ANTIVIRAL AGENTS FIELD OF THE INVENTION The invention relates to the field of pharmaceutical chemistry, in particular, with compounds, compositions and methods for treating viral infections in mammals, mediated, at least in part, by a virus in the Flaviviridae virus family. .
BACKGROUND OF THE INVENTION Chronic HCV infection is a major health problem associated with liver cirrhosis, hepatocellular carcinoma and liver failure. It is estimated that there are 170 million chronic carriers throughout the world at risk of developing liver diseases1,2. In the United States alone, more than 2.7 million people are chronically infected with HCV, and the number of deaths related to HCV in the year 2000 has been estimated between 8,000 and 10,000, a figure that is estimated to be will increase significantly in the coming years. HCV infection is insidious in a high proportion of chronically infected (and infectious) carriers, who may not experience clinical symptoms for many years. Liver cirrhosis can eventually lead to liver failure. Currentlyrecognizes that liver failure arising from chronic HCV infection is a preponderant cause of liver transplants. HCV is a member of the family of Flaviviridae RNA viruses, which affect animals and humans. The genome is a single RNA strand of about 9.6 kL lobases, and consists of an open reading frame encoding a polyprotein of about 3000 amino acids, surrounded by untranslated regions at the 5 'and 3' ends (5 'UTR). and 3 '). The polyprotein serves as a precursor for at least 10 separate viral proteins, critical for the replication and assembly of the viral particles of the progeny. The organization of the structural and non-structural proteins in the HCV polyprotein is as follows: C-El-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. As the HCV replication cycle does not comprise any DNA intermediate and the virus is not integrated into the host genome, it is theoretically possible to cure the HCV infection. Although the pathology of HCV infection mainly affects the liver, the virus is located in other cell types in the body, including lymphocytes in the peripheral blood3,4. Currently, conventional treatment for chronic HCV infection is interferon alfa (IFN-alpha)in combination with ribavirin, for which at least six (6) months of treatment are needed. IFN-alpha belongs to a family of small proteins of natural occurrence with characteristic biological effects, such as antiviral, immune regulation and antitumor activities, which are produced and secreted by most animal cells with nuclei in response to various diseases , in particular viral infections. IFN-alpha is an important regulator of growth and differentiation that affects cell communication and immune control. The treatment of HCV with interferon has frequently been associated with adverse side effects, such as fatigue, fever, chills, headaches, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders, and dysfunction of the thyroid. Ribavirin, an inhibitor of inosine 51 -monophosphate dehydrogenase (IMPDH), improves the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of patients do not eliminate the virus with the current conventional therapy of interferon-alpha (IFN) and ribavirin. More recently, standard therapy for chronic hepatitis C has been changed by the combination of pegylated IFN-alpha plus ribavirin. However, a number of patients still have effectssignificant collaterals, primarily related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated with the currently recommended doses, and the drug is teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load5, and there is a clear need for more effective antiviral therapy for HCV infection. A number of approaches are being studied to combat the virus. These include, for example, the application of antisense oligonucleotides or ribozymes to inhibit HCV replication. In addition, low molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered attractive strategies for controlling HCV infections. Among viral targets, NS3 / 4a protease / helicase and NS5b RNA-dependent RNA polymerase are considered to be the most promising viral targets for new drugs.68 8 Also through the attack of viral genes and their transcription and translation products , antiviral activity can also be obtained by attacking proteins from the host cells that are necessary for viral replication, for example, Watashi et al.antiviral activity inhibiting cyclophilins9 of host cells. As an alternative, it has been shown that a potent TLR7 agonist reduces plasma HCV levels in humans. 10 However, none of the previously described compounds has progressed beyond clinical trials 6, 8. In view of the global epidemic level of HCV and other members of the Flaviviridae virus family, and also considering the limited treatment options, there is a strong need for new effective drugs to treat infections caused by these viruses.
SUMMARY OF THE INVENTION The present invention relates to new compounds, compositions and methods for the treatment of viral infections in mammals, mediated, at least partially, by a member of the Flaviviridae family, such as HCV. Specifically, the compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug or tautomer thereof.wherein: Y is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl; HET is selected from the group consisting of a 6-membered arylene ring, a ring. 6-membered heteroarylene containing 1, 2, or 3 heteroatoms selected from N, 0, or S, and a bicyclic ring of the formulawherein HET is optionally substituted with (X) t, X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, halo, hydroxyl, and nitro; t is an integer equal to 0, 1 or 2; W1, W4, and W5 are independently N or CH; W3 is N, CH, or is a bond provided that not more than one nitrogen in the bicyclic ring is optionally oxidized to form an N-oxide; and each dotted line independently represents a single or double union between the two joined atoms, with the proviso that when one ofdotted lines is a simple union, the two contiguous atoms are each substituted with 1 or 2 hydrogen atoms to satisfy their valence; one of D or E is C-Ra and the other of D.o E is S; Ra and R are independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; Q is selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and Z is selected from the group consisting of (a) carboxy and carboxy ester; (b) -C (X4) NR8R9, wherein X4 is = 0, | = NH, or = N-alkyl, R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, alternatively, R8 and R9 together with the nitrogen atom attached thereto, form a heterocyclic, heterocyclic, heteroaryl or heteroaryl ring group substituted heteroaryl; (c) -C (X3) NR21S (0) 2R4, wherein X3 is selected from= 0, = NR24, y = S, wherein R24 is hydrogen, alkyl, or substituted alkyl; R4 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and NR22R23 wherein R21, R22 and R23 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; or alternatively, R21 and R22 or R22 and R23 together with the atoms attached thereto join to form an optionally substituted heterocyclic group; (d) -C (X2) - (R3) CR2R2 'C (= 0) R1, wherein X2 is selected from = 0, = S, y = NR1: L, where R11 is hydrogen or alkyl, R1 is selected from -0R7 and -NR8R9 wherein R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R8 and R9 are as defined above; R2 and R2 'are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or, alternatively, R2 and R2 'as defined are taken together with the carbon atom attached thereto to form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group, or, as another alternative, one of R2 or R2' is hydrogen, alkyl or substituted alkyl, and the other is attached, together with the carbon atom attached thereto, to the R7 or the oxygen atom attached thereto or R8 and the nitrogen atom bonded thereto to form a heterocyclic or substituted heterocyclic group: R3 is selected from hydrogen and alkyl or, when R2 and R2 'are not taken together to form a ring and when R2 or R2' and R7 or R8 do not join to form a heterocyclic or substituted heterocyclic group, then R3, together with the nitrogen atom attached thereto, may be taken together with one of R2 and R2 'to form a heterocyclic or substituted heterocyclic ring group; (e) -C (X2) -N (R3) CR25R26R27, in where X2 and R3 are defined above, and R25, R26 and R27 are independently selected from the group consisting of alkyl,substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, or R 25 and R 26 together with the carbon atom attached thereto form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; and (f) a carboxylic acid isostere wherein said isostere is not as defined in (a) - (e).
DETAILED DESCRIPTION OF THE INVENTION It should be understood that the terminology used in the present documentation is for the purpose of describing particular embodiments only, and should not be construed as limiting the scope of the present invention. In the present specification, and in the claims that follow it, reference will be made to a number of terms that are defined with the following meanings: As used in the present invention, "alkyl" refers to monovalent alkyl groups with between 1 and and 10 carbon atoms, preferably between 1 and 5 carbon atoms and more preferably 1 to 3 carbon atoms. Examples of this term include groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like.
"Substituted alkyl" refers to an alkyl group with from 1 to 3, and preferably 1 and 2, substituents that are selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl , substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. "Alkoxy" refers to the group "alkyl-O-", which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, p-pentoxy and similar before. "Substituted alkoxy" refers to the group "O-substituted alkyl". "Acyl" refers to the groups HC (O) -, alkyl-C (O) -, alkyl-C (O) -substituted, alkenyl-C (O) -, alkenyl-C (O) -substituted, alkynyl- C (O) -, C (O) -substituted alkynyl, C (O) - cycloalkyl, C (O) -substituted cycloalkyl, aryl-C (O) -, (C) -substituted aryl, heteroaryl -C (O) -, heteroaryl-C (O) -substituted, heterocyclic-C (O) -, and heterocyclic -C (O) -substituted. "Acylamino" refers to the group -C (0) NRfR9 where Rf and R9 are independently selected from the group consistingin hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein Rf and R9 are joined to form together with the atom of nitrogen a heterocyclic or substituted heterocyclic ring. "Acyloxy" refers to the C (0) 0- alkyl groups, C (0) 0- substituted alkyl, C (0) O- alkenyl, 0 (substituted) C (0) alkenyl, C (0) 0- alkynyl, 0 (substituted) (C) 0 alkynyl, aryl -C (0) 0-, aryl-C (0) 0- substituted, cycloalkyl- (0) 0-, cycloalkyl-C (0) 0- substituted, heteroaryl-C (0) O-, heteroaryl-C (O O- substituted, heterocyclic-C (O) 0- and heterocyclic-C (0) 0- substituted. "Alkenyl" refers to alkenyl groups having from 2 to 10 carbon atoms, preferably having 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy,cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that any hydroxyl substitution is not attached to a vinyl carbon atom (unsaturated ). "Alkynyl" refers to alkynyl groups having from 2 to 10 carbon atoms, preferably having from 2 to 6 carbon atoms, and more preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1-2. sites of alkynyl unsaturation. "Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that any hydroxyl substitution is not bound to an acetylenic carbon atom. "Amino" refers to the group -NH2. "Substituted amino" refers to the group - ^ R1,where Rh and R1 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and where Rh and R1 are attached, together with the nitrogen attached thereto, to form a heterocyclic or substituted heterocyclic group, with the proviso that Rh and R1 are not both hydrogen. When Rh is hydrogen and R1 is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When Rh and R1 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. "Aminoacyl" refers to the groups -NR ^ C (O) alkyl, -NRjC (O) substituted alkyl, -NRjC (0) -cycloalkyl, NRjC (0) substituted cycloalkyl, NRjC (0) alkenyl, -NRjC (0) substituted alkenyl,NRjC (O) alkynyl, -NRjC (0) substituted alkynyl, -NRjC (0) aryl, -NRjC (O) substituted aryl, NRjC (O) heteroaryl, -NRjC (O) substituted heteroaryl, -NRjC (O) heterocyclic, and -NR-'C (0) substituted heterocyclic where Rj is hydrogen or alkyl. "Aryl" or "Ar" refers to a monovalent carbocyclic group of 6 to 14 carbon atoms, which has asingle ring (e.g., phenyl) or multiple qondensed rings (e.g., naphthyl or anthryl), where the fused rings may be aromatic or non-aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H)) -one-7-yl, and the like), with the proviso that the point of attachment is in an aromatic ring atom. Preferred aryls include phenyl and naphthyl. "Aralkyl" or "arylalkyl" refers to the aryl-alkyl group and comprises, for example, benzyl. "Substituted aryl" refers to aryl groups that are substituted with from 1 to 3 substituents, and preferably 1 to 2 substituents, which are selected from the group consisting of hydroxyl, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, alkoxy substituted, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxyl, carboxylic esters, cyano, thiol, cycloalkyl, substituted cycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, heteroaryloxy, substituted heteroaryloxy, heterocycle, and substituted heterocycle. "Arylene" and "substituted arylene" refer to divalent aryl and divalent substituted aryl groups as defined above. "Phenylene" is an arylene group of6 members optionally substituted and comprises, for example, 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene. "Aryloxy" refers to the aryl-O- group, which includes, by way of example, phenoxy, naphthoxy and the like. "Substituted aryloxy" refers to aryl-O-substituted groups. "Carboxyl" refers to -C (= 0) OH or salts thereof, "Carboxylic esters" refers to the groups -C (0) 0-alkyl, -C (0) O-substituted alkyl, -C (0) ) O-alkenyl, C (O) O-substituted alkenyl, -C (O) O-alkynyl, -C (0) 0-substituted alkynyl, -C (0) O-aryl, -C (0) 0-aryl substituted, -C (0) -heteroaryl, -C (0) -substituted heteroaryl, -C (0) -heterocyclic, and -C (0) -substituted heterocyclic. Preferred carboxylated esters are -C (0) 0 -alkyl, -C (0) O-substituted alkyl, -C (0) 0 -aryl, and -C (0) 0 -substituted aryl. "Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms with single or multiple cyclic rings optionally comprising 1 to 3 exocarbonyl or thiocarbonyl groups. Suitable cycloalkyl groups include, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 3-oxocyclohexyl, and the like. In multiple condensed rings, one or more of the rings may be different from cycloalkyl (e.g., aryl, heteroaryl orheterocyclic) with the proviso that the point of attachment is to a carbon atom of the ring of the cycloalkyl group. In one embodiment, the cycloalkyl group does not comprise 1 to 3 exocarbonyl or thiocarbonyl groups. In another embodiment, the cycloalkyl group comprises 1 to 3 exocarbonyl or thiocarbonyl groups. It is understood that the term "exo" refers to the attachment of a carbonyl or thiocarbonyl to a carbon atom of the ring of the cycloalkyl group. "Substituted cycloalkyl" refers to a cycloalkyl group, having from 1 to 5 substituents that are selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylic esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. "Cycloalkenyl" refers to cyclic but nonaromatic alkenyl groups of 5 to 10 carbon atoms, having single or multiple cyclic rings optionally comprising 1 to 3 exocarbonyl or thiocarbonyl groups. Suitable cycloalkenyl groups include, by way of example, cyclopentyl, cyclohexenyl, cyclooctenyl, 3-oxocyclohexenyl, and the like. Inmultiple condensed rings, one or more of the rings may be other than cycloalkenyl (eg, aryl, heteroaryl or heterocyclic) with the proviso that the point of attachment is to a carbon atom of the ring of the cycloalkyl group. In one embodiment, the cycloalkenyl group does not comprise 1 to 3 exocarbonyl or thiocarbonyl groups. In another embodiment, the cycloalkenyl group comprises 1 to 3 exocarbonyl or thiocarbonyl groups. It is understood that the term "exo" refers to the attachment of a carbonyl or thiocarbonyl to a carbon atom of the cycloalkenyl group ring. "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents that are selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, aryloxy substituted, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylic esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and heterocyclic substituted with the proviso that for hydroxyl substituents the point of attachment is not a vinyl carbon atom. "Cycloalkoxy" refers to -O-cycloalkyl groups. "Substituted cycloalkoxy" refers to groups -O-cycloalkyl substituted. The term "guanidino" refers to the group NHC (= NH) NH2 and the term "substituted guanidino" refers to -NRPC (= NRP) N (Rp) 2 where each Rp is independently hydrogen or alkyl. "Halo" or "halogen" refers to fluoro, chlorine, bromine and iodine, and preferably is fluoro or chloro. "Haloalkyl" refers to an alkyl group substituted with 1 to 5 halogen groups. An example of haloalkyl is CF3. "Heteroaryl" refers to an aromatic group of 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and 1 to 4 heteroatoms which are selected from the group consisting of oxygen, nitrogen and sulfur, within the ring. Such heteroaryl groups may have a single ring (eg, pyridyl or furyl) or multiple fused rings (eg, indolizinyl or benzothienyl). The sulfur atom (s) in the heteroaryl group can (optionally) be oxidized to sulfoxide and sulfone moieties. "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents defined for substituted aryl. When a specific heteroaryl is defined as "substituted", eg. , substituted with quinoline, itunderstands that such heteroaryl contains the 1 to 3 substituents as specified above. "Heteroarylene" and "substituted heteroarylene" refer to divalent substituted heteroaryl and heteroaryl groups as defined above. "Heteroaryloxy" refers to the group -Q-heteroaryl, and "substituted heteroaryloxy" refers to the group -O-substituted heteroaryl. "Heterocycle" or "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated group with a single ring or condensed multiple rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring, which may optionally comprise from 1 to 3 exocarbonyl or thiocarbonyl groups. Preferably, said heterocyclic groups are saturated or unsaturated groups with a single ring or condensed multiple rings, between 1 and 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen within the ring. The sulfur atom (s) in the heteroaryl group can (optionally) be oxidized to sulfoxide and sulfone moieties. In multiple condensed rings, one or more of the rings may be different than heterocyclic (eg, aryl, heteroaryl or cycloalkyl) with the proviso that thepoint of attachment to a heterocyclic ring atom. In one embodiment, the heterocyclic group does not comprise 1 to 3 exocarbonyl or thiocarbonyl groups. In a preferred embodiment, the heterocyclic group comprises from 1 to 3 exocarbonyl or thiocarbonyl groups. It is understood that the term "exo" refers to the binding of a carbonyl or thiocarbonyl to a carbon atom of the heterocyclic ring. "Substituted heterocyclic" refers to heterocyclic groups that are substituted with from 1 to 3 of the same substituents defined for substituted cycloalkyl. Preferred substituents for the substituted heterocyclic groups include heterocyclic groups having from 1 to 5 atoms having substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylic esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. When a specific heterocyclic is defined as "substituted", eg. , substituted morpholino, it is understood that said heterocycle contains the 1 to 3 substituents as indicated above. Examples of heterocycles and heteroaryls include,without limitation, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinoline, carbazole, carboline , fenantridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4, 5, 6, 7-tetrahydrobenzo [b ] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also known as thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl and the like. "Heterocyclyloxy" refers to the -0-heterocyclic group, and "substituted heterocyclyloxy" refers to the -O-substituted heterocyclic group. The term "thiol" refers to the group -SH. "Isteros" are different compounds that have different molecular formulas but exhibit the same or similar properties. For example, tetrazole is an isostere of the carboxylic acid because it copies the properties of the carboxylic acid while still having very different molecular formulas. Tetrazole is one of the many possible isosteric replacements for the carboxylic acid. Other isosteres of the carboxylic acid contemplated by thepresent invention include -COOH, -S03H, -S02HNRk, P02 (Rk) 2, -CN, -P03 (Rk) 2, -0Rk, -SRk, -NHCORk, -N (Rk) 2, -CON (Rk) 2 , -CONH (0) Rk, -CONHNHS02Rk, -COHNS02Rk, and -CONRkCN, where Rk is selected from hydrogen, hydroxyl, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino , aminoalkyl, thio, thioalkyl, alkylthio, sulfonyl, alkyl, alkenyl or alkynyl, aryl, aralkyl, cycloalkyl, heteroaryl, heterocycle, and C02Rm where Rm is hydrogen alkyl or alkenyl. In addition, the carboxylic acid isosterers may include carbocycles or 5-7 membered heterocycles containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally replaced in one or more positions. The following structures are non-limiting examples of preferred isosteres contemplated in the present invention:wherein the atoms of said ring structure can be optionally substituted in one or more positions with Rk. The present invention contemplates that when chemical substituents are added to a carboxylic isostere, then the compound of the invention retains the properties of a carboxylic isostere. The present invention contemplates that when a carboxylic isostere is optionally substituted with one or more selected fractions of Rk, then the substitution can not eliminate the isosteric carboxylic acid properties of the compound of the invention. The present invention contemplates that the location of one or more substituents Rk on the isostere of the carboxylic acid will not be allowed in one or more atoms that maintain or are integral to the isosteric properties of the carboxylic acid of the compound of the invention, if said substituents could destroy the isosteric properties of carboxylic acid of the compound of the invention.
"Carboxylic acid bioisosteres" are compounds that behave as isosterers of carboxylic acids under biological conditions. Other carboxylic acid isosteres not specifically exemplified or described in this specification are also contemplated by the present invention "Metabolite" refers to any derivative produced in a subject after administration of the parent compound. The metabolite can be produced from the parent compound by various biochemical transformations in the subject such as, for example, oxidation, reduction, hydrolysis or conjugation. The metabolites include, for example, oxides and demethylated derivatives. "Thiocarbonyl" refers to group C (= S). "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium , tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalateand similar. "Prodrug" refers to the modifications recognized in the art in one or more functional groups that are metabolized in vivo to give a compound of this invention or an active metabolite thereof. Such functional groups are well known in the art and include acyl groups for hydroxyl and / or amino substitution, esters of mono-, di- and tri-phosphates in which one or more of the pendant hydroxyl groups have been converted to an alkoxy group , a substituted alkoxy, an aryloxy or a substituted aryloxy, and the like. "Treat" or "treatment" of a disease refers to l) the prevention of the disease in a patient who is predisposed or still has no symptoms of the disease; 2) the inhibition of the disease or arrest of its development, or 3) improvement or regression of the disease. "Patient" refers to mammals, which include humans and non-human mammals. A "tautomer" refers to alternative forms of a compound that differ in the position of a proton, such as the enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups that contain a ring atom attached to a -NH- portion of the ring and a portion = N- of the ring, such as pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles.
Unless otherwise indicated, the nomenclature of substituents that are not specifically defined in the present invention is determined by naming the terminal portion of the functionality followed by functionality adjacent to the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl) - (alkyl) -0-C (0) -; the term "alkykyloxy" refers to the alkyl-aryl-O- group; the term "arylalkyloxy" refers to the aryl-alkyl-O- group, "thioalkyl" refers to SH-alkyl-; "alkylthio" refers to alkyl-S-, etc. Several substituents may also have alternative but equivalent names. For example, the term 2-oxo-ethyl and the term carbonylmethyl both refer to the group -C (0) CH2-. It should be understood that, in all the substituted groups defined previously, the polymers obtained by defining the substituents with other substituents (for example, a substituted aryl having a substituted aryl group as a substituent, which in turn is substituted with a substituted aryl group, which it is also substituted with a substituted aryl group and so on) are not included in this documentation. In these cases, the maximum number of these substitutions is three. For example, serial substitutions of aryl groups substituted with two other substituted aryl groups is limited to -substituted aryl- (arylsubstituted) -substituted aryl. Likewise, it is understood that the foregoing definitions are not intended to include non-permitted substitution patterns (eg, methyl substituted with 5 fluoro groups or an alpha hydroxyl group with respect to ethylenic or acetylenic unsaturation) These unauthorized substitution patterns are well known for those trained in the art, Compounds of Formula (I) or a salt, ester, stereoisomer, prodrug or acceptable tautomer thereof are provided accordingly:(I) wherein: Y is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl; HET is selected from the group consisting of a 6-membered arylene ring, a 6-membered heteroarylene ring containing 1, 2, or 3 heteroatoms selected from N, 0, or S, and a bicyclic ring of the formulawherein HET is optionally substituted with (X) thi X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, halo, hydroxyl, and nitro; t is an integer equal to 0, 1 or 2; W1, W4, and W5 are independently N or CH; W3 is N, CH, or is a bond with the proviso that not more than one nitrogen in the bicyclic ring is optionally oxidized to form an N-oxide; and each dotted line independently represents a single or double union between the two joined atoms, with the proviso that when one of the dotted lines is a simple union, the two adjacent atoms are each substituted with 1 or 2 hydrogen atoms to satisfy its valence; one of D or E is C-Ra and the other of D or E is S; Ra and R are independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl; Q is selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and Z is selected from the group consisting of(a) carbopy and carboxy ester; (b) -C (X4) NR8R9, wherein X4 is = 0, = NH, or = N-alkyl, R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl , alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or alternatively, R8 and R9 together with the nitrogen atom bonded thereto, form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring group; (c) -C (X3) NR21S (O) 2 4 wherein X3 is selected from = 0, = NR24, y = S, wherein R24 is hydrogen, alkyl, or substituted alkyl; R4 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and NR22R23 wherein R21, R22 and R23 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; or alternatively, R21 and R22 or R22 and R23 together with the atoms attached thereto join to form an optionally substituted heterocyclic group; (d) -C (X2) - (R3) CR2R 'C (= 0) R1, wherein X2 isselect from = 0, = S, y = NR11, where R11 is hydrogen or alkyl, R1 is selected from -0R7 and -NR8R9 where R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R8 and R9 are as defined above; R2 and R2 'are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or, alternatively, R2 and R2 'as defined are taken together with the carbon atom attached thereto to form a cycloalkyl, substituted cycloalkyl, group. heterocyclic or substituted heterocyclic, or, as another alternative, one of R2 or R2 'is hydrogen, alkyl or substituted alkyl, and the other is attached, together with the carbon atom attached thereto, to the R7 or the oxygen atom bound to it or R8 and the nitrogen atom attachedthe same to form a heterocyclic or substituted heterocyclic group; R3 is selected from hydrogen and alkyl or, when R2 and R2 'are not taken together to form a ring and when R2 or R2' and R7 or R8 do not join to form a heterocyclic or substituted heterocyclic group, then R3, together with the nitrogen atom attached thereto, may be taken together with one of R2 and R2 'to form a heterocyclic or substituted heterocyclic ring group; (e) -C (X2) -N (R3) CR25R26R27, wherein X2 and R3 are defined above, and R25, R26 and R27 are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, or R 25 and R 26 together with the carbon atom attached thereto form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; and (f) a carboxylic acid isostere wherein said isostere is not as defined in (a) - (e). In another embodiment, a compound with the Formula (or) or a pharmaceutically acceptable salt or tautomer thereof is provided:(la) wherein: Y is selected from the group consisting of substituted aryl and substituted heteroaryl; X is selected independently from the group consisting of amino, nitro, alkyl, haloalkyl, and halo; t is an integer equal to 0, 1 or 2; Q is selected from the group consisting of cyclohexyl and cyclopentyl; R12 and R13 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, - (CH2) 0-3R16, and -NR17R18, or R12 and R13 and the atom of nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring with the proviso that both R12 and R13 are not both hydrogen; wherein R16 is aryl, heteroaryl, or heterocyclic; and R17 and R18 are independently hydrogen or alkyl or R17 and R18 together with the nitrogen atom to which they are attached are attached to form a heterocyclic ring with 4 to 7 atomsof ring; one of A or B is C-R and the other of A or B is S; Ra is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; and Z is selected from the group consisting of carboxyl, carboxylic esters, and a carboxylic acid isostere. In other embodiments, the present invention provides compounds of Formulas (Ib) - (Is):(Ib)(you)(if)25(Ih)fifteen(ii)25(Ik)fifteen(ID25(Iq)fifteen(Go)25(Is) wherein Z, Ra, and Y have the values that are previously defined in Formula (I) and R12 and R13 have the values that are previously defined for Formula (la). In some embodiments of each of Formula (I) and (Ia) E is S. In other embodiments, D is CH and E is S. In some embodiments of each of Formula (I) and(Ia) - (Is) where appropriate, Ra is hydrogen. In other embodiments, Ra is substituted alkyl, substituted amino, or substituted aminoalkyl. In some aspects, Ra is selected from the following substituents:In some embodiments of each of Formula (I) and (Ia) - (Is) where appropriate, Q is cycloalkyl or substituted cycloalkyl. In some embodiments Q is cycloalkyl. In other embodiments, Q is cycloalkenyl. In another embodiment Q is cyclohexyl. In another embodiment Q is cyclohexenyl. In yet another embodiment T is cyclopentyl. In some embodiments of each of Formula (I) and (Ia) - (Is) where appropriate, Z is carboxyl or carboxylic esters. In another embodiment Z is selected from C (= 0) OH, and -C (= 0) OR "where R" is alkyl. In another embodiment Z is selected from carboxyl, methyl carboxylate, and ethyl carboxylate. In yet another embodiment Z is -C (= 0) OH. In another embodiment Z is an acid isosterocarboxylic In another embodiment the carboxylic acid isostere is a carboxylic acid bioisostere. In another embodiment the carboxylic acid isostere is selected from lH-tetrazol-5-yl and 5 -oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl. In another embodiment Z is -C (= 0) NR8R9 where R8 is hydrogen and R9 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic. In another embodiment where Z is -C (= 0) NR8R9 and R8 is hydrogen, R9 is substituted alkyl. In another embodiment where Z is -C (= 0) NR8R9 and R8 is hydrogen, and R9 is substituted alkyl, the substituted alkyl comprises 1 to 2 substituents are selected from the group consisting of sulfonic acid (S03H), carboxyl, carboxylic esters, amino, substituted amino, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In another embodiment where Z is -C (= 0) NR8R9 and R8 is hydrogen, and R9 is substituted alkyl, the substituted alkyl is selected from the group consisting of 3,4-dimethoxybenzyl, 3,4-dihydroxybenzyl, 3-methoxy- -hydroxybenzyl,4 - . 4-amino sulfonylbenzyl, 4-methyl sulfonylbenzyl, (1-methyl-piperidin-3-yl) methyl, (1-methyl-pyrrolidin-3-yl) methyl, fur-2-ylmethyl, 6-methylpyridin-2-ylmethyl, 2- (l-methyl-pyrrolidin-3-yl) ethyl, 1-phenylethyl, 1- (3-methoxyphenyl) -ethyl, 1- (4-methoxyphenyl) -ethyl,N ',?' -dimethylaminoethyl, and 2- (1H-pyrazol-1-yl) ethyl. In another embodiment Z is selected from N-methyl carboxamide, N, N-dimethylcarboxamide, N-isopropyl-carboxamide, N-allyl carboxamide, and 5-hydroxy-tryptophan-carbonyl. In another embodiment Z is -C (= 0) NR8R9 wherein R9 is aryl or substituted aryl. In another embodiment where Z is -C (= 0) NR8R9, R9 is substituted aryl. In another embodiment where Z is -C (= 0) NR8R9, R9 is selected from the group consisting of 7-hydroxynaphth-1-yl, 6-hydroxynaphth-1-yl, 5-hydroxynaphth-1-yl, 6-carboxy naphtha- 2-yl, (4-HOOCCH2-) phenyl, (3,4-dicarboxy) phenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl and 2-biphenyl. In another embodiment Z is -C (= 0) NR8R9 where R9 is heteroaryl or substituted heteroaryl. In another embodiment where Z is -C (= 0) NR8R9, R9 is substituted heteroaryl. In another embodiment where Z is -C (= 0) NR8R9 and R9 is substituted heteroaryl, the substituted heteroaryl is selected from the group consisting of 4-methyl-2-oxo-2H-chromen-7-yl, 1-phenyl-4 -carboxy-lH-pyrazol-5-yl, 5-carboxypyrid-2-yl, 2-carboxypyrazin-3-yl, and 3-carboxy-2-yl. In another embodiment Z is -C (= 0) NR8R9 where R9 is heterocyclic. In another embodiment where Z is -C (= 0) NR8R9 and R9 is heterocyclic, the heterocyclic group is N-morpholino,tetrahydrofuranyl, and 1,1-dioxidotetrahydrothienyl. In another embodiment Z is -C (= 0) NR8R9 where R8 and R9, together with the nitrogen atom bonded thereto, form a heterocyclic or substituted heterocyclic ring. In another embodiment where Z is -C (= 0) NR8R9 and R8 and R9, together with the nitrogen atom attached thereto form a ring, the heterocyclic and substituted heterocyclic rings comprise rings of 4 to 8 members containing from 1 to 3 heteroatoms. In another embodiment where Z is -C (= 0) NR8R9 and R8 and R9, together with the nitrogen atom bonded thereto form an optionally substituted heterocyclic ring, the 1 to 3 heteroatoms comprise 1 to 2 nitrogen atoms. In another embodiment where Z is -C (= 0) NR8R9 and R8 and R9, together with the nitrogen atom attached thereto form an optionally substituted heterocyclic ring, the heterocyclic or substituted heterocyclic ring is selected from the group consisting of piperidine, piperidine substituted, piperazine, substituted piperazine, morpholino, substituted morpholino, thiomorpholino and substituted thiomorpholino wherein the sulfur atom of the substituted thiomorpholino or thiomorpholino ring is optionally oxidized to give sulfoxide and sulfone portions. In another embodiment where Z is -C (= 0) NR8R9 and R8 and R9, together with the nitrogen atom attached thereto form an optionally substituted heterocyclic ring, the ringheterocyclic or substituted heterocyclic is selected from the group consisting of 4-hydroxypiperidin-1-yl, 1,2,3,4-tetrahydro-3-carboxy-isoquinolin-2-yl, 4-methylpiperizin-1-yl, morpholine-4 -yl, thiomorpholin-4-yl, 4-methyl-piperazin-1-yl, and 2-oxo-piperazinyl. In another embodiment, Z is -C (X) N (R3) CR2R2 C (= 0) R1. In another embodiment, Z is -C (0) HCHR2C (= 0) R1. In another embodiment when Z is -C (X) N (R3) CR2R2 C (= 0) R1 or -C (0) NHCHR2C (= 0) R1, R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl , cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In another embodiment where Z is -C (X) N (R3) CR2R2 'C (= 0) R1 or -C (0) NHCHR2C (= 0) R1, R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl , cycloalkyl, and substituted cycloalkyl. In another embodiment where Z is -C (X) N (R3) CR2R2'c (= 0) R1 or -C (0) NHCHRC (= 0) R1, R2 is selected from the group consisting of hydrogen, methyl, 1- methylprop-1-yl, sec-butyl, hydroxymethyl, 1-hydroxyethyl-1-yl, 4-amino-n-butyl, 2-carboxyethyl-1-yl, carboxymethyl, benzyl, (lH-imidazol-4-yl) methyl , (4-phenyl) encyl, (4-phenylcarbonyl) benzyl, cyclohexylmethyl, cyclohexyl, 2-methylthioet-1-yl, iso-propyl, carbamoylmethyl, 2-carbamoylethyl-1, (4-hydroxy) benzyl, and -guanidino-n-propyl.
In another embodiment when Z is -C () N (R3) CRR2 'C (= 0) R1 O -C (0) NHCHR2C (= 0) R1, R1 is selected from the group consisting of hydroxyl, alkoxy, amino (N -morpholino), amino, and substituted amino. in another embodiment where Z is -C (X) N (R3) CR ^ 'C ^ OR1 or -C (0) NHCHR2C (= 0) R1, R1 is selected from the group consisting of hydroxyl, alkoxy, amino (N -morpholino), amino, and substituted amino, and R2 and R3, together with the carbon atom and the nitrogen atom attached thereto respectively, join to form a heterocyclic or substituted heterocyclic group. In another embodiment where Z is -C (X) N (R3) CR2R2'C (-0) R1 or -C (0) NHCHR2C (= 0) R1, R1 is selected from the group consisting of hydroxyl, alkoxy, amino ( N-morpholino), amino, and substituted amino and R2 and R3, together with the carbon atom and the nitrogen atom bonded thereto respectively, join to form a heterocyclic or substituted heterocyclic group, the heterocyclic and substituted heterocyclic groups are they are selected from the group consisting of pyrrolidinyl, 2-carboxy-pyrrolidinyl, 2-carboxy-4-hydroxypyrrolidinyl, and 3-carboxy-1,2,4,4-tetrahydroisoquinolin-3-yl. In another embodiment, Z is selected from 1-carboxamidocyclopent-1-ylaminocarbonyl, 1-carboxamido-1-methyl-et-1-ylaminocarbonyl, 5-carboxy-l, 3-dioxan-5-ylaminocarbonyl, 1- (N-methylcarboxamido ) -1- (methyl) -et-1-Ilaminocarbonyl, 1- (, -dimethylcarboxamido) -1- (methyl) -et-1-ylaminocarbonyl, 1-carboxy-l-methyl-et-l-ylaminocarbonyl, 1- (N-methylcarboxamido) -cyclobutane-aminocarbonyl, 1-carboxamido- Cyclobutane-aminocarbonyl, 1- (N, -dimethylcarboxamido) -cyclobutane-aminocarbonyl, 1- (N-methylcarboxamido) -cyclopentanaminocarbonyl, 1- (N, -dimethylcarboxamido) -cyclopentanaminocarbonyl, 1- (carboxamido) -cyclopentanaminocarbonyl, 3- [N- (4- (2-aminothiazol-4-yl) phenyl) aminocarbonyl] -piperidin-3-aminocarbonyl, 3-carboxamido-pyrrolidin-3-ylaminocarbonyl, [1- (4- (acrylic acid) -phenyl) aminocarbonyl) -cyclobutan- 1- il] aminocarbonyl, and [1-methyl-1- (4- (acrylic acid) -phenyl) aminocarbonyl) -et-l-yl] aminocarbonyl. In another embodiment, Z is -C (0) NR21S (O) 2R4. In another embodiment where Z is -C (0) NR21S (O) 2R4, R4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted ryl, heteroaryl and substituted heteroaryl. In another embodiment where Z is -C (0) NR21S (0) 2R, R4 is methyl, ethyl, isopropyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, 4-bromo-phenyl, 4-nitrophenyl or 4-methylphenyl, 4-methoxyphenyl, 2-aminoethyl, 2- (dimethylamino) ethyl, 2-N-benzyloxyaminoethyl, pyridinyl, thienyl, 2-chlorothien-5-yl, 2-methoxycarbonylphenyl, naphthyl, 3-chlorophenyl, 2-bromophenyl, 2-chlorophenyl, 4-trifluoromethoxyphenyl, 2,5-difluorophenyl, 4-fluorophenyl, 2-methylphenyl, 6-ethoxybenzo [d] thiazo-2-yl, 4-chlorophenyl, 3-methyl-5-fluorobenzo [b] thiophen-1-yl, 4-acetylaminophenyl, quinolin-8-yl, 4-t-butylphenyl, cyclopropyl, 2,5-dimethoxyphenyl,2. 5-dichloro-4-bromo-thien-3-yl, 2,5-dichloro-thien-3-yl,2. 6-dichlorophenyl, 1,3-dimethyl-5-chloro-lH-pyrazol-4-yl,3. 5-dimethylisoxazol-4-yl, benzo [c] [1, 2, 5] thiadiazol-4-yl,2. 6-difluorophenyl, 6-chloro-imidazo [2, 1-b] thiazol-5-yl, 2- (methylsulfonyl) phenyl, isoquinolin-8-yl, 2-methoxy-4-methylphenyl, 1,3,5-trimethyl -lH-pyrazol-4-yl, l-phenyl-5-methyl-lH-pyrazol-4-yl, 2,4,6-trimethylphenyl, and 2-carbamoyl-et-l-yl. In another embodiment, Z is selected from hydrogen, halo, alkyl, alkoxy, amino, substituted amino, and cyano. In another embodiment, Z is -C (X2) -N (R3) CR25R26R27, wherein X2 and R3 are defined above, and R25, R26 and R27 are alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, or R25 and R26 together with the carbon atom attached thereto form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group. In another embodiment, Z is selected from l- (6- (3-carboxyprop-2-en-l-yl) -lH-benzo [d] imidazole-2-il) cyclobutanylaminocarbonyl, 3- (6- (3-carboxyprop-2-en-1-yl) -β-benzo [d] imidazol-2-yl) -l-methylpyrrolidin-3-aminocarbonyl, 1- (1-) methyl-6- (3-carboxyprop-2-en-l-yl) -1H-benzo [d] imidazol-2-yl) cyclobutane-aminocarbonyl, 1- (benzofuran-2-yl) -5-carboxy-cyclobutane-aminocarbonyl, 1- (2-Methylthiazol-4-yl) -cyclobutane-aminocarbonyl, 1- (2-acetylamino-thiazol-4-yl) -cyclobutanamino, 1- (2-methylamino-thiazol-4-yl) -cyclobutane-aminocarbonyl, 1- (2-ethylthiazole -4 -yl) -cyclobutanylaminocarbonyl, and 1- (cyano) -cyclobutanylaminocarbonyl. In other embodiments of each of Formulas (I) and (Ia) - (Is) where appropriate, Z is carboxyl, carboxylic esters, carboxylic acid isostere, -C (0) NR8R9, or -C (O) NHS (O) 2R4, wherein R8 and R9 are as defined above and R4 is alkyl or aryl. In other embodiments Z is carboxyl, methyl carboxylate, ethyl carboxylate, 6- (DD-glucuronic acid) ester, lH-tetrazol-5-yl, 5-oxo-4,5-dihydro-l, 2,4-oxadiazole -3-yl, -2-cyano-ethylamide, N-2- (lH-tetrazol-5-yl) ethylamide, methylsulfonylaminocarbonyl, trifluoromethylsulfonylaminocarbonyl, or phenylsulfonylaminocarbonyl. In other embodiments more Z is carboxyl. In other embodiments more Z is -C (= 0) OH. In some embodiments of each of Formula (I) and (Ia) - (Is) where appropriate, Z1 is selected fromgroup consisting of hydrogen, halo, alkyl, and haloalkyl. In some embodiments of each of Formula (I) and (Ia) - (Is) where appropriate, R is CvH2v-C (O) -OR23 where v is 1, 2 or 3; and R23 is hydrogen, alkyl or substituted alkyl. In another embodiment where R is CvH2v-C (O) -OR23, v is 1. In another embodiment where R is CvH2v-C (O) -OR23, R is carboxymethyl or methylcarboxymethyl. In another embodiment R is hydrogen. In another embodiment R is CvH2v-C (0) -NR12R13 where v is1, 2 or 3; R12 and R13 are selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl substituted alkoxy, substituted alkoxy and - (CH2) 0-3R16; and R16 is aryl, heteroaryl, heterocyclic, -NR17R18; and R17 and R18 are independently selected from hydrogen, and alkyl, or alternatively, R17 and R18 together with the nitrogen atom to which they are attached are attached to form a heterocyclic ring with 4 to 7 ring atoms; or, alternatively, R12 and R13 and the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring; with the proviso that both R12 and R13 are not alkoxy and / or substituted alkoxy. In another embodiment v is 1. In another embodiment where R is CvH2v-C (O) -NR1R13, the group NR12R13 is selected from N, N-dimethylamino-carbonylmethyl,[N- (4-hydroxy-l, l-dioxidotetrahydro-3-thienyl) amino] -carbonylmethyl, (cyclopropylmethylamino) -carbonylmethyl,(prop-2-in-l-ylamino) -carbonylmethyl, (2- (morpholino) et-l-ylamino) -carbonylmethyl, (phenylsulfonylamino) -carbonylmethyl, [N-benzylamino] -carbonylmethyl, (N- (4-methylsulfonyl -benzyl) amino) -carbonylmethyl, (tryptophanyl) -carbonylmethyl, (tyrosine) -carbonylmethyl, (N- (1-carboxypropyl-1-ylamino) -carbonylmethyl, (N- (2-carboxyethyl-1-yl) -amino) -carbonylmethyl, (N- (4-carboxymethyl) -amino) -carbonylmethyl, N- [3- (? '- (4- (acrylic acid) -phenyl) carboxamido) pyrrolidin-3-yl] amino-carbonylmethyl, N- [4- ('- (4- (acrylic acid) -phenyl) carboxamido) piperidin-4-yl] amino-carbonylmethyl, [2- (N, -dimethylamino) et-l-ylamino] -carbonylmethyl, [(1- (5-methyl-4H-1,2,4-triazol-3-yl) ethyl) amino] -carbonylmethyl, (1-methyl-1- [N- (1-methyl-2-carboxy-1H-indole) - il) aminocarbonyl] et-1-ylamino-carbonylmethyl, [N- (l-methylpyrrolidin-3-yl-ethyl) -amino] -carbonylmethyl, (1-methyl-l- [N- (4- (acrylic acid) phenyl) aminocarbonyl] et-1-ylamino-carbonylmethyl, (1-methyl-l- [N- (4- ( 2-carboxy-furan-5-yl) phenyl) aminocarbonyl] et-1-ylamino-carbonylmethyl, (1-methyl-1- [N- (4- (4-carboxy-thiazol-2-yl) phenyl) aminocarbonyl] et-1-ylamino-carbonylmethyl, (2- (4-methylpiperazin-1-yl) et-1-ylamino) -carbonylmethyl, [(1-methylpyrrolidin-3-yl) methylamino] -carbonylmethyl, [N- (l-methyl-piperidin-3-yl-methyl) -amino] -carbonylmethyl, (1-piperidin-l-ylcyclopentyl) methylamino] -carbonylmethyl, (1- (acetyl) -pyrrolidin-2-ylmethyl) amino) -carbonylmethyl, [(2- (N, N-dimethylamino) -carbonyl) methylamino] -carbonylmethyl, [N- (1, l-dioxidotetrahydro-3-thienyl) methylamino] -carbonylmethyl, (N-methyl-N-cyclohexyl-amino) -carbonylmethyl, (N -methyl-N-carboxymethyl-amino) -carbonylmethyl, [N-methyl-N-benzyl-amino] -carbonylmethyl, (N-methyl-N- (N ', N' -dimethylaminoacetyl) -amino) -carbonylmethyl, [N -methyl-N-phenyl-amino] -carbonylmethyl, (N-methyl-N-isopropyl-amino) -carbonylmethyl, (N-methyl-N- (N '-methylpiperidin-4-yl) amino) -carbonylmethyl, [N -methyl-N- (l-methylpiperidin-4-yl) amino] -carbonylmethyl, [N-methyl-N- (l-methylpiperidin-4-yl-methyl) -amino] -carbonylmethyl, [N-methyl-N- (L-methylpiperidin-3-yl-methyl) -amino] -carbonylmethyl, [N-methyl-N- (l-methylpyrazin-2-yl-methyl) -amino] -carbonylmethyl, [N-methyl-N- (5 -methyl-lH-imidazol-2-ylmethyl) -amino] -carbonylmethyl, (N-methyl-N- [2- (hydroxy) et-l-yl] amino) -carbonylmethyl, (N-methyl-N- [2- (N ',' -dimethylamino) et-l-yl] amino) -carbonylmethi, N-methyl-N- [ 2- (α ', N' -diethylamino) et-1-yl] amino) -carbonylmethyl, (N-methyl-N- [2- (pyridin-2-yl) et-1-yl] amino) -carbonylmethyl, (N-methyl-N- [2- (pyridin-4-yl) et-l-yl] amino) -carbonylmethyl, [N-methyl-N- (1- (1,3-thiazol-2-yl) ethyl] ) -amino] -carbonylmethyl, (N-methyl-N- [3- (? ',?' -dimethylamino) rop-l-yl] amino) -carbonylmethyl, (N-methyl-N- (l-carboxy-2) -methylprop-l-il) -amino) -carbonylmethyl, (N-ethyl-N-propyl-amino) carbonylmethyl, (N-ethyl-N- [2- (methoxy) et-l-yl] amino) carbonylmethyl, (N-ethyl-N- [2 - (? ',?' -diethylamino) et-1-yl] amino) -carbonylmethyl, [7-methyl-2,7-diazaspiro [4,4] non-2-yl] -carbonylmethyl, (5-methyl-2, 5-diazabicyclo [2.2.1] heptyl-2-yl) -carbonylmethyl, (4-methyl-1,4-diazepane-1-yl) -carbonylmethyl, (piperidinyl) carbonylmethyl, (4-carboxy-piperidinyl) -carbonylmethyl, (3-carboxypiperidinyl) -carbonylmethyl, (-hydroxypiperidinyl) carbonylmethyl, (4- (2-hydroxyethyl-1-yl) piperidin-1-yl) carbonylmethyl, [4- (N, N-dimethylamino) -piperidin-1-yl] carbonylmethyl, (3- (N, N-dimethylamino) -methylpiperidin-1-yl) carbonylmethyl, (2- (2- (N, -dimethylamino) -et-l-yl) piperidin 1-yl) -carbonylmethyl, [4 - (4-methyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] -carbonylmethyl, (4-pyrrolidinyl piperidinyl) -carbonylmethyl, (3-pyrrolidinyl-piperidinyl) carbonylmethyl, [4- ( , N-diethylamino) -piperidin-l-yl] carbonylmethyl, (4- (azetidin-li l) -piperidin-1-yl) carbonylmethyl, (4- (piperidin-1-yl) -piperidin-1-yl) carbonylmethyl, (hexahydropyrrolo [1, 2-a] pyrazin-2 (1 H) -yl) carbonylmethyl, [(2- (N, N-dimethylamino) -methyl) morpholino] carbonylmethyl, (3,5-dimethylmorpholino) -carbonylmethyl(thiomorpholino) -carbonylmethyl, morpholino-carbonylmethyl (pyrrolidinyl) -carbonylmethyl, (2-carboxy-pyrrolidin-1-yl) carbonylmethyl, (2- (carboxy) -4-hydroxy-pyrrolidin-1-yl)carbonylmethyl, (2-carboxamide-pyrrolidin-l-yl) -carbonilmetilo, (2- (N, N-dimethylaminocarbonyl) -pyrrolidin-1-yl) -carbonilmetilo, (3- (? ', N'-dimethylamino) -pyrrolidin -1-yl) -carbonylmethyl, (3- (? ', N' -diethylamino) -pyrrolidin-1-yl) -carbonylmethyl, (3- (pyridin-3-yl) -pyrrolidin-1-yl) -carbonylmethyl, (2-pyridin-4-yl-pyrrolidin-l-yl) -carbonilmetilo, piperazin-l-yl-carbonylmethyl, (4-methylpiperazinyl) -carbonilmetilo, (4- (carboxymethyl) -piperazin-l-yl) -carbonilmetilo, (4 - (2-hydroxyethyl-1-yl) piperazin-1-yl) -carbonylmethyl, (4- (isopropyl) piperazin-1-yl) -carbonylmethyl, (4- (2-methoxyethyl-1-yl) piperazine-1- il) -carbonylmethyl, (4- (ethyl) piperazin-1-yl) -carbonylmethyl, (4- (? ', N' -dimethylaminoacetyl) -piperazin-1-yl) -carbonylmethyl, and (4- (6-methoxypyridine -2-yl) piperazin-1-yl) -carbonylmethyl. In another embodiment, R is selected from morpholinocarbonylmethyl, N, iV-dimethylaminocarbonylmethyl, (4-pyrrolidinyl-piperidin-1-yl) carbonylmethyl, piperazinylcarbonylmethyl. In some aspects, R is a morpholinocarbonylmethyl oxide, N, N-dimethylaminocarbonylmethyl, (4-pyrrolidinyl-piperidin-1-yl) carbonylmethyl, piperazinylcarbonylmethyl. In another embodiment, R is selected from [(N, N-dimethylamino) prop-2-en-l-yl] -carbonylmethyl, (N, N-dimethylpiperidin-4-trifluoroacetate -amino) acetyl, 2-(N, N-dimethylpiperidin-4-aminium trifluoroacetate) morpholino acetyl, (2- (diisopropyl) eth-l-yl) -carbonilmetilo, (pyridin-4 -ilcarbonilhidrazino) -carbonilmetilo, (N- (4 -carboxibencil) - amino) carbonylhydrazino) -carbonylmethyl, (acetylhydrazino) -carbonylmethyl, ((', N' -dimethylaminomethyl-carbonyl) hydrazino) -carbonylmethyl. In other embodiments, R is substituted alkyl, wherein said substituted alkyl is selected from the group consisting of aminoalkyl, substituted aminoalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -CH2COOH, and -CH2CONR12R13 in wherein R12 and R13 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, - (CH2) O-BR15, and -NR17R18, or R12 and R13 and the nitrogen atom to which they are attached form a heterocyclic ring substituted or unsubstituted with the proviso that both R12 and R13 are not both hydrogen; wherein R16 is aryl, heteroaryl, or heterocyclic; and R17 and R18 are independently hydrogen or alkyl or R11 and R18 together with the nitrogen atom to which they are attached are attached to form a heterocyclic ring of 4 to 7 ring atoms.
In other embodiments, R is -CH2CONR12R13 and at least one of R12 or R13 is alkyl, substituted alkyl, or heteroaryl. In some aspects at least one of R12 or R13 is methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholin-4-ethyl, or tetrazoyl-5-yl. In other aspects R is 1-methyl-piperidin-4-yl, l-methyl-piperidin-3-ylmethyl, and thiazol-2-yl carbamoyl methyl. In still other embodiments, R is -CH2CONR12R13 and R12 and R13 and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring. In some aspects R12 and R13 and the nitrogen atom to which they are attached form a substituted or unsubstituted morpholino ring, substituted or unsubstituted piperidinyl, or substituted or unsubstituted pyrrolidinyl. In other respects the morpholino, piperidinyl, or pyrrolidinyl substituted or unsubstituted selected from the group consisting of morpholino, 4-pyrrolidin-l-yl-piperidinyl, piperidinyl, 4 -hidroxipiperidinilo, 4 -carboxipiperidinilo, 4 -dimetilaminopiperidinilo, 4 -diethylaminopiperidinyl, 2-methylpyrrolidinyl, 4-morpholin-4-yl-piperidinyl,3, 5-dimethyl-morpholin-4-yl, 4-methylpiperidinyl. In some embodiments, R12 and R13 and the nitrogen atom to which they are attached together form a group selected from N, N-dimethylamino, N- (4-hydroxy-l, 1-dioxidotetrahydro-3-thienyl) amino, cyclopropylmethylamino,prop-2-in-l-ylamino, 2- (morpholino) et-l-ylamino, phenylsulfonylamino, N-benzylamino, (4-methylsulfonyl benzyl) mino, tryptophanyl, tyrosine, Nl-carboxyprop-1-ylamino, N- ( 2-carboxyethyl-1-yl) -amino, N- (4-carboxymethyl) -amino, N- [3- (α '- (4- (acrylic acid) -phenyl) carboxamido) pyrrolidin-3-yl] amino, N- [4- ('- (4- (acrylic acid) -phenyl) carboxamido) piperidin-4-yl] amino, 2- (N, redimethylamino) et-1-ylamino, (1- (5-methyl-4H -l, 2,4-triazol-3-yl) ethyl) amino, 1-methyl-l- [N- (l-methyl-2-carboxy-lH-indol-5-yl) aminocarbonyl] et-l-ylamino , N- (l-methylpyrrolidin-3-yl-ethyl) -amino, 1-methyl-l- [N- (4- (acrylic acid) phenyl) aminocarbonyl] et-l-ylamino, 1-methyl-l- [ N- (4- (2-carboxy-furan-5-yl) phenyl) aminocarbonyl] et-l-ylamino, 1-methyl-1- [N- (4- (4-carboxy-thiazol-2-yl) phenyl) ) aminocarbonyl] et-l-ylamino, 2- (4-methylpiperazin-1-yl) et-1-ylamino, (1-methylpyrrolidin-3-yl) methylamino, N- (1-methylpiperidin-3-yl-methyl) -amino, (1-piperidin-l-ylcyclopentyl) methylamino, 1- (a cetyl) -pyrrolidin-2-ylmethyl) amino, (2- (N, -dimethylamino) -carbonyl) methylamino, N- (1, l-dioxidotetrahydro-3-thienyl) methylamino, N-methyl-N-cyclohexyl-amino, N-methyl-N-carboxymethyl-amino, N-methyl-N-benzyl-amino, N-methyl-N- (', N' -dimethylaminoacetyl) -amino, N-methyl-N-phenyl-amino, N-methyl -N-isopropyl-amino, N-methyl-N- (? '-methylpiperidin-4-yl) amino, N-methyl-N- (1-methylpiperidin-4-yl) amino, N-methyl-N- (l -methylpiperidin-4 -yl-methyl) -amino, N-methyl-N- (l-methyl-piperidin-3-yl-ethyl) -amino, N-methyl-N- (l-methyl-pyrazin-2-yl-ethyl) -araine, N-methyl -N- (5-methyl-lH-imidazol-2-ylmethyl) -amino, N-methyl-N- [2- (hydroxy) et-l-yl] amino, N-methyl-N- [2 - (N ', N' -dimethylaminp) et-l-yl] mino, N-methyl-N- [2- (α ', N' -diethylamino) et-l-yl] amino, N-methyl-N- [2- (pyridin-2-yl) et-l-yl] amino, N-methyl-N- [2- (pyridin-4-yl) et-l-yl] amino, N-methyl-N- (1- (1 , 3-thiazol-2-yl) ethyl) -amino, N-methyl-N- [3- (', N' -dimethylamino) prop-1-yl] amino, N-methyl-N- (1-carboxy- 2-methylprop-1-yl) -amino, N-ethyl-N-propyl-amino, N-ethyl-N- [2- (methoxy) et-1-yl] amino, N-ethyl-N- [2- (? ', N' -diethylamino) et-l-yl] amino, 7-methyl-2,7-diazaspiro [4,4] non-2-yl, 5-methyl-2, 5-diazabicyclo [2, 2 , 1] heptyl-2-yl, 4-methyl-1,4-diazepane-yl, piperidinyl, 4-carboxy-piperidinyl, 3-carboxypiperidinyl, 4-hydroxypiperidinyl, 4- (2-hydroxyethyl-yl) piperidin-1-yl, 4- (N, N-dimethylamino) -piperidin-1-yl, 3- (N, -dimethylamino) -methyl piperidin-1-yl, 2- (2- (N, N-dimethylamino) -et-1-yl) piperidin-1-yl, 4- (4-methyl-4H-1, 2,4-triazole-3 - il) piperidin-1-yl, 4-pyrrolidinyl-piperidinyl, 3-pyrrolidinyl-piperidinyl, 4- (N, N-diethylamino) -piperidin-1-yl, 4- (azetidin-1-yl) -piperidin-1- ilo, 4- (piperidin-1-yl) -piperidin-1-yl, hexahydropyrrolo [1, 2-a] pyrazin-2 (1 H) -yl, (2- (N, N-dimethylamino) -methyl) morpholino, 3, 5-dimethylmorpholino, thiomorpholino, morpholino, pyrrolidinyl, 2-carboxypyrrolidin-1-yl, 2- (carboxy) -4-hydroxy-pyrrolidin-1-yl, 2-carboxamide-pyrrolidin-1-yl, 2- (N, N-diraethylaminocarbonyl) -pyrrolidin-1-yl, 3 - (', N' -dimethylamino) -pyrrolidin-1-yl, 3 - (', N' -diethylamino) -pyrrolidin-1-yl, 3- (pyridin-3-yl) -pyrrolidin-1-yl, 2- pyridin-4-ylpyrrolidin-1-yl, piperazin-1-yl, 4-methylpiperazinyl, 4- (carboxymethyl) -piperazin-1-yl, 4- (2-hydroxy-yl-yl) piperazin-1-yl, 4 - (isopropyl) piperazin-1-yl, 4- (2-methoxyethyl-1-yl) piperazin-1-yl, 4- (ethyl) piperazin-1-yl, 4- (3 '', N '-dimethylaminoacetyl) - piperazin-1-yl, 4- (6-methoxypyridin-2-yl) piperazin-1-yl, and 2-dimethylaminomethyl-morpholin-4-yl. In some embodiments, HET is selected from quinolinylene and substituted quinolinylene. In another embodiment, HET is selected from quinolinylene, isoquinolinylene, 7-methyl-quinolinylene, 7-trifluoromethyl-quinolinylene, 8-fluoro-quinolinylene and 7-fluoro-quinolinylene. In yet another embodiment, HET is 2- [substituted] -quinolin-6-yl, 2- [ee ^^ ???] -7-methyl-quinolinyl, 2- [substituted] -7-fluoro-quinolinyl, 2- [ substituted] -7-trifluoromethyl-quinolinyl, and 2- [substituted] -8-fluoro-quinolinyl. In some embodiments HET isoptionally substituted with (X) t where X, t, W1, W3, W4, and 5 are previously defined. In some aspects, W1 is nitrogen. In other aspects where HET is selected from the group consisting ofIn some embodiments, HET is 1,4-phenylene optionally substituted with (X) t where X and t are previously defined. In some embodiments, t is 0. In another embodiment, t is 1 and X is amino, nitro, methyl, or halo. In other embodiments, HET is selected from the following groups:In some embodiments, Y is substituted aryl or substituted heteroaryl. In some embodiments, Y is selected from the group consisting of substituted biphenyl, substituted phenyl, 6-membered heteroaryl ring optionally substituted fused to a phenyl ring and containing one, two, or three heteroatoms selected independently from the group consisting of N , 0, or S wherein the N or S heteroatoms are optionally oxidized, and 5-membered heteroaryl ring optionally substituted fused to a phenyl ring and containing one, two, or three heteroatoms selected independently from the group consisting of N, 0, or S wherein the N or S heteroatoms are optionally oxidized. In some embodiments Y is 5-membered heteroaryl ring optionally substituted fused to a phenyl ring and containing one, two, or three heteroatoms selected independently from the group consisting of N, O, or S wherein the N or S heteroatoms are oxidize optionally. In another embodiment -Y is -Ar1- (G1) wherein Ar1 is selected from arylene and heteroarylene, G1 is selected from halo, hydroxyl, nitro, cyano, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxyl and carboxyl ester; and g is an integer from 1 to 3. In another embodiment whereY is -Ar1- (G1) q, Ar1 is selected from phenyl, thiazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, and pyrrolidinyl. in another embodiment where -Y is -Ar1- (G1) q, G1 is selected from bromine, chlorine, methyl, hydroxy, methoxy, ethoxy, acetyl, acetamide, carboxy, and amino. In another embodiment Y is selected from 2,4-dimethylthiazol-5-yl, 3-bromo-4-aminophenyl, 3-amido-4-hydroxy-phenyl, 2-hydroxy-6-methoxy-phenyl, 4- (acetylamino) -phenyl, 2,4-dihydroxyphenyl, 2,4-dimethoxy-6-hydroxyphenyl, and 7-hydroxybenzofuranyl. In another embodiment Y is -Ar1-Ar2- where the group -Ar1-Ar2- is selected from the group consisting of -aryl-aryl, -aryl-substituted aryl, -substituted aryl-aryl, -substituted substituted aryl-aryl, -aryl-heteroaryl, substituted aryl-heteroaryl, substituted-aryl-heteroaryl, substituted-aryl-heteroaryl-substituted, heteroaryl-aryl, substituted heteroaryl-aryl, substituted heteroaryl-aryl, substituted heteroaryl-aryl-aryl-cycloalkyl, -aryl- substituted cycloalkyl, substituted aryl-cycloalkyl, substituted-substituted aryl-cycloalkyl, -aryl-heterocyclic, substituted aryl-heterocyclic, substituted aryl-heterocyclic, and substituted aryl-heterocyclic.
In another embodiment where Y is -Ar1-Ar2-, the group -Ar1-Ar2- is selected from the group consisting of 41-chloro-4-methoxybifen-2-yl, bifen-2-yl, bifen-4-yl, 4-amino-4'-chlorobiphen-2-yl, 4'-aminomethyl-4-methoxy-biphen-2-yl, 4-carbamoyl-4'-methoxy-biphen-2-yl, 4-carbamoyl-4'-fluoro-biphen-2-yl, 4-carbamoyl-41 -methoxybifen-2-yl, 4 -carbamoyl-4'-nitrobiphen-2-yl, 4- (carbamoylmethyl-carbamoyl) biphen-2-yl, 4- (carbamoylmethylcarbamoyl) -4'-chlorobiphen-2-yl, 4- carboxy-4 '-chlorobiphen-2-yl, 3-carboxy-4' -methoxy-2-yl,4-carboxy-4 '-methoxy-biphen-2-yl, 41 -carboxy-4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4-carboxymethoxy-biphen-2-yl, 4-carboxymethoxy-4'-chlorobiphen-2 -yl, 41-chlorobiphen-2-yl, 4'-chloro-4-chlorobiphen-2-yl, 4'-chloro-4- (dimethylaminoethylcarbamoylbiphen-2-yl, 4'-chloro-4- (2-ethoxyethoxy) bifen-2-yl, 3'-chloro-4 '-fluoro-4-methoxy-biphen-2-yl, 4'-chloro-4-fluoro-biphen-2-yl, 41-Chloro-4-hydroxybifen-2-yl, 3'-chloro-4-methoxybifen-2-yl, 4'-chloro-4-methylcarbamoylbiphen-2-yl, 4'-chloro-4- (2-methoxyethoxy) ) bifen-2-yl, 4'-chloro-4-nitrobiphen-2-yl, 4'-chloro-4- (2-oxo-2-pyrrolidin-1-ylethoxy) biphen-2-yl, 4'-chloro -4- (pyrrolidin-1-ylcarbonyl) biphen-2-yl, 4'-chloro-4- (3-pyrrolidin-1-ylpropoxy) biphen-2-yl, 4'-cyano-4-methoxy-2-yl , 3 ', 4' -dichloro-4-methoxybifen-2-yl, 4,4'-dimethoxybifen-2-yl, 3 ', 4'-dimethoxy-4- (pyrrolidin-1-ylcarbonyl) bifen-2-yl , 4'-dimethylamino-4-methoxy-biphen-2-yl, 4- (2-dimethylaminoethylcarbamoyl) biphen-2-yl, 4'-ethoxy-4-methoxy-biphen-2-yl, 4'-fluoro-4-methoxybifen-2 -yl, 4-hydroxybiphenyl, 4-methoxybiphenyl, 4-methoxy-4'-hydroxybifen-2-yl, 4- (2-methoxyethoxy) biphen-2-yl, 4-methoxy-41-methylbiphen-2-yl, 4-methoxy-3'-nitrobiphen-2-yl, 4-methoxy-4 ' -nitrobifen-2-yl, 4-methylcarbamoylbiphen-2-yl, 3 '-methyl-4-methoxybifen-2-yl, 4'-nitro-4- (pyrrolidin-1-ylcarbonyl) bifen-2-yl, 4- (2-oxo-2-pyrrolidin-1-ylethoxy) ifen-2-yl, 4- (3-pyrrolidin-1-ylpropoxy) biphen-2-yl, and 4 '-trifluoromethyl-4-methoxy-2-yl. In another embodiment where Y is -Ar1-Ar2-, the group -Ar1-Ar2 is selected from the group consisting of 4- (lH-imidazol-1-yl) phenyl, 2-furan-2-yl-5-methoxyphenyl , 5-methoxy-2-thiophen-2-ylphenyl, 2- (2,4-dimethoxypyriraidin-5-yl) -4-methoxyphenyl, 2- (pyrid-4-yl) phenyl, 3-amino-5-phenylthiophen 2-yl, 5- (4-chlorophenyl) -2-methyl-furan-2-yl, 3- (4-chlorophenyl) -5-methyl-isoxazol-4-yl, 2- (-chlorophenyl) -4-methylthiazol-5-yl 3- (3,4-Dichloro-phenyl) -isoxazol-5-yl,3, 5-dimethyl-l-phenyl-lJ-pyrazol-4-yl, 5-methyl-2-phenylthiophen-3-yl, and l-phenyl-lH-pyrazol-4-yl. In another embodiment where Y is -Ar1-Ar2-, the group -Ar1-Ar2- is selected from the group consisting of 2-cyclohexyl-N, N-dimethylamino-carbonylmethyl-5-methoxyphenyl, and 4-morpholinophenyl. In still other embodiments, Y is selected from the group consisting of substituted quinolyl, substituted benzofuryl, substituted thiazolyl, substituted furyl, substituted thienyl, substituted pyridinyl, pyrazinyl.substituted, substituted oxazolyl, substituted isoxazolyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrrolidinyl, substituted pyrazolyl, substituted isothiazolyl, substituted 1,2-oxadiazolyl, 1,2,3-substituted triazolyl, 1,3,4-thiadiazolyl substituted, substituted pyrimidinyl, substituted 1, 3, 5-triazinyl, substituted indolizinyl, substituted indolyl, substituted isoindolyl, substituted indazolyl, substituted benzothienyl, substituted benzthiazolyl, substituted purinyl, substituted quinolizinyl, substituted quinolinyl, substituted isoquinolinyl, substituted cinnolinyl, substituted phthalazinyl, substituted quinazolinyl , substituted quinoxalinyl, substituted 1,8-naphthyridinyl, and substituted pteridinyl. In some aspects, Y is substituted with one to three substituents selected independently from the group consisting of alkyl, haloalkyl, halo, hydroxyl, nitro, cyano, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy , and carboxy ester. In other aspects, Y is 2,4-dimethylthiazol-5-yl. In some embodiments, Y is selected from the corresponding Y groups in Table 1. In some embodiments, -Het-Y is:Preferred compounds of this invention or the salts, partial salts, or tautomers acceptable for pharmaceutical use thereof include those set forth in the following Table I:Table ICompu Structure Name this6-Cyclopentyl- Acid5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-1 morpholin-4 -yl-2-??? - ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid6-Cyclopentyl-5- [2- (2, 4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4-Y) acid. { [methyl- (1-methyl-j 2 piperidin-4-yl) -carbamoyl] -methyl} - 4H-Thieno [3,2- b] Irrol-2-carboxylic acid6-Cyclopentyl-4- [2- (2-dimethylaminomethyl-morpholin-4-yl) -2-5-oxo-ethyl] -5- [2- (2, 4-3-dimethyl-thiazole-5-yl) - quinolin-6-yl] - 4H-thieno [3,2- b] pyrrole-2-carboxylic acid6-Cyclopentyl-5 - "[2- (3-methoxy-phenyl) -quinolin-6-yl] -4- [(2-morpholin-4-yl-ethylcarbamoyl) -methyl] -4H-thieno acid [ 3, 2-b] pyrrole-2-carboxylic 20256-Cyclopentyl-4- [2- (3, 5-dimethyl-rorpholin-4-yl) -2-oxo-ethyl] -5- [2- (3-5-methoxy-phenyl) -quinoline-6-acid il] -4H-thieno [3, 2-b] irol-2-carboxyl10 6-Cyclopentyl-4-pyridin-4-ylmethyl-5- [2- (3-trifluoromethoxy-6-phenyl) -quinolin-6-yl] -4H-thieno [3,2- b] -prolol-2-carboxylic acidtwenty25N-. { 6-Cyclohexyl-4 - [2- (2-dimethylaminomethyl-morpholin-4-yl) -2-oxo-ethyl] -5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin- 6-yl] -4 H -thieno [3,2- b] irrol-2-carbonyl} - methanesulfonamide2- [6-Cyclohexyl-2-methanesulfonylamino-arbonyl-5- (2-o-tolyl-quinolin-6-yl) -thieno [3,2- 12 b] pyrrol-4-yl] -N-methyl-N- (1-methyl-piperidin-3-ylmethyl) -acetamide254-Cyclohexyl-5- [2- (2, 4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -6- (2- L-morpholin-4-yl-2-oxo-ethyl) - 6H-Thieno [2,3-b] pyrrole-2-carboxylic acid4-Cyclohexyl-5- [2- (2-methoxy-phenyl) -quinolin-6-yl] -6- [2-α-2- (4-pyrrolidin-1-yl-r-piperidin-l acid -yl) -ethyl] -6H-thieno [2,3-b] pyrrole-2-carboxylic acid510fifteentwenty2510fifteentwenty2510fifteentwenty25510fifteentwenty25256-Cyclohexyl-5-5- [4- (3-methyl-pyrazin-2-yl) -phenyl] -4- [2- (2- (25-methyl-pyrrolidin-1-yl) -2-oxo-) acid ethyl] -4H-10-thieno [3,2-b] pyrrole-2-carboxylic acid6-Cyclohexyl-4-15-dimethylcarbamoylmethi-5- [4- (2-ethoxy-4-methyl-pyrimidin-5-yl) -phenyl] -4H-thieno [3,2-b] pyrrole-20 2 acid -carboxylic255- [2- (4'-Chloro-methoxy-biphenyl-2-yl) -quinolin-6-yl] -6-cyclohexyl-4 - (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2-b] irrol-2-carboxylic5- [2- (4'-Chloro-4-methoxy-biphenyl-2-yl) -quinolin-6-yl] -6-cyclohexyl-4- (3-methoxy-benzyl) -4H- acidthieno [3, 2-b] pyrrole-2-carboxylic acid510fifteen2525510fifteentwenty256-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4-pyridin-4-ylmethyl-4H "-thieno [3,2- b] irrol-2-carboxyl6-Cyclohexyl-5- [2- (2, 4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- [(2-morpholin-4-yl-ethylcarbamoyl) -methyl] -4H-thieno [3, 2- b] pyrrole-2-carboxylic acid5256-cyclohexyl-4- [2- (3, 5-dimethyl-morpholin-4-yl) -2-oxo-ethyl] -5- [2- (2,4-dimethyl-thiazole-5-yl) - quinolin-6-yl] - 4H-thieno [3,2- b] pyrrole-2-carboxylic acid6-Cyclohexyl-5- [2- (2, 4-dimethyl-thiazol-5-yl) -0 N 'quinolin-6-yl] -4- (2-oxo-2-thiomorpholin-4-yl-ethyl) ) -4H-Thieno [3, 2-b] 2-carboxylic acid2510256-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (thiazol-2-ylcarbamoylmethyl) -4H-Thieno [3,2- b] Irrol-2-carboxylic acid 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4-. { [methyl- (1-methyl-piperidin-4-yl) -carbamoyl] -methyl} -4H-Thieno [3,2- b] Irrol-2-carboxylic5- [2- (5-Chloro-thiophen-2-yl) -quinolin-6-yl] -6-cyclohexyl-4 - (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno acid [3,2-b] Irol-2-carboxylic5- [2- (5-Chloro-thiophen-2-yl) -quinolin-6-yl] -6-cyclohexyl-4-pyridin-4-ylmethyl-4H-thieno [3,2-]b] pyrrole-2-carboxylic acid225255twenty2511twenty256-cyclohexyl-4- [2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -5- [2- (4-75-methyl-thiophen-2-yl) -quinolin-6 -yl] -4H-thieno [3,2-b] pyrrol-2-carboxylic acid6-cyclohexyl-5- [2- (5-methyl-thiophen-2-yl) -quinolin-6-yl] -4- (2- 76 oxo-2-thiazolidin-3-yl-ethyl) -4 H- thieno [3, 2-b] pyrrole-2-carboxylic acidtwenty256-Cyclohexyl-5- [2- (4-methyl-2-trifluoromethyl-thiazol-5-yl) -quinolin-6-yl] -4- 83 [(2-morpholin-4-yl-ethylcarbamoyl) -methyl] -4H-thieno [3, 2- b] pyrrole-2-carboxylic acid6-Cyclohexyl-4- (3-methoxy-benzyl) -5- [2- (4-methyl-2-trifluoromethyl-84-thiazol-5-yl) -quinolin-6-yl] -4H-thieno acid [3, 2-b] 2-carboxylic acid510fifteentwenty2511twenty252510twenty2525254- (2-azetidin-l-yl-2-oxo-ethyl) -6- < > cyclohexyl-5- [2- (4-j-methoxy-phenyl) -quinolin-6-yl] -4H-thieno [3,2- b] pyrrol-2-carboxylic acid6-cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- [(2-morpholin-4-yl-ethylcarbamoyl) -methyl] -4H-thieno [3, 2] -b] pyrrole-2-carboxylic acid251125twenty254- (2-azetidin-l-yl-2-oxo-ethyl) -6-cyclohexyl-5- [2- (2, 4-dimethyl-oxazol-129-yl) -quinolin-6-yl] -4H-thieno [3,2-b) Irrol-2-carboxylic acid 6-cyclohexyl-5- [2- (2,4-dimethyl-oxazol-5-yl) -quinolin-6-yl] -4- 15. { [methyl- (1-methyl-130 piperidin-4-yl) -carbamoyl] -methyl} - 4H-Thieno [3, 2- b] pyrrole-2-carboxylic acid256-cyclohexyl-4- [2- (2-dimethylaminomethyl-morpholin-4-yl) -2- 5 ?? oxo-ethyl] -5- [2- (2,4-131 dimethyl-oxazol-5-yl) -quinolin-6-yl] -4 H -thieno [3,2- b] pyrrole-2-carboxylic acid6-cyclohexyl 4- acidV diraethylcarbamoylmethi 1-5- [2- (3-fluoro-132 phenyl) -quinolin-6-yl] -4 H -thieno [3,2- b] urea-2-carboxylic acid254- carboxymethyl-6-acid5-cyclohexyl-5- [2- (4-OH-trifluoromethyl-137-phenyl) -quinolin-6-yl] -4H-thieno [3,2- b] irrol-2 -10 carboxylic6-cyclohexyl-4- (3-methoxy-benzyl) -5- [2- (4-15-Trifluoromethyl-138-phenyl) -quinolin-6-yl] -4H-thieno [3,2- b] -prolol-2-carboxylic acidtwenty256-cyclohexyl-5- [2- (4-fluoro-phenyl) -quinolin-6-yl] -4-pyridin-4-ylmethyl-4H-thieno [3,2- b] pyrrole-2-carboxylic acid6-cyclohexyl-5- [2- (4-fluoro-phenyl) -quinolin-6-yl] -4- [(2-morpholin-4-yl-ethylcarbamoyl) -methyl] -4H-thieno [3, 2] -b] irrol-2-carboxylictwenty25510fifteentwenty25256-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (3-methoxy-benzyl) -4H-thieno [3, 2-b] Irrigation2-carboxylic6-Cyclohexyl-4- [2- (2-dimethylaminomethyl-Cry-morpholin-4-yl) -2-oxo-ethyl] -5- [2- (2,4-dimethyl-thiazol-5-yl) -quinoline -6-yl] - 4H-thieno [3,2- b] irrol-2-carboxylic5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -6- (2-methyl-) acidcyclohexyl) -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] urea-2-carboxylic acid6-cyclohexyl-5- [2- (2, 4-dimethyl-thiazol-5-yl) -8- fluoro-quinolin-6-acidil] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] urea-2-carboxylic acid6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -3- (4-methyl-piperazin-1- [181-ylmethyl) -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] -prolol-2-carboxylic acid6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -8- acidfluoro-quinolin-6-yl] -4-methyl-3- 182 pyrrolidin-1-ylmethyl-4H-thieno [3,2- b] pyrrole-2-carboxylic acid2511225twenty256-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] urea-2-carboxylic acid 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl ) - quinolin-6-yl] -4- (2-oxo-2-thiomorpholin-4-yl-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acidThe present invention further provides metabolites of any of the compounds of Formula (I), (Ia) - (Is), or of the compounds in Table 1. In some aspects, the metabolite is an oxide. The present invention is also intended for pharmaceutical compositions comprising a diluent acceptable for pharmaceutical use and an effective amount for therapeutic purposes of one of the compounds described herein or mixtures of one or more of said compounds.
The present invention is further directed to methods of treating a viral infection mediated at least in part by a virus of the Flaviviridae virus family, such as HCV, in mammals, which methods comprise administering to aa mammal that has been diagnosed with said viral infection or is at risk of developing said viral infection, a pharmaceutical composition comprising a diluent acceptable for pharmaceutical use and an effective amount for therapeutic purposes of one of the compounds described herein or mixtures of one or more of said compounds. In another aspect, the present invention provides the use of the compounds of the present invention for the preparation of a medicament for treating or preventing said viral infections. In other aspects, the mammal is a human being.
In another embodiment of the present invention, methods are provided for treating or preventing viral infections in mammals in which the compounds of the present invention are administered in combination with the administration of an effective amount for therapeutic purposes of one or more active agents against HCV. . Agents active against HCV include ribavirin, levovirin, viramidine, thymosin alfa-1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, pegylated interferon-alpha, alone or in combination with ribavirin or viramidine. Preferably, the additional active agent against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or viramidine. General synthetic methodsThe compounds of this invention can be prepared from initial access materials, using the following methods and general procedures. It will be appreciated that, when typical or preferred processing conditions are provided (i.e., reaction temperatures, times, molar ratios of reagents, solvents, pressures, etc.), other processing conditions may also be used, unless otherwise indicated. . The optimum reaction conditions may vary with the particular reagents or solvents used, but these conditions can be determined by one trained in the art using conventional optimization methods. Additionally, as will be apparent to those skilled in the art, conventional protective groups may be necessary to prevent certain functional groups from being subjected to unwanted reactions. Suitable protecting groups for various functional groups, as well as appropriate conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
If the compounds of this invention contain one or more chiral centers, these compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched in stereoisomers. All of these stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, starting materials with optical activity or stereoselective reagents well known in the art. Alternatively, racemic mixtures of these compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Scheme 1In one embodiment, the compounds of Formula (I) are prepared by a cross-coupling reaction catalyzed by a transition metal as shown above in Scheme 1, where L and L 'are suitable cross-coupling substituents, P' is hydrogen, a nitrogen protecting group or R, and Z, D, E,R, Q, HET, and Y have the values defined above. Typically, one of L or L 'is a Metal based on Sn, B, Zr, or Zn (for example -BOH2, Sn (CH3) 3, etc.) and the other of L or L' is a leaving group such as halogen or sulfonate. Suitable halogens and sulfonates include Cl, Br, I, -OS02CF3, and -OSO2CH3. Suitable transition metal catalysts include Pd and Ni-based catalysts (for example Pd (PPh3) 2C12, Pd [P (Ph3)] 4, etc.). In one embodiment, one of 1.1 or 1.2 has L as -B (OH) 2 and is prepared by treating a compound of 1.1 or 1.2 where L or L 'is halogen with an excess of bis (neopentylglycolate) diboro in the presence of an amount catalyst of triphenylphosphinpalladium (II) dichloride. The resulting boric acid is coupled to the other of 1.1 or 1.2 where L is halogen or a sulfonate under Suzuki coupling conditions to form a compound of Formula (I) or an intermediate 1.3. Suitable coupling conditions include the reaction of 1.1 and 1.2 in refluxing methanol containing Pd [P (Ph) 3] 4 and NaHCO 3 for between 10 and 20 hours. When P 'is H or a protective group, the removal of the protective group followed by functionalization of the resulting NH group produces the compound (I). A specific example of this transformation is shown in Scheme 5.
Scheme 2In one embodiment, compound 1.1 can be synthesized as shown in Scheme 2 where for illustrative purposes D is CH, E is S, Z is COOP, Q is cyclohexyl, P is a hydroxyl protecting group such as alkyl, P ' it is a nitrogen protecting group, and L is halogen. Thiofen 2.1 is treated with a mixture of nitric and sulfuric acid to form the nitro compound 2.2. Reduction of the nitro group followed by protection of the resulting amine with a protecting group P 'such as t-butyloxy carbonyl gives compound 2.3. Thiophene 2.3 can be treated with a halogenating agent such as N-bromosuccinimide (NBS) to form bromide 2.4. Exposure of 2.4 with trimethylsilylacetylene, Cul, and PdCl2 (PPh3) 2 gives acetylene 2.5 which is then treated with n-Bu4NF and is exposed to microwave radiation to form 2.6. Compound 2.6 is then reacted with cyclohexanone and sodium ethoxide in ethanol under reflux conditions to form cyclohexene 2.7 which is then reduced to cyclohexane 2.8 with H2 and Pd (OH) 2 / C or with a reducing agent such as triethylsilane. Compound 2.8 can then be functionalized to introduce the R group, or the ring nitrogen can be protected followed by treatment with a halogenating agent such as NBS to form the coupling partner 2.9. Scheme 3 PgO-HET-Br + (HO) 2B-Y? PgO-HET-Y? 1.2 3.1 3.2 3.3The group L '-HET-Y 1.2 which is described in Scheme 1 can be prepared by conventional procedures well known in the art. Scheme 3 illustrates a generic method for preparing HET-Y groups suitable for use in said convergent synthesis. In Scheme 3 an aryl or heteroaryl compound substituted with bromine and hydroxyl 3.1 is employed, which is optionally further substituted with one or more X groups (not shown). If necessary, the hydroxyl group can be protected with conventional protecting groups, Pg, which are well known in the art. Compound 3.3 is formed with the reaction of 3.1 under conventional Suzuki conditions with boric acid3. 2, which can be prepared in the manner described in Scheme 1 above the corresponding Y-Br compound. When Pg is not hydrogen, the protecting group can be removed by conventional procedures. The resulting hydroxyl group of compound 3.3 below can be converted under conventional conditions into compound 1.2 for use in the coupling step of Scheme 1. In Scheme 4 below the preparation of a quinolinyl group HET-Y having a group is illustrated. Bromine suitable for a Suzuki coupling with compound 1.1. It is understood that this quinolinyl group is shown for illustrative purposes only. Scheme 4In Scheme 4, amino 2-methyl-4-nitrobenzene, compound 4,1, commercially available, is converted to the corresponding bromo-2-methyl-nitrobenzene, compound 4.2, under standard conditions using equimolar amounts of nitrite of sodium, an excess of HBr and a catalytic amount of cupric bromide. The reaction is preferably carried out by combining compound 4.1 with an excess of aqueous hydrogen bromide (eg, 48% HBr) in an inert solvent at a temperature between about -10 and 10 ° C. An equimolar amount of sodium nitrite dissolved in water is slowly added to the reaction mixture maintaining the reaction temperature. A catalytic amount of solid cuprous bromide is then added to the reaction mixture and the reaction mixture is allowed to warm to a little less than room temperature. The reaction is monitored until the cessation of nitrogen release indicates the completion of the reaction. Next, the resulting product, bromo-2-methyl-nitrobenzene, compound 4.2, can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and / or isolation. Suitable examples of compound 4.1 include commercially available variants such as 2-nitro- 3-methylaniline, 4-methyl-3-nitroaniline (both commercially available from Aldrich Chemical Company, Milwaukee, Wisconsin, USA) as well as 3-methyl-4-nitroaniline (commercially available from Lancaster Synthesis Inc.). Compound 4.2 is then converted to (E) -2- (bromo-2-nitrophenyl) vinyl dimethylamine, compound 4.4, by reaction with an excess of N, -dimethylformamide dimethylacetal, compound 4.3. The reaction is typically conducted in a suitable solvent such as DMF under an inert atmosphere. Preferably, the reaction is carried out at an elevated temperature of between about 100 ° C and about 160 ° C. The reaction is continued until it is substantially complete, which normally occurs within about 1 to 6 hours. After completion of the reaction, the resulting product can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and / or isolation. The oxidation of (E) -2- (bromo-2-nitrophenyl) vinyldimethylamine, compound 4.4, proceeds by contact with a large excess of sodium periodate to obtain bromo-2-nitrobenzaldehyde. This reaction is usually carried out in an inert diluent such as an aqueous mixture of tetrahydrofuran, dioxane, andSimilar. Preferably, the reaction is carried out under ambient conditions and is continued until it is substantially complete, which normally occurs within about 0.5 to 6 hours. After completion of the reaction, the resulting product, bromine 2-nitrobenzaldehyde, compound 4,5, can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and / or isolation. The conventional reduction of compound 4.5 makes it possible to obtain the corresponding bromo-2-aminobenzaldehyde, compound 4.10. Separately, bromo-5-methoxybenzoyl chloride, compound 4.7 (available from Maybridge), is converted to the corresponding bromo-3-acetyl-methoxybenzene, compound 4.8, by reaction with dimethylzinc. The reaction is usually carried out in a suitable inert diluent such as benzene, toluene, xylene and the like. Preferably, the dimethylzinc is present in the solvent before adding the compound 4.7, since the dimethylzinc is pyrophorus. Preferably, the reaction is initially carried out at a temperature between about -10 ° C to about 10 ° C and then it is slowly allowed to reach room temperature. TheThe reaction is continued until it is substantially complete, which normally occurs within about 0.2 to 2 hours. After completion of the reaction, the resulting product, bromo-3-acetyl-methoxy-benzene (compound 4.8) can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and / or isolation. Alternatively, bromo-5-methoxybenzoyl chloride, compound 4,7, can be prepared from the corresponding commercially available bromo-5-methoxybenzoic acid such as 2-bromo-5-methoxybenzoic acid (available from Aldrich Chemical Company, Milwaukee, Wisconsin, USA) by conversion to an acid halide. The acid halide can be prepared by contacting the carboxylic acid with an inorganic acid halide, such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, or preferably, with oxalyl chloride under conventional conditions. In general, this reaction is carried out using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at a temperature in the range from amongabout 0 ° C and about 80 ° C for between about 1 and about 48 hours. A catalyst, such as DMF, can also be used in this reaction. Compound chlorophenyl boronic acid, compound 4.9, is coupled with compound 4.8 under standard Suzuki conditions to give 3-acetyl methoxy benzene substituted with chlorophenyl, compound 4.6. The 2-, 3-, and 4-chlorophenyl boronic acids are obtained from Aldrich Chemical Company, supra. Compound 4.6 is then coupled with compound 4.10 under condensing conditions to give 2-biaryl-6-bromoquinoline, compound 4.11. This reaction is preferably conducted by combining approximately stoichiometric amounts of both compounds 4.6 and 4.10 a suitable inert diluent such as ethanol, isopropanol and the like in the presence of a suitable base such as potassium hydroxide under an inert atmosphere. Preferably, the reaction is carried out at a temperature between about 70 ° C and about 100 ° C and proceeds until it is substantially complete, which normally occurs within about 2 to 16 hours. After completion of the reaction, the resulting product, compound 4.11, can be isolated by conventional techniques such asevaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and / or isolation. Scheme 5the compounds of Formula (I) can also be prepared by other methods. In Scheme 5 one of said methods is shown where for illustrative purposes Z is COOH, D is CH, E is S, Q is cyclohexyl, and the Ra, and HET-Y groups have the values defined in compound 5.14. Hecompound 5.1 is condensed with that obtained commercially (Aldrich) 5.2 using the Friedlander conditions to form quinoline 5.3. An example of such conditions is given in Example 2 below. Compound 5.3 can be converted to the corresponding alcohol 5.4 using known methods such as with lithium aluminum hydroxide followed by re-oxidation to aldehyde 5.5 using Dess-Martin reagent. The commercially available thiophene 5.6 is converted to 5.7 by treatment with nitric acid / sulfuric acid. Compounds 5.7 and 5.5 are then refluxed together in MeOH in the presence of a catalytic amount of pyrrolidine to form the nitro-olefin 5.8. Compound 5.8 is then refluxed with triethyl phosphite to give the thieno-pyrrole derivative 5.9. The cyclohexyl ring is introduced as in Scheme 2 by heating 5.9 with cyclohexanone in the presence of acetic acid, acetic anhydride, and phosphoric acid to give 5.10. Reduction of compound 5.10 with triethylsilane gives 5.11. The acetamido portion is introduced by reacting 5.11 with 5.12 obtained commercially in DMF using standard alkylation conditions to form 5.13 which is saponified with aqueous LiOH to give the desired product 5.14.
Scheme 6they are synthesized as shown in Scheme 6 where for illustrative purposes D is S, E is CH, Z is COOP, Q is cyclohexyl, P is a hydroxyl protecting group such as alkyl, P 'is a nitrogen protecting group, L' is a leaving group such as halogen, and HET and Y have the previously defined values. Compound 6.1 is reacted with methyl cyanoacetate in the presence of a base such as diisopropylethyl amine to form the alkylated product 6.2. Exposure of 6.2 to HC1 gas gives pyrrole 6.3 which can then be converted to protected pyrrole such as 6.4 where P 'is benzyl by reaction with benzyl bromide and NaH. The ester 6.4 is then converted to aldehyde 6.5 such as by a two-step reduction procedure of 6.4 with diisobutylaluminum hydride to the corresponding alcohol followed byoxidation to aldehyde 6.5 with an oxidizing agent such as (n-Pr) 4N Ru04 / N-methylmorpholine N-oxide. Reaction of aldehyde 6.5 with methyl thioglycolate and potassium tert -butoxide in THF gives compound 6.6, which can be functionalized to give 6.7 in a manner similar to that described in Scheme 5 to introduce the cyclohexyl moiety. Similarly, the protecting group P 'can be removed from 6.7 and the group R can be introduced as described in Scheme 5 to give a compound of Formula (I). Scheme 7Scheme 7 illustrates the synthesis of intermediate 7.8 formed from the coupling of the nitro compound 7.3 with aldehyde 7.6. The nitration of thiophene 7.1 under suitable nitration conditions such as by addition to a solution of acetic anhydride and nitric acid forms theacid 7.2 which is then esterified to give the intermediate ester 7.3. Coupling partner 7.6 is prepared from 2-chloro-6-methylquinoline 7.4 which is halogenated after treatment with a suitable reagent such as NBS (N-bromosuccinimide) to give a mixture of mono and dibromide 7.5. The mixture is then refluxed in an aqueous solvent such as 50% aqueous ethanol in the presence of an amine such as hexamethylenetetramine to give, after an acid treatment, aldehyde 7.6. The nitro compound 7.3 and the aldehyde 7.6 are refluxed together in an alcohol solvent such as methanol to which a catalytic amount of an amine such as pyrrolidine is added to give the olefin 7.7, which is then treated with triethyl phosphite to form thienopyrrole 7.8 cyclized. In Example 4 details of the preparation of 7.8 are given.
Scheme 88. 3 8.48. 6 86 Scheme 8 illustrates the use of intermediate 7.8 to prepare compounds 8.2-8.6 following the methods described in Scheme 5.
Scheme 9Scheme 9 illustrates the preparation of compounds such as 9.3 following the methods described in the preceding Schemes. An example of the synthesis of compound 9.3 wherein R 'and R "together form a cyclic group is presented in Examples 9 and 10. Administration and Pharmaceutical Composition The present invention provides novel compounds possessing antiviral activity, which includes the viruses of the Flaviviridae family such as hepatitis C virus. The compounds of this invention inhibit viral replication by inhibiting the enzymes involved in replication, including RNA-dependent RNA polymerase, and can also inhibit other enzymes used in the activity or proliferation of Flaviviridae virus In general, the compounds of this invention arewill be administered in an effective amount for therapeutic use through any of the modes of administration accepted for agents having similar utilities. The actual amount used of the compound of this invention, ie, the active ingredient, will depend on numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and the form of administration, and other factors. The drug can be administered more than once a day, preferably once or twice a day. The amounts effective for therapeutic use of the compounds of the present invention may vary between about 0.01 and 50 mg per kilogram of body weight of the receptor per day; preferably about 0.01-25 mg / kg / day, more preferably between about 0.1 and 10 mg / kg / day. Accordingly, to administer to a 70 kg person, the dosage range will preferably be about 7-70 mg per day. The present invention is not limited to any particular pharmaceutical composition or vehicle, since they may vary. In general, the compounds of this invention will be administered as pharmaceutical compositions through any of the following routes: oral, systemic administration (e.g.,transdermal, intranasal or as suppository) or parenteral (for example, intramuscular, intravenous or subcutaneous). The preferred form of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. The compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable composition. Another preferred way to administer the compounds of this invention is by inhalation. The choice of formulation depends on various factors, such as the mode of administration of the drug and the biological availability of the drug substance. For administration by inhalation, the compound can be formulated as liquid solutions, suspensions, aerosol propellants or dry powders, and can be loaded into a suitable device for administration. There are various types of inhalation devices for pharmaceutical substances and nebulizers for inhalation, metered dose inhalers (MDI) and dry powder inhalers (DPI). The nebulizer devices produce a current of air at high speed that causes the therapeutic agents (which are formulated in a liquid form) to be sprayed like a mist, which will be transportedto the patient's respiratory tract. MDIs typically comprise formulations packaged with a compressed gas. When activated, the device discharges a measured amount of the therapeutic agent, thanks to the action of the compressed gas, so they constitute a reliable means to administer a fixed amount of a. agent. DPI administers therapeutic agents in the form of a free-flowing powder, which can be administered in the air stream inspired by the patient when the patient breathes with the device. In order to obtain a free flowing powder, the therapeutic agent is Formula with an excipient, such as lactose. A measured amount of the therapeutic agent is stored in the form of a capsule, and administered with each action. Recently, special pharmaceutical formulations have been developed for drugs that have poor biological availability, based on the principle that biological availability can be increased by increasing the surface area, that is, decreasing the particle size. For example, US Pat. No. 4107288 discloses a pharmaceutical formulation having particles with a size in the range of 10 to 1000 nm, in which the active material is supported in a matrix of crosslinked macromolecules. US Patent No. 5145684 describes the production of apharmaceutical formulation in which the drug substance is sprayed into nanoparticles (with an average particle size of 400 nm) in the presence of a surface modifier, and then dispersed in a liquid medium to obtain a pharmaceutical formulation having an availability Highly significant biological The compositions are composed, in general, of a compound of the present invention in combination with at least one excipient acceptable for pharmaceutical use. The acceptable excipients are non-toxic, contribute to the administration and do not adversely affect the therapeutic benefit of the claimed compounds. This excipient can be any solid, liquid, semi-solid or, in the case of an aerosol composition, a gaseous excipient which is generally available to those skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dry skim milk and similar. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum,animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, etcetera. Preferred liquid carriers, in particular for injectable solutions include water, saline, aqueous dextrose and glycols. Compressed gases can be used to disperse a compound of this invention in the form of an aerosol. The inert gases appropriate for this purpose are nitrogen, carbon dioxide, and so on. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 18th edition, 1990). The amount of the compound in a formulation can vary within the full range employed by those trained in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, between about 0.01 and 99.99% by weight of a compound of the present invention, based on the total formulation, where the remainder it will be composed of one or more appropriate pharmaceutical excipients.
Preferably, the compound is present at a level of about 1-80% by weight. Representative pharmaceutical formulations are described in the Formulation Examples that follow. Additionally, the present invention relates toA pharmaceutical composition comprising an effective amount for the therapeutic use of a compound of the present invention, in combination with an effective amount for the therapeutic use of another active agent against RNA-dependent RNA viruses, and in particular, against HCV. Agents active against HCV include, without limitation, ribavirin, levovirin, viramidine, thymosin alfa-1, an inhibitor of the serine protease NS3 of HCV, or an inhibitor of inosine monophosphate dehydrogenase, interferon-a, interferon-a pegylated (peginterferon-OI), a combination of interferon-a and ribavirin, a combination of peginterferon-a and ribavirin, a combination of interferon-a and levovirin, and a combination of peginterferon-a-and levovirin. Interferon-a includes, without limitation, recombinant interferon-2a (such as interferon ROFERON, available from Hoffman-LaRoche, Nutley, NJ), interferon-a2b (such as Intron-A interferon, available from Schering Corp., Kenilworth , New Jersey, USA), a consensus interferon and a purified interferon-a product. For a description of ribavirin and its activity against HCV, see J. O. Saunders and S.A. Raybuck, "Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential," Ann. Rep. Med. ' Chem., 35: 201-210 (2000).
Agents active against the hepatitis C virus also include agents that inhibit HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV discharge , the NS5A protein of HCV or the inosine 5'-monophosphate dehydrogenase. Other agents include nucleoside analogs for the treatment of an HCV infection. Still other compounds include those described in WO 2004/014313 and WO 2004/014852, and in the references cited in said publications. Patent applications WO 2004/014313 and WO 2004/014852 are fully incorporated into the present documentation by way of reference. Specific antiviral agents include Omega IFN (BioMedicines Inc.), BILN-2061 (Boehringer Ingelheim), Summetrel (Endo Pharmaceuticals Holdings Inc.), Roferon A (F. Hoffman-La Roche), Pegasys (F. Hoffman-La Roche) , Pegasys / Ribaravin (F. Hoffman-La Roche), CellCept (F. Hoffman-La Roche), Wellferon (GlaxoSmithKline), Albuferon-ß (Human Genome Sciences Inc.), Levovirin (ICN Pharmaceuticals), IDN-6556 (Idun Pharmaceuticals), IP-501 (Indevus Pharmaceuticals), Actimmune (InterMune Inc.), Infergen A (InterMune Inc.), ISIS 14803 (ISIS Pharamceuticals Inc.), JTK-003 (Japan Tobacco Inc.), Pegasys / Ceplene (Maxim Pharmaceuticals), Ceplene (MaximPharmaceuticals), Civacir (Nabi Biopharmaceuticals Inc.), Intron A / Zadaxin (RegeneRx), Levovirin (Ribapharm Inc.), Viramidine (Ribapharm Inc.), Heptazyme (RibozymePharmaceuticals), Intron A (Schering-Plow), PEG-Intron (Schering-Plow), Rebetron (Schering-Plow), Ribavirin (Schering-Plow), PEG-Intron / Ribavirin (Schering-Plow), Zadazim (SciClone), Rebif (Serono), IFN-D / EMZ701 (Transition Therapeutics), T67 (Tularik Inc.), VX-497 (Vertex Pharmaceuticals Inc.), VX-950 / LY-570310 (Vertex Pharmaceuticals Inc.), Omniferon (Viragen Inc. .), XTL-002 (XTL Biopharmaceuticals), SCH 503034 (Schering-Plow), isatoribine and its prodrugs A A971 and A A975 (Anadys), R1479 (Roche Biosciences), Valopicitabine (Idenix), NIM811 (Novartis), and Actilon (Coley Pharmaceuticals). In some embodiments, the compositions and methods of the present invention contain a compound of the present invention and interferon. In some aspects, interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, alpha 2A interferon, and lymphoblasoid tau interferon. In other embodiments, the compositions and methods of the present invention contain a compound of the present invention and a compound having anti-HCV activity, selected from the group consisting of interleukin 2,interleukin 6, interleukin 12, a compound that promotes the development of a helper T type 1 cell response, interfering RNA (antisense RNA, Imiqimod, ribavirin, an inhibitor of inosine 5 'monophosphate dehydrogenase, amantadine, and rimantadine. other embodiments, the compound with anti-HCV activity Ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of NS3 serine protease, and an inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, or pegylated interferon-alpha alone or in combination with Ribavirin or viramidine In other embodiments, the compound with anti-HCV activity is said active agent against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with Ribavirin or viramidine Examples In the following examples and in the schedules of In the preceding syntheses, the following abbreviations have the respective meanings: If an abbreviation has not been defined, it is assigned its meaning generally ac eptado.microliters μ? micromolar micrograms NMR Magnetic nuclear resonance br ample d double d Chemical change dd Double doubles DMEM Dulbeco's Modified Eagle's Medium DMF?,? - dimethyl formamide DMSO Dimethyl sulfoxide DTT dithiothreitol DTT EDTA ethylenediaminetetraacetic acid (EDTA) ESI Electrospray ionization Gram h or hr hours HCV Hepatite virus C HPLC high performance liquid chromatography Hz Hertz IPTG esopropyl- ß-D-International Units 50% inhibition concentration Coupling constant (in HZ, unless otherwise indicated) Peak molar Peak parent mass plus H + milligram milliliter millimolar millimole mass specimen nanomolar nanomolar nanogram nitrilotriacetic acid nucleoside triphosphate Chain reaction of the polymerase Parts per millionpsi Pounds per square inch Rp-HPLC reverse high resolution liquid chromatography simple triple tetrakes tetrakes (triphenylphosphine) pal or tetrakes adio (0) palladium TFA trifluoroacetic acid THF tetrahydrofuran Three Three (hydroxymethyl) aminometanUTP uridine triphosphateIn the following examples, compounds and intermediates useful for preparing the compounds of the present invention are established. A general guide to the synthesis protocols used to prepare these compounds is indicated above. Example 1 6-Bromo-2- (41-chloro-4-methoxy-biphenyl-2-yl) -quinoline 4.11 Step 1. 4-Bromo-2-methyl-1-nitro-benzene (4.2): To an ice solution of 10.0 g (65.7 mmol) of 3-methyl-4-nitro-phenylamine in 200 mL of acetone, 21 mL (197.2 mmol) of 48% HBr were added. 4.54 g (65.7 mmol) of NaN02 were dissolved in 20 mL of water and the amine solution was added dropwise at a rate such as to maintain the temperature below 5 ° C. The mixture was stirred at this temperature for another 10 minutes then 1.5 g (10 mmol) of solid CuBr was added in portions at a rate to maintain the temperature below 15 ° C. The reaction was completed when no more nitrogen was detected (approximately 15 minutes). The reaction mixture was evaporated to dryness; the residue was dissolved in a mixture of 500 mL of water and 750 mL of ethyl acetate. The organic phase was separated, washed with water (2x), saturated NaCl (2x) and dried (Na 2 SO 4). It was then evaporated to dryness to give the crude product as a yellow solid which was purified by filtration through a pad of 400 mL of silica gel using elution with toluene; Yield: 10.45g (73%); XH-RM (CDC13): d (ppm) 7.87 (d, 1H, J = 8.7 Hz), 7.51-7.46 (m, 2H), 2.61 (s, 3H).
Step 2. [(E) -2- (5-Bromo-2-nitro-phenyl) -vinyl] -dimethyl-amine (4.4): A mixture of 9.26 g (42.9 mmol) of compound 4.2 , 14.3 mL (107.2 mmol) of N, N-dimethylformamide dimethylacetal4.3 and 11 mL of DMF was heated under a slow argon flow at 145 ° C (bath) for two hours. The reaction mixture was then evaporated to dryness. The dark pink product crystallized upon standing; MS: 271,01 & 273.01 (M + H +); Hi-NMR (DMSO-d6): d (ppm) 7.88 (d, 1H), 7.68 (dd, 1H), 7.58 (d, 1H), 7.05 (d, 1H), , 59 (d, 1H), 2.90 (s, 6H). Step 3. 5-Bromo-2-nitro-benzaldehyde (4.5): Compound 4.4 (11.63 g (42.9 mmol)) was dissolved in 500 mL of a 1: 1 mixture of THF and water . To this solution was added 34.3 g (160 mmol) of NaI0 and the mixture was stirred at room temperature for 1 hr while the dark solution turned pale yellow with a heavy precipitate. The solid material was removed by filtration, washed twice with 100 mL ethyl acetate and the organic phases were combined and evaporated to dryness. The residue was filtered through a pad of 400 mL of silica gel using toluene for elution to obtain 7.08 g (71%) of the title compound; 1 H-NMR (DMSO-d 6): d (ppm) 10.10 (s, 1H), 8, 09-7, 99 (m, 3H). Step 4. 2-amino-5-bromo-benzaldehyde (4.10): Compound 4.10 was synthesized from 5.45 g (23.7 mmol) of compound 4.5 using the procedure of LI Smith and J. Opie (Org Synth Coll. Vol.3, 56) in 55% yield (2.6 g); MS: 199.97 & 201.97 (M + H +); 1 H-NMR (CDC13): d (ppm) 9.75 (s, 1H), 7.71 (s, 1H), 7.39 (d, 1H,J = 9.3 Hz), 7.22 (s, 2 H), 6.72 (d, 1 H, J = 9.3 Hz). Step 5. 1- (2-Bromo-5-methoxy-phenyl) -ethanone (4.8): To an ice-cold solution of 8.75 g (35 mmol) of 2-bromo-5-methoxy-benzoyl chloride in 40 mL of toluene, 9.63 mL (19.25 mmol) of a 2M solution in toluene of dimethylzinc was added under an argon atmosphere (dimethylzinc is pyrophoric - contact with air should be avoided!). The ice bath was removed and the mixture slowly warmed to room temperature. Once the reaction begins, it evolves rapidly resulting in a cloudy solution. The reaction was completed in 30 minutes. It was then cooled again to 0 ° C and stopped by adding 10 mL of ethanol. The mixture was evaporated to dryness, the residue was dissolved in a mixture of 50 mL of 1M HC1 and 100 mL of ethyl acetate. The organic phase was separated and washed with 50 mL of water (2x), brine (2x) and dried (Na2SO4). The final solution was evaporated and the oil was dried overnight under high vacuum to give 7.96 g (99%) of the title compound as a colorless liquid; 1H-RN (CDC13): d (ppm) 7.46 (d, 1H), 6.96 (d, 1H), 6.83 (dd, 1H), 3.80 (s, 3H), 2.63 (s, 3H).
Step 6. 1- (41-Chloro-4-methoxy-biphenyl-2-yl) -ethanone (4.6): A mixture of compound 4.8 (6.0 g, 26.19 mmol), 4-chlorobenzeneboronic acid (4, 51 g, 28.81 mmol) and Pd (PPh3) 4 (0.303 g, 0.262 mmol) in toluene (250 mL), MeOH (60 mL) and 2NaHCO 3 (25 mL) was stirred under argon at 80 ° C for 16 h. After removal of the solvent, the dry residue was dissolved in CHC13 (150 mL) and filtered. The solvent was evaporated and the residue was purified by chromatography using CHCl3-MeOH (70: 1) as eluent to give the title compound (6.33 g, 93%); XH NMR (CDC13): 7.36 (d, 2H, J = 8.4 Hz), 7.27-7.21 (m, 4H), 7.02 (d, 1H, J = 2.7 Hz) , 3.86 (s, 3H), 2.05 (S, 3H). MS (ESI) 261.07 (M + H). Step 7. 6-Bromo-2- (4'-chloro-4-methoxy-biphenyl-2-yl) -quinoline (4.11): Compound 4.11 (100 mg (0.5 mmol)) and compound 4.6 (130 mg (0.5 mmol)) was dissolved in 5 mL of ethanol, 800 LD of 10% KOH (1.5 mmol) was added and the mixture was kept in a 90 ° C bath under argon overnight. The solvent was evaporated and the residue was triturated with water. The semi-solid compound 4.11 was purified on a pad of 400 mL of silica gel using toluene for elution to give 2.03 g (44%) of yellow gummy material MS: 424.03 & 426.03 (M + H +); 1 H-NMR (DMSO-d 6): d (ppm) 8.20 (d, 1 H, J = 2, 1 Hz), 8.10 (d, 1 H, J = 9.0 Hz), 7.93-7.83 (m, 2H), 7.40 (d, 1H, J = 8.4Hz), 7.26-7.23 (m, 3H0, 7.16-7.03 (m, 4H), 3.85 ( s, 3H) Example 2 Step 1. 6-Bromo-2 - (2,4-dimethyl-thiazol-5-yl) -quinoline To a solution of KOH (10.32 (85%) g, 156.27 mmol ) inAnhydrous EtOH (700 mL) was added 2-amino-5-bromobenzaldehyde (10.42 g, 52.09 mmol) and 5-acetyl-2,4-dimethylthiazole (8.16 mL, 60.42 mmol). The mixture was stirred under Ar at 78 ° C for 16 h and then cooled in an ice bath. It was neutralized to pH 7 with 5 N HC1 and then evaporated to about 60 mL. Water (500 mL) was added. The formed precipitate was collected by filtration, washed thoroughly with water, and dried to give 6-bromo-2- (2,4-dimethyl-thiazol-5-yl) -quinoline (15.62 g, 94%). . Step 2. 2 - (2,4-dimethyl-thiazol-5-yl) -quinolin-6-boronic acidA mixture of 6-bromo-2- (2,4-dimethyl-thiazol-5-yl) -quinoline (15 g, 46.99 mmol), bis (neopentylglucolato) diboro (31.83 g, 141 mmol), chloride of bis (triphenylphosphine) -palladium (II) (1.65 g, 2.35 mmol), and potassium acetate (13.81 g, 141 mmol) in anhydrous SO SO (260 mL) was stirred under Ar at 90 °. C for 2 h then cooled to room temperature. The mixture was poured into water (1.2 L) and the precipitate was collected by filtration, washed with water, and dried. EtOAc (600 mL) was added to the dried solid and the insoluble solid was removed by filtration. The filtrate was evaporated and the product was adsorbed on silica gel and purified by a short pad of silica gel eluting with EtOAc-hexane (5: 2) to give 2- (2,4-dimethylthiazole-5-) acid. il) -quinolin-6-boronic (16.4 g, which still contained approximately 30% bis (glycolate)neopentyl) diboro indicated by NMR- 94% yield). Example 3 2- (2,4-Dimethyl-thiazol-5-yl) -8-fluoro-quinoline-6-boronic acid Step 1. 4-amino-3-fluoroboronic acid A mixture of 4-bromo-2- commercially available fluoroaniline (500 mg, 2.6 mmol), potassium acetate (764 mg, 7.8 mmol), [P (Ph3)] 2Pd (II) Cl2 (18 mg, 0.026 mmol) and bis (neopentylglycolate) ) diboro (1.76 g, 7.8 mmol) in 13 mL of DMSO was heated at 60 ° C under argon overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate), and concentrated. The crude product was purified using RP-HPLC to give 4-amino-3-fluoro-boric acid. Step 2. 4-Amino-3-fluoro-5-diodoboric acid 4-Amino-3-fluoroboronic acid was treated with N-iodosuccinimide in acetic acid. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate), and concentrated to give 4-amino-3-fluoro-5-iodoboric acid.
Step 3. 4-Amino-3-fluoro-5-formyl-boric acid 4-Amino-3-fluoro-5-iodoboric acid was dissolved in THF while CO was bubbled through the reaction vessel. Tetrakis (triphenylphosphino) palladium and thereaction was heated to 50 ° C. Tributyltin hydride was added. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate), concentrated, and purified to give 4-amino-3-fluoro-5-formyl-boric acid. Step 4. 2 - (2,4-Dimethyl-thiazol-5-yl) -8-fluoro-quinoline-6-boronic acid A mixture of 4-amino-3-fluoro-5-formyl-boronic acid compound, 5- acetyl-2,4-dimethylthiazole; and KOH / ethanol in 10% ethanol refluxed overnight. The reaction was concentrated, triturated with water, and purified to give 2- (2,4-dimethyl-thiazol-5-yl) -8-fluoro-quinoline-6-boric acid. EXAMPLE 4 5- (2-Chloro-quinolin-6-yl) -4H-thieno [3,2-b] indole-2-carboxylic acid ethyl ester (7.8) Step 1. 5-methyl-4-nitro-thiophene acid -2-carboxylic acid (7.2) Acetic anhydride (17 mL, 176 mmol, 5 equiv) was cooled to -78 ° C in a dry ice / acetone bath and fuming nitric acid was slowly added (6 mL, 113 mmol, 3, 2 equiv), and the mixture was heated to -20 ° C. 5-Methyl-thiophene-2-carboxylic acid 7.1 (5 g, 35.2 mmol, 1 equiv) was added slowly in small portions (QUICK EXOTHERMIA). The temperature fluctuated between -20 ° C and +10 ° C then stabilized at -20 ° C. The reaction mixture isstirred at -20 ° C for 10 min. Then the reaction mixture was quenched with ice-water to give a precipitate which was collected by filtration and washed with ice-water. The pink solid was recrystallized from EtOH / H20. The collected crystals were washed with ice-water, dried with air, and dried under vacuum to give 5-methyl-4-nitro-thiophene-2-carboxylic acid 7.2 (3.24 g, 50%) as a pink solid -Brown. The reaction was repeated on a 15 gram scale (yield 9.82 g, 50%). MS: 188.70 (M + H +); 1 H-NMR (DMSO-d 6): d (ppm) 13.77 (bs, 1H), 8.00 (s, 1H), 2.79 (s, 3H). Step 2. 5-methyl-4-nitro-thiophene-2-carboxylic acid methylester (7.3) Compound 7.2 (10 g, 53.4 mmol, 1 equiv) in eOH (100 mL) was treated with sulfuric acid (10 g). mL, 19 mmol, 3.5 equiv) and heated to reflux for 1 day. After the reaction mixture was cooled to room temperature, the solvent was evaporated. The residue was dissolved in EtOAc and quenched with saturated NaHCO 3, then the layers were separated. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated, and dried under vacuum to give 5-methyl-4-nitro-thiophene-2-carboxylic acid methyl ester 7.3 (9.95 g, 93%) as a pale brown solid. MS: 202.00(M + H +); ^ -RM (DMSO-d6): d (ppm) 8.06 (s, 1H), 3.84 (s, 3H), 2.78 (s, 3H).
Step 3. 2-Chloro-6-bromomethyl-quinoline and 2-chloro-6-dibromomethyl-quinoline (7.5) To a solution of 2-chloro-6-methylquinoline 7.4 (2 g, 11.3 mmol, 1 equiv) in Benzene (13 mL) under argon was added NBS (4 g, 23 mmol, 2 equiv) followed by benzoyl peroxide (0, 365 g, 1.13 mmol, 0.10 equiv). The mixture was refluxed for 4 h. after cooling to room temperature, the solvent was evaporated, and the residue was dissolved in DCM, and washed with saturated NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified by ISCO (DCM: Hex = 4: 1) to give 2-chloro-6-bromomethyl-quinoline and 2-chloro-6-dibromomethyl-quinoline 7.5 (3 g, 80%) as a white solid. which consisted of a 1: 8 mixture of monobromo-quinoline: dibromo-quinoline according to HPLC. DC TLC gradient: Hex = 4: 1. 2-Chloro-6-bromomethyl-quinoline: MS: 255.65 & amp;; 257.65 (M + H +); 2-chloro-6-dibromomethyl-quinoline: MS: 333.80 & 335.80 & 337.80 (M + H +). Step 4. 2-Chloro-quinoline-6-carbaldehyde (7.6) The 1: 8 mixture of brominated quinolines 7.5 (3 g, 9.24 mmol, 1 equiv) and hexamethylenetetramine (3.89 g, 28 mmol, 3 equiv) were heated to reflux in 50% aqueous ethanol (16 mL) for 1 h. After cooling to room temperature, water (10 mL) was added followed by the slow addition of 12N HC1 (1.50 mL) for 5 min. The reaction mixture isheated to reflux for 0.5 h then cooled to room temperature. The reaction mixture was added to brine and extracted with DCM 4X. The collected organics were washed with 2X brine, dried (Na2SO4), filtered, and concentrated. The solid was dried in vacuo to give 2-chloro-quinoline-6-carbaldehyde 7.6 (1.63 g, 92%) as a white solid which was used without further purification. S: 192.00 (M + H +); 1 H-NMR (DMSO-d 6): d (ppm) 10.17 (s, 1H), 8.69 (m, 1H), 8.68 (d, 1H, J = 8.4 Hz), 8.21 (dd, 1H, J = 9.0 Hz and 1.8 Hz), 8.09 (dd, 1H, J = 8.4 Hz and 0.60 Hz), 7.75 (d, 1H, J = 8 , 4 Hz). Step 5. 5- (E) -2- (2-Chloro-quinolin-6-yl) -vinyl] -4-nitro-thiophene-2-carboxylic acid methyl ester (7.7) A solution of compound 7.3 (1, 71 g, 8.51 mmol, 1 equiv) in MeOH (35 mL) was treated with compound 7.6 (1.63 g, 8.51 mmol, 1 equiv). The reaction mixture was heated to reflux until a solution was obtained. Then a catalytic amount of pyrrolidine (70DL, 0.0605 g, 0.851 mmol, 0.10 equiv) was added. The reaction mixture was heated to reflux overnight. After cooling to room temperature, evaporation of the solvent gave a residue which was purified by ISCO (gradient Hex: EtOAc = 100: 0 to 0: 100) to give methyl ester of 5- [(E) -2- (2- chloro-quinolin-6-yl) -vinyl] -4-nitro-thiophene-2-carboxylic acid 7.7 (2.62 g, 82%) as an orange-red solid. TLC gradient Hex: EtOAc= 1: 1 MS: 375.70 (M + H +); ^ -NMR (DMSO-d6): d (ppm) 8.50 (d, 1H, J = 8.7 Hz), 8.34 (bs, 1H), 8.18 (m, 1H), 8.16 (bs, 1H), 8.00 (d, 1H, J = 9.0 Hz), 7.80 (d, 1H, J = 16.5 Hz), 7.65 (d, 1H, J = 8, 7 Hz), 7.30 (d, 1H, J = 17.4 Hz), 3.89 (s, 3H). Step 6. 5- (2-Chloro-quinolin-6-yl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid methyl ester (7.8) A solution of compound 7.7 (2.62 g, , 00 mmol, 1 equiv) in triethyl phosphite (7 mL) was heated to reflux (160 ° C) for 2 h. After cooling to room temperature, the solvents [P (OEt) 3 bp 153-157 ° C; OP (OEt) 3 bp 215 ° C] were evaporated under high vacuum maintaining the water bath at 70 ° C. The residue was placed in EtOAc and precipitated with n-hexane. The solid was collected by filtration and washed with 5% EtOAc / n-hexane. After drying with air for a few minutes, the solid was dried under vacuum to give the sought compound 7.8 (960 mg, 40%) as a brown-yellow solid. TLC gradient Hex: EtOAc = 1: 1. MS: 343.00 (M + H +); H-NMR (DMSO-d6): d (ppm) 12.3 (bs, 1H), 8.39 (m, 2H), 8.24 (d, 1H, J = 8.7 Hz), 8.00 (d, 1H, J = 8.7 Hz), 7.71 (s, 1H), 7.61 (d, 1H, J = 9.0 Hz), 7.16 (s, 1H), 3.82 (s, 3H). Example 5 6-Cyclohex-l-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4ff acid -tiene [3, 2-b] irol-2-carboxylic acid (compound 186)Step 1. 5- [2- (2-Fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3, 2-b] irrol-2-carboxylic acid ethyl ester (8.2a) A reaction vessel of Microwave was charged with 387 mg (1.13 mmol) of compound 7.8 (Example 4), 237 mg (1.69 mmol, 1.5 eq) of boric 2-fluorophenyl acid and 65 mg (0.057 mmol, 0.05 eq). ) of Pd (PPh3) 4. To this was added 12 mL of dioxane and 4 mL of 1M aqueous K3P04. The reaction vessel was sealed, and subsequently degassed and purged with Ar (2x). The reaction mixture was then heated by microwave at 120 ° C for 10 min. HPLC analysis confirmed that compound 7.8 was completely consumed. The reaction mixture was allowed to cool to room temperature, during which time a precipitate formed. The precipitate was collected by filtration, washed with cold H20 and dried under vacuum to give 399 mg (88%) of 5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H methyl ester. - [3, 2-b] pyrrole-2-carboxylic acid 8.2a as a yellow powder. MS: 403.1 (M + H +). Step 2. Methyl ester of 6-cyclohex-l-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3,2- b] pyrrole-2-carboxylic acid ( 8.3a) A microwave reaction vessel was charged with 245 mg (0.61 mmol) of compound 8.2a, 947 L (9.15 mmol, 15 eq) of cyclohexanone, 500 L of acetic anhydride, 500 L of H3PO4 85 % and 4 mL of acetic acid. The recipient of theThe reaction was sealed and heated by microwave at 180 ° C for 75 min. HPLC analysis confirmed the total consumption of compound 8.2a. The reaction mixture was poured into 50 mL of NH 4 OH (concentrated, aqueous) at 0 ° C. The aqueous mixture was then diluted with H20 and extracted with ethyl acetate (3x). The combined extracts were then washed with HC1 (1M, aqueous), NaHCO3 (saturated, aqueous) and brine. The organic phase was then dried over Na2SO4, filtered and concentrated to give 6-cyclohex-l-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thienoic acid methyl ester. [3, 2-b] pyrrole-2-carboxylic 8.3a. The crude residue was dried under vacuum and used without further purification. MS: 483.1 (M + H +). Step 3. 6-Cyclohex-l-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) - acid 4H-Thieno [3,2-b] Irrol-2-carboxylic acid (compound 186) A reaction vessel was charged with 75 mg (0.16 mmol) of compound 8.3a and dissolved with 8 mL of DMF. Then 11 mg (0.31 mmol, 2 eq) of NaH (67% in mineral oil) was added and the reaction mixture was allowed to stir at room temperature. After 15 min 36 L (0.31 mmol, 2 eq) of 2-chloro-l-morpholin-4-yl-ethanone were added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. After 3 h, HPLC and LC-MS analysis confirmed that compound 8.3a had been completely consumed. The mixture ofThe reaction was stopped by adding 0.1 mL of H20, poured into a 50 mL vessel and concentrated. Then cold H20 was added to the crude residue to precipitate the methyl ester as a dark powder. The solids were collected by centrifugation and washed again with H20. The methyl ester was then transferred to a reaction vessel and dissolved with 3 mL of THF, 1 mL of MeOH and 1 mL of LiOH (1M, aqueous). The reaction mixture was then heated to 50 ° C and carefully monitored by HPLC analysis and LC-MS. Upon completion of the conversion, the reaction mixture was neutralized with 0.5 mL of HC1 (2M, aqueous) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to give 35 mg (37%) of 6-cyclohex-l-enyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (compound 186) as an orange powder. MS: 596.2 (M + H +); X H NMR (DMSO-d 6): d (ppm) 8.55 (d, J = 8.1, 1H), 8.17 (d, J = 8.7, 1H), 8.09 (td, J = 7.9, 1.7, 1H), 8.03-7.99 (m, 2H), 7.91 (s, 1H), 7.73 (dd, J = 8.4, 1.7, 1H) ), 7.65-7.58 (m, 1H), 7.48-7.41 (m, 2H), 5.81-5.78 (m, 1H), 5.00 (s, 2H), 3.48-3.33 (m, 8H), 2.12 (br s, 2H), 1.99 (br s, 2H), 1.54 (br s, 4H).
EXAMPLE 6 6-Cyclohex-l-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-) acid oxo-ethyl) -4ff-thieno [3,2-b] pyrrole-2-carboxylic acid (compound 187) Step 1. 5- [2- (2,4-Dimethyl-thiazol-5-yl) -quinolin acid methyl ester -6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (8.2b) A microwave reaction vessel was charged with 500 mg (1.46 mmol) of compound 7.8 (Example 4), 436 mg (1.82 mmol, 1.25 eq) of 2,4-dimethyl-thiazole-5-boronic acid pinacolyester and 84 mg (0.073 mmol, 0.05 eq) of Pd (PPh3). To this was added 12 mL of dioxane and 4 mL of K3P04 (1M, aqueous). The reaction vessel was sealed, and subsequently degassed and purged with Ar (2x). The reaction mixture was then heated by microwave at 120 ° C for 10 min. HPLC analysis confirmed that compound 7.8 was completely consumed. The reaction mixture was allowed to cool to room temperature, during which time a precipitate formed. The precipitate was collected by centrifugation, washed with cold H20 and dried under vacuum to give 506 mg (81%) of 5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin- methyl ester. 6-yl] -4H-thieno [3,2- b] pyrrole-2-carboxylic acid 8.2b as a yellow powder. MS: 420.1 (M + H +).
Step 2. Methyl ester of 6-cyclohex-l-enyl-5- [2- (2, 4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (8.3b) A microwave reaction vessel was charged with 200 mg ( 0.48 mmol) of compound 8.2b, 74D pL (7.16 mmol, 15 eq) of cyclohexanone, 400 pL of acetic anhydride, 400 pL of 85% H3P04 and 4 mL of acetic acid. The reaction vessel was sealed and heated by microwave at 150 ° C for 100 min. HPLC analysis confirmed that compound 8.2b had been completely consumed. The reaction mixture was poured into 50 mL of NH 4 OH (concentrated, aqueous) at 0 ° C. The aqueous mixture was then diluted with H20 and extracted with ethyl acetate (3x). The combined extracts were then washed with HC1 (1M, aqueous), NaHCO3 (saturated, aqueous) and brine. The organic phase was then dried over Na 2 SO 4, filtered and concentrated to give 6-cyclohex-l-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-methyl ester. il] -4H-thieno [3,2- b] pyrrole-2-carboxylic 8.3b. The crude residue was dried under vacuum and used without further purification. MS: 500.1 (M + H +). Step 3. 6-Cyclohex-l-enyl-5 - [2 - (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2) acid -oxo-ethyl) -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (Compound 187) A reaction vessel was charged with 56 mg (0.11 mmol) of compound 8.3b and was dissolved- with 4 mL of DMF.
Then 9 mg (0.22 ramol, 2 eq) of NaH (60% in mineral oil) were added and the reaction mixture was allowed to stir at room temperature. After 15 min 26 pL (0.22 mmol, 2 eq) of 2-chloro-l-morpholin-4-yl-ethanone were added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. after 6 h, HPLC and LC-MS analysis confirmed that compound 8.3b had been completely consumed. The reaction mixture was stopped by adding 0.1 mL of H20, poured into a 50 mL vessel and concentrated. Then cold H20 was added to the crude residue to precipitate the methyl ester as a dark powder. The solids were collected by centrifugation and washed again with H20. The methyl ester was then transferred to a reaction vessel and dissolved with 3 mL of THF, 1 mL of MeOH and 1 mL of LiOH (1M, aqueous). The reaction mixture was then heated to 50 ° C and carefully monitored by HPLC analysis and LC-MS. Upon completion of the conversion, the reaction mixture was neutralized with 0.5 mL of HC1 (2M, aqueous) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to give 15 mg (22%) of 6-cyclohex-l-enyl-5- [2- (2,4-dimethyl-thiazol-5-yl) - quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (Compound 187) as an orange powder. MS:613.2 (+? +); XU NMR (DMS0-d6): d (ppm) 8.51 (d, J = 8.7, 1H), 8.04 (d, J = 8.7, 1H), 7.97-7.90 ( m, 3H), 7.68 (dd, J = 8.7, 2.0, 1H), 5.78 (br s, 1H), 4.99 (s, 2H), 3.46-3.32. (m, 8H), 2.76 (s, 3H), 2.71 (s, 3H), 2.11 (br s, 2H), 1.97 (br s, 2H), 1.53 (br s , 4H). EXAMPLE 7 6-Cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno acid [3 , 2-b] pyrrole-2-carboxylic acid (compound 188) Step 1. Methyl ester of 6-cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4H-thieno [3, 2-b] Irrol -2-carboxylic (8.4a) A microwave reaction vessel was charged with 235 mg (0.49 mmol) of compound 8.3a (Example 5, Step 2), 116 L (0.73 mmol, 1.5 eq) of triethylsilane and 5 mL of TFA. The reaction vessel was sealed and heated by microwave at 70 ° C for 5 min. Analysis by LC-MS confirmed that compound 8.3a had been completely consumed. The reaction mixture was poured into a 50 mL container and concentrated to give 6-cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4.H-thieno-methyl ester. 3, 2-b] pyrrole-2-carboxylic acid 8.4a as a red powder. The crude residue was dried under vacuum and used without further purification. MS: 485.1 (M + H +). Step 2. 6-Cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin- acid6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4-tf-thieno [3,2- b] pyrrole-2-carboxylic acid (compound 188) A reaction vessel was charged with 307 mg (0.63 mmol) of compound 8.4a was dissolved with 20 mL of DMF. Then 50 mg (1.26 mmol, 2 eq) of NaH (60% in mineral oil) was added and the reaction mixture was allowed to stir at room temperature. After 15 min 146 L (1.26 mmol, 2 eq) of 2-chloro-l-morpholin-4-yl-ethanone was added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. After 75 min, HPLC and LC-MS analysis confirmed that compound 8.4a had been completely consumed. The reaction mixture was quenched by adding 0.5 mL of H20, poured into a 50 mL vessel and concentrated. Then cold H20 was added to the crude residue to precipitate the methyl ester as a dark powder. The solids were collected by centrifugation and washed again with H20. The methyl ester was then transferred to a reaction vessel and dissolved with 6 mL of THF, 2 mL of MeOH and 2 mL of LiOH (1M, aqueous). The reaction mixture was then heated to 50 ° C and carefully monitored by HPLC analysis and LC-MS. Upon completion of the conversion, the reaction mixture was neutralized with 1 mL of HC1 (2M, aqueous) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA. The mixture was then filtered and purified by HPLCof reverse phase to give 107 mg (28%) of 6-cyclohexyl-5- [2- (2-fluoro-phenyl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2- oxo-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (compound 188) as an orange powder. MS: 598.2 (M + H +); XH NMR (DMS0-d6): d (ppm) 8.58 (d, J = 8.3, 1H), 8.22 (d, J = 8.6, 1H), 8, 11-7, 99 · (m, 3H), 7.86 (s, 1H), 7.73 (dd, J = 8.6, 2.0, 1H), 7.65-7.58 (m, 1H), 7.48. -7.42 (m, 2H), 5.01 (s, 2H), 3.51-3.37 (m, 8H), 2.59 (m, 1H), 2, 53-1, 25 (m , 10H). EXAMPLE 8 6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) acid -4H-Thieno [3,2-b] pyrrole-2-carboxylic acid (compound 189) Step 1. Methyl ester of 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin -6-yl] -4H-thieno [3,2-b] pyrrole-2-carboxylic acid (8.4b) A 100 mL balloon was charged with 360 mg (0.72 mmol) of compound 8.3b (Example 6, Step 2), 172 pL (1.08 mmol, 1.5 eq) triethylsilane and 7 mL of TFA. The reaction mixture was capped and allowed to stir at room temperature for 1 h. The LC-MS analysis confirmed that compound 8.3b had been completely consumed. The reaction mixture was concentrated to give 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] methyl ester. ] pyrrole-2-carboxylic 8.4b. The crude residue was dried atvacuum and was used without further purification. MS: 502.1 (M + H +). Step 2. 6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-morpholin-4-yl-2-oxo-ethyl) acid ) -4H-Thieno [3,2-b] Irrol-2-carboxylic acid (compound 189) A reaction vessel was charged with 361 mg (0.72 mmol) of Compound 8.4b and dissolved with 20 mL of DMF. Then 58 mg (1.44 mmol, 2 eq) of NaH (60% in mineral oil) were added and the reaction mixture was allowed to stir at room temperature. After 15 min 167 L (1.44 mmol, 2 eq) of 2-chloro-l-morpholin-4-yl-ethanone were added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. After 60 min, HPLC and LC-MS analysis confirmed that compound 8.4b had been completely consumed. The reaction mixture was quenched by adding 0.5 mL of H20, poured into a 50 mL vessel and concentrated. Then cold H20 was added to the crude residue to precipitate the methyl ester as a dark powder. The solids were collected by centrifugation and washed again with H20. The methyl ester was then transferred to a reaction vessel and dissolved with 6 mL of THF, 2 mL of MeOH and 2 mL of LiOH (1M, aqueous). The reaction mixture was then heated to 50 ° C and carefully monitored by HPLC and LC-MS analysis. When the conversion is complete, the reaction mixtureneutralized with 1 mL of HC1 (2M, aqueous) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to give 178 mg (39%) of 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-acid. il] -4- (2-morpholin-4-yl-2-oxo-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (Compound 189) as an orange powder. MS: 615.2 (M + H +); ? NMR (DMS0-d6): d (ppm) 8.53 (d, J = 8.3, 1H), 8.08 (d, J = 8.6, 1H), 7.96-7.93 (m , 2H), 7.86 (s, 1H), 7.68 (dd, J = 8.6, 1.8, 1H), 5.00 (s, 2H), 3.51-3.36(m, 8H), 2.76 (s, 3H), 2.71 (s, 3H), 1.86-1.20 (m, 10H). EXAMPLE 9 6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-oxo-2-thiomorpholin-4-yl-ethyl) acid) 4H-thieno [3,2-b] pyrrole-2-carboxylic acid (compounds 44 and 190) Step 1. 4-tert-butoxycarbonylmethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-) methyl ester thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (9.1) A reaction vessel was charged with 191 mg (0.38 mmol) of compound 8.4 b (Example 8, Step 1) and dissolved with 15 mL of DMF. Then 30 mg (0.76 mmol, 2 eq) of NaH (60% in mineral oil) was added and the reaction mixture was allowed to stir at room temperature. After 15 min, 112 pL (0.76 mmol, 2 eq) of 2-tert-butylbromoacetate was added in 1 portion and the reaction mixture was added.let continue stirring at room temperature. The reaction was monitored by HPLC and LC-MS analysis. Upon completion of the conversion of compound 8.4b, the reaction mixture was quenched by adding 0.5 mL of H20, poured into a 50 mL vessel and concentrated. Then cold H20 was added to the crude residue to precipitate the methyl ester as a dark powder. The solids were collected by centrifugation and washed again with H20. The methyl ester of 4-tert-butoxycarbonylmethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3, 2-b] crude pyrrole-2-carboxylic acid 9.1 was then dried under vacuum and used without further purification. MS: 616.1 (M + H +). Step 2. 4-Carboxymethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno methyl ester [3, 2-b] pyrrole-2-carboxylic acid (9.2) A 50 mL vessel was charged with 234 mg (0.38 mmol) of compound 9.1 and dissolved with 5 mL of HC1 in 4M dioxane. Then 250 L (5% v / v) of anisole was added and the reaction mixture was allowed to stir at room temperature. After HPLC and LC-MS analysis indicated complete conversion of compound 9.1, the reaction mixture was concentrated. 4-Carboxymethyl-6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4H-thieno [3,2-b] pyrrolemethyl ester 2-crude carboxylic acid 9.2 then dried briefly under vacuum and was used withoutadditional purification. MS: 560.1 (M + H +). Step 3. 6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2-oxo-2-thiomorpholin-4-yl-ethyl) acid ) -4H-Thieno [3,2-b] pyrrol-2-carboxylic acid (compound 190) A reaction vessel was charged with 107 mg (0.19 mmol) of compound 9.2 and dissolved with 3 mL of DMF. Then 86 mg (0.23 mmol, 1.2 eq) of HBTU and 73 μ? · (0.42 mmol, 2.2 eq) of DIEA were added and the reaction mixture was allowed to stir at room temperature. After 15 min 24 pL (0.24 mmol, 1.25 eq) of thiomorpholine was added in 1 portion and the reaction mixture was allowed to continue stirring at 35 ° C. After analysis by HPLC and Lc-MS confirmed that compound 9.2 was completely consumed, the reaction mixture was concentrated under high vacuum. Then cold H20 was added to the crude residue to precipitate the methyl ester. The solids were collected by centrifugation and washed again with H20. The methyl ester was then transferred to a reaction vessel and dissolved with 3 mL of THF, 1 mL of MeOH and 1 mL of LiOH (1M, aqueous). The reaction mixture was then heated to 50 ° C and carefully monitored by HPLC and LC-MS analysis. Upon completion of the conversion, the reaction mixture was neutralized with 0.5 mL of HC1 (2M, aqueous) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA. The mixture was then filtered and purifiedby reverse phase HPLC to give 24 mg (20%) of 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2- oxo-2-thiomorpholin-4-yl-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (compound 190) as an orange powder. S: 631.2 (M + H +); X H NMR (DMSO-d 6): d (ppm) 8.53 (d, J = 8.8, 1H), 8.08 (d, J = 8.8, 1H), 7.95-7.87 ( m, 3H), 7.68 (dd, J = 8.5, 2.0, 1H), 5.00 (s, 2H), 3.67-3.57 (m, 4H), 2.76 ( s, 3H), 2.71 (s, 3H), 2.47-2.35 (m, 4H), 1.86-1.21 (m, 10H). EXAMPLE 10 6-Cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-yl] -4- (2 -oxo-2-piperidin-1-yl) acid ethyl) -4H-thieno [3,2-b] irrol-2-carboxylic acid (compounds 35 and 191) A reaction vessel was charged with 107 mg (0.19 mmol) of compound 9.2 (Example 9, Step 2) and it was dissolved with 3 mL of DMF. Then 86 mg (0.23 mmol, 1.2 eq) of HBTU and 73 L (0.42 mmol, 2.2 eq) of DIEA were added and the reaction mixture was allowed to stir at room temperature. After 15 min 24 pL (0.24 mmol, 1.25 eq) of piperidine was added in 1 portion and the reaction mixture was allowed to continue stirring at 35 ° C. After analysis by HPLC and Lc-MS confirmed that compound 9.2 was completely consumed, the reaction mixture was concentrated under high vacuum. Then cold H20 was added to the crude residue to precipitate the methyl ester. The solids were collected by centrifugation and washed again withH20 The methyl ester was then transferred to a reaction vessel and dissolved with 3 mL of THF, 1 mL of MeOH and 1 mL of LiOH (1M, aqueous). The reaction mixture was then heated to 50 ° C and carefully monitored by HPLC analysis and LC-MS. Upon completion of the conversion, the reaction mixture was neutralized with 0.5 mL of HC1 (2M, aqueous) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to give 24 mg (21%) of 6-cyclohexyl-5- [2- (2,4-dimethyl-thiazol-5-yl) -quinolin-6-acid. il] -4- (2-oxo-2-piperidin-1-yl-ethyl) -4H-thieno [3,2- b] pyrrole-2-carboxylic acid (compound 191) as an orange powder. MS: 613.2 (M + H +); XH NMR (DMSO-d6): d (ppm) 8.52 (d, J = 8.5, 1H), 8.07 (d, J "= 8.5, 1H), 7.95-7.92 (m, 2H), 7.82 (s, 1H), 7.69 (d, J = 8.2, 1H), 5.96 (s, 2H), 3.38-3.26 (m, 4H) ), 2.76 (s, 3H), 2.71 (s, 3H), 1.86-1, 24 (m, 16H). Prophetic compounds 1-34, 36-43, and 45-185 in the Table I can be prepared in a similar manner according to the general synthetic methods and examples as described Biological Examples Biological Example 1. Anti-Hepatitis C Activity Compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by means of theinhibition of other enzymes necessary for the replication cycle, or by other routes. Several trials have been published to determine these activities. A general method for determining the large increase of HCV virus in culture was disclosed in US Pat. No. 5,738,985 by Miles et al. In vitro assays have been described in Ferrari et al. Jnl. of Vir. , 73: 1649-1654, 1999; Ishii et al., Hepatology, 29: 1227-1235, 1999; Lohmann et al., Jnl de Bio. Chem., 274: 10807-10815, 1999; and Yamashita et al., Jnl. of Bio. Che., 273: 15479-15486, 1998. WO 97/12033, filed on September 27, 1996, by Emory University, listing C. Hagedorn and A. Reinoldus as inventors, claim priority to United States Provisional Patent Application Serial No. 60 / 004,383, filed in September 1995, which described an HCV polymerase assay that can be used to evaluate the activity of the components described herein. Another HCV polymerase assay was reported by Bartholomeusz, et al., Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996: l (Supp 4) 18-24. Some studies measuring reductions in kinase activity from drugs for HCV were disclosed in U.S. Pat. No. 6,030,785, by Katze et al.,Patent of the E.E.U.U. No. 6,228,576, Delvecchio, and U.S. Patent. No. 5,759,795 by Jubin et al. Certain studies measuring the protease inhibitory activity of proposed HCV drugs were disclosed in US Pat. No. 5,861,267 by Su et al., U.S. Patent. No. 5,739,002 by De Francesco et al., And Patent of the US. No. 5,597,691 by Houghton et al. Biological Example 2. Replicon Assay One cell line, ET (Huh-lucubineo-ET), was used for the studies of the compounds for the inhibition of RNA polymerase dependent on HCV RNA. The ET cell line was stably transfected with RNA transcripts containing an I389luc-ubi-neo / NS3 -3 '/ ET; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and polyprotein NS3-5B directed by E CV-IRES with adaptive mutations for cell culture (E1202G; T1280I; K1846T) (Krieger et al, 2001 and unpublished). ET cells were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM Glutamine, Penicillin (100 IU / mL) / Streptomycin (100 g / mL), 1 x non-essential amino acids, and 250 g / mL of G418 ("Geneticin"). All available at Life Technologies (Bethesda, MD). Cells were plated at 0.5-1.0 x 10 4 cells / well in 96-well plates and incubated for24 hours before adding the compound to be tested. The compounds were added to the cells to achieve a final agreement of 0, 1 nM to 50 ym and a final concentration of DMSO of 0.5%. The luciferase activity was measured 48-72 hours later by the addition of a lysis buffer and the substrate (catalog number Glo-lysis buffer E2661 and Bright-Glo luciferase system E2620 Promega, Madison, WI). The cells should not be very confluent during the test. Percent inhibition of replication was plotted against a control compound. Under the same condition, the cytotoxicity of the compounds was determined using a cell proliferation reagent WST-1 (Roche, Germany). The compounds that have antiviral activity, but without significant cytotoxicities, were selected to determine EC50 and TC50, the effective concentration and the toxic concentration at which 50% of the maximum inhibition is observed. For these determinations, a serial dilution of 2 times, in 10 points, was used for each compound, which covers a concentration range of 1000 times. The IC50 and TC50 values were calculated by adjusting the inhibition%, at each concentration, to the following equation:% inhibition = 100% / [(IC50 / [I]) b + 1] where b is the Hill coefficient .
In some aspects, the compounds of Formula (I) will have an EC50 equal to or less than 50 DM when tested according to the test of Example 2. In other aspects, the EC50 is equal to or less than 10 DM. In still other aspects, the EC50 is equal to or less than 5.DM. When tested at 6.25 DM, it was found that compounds 186-191 had respectively the following percentage values of inhibition 75, 63, 99, 100, 98 and 97. Biological Example 3. Cloning and expression of recombinant HCV-NS5b The coding sequence of the NS5b protein was cloned by PCR from pFKI389luc / NS3 -3 '/ ET as described by Lohmann, V., et al. (1999) Science 285, 110-113 using the primers shown on page 266 of WO 2005/012288. The cloned fragment lacks the 21 terminal C amino acid residues. The cloned fragment was inserted into an IPTG-inducible expression plasmid that provides a labeled epitope of (His) 6 at the carboxy terminus of the protein. The recombinant enzyme was expressed in XL-1 cells and after induction of expression, the protein was purified using affinity chromatography on a nickel-NTA column. The storage conditions were 10 mMof Tris-HCl pH 7.5, 50 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 20% glycerol at -20 ° C. Biological Example 4. Enzyme Assay HCV-NS5b Polymerase activity was assayed by measuring the incorporation of radiolabelled UTP into an RNA product using a biotinylated heteropolymer template, which includes a portion of the HCV genome. Typically, the assay mixture (50 pL) contains 10 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 0.2 mM EDTA, 10 mM KC1, 1 unit / pL RNAsin, 1 mM DTT, 10 μ? of each NTP, including [3H] -UTP, and 10 ng / pL of heteropolymer template. The compounds tested initially were dissolved in 100% DMSO and re-diluted in an aqueous buffer containing 5% DMSO. Typically, the compounds were tested at concentrations between 1 nM and 100 μ ?. The reactions were started with the addition of the enzyme and continued at 37 ° C for 2 hours. The reactions were quenched with 8 pL of 100 mM EDTA and the reaction mixtures (30 pL) were transferred to microtiter plates by scintillation proximity covered of streptavidin (FlashPlates) and incubated at 4 ° C overnight. The incorporation of radioactivity was determined by scintillation counter (cpm).
EXAMPLES OF FORMULATIONThe following are representative pharmaceutical formulations containing a compound of the formula (I). Formulation Example 1 Tablet Formulation The following ingredients are intimately mixed and pressed into individual tablets.
Compressed ingredient, mg compound 400 corn starch 50 Croscarmellose sodium 25 lactose 120 Magnesium stearate 5Formulation Example 2 Capsule Formulation The following ingredients are intimately mixed and loaded into a rigid shell gelatin capsule. Quantity per Ingredient capsule, mg compound 200 Lactose, spray dried 148Magnesium stearateFormulation Example 3 Formulation for suspension The following ingredients are mixed to form a suspension for oral administration. Ingredient Compound quantity 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulated sugar 25.0 g Sorbitol (70% solution) 13.00 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL dyes 0.5 mg Distilled water can. suf. up to 100 miFormulation Example 4 Injectable formulation The following ingredients are mixed to form injectable formulation.
Ingredient Amount Compound 0.2 mg-20 mg Buffer solution 2.0 mL of sodium acetate, 0.4 M HC1 (1N) or NaOH (1N) cant. Suf. Suitable pH Water (distilled, sterile) can. suf. up to 20 miFormulation Example 5 Suppository Formulation A suppository with a total weight of 2.5 g was prepared by mixing the compound of the invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acids, Riches-Nelson, Inc., New York) , and with the following composition: Ingredient Compound quantity 500 mg Witepsol® H-15 restREFERENCES The following publications are cited in this application by means of superscripts: 1. Szabo, E. et al., Pathol. Oncol. Res. 2003, 9: 215-221. 2. Hoofnagle J.H., Hepatology 1997, 26: 15S-20S. 3. Thomson B.J. and Finch R.G., Clin. Mlcrobial Infect. 2005, 11: 86-94. 4. Moriishi K. and Matsuura Y., Antivir. Che. Chemother. 2003, 14: 285-297. 5. Fried, M.W., et al. N. Engl. J Med 2002, 347: 975-982. 6. Ni, Z. J. and Wagman, A. S. Curr. Opin. Drug Discov. Devel. 2004, 7, 446-459. 7. Beaulieu, P. L. and Tsantrizos, Y. S. Curr. Opin. Investig. Drugs 2004, 5, 838-850. 8. Griffith, R. C. et al., Ann. Rep. Med. Chem 39, 223-237, 2004. 9. Watashi, K. et al., Molecular Cell, 19, 111-122, 2005 10. Horsmans, Y. et al., Hepatology, 42, 724-731 , 2005