carbamic acid was reacted together in DMSO with the addition of KOH to give the title product.

Example 245B Tert-butyl acid ester. { 4- [2-amino-4- (6-bromo-1 H -benzoimidazol-2-yl) -phenoxy] -phenyl} -carbamic The product of Example 245A was reacted according to the procedures of Examples 147B and 147C to provide title product.

Example 245C [2- (4-Amino-phenoxy) -5- (6-bromo-1 H -benzoimidazol-2-yl) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-) il) -amine The product of Example 245B was reacted with the product of Example 36E in HOAc and placed in a pre-heated oil bath at 120 ° C. The solvent was removed under a stream of N2. The product was deprotected through dissolution in a 1: 1 mixture of TFA in DCM and stirred at room temperature. The crude material was purified by HPLC with TFA to give the title product as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d 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-butyl-pyrido [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, the mixture was then cooled to room temperature, the solvent was removed and the residue was purified by column chromatography on silica. gel to provide the title product. 1H NMR (300 MHz, DMSO-D6) d 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-Am ino-phenylsulfanyl) -5- (2-chloro-thiazol-5-ylmethoxy) -phen isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 247A Tert-butyl acid ester. { 4- [2-amino-4- (2-chloro-thiazol-5-ylmethoxy) -phenylsulfanyl] -phenyl} -carbamic 2-Chloro-5- (4-chloro-3-nitro-phenoxymethyl) -thiazole (from Example 25A) was reacted with 4-aminothiophenol in anhydrous ethanol and refluxed under a nitrogen atmosphere. The reaction was cooled to room temperature and the ethanol was removed by rotary evaporation. The residue was taken up 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. Titration of the solid with 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 carbonate in 1,4-dioxane was heated to reflux under an atmosphere of nitrogen, and then additional Boc anhydride was added and the reaction was allowed to reflux. The reaction was cooled to room temperature and the solvent was removed by rotary evaporation in vacuo. The resulting solid was titrated with 2.5% ethyl acetate / methylene chloride to obtain 4- (4 - ((2-chlorothiazol-5-yl) methoxy) -2-nitrophenylthio) phenylcarbamate tert -butyl.

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 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 under vacuum to provide the title compound.

Example 247B [244-Amino-phenylsulfanyl) -5- (2-chloro-thiazol-5-ylmethoxy) -phenyl] - (7-iso-yl-pyrido [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, the mixture was then cooled to room temperature, the solvent was removed under vacuum and a mixture of dichloromethane / trifluoroacetic acid was added. / 1 and the residue was then stirred at room temperature for 2 hours followed by removal of the solvent under vacuum and the residue was purified by HPLC with TFA to give the title product as a trifluoroacetic acid salt. H NMR (300 MHz, DMSO-D6) d 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, 1 H); S (ESI +) m / z 535 (M + H) +.

EXAMPLE 248 Ter-bufílico acid ester. { 4- [2- (7-tert-Butyl-pyrido [2,3-d] -pyrimidin-4-ylamino) -4- (2-chloro-thiazol-5-ylmethoxy) -phenylsulfan] I] - f -enyl} -carbamic The product of Example 247A was heated at 130 ° C in acetic acid with the product of Example 127A for 15 minutes, the mixture was then cooled to room temperature, the solvent was removed and the residue was purified by HPLC with TFA to provide the title product as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d ppm: 1.43 (d, J = 11.40 Hz, 15H) 2.73 (s, 1 H) 5.36 (s, 2H) 7.00 (d, 1 H) 7.13 (d, J = 8.46 Hz, 2H) 7.25 (d, 1 H) 7.33 (d, J = 8.46 Hz, 3H) 7.81 (s, 2H) 8.62 (S, 1 H) 8.78 (s, 1 H) 9.39 (s, 1 H) 10.49 (bs, 1 H); MS (ESI +) m / z 649 (M + H) +.

Example 249 [2- (4-Amino-phenylsulfanyl) -5- (2-chloro-thiazol-5-ylmethoxy) -phenyl] - (7-tert-butyl-pyrido [2,3-d] pyrimidin-4-yl) ) -amina The product of Example 248 was added to a 1/1 dichloromethane / trifluoroacetic acid mixture and the solution was stirred at room temperature for 2 hours followed by removal of the solvent under vacuum and the resulting residue was purified by HPLC with TFA for provide the title product as a salt of trifluoroacetic trif acid. 1H NR (300 MHz, DMSO-D6) d 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-Amino-phenylsulfanyl) -5- (6-bromo-1H-benzoimidazol-2-yl) -phenyl] - (7-isopropyl-pyrido [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 procedure of Example 216B substituting 4-chloro-3-nitrobenzaldehyde for the product of Example 216a, which was then subjected to the conditions of Example 216C to provide the title product.

Example 250B [2- (4-Amino-phenylsulfanyl) -5- (6-bromo-1H-benzoimidazol-2-yl) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) ) -amine The product of Example 250A was reacted according to The procedures of Examples 147B, 147C and 147C to provide a crude residue that was purified through HPLC with TFA to provide the title product as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) d ppm: 1.38 (d, J = 6.62 Hz, 6H) 3.26-3.40 (m, 1 H) 6.64 (d, J = 8.46 Hz, 2H) 7.03 (d, J = 8.46 Hz, 1 H) 7.17 (d, J = 8.46 Hz, 2H) 7.35 (dd, J = 8.46, 1.84 Hz, 1 H) 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, 1 H) 8.18 (s, 1 H) 8.89 (s, 1H) 9.05 (d, J = 8.82 Hz, 1 HOUR); S (ESI +) m / z 584 (M + H) +.

Example 251 [2- (4-Amho-phenylsulfanyl) -5- (3-f luoro-benzyloxy) -phenyl] - (7- isopropyl-pyrido [2,3-d.] Pyrimidin-4-yl) - amine Example 251 A-tert-butyl ester of acid. { 4- [2-amino-4- (3-f luoro-benzyloxy) phenylsulfanyl] -phenyl} -carbamic The product of Example 57B was reacted with 4-aminothiophenol according to the procedure of Example 214B followed by reaction according to the procedures of Examples 214C and 214D to provide the title product.

Example 251 B [2- (4-Amino-phenylsulfanyl) -5- (3-fluoro-benzyloxy) -phenyl] - (7-isopropyl-pyrid [2,3-d] pyrimidn-4-) il) -amine The product of Example 251A was heated at 130 ° C in acetic acid with the product of Example 36E for 15 minutes, the mixture was then cooled to room temperature, the solvent was removed under vacuum and a dichloromethane / trifluoroacetic acid mixture was added. 1/1 and the residue was then stirred at room temperature for 2 hours followed by removal of the solvent under vacuum and the residue was purified by column chromatography on silica gel to provide the title product. 1H NMR (300 MHz, DMSO-D6) d 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-Amino-phenylsulfanyl) -5- (3-fluoro-benzyloxy) -pheny] - (7-tert-butyl-pyrido [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, the mixture was then cooled to room temperature, the solvent stirring under vacuum and a mixture of dichloromethane / trifluoroacetic acid 1/1 was added and the residue was then stirred at room temperature for 2 hours followed by removal of the solvent under vacuum and the residue was purified by HPLC with TFA to provide the product of the title as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) 8 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); S (ESI +) m / z 526 (M + H) +.

Example 253 [5-Benzyloxy-2- (4-dimethylamino-phenylsulfanyl) -phenyl] - (7-isopropyl-pyrido [2,3-d] pyrimidin-4-yl) -amine Example 253A 5-Benzyloxy-2- (4-dimethylamino-phenylsulfanyl) -phenylamine The product of Example 214B (1.0g, 0.284 mmole) was placed in a tube together with formic acid (5 ml), dioxane (5 ml), and 37% aqueous formaldehyde (5 ml). The tube was sealed and heated at 110 ° C for 20 minutes. The mixture was cooled to room temperature, the solvent was removed and the resulting residue was purified by column chromatography on silica gel followed by reduction of the nitro group according to the procedure of Example 214D to provide the title product (411 mg, 43%). %).

Example 253B [5-Benzyloxy-2- (4-dimethylamino-phenylsulfanyl) -phenyl] - (7-isopropyl-pyrido [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 a preheated oil bath at 130 ° C for 20 minutes. The reaction mixture was then cooled to room temperature and the solvent was evaporated under vacuum to provide the title compound as an acetic acid salt. H NMR (300 MHz, DMSO-D6) d ppm: 1.36 (d, J = 7.0Hz, 6H), 2.81 (s, 6H), 3.30 (m, 1H), 5.10 (s, 2H), 6.45 (d, J = 9.2Hz, 2H), 7.07 (d, J = 8.8Hz, 2H), 7.12 (m, 2H), 7.25 (d, J = 8.8Hz, 1H), 7.40 (m, 5H), 7.94 (m, 1H), 8.78 (s, 1H), 8.99 (m, 1H), 11.70 (bs, 1H); MS (ESI) m / z 522 (M + H) +.

Example 254 4-Brorno-N- [3- (pyrido [2,3-d] pyrimidin-4-ylamino) -phenyl] -benzamide Example 254A 4-Bromo-N- (3-nitro-phenyl) -benzamide The title compound was prepared according to the procedure of Example 255A by replacing 3-nitro-phenylamine for 4-fluoro-3-nitro-animline and substituting 4-bromo-benzoyl chloride for 3-trif luoromethyl-benzoyl chloride to provide the product of the title (3.373 g, 90%) Example 254B 4-Bromo-N- (3-amino-phenyl) -benzamide The title compound was prepared according to the procedure of Example 255B by replacing the product of Example 254A for the product of Example 255A to provide 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) was stirred in a pre-heated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (25.0 mg, 30%). 1H NR (300 MHz, DMSO-D6) d 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-Hydroxy-phenylsulfanyl) -3- (7-methyl-pyrido [2,3-d] pyrimidin-4 < ylamino) -phenyl] -3-trif-loromethyl-benzamide Example 255A N- (4-Fluoro-3-niiro-phenyl) -3-trifluoromethyl-benzamide A solution of 4-fluoro-3-nitro-aniline (2.00g, 12.8 mmol), 3-trifluoromethyl-benzoyl chloride (1.895ml, 12.8mmol), Hunig's base (4463mL, 25.6mmol) in tetrahydrofuran (50m1) ) was stirred at room temperature for 1 hour. Water (450 ml) was then added to the solution and the resulting solid was collected through filtration and dried in a vacuum oven to provide the title compound (3.311 g, 97%).

Example 255B N- [4- (4-Hydroxy-f in ilsulfanyl) -3- nitro -fe or I] - 3 - 1 r i f luoromethylbenzamide A solution of the product of Example 255A (2.00 g, . 80 mmol), 4-hydroxythiophenol (0.732 g, 5.80 mmol) and potassium carbonate (1604 g, 11.6 mmol) in N, N-dimethylformamide (40 ml) was heated at 80 ° C 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 x 150 ml), the extracts Combine was dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (2.52 g, 100%).

Example 255C N- [3-Amino-4- (4-hydroxy-phenylsulfanyl) -phenyl] -3-trifluoromethyl-benzamide 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), tetrahydrofuran (18 mL), and water solution (6 mi) was heated to reflux for 3 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was diluted with water (50 ml) and extracted with dichloromethane (2 x 100 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.60 g, 97%).

Example 255D - [4- (4-Hydroxy-phenylsulfanyl) -3- (7-metM-pyrido [2,3-d] pyrimidin-4-ylamino) -phenyl] -3-trifluoromethyl-benzamide 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 a pre-heated oil bath at 130 ° C. during 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (11 mg, 10%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.74 (s, 3 H), 6.70 (d, J = 8.82 Hz, 2 H), 7.18 (d, J = 8.46 Hz, 3 H), 7.64 (dd, J = 8.46, 2.21 Hz, 1H), 7.79 (t, J7.72 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 (MH) -.

Biological Evaluation The representative compounds of the invention were analyzed according to the tests described below. The following acronyms were used here: IC50 50% inhibitory concentration TC50 50% concentration of DMEM toxicity Essential Medium Modified with Dulbecco RNA ribonucleic acid RT-PCR reverse transcriptase polymerase chain reaction SEAP secreted alkaline phosphatase The hepatitis C virus genome encodes a large polyprotein, which after processing produces the components functions necessary to synthesize progeny RNA. Selective cell lines that produce high and sustained levels of sub-genomic HCV RNA (replicons) have been derived from human hepatoma cells (Huh7) as described in Ikeda et al., J. VIROLOGY, 76 (6): 2997 -3006 (2002), and Blight et al., SCIENCE, 290: 1972-1974 (2000). The mechanism of RNA replication in these cell lines is considered identical to the replication of full-length HCV RNA in infected hepatocytes. The compounds of this invention are inhibitors of HCV RNA replication in replicon assay systems described below.

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

A. RNA Assay and SEAP Assay The purpose of these assays was to evaluate the efficiency of the compounds to inhibit the replication of replicons 1a and 1b of the HCV genotype in vitro. Replicon 1a and / or 1b cells of the genotype were plated at 3-5 x 103 cells per well in a 96-well plate. cavities in a DMEM medium containing 5% fetal calf serum. The next day, the culture medium was removed and replaced with a fresh medium containing eight serial dilutions of the compound. The untreated control culture was treated in an identical manner except that no inhibitor was added to the medium. Plates were incubated in a C02 incubator at 37 ° C. On day 4, 100 μ? of lysis pH regulator (RTL) (Qiagen) to each cavity after the removal of the culture. The RNA was purified according to the manufacturer's recommendations (Qiagen RNAeasy) and eluted in 200 μ? OF WATER. The level of HCV RNA was quantified from portions (5 μ? Of 200 μ?) Of the purified RNA through the RT-PCR method in real time. The primers and probe were derived from a specific sequence in Region 5 'Untranslated (5'UTR). The RT-PCR reaction was performed at 48 ° C for 30 minutes, followed by 40 cycles set at 95 ° C, 15 s; 54 ° C, 30 s; and 72 ° C, 40 s. Alternatively, SEAP activity was measured in each culture supernatant after four days of incubation with the compound according to the manufacturer's instructions. The reduction percentage of HCV RNA or SEAP in the presence of the compound was calculated and the 50% inhibitory concentration (IC50) was calculated through a non-linear regression analysis using the Prism program (version 4.0, GraphPad software, San Diego , CA). When tested using the above method, the representative compounds of the present invention inhibited the replication of the inhibited HCV replicon with IC50 values in the scale from approximately 0.3 nM to approximately 100 μ ?.

B. Cytotoxicity Assay The purpose of this assay was to determine the toxicity of the compounds in viral host cells in vitro. The cytotoxicity of the compounds was measured using a cell proliferation / viability assay based on mitochondrial enzyme in replicon cells. Briefly, HCV replicon cells were plated at 3-5 x 10 3 pro cavity cells in a 96-well plate in a DMEM medium containing 5% FCS. On day 1, the culture medium was removed and replaced with a fresh medium containing eight serial dilutions of the compound. The untreated control culture was treated in an identical manner except that no inhibitor was added to the medium. Plates were incubated in a C02 incubator at 37 ° C. On day 4, a supply solution of the tetrazolium salt, MTT (4 mg / ml in PBS, Sigma # cat.M 2128) was added to each cavity at 25 μ? per cavity. The plates were incubated for a further 4 hours, treated with 20% SDS plus 0.02 N HCI at 50 μ? per cavity to use the cells. After an overnight incubation, the optical density was measured by reading the plates at 570/650 nm wavelengths. The percentage of reduction of the formazan blue color formed in relation to the control was calculated and the 50% toxicity concentration (TC50) was calculated through a non-linear regression analysis using the Prism program (version 4.0, GraphPad software, San Diego, CA). When treated using the above method, the TC50 values of the representative compounds of the present invention were greater than the corresponding IC50 values of these compounds.

Pharmaceutical Compositions and Uses The present invention modalizes pharmaceutical compositions comprising the compounds of the invention. As a non-limiting example, a pharmaceutical composition of the present invention comprises one or more compounds of this invention, wherein each compound is independently selected from Formulas I, II, III, IV, V, VI, VII or VIII. Preferably, each compound is independently selected from Examples 1 -255. The present invention also modalizes pharmaceutical compositions comprising pharmaceutically acceptable salts, solvates, or prodrugs of the compounds of this invention. The pharmaceutically acceptable salts can be zwitterions or derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable salt of a compound of the invention retains the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation, or allergic response, has a reasonable benefit / risk ratio, and is effective for its use intended and not biologically or otherwise undesirable. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanpropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate , hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Groups containing basic nitrogen can also be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl, propyl or butyl chlorides, bromides or iodides), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl or diamyl) sulfates), long-chain halides (for example decyl, lauryl, myristyl or stearyl chlorides, bromides or iodides), aralkyl halides (for example, benzyl or phenethyl bromides). Other salts that can be used in the present invention include salts with alkaline or alkaline earth metals, such as sodium, potassium, calcium or magnesium, or with organic bases. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, acid oxalic, maleic acid, succinic acid, citric acid, or other suitable inorganic or organic acids. The present invention also modalizes pharmaceutical compositions comprising a compound of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. In a non-limiting example, a pharmaceutical composition of the present invention includes 1,2,3 or more compounds of the invention (or salts, solvates or prodrugs thereof), and 1, 2, 3 or more therapeutic agents. By way of illustration and not limitation, these other therapeutic agents may be selected from antiviral agents (eg, anti-HIV agents or other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, or anti-inflammatory agents. lamatorios Specific examples of these other therapeutic agents include, but are not limited to, ribavirin; interferons (for example, IFN alpha 2a or 2b); protease inhibitors; immunosuppressants; antibodies (e.g., monoclonal or therapeutic chimeric antibodies); Antisense siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); agents to test cirrhosis and inflammation in the liver; IFN Omega (BioMedicines Inc., Emeryville, CA); serine protease inhibitor BILN-2061 (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); antiviral from Summetrel (endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegays and PEGylated Ribavirin IFN-alpha 2a / ribavirin (F.

Hoffmann-La Roche LTD, Basel, Switzerland); immunosuppressant of HCV IgG CellCept (F.Hoffmann-La Roche LTD, Basel, Switzerland); IFN-alpha lymphoblastoid Wellferon (GalxoSmithKIine foot, Uxbridge, UK); Albumin IFN-alpha 2b Albuferon-alpha (Human Genome Sciences Inc., Rockville, MD); Levovirin ribaviridine (ICN Pharmaceuticals, Costa Mesa, CA); inhibitor of IDN-6556 caspase (Idun Pharmaceuticals Inc., San Diego, CA); anti-ibrotic IP-501 (Indevus Pharmaceuticals Inc., Lexington, MA); INF-Actimmune range (InterMune Inc., Brisbaen, CA); Infergen to IFN alfacon-1 (InterMune Inc., Brisbaen, CA); ISIS 14803 antisense (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmacueticals Inc., New York, NY); inhibitor JTK-003 RdRp (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); Ceplene immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); immunosuppressant HCV IgG Civacir (Nabi Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-alpha 2b / alpha 1-thymosin (RegeneRx Biopharmaceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); inhibitor of Levovirin IMPDH (Ribapharm Inc., Costa Mesa, CA); inhibitor of Viramidine IMPDH (Ribapharm Inc., Costa Mesa, CA); Heptazyme ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); Intron A IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); PEG-Intron PEGylated IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); Rebetron IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Ribavirin (Schering-Plow) Corporation, Kenilworth, NJ); PEG-Intron / PEGylated Ribavirin IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Zadazim immune modulator (SciClone Pharmacueticals Inc., San Mateo, CA); Rebif IFN-beta 1a (Serono, Geneva, Switzerland), IFN-beta and EMZ701 IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67 beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); inhibitor of VX-497 IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); serine protease inhibitor VX-950 / LY-570310 (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); Natural IFN-alpha Omniferon (Viragen Inc., Plantatiom FL); Monoclonal antibody XTL-002 (XTL (hereinafter composed SCH503034, Schering-Plow Co.); Y hereinafter compound GS9137, Gilead Sciences, Inc., Foster City, CA). Any other desirable therapeutic agent (s) may also be included in a pharmaceutical composition of the present invention. In one embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more than other antiviral agents. In another embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other anti-HCV agents. In one example, each of the compounds of the present invention is independently selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255, and each of the other anti-aging agents. HCV is independently selected from inhibitors of HCV RNA-dependent polymerase (eg, nucleoside or non-nucleoside polymerase inhibitors), HCV protease inhibitors, or HCV helicase inhibitors. In a further embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and two or more other anti-HCV inhibitors. Preferably, each compound of the present invention is independently selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255. The other anti-HCV inhibitors can be selected from the same class of inhibitor (for example, all of these are selected from RNA polymerase inhibitors dependent on HCV RNA, or HCV protease inhibitors), or are selected from different classes of inhibitor (e.g., one or more are selected from an RNA polymerase inhibitor dependent on HCV RNA and the other or others are selected from HCV protease inhibitors).

In still another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and at least one RNA polymerase inhibitor dependent on HCV RNA. Preferably, each compound of the present invention is independently selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and at least one HCV protease inhibitor. Preferably, the compound of the present invention is independently selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255. In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and at least one RNA polymerase inhibitor dependent on HCV RNA, and at least one HCV protease inhibitor. Preferably, the compound of the present invention is independently selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255. In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and two or more anti-HCV agents, each of which is independently selected from inhibitors of RNA polymerase dependent on HCV RNA or inhibitors of HCV protease. Preferably, the 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, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and three or more other anti-HCV agents, each of which is independently selects HCV RNA-dependent RNA polymerase inhibitors or HCV protease inhibitors. Preferably, the compound of the present invention is independently selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255. Non-limiting examples of HCV RNA-dependent RNA polymerase inhibitors include those described in WO 0190121 (A2), US 6348587B1, WO 0160315, WO 0132153, EP 1162196A1, and WO 0204425. Non-limiting examples of HCV protease inhibitors include BILN-2061, VX-950, and SCH503034. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and one or more other antiviral agents, such as anti-HBV or anti-HIV agents. -VIH. Non-limiting examples of anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC -125, L-870812, S-1360, enfuvirtide, T-1249, and other inhibitors of HIV protease, reverse transcriptase, integrase or fusion. Other desirable antiviral agents may also be included in a pharmaceutical composition of the present invention, as appreciated by those skilled in the art. In one embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255, or a salt , solvate or prodrug thereof, and at least one anti-HBV agent. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255, or a salt , solvate or prodrug thereof, and at least one anti-HIV agent. In yet another embodiment, a pharmaceutical composition of the present invention comprises 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 or prodrug thereof, and at least one anti-hepatitis A, anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agent.

In still another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas I, II, III, IV, V, VI, VII or VIII, or Examples 1-255, or a salt, solvate or prodrug thereof, and at least one agent suitable for the treatment of liver inflammation. A pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of pharmaceutically acceptable carriers / excipients include sugars (e.g., lactose, glucose or sucrose), starches (e.g., corn starch or potato starch), cellulose or its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose or cellulose acetate), oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g., polyethylene glycol), pH regulating agents (eg, magnesium hydroxide or aluminum hydroxide), agar, alginic acid, tragacanth powder, malt, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol or buffer solutions of phosphate pH. Also, in a pharmaceutical composition of the present invention, as appreciated by those skilled in the art, lubricants, coloring agents, release agents, coating agents, sweeteners, flavoring or perfume-providing agents, or antioxidants may be included.

A pharmaceutical composition of the present invention can be administered to a patient in need thereof through a variety of routes, such as oral, parenteral, sublingual, rectal, topically or through a spray for inhalation. Topical administration may involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intramuscular or intrasternal injections, and infusion techniques. The pharmaceutical compositions of the present invention can be formulated based on their routes of administration using methods well known in the art. For example, a sterile injectable preparation can be prepared as a sterile injectable aqueous or oleaginous suspension., using suitable dispersing agents or humectants and suspending agents. Suppositories for rectal administration can be prepared by mixing drugs with a suitable non-irritating excipient such as cocoa butter or polyethylene glycols, which are solid at ordinary temperatures but liquid at rectal temperature and, therefore, will melt in the rectum and they will release the drugs. The solid dosage forms for oral administration can be capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compounds can be mixed with at least one inert diluent such as sucrose, lactose or starch. The solid dose forms can also be comprise other substances in addition to inert diluents, such as lubricating agents. In the case of capsules, tablets and pills, the dosage forms can also comprise pH regulating agents. The tablets and pills can also be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents commonly used in the art. The liquid dosage forms may also comprise wetting, emulsifying, suspending, sweetening, flavoring or perfume-providing agents. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes, as described in the patent of E.U.A. No. 6,703,403. The formulation of drugs that are applicable to the present invention is generally discussed in, for example, Hoover, John E., REM I NGTON'S PHARMACEUTICAL SCIENCES (ack Publishing Co., Easton, PA: 1975), and Lachman, L, eds. , PHARMACEUTICALS DOSAGE FORMS (Marcel Decker, New York, NY, 1980). The present invention also modalizes methods for using the compounds of the present invention (or salts, solvates or prodrugs thereof) to inhibit the replication of HCV. In one embodiment, the methods comprise contacting the HCV virus with an effective amount of a compound of the present invention (or salts, solvates or prodrugs thereof), thus inhibiting the replication of the HCV virus. In another embodiment, the methods comprise contacting cells infected with HCV virus with an effective amount of a compound of the present invention (or salts, solvates or prodrugs thereof), thereby inhibiting the replication of the HCV virus in the cells. In yet another embodiment, the methods comprise contacting the HCV virus or infected cells with an effective amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof), thus inhibiting the replication of the HCV virus. As used herein, "inhibit" means to significantly reduce, or abolish, the activity that is being inhibited (e.g., viral replication). In many cases, the representative compounds of the present invention can reduce the replication of the HCV virus (eg, in the HCV replicon assays as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more. The compounds of the present invention can inhibit all HCV subtypes. Examples of HCV subtypes that are operable for the present invention include, but are not limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including genotypes 1a, 1b, 2a, 2b, 2c or 3c of HCV. In one embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of HCV genotype 1a. In another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs of the themselves) are used to inhibit the replication of HCV genotype 1b. In yet another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of both 1a and 1b HCV genotypes. The present invention also modalizes methods for using the compounds of the present invention (or salts, solvates or prodrugs thereof) to treat HCV infection. These methods typically comprise administering a therapeutically amount of a compound of the present invention (or a salt, solvate or prodrug thereof) to a patient with HCV, thereby reducing the viral level of HCV in the patient's blood or liver. As used herein, the term "treating" refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition, or one or more symptoms of said disorder or condition to which said term is applied. The term "treatment" refers to the act of treating. In a modality, the methods comprise administering an effective therapeutic amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof) to a patient with HCV, thereby reducing the viral level of HCV in the blood or liver of the patient. Preferably, the compound (s) employed in these methods has Formulas I, II, III, IV, V, VI, VII or VIII, or is selected from Examples 1-255, or is a salt, solvate or drug thereof . In another aspect, the present invention modalizes methods for using a pharmaceutical composition of the present invention to treat an HCV infection. Any pharmaceutical composition described herein can be used for this purpose. These methods typically comprise administering an effective therapeutic amount of a pharmaceutical composition of the present invention to a patient with HCV, thereby reducing the viral level of HCV in the patient's blood or liver. When the pharmaceutical composition includes other therapeutic agents, it may also treat other diseases, disorders or conditions in the patient. In one embodiment, the pharmaceutical composition which is administered comprises 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 is a salt, solvate or drug thereof, and at least one other anti-HCV agent selected from inhibitors of RNA polymerase dependent on HCV RNA, HCV protease inhibitors or HCV helicase inhibitors. In another embodiment, the pharmaceutical composition that is administered comprises 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 is a salt, solvate or drug thereof, and at least other anti-HCV agents, each of which is independently selected from inhibitors of RNA polymerase dependent on HCV RNA, HCV protease inhibitors or HCV helicase inhibitors . In yet another embodiment, the pharmaceutical composition that is administered comprises at least a compound of the present invention selected from Formulas I, II, III, IV, V, VI, VII or VIII, or from Examples 1 -255, or is a salt, solvate or drug thereof, and 1, 2 or more inhibitors of RNA polymerase dependent on HCV RNA (for example those described in WO 0190121 (A2), US 6348587 B1, WO 0160315, WO 0132153, EP 1162196 A1 and WO 0204425). In yet another embodiment, the pharmaceutical composition that is administered comprises 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 is a salt, solvate or drug thereof, and 1, 2 or more inhibitors of HCV protease (e.g., BILN-2061, VX-950 and SCH503034). In yet another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from Formulas I, II, III, IV, V, VI, VII or VIII, or from Examples 1-255, or is a salt, solvate or drug thereof, and at least one anti-HIV agent, anti-HBV agents, anti-hepatitis A agents, anti-hepatitis D agent, anti-hepatitis E agents, or anti-hepatitis G agents. further aspect, the present invention provides methods for using a compound (s) of the present invention and another therapeutic agent (s) to treat HCV infection. The methods comprise administering an effective therapeutic amount of a compound (s) of the present invention and another therapeutic agent (s) to a patient with HCV, thereby reducing the viral level of HCV in the blood or liver of the patient. Each compound of the present invention of the present invention (or a salt, solvate or prodrug thereof) and the therapeutic agent (s) can be combined in a single formulation and administered simultaneously to the patient. They can also be administered simultaneously but in different formulations. In addition, they can be administered sequentially. In one embodiment, the compound (s) of the present invention that is administered includes one or more compounds selected from Formulas I, II, III, IV, V, VI, VII or VIII, or from Examples 1-255, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes one or more agents selected from inhibitors of RNA polymerase dependent on HCV RNA, HCV protease inhibitors or HCV helicase inhibitors. . In another embodiment, the compound (s) of the present invention that is administered includes one or more compounds selected from Formulas I, II, III, IV, V, VI, VII or VIII, or of Examples 1-255, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes two or more agents selected from HCV RNA-dependent RNA polymerase inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In yet another embodiment, the compound (s) of the present invention which is administered includes one or more compounds selected from Formulas I, II, III, IV, V, VI, VII or VIII, or from Examples 1-255, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes one, two or more HCV RNA dependent RNA polymerase inhibitors (for example, those described in WO 0190121 (A2), US 6348587B1, WO 0160315, WO 0132153, EP1162196A1 and WO 0204425). In still another embodiment, the compound (s) of the present invention which is administered includes one or more compounds selected from Formulas I, II, III, IV, V, VI, VII or VIII, or from Examples 1-255, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes one, two or more HCV protease inhibitors (e.g., BILN-2061, VX-950 and SCH503034). A compound of the present invention (or a salt, solvate or prodrug thereof) can also be co-administered with other desired drugs, such as anti-HIV agents, anti-HBV agents, anti-hepatitis A agents, anti-hepatitis agents. D, anti-hepatitis E agents, anti-hepatitis G agents, or other antiviral drugs. A compound of the present invention (or a salt, solvate or prodrug thereof) can be administered to a patient in a single dose or divided doses. A typical daily dose may vary, without limitation, from 0.1 to 200 mg / kg of body weight, such as 0.25 to 100 mg / kg of body weight. Individual dose compositions may contain these amounts or sub-multiples thereof to form the daily dose. Preferably, each dose contains a sufficient amount of a compound of the present invention that is effective to reduce the viral load of HCV in the blood or liver of the patient. The amount of the active ingredient, or the active ingredients that are combined to produce an individual dosage form may vary depending on the host treated and the particular mode of administration. It should be understood that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, administration, excretion rate, drug combination, and the severity of the therapy that the particular disease experiences. In still another aspect, the compounds of Formulas I, II, III, IV, V, VI, VII or VIII, or their pharmaceutically acceptable salts, stereoisomers or tautomers, can be administered as a single pharmaceutical agent, or used in combination with one or more other agents, to treat infections or symptoms associated with other viruses that contain RNA. The treatment or prevention of infection caused by RNA-containing viruses can be provided through a combination therapy comprising a therapeutically effective amount of a first anti-viral agent provided by one or more compounds, or salts thereof, of the Formulas I, II, III, IV, V, VI, VII or VIII, together with a therapeutically effective amount of a second agent provided by one or more compounds selected from the group consisting of another anti-viral agent; a host immune modulator; interferon-derivative, such as interferon-alpha, interferon-alpha to pegylated, interferon-beta, and interferon-gamma; a cytokine; a vaccine; a nucleoside analogue; inhibitors of key enzymes that result in HCV dysfunction, examples of such enzymes are HCV metalloprotease, HCV serine protease, inosine monophosphate dehydrogenase (IMPDH), and HCV helicase; inhibitors of viral particle proteins such as HCV NS4B protein, and HCV NS5a protein; and agents that inhibit HCV function, such as HCV entry, HCV assembly, and HCV discharge. Also included are vaccines comprising HCV antigens or auxiliary antigen combinations directed against HCV. Also included are agents that interact with host cellular components to block viral protein synthesis by inhibiting the translation step initiated by the internal ribosome entry site (IRES) of HCV viral replication or to block viral particle maturation and release. with agents targeting the membrane protein virophorin family such as, for example, HCV P7. In one embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of Formulas I, II , III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to a method for treating or preventing infection caused by a virus containing RNA comprising co-administering a patient with the need of said treatment, one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound of Formulas I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents selected from the group consisting of interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an auxiliary, and a second antiviral agent, or a combination thereof, with an amount Therapeutically effective of a compound of Formulas I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent that inhibits HCV replication by inhibiting host cell functions associated with viral replication, or a combination thereof, with a therapeutically amount effective 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 is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with 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 is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents treating patients with disease caused by hepatitis B infection (HBV), with a therapeutically effective amount of a compound of Formulas I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents treating patients with disease caused. by infection with human immunodeficiency virus (HIV), with a therapeutically effective 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" (or "co-therapy") is intended to encompass the administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is also intended to encompass the co-administration of these agents in a substantially simultaneous form, such as through oral ingestion or an individual capsule having a fixed ratio of these active agents or ingestion of multiple separate capsules for each agent. "Combination therapy" will also include simultaneous or sequential administration via oral, intravenous, intramuscular or other parenteral routes in the body, including direct absorption through mucous membrane tissues, such as those found in the passages of senos. Sequential administration also includes drug combinations, wherein the individual agents can be administered at different times and / or different routes but which act in combination to provide a beneficial effect., for example, through co-action of pharmacokinetic or pharmacodynamic effects of each agent. The present invention also relates to the use of the compounds of the invention, or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the manufacture of medicaments for the treatment of HCV or other viral infections. In one embodiment, the present invention relates to the use of compounds of the present invention selected from the 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 salts, solvates or prodrugs thereof) for the manufacture of a medicament for the treatment of HCV infection, wherein each of the two or more compounds independently is selected from Formulas I, II, III, IV, V, VI, VII or VIII. In yet another embodiment, the present invention modalizes the use of at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one additional therapeutic agent for the manufacture of a medicament for the treatment of HCV infection. Preferably, the compound (s) of the present invention is selected from Formulas I, II, III, IV, V, VI, VII or VIII), and the additional therapeutic agent (s) may be selected, by way of illustration and not limitation, antiviral agents (eg, anti-HIV agents or other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, and anti-inflammatory agents. Specific examples of additional therapeutic agents include, but are not limited to, ribavirin; interferons (for example, IFN alpha 2a or 2b); protease inhibitors; immunosuppressants; antibodies (e.g., monoclonal or therapeutic chimeric antibodies); antisense or siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); agents for the treatment of cirrhosis and inflammation of the liver; Omega IFN (BioMedicines Inc., Emeryville, CA); serine protease inhibitor BILN-2061 (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); antiviral from Summetrel (endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegays and PEGylated Ribavirin IFN-alpha 2a / ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); immunosuppressant of HCV IgG CelICept (F. Hoffmann-La Roche LTD, Basel, Switzerland); IFN-alpha lymphoblastoid Wellferon (GalxoSmithKIine foot, Uxbridge, UK); Albumin IFN-alpha 2b Albuferon-alpha (Human Genome Sciences Inc., Rockville, MD); Levovirin ribaviridine (ICN Pharmaceuticals, Costa Mesa, CA); inhibitor of IDN-6556 caspase (Idun Pharmaceuticals Inc., San Diego, CA); IP-501 antifibrotic (Indevus Pharmaceuticals Inc., Lexington, MA); INF-Actimmune range (InterMune Inc., Brisbaen, CA); Infergen to IFN alfacon-1 (InterMune Inc., Brisbaen, CA); ISIS 14803 antisense (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmacueticals Inc., New York, Y); inhibitor JTK-003 RdRp (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); Ceplene immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); immunosuppressant HCV IgG Civacir (Nabi Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-alpha 2b / alpha 1-thymosin (RegeneRx Biopharmaceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); inhibitor of Levovirin IMPDH (Ribapharm Inc., Costa Mesa, CA); inhibitor Viramidine IMPDH (Ribapharm Inc., Costa Mesa, CA); Heptazyme ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); Intron A IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); PEG-Intron PEGylated IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); Rebetron IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Ribavirin (Schering-Plow Corporation, Kenilworth, NJ); PEG-Intron / PEGylated Ribavirin IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Zadazim immune modulator (SciClone Pharmacueticals Inc., San Mateo, CA); Rebif IFN-beta 1a (Serono, Geneva, Switzerland), IFN-beta and EMZ701 IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); inhibitor of T67 beta-tubulin (Tularik Inc., South San Francisco, CA); inhibitor of VX-497 IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); serine protease inhibitor VX-9507LY-570310 (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); Natural IFN-alpha Omniferon (Viragen Inc., Plantatiom FL); monoclonal antibody XTL-002 (XTL Biopharmaceuticals); VX-950 compound (Vértex Pharmaceuticals Inc.); compound SCH503034 (Schering-Plow Co.); and compound GS9137 (Gilead Sciences, Inc., Foster City, CA). In still another embodiment, the present invention modalizes the use of at least one compound of the present invention (or a salt, soivate or prodrug thereof) and at least one additional anti-viral agent for the manufacture of a medicament for the viral infection treatment. Preferably, the compound (s) of the present invention is selected from Formulas I, II, III, IV, V, VI, VII or VIII, and the additional antiviral agent (s) may be selected, without limitation, from anti-HCV or anti-HIV agents. In one example, the present invention modalizes 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 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 HCV RNA-dependent RNA polymerase (eg, nucleoside or non-nucleoside polymerase inhibitors) or inhibitors of HCV protease. In another example, the present invention modalizes the use of at least one compound of the present invention selected from Formulas 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 can be independently selected from inhibitors of RNA polymerase dependent on HCV RNA or HCV protease inhibitors. In still another embodiment, the present invention modalizes 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 one anti-HIV agent for the manufacture of a medicament for the treatment of HCV or HIV infection. In yet another embodiment, the present invention modalizes 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 one anti-hepatitis A, anti-hepatitis B, anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agent for the manufacture of a medicament for the treatment of viral hepatitis. In a further embodiment, the present invention modalizes the use of at least one compound of the present invention selected from Formulas I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof) ), and at least one agent for treating inflammation of the liver, for the manufacture of a medicament for the treatment of hepatitis C. The foregoing description of the present invention provides the illustration and the description, but is not intended to be exhaustive or to limit the invention to what is just described. Modifications and variations are possible in view of the above teachings or can be acquired from the practice of the invention. In this way, it should be noted that the scope of the invention is defined by the claims and their equivalents.

Claims (20)

1. - A compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula I, wherein: IA and B are each independently selected from carbocyclyl or heterocyclyl, and each independently is substituted with one or more of R18, wherein R18 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, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls -OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRs) Rs', -Ls-S (0) Rs, -Ls-S02Rs, - Ls-C (0) N (RsRs '), -Ls-N (Rs) C (0) RS', -Ls-C (= NRS) N (RS-Rs "). -Ls- N (Rs) C (= N Rs) RS ', -Ls-N (Rs) C (0) N (Rs.Rs ||). -Ls-N (Rs) S02Rs., -Ls-S02N (RsRs), and -Ls- N (Rs) S02N (Rs Rs); W, and W2, each is selected from N or C (R33); Z is a bond, -CR41R41- or -NR41-, wherein R41 and R41 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; R10 and R33 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -Ls-0-Rs, -Ls-S-Rs, - Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RSRS), - LS-C (= NRS) RS-, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs-, -Ls-C (= NRs) N (Rs Rs'), -Ls- N (Rs-) C (= NRs) Rs ··, -Ls-N (Rs) C (0) N (Rs.Rs-). -Ls-N (Rs) S02Rs-, -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs' |). -LE-Q-LE - (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18); X is selected from the group consisting of a link, -Ls-0-, -Ls-S-, -Ls-C (O) -, -Ls-N (RS) -, - Ls-N (Rs) C (0) -, -Ls-C (0) N (Rs) -, -Ls-N (Rs) C (0) 0-, -Ls-OC (0) N (Rs) -Ls-N (Rs) C (0) N (Rs) -, -Ls-C (= NRS) N (RS) -, -Ls-N (RS) C (= NRS) -, -Ls-S (0) -, -Ls-S02-, -Ls-C (0) 0 -and -Ls-OC ( OR)-; R22 is carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R26, wherein R26 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl , phosphate, azido, alkyl, alkenyl, alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS '), -Ls- C (= NRs) Rs ', -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) RS', -Ls -C (= NRs) N (RS'Rs "). -Ls-N (Rs-) C (= NRs) Rs", -Ls-N (Rs) C (0) N (Rs-Rs-). -Ls-N = C (NRsRs ') (NRsRs |), -Ls-N (Rs) S02RS', -Ls-S02N (RSRs), -Ls-N (Rs) S02N (Rs-Rs- |). - LE-Q-LE- (C3-C18 carbocyclyl) and -LE-Q-LE '- (heterocyclyl of M3-M18); or R22 is alkyl, alkenyl or alkynyl, and is optionally substituted with one or more of R26; or R22 is hydrogen; Y is selected from the group consisting of a bond, -O-, -C (O) -, -S (0) 2-, -S (O) -, -OS (0) 2-, - OS (O) -, -C (0) 0-, -OC (O) -, -OC (0) 0-, -C (0) N (R15) -, -N (R15) C (0), -C (0 ) N (R15) 0-, - N (R15) C (0) 0-, -C (0) N (R15) N (R15 '), -S-, -C (S) -, -C (S ) 0-, -OC (S) -, -C (S) N (R15), -N (R15) -, -N (R15) C (S) -, -N (R15) S (0) -, -N (R15) S (0) 2-, -S (0) 2N (R15) -, S (0) N (R15), -C (S) N (R 5) 0-, and -C (S) ) N (RS) N (R15 ') -, where R15 and R15 > are independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl; R50 is -L1-A1, wherein A1 is selected from the group consisting of carbocyclyl, heterocyclyl, alkyl, alkenyl and alkynyl, and L1 is selected from the group consisting of a bond, alkylene, alkenylene and alkynylene, wherein A1 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl , -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS-) . -Ls-C (= NRs) Rs-, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls- N (Rs) C (0) Rs, -Ls-C (= NRs) N (RS'Rs "). -Ls-N (RS ') C (= NRs) Rs", -Ls-N (RS) C (0) N (RS'-RS "). -LS-N (RS) S02RS'-, -LS-S02N (RsRs), -LS-N (RS) S02N (Rs) RS "), -LE-Q-LE- (C3-Ci8 carbocyclyl) and -L £ -Q-LE- (heterocyclyl of M3-M, 8), and wherein L1 is optionally substituted with one or more of R38 , and R38 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkoxy, thioalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylamino, alkoxycarbonylamino, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs' ), -Ls-C (= NRs) Rs, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) RS ', -Ls-C (= NRs) N (Rs Rs), -Ls-N (Rs.) C (= NRs) Rs ·, -Ls-N (Rs) C (0) N (Rs Rs "), -Ls-N (Rs) S02Rs, -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs "). carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, -LE-Q-LE. - (C3-Ci8 carbocyclyl) and - LE-Q-LE- (M3-M18 heterocyclyl); Ls is independently selected at each occurrence of the group consisting of a bond, alkylene, alkenylene and alkynylene; Rs, Rs1 and Rs "are independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl , alkoxycarbonylamino and alkoxycarbonylaminoalkyl; LE and LE 'are independently selected in each occurrence of the group consisting of a bond, alkylene, alkenylene and alkynylene; Q is independently selected at each occurrence from the group consisting of a bond, alkylene, alkenylene, alkynylene, -S-, -O-, -C (O) -, -N (RS) -, -N (Rs) C ( 0), -C (0) N (Rs) -, - N (Rs) C (0) 0-, -OC (0) N (Rs) -, -N (Rs) C (0) N (Rs) -, -C (= NRS) N (RS) -, -N (RS) C (= NRS) -, -S (O) -, -S02-, -0-S02-, -S02-0-, - OS (O), -S (0) -0-, -C (0) 0- and -OC (O); R10, R15, R15 ', R18, R26, R30, R33, R35, R38, R41, and R41 are independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy , mercapto, nitro, cyano, amino, carboxy, formyl, phosphate and azido; and each carbocyclyl portion of C3-C18 and heterocyclyl of M3-M18 in -LE-Q-LE '- (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18) is optionally independently substituted in each occurrence with at least one substituent selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy , alkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino, and alkoxycarbonylaminoalkyl.

2. The compound, tautomer or salt according to claim 1, wherein: A and B are independently selected from a carbocyclyl of C Cn or hete roci the i lo of M-4, and are optionally substituted with one or more of R18, wherein R 8 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, d-C6 alkyl, alkenyl C2-C6, C2-C6 alkynyl, C3-C6 carbocyclyl, heterocycle of M3-6, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs. -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRs) Rs', -Ls-S (0) Rs. -Ls-S02Rs, -Ls-C (0) N (RsRs.), -Ls-N (Rs) C (0) RS ', -Ls-C (= NRs) N (Rs'Rs'. -LS- N (RS) C (= NRS) RS ·, -Ls-N (Rs) C (0) N (Rs-Rs ||). -Ls-N (Rs) S02Rs., -Ls-S02N (RsRs), and -Ls-N (Rs) S02N (RS'Rs ||); W, and W2 each is selected from N or C (R33); Z is a bond, -CR 1R41 - or -NR41-, where R41 and R41 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R10 and R33 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl of -Ce, alkenyl of C2-C6, alkynyl of C2-C6, carbocyclyl of C3-C6, heterocyclyl of M3- M6, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs, -Ls- C (= NRs) Rs-, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs., -Ls -C (= NRs) N (Rs.Rs), -Ls- N (Rs-) C (= NRs) Rs ", -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs-, -Ls-S02N (RsRs'), -Ls-N (Rs) S02N (Rs Rs | ·), -LE-Q-LE- (carbocyclyl of C3-Ci8) and -LE-Q- LE- (heterocyclyl of M3-18); X is selected from the group consisting of a bond, -Ls-0-, -Ls-S-, -Ls-C (O) -, -Ls-N (RS) - , - Ls-N (Rs) C (0) -, -Ls-C (0) N (Rs) -, -Ls-N (Rs) C (0) 0-, -l_s-OC (0) N ( Rs) -Ls-N (Rs) C (0) N (Rs) -, -Ls-C (= NRs) N (Rs) -, -Ls-N (RS ') C (= NRs) -, -Ls -S (0) -, -Ls-S02-, -Ls-C (0) 0-y -Ls-OC (0) -; R22 is C4-Cn carbocyclyl or M4-Mn heterocyclyl, and is optionally substituted with one or more of R26, wherein R26 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ^ alkyl- Ce, C2-C6 alkenyl, C2-C6 alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS.), - Ls-C (= N Rs) Rs , -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls- N (Rs) C (0) Rs-, -Ls-C (= NRs) N (Rs-Rs "). -Ls-N (Rs.) C (= NRs) Rs ", -Ls-N (Rs) C (0) N (RS'Rs · |), -Ls-N = C (NRsRs ') (NRsRs') , -Ls-N (Rs) S02RS ', -Ls-S02N (RSRs), -Ls-N (Rs) S02N (Rs Rs ||). - LE-Q-LE- (C3-C18 carbocyclyl) and - LE-Q-LE- (heterozyme the I o of M3-Mi8) or R22 is C-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and is optionally substituted with one or more of R26 or R22 is hydrogen, and is selected from the group consisting of a bond, -Ls-0-, -Ls-C (O) -, -Ls-S (0) 2-, -Ls-S (O) -, -Ls-OS (0) 2-, -Ls-OS (0) -, -Ls- C (0) 0, -Ls-OC (O) -, -Ls-OC (0) 0-, -Ls-C (0) N (R15) -, -Ls-N (R15) C (0), -Ls-C (0) N (R 5) 0-, -Ls-N (R15) C (0) 0-, - Ls-C (O) N (R 15) N (R 15), -Ls- S-, -Ls-C (S) -, -Ls-C (S) 0-, -Ls-OC (S) -, - Ls-C (S) N (5), -LS-N (R15) -, -LS-N (R 5) C (S) -, -Ls-N (R 5) S (0) -, -Ls- (R 15) S (0) 2-, -Ls-S (0 ) 2N (R15) -, -Ls-S (0) N (R15), -Ls-C (S) N (R) 0-, and -LS-C (S) N (R1S) N (R15 ') -, wherein R15 and R15 are independently selected at each occurrence from the group consisting of hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R50 is -L1-A1, wherein A1 is selected from the group consisting of C4-Cn carbocyclyl, M4-Mn heterocyclyl, alkyl, alkenyl, and alkynyl, and L1 is selected from the group consisting of a bond, alkylene, alkenylene and alkynylene, wherein A1 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate , azido, alkyl C2-C6 alkenyl, C2-C6 alkynyl, -Ls-O-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0 ) ORs, -Ls-N (RSRs), -LS-C (= NRS) RS-, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (Rs S '). -Ls- N (Rs) C (0) Rs, -LS-C (= NRS) N (RS Rs), -Ls-N (Rs-) C (= NRs) Rs-, -Ls-N (RS) C (0) N (RS'-Rs ·), -LS-N (RS) S02RS'-, -LS-S02N (RsRs), -LS-N (RS) S02N (Rs RS "), -LE-Q -LE- (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M, 8), and wherein L1 is optionally substituted with one or more of R38, and R38 is independently selected at each occurrence of the group that consists of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, Ci-C6 alkoxy, d-C6 thioalkoxy, d-C6 alkylcarbonyl, Ci-C6 alkoxycarbonyl, alkylcarbonyloxy Ci-C6, alkylamino of d-C6, alkoxycarbonylamino of d-C6, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls -C (0) ORs, -Ls-N (RsRs), -LS-C (= NRS) RS., -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs ), -Ls-N (Rs) C (0) Rs, -LS-C (= NRS) N (RS Rs.), -LS-N (RS) C (= NRS) RS-, -Ls-N ( Rs) C (0) N (Rs Rs "), -Ls-N (Rs) S02RS ', -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs ·), carbocyclyl, heterocyclyl, carbocyclylalkyl of d-C6, heterocyclylalkyl of -Ce, -LE-Q-LE. - (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18); Ls is independently selected in each occurrence of the a group consisting of a bond, C ^ -Ce alkylene, C2-C6 alkenylene and C2-C6 alkynylene, Rs, Rs1 and Rs1 'are independently selected at each occurrence from the group consisting of hydrogen, d-Ce alkyl , alkenyl C2-C6 alkynyl, C2-C6 alkynyl, C4-C2-alkoxy d-Ce alkoxy, d-Ce alkyl-C6-alkoxy, d-C6 alkoxy-d6-C6 alkoxy C, thioalkoxy of C! -Ce-Ci-C6 alkyl, d-C6 alkylcarbonyl, d-C6 alkylcarbonyl-C ^ -6 alkyl, CrC6 alkoxycarbonyl, C, -C6-alkoxycarbonyl -C6, Ci-C6 alkylcarbonyloxy, d-C6-C6 alkylcarbonyloxy, C! -Ce alkylamino, d-C6 alkylamino Ci-C6 alkyl,?, -? Alco alkoxycarbonylamino and dicarboxylamino alkoxycarbonylamino C6-d-Ce alkyl; LE and · are independently selected in each occurrence of the group consisting of a bond, alkylene of d-C6, alkenylene of C2-C6 and alkynylene of C2-C6; Q is independently selected at each occurrence from the group consisting of a bond, Ci-C6 alkylene, dd alkenylene, C2-C6 alkynylene, -S-, -O-, -C (O) -, -N (RS ) -, -N (Rs) C (0), -C (0) N (Rs) -, -N (Rs) C (0) 0-, -OC (0) N (Rs) -, -N ( Rs) C (0) N (Rs) -, -C (= NRS) N (RS ') -, -N (RS.) C (= NRS) -, -S (O) -, -S02-, - 0-S02-, -S02-0-, -OS (O), -S (0) -0-, -C (0) 0- and -OC (O); R10, R15, R15 ', R18, R26, R30, R33, R35, R38, R41, and R41 are independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy , mercapto, nitro, cyano, amino, carboxy, formyl, phosphate and azido; and each carbocyclyl portion of C3-C18 and heterocyclyl of M3-M18 in -LE-Q-LE .- (C3-C18 carbocyclyl) and -LE-Q-LE - (heterocyclyl of M3-M18) is independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, dd alkoxy, thioalkoxy Ci-C6, Ci-C6 alkoxy Ci-C6 alkyl, dd-Ci-C6 alkyl thioalkoxy, dd alkylcarbonyl, d-alkyl d6 alkylcarbon, dd alkoxycarbonyl, dd alkoxycarbonyl dd, dd alkylcarbonyloxy, dd alkyl alkylcarbonyloxy of C 1 -C 6, C 1 -C 6 alkylamino, C 1 -C 6 alkylamino C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino, and dC 6 alkoxycarbonylamino CrC 6 alkyl.

3. The compound, tautomer or salt according to claim 1, wherein: Y is -L, -0-, -Ls-S- or -LS-N (R15); and A1 is C4-C carbocyclyl or 4- n-heterocyclyl and is optionally substituted with one or more of R30.

4. The compound, tautomer or salt according to one of claims 1-3, wherein A and B are each independently selected from C5-C6 carbocyclyl or M5-M6 heterocyclyl and are each independently optionally replaced with one more than R18.

5. The compound, tautomer or salt according to one of claims 1-4, wherein W, and W2 are N, and Z is -NR41-.

6. The compound, tautomer or salt according to one of claims 1-5, wherein X is -O- or -S-, and R22 is C5-C6 carbocyclyl or 5-M6 heterocyclyl and is optionally substituted with one or more of R26. 7.- The compound, tautomer or salt according to one of the Claims 1-6, wherein the portion select from the group that consists of where Q is N or C (R33); Y 1 or R R17, R33 and R35 each is independently selected in each occurrence of the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl of C! -Ce, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocyclyl, heterocyclyl of M3-M6, -Ls-0-Rs, -Ls-S-Rs, -l_s-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS '), -Ls-C (= NRs) Rs', -Ls-S (0) Rs, -Ls- S02Rs, -Ls-C (0) N (RsRs <), - -N (Rs) C (0) Rs., -Ls-C (= NRS) N (RS-Rs "). -LS-N ( RS ') C (= NRS) RS .., -Ls-N (Rs) C (0) N (Rs Rs ||), -Ls-N (Rs) S02RS', -Ls-S02N (RsRs), - Ls-N (Rs) S02N (Rs Rs |). -LE-Q-LE - (carbocyclyl of C3-C18) and -LE-Q-LE - (heterocyclyl of M3- 18) 8.- The compound, tautomer or salt according to one of claims 1-7, wherein R22 is and is optionally substituted with one or more of R, and wherein R is hydroxy, amino, C 1 -C 6 alkylamino, C 1 -C 4 alkoxy, C -C 6 alkoxycarbonylamino or Ci-C 6 alkylcarbonyloxy. 9. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has the Formula II: ? wherein: R6 is selected from the group consisting of hydrogen and cyano; R8 is selected from the group consisting of hydrogen and arylalkyl; R25 is selected from the group consisting of hydrogen and alkyl; R37 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and cycloalkyl; R42 is selected from the group consisting of arylsulfanyl, heteroarylsulfanyl and aryloxy; wherein R42 is optionally substituted with one or more substituents independently selected from R46; R46 is one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, dialkylamino and alkoxycarbonylamino; R70 is selected from the group consisting of aryl, and heterocycle; wherein R70 is optionally substituted with R75; R 75 is one or more substituents independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, alkyl, haloalkyl and aryl. 10. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula III: wherein R is selected from the group consisting of hydrogen, alkylcarbonyl and haloaryl. 11. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula IV: IV wherein: Q is selected from the group consisting of N and CH; R1 is selected from the group consisting of alkylsulfanyl, cyanoalkylsulfanyl and alkyl; R19 is selected from the group consisting of alkyl and haloarylalkoxy; R56 is selected from the group consisting of hydrogen, hydroxy, alkyl, and alkylcarbonylamino. 12. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has the Formula V: wherein: R5 is selected from the group consisting of hydrogen and alkylsulfanyl; R29 is selected from the group consisting of alkyl, arylalkoxy, halogen, and haloarylalkoxy; R47 is selected from the group consisting of alkyl, haloalkyl, alkylsulfanyl, arylalkylsulfanyl, and heterocycle; R64 is selected from the group consisting of hydrogen, alkoxy and alkyl; R66 is selected from the group consisting of hydrogen, hydroxy, aryloxy, alkylsulfonyloxy, alkylcarbonylaminosulfonoyloxy, haloarylsulfonyloxy, cyano, arylaxy, alkylcarbonylamino, halogen and alkyl; R81 is selected from the group consisting of hydrogen, alkoxy and carbonyl, 13. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula VI: SAW wherein: R73 is alkyl; R76 is selected from the group consisting of hydroxy, alkylaminocarbonyl and alkylcarbonylamino. 14. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula VII: where: A is selected from the group consisting of O and S; R21 is selected from the group consisting of hydrogen and hydroxy; or R21 taken together with R39 form a heterocycle of 5-12 members containing at least two heterogeneous atoms selected from the group consisting of O, N, and S; wherein the heterocycle is optionally substituted aryl or halogen; R39 is selected from the group consisting of hydrogen, alkyl, arylalkenyl, dialkylamino, heteroaryl, haloheteroaryl, haloarylaminosulfonyl, arylsulfonyloxy, alkylcarbonyloxy; cycloalkylaminocarbonyl, arylalkoxycarbonylamino, haloheteroaryl, alkoxycarbonyl, and NH-R99; R99 is selected from the group consisting of hydrogen, arylalkyl, cycloalkylalkyl, aryl, heteroaryl, haloarylalkylamino, arylalkylamino, and alkyheteroaryl; R67 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcycloalkyl; R96 is selected from the group consisting of hydrogen, hydroxy, amino, alkoxy, arylsulfonyloxy, alkylcarbonylamino, alkoxy, halogen, alkoxycarbonyloxy, haloalkoxycarbonylamino and arylalkoxy. 15. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has the Formula VIII: vm wherein: R23 is selected from the group consisting of hydrogen, alkoxyaryl, alkoxyarylsulfonyl, hydroxyarylsulfanyl, haloarylalkoxy, cyanoarylalkoxy and arylalkoxy; R31 is selected from the group consisting of hydrogen and halogen; R49 is selected from the group consisting of hydrogen, arylalkoxy, haloarylcarbonylamino, alkoxyarylcarbonylamino, arylalkenyl, arylalkyl, halogen, cyano, haloaryloxyalkyl, alkyl, alkoxyarylsulfanyl, haloheteroaryl, and alkoxycarbonyl; R52 is selected from the group consisting of hydrogen, halogen, hydroxyaryloxy alkyl, aryloxy, hydroxyalkylaryloxy, alkoxyarylalkyl, alkoxyaryloxy, alkylarylalkoxyarylamino, arylalkyl, heteroaryl and aminoaryloxy; R77 is selected from the group consisting of hydrogen, alkyl and cycloalkyl. 16. - A pharmaceutical composition comprising a compound, tautomer or salt according to one of claims 1-15. 1

7. - A method to inhibit HCV virus replication, which comprises contacting the HCV virus with an effective amount of a compound, tautomer or salt according to one of claims 1-15, thereby inhibiting the replication of said virus. 1

8. A method for treating an HCV infection, comprising administering an effective amount of a compound, tautomer or salt according to one of claims 1-15 to a patient with HCV, thereby reducing the viral level of HCV in the blood or liver of the patient. 19.- The use of a compound, tautomer or salt according to one of claims 1-15 for the manufacture of a medicament for the treatment of HCV infection or for inhibiting HIV replication. 20. A process for making a compound according to one of claims 1-15, comprising the steps described in one of the schemes 1-8.