chemical compounds

专利摘要:
Compounds of Formula (I), specifically inhibitors of the hepatitis B virus and / or the hepatitis D virus, more specifically compounds that inhibit the HBe antigen and the HBs antigen in an individual, for the treatment of viral infections and methods of preparation and use of such compounds.
公开号:BR112020006456A2
申请号:R112020006456-4
申请日:2018-10-05
公开日:2020-10-06
发明作者:John G. Catalano；Pek Yoke CHONG；Hamilton D. Dickson；Martin R. LEIVERS；Jason Gordon Weatherhead
申请人:Glaxosmithkline Intellectual Property Development Limited；
IPC主号:

专利说明:

[001] [001] The present invention relates to compounds useful for the treatment of HBV in animals, and more particularly for the treatment of HBV in humans. BACKGROUND OF THE INVENTION
[002] [002] Hepatitis B is a viral disease transmitted parenterally by contaminated material, such as blood and blood products, contaminated needles, sexually and vertically from infected mothers or those carrying their offspring. In areas of the world where the disease is common, vertical transmission at an early age results in a high proportion of infected individuals who become chronic carriers of hepatitis B. It is estimated by the World Health Organization that more than 2 billion people have been infected worldwide, with about 4 million acute cases per year, 1 million deaths per year and 350-400 million chronic carriers. Approximately 25% of carriers die from chronic hepatitis, cirrhosis or liver cancer and nearly 75% of chronic carriers are Asian. The hepatitis B virus (HBV) is the second most significant carcinogen behind tobacco, causing 60% to 80% of all primary liver cancer. HBV is 100 times more contagious than HIV.
[003] [003] HBV is transmitted through percutaneous or parental contact with infected blood, body fluids and sexual intercourse. HBV is able to stay on any surface with which it comes in contact for about a week, for example, table tops, razors, blood stains, without losing infection. However, HBV cannot cross the skin or the mucous membrane barrier. Some break in this barrier, which may be minimal and insignificant, is necessary for transmission.
[004] [004] HBV is a small enveloped DNA virus belonging to the hepadnavirus family. The virus replicates through an intermediate form of RNA by reverse transcription, which in practice relates them to the retrovirus, such as HIV. Although replication occurs in the liver, the virus spreads to the blood, where proteins and viral antibodies against them are found in infected people. HBV is often more infectious than HIV, due to the higher concentrations of HBV virus found in the bloodstream at any time.
[005] [005] HBV infection results in the production of two different particles: 1) the HBV virus itself (or Dane particle) which includes a viral capsid assembled from the HBV core antigen protein (HBcAg) and is covered by heptitis B surface antigen (HBsAg) and is capable of reinfecting cells and 2) subviral particles (or SVPs) that are high density lipoprotein type particles, composed of lipids, cholesterol, cholesterol esters and the small and medium forms of hepatitis B surface antigen (HBsAg) that are non-infectious. For each viral particle produced, 1,000-
[006] [006] The hepatitis D virus (HDV) uses HBsAg to form its viral structure (Taylor, 2006, Virology, 344: 71-76) and, as such, HDV infection can only occur in individuals with concomitant infection you by HBV. Although the incidence of HDV co-infection in asymptomatic patients with HBV and chronic HBV-related liver disease is low in countries with a low incidence of HBV infection, it is a significant complication in individuals infected with HBV in countries with a high incidence of HBV infection. HBV and may increase the rate of progression from liver disease to fulminant hepatitis. As such, the clear unmet medical need for HBV infection is even more urgent in individuals co-infected with HBV / HDV.
[007] [007] Current conventional treatment methods for HBV include immunotherapies based on interferon or α1 thymosin and the suppression of viral production by inhibition of HBV polymerase (for example, "nucs"). HBV polymerase inhibitors are effective in reducing viral production, however, they have little or no effect on the rapid reduction of HBsAg blood levels or can slowly reduce HBsAg with long-term treatment in a limited number patients (as is the case with tenofovir disoproxyl fumarate). Interferon-based immunotherapy can achieve a similar reduction in viral production and early removal of HBsAg from the blood, however, only in a small percentage of treated individuals. The generally accepted role of HBsAg in the blood is to sequester anti-HBsAg antibodies and allow infectious viral particles to escape from immune detection, which is probably one of the reasons why HBV infection remains a chronic condition. In addition, HBsAg, HBeAg and HBcAg have immunoinhibitory properties, as discussed below, and the persistence of these viral proteins in the blood of patients after administration of any of the treatments currently available for HBV, as described above , is likely to have a significant impact on preventing patients from achieving immune control of their HBV infection.
[008] [008] Although the three primary HBV proteins (HBsAg, HBe-Ag and HBcAg) have immunoinhibitory properties (see below), HBsAg comprises the overwhelming majority of the HBV protein in the circulation of individuals infected with HBV. In addition, while HBeAg removal (via seroconversion) or reductions in serum viremia are not correlated with the development of sustainable control
[009] [009] Therefore, in the absence of any current treatment regimen that can restore HBV immune control in a large proportion of patients, it is necessary to provide effective treatment against HBV infection and HBV / HDV co-infection, which can restore immune control in most patients.
[0010] [0010] Hepatitis B viral infections, in conjunction with Hepatitis D viral infections, are a continuing medical problem because, like any rapidly replicating infectious agent, there are continuous mutations that help some HBV subpopulations resistant to current treatment regimes. Currently, there are no effective therapeutic agents for the treatment of humans infected with HBV and / or Hepatitis D (HDV) infections that result in seroconversion to the virus in the body, or that cause a 90% reduction in the antigen in humans. comparison to baseline numbers before treatment in people suffering from a hepatitis B viral infection. Currently, therapies recommended for chronic HBV and / or HDV infection by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include interferon alfa (INFα),
[0011] [0011] The nucleoside and nucleotide therapies entecavir and tenofovir are successful in reducing viral load, but the seroconversion rates of HBeAg and loss of HBsAg are even lower than those obtained with IFNα therapy. Other similar therapies, including lamivudine (3TC), telbivudine (LdT) and adefovir are also used, however, for nucleoside / nucleotide therapies in general, the emergence of resistance limits therapeutic efficacy.
[0012] [0012] Recent clinical research has found a correlation between seroconversion and reductions in HBeAg (Fried et al (2008) Hematology 47: 428) and reductions in HBsAg (Moucari et al (2009) Hepatology 49: 1151). Reductions in antigen levels may have allowed the immune control of HBV infection, because high levels of antigens are believed to induce immune tolerance. Current nucleoside therapies for HBV are capable of drastic reductions in serum HBV levels, but have little impact on HBeAg and HBsAg levels. Antisense therapy differs from nucleoside therapy in that it can directly direct transcripts to antigens and thus reduce serum levels of HBeAg and HBsAg. However, antisense therapy is expensive and requires intravenous delivery.
[0013] [0013] Thus, there is a need in the art to discover and develop new antiviral therapies. More particularly, new anti-HBV therapies capable of increasing HBeAg and HBsAg seroconversion rates are needed. These serum markers are
[0014] [0014] Modalities of the present invention represent the compounds of Formula I: Formula I in which W and Y are independently C or N, with the proviso that W and Y are not equally C; where if W is C, then R1 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; and if Y is C, then R4 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3 to 8 membered hetero-cycloalkyl or 3 to 8 membered hetero-cycloalkyl,
[0015] [0015] Another embodiment provides a compound of Formula IA or Formula IB: or Formula IA Formula IB wherein C * is a carbon atom stereocenter that has a configuration that is (R) or (S); W and Y are independently C or N, with the proviso that W and Y are not equally C; wherein if W is C, then R1 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; hetero-
[0016] [0016] In another particular embodiment of the invention, compounds of Formula I, Formula IA or Formula IB are provided as described here, including salts and prodrugs thereof, where R10 is selected from –CO2H, –B (OH) 2 , –NHSO2R25 ', - NCO2R25,,,,,,
[0017] [0017] In another particular embodiment of the invention, compounds of Formula I, Formula IA or Formula IB are provided, including salts and prodrugs thereof, wherein R1, R2, R3, R4, R5, R6, R7, R9 and R11 are as described here; R8 is isopropyl; and
[0018] [0018] In another embodiment, a compound of Formula I, Formula IA or Formula IB is provided, including salts and prodrugs thereof, where R1, R2, R3, R4, R9 and R11 are as described; R5, R6 and R7 are H; R8 is isopropyl;
[0019] [0019] In particular modalities, a method is provided for the treatment of a hepatitis B infection or hepatitis B / hepatitis D co-infection, particularly a method for the treatment of a hepatitis B infection or hepatitis B / hepatitis co-infection In a human, the method comprising administering to an individual in need of such treatment a compound of Formula I, IA or IB, as described herein.
[0020] [0020] In yet another embodiment, the present invention provides a method for the treatment of a hepatitis B infection or hepatitis B / hepatitis D co-infection, particularly a method for the treatment of a hepatitis B infection or hepatitis co-infection B / hepatitis D in a human, the method comprising administering to a subject in need of such treatment a first pharmaceutically acceptable agent comprising a compound of Formula I, Formula IA or Formula IB, as described herein, in combination with a second pharmaceutically acceptable agent that stimulates immune function and a third pharmaceutically acceptable agent comprising an antiviral compound.
[0021] [0021] In still other modalities, the administration of a compound of Formula I, IA or IB, as described here, inhibits the release of hepatitis B surface antigen (HBsAg), of the HB core antigen protein ( HBcAg) and / or the hepatitis B precore protein known as the HBV e-antigen antigen (HBeAg) from infected heptocytes. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] [0022] The modalities of the present invention present compounds that inhibit the levels of HBe and / or HBs antigens in an individual infected with the hepatitis B virus and, therefore, are useful for the treatment of hepatitis B virus infections. and diseases and symptoms associated with these virus infections. The previous characteristics of the invention will be more easily understood by reference to the following detailed description, made with reference to the accompanying Tables, in which:
[0023] [0023] Table 1 is a list of Formula I compounds described herein.
[0024] [0024] Table 2 is a list of R10 substituents for compounds of Formula I, as described herein.
[0025] [0025] Table 3 is a summary of HepAD38 cells - HBsAg and cytotoxicity ELISA assays showing EC50 values measured for a compound tested against HBs antigens (HBsAg). DETAILED DESCRIPTION OF SPECIFIC MODALITIES
[0026] [0026] Throughout this application, references are made to various modalities related to compounds, compositions and methods. The various modalities described are intended to provide a variety of illustrative examples and should not be interpreted as descriptions of alternative species. Instead, it should be noted that the descriptions of the various modalities provided here may be overlapping in scope. The modalities discussed here are merely illustrative and are not intended to limit the scope of the present invention.
[0027] [0027] It should be understood that the terminology used here is intended to describe only particular modalities and is not intended to limit the scope of the present invention. In this specification and in the following claims, reference will be made to various terms that must be defined to have the following meanings.
[0028] [0028] When used herein, unless otherwise specified, "alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 14 carbon atoms and, in some modalities, 1 to 6 atoms of carbon. The term "alkyl" includes, for example, straight and branched hydrocarbyl groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3) 2CH-), n- butyl (CH3CH2CH2CH2-), isobutyl (((CH3) 2CHCH2-), sec-butyl (((CH3) (CH3CH2) CH-), t-butyl ((CH3) 3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3) 3CCH2-). Alkyl groups can also be substituted, for example, with one or more alkyl substituents, cycloalkyl-
[0029] [0029] "Alkoxy" or "alkoxy" refers to the group -O-alkyl in which alkyl is defined here. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, morpholinylpropoxy, piperidinyloxy. Alkoxyl groups can also be substituted, for example, with one or more alkyl, cycloalkyl, hetero-cycloalkyl, alkoxy, amino, amino alkyl, thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl substituents.
[0030] [0030] "Amino" refers to the group -NRaRb where Ra and Rb are independently selected from hydrogen, hydroxy, alkyl or substituted alkyl, substituted alkenyl or alkenyl, substituted aryl or aryl, substituted cycloalkyl or cycloalkyl, hetero -cycloalkyl or substituted hetero-cycloalkyl, heteroaryl or substituted heteroaryl, and where Ra and Rb are optionally joined together with the nitrogen attached to them to form a heterocyclic group. When Ra is hydrogen and Rb is alkyl, the amino group is sometimes referred to here as alkylamino or aminoalkyl. When Ra and Rb are alkyl, the amino group is sometimes referred to here as dialkylamino. When referring to a monosubstituted amino, it means that Ra or Rb is hydrogen, but not both. When referring to a disubstituted amino, it means that neither Ra nor R6 is hydrogen.
[0031] [0031] "Aryl" refers to an aromatic group of 5 to 14 carbon atoms and no heteroatom in the ring and having a single ring (for example, phenyl) or multiple condensed (fused) rings (for example, naphthyl or anthryl) ). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that do not have hetero atoms in the ring, the term “Arila” or “Ar” applies when the point of attachment is at an aromatic carbon atom (eg 5,6,7,8 tetrahydronaphthalene-2-yl is a group
[0032] [0032] "Cycloalkyl" refers to a cyclic saturated or partially saturated group of 3 to 14 carbon atoms and no ring heteroatom and having a single ring or multiple rings including fused ring systems bridge and spiro. For multi-ring systems having aromatic and non-aromatic rings that do not have heteroatoms in the ring, the term “cycloalkyl” applies when the point of attachment is on a non-aromatic carbon atom (for example, 5,6 , 7.8, -tetrahydronaphthalene-5-yl). The term "Cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Cycloalkyl groups can also be substituted, for example, with one or more alkyl, cycloalkyl, hetero-cycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl substituents.
[0033] [0033] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.
[0034] [0034] "Haloalkyl" refers to the substitution of alkyl groups with 1 to 9 (for example, when the alkyl group has 3 carbon atoms, such as a t-butyl group totally substituted with halogen) or in some modalities 1 to the 3 halo groups (for example, trifluoro-methyl).
[0035] [0035] "Hydroxy" or "hydroxyl" refers to the -OH group.
[0036] [0036] “Heteroaryl” refers to an aromatic group of 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, sulfur, phosphorus, silicon and boron, and includes single ring systems ( for example imidazolyl) and multiple rings (for example, benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems, including fused, bridged and spiro ring systems having aromatic and non-aromatic rings, the term “heteroaryl” applies if there is at least one heteroatom in the ring and the point of attachment is on an atom of one aromatic ring (for example, 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In some modalities, the atom (s) in the nitrogen ring and / or the heteroaryl group ring (s) are (are) optionally oxidized (s) to provide the N-oxide moieties (N → O), sulfinyl or sulfonyl. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, in phthalazole , naphthylpriidyl, oxazolyl, quinolyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindylyl, quinazolol, quinazolol, quinazolol, indoline , tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenantridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazine, and phenothiazine. Heteroaryl groups can also be substituted, for example, with one or more alkyl, cycloalkyl, hetero-cycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl substitutes.
[0037] [0037] "Heterocyclic" or "heterocycle" or "hetero-cycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic group having 1 to 14 carbon atoms and 1 to 6 hetero atoms selected from nitrogen, sulfur , phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged and spiro ring systems. For multiple ring systems with aromatic and / or non-aromatic rings, the terms "heterocyclic", "heterocyclic", "hetero-cycloalkyl" or "heterocyclyl" apply when there is at least one heteroatom in the ring and the point of attachment is on an atom of a non-aromatic ring (e.g. 1,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl and decahydroquinolin-6 -ila). In one embodiment, the nitrogen, phosphorus and / or sulfur atom (s) of the heterocyclic group are optionally oxidized to provide the N-oxide, phosphinan oxide, sulfinyl, sulfonyl moieties. More specifically, heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (for example, C3-C10) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive to the number of hetero atoms. Heterocyclyl or hetero-cycloalkyl groups can also be substituted, for example, with one or more alkyl, cycloalkyl, hetero-cycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl substituents.
[0038] [0038] Examples of heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazol, carboline, phenantridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxine, imidazine, imidazine, phenazazine oxazole, oxopyrrolidine, piperidine, piperazine, indoline, phthalimide, quinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene,
[0039] [0039] "Fused heterocyclic" or "fused heterocyclyl" refers to a 3- to 10-membered cyclic substituent formed by replacing two hydrogen atoms with different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure of cyclopentatiazole:. Fused heterocyclyl groups can also be substituted, for example, with one or more alkyl, cycloalkyl, hetero-cycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl substituents.
[0040] [0040] "Fused aryl and fused heteroaryl" refers to a 5-6 membered aryl structure or fused heteroaryl structure with a 5-6 membered aryl, heteroaryl or cycloalkyl ring on different carbon atoms in the structure of aryl or in the hetero-aryl structure, which can be substituted on one of the carbons in the fused aryl or fused heteroaryl and connected to the nucleus molecule in another of the carbons, as exemplified by the following structures of cyclopenttyltiazole, quinoline or naphthalene: ,. Fused aryl and fused heteroaryl groups can also be substituted, for example, with one or more alkyl, cycloalkyl, hetero-cycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halo or haloalkyl substituents.
[0041] [0041] "Compound", "compound", "chemical entity", and "chemical entities" when used herein refer to a compound covered by the generic formulas described here, any subgenre of these generic formulas, and any forms of the compounds within the generic and subgeneric formulas, including racemates, stereoisomers, and tautomers of the compound or compounds.
[0042] [0042] The term “heteroatom” means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N (O) {N - —O} and sulfur such as S (O) and S (O ) 2, and the quaternized form of any basic nitrogen.
[0043] [0043] "Oxazole" and "oxazolyl" refers to a 5-membered heterocyclic ring containing nitrogen and oxygen as heteroatoms and likewise contains three carbons and can be substituted on one of the three carbons and can be connected to another molecule in other of the three carbons, as exemplified by any of the following structures, in which the oxazolidinone groups shown here are linked to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:,.
[0044] [0044] "Oxopyrrolidine" and "oxopyrrolidinyl" refers to a 5-membered heterocyclic ring containing nitrogen and 4 carbons that is replaced in one of the carbons in the heterocyclic ring by a carbonyl and can be connected to another substituent in another carbon in the heterocyclic ring, as exemplified by the structure below:
[0045] [0045] "Pyridine" and "pyridinyl" refers to a 6-membered heteroaryl ring containing one nitrogen and 5 carbons that can also be substituted on one or more of the carbons on the heteroaryl ring, and can be connected to another substituent on another carbon in the heteroaryl ring, as exemplified by the structures below:,,,.
[0046] [0046] "Thiazole" and "thiazolyl" refers to a 5-membered heteroaryl containing a sulfur and nitrogen in the heteroaryl ring and 3 carbon in the heteroaryl ring that can also be substituted in one or more of the carbons in the heteroaryl ring, and can be connected to another substituent on another carbon in the heteroaryl ring, as exemplified by the structures below:,,,.
[0047] [0047] "Pyrimidine" and "pyrimidinyl" refers to a 6-membered heteroaryl ring containing two nitrogens in the heteroaryl ring and 4 carbons in the heteroaryl ring that can be substituted on one or more of the carbons in the heteroaryl ring, and can be connected to another substituent on another carbon in the heteroaryl ring, as exemplified by the structures below:,.
[0048] [0048] "Racematos" refers to a mixture of enantiomers. In an embodiment of the invention, the compounds of Formulas I, or pharmaceutically acceptable salts thereof, are enantiomerically enriched with an enantiomer in which all of the said chiral carbons are in one configuration. In general, reference to an enantiomerically enriched compound or salt is intended to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all the enantiomers of the compound or salt.
[0049] [0049] "Solvate" or "solvates" of a compound refer to compounds, as defined above, that are linked to a stoichiometric or non-stoichiometric amount of a solvent. The solvates of a compound include solvates of all forms of the compound. In certain embodiments, the solvents are volatile, non-toxic and / or acceptable for administration to humans in small amounts of trace. Suitable solvates include water.
[0050] [0050] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
[0051] [0051] "Tautomer" refers to alternative forms of a compound that differs in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups that contain an atom in the attached ring also to an -NH- portion of the ring and an = N- portion of the ring, such as pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles.
[0052] [0052] "Uncle" or "thiol" refers to the group –SR where R is selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocyclic. When R is H, the thio group is sometimes referred to here as a thiol group, and when R is alkyl, the thio group is sometimes referred to here as a thioalkyl or alkylthio group. Sulfur can also bond to another carbon or atom in the same molecule to form a heterocyclic group.
[0053] [0053] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counterions well known in the art and include, by way of example only sodium, potassium, calcium, magnesium, ammonium and tetra - alkylammonium, and when the molecule contains basic functionality,
[0054] [0054] "Patient" or "individual" refers to mammals and includes humans and non-human mammals.
[0055] [0055] "Treating" or "treating" a disease in a patient refers to 1) preventing the disease from occurring in a patient who is predisposed or still has no symptoms of the disease; 2) inhibit the disease or interrupt its development; or 3) improve or cause the disease to regress.
[0056] [0056] Wherever the dashed lines occur adjacent to single connections denoted by solid lines, the dashed line represents an optional double bond in this position. Likewise, wherever the dashed circles appear within ring structures denoted by solid lines or solid circles, then the dashed circles represent one to three optional double bonds arranged according to their appropriate valence, taking into account ration if the ring has any optional replacements around the ring, as will be known to someone skilled in the art. For example, the dashed line in the structure below may indicate a double bond in this position or a single bond in this position:.
[0057] [0057] Similarly, ring A below can be a cyclohexyl ring without double bonds or it can also be a phenyl ring with three double bonds arranged in any position that still represents the suitable valence for a phenyl ring. Likewise, in ring B below, any one of X1-X5 can be selected from: C, CH or CH2, N or NH, and the dashed circle means that ring B can be a cyclohexyl or phenyl ring or a heterocycle containing N without double bonds or a heteroaryl ring containing N with one to three double bonds arranged in any position that still represents the appropriate valence:.
[0058] [0058] Where specific compounds or generic formulas are designed that have aromatic rings, such as aryl or heteroaryl rings, then it will be understood by someone skilled in the art that the particular aromatic location of any double bonds is a mixture of equivalent positions even if they are designed in different locations from compound to compound or from formula to formula. For example, in the two pyridine rings (A and B) below, the double bonds are drawn in different locations; however, they are known to be the same structure and compound:.
[0059] [0059] Unless otherwise indicated, nomenclature of substituents that are not explicitly defined here is achieved by naming the terminal portion of the functionality followed by the adjacent functionality towards the fixation point. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl) - (alkyl) -O-C- (O). In a term like "-C (Rx) 2", it must be understood that the two groups Rx can be the same, or they can be different if R x is defined as having more than one possible identity. In addition, certain substitutes are drawn as –RxRy, where the “-” indicates a bond adjacent to the parent molecule and Ry being the terminal portion of the functionality. Similarly, it is understood that the definitions above are not intended to include disallowed substitution patterns (for example, methyl substituted with 5 fluorine groups). Such non-permitted substitution patterns are well known to those skilled in the art.
[0060] [0060] In accordance with an embodiment of the present invention, compounds of Formula I or a salt or prodrug of the same Formula I are provided in which W and Y are independently C or N, with the proviso that W and Y are not also C; wherein if W is C, then R1 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1-6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; and if Y is C, then R4 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1-6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; where if W is N, then R1 will be absent; and if Y is N, then R4 will be absent; R2 and R3 are independently selected from hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered hetero-cycloalkyl or 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; R5 and R6 are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x– phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R7 and R8 are independently hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x– phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, where the 3- to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ;
[0061] [0061] A particular embodiment provides a compound according to Formula I, Formula IA or Formula IB as described here, wherein: R1 is selected from hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, C1-6 unsubstituted alkyl or C1-6 halo-substituted alkyl, C1-6 alkoxy unsubstituted or C1-6 halo-substituted alkoxy; C3-7 cycloalkyl or C3-7 halo-substituted cycloalkyl; monocyclic hetero-cycloalkyl containing N, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or –OR12; R2 and R3 are independently OR12; R4 is selected from hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, C1-6 unsubstituted alkyl or C1-6 halo-substituted alkyl, C1-6 alkoxy unsubstituted or C1-6 halo-substituted alkoxy; C3-7 cycloalkyl or C3-7 halo-substituted cycloalkyl; monocyclic hetero-cycloalkyl containing N, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or –OR12; R6 and R7 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring comprising a hetero-atom or two or more heteroatoms, optionally substituted with
[0062] [0062] Another embodiment provides a compound of Formula I, Formula IA or Formula IB as described here, R9 is as described here and R10 is a substituent shown in Table 2, or R9 is a bond and R9 and R10 together form a oxaborol ring; or a pharmaceutically acceptable salt thereof.
[0063] [0063] Another particular modality provides a compound of Formula I, Formula IA or Formula IB as described here, R9 is as described here and R10 is a substituent shown in Table 2, or R9 is a bond and R9 and R10 together they form an oxaborol ring; and R12 is C1-6 unsubstituted alkyl; or a pharmaceutically acceptable salt thereof.
[0064] [0064] Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described here, where W and Y are as described here, R1, R2, R3 and R4 are independently OR12; R9 is as described here and R10 is a substituent shown in Table 2, or R9 is a bond and R9 and R10 together form an oxaborol ring; and R12 is as described here; or a pharmaceutically acceptable salt thereof.
[0065] [0065] Another embodiment of the invention provides a compound of Formula I, Formula IA or Formula IB or a pharmaceutically salt thereof, as described herein, wherein R9 is a bond and R9 and R10 together
[0066] [0066] Yet another embodiment of the invention provides a compound of Formula I, Formula IA or Formula IB or a pharmaceutically salt thereof, as described herein, wherein W and Y are as described herein; R1 and R4, are as described; R2 and R3 are independently selected from hydrogen, hydroxy, halogen, cyano, amino, uncle, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 alkoxy substituted; C3-8 cycloalkyl or C3-8 cycloalkyl substituted; C2-8 alkenyl or C2-8 substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, or –OR12; R5 and R6 are independently hydrogen, hydroxy, halogen, cyano, amino, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C2- 8 alkenyl or C2-8 substituted alkenyl; substituted aryl or aryl, heteroaryl or substituted aryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R7 and R8 are independently hydrogen, hydroxy, halogen, cyano, amino, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C2- 8 alkenyl or C2-8 substituted alkenyl; substituted aryl or aryl, heteroaryl or substituted aryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, where the 3- to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ;
[0067] [0067] Another embodiment of the invention provides a compound of Formula I, Formula IA or Formula IB or a pharmaceutically salt thereof, as described herein, where W and Y are each N.
[0068] [0068] A particular embodiment of the invention provides a compound of Formula I, Formula IA or Formula IB or a pharmaceutically salt thereof, as described herein, wherein W and Y are as described herein; R1, R2, R3 and R4 are independently H or OR12; and R5 and R6 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, in that the 3- to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ.
[0069] [0069] Another particular embodiment of the invention provides a compound of Formula I, Formula IA or Formula IB or a pharmaceutically salt thereof, as described herein, wherein W and Y are as described herein; R2 and R3 are independently H or OR12; and R6 and R7 together form a 3- to 8-membered cycloalkyl ring or hetero-cycloalkyl ring comprising a heteroatom or two or more heteroatoms, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ, wherein the heteroatom in the heteroalkyl ring is NR20, and the two or more heteroatoms are selected from N, NR22, O, S, SR22 and SR22R22ꞌ.
[0070] [0070] Another particular embodiment of the invention provides a compound of Formula I, Formula IA or Formula IB or a pharmaceutically salt thereof, as described herein, wherein
[0071] [0071] Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described here, wherein R2 and R3 are independently OR12; R5 and R6 together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, optionally substituted with R13 and R14, where the heteroatom in the heteroalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R10 is a substituent shown in Table 2, or R9 is a bond and R9 and R10 together form an oxaborol ring; R11 is H; R12 is C1-6 unsubstituted alkyl; and R13 and R14 or R13ꞌ and R14ꞌ together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, optionally substituted with oxygen, halogen, hydroxy, amine, cyan, C1- 6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy, wherein the heteroatom in the heteroalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; or a pharmaceutically acceptable salt thereof.
[0072] [0072] Yet another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein, wherein R2 and R3 are independently OR12; R7 and R8 together form a 3- to 8-membered ring, optionally substituted with R17 and R18; R10 is a substituent shown in Table 2 or R9 is a bond and R9 and R10 together form an oxaborol ring; R11 is H; R12 is C1-6 unsubstituted alkyl; and R17 and R18 or R17ꞌ and R18ꞌ together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, optionally substituted with oxygen, halogen, hydroxy, amine, cyan, C1- 6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy,
[0073] [0073] Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described here, wherein R2 and R3 are independently OR12; and R5 and R6 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with R13, R14, R13ꞌ and / or R14ꞌ, where the heteroatom in the heteroalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, or a pharmaceutically acceptable salt thereof.
[0074] [0074] Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described here where R2 and R3 are independently OR12; and R7 and R8 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with R17, R18, R17ꞌ and / or R18ꞌ, wherein the heteroatom in the heteroalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, or a pharmaceutically acceptable salt thereof.
[0075] [0075] Even more particular embodiments provide compounds of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof as described herein, wherein R1, R2, R3 and R4 are as described; and (A) R5 and R6 are independently hydroxy, halogen, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ, where the heteroatom in the hetero-cycloalkyl ring is selected from among O, N, NR22, S, SR22 or SR22R22ꞌ; and
[0076] [0076] In particular embodiments, a compound of Formula I, Formula IA, or Formula IB is provided as described, where the compound is selected from the compounds of Table 1, where R10 is as described here or a substituent shown in Table 2, or a tautomer thereof.
[0077] [0077] In particular embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided as described herein, where W is N; Y is C; R1 will be absent; R2 and R3 are independently selected from hydrogen, hydroxy, halogen, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C2-8 alkenyl or C2-8 alkenyl substituted, or -OR12, R4 is H; R6 and R7 together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ; R11 is H; and R15, R15ꞌ, R16 and / or R16ꞌ are independently hydrogen, hydroxy, halogen, amino, cyano, C1-6 alkyl, or C1-6 alkoxy.
[0078] [0078] In a particular embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided as described herein, where W is N; Y is C: R1 will be absent; R2 is halogen; R3 is OR12; and R4 is H.
[0079] [0079] In another particular embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided as described herein, wherein W is N; Y is C; R1 will be absent; R2 is halogen and R3 is –OR12; R4 is H; R6 and R7 together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ; R11 is H; and R15, R15ꞌ, R16 and / or R16ꞌ are independently C1-6 alkyl.
[0080] [0080] In another particular embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided as described here, wherein: R6 and R7 together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ.
[0081] [0081] In another particular embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided as described herein, wherein: R7 and R8 together form a 3 to 8 membered cycloalkyl ring or 3 to 8 hetero-cycloalkyl ring limbs, optionally substituted with R17 and R18, in which the heteroatom in the hetero-cycloalkyl ring is selected from O, N, NR22, S, SR22 or SR22R22ꞌ.
[0082] [0082] In a particular embodiment, a compound selected from the group consisting of: (4bR, 7aS) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b , 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic; (4bS, 7aR) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1 , 2-h] [1,7] naphthyridine-10-carboxylic; (4bR, 7aS) -2-cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1 , 2-h] [1,7] naphthyridine-10-carboxylic; 2-Cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [ 1.7] naphthyridine-10-carboxylic; (7aR) -2-cyclopropyl-4b-hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic; (7aR) -2-chloro-4b-hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic;
[0083] [0083] In a particular embodiment, a compound selected from:,,,,,,,,,,,, or, or a pharmaceutically acceptable salt thereof is provided.
[0084] [0084] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0085] [0085] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0086] [0086] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0087] [0087] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0088] [0088] In a particular embodiment, a compound is provided whose structure is:
[0089] [0089] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0090] [0090] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0091] [0091] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0092] [0092] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0093] [0093] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0094] [0094] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0095] [0095] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0096] [0096] In a particular embodiment, a compound is provided whose structure is:, or a pharmaceutically acceptable salt thereof.
[0097] [0097] In a particular embodiment, a compound is provided whose structure is:
[0098] [0098] In accordance with an embodiment of the present invention, a compound having the structure of Formula I, IA or IB is provided in which the compounds are selected from: where W and Y are independently N or C, with the proviso that W and Y are not equally C, and where R10 is as described here or a substituent shown in Table 2 and Y 'is,,,,,, substituted heterocycle or heterocycle, heteroaryl or substituted heteroaryl, where R and Rꞌ are independently alkyl or substituted alkyl.
[0099] [0099] In particular modalities, compounds of Formula I, IA or IB are provided in which the compounds are selected from: or in which W and Y are independently N or C, with the proviso that W and Y are not equally C, and where R10 is as described here or a substituent shown in Table 2.
[00100] [00100] In particular modalities, compounds of Formula I, IA or IB are provided in which the compounds are selected from:
[00101] [00101] In another embodiment of the present invention, compounds of Formula I, Formula IA or Formula IB are selected from:, where W and Y are independently N or C, with the proviso that W and Y are not equally C, and in that R10 is a substituent described here or a substituent shown in Table 2, and R is hydrogen, hydroxy,,,,,, hetero-cycloalkyl or substituted hetero-cycloalkyl, heteroaryl or substituted heteroaryl, where Rꞌ and Rꞌꞌ are independently alkyl or substituted alkyl.
[00102] [00102] In another embodiment of the present invention, a compound of Formula I, Formula IA or Formula IB is provided as shown: or: where R1, R2, R3, R4, R9 and R11 are as described, W and Y are independent - pending N or C, with the proviso that W and Y are not equally C, and where R10 is as described here or selected from the substituents shown in Table 2, and R 'and R are independently selected from hydrogen , hydroxyl, halo, alkyl or substituted alkyl, substituted alkylene or alkylene, substituted carbocycle or carbocycle, substituted hetero-cycloalkyl or hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, wherein said substituted R and Rꞌ groups can be substituted with hydroxyl, halo, alkyl, alkylene, cycloalkyl, heterocycle, aryl, heteroaryl; or R and Rꞌ together form a spiro ring, fused or bridged carbocyclic or heterocyclic.
[00103] [00103] In another embodiment of the present invention, a compound having the structure of Formula I, IA or IB is provided, in which the compound is selected from:
[00104] [00104] In another particular embodiment, a compound of Formula I, IA or IB is provided as indicated: where R4, R5, R6, R9, and R11 are as described, W and Y are independently N or C, with the condition that W and Y are not equally C, and where R10 is as described here or is selected from the substituents shown in Table 2, R1 is as described, R2 and R3 are independently selected from:,,,
[00105] [00105] In one embodiment, a compound of Formula I, Formula IA or Formula IB is provided as described herein or a pharmaceutically salt thereof, wherein: (A) R5 and R6 are independently hydroxy, halogen, cyano , amino alkyl or substituted alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, - CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ, where the heteroatom in the hetero-cycloalkyl ring is selected from among O, N, NR22, S, SR22 or SR22R22ꞌ; and R7 and R8 are independently hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkylene; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or (B) R5 and R8 are independently hydrogen, hydroxy, halogen, cyano, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkylene; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; and R6 and R7 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring comprising
[00106] [00106] In one embodiment, a Formula I, Formula IA or Formula IB compound is provided as described herein or a pharmaceutically salt thereof, wherein the compound is selected from the compounds of Table 1, and in which R10 is as described here or is a substituent shown in Table 2, or a tautomer thereof.
[00107] [00107] In one embodiment, a method of treating or preventing viral infection is provided in an individual susceptible to or suffering from viral infection comprising administering to the individual an inhibitor of an HBe antigen or HBs in which the inhibitor is a compound of Formula I , Formula IA or Formula IB as described here.
[00108] [00108] In one embodiment, a method of treating or preventing hepatitis B virus infection is provided in an individual susceptible to or suffering from hepatitis B virus infection, comprising administering to the individual an antigen inhibitor HBe or HBs where the inhibitor is a compound of Formula I, Formula IA or Formula IB as described herein.
[00109] [00109] In one embodiment, a method of treating or preventing hepatitis B virus infection is provided in an individual susceptible to or suffering from hepatitis B virus infection comprising administering to the individual an inhibitor of an HBe or HBs antigen wherein the inhibitor comprises a compound of Table 1 where R10 is a substituent shown in Table 2 or a tautomer thereof, or where the inhibitor is a compound of Table IB.
[00110] [00110] In one embodiment, a method of inhibiting the level of the HBe or HBs antigen in a mammal is provided, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB as described herein or a pharmaceutically acceptable salt, solvate or hydrate thereof.
[00111] [00111] In a particular embodiment, a method of inhibiting the level of the HBe or HBs antigen in a mammal is provided, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB as described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the mammal is a human.
[00112] [00112] In one embodiment, a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB as described herein is provided.
[00113] [00113] In one embodiment, a Formula I, Formula IA or Formula IB compound as described herein, or a pharmaceutical composition thereof, is provided for use in therapy.
[00114] [00114] In one embodiment, a Formula I, Formula IA, or Formula IB compound as described herein, or a pharmaceutical composition thereof, is provided for use in the treatment of a viral infection.
[00115] [00115] In one embodiment, a Formula I, Formula IA or Formula IB compound as described herein, or a pharmaceutical composition thereof, is provided for use in the treatment of a viral infection, wherein the viral infection is a virus infection hepatitis B.
[00116] [00116] In one embodiment, use of a compound of Formula I, Formula IA or Formula IB as described herein, or a pharmaceutical composition thereof, is provided in the manufacture of a medicament for use in the treatment of a virus infection hepatitis B in a human.
[00117] [00117] In one embodiment, a Formula I, Formula IA, or Formula IB compound as described herein, or a pharmaceutical composition thereof, is provided for use in medical therapy.
[00118] [00118] In one embodiment, a Formula I, Formula IA or Formula IB compound as described herein, or a pharmaceutical composition thereof, is provided for use in treating the prevention of a hepatitis B virus infection in a human.
[00119] [00119] In one embodiment, a Formula I, Formula IA or Formula IB compound as described herein, or a pharmaceutical composition thereof, is provided for use in inhibiting the level of the HBe or HBs antigen in a mammalian HBsAg in vitro.
[00120] [00120] Compounds described herein can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis and trans isomers, enantiomers (-) - and (+) -, enantiomers (R) and (S), diastereomers, isomers (D), isomers (L), racemic mixtures of the same and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures
[00121] [00121] The optically active (R) and (S) isomers and d and l isomers can be prepared using chiral syntones or chiral reagents, or resolved using conventional techniques. If, for example, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is separated. cleaved to provide the desired pure enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by the resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art and subsequent recovery of the pure enantiomers. In addition, the separation of enantiomers and diastereomers is often carried out using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (for example, formation of carbamates from amines).
[00122] [00122] In another embodiment of the invention, a Formula I, Formula IA or Formula IB compound is provided for use in therapy.
[00123] In another embodiment of the invention, a Formula I, Formula IA or Formula IB compound is provided for use in the treatment of a viral infection.
[00124] [00124] In another embodiment of the invention, a use of a compound of Formula I, Formula IA or Formula IB is provided in the manufacture of a medicament for use in the treatment of a viral infection in a human.
[00125] [00125] In another embodiment of the invention, a pharmaceutical composition is provided comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I, Formula IA or Formula IB.
[00126] [00126] In one embodiment, the pharmaceutical formulation containing a compound of Formula I, Formula IA or Formula IB or a salt thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In another modality, the formulation is a nanoparticle formulation.
[00127] [00127] In one embodiment, the pharmaceutical formulation containing a compound of Formula I, Formula IA or Formula IB or a salt thereof is a formulation adapted for oral, rectal, topical or intravenous formulation, wherein the pharmaceutical formulation optionally comprises any one or more of a pharmaceutically acceptable carrier, adjuvant or vehicle.
[00128] [00128] In one embodiment, the compounds of Formula I, Formula IA or Formula IB are formulated for oral administration, and can be administered as a conventional preparation, for example, as any dosage form of a solid agent, such as compressed - of powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent like syrup and elixir. In one embodiment, the compounds of Formula I, Formula IA or Formula IB are formulated for parenteral administration and can be administered as an aqueous or oily suspension for injection, or a nasal drop. In the preparation of a parenteral formulation with a compound of Formula I, Formula IA or Formula IB, excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers
[00129] [00129] Pharmaceutical formulations adapted for oral administration can be presented as discrete units, as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or creams; or liquid oil-in-water emulsions or liquid water-in-oil emulsions.
[00130] [00130] For example, for oral administration in the form of a tablet or capsule, the compound of Formula I, Formula IA or Formula IB can be combined with a pharmaceutically acceptable, non-toxic, oral inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by grinding the compound of Formula I, Formula IA or Formula IB to a suitable fine size and mixing with a similarly crushed pharmaceutical carrier, such as an edible carbohydrate, such as starch or mannitol. Flavoring, preserving, dispersing and coloring agent may also be present.
[00131] [00131] The capsules are prepared by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Sliding agents and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. A disintegrating or solubilizing agent, such as agar, calcium carbonate or sodium carbonate can also be added
[00132] [00132] In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated, for example, by preparing a powder mixture, granulating or deforming, adding a lubricant and disintegrant and pressing on the tablets. A powder mixture is prepared by mixing the compound, properly ground, with a diluent or base as described above and, optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and / or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powdered mixture can be granulated by moistening with a binder, such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a sieve. As an alternative to granulation, the powder mixture can be passed through the tablet machine and the result is deformations formed imperfectly, broken into granules. The granules can be lubricated to prevent adherence to the tablet-forming matrices by adding stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture
[00133] [00133] Oral fluids, such as solutions, syrups and elixirs, can be prepared in unit dosage form, so that a certain amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavor, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, such as peppermint oil or natural or saccharine sweeteners or other artificial sweeteners, and the like can also be added.
[00134] [00134] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. Formulations of Formula I, Formula IA or Formula IB compounds can also be prepared to prolong or sustain the release of the compound, such as by coating or incorporating particulate material in polymers, waxes or the like.
[00135] [00135] The compounds of Formula I, Formula IA or Formula IB or salts, solvates or hydrates, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
[00136] [00136] The compounds of Formula I, Formula IA or Formula IB or salts, solvates or hydrates thereof, can also be released by the use of monoclonal antibodies as individual vehicles to which the molecules of the compound are attached. The compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol or polyethylene oxide-polylysine substituted by palmitoyl residues. In addition, the compounds can be coupled to a class of biodegradable polymers useful in obtaining a controlled release of a drug, for example, polylactic acid, polypeptide caprolactone, polyhydroxy butyric acid, polyoretesters, polyacetals, polydi -hydropyranes, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
[00137] [00137] Pharmaceutical formulations adapted for transdermal administration can be presented as discreet adhesives designed to remain in close contact with the recipient's epidermis for an extended period of time. For example, Formula I, Formula IA or Formula IB compounds can be released from an adhesive by iontophoresis, as generally described in Pharmaceutical Technology Research, 3 (6), 318 (1986).
[00138] [00138] Pharmaceutical formulations adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. When formulated in an ointment, the active ingredient can be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil cream in water base or a water in oil base.
[00139] [00139] Pharmaceutical formulations adapted for rectal administration can be presented as suppositories or as enemas.
[00140] [00140] Pharmaceutical formulations adapted for nasal administration in which the carrier is a solid include a coarse powder having a particle size, for example, in the range of 20 to 500 microns, which is administered in the manner in which the snuff is taken, ie, by rapid inhalation through the nasal passage of a container of powder kept close to the nose. Suitable formulations in which the vehicle is a liquid, for administration as a nasal spray or as nasal gums, include aqueous or oily solutions of the active ingredient.
[00141] [00141] Pharmaceutical formulations adapted for administration by inhalation include fine particulate powders or mists, which can be generated through various types of pressurized aerosols, nebulizers or insufflators with a metered dose.
[00142] [00142] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats and solutes that make the formulation isotonic with the intended recipient's blood; and sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents. The formulations can be presented in single dose or multiple dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.
[00143] [00143] It should be understood that, in addition to the ingredients particularly mentioned above, the formulations described herein may include other agents conventional in the art, taking into account the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
[00144] [00144] A therapeutically effective amount of a Formula I, Formula IA or Formula IB compound will depend on several factors, including, for example, the age and weight of the human or other animal, the exact condition requiring treatment and its severity, the nature of the formulation and the administration routine and, finally, will be at the discretion of the attending physician or veterinarian. An effective amount of a salt or hydrate thereof can be determined as a proportion of the effective amount of the compound of Formula I, Formula IA or Formula IB or salts, solvates or hydrates per se.
[00145] [00145] Modalities of the present invention provide the administration of a Formula I, Formula IA or Formula IB compound to a healthy or virus-infected patient, as a single agent or in combination with (a) another agent that is effective in treating or preventing the hepatitis B virus and the hepatitis D virus, (b) another agent that improves the immune response and robustness, or (c) another agent that reduces inflammation and / or pain.
[00146] [00146] It is thought that the compounds of Formula I, Formula IA or Formula IB or salts, solvates or hydrates thereof, have activity in preventing, interrupting or reducing the effects of the hepatitis B virus, inhibiting the HBe and / or antigens HBs, thus interfering with or preventing the virus from remaining in the host cell and rendering the virus unable to replicate.
[00147] [00147] Therefore, a method of treating a hepatitis B virus and / or hepatitis D virus is provided by administering a therapeutically effective amount of a compound of Formula I,
[00148] [00148] In another aspect of the present invention, a method is provided to reduce HBe and / or HBs antigens in a mammal, by administering to said mammal a therapeutically effective amount of a Formula I, Formula IA or Formula IB compound or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the mammal is a human.
[00149] [00149] In other embodiments, the compounds of the present invention can be used in combination with one or more antiviral or anti-inflammatory therapeutic agents useful in the prevention or treatment of viral diseases or associated pathophysiology. Thus, the compounds of the present invention and their salts, solvates or other pharmaceutically acceptable derivatives thereof, can be used alone or in combination with other antiviral or anti-inflammatory therapeutic agents.
[00150] [00150] The compounds of the present invention and any (any) other pharmaceutically active agent (s) can be administered together or separately and, when administered separately, administration can occur simultaneously or sequentially. in any order. The amounts of the compounds of the present invention and the other pharmaceutically active agent (s) and the relative times of administration will be selected to achieve the desired combined therapeutic effect. The combination administration of a compound of the present invention and pharmaceutically acceptable salts, solvates or other derivatives thereof with other treatment agents can be in combination by concomitant administration in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions, each including one of the compounds.
[00151] [00151] Alternatively, the combination can be administered separately in a sequential manner, in which one treatment agent is administered first and the other second or vice versa. This sequential administration can be closed in time or remote in time. The quantities of the Formula I, Formula IA or Formula IB compound (s) or their salts and the other pharmaceutically active agent (s) and the relative administration times will be selected to achieve the desired combined therapeutic effect.
[00152] [00152] More particularly, the modalities provide a method as described, comprising administering an additional agent selected from an antiviral agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory agent (NSAID), an agent antifungal, an antiparasitic agent, an anti-nausea agent, an antidiarrheal agent or an immunosuppressive agent. In certain embodiments, the antiviral agent is an anti-hepatitis B agent or an anti-hepatitis C agent. Even more particularly, the additional agent is administered as part of a single dosage form of said pharmaceutical formulation, or as a separate dosage.
[00153] [00153] The present invention is directed to compounds, compositions and pharmaceutical compositions that are useful as new treatments and / or preventive therapies for virus infections. While not wishing to be bound by any particular theory, it is believed that the present compounds are able to inhibit the levels of HBe and HBs antigens in an individual infected with the hepatitis B virus or who suffers from a chronic hepatitis viral infection B. By reducing the levels of HBe and HBs antigens in an individual infected with the hepatitis B virus, the compounds described here are effective in the treatment of hepatitis B infections and secondary disorders, such as liver cirrhosis, liver failure and liver cancer, often associated with hepatitis B virus infections.
[00154] [00154] Therefore, in another embodiment of the present invention, a method of treating or preventing an infection by the hepatitis B virus is provided in an individual suffering from HBV infection, comprising administering to the individual an inhibitor of antigen. - HBe and / or HBs genos, where the inhibitor is a compound of Formula I, Formula IA or Formula IB.
[00155] [00155] In another embodiment of the present invention, a method of treating an infection by the hepatitis B virus and / or an infection by the hepatitis D virus is provided in an individual suffering from the virus infection, comprising administering to the individual a compound from Table 1.
[00156] [00156] In some embodiments, a method is provided for the treatment of a viral infection in an individual mediated at least in part by a virus of the hepatitis B family and / or the hepatitis D family, comprising administering to the individual a composition comprising a compound of any of Formula I, Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.
[00157] [00157] In yet another aspect, another embodiment of the present invention provides a method for inhibiting the progression of a viral infection in an individual at risk of infection with a hepatitis B virus and / or hepatitis D virus, comprising administering to the individual a therapeutically effective amount of the compound of Formula I, Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.
[00158] [00158] In yet another aspect, another embodiment of the present invention provides a method for preventing viral infection in an individual at risk of infection with a hepatitis B virus and / or a virus.
[00159] [00159] In yet another aspect, another embodiment of the present invention provides a method of treating a virus infection in an individual suffering from said virus infection, comprising administering to the individual a therapeutically effective amount of the compound Formula I, Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.
[00160] [00160] Pharmaceutical compounds, methods and compositions for the treatment of viral infections, administering the compounds of Formula I, Formula IA or Formula IB in therapeutically effective amounts are described. Methods for the preparation of Formula I, Formula IA or Formula IB compounds and methods of using the compounds and pharmaceutical compositions thereof are likewise described. In particular, the treatment and prophylaxis of viral infections such as those caused by hepatitis B and / or hepatitis D are described.
[00161] [00161] In other embodiments, the compounds described here are useful for treating infections in an individual where the infection is caused by a strain resistant to multiple drugs of the hepatitis B virus and / or a hepatitis D virus.
[00162] [00162] In other embodiments, the compound of the present invention, or a pharmaceutically salt thereof, is chosen from the compounds mentioned in Table 1.
[00163] [00163] The compounds of the present invention having Formula I, Formula IA or Formula IB
[00164] [00164] Other embodiments provide compounds of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof as described here, wherein: R5 and R6 together form a 3- to 8-membered cycloalkyl ring or 3-hetero-cycloalkyl ring 8-membered, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, where the 3 to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ.
[00165] [00165] Other particular embodiments provide compounds of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof as described herein, wherein: R6 and R7 together form a 3- to 8-membered cycloalkyl ring or hetero-cycloalkyl ring comprising a heteroatom or two or more heteroatoms, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ, where the one heteroatom in the heteroalkyl ring is NR20, and the two or more heteroatoms are selected from N, NR22, O, S , SR22 and SR22R22ꞌ.
[00166] [00166] Other particular embodiments provide compounds of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof as described herein, wherein: R7 and R8 together form a 3- to 8-membered cycloalkyl ring or hetero-cycloalkyl ring 3 to 8 members, optionally substituted with R17, R17ꞌ, R18 and / or R18ꞌ, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ.
[00167] [00167] Suitable synthetic routines are described below in the general reaction schemes below. The skilled technician will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable under the conditions of the reaction. The protecting group can be removed at a suitable point in the sequence of the reaction to provide a desired intermediate or target compound. Suitable protecting groups and methods for protecting and unprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some cases, a substituent may be selected specifically to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is useful as an intermediate compound or is a desired substituent on a target compound. Abbreviations
[00168] [00168] In the description of the examples, chemical elements are identified according to the Periodic Table of Elements. The abbreviations and symbols used here are in accordance with the common use of such abbreviations and symbols by those versed in chemical techniques. The following abbreviations are used here: AcOH acetic acid Ac2O acetic acid aq aqueous B4 (S) -2 - (((benzyloxy) carbonyl) amino) -3- (4- (trifluoromethyl) piperidin-1-yl) propanoic acid
[00169] [00169] Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all temperatures are expressed in oC (degrees centigrade). Unless otherwise indicated, all reactions are conducted under an inert atmosphere at room temperature.
[00170] [00170] All temperatures are given in degrees Celsius, all solvents have the highest purity available and all reactions take place under anhydrous conditions in an atmosphere of argon (Ar) or nitrogen (N2), when necessary.
[00171] [00171] The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled technician in preparing and using the compounds, compositions and methods of the present invention.
[00172] [00172] Although particular embodiments of the present invention are described, the skilled technician will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
[00173] [00173] When used here, the symbols and conventions used in these processes, schemes and examples are consistent with those used in contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.
[00174] [00174] All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in oC (degrees centigrade). All reactions are conducted under an inert atmosphere at room temperature, unless otherwise noted, and all solvents are of the highest purity available, unless otherwise indicated.
[00175] [00175] The 1H NMR spectra (hereinafter also "NMR") were recorded on a Variant Unity-400 spectrometer. Chemical shifts are expressed in parts per million (ppm,  units). Coupling constants are in units of hertz (Hz). The split patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
[00176] [00176] Rapid chromatography was performed on Merck Silica gel 60 (230 - 400 mesh) or using a Teledyne Isco Combirápida® Combination with disposable normal phase Redi-Sep® columns. Mass spectra were performed in an open access LC-MS system using electrospray ionization. The analytical low resolution mass spectra (MS) were recorded on the Waters SQD instrument with the UPLC analysis conducted on a Phenomenex® Kinetex® 1.7um, 2.1 x 50 mm XB-C18 column in 40CSQ using a gradient elution. Solvent A: 0.2% formic acid (FA) in water; Solvent B: FA 0.15% in acetonitrile; gradient from 1% to 99% solvent B over 1.1 minutes and remaining stable at 99% solvent B for another 0.4 minutes, at a flow rate of 1 ml / min. Synthetic Preparation of Compounds General protocols for preparing compounds as described here are shown below in Schemes 1 - 15. Scheme 1
[00177] [00177] Particular compounds described here can be made according to Scheme 1. For example, compound 4 can be prepared by reacting compound 1 with an appropriately substituted 4-pyranone, as shown, in acetic acid or ethanol , with heat. Reductive catalysis of 2 by treating compound 2 with Pd (II) catalyst with an appropriate base such as potassium acetate in an appropriate solvent such as N, N-dimethylacetamide (DMA) or N, N-dimethylformamide (DMF) at 90-120 ° C, it produces molten tricyclic carboxylate compound 3. Compound 3 is then subjected to hydrolysis of the ester under acidic or basic conditions to produce carboxylic acid 4. Another chemical manipulation of the carboxylic acid may take to additional R10 groups.
[00178] [00178] Alternatively, compounds described here can be prepared according to Scheme 2. Scheme 2 Legend of the figures: - heat - Pd (II) catalyst - Acid or basic hydrolysis - where X is Br or I, and W, Y, R5, R6, R7 and R8 are as described here
[00179] [00179] As shown in Scheme 2, compound 2 can be prepared by reacting compound 1 with an appropriately substituted 4-pyranone, as shown, in acetic acid or ethanol, with heat. Reductive catalysis of 2 by treating compound 2 with Pd (II) catalyst with an appropriate base such as potassium acetate in an appropriate solvent such as N, N-dimethylacetamide (DMA) or N, N-dimethylformamide (DMF) at 90 -120 ° C, produces molten tricyclic carboxylate compound 3. Compound 3 is then subjected to ester hydrolysis under acidic or basic conditions to produce carboxylic acid 4. As with Scheme 1, another chemical manipulation of carboxylic acid can lead to additional R10 groups. Scheme 3 for Preparation of Compound of Example 1 (Compound 220)
[00180] [00180] One flask was loaded with a stir bar, 5-bromo-2-chloro-3-methoxypyridine (16.5 g, 74.2 mmol), tris (dibenzylidene acetone) dipaladium (0) (1.02 g, 1.11 mmol), xantphos (1.16 g, 2.00 mmol), and sodium tert-butoxide (12.6 g, 131 mmol). The flask was purged with a stream of nitrogen for 30 minutes. Tetrahydrofuran (THF) (300 ml) was degassed with nitrogen for 30 minutes. 2,2-dimethylcyclopentan-1-one (11.2 ml, 89 mmol) was added to the degassed tetrahydrofuran (THF) (300 ml) and this solution added to the nitrogen purged flask that contained the initial substrate. The mixture was heated to reflux under nitrogen for 3 hours. The mixture was allowed to cool to room temperature and filtered through a plug of silica over nitrogen. The buffer was washed with tetrahydrofuran and the filtrate concentrated. The residue was dissolved in minimal dichloromethane and injected into a column of silica. The column was eluted 1 minute with hexanes and then a rapid gradient (3 minutes) to 20% ethyl acetate / hexanes, and then isocratic to 20% ethyl acetate / hexanes until the product eluted . The fractions were concentrated to produce 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-one (10.7 g, 42.1 mmol, 56.8% yield) as an oil. LCMS (ESI) m / z 254.2 (M + 1). Step 2: 5- (6-Chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentanamine (trans / cis mixture)
[00181] [00181] A stirring mixture of 5- (6-chloro-5-methoxypyridin-3-yl) - 2,2-dimethylcyclopentan-1-one (trans / cis mixture) (10.7 g, 42.2 mmol) and ammonium acetate (32.5 g, 422 mmol) in methanol (200 mL) was degassed with a stream of nitrogen for 25 minutes. Sodium cyanoborohydride (5.30 g, 84 mmol) was added and the mixture heated to 65 ° C over the weekend. The reflux condenser was removed, and the oil bath heated to 80 ° C, allowing the reaction mixture to concentrate at ~ 70% of the original volume for 4 hours. The reflux condenser was switched on again, and the mixture heated to strong reflux overnight (oil bath at 80 ° C). The mixture was concentrated, and the residue was suspended in ~ 300 ml of dichloromethane. The mixture was stirred vigorously for ~ 30 minutes. The solids were filtered, and the filter cake washed with dichloromethane. The filtrate was concentrated to yield 22 g of crude 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-amine (trans / cis mixture). The raw material was purified by chromatography on silica eluting with a gradient of 0% to 10% 2M ammonia / methanol in dichloromethane. The fractions were concentrated to produce 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-amine (trans / cis mixture) (9.04 g, 35.5 mmol, 84% income). LCMS (ESI) m / z 255.2 (M + 1). Step 3: 5- (2-Amino-3,3-dimethylcyclopentyl) -2-chloro-6-iodopyridin-3-ol (trans / cis mixture)
[00182] [00182] Boron tribromide (6.71 mL, 71.0 mmol) was slowly added dropwise to a vigorous stirring solution of 5- (6-chloro-5-methoxypyridin-3-yl) -2, 2-dimethylcyclopentan-1-amine (trans / cis mixture) (9.04 g, 35.5 mmol) in 1,2-dichloroethane (DCE) (175 ml). The mixture was stirred at room temperature for 30 minutes, and then heated to 70 ° C overnight. The mixture was cooled in an ice bath, and then carefully quenched with slow addition of methanol. Additional methanol (100 ml) was added. The mixture was warmed to room temperature, stirred for 30 minutes, and concentrated to leave ~ 17 g of crude 5- (2-amino-3,3-dimethylcyclopentyl) -2-chloropyridin-3-ol (trans / cis mixture ). Water (200 mL) was added to the raw material and stirred with a stir bar. Potassium carbonate (24.5 g, 177 mmol) was added slowly and carefully in portions to control effervescence. The mixture was stirred for 10 minutes after completing the addition of potassium carbonate. The aqueous mixture was tested with the pH paper to ensure that the mixture was basic. The aqueous mixture was extracted 1 time with 100 ml of dichloromethane. LC-MS indicated only impurities in the organic layers and only 5- (2-amino-3,3-dimethylcyclopentyl) -2-chloropyridin-3-ol (trans / cis mixture) in the aqueous layer. The organic phase was discarded, and the aqueous layer transferred from the separating funnel to a round bottom flask before Iodine (18.0 g, 71.0 mmol) was added. The mixture was stirred during the night
[00183] [00183] 5- (2-Amino-3,3-dimethylcyclopentyl) -2-chloro-6-iodopyridin-3-ol (trans / cis mixture) (6.6 g, 18 mmol) and ethyl 4-oxo-4H -pyran-3-carboxylate (3.94 g, 23.4 mmol) in acetic acid (150 mL) were stirred at 100 ° C for 3 hours. The mixture was allowed to cool to room temperature and concentrated to dryness under vacuum. Toluene was added and rotovaped several times to help get rid of the remaining acetic acid. Final evaporation yielded ethyl 1- (5- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4-dihydropyridine-3-carboxylate crude. LCMS (ESI) m / z 517.1 (M + 1). Ethyl 1- (5- (6-chloro-5-
[00184] [00184] A round bottom flask containing a stir bar, ethyl 1- (5- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -2,2-dimethylcyclopentyl ) -4-oxo-1,4-dihydropyridine-3-carboxylate (trans / cis mixture) (5.57 g, 9.46 mmol), potassium acetate (4.64 g, 47.3 mmol), and palladium (II) bromide (0.50 g, 1.89 mmol) was purged with nitrogen for 20 minutes using a septum with needle inside / needle outside.
[00185] [00185] To a solution of ethyl 2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [ 1,2- h] [1,7] naphthyridine-10-carboxylate (trans / cis mixture) (3.15 g, 6.83 mmol) in 1,4-dioxane (40 mL) a solution of mono- lithium hydroxide hydrate (1.434 g, 34.2 mmol) in water (30 mL). The mixture was heated to 70 ° C for 3 hours. LC-MS indicated complete conversion to the desired racemic cis product. The mixture was allowed to cool to room temperature and diluted with 0.5M hydrochloric acid (100 mL). The precipitate was collected by filtration, and the filter mass was washed completely with water. The filter mass was air-dried for several hours with a vacuum in a Buchner funnel until solids no longer appear moist by visual inspection. The filter mass was dissolved in 150 ml of dichloromethane. Complete dissolution required stirring for several minutes. The solution was dried over sodium sulfate and concentrated to produce 2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (cis racemic) (2.6 g, 6.01 mmol, 88% yield).
[00186] [00186] The racemate was purified in several batches using the following conditions: Column = Chiralpak IC, 10 mm x 250 mm (5u); Mobile phase = 3: 1 MeOH / EtOH + 0.1% TFA; Flow rate = 10 mL / min; Injection volume = 500 uL (30 mg / mL conc., DCM used as the injection solvent); Collection wave length = 254 nm. The fractions corresponding to peak 1 were concentrated. The residues were suspended in ethyl ether, sonicated, stirred for 10 minutes, and then the stirring mixture was cooled in an ice bath. The solids were collected by vacuum filtration, air-dried and dried under high vacuum to produce (4bR, 7aS) -2- Chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (1.24 g, 2.87 mmol, 42% yield) as white solids.
[00187] [00187] To a solution of 5-bromo-2-chloro-3-methoxypyridine (100 g, 449 mmol) in THF (2 L) were added NaOtBu (76.02 g, 791 mmol), Xantphos (7.01 g , 12.1 mmol) and 2,2-dimethylcyclopentan-1-one (65.56 g, 584.6 mmol). The reaction mixture was degassed with nitrogen for 30 minutes. Pd2 (dba) 3 was added to the reaction, and the reaction mixture was stirred at 70oC for 3 h. After completion of the reaction, the reaction mixture was filtered through silica gel (60-120) pad and washed with THF. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (230-400 silica gel) using 0-30% ethyl acetate in petroleum ether as an eluent. Fractions were collected and concentrated to provide the title compound (61 g, 54% yield), LCMS (ESI) m / z 253.9 (M + 1). Step 2: 5- (6-Chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-amine (trans / cis mixture)
[00188] [00188] To a solution of 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-one (60 g, 236.5 mmol) in methanol (1.2 L) NH4OAc (182 g, 2365 mmol) is added. The reaction mixture was degassed with nitrogen for 30 minutes. NaBH3CN was added
[00189] [00189] To a solution of 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-amine (60 g, 236 mmol) in 1,2-Dichloroethane (DCE) (1300 mL), BBr3 (22.27 mL, 236 mmol) was added, and the reaction mixture was stirred at 70 ° C for 16 h. After completion of the reaction, methanol (1.5 L) was added to the reaction mixture slowly dropwise at 0 ° C and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was taken up in water (1 L) and the pH was adjusted to basic using potassium carbonate (325 g, 2355 mmol). The aqueous layer was washed with DCM (200 ml). To the aqueous layer, iodine (120 g, 471 mmol) was added and stirred at room temperature for 16 h. After the completion of the reaction, sodium sulfite (200 g) was added to quench excess iodine. Acetic acid (250 mL) was added and extracted with 2-methyl THF (2 * 1L). The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude product was triturated with 20% dichloromethane in hexane (2 * 600 ml). The obtained solid was filtered and dried to provide the title compound (35 g, 21.89% yield). LCMS (54%) (ESI) m / z: 367 (M + 1). Step 4: Ethyl 1- (5- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4-dihydropyridine-3-carboxylate ( trans mix
[00190] [00190] A suspension of 5- (2-amino-3,3-dimethylcyclopentyl) -2-chloro-6-iodopyridin-3-ol (87 g, 237 mmol), ethyl 4-oxo-4H-pyran-3- carboxylate (45.9 g, 273 mmol) and acetic acid (1.8 L) was stirred at 100 ° C for 3 h. After completion of the reaction, the reaction mixture was concentrated and coevaporated with toluene (4 * 200 mL), and the residue was purified by column chromatography (230-400 silica gel) using 10 ~ 15% MeOH in DCM as an eluent. The fractions were collected and concentrated to provide the title compound (51 g, 22% yield) as a dark brown solid. LCMS (53%) (ESI) m / z: 517 (M + 1). Step 5: Ethyl 1- (5- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4-dihydropyridine -3-carboxylate (trans / cis mixture)
[00191] [00191] To a solution of ethyl 1- (5- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4-dihydropyridine- 3-carboxylate (51 g, 99 mmol) in N, N-Dimethylformamide (580 ml) were added K2CO3 (68.2 g, 493 mmol) and 1-bromo-3-methoxypropane (30.2 g, 197 mmol). The reaction mixture was stirred at 60 ° C for 1 h. After completion of the reaction, the reaction mixture was quenched with chilled water (1500 mL) and extracted with DCM (2 L). The combined organic layers were washed with brine (500 ml), dried over
[00192] [00192] To a solution of ethyl 1- (5- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4 -dihydropyridine-3-carboxylate (52 g, 88 mmol) in N, N-Dimethylformamide (550 ml) potassium acetate (43.3 g, 442 mmol) was added. The reaction mixture was degassed with nitrogen for 20 minutes. Palladium (II) bromide (4.70 g, 17.66 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 100 ° C for 16 h. After completion of the reaction, the reaction mixture was filtered through celite and washed with DCM. The organic phase was washed with water (250 ml), dried over Na2SO4 and concentrated. The crude was purified by column chromatography (230-400 silica gel) using 2 ~ 5% MeOH in DCM as an eluent. The fractions were collected and concentrated to provide the title compound (20 g, 42% yield). LCMS (ESI) m / z: 461.1 (M + 1). Step 7: (4bR, 7aS) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic
[00193] [00193] To a solution of Ethyl 2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [ 1,2-h] [1,7] naphthyridine-10-carboxylate (17.5 g, 38 mmol) in 1,4-Dioxane (150 mL) and water (150 mL) was added lithium hydroxide.H2O (7 , 9 g, 190.14 mmol). The reaction mixture was heated to 70 ° C for 2 h.
[00194] [00194] 2-Chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2- h] [1,7] naphthyridine-10-carboxylic (cis racemic) (500 mg) was purified by chiral chromatography. Column = Chiralpak IC, 10 mm x 250 mm (5u), Mobile phase = 3: 1 MeOH / EtOH + 0.1% TFA, Flow rate = 10 mL / min, Injection volume = 500 uL (30 mg / conc. mL); DCM used as an injection solvent, Collection wavelength = 254 nm. Peak 2 was concentrated to produce (4bS, 7aR) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexa -hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (190 mg, 0.438 mmol, 38% yield) as a white solid. LCMS (ESI) m / z 433.3 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 1 H), 7.60 (s, 1 H), 7.40 (s, 1 H), 4.69 (d, J = 8.98 Hz, 1 H), 4.18 - 4.36 (m, 2 H), 3.84 - 3.96 (m, 1 H), 3.48 (t, J = 6.25 Hz, 2 H), 3.23 (s, 3 H), 2.30 - 2.43 (m, 1 H), 2.18 - 2.28 (m, 1 H), 2.00 (quin, J = 6.15 Hz, 2 H), 1.53 - 1.64 (m, 1 H), 1.37 - 1.48 (m, 1 H), 1.12 (s, 3 H), 0.37 (s, 3 H). Example 3: (Compound 222) (4bR, 7aS) -2-cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexa- hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic
[00195] [00195] A reaction flask containing a stir bar, (4bR, 7aS) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7, 7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (81 mg, 0.19 mmol), potassium carbonate (103 mg, 0.748 mmol), acid cyclopropylboronic (32.1 mg, 0.374 mmol), and tetra-cis (triphenylphosphine) palladium (0) (43.2 mg, 0.037 mmol) was purged completely with a stream of nitrogen (needle in / needle out). 1,4-Dioxane (2 mL) was added, and the reaction vial was placed in a heating block that was preheated to 100 ° C. The mixture was heated to 100 ° C overnight. The reaction mixture was allowed to cool to room temperature, and then diluted with 2-methyltetrahydrofuran and water. Acetic acid was added slowly and carefully (effervescence) until the aqueous phase has been neutralized. The mixture was extracted 2 times with 2-methyltetrahydrofuran. The combined organic layers were washed with brine and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were combined and concentrated until a white precipitate was observed. A small amount of acetonitrile was added, and the solution became clear. The solution was lyophilized to produce (4bR, 7aS) -2-cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-
[00196] [00196] A reaction flask containing a stir bar, ethyl 2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexa- hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylate (racemic cis) (200 mg, 0.434 mmol), potassium carbonate (240 mg, 1.74 mmol), cyclopropylboronic acid ( 74.5 mg, 0.868 mmol), and tetra-cis (triphenylphosphine) palladium (0) (100 mg, 0.087 mmol) was purged completely with a stream of nitrogen (needle in / needle out). 1,4-Dioxane (4 mL) was added, and the reaction vial was placed in a heating block that was preheated to 100 ° C. The mixture was heated to 100 ° C for 3 hours. Additional cyclopropylboronic acid (74.5 mg, 0.868 mmol) and tetracis (triphenylphosphine) palladium (0) (100 mg, 0.087 mmol) were added, and the mixture continued to warm to
[00197] [00197] Potassium tert-butoxide (13.3 mg, 0.119 mmol) was added to a solution of (4bR, 7aS) -2-cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl- 11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (13 mg, 0.030 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL) at room temperature and stirred overnight. The mixture was injected into a medium pressure reverse phase column and eluted (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were lyophilized to produce (7aR) -2-cyclopropyl-4b-hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexa - hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (single isomer) (6 mg, 0.013 mmol, 43.6% yield) as an off-white powder. LC-MS and NMR were consistent with the desired product. LCMS (ESI) m / z 455.3 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1 H), 7.50 (s, 2 H), 6.11 (s, 1 H), 4.62 (s, 1 H ), 4.12 - 4.35 (m, 2 H), 3.51 (t, J = 6.05 Hz, 2 H), 3.24 (s, 3 H), 2.57 - 2.68 (m, 1 H), 2.11 - 2.24 (m, 1 H), 2.02 (quin, J = 6.15 Hz, 2 H), 1.56 - 1.70 (m, 1 H ), 1.13 - 1.26 (m, 4 H), 0.97 - 1.10 (m, 4 H), 0.24 (s, 3 H).
[00198] [00198] Potassium tert-butoxide (15.5 mg, 0.139 mmol) was added to a solution of (4bR, 7aS) -2-chloro-3- (3-methoxypropoxy) - 7,7-dimethyl- 11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (15 mg, 0.035 mmol) in dimethyl sulfó - oxide (DMSO) (1 mL) at room temperature and stirred for 2 hours. The mixture was injected into a medium pressure reverse phase column and eluted (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were lyophilized to produce (7aR) -2-chloro-4b-hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexa -hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (7 mg, 0.015 mmol, 44.6% yield) as a white powder. LCMS (ESI) m / z 449.1 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (s, 1 H), 7.78 (s, 1 H), 7.44 (s, 1 H), 6.28 (s, 1 H ), 4.70 (s, 1 H), 4.18 - 4.43 (m, 2 H), 3.49 (t, J = 6.25 Hz, 2 H), 3.24 (s, 3 H), 2.59 - 2.73 (m, 1 H), 2.21 (dt, J = 13.47, 8.88 Hz, 1 H), 2.01 (quin, J = 6.15 Hz , 2 H), 1.58 - 1.71 (m, 1 H), 1.21 - 1.29 (m, 1 H), 1.18 (s, 3 H), 0.27 (s, 3 H). Example 7: (Compound 226) (7aR) -2-Chloro-4b-methoxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-
[00199] [00199] Sodium hydride (60% in mineral oil) (1.87 mg, 0.047 mmol) was added to a stirring solution of (7aR) -2-chloro-4b-hydroxy-3- (3-methoxypropoxy) acid -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (7 mg , 0.016 mmol) and methyl iodide (2.9 µl, 0.047 mmol) in N, N-dimethylformamide (DMF) (0.5 mL). The mixture was stirred for 2 hours. The mixture was heated to 80 ° C for 2 hours. The mixture was allowed to cool to room temperature and quenched with water. The mixture is stirred for 20 minutes. The mixture was injected in a medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were lyophilized to produce (4bS, 7aR) -2-chloro-4b-methoxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11 -hexa- hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic as an off-white powder. LCMS (ESI) m / z 463.2 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (s, 1 H), 7.78 (s, 1 H), 7.46 (s, 1 H), 4.92 (s, 1 H ), 4.26 - 4.42 (m, 2 H), 3.49 (t, J = 6.25 Hz, 2 H), 3.24 (s, 3 H), 2.94 (s, 3 H), 2.66 (dt, J = 13.56, 6.68 Hz, 1 H), 2.19 - 2.33 (m, 1 H), 2.01 (quin, J = 6.15 Hz , 2 H), 1.63 - 1.74 (m, 1 H), 1.28 - 1.40 (m, 1 H), 1.19 (s, 3 H), 0.29 (s, 3 H). Example 8 (Compound 227) and Example 9 (Compound 228)
[00200] [00200] A mixture of (4bR, 7aS) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (61 mg, 0.141 mmol) in sodium hydroxide (2M) (4 mL, 8 mmol) was heated to 150 ° C in a microwave reactor for 1 hour. The mixture was injected into a medium pressure reverse phase column and eluted (C18 / acetonitrile / water / 0.1% formic acid / 0% to 100% gradient). 2 sets of fractions were lyophilized separately to produce: Example 8: (4bR, 7aS) -2-hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6, 7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic (20 mg, 0.048 mmol, 34% yield). LCMS (ESI) m / z 415.2 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 - 11.71 (m, 1 H), 8.53 (s, 1 H), 7.44 (s, 1 H), 6.97 - 7.27 (m, 1 H), 4.61 (d, J = 8.98 Hz, 1 H), 4.00 - 4.19 (m, 2 H), 3.73 (br. S., 1 H), 3.45 (t, J = 6.05 Hz, 2 H), 3.23 (s, 3 H), 2.11 - 2.33 (m, 2 H), 1.96 (quin , J = 6.25 Hz, 2 H), 1.50 - 1.61 (m, 1 H), 1.31 - 1.45 (m, 1 H), 1.11 (s, 3 H), 0.42 (s, 3 H). Example 9: (4bR, 7aS) -2-chloro-3-hydroxy-7,7-dimethyl-11-oxo-
[00201] [00201] One flask was loaded with a stir bar, 5-bromo-2-chloro-3-methoxypyridine (5.8 g, 26 mmol), tris (dibenzylidenoacetone) dipaladium (0) (0.358 g, 0.391 mmol), and sodium tert-butoxide (4.41 g, 45.9 mmol). The flask was purged with a stream of nitrogen before 4- (benzyloxy) -3,3-dimethylbutan-2-one (5.45 g, 26.4 mmol) in tetrahydrofuran (THF) (100 ml) was added - of. The mixture was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature and diluted with water. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate
[00202] [00202] A mixture of 4- (benzyloxy) -1- (6-chloro-5-methoxypyridin-3-yl) - 3,3-dimethylbutan-2-one (3 g, 8.6 mmol) and ammonium acetate (9.97 g, 129 mmol) in methanol (50 mL) was stirred at room temperature overnight. Sodium cyanoborohydride (1.08 g, 17.3 mmol) was added, and the mixture heated to 60 ° C overnight. The mixture was allowed to cool to room temperature, concentrated to ~ 15 mL, quenched with 1M sodium hydroxide, and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to produce crude 4- (benzyloxy) -1- (6-chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-amine (2.84 g, 5.62 mmol, 65% yield). LCMS (ESI) m / z 349.3 (M + 1). Step 3: 5- (2-Amino-4-hydroxy-3,3-dimethylbutyl) -2-chloropyridin-3-ol
[00203] [00203] Boron tribromide (2.66 mL, 28.1 mmol) was added dropwise to a solution of 4- (benzyloxy) -1- (6-chloro-5-methoxypyridin-3-yl) - 3,3-dimethylbutan-2-amine (2.84 g, 5.62 mmol) in 1,2-dichloroethane (DCE) (100 mL) at 0 ° C.
[00204] [00204] Iodine (233 mg, 0.919 mmol) was added to a stirring mixture of 5- (2-amino-4-hydroxy-3,3-dimethylbutyl) -2-chloropyridin-3-ol (225 mg, 0.919 mmol ) and potassium carbonate (381 mg, 2.76 mmol) in water (10 mL). The mixture was stirred at room temperature for 2 hours. Solid sodium sulphite was added in portions to the mixture until the color disappeared. The aqueous mixture was injected into a medium pressure C18 reverse phase column, and then eluted with acetonitrile / water / 0.1% formic acid / 0% to 50% gradient. The combined fractions were lyophilized to produce 5- (2-amino-4-hydroxy-3,3-dimethylbutyl) -2-chloro-6-iodopyridin-3-ol (164 mg, 0.443 mmol, 48.1% yield) like a white solid. LCMS (ESI) m / z 371.0 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1 H), 7.20 (s, 1 H), 3.13 - 3.41 (m, 2 H), 2.70 - 2.88 (m, 2 H), 2.29 - 2.39 (m, 1 H), 0.92 (s, 3 H), 0.84 (s, 3 H). Step 5: Ethyl 1- (4-acetoxy-1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1,4- dihydropyridine-3-carboxylate
[00205] [00205] 5- (2-Amino-4-hydroxy-3,3-dimethylbutyl) -2-chloro-6-iodopyridin-3-ol (164 mg, 0.443 mmol) and ethyl 4-oxo-4H-pyran-3 -carboxylate (83 mg, 0.494 mmol) in acetic acid (4 mL) were stirred at 100 ° C for 4 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid
[00206] [00206] Ethyl 1- (4-acetoxy-1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1,4- dihydropyridine-3-carboxylate (27 mg, 0.048 mmol), potassium carbonate (26.5 mg, 0.192 mmol), and 1-bromo-3-methoxypropane (19 mg, 0.124 mmol) were stirred at room temperature during night. The mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride (aq), and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were lyophilized to produce ethyl 1- (4-acetoxy-1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-yl) - 4-oxo-1,4-dihydropyridine-3-carboxylate (15 mg, 0.024 mmol, 49.2% yield) as a white powder. LCMS (ESI) m / z 635.9 (M + 1). Step 7: 2-Chloro-6- (1-hydroxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1, 2-h] [1,7] naphthyridine-9-
[00207] [00207] A round bottom flask containing a stir bar, ethyl 1- (4-acetoxy-1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) - 3 , 3-dimethylbutan-2-yl) -4-oxo-1,4-dihydropyridine-3-carboxylate (14 mg, 0.022 mmol), potassium acetate (4.33 mg, 0.044 mmol), and palladium bromide (II) (1.2 mg, 4.4 µmol) was purged with nitrogen for 15 minutes. N, N-Dimethylacetamide (DMA) (1 mL) was purged with nitrogen for 5 minutes before being added to the reaction vessel. The reaction vessel was placed in an oil bath, which was preheated to 90 ° C, and the mixture stirred for 3 hours. The mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient ). The fractions were combined and basified with 1M sodium hydroxide. The mixture was heated to 60 ° C overnight, cooled to room temperature and concentrated. The residue was dissolved in water and acidified to pH = 3-4 with 1M hydrochloric acid. The mixture was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 0% to 100% gradient). The fractions were lyophilized to produce 2-chloro-6- (1-hydroxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (3 mg, 6.9 µmol, 31% yield). LCMS (ESI) m / z 437.2 (M + 1). General Scheme 6 for the Preparation of Example Compounds 11-25
[00208] [00208] A solution of 1- (6-chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-one (2.54 g, 10.50 mmol), (R) -2-methylpropane -2-sulfinamide (2.55 g, 21.00 mmol) and Ti (OEt) 4 (5.99 g, 26.3 mmol) in toluene (8.5 mL) was stirred for 10 min at 60 ° C, and the vessel was then evacuated. The reaction mixture was stirred at 60 ° C under vacuum for 24 h. The vessel was repressurized with nitrogen and toluene (5 ml) and THF (35 ml) were added. The LiBH4 solution (15.8 mL, 2M in THF, 31.5 mmol) was added slowly. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with THF (130 ml) and brine (3 ml), stirred for 30 min, and then filtered through celite. The filtrate was evaporated and purified by silica gel chromatography (0-100% EtOAc / hexanes) to provide (R) -N - ((S) -1- (6-chloro-5-methoxypyridin-3- il) -3,3-dimethylbutan-2-yl) -2-methylpropane-2-sulfinamide (2.58 g, 71%) as the main diastereomer. LCMS (m / z, ES +) = 346.9, 348.1 (M + 1). Step 2: (S) -5- (2-Amino-3,3-dimethylbutyl) -2-chloropyridin-3-ol
[00209] [00209] A solution of (R) -N - ((S) -1- (6-chloro-5-methoxypyridin-3-yl) - 3,3-dimethylbutan-2-yl) -2-methylpropane-2- sulfinamide (2.56 g, 7.38 mmol) in 1,2-dichloroethane (36.9 ml) was stirred at 0 ° C. Boron tribromide (4.88 ml, 51.7 mmol) was added slowly. The reaction mixture was removed from the cooling bath and stirred overnight at RT. The solution was cooled to 0 ° C and quenched by the careful addition of MeOH. The resulting suspension was evaporated. EtOAc was added, and the solid was collected by filtration, washed with EtOAc and dried to provide (S) -5- (2-amino-3,3-dimethylbutyl) -2-chloropyridin-3-ol, as the bis salt HBr. (2.89 g, quant.) LCMS (m / z, ES +) = 229.1, 231.1 (M + 1). Step 3: (S) -tert-Butyl (1- (6-chloro-5-hydroxypyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate
[00210] [00210] Triethylamine (0.95 mL, 6.85 mmol) was added to a stirred suspension of (S) -5- (2-amino-3,3-dimethylbutyl) -2-chloropyridin-3-ol. 2HBr (1.36 g, 3.42 mmol) and Boc anhydride (0.87 mL, 3.73 mmol) in THF (34.2 mL), and the reaction mixture was stirred at 60 ° C for 1 h , and then evaporated to dryness. The solid was suspended in diethyl ether, isolated by filtration, and then partitioned between EtOAc and water. The aqueous layer was extracted with CH2Cl2 (4x), and the combined organic phases were dried (Na2SO4), filtered and evaporated to provide (S) -tert-butyl (1- (6-chloro-5-hydroxypyridin-3- il) -3,3-dimethylbutan-2-yl) carbamate (assumed amount). LCMS (m / z, ES +) = 329.6, 331.2 (M + 1). Step 4: (S) -tert-Butyl (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate
[00211] [00211] Iodine (0.87 g, 3.42 mmol) was added to a stirred solution of tert-butyl (S) - (1- (6-chloro-5-hydroxypyridin-3-yl) -3, 3-dimethylbutan-2-yl) carbamate (1.13 g, 3.42 mmol) and K2CO3 (1.42 g, 10.26 mmol) in water (8.6 mL) and 1,4-dioxane (8, 6 mL). The reaction mixture was stirred overnight in rt. More iodine (0.20 g, 0.79 mmol) and K2CO3 (0.40 g, 7.23 mmol) were added, and the reaction mixture was heated at 40 ° C for 5 h. Solid Na2SO3 was added, while stirring until the solution is no longer dark brown. The solution was diluted with brine and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated to provide (S) -tert-butyl (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2 -yl) carbamate as a yellow foam (1.56 g, quant.). LCMS (m / z, ES +) = 455.1, 457.1 (M + 1). Step 5: (S) -tert-Butyl (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -
[00212] [00212] A solution of tert-butyl (S) - (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (0.83 g , 1.84 mmol), K2CO3 (0.76 g, 5.51 mmol), and 1-bromo-3-methoxypropane (0.56 g, 3.67 mmol) in DMF (12.2 mL) was heated to 80 ° C for 3 h. The reaction mixture was evaporated to dryness, and the residue was taken up in CH2Cl2 and H2O. The aqueous phase was extracted CH2Cl2 (2x), and the combined organic layers were dried (Na2SO4), filtered and evaporated to provide tert-butyl (S) - (1- (6-chloro-2-iodo-5- ( 3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (0.97 g, quant.) As an off-white solid. LCMS (m / z, ES +) = 527.2, 529.2 (M + 1). Step 6: (S) -Ethyl 1- (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) - 3,3-dimethylbutan-2-yl) -4-oxo -1,4-dihydropyridine-3-carboxylate
[00213] [00213] 4 M hydrogen chloride in dioxane (6.89 mL, 27.5 mmol) was added to a solution of tert-butyl (S) - (1- (6-chloro-2-iodine-5- ( 3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (967 mg, 1.84 mmol) in CH2Cl2 (7 mL). The reaction mixture was stirred at rt for 3 h and evaporated to dryness. The solid was dissolved in CH2Cl2 (1 ml) and Et3N (1 ml), and then evaporated to dryness. The residue was taken up in saturated NaHCO3 and CH2Cl2. The aqueous phase was extracted with CH2Cl2 (2x), and the combined organic layers were dried (Na2SO4), filtered and evaporated to provide (S) -1-
[00214] [00214] A flask containing ethyl (S) -1- (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1,4-dihydropyridine-3-carboxylate (0.59 g, 1.03 mmol), potassium acetate (0.20 g, 2.06 mmol), and palladium (II) bromide (0.055 g, 0.21 mmol) was purged with nitrogen. Degassed N, N-dimethylacetamide (DMA) (10.3 mL) was added, and the reaction mixture was heated to 90 ° C for 24 h. The solvent was removed by evaporation, and the residue was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide ethyl (S) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (326 mg, 71 %) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1 H), 7.49 (s, 1 H), 7.02 (s, 1 H), 4.40 (q, J = 7, 0 Hz, 2 H), 4.13 - 4.26 (m, 2 H), 3.93 (d, J = 6.6 Hz, 1 H), 3.62 (m, 2 H), 3, 42 - 3.51 (m, 1 H), 3.38 (s, 3 H), 3.17 -
[00215] [00215] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2 -h] [1.7] naphthyridine-9-carboxylate (42 mg, 0.094 mmol) in 1M LiOH (1.7 mL) and MeOH (1.7 mL) was stirred at 50 ° C for 1.5 h. 1M citric acid (2 ml) was added, and the reaction mixture was stirred for several minutes. The white solid was collected by filtration, washed with water and dried to provide (S) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-di- hydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (35.5 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 16.31 (s, 1 H), 8.81 (s, 1 H), 7.75 (s, 1 H), 7.30 (s, 1 H ), 4.68 (d, J = 6.3 Hz, 1 H), 4.19 - 4.32 (m, 2 H), 3.40 - 3.60 (m, 4 H), 3.26 (s, 3 H), 2.04 (quin, J = 6.2 Hz, 2 H), 0.75 (s, 9 H); LCMS (m / z, ES +) = 421.3, 423.2 (M + 1). Example 12 (Compound 231) (S) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylic Step 1: (S) -tert-Butyl (1- (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridin-3-yl) -3,3-dimethylbutan- 2-yl) carbamate
[00216] [00216] A solution of tert-butyl (S) - (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (0.73 g , 1.60 mmol), K2CO3 (0.66 g, 4.78 mmol), and (bromomethyl) cyclopropane (0.43 g, 3.19 mmol) in DMF (10.6 mL) was heated to 80 ° C for 3 h. The reaction mixture was evaporated to dryness, and the residue was taken up in CH2Cl2 and H2O. The aqueous phase was extracted with CH2Cl2 (2x), and the combined organic layers were dried (Na2SO4), filtered and evaporated to provide tert-butyl (S) - (1- (6-chloro-5- (cyclopropylmethoxy ) - 2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (0.81 g, quant.) As an off-white solid. LCMS (m / z, ES +) = 508.8, 511.1 (M + 1). Step 2: (S) -Ethyl 1- (1- (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridin-3-yl) - 3,3-dimethylbutan-2-yl) -4-oxo-1, 4-dihydropyridine-3-carboxylate
[00217] [00217] 4 M hydrogen chloride in dioxane (5.98 mL, 23.9 mmol) was added to a solution of tert-butyl (S) - (1- (6-chloro-5- (cyclopropylmethoxy) -2 -iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (812 mg, 1.60 mmol) in CH2Cl2 (6 mL). The reaction mixture was stirred at rt for 3 h and evaporated to dryness. The solid was dissolved in CH2Cl2 (1 ml) and Et3N (1 ml), and then evaporated to dryness. The residue was taken up in saturated NaHCO3 and CH2Cl2. The aqueous phase was extracted with CH2Cl2 (2x), and the combined organic layers were dried (Na2SO4), filtered and evaporated to provide (S) -1- (6-chloro-2-iodo-5- (cyclopropylmethoxy) ) pyridin-3-yl) -3,3-dimethylbutan-2-amine. LCMS (m / z, ES +) = 409.1, 411.1 (M + 1).
[00218] [00218] A solution of the above amine and ethyl 4-oxo-4H-pyran-3-carboxylate (295 mg, 1.76 mmol) in acetic acid (16.0 mL) was stirred at 100 ° C for 7 h. The reaction mixture was evaporated to dryness, and the residue was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide ethyl (S) -1- (1 - (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1,4-dihydropyridine-3-carboxylate (453 mg , 51%) as a brown solid. LCMS (m / z, ES +) = 559.4, 561.1 (M + 1). Step 3: (S) -Ethyl 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1 , 7] naphthyridine-9-carboxylate
[00219] [00219] A vial containing ethyl (S) -1- (1- (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo -1,4-dihydropyridine-3-carboxylate (0.45 g, 0.81 mmol), potassium acetate (0.16 g, 1.62 mmol), and palladium (II) bromide (0.043 g, 0.16 mmol) was purged with nitrogen. Degassed N, N-dimethylacetamide (DMA) (8.1 mL) was added, and the reaction mixture was heated to 90 ° C for 24 h. The solvent was removed by evaporation, and the residue was taken up in CH2Cl2 and water and filtered through celite. The organic phase was evaporated to dryness, and the residue was purified by reverse phase chromatography (10-100% CH3CN / H2O (0.1% formic acid)) to provide ethyl (S) -6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine- 9- carboxylate (216 mg, 62%) as an off-white solid. LCMS (m / z, ES +) = 431.2, 433.2 (M + 1); > 97% e.e. by chiral HPLC. Step 4: (S) -6- (Tert-butyl) -3- (cyclopropylmethoxy) -2-methyl-10-oxo- 6,10-dihydro-5H-pyrido [1,2-h] [1 , 7] naphthyridine-9-carboxylic
[00220] [00220] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylate (52.7 mg, 0.12 mmol), Pd (PPh3) 4 (28 mg, 0.024 mmol), potassium carbonate (34 mg, 0.25 mmol), and trimethylboroxine (46 mg, 0.37 mmol) in 1,4-dioxane (0.61 ml) was heated to 100 ° C overnight. The reaction mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was evaporated, and the residue was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide (S) -ethyl 6- (tert- butyl) -3- (cyclopropylmethoxy) -2- methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (36.5 mg , 73%). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1 H), 7.56 (s, 1 H), 6.80 (s, 1 H), 4.40 (q, J = 7, 0 Hz, 2 H), 3.87 (s, 3 H), 3.39 - 3.48 (m, 1 H), 3.10 - 3.18 (m, 1 H), 2.50 (s , 3 H), 1.41 (t, J = 7.0 Hz, 3 H), 0.69 (m, 2 H), 0.40 (m, 2 H); LCMS (m / z, ES +) = 411.4 (M + 1).
[00221] [00221] A solution of the above ester in 1M LiOH (0.9 ml) and MeOH (0.9 ml) was heated to 50 ° C for 1.5 h. 1M citric acid (1.2 ml) was added, and the reaction mixture was stirred for 15 min. The solid was collected by filtration, washed with water and dried to provide (S) -6- (tert-butyl) -3- (cyclopropylmethoxy) -2-methyl-10-oxo-6,10-dihydro-5H acid -pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (27.7 mg, 59% for 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 16.53 (br. S., 1 H), 8.77 (s, 1 H), 7.44 (s., 1 H), 7.42 ( s, 1 H), 4.58 - 4.69 (m, 1 H), 3.98 (m, 2 H), 3.46 - 3.55 (m, 2 H), 2.43 (s, 3 H), 1.22 - 1.36 (m, 1 H), 0.73 (s, 9 H), 0.65-0.55 (m, 2 H), 0.33 - 0.44 ( m, 2 H); LCMS (m / z, ES +) = 383.2 (M + 1). Example 13 (Compound 232)
[00222] [00222] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylate (47.7 mg, 0.11 mmol), Pd (PPh3) 4 (25 mg, 0.021 mmol), potassium carbonate (29 mg, 0.21 mmol) and trimethylboroxine (40 mg, 0.32 mmol) in 1,4-dioxane (0.53 mL) was heated to 100 ° C overnight. The reaction mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was evaporated, and the residue was purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH) in hexanes) to provide (S) -ethyl 6- (tert-butyl) -3 - (3-methoxypropoxy) -2-methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (41.3 mg, 91 %) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1 H), 7.27 (s, 1 H), 6.86 (s, 1 H), 4.39 (q, J = 7, 0 Hz, 2 H), 4.05 - 4.17 (m, 2 H), 3.91 (d, J = 6.6 Hz, 1 H), 3.63-3.55 (m, 2 H ), 3.49-3.41 (m, 1 H), 3.38 (s, 3 H), 3.15 (d, J = 16.8 Hz, 1 H), 2.46 (s, 3 H), 2.12 (quin, J = 6.1 Hz, 2 H), 1.40 (t, J = 7.0 Hz, 3 H), 0.84 (s, 9 H); LCMS (m / z, ES +) = 429.4 (M + 1).
[00223] [00223] A solution of the above ester in 1M LiOH (1 ml) and MeOH (1 ml) was heated to 50 ° C for 1.5 h. 1M citric acid (1.2 ml) was added, and the reaction mixture was stirred for 15 min. The solid was collected by filtration, washed with water and dried to provide (S) -6- (tert-butyl) -3- (3-methoxypropoxy) -2-methyl-10-oxo-5,10 - dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (27.6 mg, 65% over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ ppm 16.53 (s, 1 H), 8.77 (s, 1 H), 7.46 (s, 1 H), 7.44 (s, 1 H ), 4.64
[00224] [00224] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylate (53 mg, 0.12 mmol), Pd (PPh3) 4 (28 mg, 0.025 mmol), potassium carbonate (51 mg, 0.37 mmol) and cyclopropylboronic acid ( 21 mg, 0.25 mmol) in 1,4-dioxane (1.2 mL) was heated to 100 ° C overnight. The reaction mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was evaporated, and the residue was purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH) in hexanes) to provide (S) -ethyl 6- (tert-butyl) -2-cyclopropyl -3- (cyclopropylmethoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (53.3 mg, 99%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (s, 1 H), 7.42 (s, 1 H), 6.77 (s, 1 H), 4.38 (q, J = 7, 3 Hz, 2 H), 3.88 (m, J = 6.8, 2.1 Hz, 2 H), 3.43 (dd, J = 16.8, 7.0 Hz, 1 H), 3 , 11 (d, J = 16.8 Hz, 1 H), 2.56 - 2.47 (m, 1 H), 1.39 (t, J = 7.0 Hz, 3 H), 1.35 - 1.29 (m, 1 H), 1.22 - 1.29 (m, 1 H), 1.04 - 1.19 (m, 2 H), 0.93 - 1.01 (m, 2 H), 0.82 (s, 9 H), 0.63 - 0.73 (m, 2 H), 0.44 - 0.38 (m, 2 H); LCMS (m / z, ES +) = 437.4 (M + 1).
[00225] [00225] A solution of the above ester in 1M LiOH (1.2 ml) and MeOH (1.2 ml) was heated to 50 ° C for 2 h. 1M citric acid (1.5 ml) was added, and the reaction mixture was stirred for 15 min. The solid was collected by filtration, washed with water and dried to provide (S) -6- (tert-butyl) -2-cyclopropyl-3- (cyclopropylmethoxy) - 10-oxo-5,10-dihydro-6H -pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (38.8 mg, 77% over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 16.53 (s, 1 H), 8.76 (s, 1 H), 7.38 (s, 1 H), 7.35 (s, 1 H ), 4.62 (d, J = 6.3 Hz, 1 H), 4.05 - 3.94 (m, 2 H), 3.42 - 3.55 (m, 1 H), 3.30 - 3.28 (m, 1 H), 1.26 - 1.44 (m, 1 H), 0.93 - 1.06 (m, 4 H), 0.72 (s, 9 H), 0 , 65 - 0.59 (m, 2 H), 0.43 - 0.5 (m, 2 H); LCMS (m / z, ES +) = 409.2 (M + 1). Example 15 (Compound 234) (S) -6- (tert-Butyl) -2-cyclopropyl-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylic
[00226] [00226] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylate (46 mg, 0.10 mmol), Pd (PPh3) 4, (24 mg, 0.020 mmol), potassium carbonate (42 mg, 0.31 mmol) ), and cyclopropylboronic acid (18 mg, 0.21 mmol) in 1,4-dioxane (1.0 mL) was heated to 100 ° C overnight. The reaction mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was evaporated, and the residue was purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH) in hexanes) to provide (S) -ethyl 6- (tert-butyl) -2-cyclopropyl-3- (3-methoxypropoxy) -10-oxo- 6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (43.6 mg , 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (s, 1 H), 7.45 (s, 1 H), 6.83 (s, 1 H), 4.39 (q, J = 7, 0 Hz, 2 H), 4.13 (m, 2 H), 3.89 (d, J = 6.6 Hz, 1 H), 3.62 (m, 2 H), 3.39 - 3, 46 (m, 1 H), 3.38 (s, 3 H), 3.13 (d, J = 16.8 Hz, 1 H), 2.40 - 2.50 (m, 1 H), 2 , 15 (quin, J =
[00227] [00227] A solution of the above ester in 1M LiOH (1.2 ml) and MeOH (1.2 ml) was heated to 50 ° C for 2 h. 1M citric acid (1.5 ml) was added, and the reaction mixture was stirred for 15 min. The solid was collected by filtration, washed with water and dried to provide (S) -6- (tert-butyl) -2-cyclopropyl-3- (3-methoxypropoxy) - 10-oxo-5,10-dihydro acid -6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (27.2 mg, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 16.53 (s, 1 H), 8.76 (s, 1 H), 7.43 (s, 1 H), 7.35 (s, 1 H ), 4.62 (d, J = 6.3 Hz, 1 H), 4.11 - 4.24 (m, 2 H), 3.42 - 3.57 (m, 4 H), 3.26 (s, 3 H), 2.41 - 2.46 (m, 1 H), 2.05 (quin, J = 6.2 Hz, 2 H), 0.94 - 1.06 (m, 4 H ), 0.73 (s, 9 H); LCMS (m / z, ES +) = 427.2 (M + 1). Example 16 (Compound 235) (R) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-methoxy-10-oxo-6,10-dihydro-5H-pyrido acid [1,2-h ] [1,7] naphthyridine-9-carboxylic Step 1: (S) -N - ((R) -1- (6-Chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-yl ) -2-methylpropane-2-sulfinamide and (S) -N - ((S) -1- (6-Chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-yl) -2- methylpropane-2-sulfinamide and
[00228] [00228] A solution of 1- (6-chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-one (2.56 g, 10.57 mmol), (S) -2-methylpropane -2-sulfinamide (2.56 g, 21.14 mmol) and Ti (OEt) 4 (6.03 g, 26.4 mmol) in toluene (8.5 mL) was stirred for 10 min at 60 ° C, and the vessel was then evacuated.
[00229] [00229] A solution of (S) -N - ((R) -1- (6-chloro-5-methoxypyridin-3-yl) - 3,3-dimethylbutan-2-yl) -2-methylpropane-2- sulfinamide (1.82 g, 5.26 mmol) in 1,2-dichloroethane (26.3 ml) was stirred at 0 ° C. Boron tribromide (3.48 mL, 36.8 mmol) was added slowly. The reaction mixture was removed from the cooling bath and stirred overnight at RT. The solution was cooled to 0 ° C and quenched by the careful addition of MeOH. The resulting suspension was evaporated. EtOAc was added, and the solid was collected by filtration, washed with EtOAc and dried to provide (S) -5- (2-amino-3,3-dimethylbutyl) -2-chloropyridin-3-ol, as the bis salt HBr. (2.1 g, quant.) LCMS (m / z, ES +) = 229.2, 231.2 (M + 1). Step 3: (R) -tert-Butyl (1- (6-chloro-5-hydroxypyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate
[00230] [00230] A stirred suspension of (R) -5- (2-amino-3,3-dimethylbutyl) - 2-chloropyridin-3-ol. 2HBr (1.0 g, 2.51 mmol) and Boc anhydride (0.80 g, 3.67 mmol) in THF (25.1 mL) was stirred at 60 ° C for 1.5 h. THF (10 ml) and triethylamine (0.35 ml, 2.51 mmol) were added, and the reaction mixture was stirred for another 30 min. Additional triethylamine (0.35 mL, 2.51 mmol) was added, and the reaction mixture was stirred at 60 ° C for 1 h. The solution was then evaporated to dryness. The solid was suspended in diethyl ether, isolated by filtration and washed with additional diethyl ether. The solid was taken up in EtOAc and washed with dilute aqueous NaHCO3 and brine. The organic phase was dried (Na2SO4), filtered and evaporated to provide (R) -tert-butyl (1- (6-chloro-5-hydroxypyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (1.01 g, 99%) as a light yellow solid. LCMS (m / z, ES +) = 329.2, 331.2 (M + 1). Step 4: (R) -tert-Butyl (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-
[00231] [00231] Iodine (0.64 g, 2.51 mmol) was added to a stirred solution of tert-butyl (R) - (1- (6-chloro-5-hydroxypyridin-3-yl) -3, 3-dimethylbutan-2-yl) carbamate (0.83 g, 2.51 mmol) and K2CO3 (1.04 g, 7.53 mmol) in water (6.3 mL) and 1,4-dioxane (6, 3 mL). The reaction mixture was stirred at RT for 1.5 h.
[00232] [00232] Solid Na2SO3 was added, while stirring until the solution is no longer dark brown. The solution was diluted with brine and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to provide (R) -tert-butyl (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3.3 -dimethylbutan-2-yl) carbamate as a yellow foam (0.38 g, 34%). LCMS (m / z, ES +) = 455.4, 457.1 (M + 1). Step 5: (R) -tert-Butyl (1- (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate
[00233] [00233] A solution of tert-butyl (R) - (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (0.3819 g , 0.840 mmol), K2CO3 (0.35 g, 2.52 mmol), and (bromomethyl) cyclopropane (0.23 g, 1.68 mmol) in DMF (5.6 mL) was heated at 80 ° C for 3 h . The reaction mixture was evaporated to dryness, and the residue was taken up in CH2Cl2 and H2O. The aqueous phase was extracted with CH2Cl2 (2x), and the combined organic layers were dried (Na2SO4), filtered and evaporated to provide tert-butyl (R) - (1- (6-chloro-5- (cyclopropylmethoxy) -2 -
[00234] [00234] 4 M hydrogen chloride in dioxane (3.06 mL, 12.25 mmol) was added to a solution of tert-butyl (R) - (1- (6-chloro-5- (cyclopropylmethoxy) -2 -iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (0.42g, 0.82 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at rt for 3 h and evaporated to dryness. The solid was dissolved in CH2Cl2 (1 ml) and Et3N (1 ml), stirred, and then evaporated to dryness. The residue was taken up in saturated NaHCO3 and CH2Cl2. The aqueous phase was extracted with CH2Cl2 (2x), and the combined organic layers were dried (Na2SO4), filtered and evaporated to provide (R) -1- (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridine- 3-yl) -3,3-dimethylbutan-2-amine. The solution of the above amine and ethyl 4-oxo-4H-pyran-3-carboxylate (151 mg, 0.90 mmol) in acetic acid (8.2 ml) was stirred at 100 ° C for 7 h. The reaction mixture was evaporated to dryness, and the residue was purified by reverse phase chromatography (5- 100% CH3CN / H2O (0.1% formic acid)) to provide ethyl (R) -1- (1- (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1,4-dihydropyridine-3-carboxylate ( 389 mg, 85%) as a light brown solid. LCMS (m / z, ES-) = 575.2, 577.2 (M-1). Step 7: (R) -Ethyl 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1 , 7] naphthyridine-9-carboxylate
[00235] [00235] A vial containing ethyl (R) -1- (1- (6-chloro-5- (cyclopropylmethoxy) -2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4- oxo-1,4-dihydropyridine-3-carboxylate (0.39 g, 0.70 mmol), potassium acetate (0.14 g, 1.39 mmol), and palladium (II) bromide (0.037 g , 0.14 mmol) was purged with nitrogen. Degassed N, N-dimethylacetamide (DMA) (7.0 mL) was added, and the reaction mixture was heated to 90 ° C for 24 h. The solution was purified by reverse phase chromatography (10-100% CH3CN / H2O (0.1% formic acid)) to provide ethyl (R) -6- (tert-butyl) -2-chloro-3- ( cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (167 mg, 56%). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1 H), 7.49 (s, 1 H), 6.96 (s, 1 H), 4.40 (q, J = 7, 3 Hz, 2 H), 3.96 (d, J = 7.0 Hz, 2 H), 3.93 (d, J = 6.6 Hz, 1 H), 3.46 (dd, J = 17 , 0, 6.8 Hz, 1 H), 3.19 (d, J = 16.8 Hz, 1 H), 1.41 (t, J = 7.0 Hz, 3 H), 1.30 - 1.37 (m, 1 H), 0.85 (s, 9 H), 0.76 - 0.70 (m, 2 H), 0.41 - 0.48 (m, 2 H); LCMS (m / z, ES-) = 429.4, 431.4 (M-1). Step 8: (R) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-methoxy-10-oxo- 6,10-dihydro-5H-pyrido [1,2-h] [1 , 7] naphthyridine-9-carboxylic
[00236] [00236] A solution of ethyl (R) -6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylate (33 mg, 0.077 mmol), NaB (OMe) 4 (36 mg, 0.23 mmol), tBuXPhos (6.5 mg, 0.015 mmol) and Pd2 (dba) 3 (7.0 mg, 7.66 µmol) in DMF (0.77 ml) was heated to 80 ° C for 2 h. The reaction mixture was filtered through celite, and the celite was rinsed with EtOAc and CH2Cl2. The filtrate was evaporated, and the residue was purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH) in hexanes) to provide ethyl (R) -6- (tert-butyl) -3 - (cyclopropylmethoxy) -2-methoxy-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (27 mg, 83%). 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1 H), 7.42 (s, 1 H), 6.80 (s, 1 H), 4.39 (q, J = 7, 0 Hz, 2 H), 4.05 (s, 3 H), 3.94 - 3.85 (m, 3 H), 3.42 (dd, J = 16.6, 6.8 Hz, 1 H ), 3.09 (d, J = 16.8 Hz, 1 H), 1.37 - 1.40 (t, J = 7.2 Hz, 4 H), 1.27 - 1.37 (m, 1 H), 0.85 (s, 9 H), 0.66 - 0.75 (m, 2 H), 0.42 - 0.37 (m, 2 H); LCMS (m / z, ES +) = 427.4 (M + 1).
[00237] [00237] A solution of the above ester in 1M LiOH (1 ml) and MeOH (1 ml) was heated to 50 ° C for 2 h. The reaction mixture was filtered through an acrodisc filter to remove fine particles and 1M citric acid (1 ml) was added to the clear filtrate. The precipitate was collected by filtration, washed with water and dried to provide (R) -6- (tert-butyl) -3- (cyclopropylmethoxy) -2-methoxy-10-oxo-5,10-dihydro acid - 6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (19 mg, 62% over 2 steps) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 16.53 (s, 1 H), 8.77 (s, 2 H), 7.40 (s, 2 H), 7.36 (s, 2 H ), 4.62 (d, J = 6.8 Hz, 1 H), 3.97 (s, 3 H), 3.96 - 3.89 (m, 2 H), 3.49 - 3.40 (m, 1 H), 1.22 - 1.32 (m, 1 H), 0.75 (s, 9 H), 0.57 - 0.65 (m, 2 H), 0.31 - 0 , 40 (m, 2 H); LCMS (m / z, ES +) = 399.2 (M + 1). Example 17 (Compound 236) (S) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-methoxy-10-oxo-6,10-dihydro-5H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylic
[00238] [00238] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylate (52 mg, 0.12 mmol), NaB (OMe) 4 (57 mg, 0.36 mmol), tBuXPhos (10.3 mg, 0.024 mmol) and Pd2 (dba ) 3 (11.0 mg, 0.012 mmol) in DMF (1.2 mL) was heated to 80 ° C for 2 h. The reaction mixture was filtered through celite, and the celite was rinsed with EtOAc and CH2Cl2. The filtrate was evaporated, and the residue was purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH) in hexanes) to provide ethyl (S) -6- (tert-butyl) -3 - (cyclopropylmethoxy) -2-methoxy-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (32 mg, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1 H), 7.44 (s, 1 H), 6.80 (s, 1 H), 4.40 (q, J = 7, 2 Hz, 2 H), 4.06 (s, 3 H), 3.89 (m, 3 H), 3.42 (dd, J = 16.8, 7.0 Hz, 1 H), 3, 09 (d, J = 16.4 Hz, 1 H), 1.40 (t, J = 7.0 Hz, 3 H), 1.31 - 1.37 (m, 1 H), 0.84 ( s, 9 H), 0.68 - 0.75 (m, 2 H), 0.36 - 0.43 (m, 2 H); LCMS (m / z, ES +) = 427.4 (M + 1).
[00239] [00239] A solution of the above ester in 1M LiOH (0.75 ml) and MeOH (0.75 ml) was heated to 50 ° C for 2 h. 1M citric acid (0.75 mL) was added to the reaction mixture, and the precipitate was collected by filtration, washed with water and dried to provide (S) -6- (tert-butyl) -3- ( cyclopropylmethoxy) -2-methoxy-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (26.5 mg, 55% over 2 steps ) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 16.11 (s, 1 H), 8.45 (s, 1 H), 7.65 (s, 1 H), 6.83 (s, 1 H), 4.08 (s, 3 H), 4.04 (d, J = 6.8 Hz, 1 H), 3.92 (m, 2 H), 3.48 (dd, J = 17.1, 7 , 3 Hz, 1 H), 3.16 (d, J = 17.1 Hz, 1 H), 1.31 - 1.43 (m, 1 H), 0.86 (s, 9 H), 0 , 69 - 0.78 (m, 2 H), 0.41 (m, 2 H); LCMS (m / z, ES +) = 399.3 (M + 1). Example 18 (Compound 237) (S) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-hydroxy-10-oxo-6,10-dihydro-5H-pyrido acid [1,2-h ] [1,7] naphthyridine-9-carboxylic
[00240] [00240] The demethylated product was formed as a by-product of the reaction that produced ethyl (S) -6- (tert-butyl) -3- (cyclopropylmethoxy) -2- methoxy-10-oxo-5,10-dihydro- 6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate and was collected as mixed fractions that were combined. Repurification by reverse phase chromatography (10-100% CH3CN / H2O (0.1% formic acid)) provided (S) -ethyl 6- (tert-butyl) -3- (cyclopropylmethoxy) -2-hydroxy-10 -oxo-6,10-dihydro-5H-pyrido [1,2-1 h] [1,7] naphthyridine-9-carboxylate (8.3 mg, 17%). H NMR (400 MHz, CDCl3) δppm 8.18 (s, 1 H), 6.85 (s, 1 H), 6.55 (s, 1 H), 4.37 (q, J = 7.0 Hz, 2 H), 3.83 - 3.97 (m, 3 H), 3.33 (dd, J = 16.8, 6.6 Hz, 1 H), 2.95 (d, J = 17 , 2 Hz, 1 H), 1.33 - 1.42 (m, 4 H), 0.65 - 0.74 (m, 2 H), 0.40 (m, 2 H); LCMS (m / z, ES +) = 413.3 (M + 1).
[00241] [00241] A solution of the above ester in 1M LiOH (0.5 ml) and MeOH (0.5 ml) was heated to 50 ° C for 2 h. 1M citric acid (0.5 mL) was added to the reaction mixture, and the solution was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide acid ( S) -6- (tert-butyl) -3- (cyclopropylmethoxy) -2-hydroxy-10-oxo-5,10-dihydro-6H-pyrido [1,2- h] [1,7] naphthyridine- 9-carboxylic (6.4 mg, 14% over 2 steps) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 15.72 (br. S., 1 H), 8.44 (s, 1 H), 7.38 (s, 1 H), 6.66 (s, 1 H), 4.04 (d, J = 4.9 Hz, 1 H), 3.96 (d, J = 6.8 Hz, 2 H), 3.40 - 3.53 (m, 1 H) , 3.04 (d, J = 17.1 Hz, 1 H), 1.34 - 1.45 (m, 1 H), 0.89 (s, 9 H), 0.77 - 0.72 ( m, 2 H), 0.47 - 0.42 (m, 2 H); LCMS (m / z, ES +) = 385.2 (M + 1). Example 19 (Compound 238) (S) -6- (tert-Butyl) -2-methoxy-3- (3-methoxypropoxy) -10-oxo-6,10-di-
[00242] [00242] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylate (46.8 mg, 0.10 mmol), NaB (OMe) 4 (49 mg, 0.31 mmol), tBuXPhos (8.9 mg, 0.021 mmol) and Pd2 (dba) 3 (9.6 mg, 0.010 mmol) in DMF (1.0 ml) was heated to 80 ° C for 2 h. The reaction mixture was filtered through celite, and the celite was rinsed with CH2Cl2. The filtrate was evaporated, and the residue was returned to the reaction conditions with more reagents: NaB (OMe) 4 (49 mg, 0.31 mmol), tBuXPhos (8.9 mg, 0.021 mmol) and Pd2 (dba) 3 (9.6 mg, 0.010 mmol) in DMF (1.0 mL) at 80 ° C for another 3 h. The reaction mixture was filtered through celite, and the celite was rinsed with CH2Cl2. The filtrate was evaporated, and the residue was purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH) in hexanes) to provide ethyl (S) -6- (tert-butyl) -2-methoxy -3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1 H), 7.44 (s, 1 H), 6.86 (s, 1 H), 4.40 (q, J = 7, 3 Hz, 2 H), 4.19 - 4.12 (m, 2 H), 4.05 (s, 3 H), 3.90 (d, J = 6.6 Hz, 1 H), 3, 61 - 3.55 (m, 2 H), 3.42 (dd, J = 16.8, 7.0 Hz, 1 H), 3.37 (s, 3 H), 3.11 (d, J = 16.8 Hz, 1 H), 2.15 (quin, J = 6.2 Hz, 2 H), 1.40 (t, J = 7.0 Hz, 3 H), 0.86 (s, 9 H); LCMS (m / z, ES +) = 445.0 (M + 1).
[00243] [00243] A solution of the above ester in 1M LiOH (0.75 ml) and MeOH (0.75 ml) was heated to 50 ° C for 2 h. 1M citric acid (0.75 mL) was added to the reaction mixture, and the solution was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide acid ( S) -6- (tert-butyl) -2-methoxy-3- (3-
[00244] [00244] The demethylated product was formed as a by-product of the reaction that produced ethyl (S) -6- (tert-butyl) -2-methoxy-3- (3-methoxypropoxy) - 10-oxo-5,10-di- hydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate and was collected as mixed fractions that were combined and subjected to hydrolysis conditions without further purification. The solution of the ester in 1M LiOH (0.5 ml) and MeOH (0.5 ml) was heated to 50 ° C for 2 h. 1M citric acid (0.5 mL) was added to the reaction mixture, and the solution was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide (S) -6- (tert-butyl) -2-hydroxy-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylic (3.4 mg, 8% over 2 steps) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 15.76 (br. S., 1 H), 8.42 (s, 1 H), 7.47 (s, 1 H), 6.70 (s, 1 H), 4.20 (t, J = 6.1 Hz, 2 H), 4.04 (d, J = 6.3 Hz, 1 H), 3.61 - 3.76 (m, 2 H) , 3.48 (dd, J = 17.1, 6.8 Hz, 1 H), 3.41 (s, 3 H), 3.04 (d, J = 17.1 Hz, 1 H), 2 , 21 (quin, J = 6.0 Hz, 2 H), 0.89 (s, 9 H); LCMS (m / z, ES +) = 403.2 (M + 1).
[00245] [00245] A solution of ethyl (S) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylate (88.4 mg, 0.20 mmol), potassium isopropenyltrifluoroborate (58 mg, 0.39 mmol), sodium carbonate (63 mg, 0.59 mmol) and Pd (PPh3) 4 (23 mg, 0.020 mmol) in ethanol (2.0 ml) was stirred at 80 ° C overnight. The reaction mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was evaporated, and the residue was purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH) in hexanes) to provide ethyl (S) -6- (tert-butyl) -3- ( 3-methoxypropoxy) -10-oxo-2- (prop-1-en-2-yl) -5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9- carboxylate (87.5 mg, 98%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1 H), 7.54 (s, 1 H), 7.00 (s, 1 H), 5.91 (s, 1 H), 5.54 (s, 1 H), 4.39 (q, J = 7.0 Hz, 2 H), 4.07 - 4.22 (m, 2 H), 3.93 (d, J = 6 , 6 Hz, 1 H), 3.61 - 3.56 (m, 2 H), 3.48 (dd, J = 17.0, 6.8 Hz, 1 H), 3.37 (s, 3 H), 3.19 (d, J = 16.8 Hz, 1 H), 2.25 (s, 3 H), 2.13 (quin, J = 6.1 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H), 0.85 (s, 9 H); LCMS (m / z, ES +) = 455.9 (M + 1).
[00246] [00246] The title compound was isolated as a by-product by hydrolysis promoted by base during an oxidation reaction of ethyl (S) -6- (tert-butyl) -3- (3-methoxypropoxy) -10-oxo-2 - (prop-1-en-2-yl) -5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (30.3 mg, 0.067 mmol) with trimethylsulfoxonium iodide (31 mg, 0.14 mmol) and KOtBu (15 mg, 0.13 mmol) in DMSO (0.64 mL) and THF (0.27 mL). Purification of the reaction mixture by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) provided (S) -6- (tert-butyl) -3- acid (3 -methoxypropoxy) -10-oxo-2- (prop-1-en-2-yl) -6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (4.8 mg, 17%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 16.16 (s, 1 H), 8.47 (s, 1 H), 7.78 (s, 1 H), 7.04 (s, 1 H), 5.95 (s, 1 H), 5.59 (s, 1 H), 4.26 - 4.12 (m, 2 H), 4.07 (d, J = 6.8 Hz, 1 H) , 3.62 - 3.57 (m, 2 H), 3.53 (dd, J = 17.3, 7.1 Hz, 1 H), 3.38 (s, 3 H), 3.26 ( d, J = 17.1 Hz, 1 H), 2.26 (s, 3 H), 2.15 (quin, J = 6.0 Hz, 2 H), 0.87 (s, 9 H); LCMS (m / z, ES +) = 427.3 (M + 1). Example 22: (Compound 241) (S) -6- (tert-Butyl) -2-isopropyl-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1, 2-h] [1,7] naphthyridine-9-carboxylic
[00247] [00247] A solution of ethyl (S) -6- (tert-butyl) -3- (3-methoxypropoxy) - 10-oxo-2- (prop-1-en-2-yl) -5,10-di -hydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (11.9 mg, 0.026 mmol) and 10% Pd / C (catalytic) in MeOH (1 mL) was stirred under 4.22 kg / cm2 (60 psi) of H2 for 1.5 h. The reaction mixture was filtered through celite and evaporated to dryness to provide (S) -ethyl 6- (tert-butyl) -2-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate, which was used without further purification.
[00248] [00248] A solution of the above ester in 1M LiOH (0.7 ml) and MeOH (0.7 ml) was heated to 50 ° C for 2 h. 1M citric acid (0.8 ml) was added, and the reaction mixture was stirred for 15 min. The precipitate was collected by filtration, washed with water and dried to provide (S) -6- (tert-butyl) -2-isopropyl-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro acid -6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (9.3 mg, 83% over two steps) as a whitish solid. 1H NMR (400 MHz, CDCl3) δ ppm 16.26 (s, 1 H), 8.46 (s, 1 H), 7.83 (s, 1 H), 6.91 (s, 1 H), 4.08 - 4.21 (m, 2 H), 4.05 (d, J = 6.8 Hz, 1 H), 3.66 - 3.58 (m, 2 H), 3.41 - 3 , 55 (m, 2 H), 3.38 (s, 3 H), 3.22 (d, J = 17.1 Hz, 1 H), 2.14 (quin, J = 6.0 Hz, 2 H), 1.27 (d, J = 6.8 Hz, 6 H), 0.85 (s, 9 H); LCMS (m / z, ES +) = 429.3 (M + 1). Example 23: (Compound 243) (S) -6- (tert-Butyl) -2-chloro-3- (3-methoxypropoxy) -8-methyl-10-oxo-6,10-dihydro-5H- acid pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic Step 1: Ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate
[00249] [00249] A solution of ethyl 3-oxobutanoate (3.64 g, 28 mmol) in 20 mL of THF was added by syringe pump (dropwise) to a vessel containing NaH (60% dispersion in mineral oil) ( 1.176 g, 29.4 mmol) which was cooled to 0 ° C during the addition. The reaction mixture was stirred at RT for 1 h after the addition was completed, and then cooled again to 0 ° C. The solution of 3-chloroacryloyl chloride (3.50 g, 28 mmol) in 20 mL of THF was slowly added to the syringe-cooled reaction mixture over 1 h. After the addition was complete, the reaction mixture was stirred at RT overnight, and then heated under reflux for 2.5 h. The reaction mixture was diluted with water and extracted with Et2O (4x) and CH2Cl2 (2x). The combined organic extracts were dried (Na2SO4), filtered, evaporated and purified by chromatography on silica gel (0-100% EtOAc / hexanes) to provide ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate ( 2.65 g, 52%) as a brown liquid. 1H NMR (400 MHz, CDCl3) δ ppm 7.66 (d, J = 5.9 Hz, 1 H), 6.36 (d, J = 5.9 Hz, 1 H), 4.39 (q, J = 7.3 Hz, 2 H), 2.38 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H); LCMS (m / z, ES +) = 183.1 (M + 1). Step 2: (S) -Ethyl 1- (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) - 3,3-dimethylbutan-2-yl) -2-methyl -4-oxo-1,4-dihydropyridine-3-carboxylate
[00250] [00250] A solution of (S) -1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-amine, Hydrochloride (196 mg, 0.42 mmol) and ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate (0.23 g, 1.27 mmol) in HOAc (4.2 mL) was stirred at 100 ° C for 10 h . The reaction mixture was evaporated to dryness, taken up in CH2Cl2 and saturated NaHCO3 and stirred for 1 h. The organic layer was isolated
[00251] [00251] One vial containing ethyl (S) -1- (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-yl) - 2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (67.4 mg, 0.11 mmol), potassium acetate (22 mg, 0.23 mmol), and palladium bromide (II ) (6.1 mg, 0.023 mmol) was purged with nitrogen. Degassed DMF (1.1 ml) was added, and the reaction mixture was heated to 90 ° C for 24 h. The solution was cooled in RT, additional palladium (II) bromide (6.1 mg, 0.023 mmol) was added, and the reaction mixture was heated to 90 ° C for another 6 h. The solvent was removed by evaporation, and the residue was purified by chromatography on silica gel (0-100% 3: 1 (EtOAc / EtOH) in hexanes) to provide ethyl (S) -6- (tert-butyl) ) -2-chloro-3- (3-methoxypropoxy) -8-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (12.1 mg, 23%) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.48 (s, 1 H), 7.00 (s, 1 H), 4.34 - 4.45 (m, 3 H), 4.13 - 4 , 24 (m, 2 H), 3.65 - 3.58 (m, 2 H), 3.31 - 3.41 (m,
[00252] [00252] A solution of (S) -ethyl 6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -8-methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylate (12.1 mg, 0.026 mmol) in 1M LiOH (0.5 mL) and MeOH (0.5 mL) was heated to 50 ° C for 2 h, and then 60 ° C for 2 h. 1M citric acid (0.7 mL) was added to the reaction mixture. The solution was evaporated to dryness, and the residue was purified by reverse phase chromatography (5-90% CH3CN / H2O (0.1% formic acid)) to provide (S) -6- (tert-butyl acid) ) -2-chloro-3- (3-methoxypropoxy) -8-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (7.0 mg, 62%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 17.61 (br. S., 1 H), 7.82 (s, 1 H), 7.05 (s, 1 H), 4.81 (d, J = 5.4 Hz, 1 H), 4.15 - 4.28 (m, 2 H), 3.67 - 3.57 (m, 2 H), 3.49 - 3.41 (m, 1 H), 3.38 (s, 3 H), 3.25 (d, J = 17.6 Hz, 1 H), 3.18 (s, 3 H), 2.17 (quin, J = 6, 0 Hz, 2 H), 0.81 (s, 9 H); LCMS (m / z, ES +) = 435.2, 437.2 (M + 1). Example 24: (Compound 243) (S) -6- (tert-Butyl) -2- (hydroxymethyl) -3- (3-methoxypropoxy) -10-oxo- 5,10-dihydro-6H-pyrido [ 1,2-h] [1,7] naphthyridine-9-carboxylic
[00253] [00253] A solution of tert-butyl (S) - (1- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (2.18 g , 4.79 mmol), K2CO3 (1.99 g, 14.38 mmol), (bromomethyl) benzene (0.86 mL, 7.19 mmol) in DMF (32.0 mL) was heated to 80 ° C for 3 h. The reaction mixture was evaporated to dryness, and the residue was taken up in CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (2x), and the combined organic phases were dried (Na2SO4), filtered and evaporated to provide tert-butyl (S) - (1- (5- (benzyloxy) -6-chloro- 2- iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate (assumed quantity), which was taken to the next step without further purification. LCMS (m / z, ES +) = 545.4, 547.0 (M + 1). Step 2: Ethyl (S) -1- (1- (5- (benzyloxy) -6-chloro-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1, 4-dihydropyridine-3-carboxylate
[00254] [00254] HCl (4M in dioxane) (11.98 mL, 47.9 mmol) was added to a solution of tert-butyl (S) - (1- (5- (benzyloxy) -6-chloro-2-iodopyridine -3- yl) -3,3-dimethylbutan-2-yl) carbamate (2.61 g, 4.79 mmol) in CH2Cl2 (6 mL), and the reaction mixture was stirred at RT for 3 h. The mixture was evaporated to dryness, and the residue was taken up in saturated NaHCO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2x), and the combined organic phases were dried (Na 2SO4), filtered and evaporated to produce a brown oil.
[00255] [00255] A solution of the above amine and ethyl 4-oxo-4H-pyran-3-carboxylate (0.89 g, 5.27 mmol) in HOAc (24 mL) was stirred at 100 ° C for 7 h. The reaction mixture was evaporated, the residue was taken up in CH2Cl2 and saturated NaHCO3, and the solution was vigorously stirred for 30 min. The aqueous phase was extracted with CH2Cl2 (5 x 10 mL), and the combined organic phases were dried (Na2SO4), filtered, evaporated and purified by chromatography on silica gel (0-100% (3: 1 EtOAc: EtOH ) in hexanes) to provide ethyl (S) -1- (1- (5- (benzyloxy) -6-chloro-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo -1,4-dihydropyridine-3-carboxylate (1.39 g, 49%) as a brown solid. LCMS (m / z, ES +) = 596.1, 597.2 (M + 1). Step 3: Ethyl (S) -3- (benzyloxy) -6- (tert-butyl) -2-chloro-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1 , 7] naphthyridine-9-carboxylate
[00256] [00256] A vial containing ethyl (S) -1- (1- (5- (benzyloxy) -6-chloro-2-iodopyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo -1,4-dihydropyridine-3-carboxylate (1.39 g, 2.34 mmol), potassium acetate (460 mg, 4.68 mmol), and palladium (II) bromide (125 mg, 0, 47 mmol) was purged with nitrogen. Degassed DMF (23.4 ml) was added, and the reaction mixture was heated to 90 ° C for 24 h. The solvent was removed by evaporation, and the residue was dissolved in CH2Cl2, filtered through celite and purified by chromatography on silica gel (0-100% 3: 1
[00257] [00257] A solution of ethyl (S) -3- (benzyloxy) -6- (tert-butyl) -2-chloro-10-oxo-5,10-dihydro-6H-pyrido potassium salt [1 , 2-h] [1,7] naphthyridine-9-carboxylate (0.34 g, 0.74 mmol), trifluoro (vinyl) -1,4-borane (0.20 g, 1.48 mmol), sodium carbonate (0.24 g, 2.22 mmol) and Pd (PPh3) 4 (85 mg, 0.074 mmol) in EtOH (7.4 mL) was stirred at 80 ° C overnight. The reaction mixture was diluted with CH2Cl2, filtered through celite and evaporated. The residue was purified by chromatography on silica gel (0-100% 3: 1 (EtOAc / EtOH) in hexanes) to provide ethyl (S) -3- (benzyloxy) -6- (tert-butyl) -10- oxo-2-vinyl-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (251 mg, 74%) as a whitish foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (s, 1 H), 7.39 - 7.73 (m, 7 H), 7.00 (s, 1 H), 6.59 (d, J = 6.6 Hz, 1 H), 5.54 (d, J = 10.5 Hz, 1 H), 5.09 - 5.24 (m, 2 H), 4.40 (q, J = 7.0 Hz, 2 H), 3.90 - 4.01 (m, 1 H), 3.39 - 3.55 (m, 1 H), 3.13 - 3.24 (m, 1 H) , 1.41 (t, J = 7.0 Hz, 3 H), 0.84 (s., 9 H); LCMS (m / z, ES +) = 459.1, 460.4 (M + 1). Step 5: (S) -Ethyl 6- (tert-butyl) -3-hydroxy-2- (hydroxymethyl) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1 , 7] naphthyridine-9-carboxylate
[00258] [00258] To a solution of ethyl (S) -3- (benzyloxy) -6- (tert-butyl) -10-oxo- 2-vinyl-5,10-dihydro-6H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylate (251 mg, 0.55 mmol) in THF (5.5 mL) and water (1.4 mL) at 0 ° C was added osmate dihydrate potassium (20.2 mg, 0.055 mmol) followed by sodium periodate (468 mg, 2.19 mmol). After the addition was complete, the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with CH2Cl2 and water, stirred and filtered through celite. The combined organic phases were dried (Na2SO4), filtered, evaporated and purified by chromatography on silica gel (0-100% 3: 1 (EtOAc / EtOH) in CH2Cl2) to provide ethyl (S) -3- (benzyloxy) -6- (tert-butyl) -2-formyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (assumed amount) . LCMS (m / z, ES +) = 461.3 (M + 1).
[00259] [00259] A solution of the above aldehyde and 10% Pd / C (catalytic) in EtOH (20 mL) was stirred under 4.22 kg / cm2 (60 psi) of H2 overnight. The reaction mixture was filtered through celite and evaporated to provide ethyl (S) -6- (tert-butyl) -3-hydroxy-2- (hydroxymethyl) -10-oxo- 5,10-dihydro- 6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (122.1 mg, 60%), which was taken to the next step without purification. LCMS (m / z, ES +) = 373.3 (M + 1). Step 6: Ethyl (S) -6- (tert-butyl) -2- (hydroxymethyl) -3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylate
[00260] [00260] 1-Bromo-3-methoxypropane (44.3 µl, 0.39 mmol) was added to a solution of ethyl (S) -6- (tert-butyl) -3-hydroxy-2- (hydroxymethyl) ) - 10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (122.1 mg, 0.33 mmol) and potassium carbonate ( 136 mg, 0.98 mmol)
[00261] [00261] A solution of ethyl (S) -6- (tert-butyl) -2- (hydroxymethyl) -3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1 , 2-h] [1.7] naphthyridine-9-carboxylate (29 mg, 0.065 mmol) in 1M LiOH (0.65 ml) and MeOH (0.65 ml) was heated to 50 ° C for 2 h. 1M citric acid (1 ml) was added, and the reaction mixture was evaporated to dryness. The residue was purified by reverse phase chromatography (5-90% CH3CN / H2O (0.1% formic acid)) to provide (S) -6- (tert-butyl) -2- (hydroxymethyl) -3 acid - (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic (18.5 mg, 68%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 15.96 (s, 1 H), 8.49 (s, 1 H), 7.74 (s, 1 H), 7.02 (s, 1 H), 4.79 (d, J = 4.4 Hz, 2 H), 4.14 - 4.27 (m, 2 H), 4.10 (d, J = 6.3 Hz, 1 H), 3, 90 (t, J = 4.9 Hz, 1 H), 3.62 - 3.53 (m, 3 H), 3.37 (s, 3 H), 3.29 (d, J = 17.1 Hz, 1 H), 2.13 (quin, J = 5.9 Hz, 2 H), 0.86 (s, 9 H); LCMS (m / z, ES-) = 415.3 (M-1). Example 25: (Compound 244) (S) -6- (tert-Butyl) -2-cyclopropyl-11-hydroxy-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H- acid pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic Step 1: Ethyl 4- (benzyloxy) -2 - ((dimethylamino) methylene) -3-oxobutanoate
[00262] [00262] DMF-DMA (5.70 mL, 42.5 mmol) was added to a solution of ethyl 4- (benzyloxy) -3-oxobutanoate (6.70 g, 28.4 mmol) in toluene (30 mL), and the reaction mixture was stirred overnight and evaporated to dryness. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to provide ethyl 4- (benzyloxy) -2 - ((dimethylamino) methylene) -3-oxobutanoate (6.78 g, 82%) like a yellow oil. LCMS (m / z, ES +) = 292.6 (M + 1). Step 2: Ethyl 5- (benzyloxy) -4-oxo-4H-pyran-3-carboxylate
[00263] [00263] Ethyl formate (10.2 ml, 126 mmol) was slowly added to a suspension of potassium tert-butoxide (3.54 g, 31.6 mmol) in 24 ml of THF at 0 ° C. After the addition was completed, the reaction mixture was stirred for another 15 min at 0 ° C and a solution of ethyl 4- (benzyloxy) -2 - ((dimethylamino) methylene) -3-oxobutanoate (4.6 g, 15.8 mmol) in 24 mL of THF was added dropwise using an addition funnel. After the addition was complete, the reaction mixture was removed from the ice bath and stirred at RT overnight. 1 M HCl (50 ml) was added, and the solution was extracted with EtOAc (2x). The combined organic phases were dried (Na2SO4), filtered, evaporated and purified by chromatography on silica gel (0-100% EtOAc in hexanes) to provide ethyl 5- (benzyloxy) -4-oxo-4H-pyran-3- carboxylate (1.48 g, 34%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (s, 1 H), 7.55 (s, 1 H), 7.32 - 7.43 (m, 5 H), 5.12 (s, 2 H), 4.37 (q, J = 7.0 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H); LCMS (m / z, ES +) = 275.5 (M + 1). Step 3: (S) -Eeth 5- (benzyloxy) -1- (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2- il) -4-oxo-1,4-dihydropyridine-3-carboxylate
[00264] [00264] A solution of (S) -1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-amine, hydrochloride (0.402 g, 0.87 mmol) and ethyl 5- (benzyloxy) -4-oxo-4H-pyran-3-carboxylate (0.38 g, 1.37 mmol) in HOAc (8.7 mL) was stirred at 100 ° C for 10 h. The reaction mixture was evaporated to dryness, taken up in CH2Cl2 and saturated NaHCO3 and stirred for 1 h. The aqueous layer was extracted with CH2Cl2 and EtOAc (2x). The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was dissolved in EtOH (8 ml) and heated to 80 ° C overnight. The reaction mixture was evaporated to dryness, and the residue was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide ethyl (S) -5- (benzyloxy ) -1- (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1,4-di - hydropyridine-3-carboxylate (89.8 mg, 15%) as a brown solid. LCMS (m / z, ES +) = 683.7, 685.7 (M + 1). Step 4: (S) -Ethyl 11- (benzyloxy) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [ 1,2-h] [1,7] naphthyridine-9-carboxylate
[00265] [00265] A vial containing ethyl (S) -5- (benzyloxy) -1- (1- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -3,3-dimethylbutan -2-yl) -4-oxo-1,4-dihydropyridine-3-carboxylate (89.8 mg, 0.13 mmol), potassium acetate (26 mg, 0.26 mmol), and palladium bromide (II) (7.0 mg, 0.03 mmol) was purged with nitrogen. Degassed DMF (1.3 ml) was added, and the reaction mixture was heated to 90 ° C for 24 h. The reaction mixture was filtered through celite, the solvent was removed by evaporation, and the residue was purified by chromatography on silica gel (0-100% 3: 1 (EtOAc / EtOH) in hexanes) to provide ethyl (S) -11- (benzyloxy) -6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylate (47.9 mg, 66%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1 H), 7.73 (d, J = 6.2 Hz, 2 H), 7.28 - 7.36 (m, 3 H) , 6.94 (s, 1 H), 5.26 (br., 2 H), 4.35 (q, J = 6.4 Hz, 2 H), 4.21 - 4.10 (m , 2 H), 3.82 - 3.92 (m, 1 H), 3.56 - 3.67 (m, 2 H), 3.46 - 3.37 (m, 1 H), 3.39 (s, 3 H), 2.98 (d, J = 16.0 Hz, 1 H), 2.13 (quin, J = 5.9 Hz, 2 H), 1.40 - 1.31 (m , 3 H), 0.71 (s, 9 H); LCMS (m / z, ES +) = 555.4, 557.3 (M + 1). Step 5: (S) -Ethyl 11- (benzyloxy) -6- (tert-butyl) -2-cyclopropyl-3- (3-
[00266] [00266] A solution of ethyl (S) -11- (benzyloxy) -6- (tert-butyl) -2-chloro- 3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H -pyrido [1,2- h] [1,7] naphthyridine-9-carboxylate (47.9 mg, 0.086 mmol), Pd (PPh3) 4 (20 mg, 0.017 mmol), potassium carbonate (36 mg, 0 , 26 mmol) and cyclopropylboronic acid (15 mg, 0.17 mmol) in 1,4-dioxane (0.9 mL) was heated at 100 ° C for 2 days. The reaction mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was evaporated, and the residue was purified by reverse phase chromatography (5-100% CH3CN / H2O (0.1% formic acid)) to provide (S) -ethyl 11- (benzyloxy) -6- ( tert-butyl) -2-cyclopropyl-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate ( 14.7 mg, 30%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1 H), 7.66 (d, J = 7.0 Hz, 2 H), 7.27 - 7.20 (m, 3 H) , 6.82 (s, 1 H), 5.45 (d, J = 10.9 Hz, 1 H), 5.21 (d, J = 10.9 Hz, 1 H), 4.46 - 4 , 38 (m, 2 H), 4.04 - 4.20 (m, 2 H), 3.89 (d, J = 5.5 Hz, 1 H), 3.65 - 3.56 (m, 2 H), 3.38 (s, 3 H), 3.30 (dd, J = 16.0, 6.2 Hz, 1 H), 3.03 (d, J = 16.0 Hz, 1 H ), 2.39 - 2.49 (m, 1 H), 2.13 (quin, J = 6.1 Hz, 2 H), 1.42 (t, J = 7.2 Hz, 3 H), 1.07 - 1.15 (m, 1 H), 0.96 - 1.04 (m, 1 H), 0.88 - 0.96 (m, 1 H), 0.80 - 0.86 ( m, 1 H), 0.77 (s, 9 H); LCMS (m / z, ES +) = 561.8 (M + 1). Step 6: (S) -6- (tert-Butyl) -2-cyclopropyl-11-hydroxy-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1, 2-h] [1,7] naphthyridine-9-carboxylic
[00267] [00267] A solution of ethyl (S) -11- (benzyloxy) -6- (tert-butyl) -2-cyclopropyl-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H -pyrido [1,2- h] [1,7] naphthyridine-9-carboxylate (14.7 mg, 0.026 mmol) and 10% Pd / C (catalytic) in MeOH (5 mL) was stirred under 1 atm of H2 for 1.5 h.
[00268] [00268] To a solution of methyl 5-hydroxynicotinate (100 g, 0.65 mol) in DMF (1000 mL), NCS (130.5 g, 0.97 mol) was added, and the reaction mixture was heated to 80 ° C for 16 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was taken up in EtOAc (2L) and washed with saturated sodium chloride solution (500 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on 230-400 silica gel using 0-30% ethyl acetate in petroleum ether as an eluent. The fractions were collected and concentrated to provide the title compound as yellow oil (60 g, 49% yield), LCMS (ESI) m / z 187.9 (M + 1). Step 2: 2-Chlorine-5- (hydroxymethyl) pyridin-3-ol
[00269] [00269] A solution of methyl 6-chloro-5-hydroxynicotinate (60 g, 0.32 mol) in THF (600 ml) was added dropwise to lithium aluminum hydride (160 ml, 0.32 mol, 2 , 0 M in THF) at -50 ° C under nitrogen atmosphere. The reaction mixture was stirred at -25 ° C for 2 h. EtOAc (1000 ml), water (50 ml) and aq. (500 ml) were added dropwise to the reaction mixture at -25 ° C. The mixture was filtered through a pad of celite, washed with
[00270] [00270] To a solution of 2-chloro-5- (hydroxymethyl) pyridin-3-ol (3.5 g, 22.01 mmol) in THF (35 mL), water (35 mL), K2CO3 (6.1 g, 44.24 mmol) and iodine (5.84 g, 23.11 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 ° C and quenched with aq. (50 mL). Ethyl acetate (150 mL) was added to it, the organic layer was separated and discarded. The aqueous layer was acidified with aq. At 1.5N until pH = 6 and extracted with ethyl acetate (150 mL). The organic layer was separated, washed with water (25 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the title compound as a whitish solid (4 g, 64.5% yield). LCMS (ESI) m / z: 283.7 (M-H). Step 4: (6-Chlorine-2-iodo-5-methoxypyridin-3-yl) methanol
[00271] [00271] To a solution of 2-chloro-5- (hydroxymethyl) -6-iodopyridin-3-ol (4 g, 14.03 mmol) in acetonitrile (50 mL), K2CO3 (3.87 g, 28.06 mmol) and methyl iodide (MeI) (5.97 g, 42.10 mmol) were added, and the reaction mixture was heated at 80 ° C for 2 h in a sealed tube. The reaction mixture was quenched with water (100 ml), acidified with 1.5N HCl (pH = 6) and extracted with ethyl acetate (150 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated
[00272] [00272] To a solution of (6-chloro-2-iodo-5-methoxypyridin-3-yl) methanol (2.2 g, 7.35 mmol) in DCM (20 mL) was added CBr4 (3.6 g , 11.35 mmol) and PPh3 (2.3 g, 8.82 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure to acquire the crude product. This was purified by column chromatography on 60-120 mesh silica gel using 0-20% EtOAc in petroleum ether as an eluent. The fractions were collected and concentrated to provide the title compound as an off-white solid (2.4 g, 92% yield). LCMS (ESI) m / z: 363.6 (M + H). Step 6: Ethyl 2 - (((6-chloro-2-iodo-5-methoxypyridin-3-yl) methyl) -2,3-dimethylbutanoate
[00273] [00273] To a solution of diisopropylamine (2.43 mL, 17.38 mmol) in dry THF (20 mL) was added n-BuLi (10.86 mL, 17.38 mmol, 1.6M in Hexane) dropwise drop at -78 ° C. The reaction mixture was stirred at the same temperature for 30 min. Ethyl 2,3-dimethylbutanoate (2.3 g, 16.57 mmol) in THF (20 mL) was added to the reaction mixture, and the reaction mixture was stirred at -78 ° C for 1 h. 3- (bromomethyl) -6-chloro-2-iodo-5-methoxypyridine (3 g, 8.28 mmol) in THF (20 mL) was added
[00274] [00274] To a solution of ethyl 2 - ((6-chloro-2-iodo-5-methoxypyridin-3-yl) methyl) -2,3-dimethylbutanoate (3 g, 7.05 mmol) in DMSO (9 mL ), 5M NaOH solution (21.6 mL, 98.11 mmol) was added, and the reaction mixture was stirred at 120 ° C for 6 h. The reaction mixture was cooled to 0 ° C, acidified with HCl concentrate until pH = 1. After diluting with water (50 mL), it was extracted with EtOAc (2X100 L). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to acquire the crude product. The crude product was purified by column chromatography on 230-400 silica gel using 0-10% MeOH in DCM to provide 2 - ((6-chloro-2-iodo-5-methoxypyridin-3-yl) acid methyl) -2,3-dimethylbutanoic (500 mg, 18% yield) (LCMS (ESI) m / z: 397.8 (M + 1)). Step 8: 1- (6-Chloro-2-iodo-5-methoxypyridin-3-yl) -2,3-dimethylbutan-2-
[00275] [00275] To a solution of 2 - ((6-chloro-2-iodo-5-methoxypyridin-3-yl) methyl) -2,3-dimethylbutanoic acid (1 g, 2.5 mmol) in toluene (30 mL ), triethylamine (0.57 g, 5.5 mmol) and diphenyl phosphoryl azide (1.52 g, 5.5 mmol) were added, and the reaction mixture was stirred at 80 ° C for 2 h. The reaction mixture was cooled to room temperature and concentrated HCl (8.4 ml) was added to the reaction mixture dropwise over 30 min at 0 ° C. The reaction mixture was stirred at 60 ° C for 2 h. The reaction mixture was cooled to 0 ° C and basified with 1N aqueous NaOH solution until pH = 10. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2X50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated to acquire a brown gummy solid. This was purified by column chromatography on 230-400 silica using 0-3% MeOH in DCM to provide the title compound as a yellow oil (800 mg, 87% yield). LCMS (ESI) m / z: 368.8 (M + 1). Step 9: Ethyl 1- (1- (6-chloro-2-iodo-5-methoxypyridin-3-yl) -2,3-dimethylbutan-2-yl) -4-oxo-1,4-dihydropyridine- 3-carboxylate
[00276] [00276] To a solution of 1- (6-chloro-2-iodo-5-methoxypyridin-3-yl) -2,3-dimethylbutan-2-amine (800 mg, 2.17 mmol) in acetic acid (25 ml), ethyl 4-oxo-4H-pyran-3-carboxylate (0.547 g, 3.2 mmol) was added, and the reaction mixture was stirred at 100 ° C for 8 h. The reaction mixture
[00277] [00277] To a solution of ethyl 1- (1- (6-chloro-2-iodo-5-methoxypyridin-3-yl) -2,3-dimethylbutan-2-yl) -4-oxo-1,4- dihydropyridine-3-carboxylate (300 mg, 0.57 mmol) in N, N-Dimethylformamide (7.5 mL) potassium acetate (283 mg, 2.89 mmol) was added. The reaction mixture was degassed with nitrogen for 20 minutes. Palladium (II) bromide (30 mg, 0.11 mmol) was added to the reaction mixture and stirred at 90 ° C for 16 h. The reaction mixture was cooled to room temperature, filtered through celite and washed with DCM. The solvents were removed under reduced pressure, and the crude was purified by column chromatography on 230-400 silica gel using 0-10% MeOH in DCM as an eluent. Fractions were collected and concentrated to provide the title compound (150 mg, 68% yield) as a brown solid. LCMS (ESI) m / z: 390.9 (M + 1). Step 11: 2-Chloro-3-hydroxy-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9 acid -carboxylic
[00278] [00278] To a solution of ethyl 2-chloro-6-isopropyl-3-methoxy-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7 ] naphthyridine-9-carboxylate (150 mg, 0.38 mmol) in 1,2-Dichloroethane (DCE) (6.45 mL), BBr3 (288 mg, 1.15 mmol) was added, and the reaction mixture was stirred at 70 ° C for 16 h. The reaction mixture was cooled to -10 ° C, methanol (15 ml) was added to the reaction mixture dropwise, and then stirred at room temperature for 30 minutes. The reaction mixture was concentrated to acquire the crude compound (150 mg) as a brown solid. LCMS (ESI) m / z: 348.9 (M + 1). This raw product was taken to the next stage. Step 12: Methyl-2-chloro-3- (cyclopropylmethoxy) -6-isopropyl-6-methyl-10-oxo- 5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate-Isomer-1 and Methyl -2-chloro-3- (cyclopropylmethoxy) -6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylate-Isomer-2 Isomer 1 Isomer 2
[00279] [00279] To a solution of 2-chloro-3-hydroxy-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7 ] naphthyridine-9-carboxylic (150 mg, 0.43 mmol) in DMF (2 mL), K2CO3 (594 mg, 4.3 mmol) and (bromomethyl) cyclopropane (464 mg, 3.44 mmol) were added, and the reaction mixture was stirred at 80 ° C for 5 h. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was stirred with MeOH (10 ml) at room temperature for 30 min. The solvent was removed under reduced pressure and diluted with DCM (20 ml). The organic layer was washed with water (15 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to acquire the compound as an isomer mixture that was separated by supercritical liquid chromatography.
[00280] [00280] To a solution of methyl-2-chloro-3- (cyclopropylmethoxy) -6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [ 1.7] naphthyridine-9-carboxylate-Isomer-1 (50 mg, 0.11 mmol) in Methanol (2 ml) and H2O (0.5 ml), lithium hydroxide (25 mg, 0.59 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure, and the residue was taken up in water (3 ml) and acidified with 1.5 N HCl to pH ~ 3. The obtained solid was filtered, washed with water (5 ml) ), dried under vacuum and purified by prep. to purchase the title compound (15 mg, yield 31.2%) as an off-white solid. LCMS (ESI) m / z: 403.1 (M + 1). 1H NMR; 400 MHz, DMSO-d6: δ ppm 8.57 (s, 1 H), 7.72 (s, 1 H), 7.39 (s, 1 H), 4.10 - 4.07 (m, 2 H), 3.36 - 3.35 (m, 2 H), 1.91 -
[00281] [00281] To a solution of methyl 2-chloro-3- (cyclopropylmethoxy) -6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1 , 7] naphthyridine-9-carboxylate-Isomer-2 (50 mg, 0.11 mmol) in Methanol (2 ml) and H2O (0.5 ml), lithium hydroxide (25 mg, 0.59 mol) was added , and the reaction mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure, and the residue was taken up in water (3 ml) and acidified with 1.5 N HCl to pH ~ 3. The obtained solid was filtered, washed with water (5 ml) ) and dried under vacuum for 16 h to acquire the title compound as an off-white solid (30 g, 62% yield). LCMS (ESI) m / z: 402.9 (M + 1). 1H NMR; 400 MHz, DMSO-d6: δ ppm 8.57 (s, 1 H), 7.71 (s, 1 H), 7.39 (s, 1 H), 4.09 - 4.08 (m, 2 H), 3.39 - 3.38 (m, 2 H), 1.90 - 1.87 (m, 1 H), 1.70 (s, 3 H), 1.32 - 1.28 (m , 1 H), 1.11 - 1.07 (m, 3 H), 0.83 - 0.81 (m, 5 H), 0.63 - 0.62 (m, 2H). Example 28: (Compound 247) 2-Cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic-isomer-1 isomer 1
[00282] [00282] To a stirred solution of methyl 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2- h ] [1,7] naphthyridine-9-carboxylate (570 mg, 1.311 mmol) in 1,4-Dioxane (11.4 mL), potassium carbonate (362 mg, 2.62 mmol) was added and purged with Nitrogen for 5 min Cyclopropylboronic acid (225 mg, 2.62 mmol) was added followed by Pd (PPh3) 4 (303 mg, 0.262 mmol) and purged with nitrogen for 5 min. The reaction mixture was heated to 100 ° C in a sealed tube for 16 h. The reaction mixture was concentrated completely under reduced pressure, and the residue was diluted with DCM (100 ml) and washed with water (40 ml), brine (40 ml). The organic layer was separated, dried over sodium sulfate and concentrated, and the crude was purified by chromatography on Isolera ™ silica and eluted with 3% MeOH in DCM. The collected fractions were completely concentrated to acquire the compound as a mixture of isomers. Then, the compound was purified by preparative HPLC followed by chiral SFC. The fractions collected from Isomer-1 (first elution peak) and Isomer-2 (second elution peak) were concentrated separately under reduced pressure to acquire methyl-2-cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate-Isomer-1 (60 mg, 10.3% yield ) as colorless oil and methyl-2-cyclopropyl-6-isopropyl- 3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-
[00283] [00283] To a solution of methyl-2-cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2- h ] [1,7] naphthyridine-9-carboxylate, Isomer-1 (60 mg, 0.136 mmol) in methanol (2.4 mL) were added LiOH (16.31 mg, 0.681 mmol) and water (0.60 ml) at room temperature, and the reaction mixture was stirred at rt for 2 h. The solvents in the reaction mixture were removed under reduced pressure, and the residue was dissolved in water (2 ml). This solution was acidified with 1.5N HCl to pH 6 at 0 ° C. The obtained solid was filtered, washed with water and n-pentane and dried to acquire the title compound as a pale brown solid (15 mg, 25.3%). LCMS (ESI) m / z: 427.2 (M + 1). 1H NMR (400MHz, DMSO-d6): δ ppm 8.54 (s, 1 H), 7.44 (s, 2 H), 4.19 - 4.18 (m, 2 H), 3.53 ( t, J = 6 Hz, 2 H), 3.29 - 3.27 (m, 5 H), 2.05 (t, J = 6 Hz, 2 H), 1.84 -1.82 (m, 1H), 1.68 (s, 3 H), 1.03 - 1.01 (m, 4 H), 0.82 (d, J = 6.5 Hz 3 H), 0.61 (d, J = 6.6Hz, 3H) Step 2A: 2-Cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylic- Isomer-2 Isomer 2
[00284] [00284] To a solution of methyl-2-cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2- h ] [1.7] naphthyridine-9-carboxylate-Isomer-2 (90 mg, 0.204 mmol) in Methanol (3.6 mL) were added LiOH (24.46 mg, 1.021 mmol) and Water (0.90 ml) at room temperature, and the reaction mixture was stirred at rt for 2 h.
[00285] [00285] One flask was loaded with a stir bar, xanthphos (0.225 g, 0.388 mmol), tris (dibenzylidenoacetone) dipaladium (0) (0.198 g, 0.216 mmol), and sodium tert-butoxide (2.43 g, 25.3 mmol). The flask was purged with a stream of nitrogen before a solution of 5-bromo-2-chloro-3-methoxypyridine (3.2 g, 14.4 mmol) and 3,3-dimethylbutan-2-one (2 , 16 ml, 17.3 mmol) in tetrahydrofuran (THF) (50 ml) is added. The mixture was heated to reflux overnight. The mixture was allowed to cool to room temperature and diluted with water. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to produce 1- (6-chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-one (3.07 g , 12.7 mmol, 88% yield). 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 7.74 (d, J = 1.56 Hz, 1 H), 7.10 (d, J = 1.56 Hz, 1 H), 3.89 ( s, 3 H), 3.77 (s, 2 H), 1.20 (s, 9 H). Step 2: 1- (6-Chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-amine
[00286] [00286] A mixture of 1- (6-chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan-2-one (3.07 g, 12.7 mmol) and ammonium acetate (14.7 g, 191 mmol) in methanol (50 mL) were stirred for 1 hour at room temperature before sodium cyanoborohydride (2.00 g, 31.8 mmol) was added in portions.
[00287] [00287] Boron tribromide (2.82 mL, 29.9 mmol) was added dropwise to a solution of 1- (6-chloro-5-methoxypyridin-3-yl) -3,3-dimethylbutan- 2-amine (1.45 g, 5.97 mmol) in 1,2-dichloroethane (DCE) (30 ml) at 0 ° C. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS showed significant conversion to the desired product, but starting material was still present. The solids that formed during the night were broken, and the mixture stirred for an additional 24 hours at room temperature. The mixture was cooled to 0 ° C and quenched with careful dropwise addition of methanol. After excess BBr3 completely extinguished, additional methanol (100 mL) was added. The mixture was stirred for 1 hour and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 0% to 100% gradient). The fractions were lyophilized to produce 5- (2-amino-3,3-dimethylbutyl) -2-chloropyridin-3-ol (1.33 g, 5.81 mmol, 97% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (s, 1 H), 7.83 - 8.16 (m, 2 H), 7.74 (d, J = 1.95 Hz, 1 H), 7.21 (d, J = 1.56 Hz, 1 H), 2.82 - 3.02 (m, 2 H), 2.35 - 2.43 (m, 1 H), 0, 94 (s, 9 H). LCMS (ES +) (m / z): 229, 231 (M + 1). Step 4: tert-Butyl (1- (6-chloro-5-hydroxypyridin-3-yl) -3,3-dimethylbutan-2-yl) carbamate
[00288] [00288] di-tert-Butyl dicarbonate (1.52 g, 6.98 mmol) was added to a stirring mixture of 5- (2-amino-3,3-dimethylbutyl) -2-chloropyridin-3-ol ( 1.33 g, 5.81 mmol) and triethylamine (2.43 mL, 17.4 mmol) in N, N-dimethylformamide (DMF) (30 mL). The mixture was stirred at room temperature for 1 hour. LC-MS showed minimal conversion
[00289] [00289] Under nitrogen, a solution of N-bromosuccinimide (471 mg, 2.65 mmol) in 2 mL of DMF was added slowly dropwise to a 0 ° C solution of tert-butyl (1- (6 -chloro-5-hydroxypyridin-3-yl) - 3,3-dimethylbutan-2-yl) carbamate (791 mg, 2.405 mmol) in N, N-dimethylformamide (DMF) (25 mL), and the mixture stirred in a reaction strip that was protected from light by aluminum foil. The cold bath was maintained between -25 ° C and -20 ° C for 30 minutes. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid).
[00290] [00290] (Bromomethyl) cyclopropane (0.221 mL, 2.38 mmol) was added to a stirring mixture of tert-butyl (1- (2-bromo-6-chloro-5-hydroxypyridin-3-yl) - 3,3-dimethylbutan-2-yl) carbamate (485 mg, 1.19 mmol) and potassium carbonate (658 mg, 4.76 mmol) in N, N-dimethylformamide (DMF) (5 ml). The mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate and concentrated to produce tert-butyl (1- (2-bromo-6-chloro-5- (cyclopropylmethoxy ) pyridin-3-yl) -3,3-dimethylbutan-2-yl) crude carbamate. The intermediate was dissolved in dichloromethane (DCM) (5.00 ml) before hydrogen chloride (4M in dioxane) (5 ml, 20 mmol) was added. The mixture was stirred for 4 hours and concentrated to produce a white solid. Saturated sodium bicarbonate was added, and the mixture extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to produce 1- (2-bromo-6-chloro-5-
[00291] [00291] 1- (2-Bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) -3,3-dimethylbutan-2-amine (375 mg, 1.04 mmol) and ethyl 4-oxo- 4H-pyran-3-carboxylate (174 mg, 1.04 mmol) in acetic acid (10 mL) was stirred at 100 ° C for 4 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 0% to 100% gradient). The fractions were concentrated, and the lyophilized residue (water / acetonitrile) to produce ethyl 1- (1- (2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) -3,3-dimethylbutan-2 -yl) -4-oxo-1,4-dihydropyridine-3-carboxylate (420 mg, 0.821 mmol, 79% yield) as a white powder. LCMS (ES +) (m / z): 511, 513, 515 (M + 1). Step 8: Ethyl 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine -9-carboxylate
[00292] [00292] A reaction flask containing a stir bar, ethyl 1- (1- (2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) -3,3-dimethylbutan-2-yl) -4-oxo-1,4-dihydropyridine-3-carboxylate (395 mg, 0.772 mmol), potassium acetate (151 mg, 1.543 mmol), and chlorine [(tri-tert-butylphosphine) -2- (2 -aminobiphenyl)] palladium (II) (79 mg, 0.15 mmol) was purged with nitrogen for 15 minutes.
[00293] [00293] A solution of lithium hydroxide monohydrate (1.6 mg, 0.039 mmol) in water (1 mL) was added to a solution of ethyl 6- (tert-butyl) -2-chloro-3- ( cyclopropylmethoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (2.0 mg, 3.9 µmol) in methanol (1 ml), and the mixture heated to 60 ° C for 3 hours.
[00294] [00294] Ethyl 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine Racemic-9-carboxylate (153 mg) was purified by chiral chromatography using the following conditions: Column = Chiralpak IC, 10 mm x 250 mm (5u); Mobile phase = 95: 5 MeCN / H2O + 0.1% formic acid; Flow rate = 10 mL / min: Injection volume = 300 uL (18 mg / mL conc.); Collection wave length: 254 nm. The fractions were concentrated to produce ethyl 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylate (isomer 1) (48 mg). LCMS (ES +) (m / z): 431, 433 (M + 1). Step 2: 6- (tert-Butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine acid -9-carboxylic (isomer 1) Isomer 1
[00295] [00295] A solution of lithium hydroxide monohydrate (38.8 mg, 0.925 mmol) in water (2 mL) was added to a solution of ethyl 6- (tert-butyl) -2-chloro-3- ( cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (isomer 1) (48 mg, 0.092 mmol) in methanol (2 ml), and the mixture heated to 60 ° C for 3 hours. The mixture was cooled to room temperature and acidified with 3 ml of 1M hydrochloric acid. The solids were collected by filtration. The filtrate was injected into a medium pressure reverse phase column. The collected solid was dissolved in DMF and injected into the reverse phase column. The column was eluted (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were lyophilized to produce 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [ 1.7] naphthyridine-9-carboxylic (isomer
[00296] [00296] Ethyl 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine Racemic-9-carboxylate (153 mg) was purified by chiral chromatography using the following conditions: Column = Chiralpak IC, 10 mm x 250 mm (5u); Mobile phase = 95: 5 MeCN / H2O + 0.1% formic acid; Flow rate = 10 mL / min: Injection volume = 300 uL (18 mg / mL conc.); Collection wave length: 254 nm. The fractions were concentrated to produce ethyl 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylate (isomer 2) (46 mg). LCMS (ES +) (m / z): 431, 433 (M + 1).
[00297] [00297] A solution of lithium hydroxide monohydrate (37.2 mg, 0.886 mmol) in water (2 mL) was added to a solution of ethyl 6- (tert-butyl) -2-chloro-3- ( cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylate (isomer 2) (46 mg, 0.089 mmol) in methanol (2 ml), and the mixture heated to 60 ° C for 3 hours. The mixture was allowed to cool to room temperature and was acidified with 3 ml of 1M hydrochloric acid. The solids were collected by filtration. The filtrate was injected into a medium pressure reverse phase column. The collected solid was dissolved in DMF and in the same way injected into the reverse phase column. The column was eluted (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were lyophilized to produce 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylic (isomer 2) (34 mg, 0.084 mmol, 95% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (s, 1 H), 7.67 (s, 1 H), 7.25 (s, 1 H), 4.63 (d, J = 6.64 Hz, 1 H), 3.96 - 4.11 (m, 2 H), 3.33 - 3.54 (m, 2 H), 1.19 - 1.33 (m, 1 H) , 0.70 (s, 9 H), 0.56 - 0.62 (m, 2 H), 0.30 - 0.42 (m, 2 H). LCMS (ES +) (m / z): 403, 405 (M + 1). Scheme 12 - Preparation of YYYY Type Compounds (for example, Compounds 250, 251, 255 and 256)
[00298] [00298] 6-Bromo-5-methylpyridin-3-ol (10.4 g, 55.3 mmol) and NCS (8.12 g, 60.8 mmol) in N, N-dimethylformamide (DMF) (150 mL ) were heated to 80 ° C for 2 hours. The mixture was allowed to cool to room temperature, quenched with brine and extracted 3 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica eluting with a gradient of 0% to 50% ethyl acetate in hexanes. The fractions were concentrated to produce 6-bromo-2-chloro-5-methylpyridin-3-ol (7.85 g, 35.3 mmol, 63.8% yield) as a white powder. LCMS (ES +) (m / z): 222, 224, 226 (M + 1). Step 2: 2-Bromo-6-chloro-5- (cyclopropylmethoxy) -3-methylpyridine
[00299] [00299] 6-Bromo-2-chloro-5-methylpyridin-3-ol (1.1 g, 4.9 mmol), potassium carbonate (2.73 g, 19.8 mmol) and (bromomethyl) cyclopropane (1.01 ml, 10.4 mmol) in N, N-dimethylformamide (DMF) (10 ml) were stirred at room temperature overnight. The mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate and concentrated to produce 2-bromo-6-chloro-5- (cyclopropylmethoxy) -3-methylpyridine (1 , 18 g, 4.27 mmol, 86% yield) as a white solid. LCMS (ES +) (m / z): 276, 278, 280 (M + 1). Step 3: 2-Bromo-3- (bromomethyl) -6-chloro-5- (cyclopropylmethoxy) pyridine
[00300] [00300] N-Bromosuccinimide (0.801 g, 4.50 mmol) and AIBN (0.049 g, 0.30 mmol) were added to a stirring solution of 2-bromo-6-chloro-5- (cyclopropylmethoxy) -3- methylpyridine (1.0 g, 3.0 mmol) in carbon tetrachloride (15 mL). The mixture was heated to 85 ° C for 5 hours. Additional AIBN (0.049 g, 0.300 mmol) was added, and the mixture allowed to warm up overnight. The mixture was allowed to cool to room temperature, and the solids were collected by filtration. The filtrate was extinguished with water and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried
[00301] [00301] n-Butyllithium (2.5 M in hexanes) (1.04 mL, 2.59 mmol) was added dropwise to a -78 ° C solution of diisopropylamine (0.369 mL, 2.59 mmol) in tetrahydrofuran (THF) (10 ml). The mixture was allowed to warm to room temperature and stirred for 15 minutes. The mixture was cooled to -78 ° C before ethyl cyclobutanocarbonoxylate (0.317 ml, 2.46 mmol) was added dropwise. The mixture was heated to 0 ° C and stirred for 15 minutes. The solution of 2-bromo- 3- (bromomethyl) -6-chloro-5- (cyclopropylmethoxy) pyridine (730 mg, 1.23 mmol) in tetrahydrofuran (THF) (3.33 mL) was added dropwise . The mixture was stirred for an additional 10 minutes at 0 ° C, and then quenched with saturated ammonium chloride. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The fractions were concentrated to produce ethyl 1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-
[00302] [00302] A solution of lithium hydroxide monohydrate (365 mg, 8.69 mmol) in water (3 mL) was added to a solution of ethyl 1 - (((2-bromo-6-chloro-5- ( cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutane-1-carboxylate (350 mg, 0.869 mmol) in 1,4-dioxane (5 ml), and the mixture heated at 60 ° C for 4 hours. The mixture was allowed to cool to room temperature, quenched with saturated ammonium chloride and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to produce 1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutane-1- acid carboxylic acid (325 mg, 0.867 mmol, quantitative) as a white solid. LCMS (ES +) (m / z): 374, 376, 378 (M + 1). Step 6: 1 - (((2-Bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutanamine and 5 - ((1-aminocyclobutyl) methyl) -6-bromo-2-chloropyridin-3 -ol
[00303] [00303] Diphenyl phosphorazidate (0.394 mL, 1.83 mmol) was added dropwise to a stirring mixture at 0 ° C of 1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3 acid) -yl) methyl) cyclobutane-1-carboxylic (311 mg, 0.830 mmol) and triethylamine (0.255 mL, 1.83 mmol) in toluene (10 mL). The mixture was allowed to warm to room temperature and stirred for 15 minutes before being heated to 80 ° C for 1 hour. LC-MS showed clean conversion to 2-bromo-6-chloro-5- (cyclopropylmethoxy) -3 - ((1-isocyanatocyclobutyl) methyl) pyridine. The mixture was allowed to cool to room temperature before 5N hydrogen chloride (5 mL, 25 mmol) and 1,4-dioxane (10 mL) were added. The mixture was heated to 80 ° C with vigorous stirring for 3 hours. The mixture was concentrated, and the residue purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). Two sets of fractions were concentrated separately to produce the following products: 5 - ((1-aminocyclobutyl) methyl) -6-bromo-2-chloropyridin-3-ol (170 mg, 0.583 mmol, 70.2% income). LCMS (ES +) (m / z): 291, 293, 295 (M + 1) 1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutan-1-amine (50 mg, 0.145 mmol, 17.43% yield). LCMS (ES +) (m / z): 345, 347, 349 (M + 1). Step 7: Ethyl 4-oxo-4H-pyran-3-carboxylate
[00304] [00304] Ethyl formate (23.6 ml, 292 mmol) was slowly added to a suspension of KOtBu (6.06 g, 54.0 mmol) in 50 ml of THF at 0 ° C. The reaction mixture is stirred for 15 min at 0 ° C and a pre-cooled (0 ° C) solution of ethyl 2 - ((dimethylamino) methylene) -3-oxobutanoate (5 g, 27.0 mmol) in 45 mL of THF was added by cannula transfer. After the addition was complete, the solution was removed from the cooling bath, stirred at rt overnight, and quenched by the addition of 1M aqueous HCl (80 ml). The mixture was extracted with EtOAc (3 x 25 ml) and CH2Cl2 (5 x 25 ml). The organic layers were grouped, dried (Na2SO4), filtered, evaporated and purified by chromatography on silica gel (0-100% EtO-
[00305] [00305] 5 - ((1-Aminocyclobutyl) methyl) -6-bromo-2-chloropyridin-3-ol (170 mg, 0.583 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate (98 mg, 0 , 58 mmol) in acetic acid (5 mL) were stirred at 100 ° C for 4 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was diluted with toluene, and the mixture concentrated to remove the remaining acetic acid. The residue was dissolved in N, N-dimethylformamide (DMF) (2 ml) before potassium carbonate (322 mg, 2.33 mmol) and (bromomethyl) cyclopropane (0.113 ml, 1.17 mmol) were added. The mixture was stirred at room temperature for 6 hours to produce a crude mixture of ethyl 1- (1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutyl) - 4-oxo- 1,4-dihydropyridine-3-carboxylate in DMF. In a separate reaction flask, 1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutan-1-amine (50 mg, 0.145 mmol) and ethyl 4-oxo- 4H-pyran-3-carboxylate (24.3 mg, 0.145 mmol) in acetic acid (1 ml) was stirred at 100 ° C overnight. The mixture was allowed to cool to room temperature, and then combined with the previous raw mixture of ethyl 1- (1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutyl) -4-oxo-1,4-dihydropyridine-3-carboxylate in DMF
[00306] [00306] A reaction flask containing a stir bar, ethyl 1- (1 - ((2-bromo-6-chloro-5- (cyclopropylmethoxy) pyridin-3-yl) methyl) cyclobutyl) -4-oxo-1 , 4-dihydropyridine-3-carboxylate (100 mg, 0.202 mmol), potassium acetate (39.6 mg, 0.403 mmol) and chlorine [(tri-tert-butylphosphine) -2- (2-aminobiphenyl)] palladium (II) (20.7 mg, 0.040 mmol) was purged with nitrogen for 15 minutes. N, N-Dimethylacetamide (DMA) (2 mL) was purged with nitrogen for 5 minutes before being added to the reaction vial. The reaction flask was placed in a heating block that was preheated to 90 ° C, and the mixture stirred overnight. The reaction mixture was allowed to cool to room temperature, filtered through a cotton plug and purified by medium-phase chromatography.
[00307] [00307] A solution of lithium hydroxide monohydrate (25.2 mg, 0.600 mmol) in water (1 mL) was added to a solution of ethyl 2'-chloro-3 '- (cyclopropylmethoxy) -10'- oxo-5 ', 10'-dihydrospiro [cyclobutane-1,6'-pyrido [1,2-h] [1,7] naphthyridine] -9'-carboxylate (30 mg, 0.060 mmol) in methanol (1 ml), and the mixture heated to 60 ° C for 3 hours. The mixture was allowed to cool to room temperature and acidified with 1M hydrochloric acid. The mixture was diluted with DMF to dissolve the sample, and then purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The combined fractions were lyophilized to produce 2'-chloro-3 '- (cyclopropylmethoxy) -10'-oxo-5', 10'-dihydrospiro [cyclobutane-1,6'-pyrido [1,2-h] [1.7] naphthyridine] -9'-carboxylic (22 mg, 0.056 mmol, 94% yield) as an off-white powder. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (s, 1 H), 7.68 (s, 1 H), 7.27 (s, 1 H), 4.07 (d, J = 7.03 Hz, 2 H), 3.44 (s, 2 H), 2.61 - 2.75 (m, 2 H), 2.00 - 2.12 (m, 2 H), 1, 78 - 1.95 (m, 2 H), 1.25 - 1.37 (m, 1 H), 0.57 - 0.68 (m, 2 H), 0.33 - 0.40 (m, 2 H). LCMS (ES +) (m / z): 387, 389 (M + 1). Example 32 (Compound 251)
[00308] [00308] 2'-Chloro-3 '- (cyclopropylmethoxy) -10'-oxo-5', 10'-dihydrospiro [cyclobutane-1,6'-pyrido [1,2-h] [1,7 ] naphthyridine] -9'-carboxylic (10 mg, 0.026 mmol) and sodium methoxide (0.5 M in methanol) (0.517 mL, 0.259 mmol) were heated to 65 ° C for 2 hours. Dioxane (0.5 ml) was added, and the mixture heated to 100 ° C. The flask was initially left uncapped so that most of the methanol was distilled. The reaction flask was capped and stirred at 100 ° C for 1.5 hours. The mixture was allowed to cool to room temperature, acidified with 1N HCl and purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 10% to 100% gradient). The lyophilized fractions to produce 2 ', 3'-dimethoxy-10'-oxo-5', 10'-dihydrospiro [cyclobutane-1,6'-pyrido [1,2-h] [1,7 ] naphthyridine] -9'-carboxylic (1.5 mg, 4.03 µmol, 15.6% yield) as a white solid. 1H NMR (400 MHz, CHLORINE-FORM) -δ ppm 8.90 (s, 1 H), 7.65 (s, 1 H), 6.93 (s, 1 H), 4.08 (s, 3 H), 3.97 (s, 3 H), 3.26 (s, 2 H), 2.57 - 2.75 (m, 2 H), 2.15 - 2.29 (m, 2 H ), 2.00 - 2.12 (m, 2 H). LCMS (ES -) (m / z): 341 (M-1) -. Scheme 13 - Preparation of Compounds As Example 33 (Compound 252)
[00309] [00309] A mixture of 2-hydroxy-5,6-dimethylnicotinonitrile (10 g, 67.5 mmol) in POCl3 (100 ml) was refluxed for 10 h and was concentrated. The residue was basified with 10% aqueous NaOH solution and filtered. The filter mass was washed with H2O. The filtrate was extracted with DCM (200 mL x 2). The organic layers were combined, washed with brine (200 ml), dried over anhydrous Na2SO4 and concentrated to produce 9.8 g of crude 2-chloro-5,6-dimethylnicotinonitrile as a yellow solid. LCMS (ESI) m / z: 167,1,169.1 (M / M + 2) +. Step 2: 2-Chlorine-5,6-dimethylnicotinaldehyde
[00310] [00310] To a -78 ° C solution of 2-chloro-5,6-dimethylnicotinonitrile (1.6 g, 9.6 mmol) in DCM (20 ml), DIBAL-H (5.76 ml, 2 mol / L in hexane) was added. The resulting mixture was stirred at the same temperature for 2 h. The reaction was quenched by adding ice water. Then, the mixture was acidified with 1N HCl at pH = ~ 6 and extracted with DCM (100 mL x 2). The organic layers were combined, washed with brine (50 ml), dried over anhydrous Na2SO4 and concentrated to produce 1.5 g of crude 2-chloro-5,6-dimethylnicotinaldehyde as a white solid. LCMS (ESI) m / z: 170,1,172.1 (M / M + 2) +. Step 3: 2-Chlorine-3- (1,3-dioxolan-2-yl) -5,6-dimethylpyridine
[00311] [00311] A mixture of 2-chloro-5,6-dimethylnicotinaldehyde (1.5 g, 8.84 mmol), ethane-1,2-diol (1.1 g, 17.68 mmol), PPTS (444, 3 mg, 1.768 mmol) in toluene (20 ml) was refluxed for 12 h. The reaction mixture was cooled in ta and extracted with EtOAc (100 ml x 2). The organic layers were combined, washed with aqueous NaHCO3 solution (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50% EtOAc in PE) to provide 2-chloro-3- (1,3-dioxolan-2-yl) - 5,6-dimethylpyridine (1.35 g, 71.5% yield) as a colorless oil. LCMS (ESI) m / z: 214,1,216.1 (M / M + 2) +. Step 4: 1- (3- (1,3-Dioxolan-2-yl) -5,6-dimethylpyridin-2-yl) -3-methylbutan-2-one
[00312] [00312] A mixture of 2-chloro-3- (1,3-dioxolan-2-yl) -5,6-dimethylpyridine (1.35 g, 6.32 mmol), 3-methylbutan-2-one (653 mg, 7.58 mmol), Pd (dtbpf) Cl2 (411.9 mg, 0.632 mmol) and t-BuONa (1.52 g, 15.8 mmol) in THF (20 ml) was heated to 60 ° C for 3 h. The reaction mixture was cooled in ta and filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-70% EtOAc in PE) to provide 1- (3- (1,3-dioxolan-2-yl) - 5.6-
[00313] [00313] To a solution of 1- (3- (1,3-dioxolan-2-yl) -5,6-dimethylpyridin-2-yl) -3-methylbutan-2-one (231 mg, 0.878 mmol) in MeOH (10 ml) was added NH4OAc (683.1 mg, 8.78 mmol) at room temperature. After the mixture was stirred for 30 min, NaBH3CN (82.8 mg, 1.317 mmol) was added to the mixture at 0 ° C. Then, the resulting mixture was stirred at 50 ° C for 10 h. The reaction mixture was cooled in ta and concentrated. The residue was diluted with H2O (20 ml), basified in ph ~ 10 with 10% NaOH solution. The aqueous mixture was extracted with DCM (2X). The organic layers were combined, washed with brine (30 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 236 mg of 1- (3- (1,3-dioxolan-2-yl) -5.6 -dimethylpyridin-2-yl) -3-methylbutan-2-amine crude. LCMS (ESI) m / z: 265.3 (M + 1) +. Step 6: 7-Isopropyl-2,3-dimethyl-7,8-dihydro-1,6-naphthyridine
[00314] [00314] To a solution of 1- (3- (1,3-dioxolan-2-yl) -5,6-dimethylpyridin-2-yl) -3-methylbutan-2-amine (70 mg, 0.264 mmol) in THF (10 mL), 10% aqueous HCl solution (2 mL) was added. The resulting mixture was heated to 50 ° C for 10 h. After being cooled in ta, the mixture was concentrated. The residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to produce 7-isopropyl-
[00315] [00315] A solution of 7-isopropyl-2,3-dimethyl-7,8-dihydro-1,6-naphthyridine (20 mg, 0.099 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate ( 55.86 mg, 0.3 mmol) in EtOH (5 mL) was heated to 85 ° C for 10 h. After being cooled to room temperature, the mixture was concentrated. The residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to produce ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro -6H-pyrido [2,1-f] [1,6] naphthyridine-9-carboxylate (20 mg, 58.9% yield). LCMS (ESI) m / z: 343.2 (M + 1) +. Step 8: Ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido [2,1- f] [1,6] naphthyridine-9-carboxylate
[00316] [00316] To a solution of ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro-6H-pyrido [2,1-f] [1,6] naphthyridine -9-carboxylate (20 mg, 0.058 mmol) in DME (5 ml) p-chloranil (12.3 mg, 0.05 mmol) was added. The mixture was heated to 80 ° C for 3 h. After being cooled in ta, the mixture was concentrated. The residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to provide ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-
[00317] [00317] To a solution of ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido [2,1-f] [1,6] naphthyridine-9-carboxylate (15 mg, 0.044 mmol) in MeOH (5 ml), NaOH (7 mg, 0.176 mmol) dissolved in H2O (1 ml) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH ~ 5 with 1N HCl. Then, the mixture was diluted with EtOAc (20 ml) and H2O (20 ml), and then extracted with EtOAc (20 ml x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase HPLC (Column C18.5% -100% MeCN in H2O, with 0.1% formic acid in H2O) to produce 6-isopropyl-2,3-dimethyl-10-oxo acid -5,10-dihydro-6H-pyrido [2,1-f] [1,6] naphthyridine-9-carboxylic (5 mg, 36.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1 H), 8.25 (s, 1 H), 7.43 (s, 1 H), 4.63 - 4.58 (m , 1 H), 3.56 - 3.50 (m, J = 16.8, 5.3 Hz, 1 H), 3.18 (d, J = 16.6 Hz, 1 H), 2.48 (s, 3 H), 2.31 (s, 3 H), 1.64 - 1.57 (m, 1 H), 0.84 (d, J = 6.6 Hz, 3 H), 0, 69 (d, J = 6.7 Hz, 3H). LCMS (ESI) m / z: 313.2 (M +1) +. Example 34 (Compound 253) 2-Chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1 , 2-h] [1,7] naphthyridine-10-carboxylic (cis racemic)
[00318] [00318] One flask was loaded with a stir bar, 5-bromo-2-chloro-3-methoxypyridine (9.9 g, 44 mmol), tris (dibenzylidene acetone) dipaladium (0) (0.611 g, 0.668 mmol), xantphos (0.695 g, 1.202 mmol), and sodium tert-butoxide (7.5 g, 78 mmol). The flask was purged with a stream of nitrogen before 2,2-dimethylcyclopentan-1-one (8.38 ml, 66.8 mmol) in tetrahydrofuran (THF) (200 ml) was added. The mixture was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature, filtered, and the filter mass was washed with ethyl acetate. The filtrate was diluted with additional ethyl acetate, washed with brine and concentrated, and the residue purified by chromatography on silica eluting with a gradient of 0% to 30% ethyl acetate in hexanes. The fractions were concentrated to produce 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-one (4.6 g, 18 mmol, 41% yield) as an oil. 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 7.82 (d, J = 1.56 Hz, 1 H), 7.13 (d, J = 1.95 Hz, 1 H), 3.91 ( s, 3 H), 3.36 - 3.47 (m, 1 H), 2.45 (m, 1 H), 1.96 - 2.17 (m, 2 H), 1.79 - 1, 92 (m, 1 H), 1.18 (s, 3 H), 1.07 (s, 3 H). LCMS (ES +) (m / z): 254.2 (M + 1). Step 2: 5- (6-Chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentanamine (cis / trans isomers)
[00319] [00319] A mixture of 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-one (4.6 g, 18 mmol) and ammonium acetate (21 g, 270 mmol ) in methanol (75 ml) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (2.28 g, 36.3 mmol) was added, and the mixture heated to 60 ° C overnight, and then to 65 ° C for an additional 24 hours. The mixture was allowed to cool to room temperature, concentrated to ~ 20 mL, quenched with 1M sodium hydroxide and extracted 3 times with 2-methyltetrahydrofuran. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 0% to 100% gradient). The fractions were concentrated to produce 5- (6-chloro-5-methoxypyridin-3-yl) -2,2-dimethylcyclopentan-1-amine (2.63 g, 10.3 mmol, 57% yield) as a mixture of cis / trans isomers. LCMS (ES +) (m / z): 255.2 (M + 1). Step 3: 5- (2-Amino-3,3-dimethylcyclopentyl) -2-chloropyridin-3-ol (cis / trans isomers)
[00320] [00320] Boron tribromide (4.82 mL, 51.0 mmol) was slowly added dropwise to a vigorous stirring solution of 5- (6-chloro-5-methoxypyridin-3-yl) -2, 2-dimethylcyclopentan-1-amine (2.6 g, 10.2 mmol) (cis / trans isomers). The mixture was heated to 70 ° C overnight. The mixture was allowed to cool to room temperature, and then cooled to 0 ° C. The mixture was carefully quenched with slow addition of methanol. An additional 50 mL of methanol was added, and the mixture stirred for 30 minutes before being concentrated. The residue was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1% formic acid / 0% at
[00321] [00321] Iodine (2.29 g, 9.01 mmol) was added to a stirring mixture of 5- (2-amino-3,3-dimethylcyclopentyl) -2-chloropyridin-3-ol (2.17 g, 9.01 mmol) and potassium carbonate (3.74 g, 27.0 mmol) in water (40 mL). The mixture was stirred at room temperature for 2 hours. Solid sodium sulfite (2.39 g, 18.9 mmol) was added in portions, and the mixture stirred for 30 minutes. The aqueous mixture was adjusted to pH = ~ 3 with 3N hydrochloric acid. The mixture was filtered. LC-MS showed that the solid contained a small amount of product, but was discarded. The wash was concentrated to ~ 50 mL and injected into a medium pressure C18 ISCA reverse phase column, which was eluted with acetonitrile / water / 0.1% formic acid / 0% to 100% gradient. 2 sets of fractions were lyophilized separately. Peak 1 = 5- (2-amino-3,3-dimethylcyclopentyl) -2-chloro-6-iodopyridin-3-ol (trans racemic) (1.17 g, 3.19 mmol, 35% yield) . 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1 H), 7.26 (s, 1 H), 2.99 - 3.15 (m, 2 H), 2.05 - 2.19 (m, 1 H), 1.51 - 1.64 (m, 2 H), 1.22 - 1.35 (m, 1 H), 1.09 (s, 3 H), 0, 95 (s, 3 H). LCMS (ES +) (m / z): 367.1 (M + 1). Peak 2 = 5- (2-amino-3,3-dimethylcyclopentyl) -2-chloro-6-iodopyridin-3-ol (cis racemic contaminated with ~ 20% trans racemic) (924 mg, 2.01 mmol , 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1 H), 7.20 (s, 1 H), 3.41 - 3.53 (m, 1 H), 3.28 ( d, J = 5.86 Hz, 1 H), 2.07 - 2.19 (m, 1 H), 1.81 - 1.95 (m, 1 H), 1.68 - 1.77 (m , 1 H), 1.47 - 1.57 (m, 1 H), 1.14 (s, 3 H), 1.08 (s, 3 H). LCMS (ES +) (m / z): 367.1 (M + 1). Step 5: Ethyl 1- (5- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4-dihydropyridine-3-carboxylate ( racemic cis)
[00322] [00322] 5- (2-Amino-3,3-dimethylcyclopentyl) -2-chloro-6-iodopyridin-3-ol (cis racemic) (924 mg, 2.02 mmol) (contaminated with ~ 20% trans) and ethyl 4-oxo-4H-pyran-3-carboxylate (466 mg, 2.77 mmol) in acetic acid (13 ml) were stirred at 100 ° C for 4 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted 2 times with dichloromethane. Brine was added to the aqueous phase, and the mixture extracted 2 more times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica eluting with a gradient of 0% to 10% methanol in dichloromethane. The fractions were concentrated to produce ethyl 1- (5- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4-dihydropyridine-3 -carboxylate (cis racemic) (346 mg, 0.670 mmol, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (br. S., 1 H), 7.78 (d, J = 1.95 Hz, 1 H), 7.43 (dd, J = 7.81, 2.34 Hz, 1 H), 7.07 (s, 1 H), 6.04 (d, J = 7.42 Hz, 1 H), 4.54 (d, J = 7, 42 Hz, 1 H), 4.03 - 4.17 (m, 2 H), 3.82 - 3.95 (m, 1 H), 2.15 - 2.27 (m, 2 H), 1 .99 (dt, J = 13.66,
[00323] [00323] Ethyl 1- (5- (6-chloro-5-hydroxy-2-iodopyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1,4-dihydropyridine-3-carboxylate ( racemic cis) (346 mg, 0.670 mmol), potassium carbonate (463 mg, 3.35 mmol), and 1-bromo-3-methoxypropane (205 mg, 1.34 mmol) in N, N-dimethylformamide (DMF) (5 mL) were stirred at room temperature overnight. The mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by chromatography to produce ethyl 1- (5- (6-chloro-2-iodo-5- (3-methoxypropoxy) pyridin-3-yl) -2,2-dimethylcyclopentyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate (341 mg, 0.579 mmol, 86% yield). LCMS (ES +) (m / z): 589.2 (M + 1). Step 7: Ethyl 2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2- h] [1,7] naphthyridine-10-carboxylate (cis racemic)
[00324] [00324] A round-bottomed flask with a septum containing a stir bar, ethyl 1- (5- (6-chloro-2-iodine-5- (3-
[00325] [00325] A solution of lithium hydroxide monohydrate (113 mg, 2.70 mmol) in water (2 mL) was added to a solution of ethyl 2-chloro-3- (3-methoxypropoxy) -7.7 -dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylate (racemic cis) (150 mg , 0.270 mmol) in methanol (3 ml), and the mixture heated to 65 ° C for 1 hour. The mixture was allowed to cool, diluted with water, acidified with 1M HCl and extracted 3 times with 2-methyltetrahydrofuran. The combined organic layers were washed with brine and concentrated. The residue was purified by chromatography on silica eluting with a gradient of 0% to 10% methanol in dichloromethane. The fractions were concentrated to produce 2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1 , 2-h] [1,7] naphthyridine-10-carboxylic (cis racemic) (95 mg, 0.219 mmol, 81% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (s, 1 H), 7.63 (s, 1 H), 7.43 (s, 1 H), 4.72 (d, J = 9.37 Hz, 1 H), 4.21 - 4.39 (m, 2 H), 3.89 - 3.99 (m, 1 H), 3.51 (t, J = 6.05 Hz , 2 H), 3.26 (s, 3 H), 2.33 - 2.44 (m, 1 H), 2.19 - 2.31 (m, 1 H), 1.96 - 2.08 (m, 2 H), 1.55 - 1.66 (m, 1 H), 1.40 - 1.51 (m, 1 H), 1.15 (s, 3 H), 0.40 (s , 3 H). LCMS (ES +) (m / z): 433.3 (M + 1).
[00326] [00326] Additional general synthetic protocols for preparing the compounds as described herein are shown below in Scheme 15. Scheme 15- Compounds of Type Compounds Where R10 is from Table 2)
[00327] [00327] The cryopreserved primary human hepatocyte vials were placed in a water bath at 37 ° C until defrost. The cells were pooled, gently resuspended in differentiation medium (Williams medium containing differentiation supplement, GlutaMax-1 ™ and penicillin / streptomycin) and counted using a hemacytometer. The cells were pelleted by centrifugation at 1000 x g for 10 min and resuspended at a density of 5.5 x 105 cells / mL in differentiation medium. 100 µL of seed was sown
[00328] [00328] HBV stocks were prepared by ultrafiltration of HepG2.2.15 cell culture media. To prepare a functioning virus stock with a multiplicity of infection (MOI) of 100, the HBV stock was added to the differentiation medium containing 4% polyethylene glycol to achieve a concentration of 5.5 x 107 copies of HBV DNA / ml. The cell medium was replaced by 100 µL of the virus stock in operation in columns 1-11 and with differentiation medium in column 12. The plates were incubated at 37 ° C and 5% CO2 for approximately 24 hours.
[00329] [00329] The compounds were resuspended in DMSO and serially diluted 3 times in DMSO to form a 10-point dilution series at 200X the desired final concentrations. Columns 11 and 12 contained DMSO. Using a Biomek FX, 2.5 µL of each compound dilution was stamped on 96-well U-bottom plates, making 3 copies. The compost plates were sealed and stored at -20 ° C. After equilibration at room temperature, the plates of the compound were diluted 200 times with test medium (differentiation medium plus 1 mM ABT). The medium in the cell plates was replaced by 150 µL of the diluted compounds. The highest final concentration of the compound was 20 µM. The plates were incubated at 37 ° C and 5% CO2. Compound treatments were repeated on days 4 and 9 after the initial treatment. Readings of HBsAg and HBeAg ELI-SAs were performed on days 9 and 14.
[00330] [00330] On days 9 after the initial treatment, the medium was transferred from each cell plate to a U-bottom plate and stored at -80 ° C. On day 14 after the initial treatment, the cell plates were washed once with PBS and stored at -80 ° C.
[00331] [00331] Frozen plates containing the collected medium were equilibrated at room temperature in a biosafety cabinet for approximately 30 min. The HBs Ag ELISA kit was used according to the manufacturer's instructions. Briefly, the ELISA plates and solutions were equilibrated at room temperature for approximately 1 hour, and the plates were washed once with 300 µL of 1X wash buffer. 100 µL of 1X enzyme conjugate solution, 120 µL of PBS containing 10% FBS and 30 µL of collected medium were placed in each well. The assay plates were sealed and incubated at 37 ° C for approximately 2 hours. The plates were washed 4 times with 195 mL of 1X wash buffer and dried completely inverted on paper towels. 195 µL of chromogen / substrate solution were added to each well and incubated at room temperature for approximately 5 min. 100 µL of the stop solution was added to each well, and the plates were read in a Molecular Devices SpectraMax® 384 Plus microplate reader at 450 nm. The IC50s were determined using the GraphPad Prism: Four parameter logistic curve with the equation Y = Lower + (Upper-Lower) / (1 + 10 ^ ((LogIC50- X) * Hill's slope)). HBe Ag ELISA
[00332] [00332] Frozen plates containing the collected medium were equilibrated at room temperature in a biosafety cabinet for approximately 30 min. The HBeAg ELISA kit was used according to the manufacturer's instructions. Briefly, the ELISA plates and solutions were equilibrated at room temperature for approximately 1 hour and the plates were washed once with 300 µL of 1X wash buffer. 80 µL of PBS containing 10% FBS and 20 µL of collected medium were placed in each well. The assay plates were sealed and incubated at 37 ° C for approximately 1 hour. The plates were washed twice with 300 ml of 1X wash buffer and dried completely inverted on paper towels. 100 µL of 1X enzyme conjugate solution was placed in each well. The assay plates were sealed and incubated at 37 ° C for at least 1 hour. The plates were washed 3 times with 300 ml of 1X wash buffer and dried completely inverted on paper towels. 100 µL of chromogen / substrate solution was added to each well and incubated at room temperature for approximately 5 min. 100 µL of the stop solution was added to each well and the plates were read in a Molecular Devices SpectraMax 384 Plus microplate reader at 450 nm. Data analysis
[00333] [00333] IC50s were determined using the GraphPad Prism: Four parameter logistic curve with the equation Y = Lower + (Upper-Lower) / (1 + 10 ^ ((LogIC50-X) * Hill's declivity)). The IC50 values for 50% reduction in HBs and HBe antigens for the tested compounds are shown in Table 1 on days 9 and 14. As can be seen from the IC50 values, the tested compounds exhibited 50% inhibition of the antigens HBe and HBs at values between <0.22 µM and 0.0069 µM.
[00334] [00334] The modalities of the invention described above are intended to be merely exemplary; numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications must be within the scope of the present invention, as defined in any attached claim. Example 36 HepAD38 cells - HBsAg ELISA and cytotoxicity assays
[00335] [00335] HepAD38 cells are kept in flasks coated with collagen in cell culture medium (DMEM / F12 containing 10% fetal bovine serum (FBS), GlutaMax-1, penicillin / streptomycin, non-essential amino acids, Pyruvate of Na 250 µg / mL of geneticin and 1 µg / mL of doxycycline). Compound solutions are prepared in DMSO and the compound is serially diluted to final concentrations of 4000, 1000, 250, 62.5, 15.6, 3.91, 0.977, 0.244, 0.061 and 0.015 µM. The cells are then trypsinized and the cells are placed
[00336] [00336] Mean values of% inhibition of duplicate assay plates are plotted on the GraphPad Prism to determine an IC value: Four parameter logistic curve with equation Y = Lower + (Lower) / (1 + 10 ^ ((LogIC50- X)) * Hill's declivity)) pIC50 = log (-IC50 in M)
TABLE 1 Example / Esqu Compound No. Structure Name ema No.
(4bR, 7aS) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-220 1 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2- h] [1,7] naphthyridine-10-carboxylic acid (4bS, 7aR) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 221 2 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic acid (4bR, 7aS) -2-cyclopropyl-3- (3- methoxypropoxy) -7,7-dimethyl-11-oxo-222 3 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10- carboxylic acid 2-Cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-223 4b, 5,6,7,7a, 11-hexa- 4 hydrocyclopenta [f] pyrido [1,2 - h] [1,7] naphthyridine-10-carboxylic (cis-racemic) (7aR) -2-cyclopropyl-4b-hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 224 5 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic acid (7aR) -2-chloro-4b-hydroxy -3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 225 6 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2- h] [1, 7] naphthyridine-10-carboxylic acid (7aR) -2-chlorine -4b-methoxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 226 7 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2- h ] [1,7] naphthyridine-10-carboxylic acid (4bR, 7aS) -2-Hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 227 8 4b, 5,6,7, 7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic acid (4bR, 7aS) -2-chloro-3-hydroxy-7,7- 228 dimethyl- 11-oxo-4b, 5,6,7,7a, 11-hexa- 9 hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic
Example / Esqu Compound No. Structure Name ema No.
2-Chloro-6- (1-hydroxy-2- 229 methylpropan-2-yl) -3- (3-methoxypropoxy) - 10 10-oxo-6,10-dihydro-5H-pyrido [1,2 - h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-Butyl) -2-chloro-3- (3- 230 methoxypropoxy) -10-oxo-6,10-dihydro - 11 5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -3- 231 (cyclopropylmethoxy) -2-methyl-10-oxo- 12 6,10-dihydro-5H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -3- (3- 232 methoxypropoxy) -2-methyl-10-oxo-6,10-13 dihydro-5H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -2-cyclopropyl-3- 233 (cyclopropylmethoxy) -10-oxo-6,10-di-14 hydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic acid (S) - 6- (tert-butyl) -2-cyclopropyl-3- 234 (3-methoxypropoxy) -10-oxo-6,10-di-15 hydro-5H-pyrido [1,2-h] [1,7] naphthyridine -9- carboxylic acid (R) -6- (tert-butyl) -3- 235 (cyclopropylmethoxy) -2-methoxy-10-oxo-16 6,10-dihydro-5H-pyrido [1,2- h ] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -3- 236 (cyclopropylmethoxy ) -2-methoxy-10-oxo- 17 6,10-dihydro-5H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl ) -3- 237 (cyclopropylmethoxy) -2-hydroxy-10-oxo-18 6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic
Example / Esqu Compound No. Structure Name ema No.
(S) -6- (tert-Butyl) -2-methoxy-3- (3- 238 methoxypropoxy) -10-oxo-6,10-dihydro-19 5H-pyrido [1,2-h] [ 1.7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -2-hydroxy-3- (3- 239 methoxypropoxy) -10-oxo-6,10-dihydro-20 5H- pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -3- (3- 240 methoxypropoxy) -10-oxo-2- (prop-1 -en- 21 2-yl) -6,10-dihydro-5H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) - 2-isopropyl-3- 241 (3-methoxypropoxy) -10-oxo-6,10-di-22 hydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -2-chloro-3- (3- 242 methoxypropoxy) -8-methyl-10-oxo-6,10- 23 dihydro-5H-pyrido [1,2- h] [ 1.7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -2- 243 (hydroxymethyl) -3- (3-methoxypropoxy) -10-24 oxo-5,10-dihydro- 6H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylic acid (S) -6- (tert-butyl) -2-cyclopropyl- 244 11-hydroxy-3- (3-methoxypropoxy) - 10-25 oxo-5,10-dihydro-6H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylic acid (2-chloro-3- (cyclopropylme (6) isopropyl-6-methyl-10-oxo-5,10-dihydro-26 6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic acid (2-chlorine) -3- (cyclopropylmethoxy) -6- 246 isopropyl-6-methyl-10-oxo-5,10-dihydro-27 6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic
Example / Esqu Compound No. Structure Name ema No.
2-Cyclopropyl-6-isopropyl-3- (3- 247 methoxypropoxy) -6-methyl-10-oxo-5,10- 28 dihydro-6H-pyrido [1,2- h] [1,7] naphthyridine-9-carboxylic acid 2-Cyclopropyl-6-isopropyl-3- (3- 248 methoxypropoxy) -6-methyl-10-oxo-5,10-29 dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic acid 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo-6,10-di-249 30 hydro-5H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylic (isomers 1 and 2) 2'-chloro-3 'acid - (cyclopropylmethoxy) - 10'-oxo-5', 10'-di- 250 31 hydrospiro [cyclobutane -1,6'- pyrido [1,2-h] [1,7] naphthyridine] -9'- carboxylic acid 2 ', 3'-dimethoxy-10'-oxo-5', 10'-di- 251 hydro-spiro [cyclobutane-1,6'- 32 pyrido [1,2-h] [1,7] naphthyridine] -9'-carboxylic acid 6-Isopropyl-2,3-dimethyl-10-oxo-252 33 5,10- dihydro-6H-pyrido [2,1- f] [1,6] naphthyridine-9-carboxylic acid 2-Chloro-3- (3-methoxypropoxy) -7,7-253 dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexa- 34 hydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic acid 3 '- (cyclopropylmethoxy) -2'- (difluoromethyl) - 11'-fluoro -10'-oxo- 254 35 5 ', 10'-dihydrospiro [cyclobutane-1,6'- pyrido [1,2-h] [1,7] naphthyridine] -9'- carboxylic acid 2' - ( difluoromethyl) -11'-fluoro-10'- oxo-3 '- (((tetrahydrofuran-3-yl) methoxy) - 255 36 5', 10'-dihydrospiro [cyclobutane-1,6'-pyrido [ 1,2-h] [1,7] naphthyridine] -9'- carboxylic
Example / Esqu Compound No. Structure Name ema No.
(S) -3- (cyclopropylmethoxy) -2- (difluoromethyl) -11-fluoro-6-isopropyl-6- 256 37 methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylic acid (6S) -2- (difluoromethyl) -11-fluoro- 6-isopropyl-6-methyl-10-oxo-3 - (((tetra- 257 38 hydrofuran- 3-yl) methoxy) -6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic TABLE 2 R10 = R10 = R10 = R10 = -OH -ORa
R10 = R10 = R10 = R10 =
R10 = R10 = R10 = R10 =
‡ (R9 forms an oxaborol ring with position R10 of the pyridine ring)
‡ (R9 forms an oxaborol ring with position R10 of the pyridine ring)
R10 = R10 = R10 = R10 =
R10 = R10 = R10 = R10 =
-CO2H -B (OH) 2 -NHSO2R25 '-NCO2R25 where Ra, Ra' and Ra ”are independently selected from hydroxy, alkyl or substituted alkyl, substituted cycloalkyl or cycloalkyl, substituted hetero-cycloalkyl or substituted hetero-cycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; with the proviso that Ra is not hydroxy when attached to an oxygen group Rb, Rb 'and Rb ”are independently selected from hydrogen, halo, hydroxy, alkyl or substituted alkyl, substituted alkoxy or alkoxy, cycloalkyl or substituted cycloalkyl, substituted hetero-cycloalkyl or hetero-cycloalkyl, substituted thio or thioalkyl, substituted amino or amino, substituted aryl or aryl, heteroaryl or substituted aryl; R25 and R25 'are independently selected from H, OH, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkenyl, substituted hetero-cycloalkyl or hetero-cycloalkyl, substituted aryl and substituted and heteroaryl or substituted heteroaryl; and wherein the above substituents for R10 may exist as tautomers of the structures shown.
TABLE 3 Data of Hep AD38, HBsAg and Cell tox - EC50 (M) HepAD38, HBsAg Cell tox Example No.
Compound No. (EC50, µM) (EC50, M)
1 ++++ -
220
2 ++ -
221
3 ++++ -
222
4 ++++ -
223
5 +++ -
224
6 ++ -
225
7 ++ -
226
8 + -
227
9 + -
228
10 +++ -
229
11 ++++ -
230
12 ++++ -
231
13 ++++ -
232
14 ++++ -
233
15 ++++ -
234
16 + -
235
17 ++++ -
236
18 + -
237
19 ++++ -
238
20 + -
239
21 ++++ -
240
22 ++++ -
241
23 + -
242
24 +++ -
243
25 ++++ -
244
26 +++ -
245
27 + -
246
28 ++++ -
247
29 ++ -
248
30 +++ -
249-R (racemate)
30-A ++++ -
249
30-B + -
249
31 +++ -
250
32 ++ -
251
33 + -
252
34 ++++ -
253
Table Legend: - isomer where: -  (cell tox) + ≥ ++  e≥ +++ e≥ ++++  

权利要求:
Claims (43)
[1]
1. Compound characterized by the fact that it presents Formula I Formula I in which W and Y are independently C or N, with the proviso that W and Y are not equally C; where if W is C, then R1 will be hydrogen, hydroxy, halogen, cyano, amino or substituted amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered hetero-cycloalkyl or 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; and if Y is C, then R4 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; where if W is N, then R1 will be absent; and if Y is N, then R4 will be absent; R2 and R3 are independently selected from hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1-6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; R5 and R6 are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, substituted alkoxy or alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; substituted aryl or aryl, heteroaryl or substituted aryl, - CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R7 and R8 are independently hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkylene; aryl or substituted aryl, heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, in whereas the 3- to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ; or R6 and R7 together form a 3- to 8-membered cycloalkyl ring or hetero-cycloalkyl ring comprising a heteroatom or two or more heteroatoms, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ, where the one heteroatom in the heteroalkyl ring is NR20, and the two or more heteroatoms are selected from N,
NR22, O, S, SR22 and SR22R22ꞌ; or R7 and R8 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with R17, R17ꞌ, R18 and / or R18ꞌ, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R9 is a bond, hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkenyl, substituted hetero-cycloalkyl or substituted hetero-cycloalkyl, aryl or substituted aryl , heteroaryl or substituted heteroaryl, –CxH2x – phenyl or - O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R10 is a substituent shown in Table 2 or a tautometer thereof; or R9 is a bond and R9 and R10 together form an oxaborol ring; R11 is hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; hetero-cycloalkyl or substituted hetero-cycloalkyl, aryl, heteroaryl, –CxH2x – phenyl or - O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R12 is hydrogen; substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted hetero-cycloalkyl or hetero-cycloalkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl; R13, R13ꞌ, R14 and R14ꞌ are independently hydrogen, hydroxy, halogen, amino, amino alkyl, cyano, C1-6 alkyl, C1-6 alkoxy, carbonyl, carboxamide, amide; or R13 and R13ꞌ or R14 and R14ꞌ together form a 3-8 membered cycloalkyl ring or 3-8 membered heterocycloalkyl ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C1-6 alkyl, C3 -8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy, where the heteroatom in the heterocycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R15, R15ꞌ, R16 and R16ꞌ are independently hydrogen, hydroxy, halogen, amino, cyano, C1-6 alkyl, or C1-6 alkoxy; or R15 and R15ꞌ or R16 and R16ꞌ together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C1-6 alkyl, C3- 8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy, wherein the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R17, R17ꞌ, R18 and R18ꞌ are independently hydrogen, hydroxy, halogen, amino, cyano, C1-6 alkyl, or C1-6 alkoxy; or R17 and R18 or R17ꞌ and R18ꞌ together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C1-6 alkyl, C3 -8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R19, R19ꞌ and R19ꞌꞌ are independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, phenyl, C1-6 alkylimidol, C1-6 alkyltriazole, C1-6 alkylthetrazole, C1-6 alkylthiazole, C1-6 alkyloxazole, C1-6 alkyldioxazole; C1-6 alkyloxazolidone; and R20 and R21 are independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, phenyl, C1-6 alkylimidizole, C1-6 alkyltriazole, C1-6 alkylthetrazole, C1-6 alkylthiazole, C1-6 alkyloxazole, C1-6 alkyldioxazole; C1-6 alkyloxazolidone, or R20 and R21 together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form carboxyl substituted pyrrolidinyl, carboxyl substituted piperidinyl or carboxyl substituted morpholinyl; and R22 and R22ꞌ are independently selected from hydrogen, oxygen, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C2 -6 alkenyl or C2-6 substituted alkenyl, aryl or substituted aryl, including substituted or unsubstituted C1-6 alkylimidizole, substituted or unsubstituted C1-6 alkylthiazole, C1-6 alkylthetrazole, C1-6 alkylthiazole, Substituted or unsubstituted C1-6 alkyloxazole, C1-6 alkyldioxazole; C1-6 alkyloxazolidone; -COR19, -COOR19ꞌ, -CSOR19ꞌꞌ, -CONR20R21, or a pharmaceutically acceptable salt thereof.
[2]
2. A compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R5 and R6 together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, where the 3- to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ.
[3]
A compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R6 and R7 together form a 3- to 8-membered cycloalkyl ring or hetero-cycloalkyl ring comprising a heteroatom or two or more heteroatoms, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ, where the one heteroatom in the heteroalkyl ring is NR20, and the two or more heteroatoms are selected from N, NR22, O, S, SR22 and SR22R22ꞌ.
[4]
A compound of Formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R7 and R8 together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, optionally substituted with R17, R17ꞌ, R18 and / or R18ꞌ, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ.
[5]
5. Compound characterized by the fact that it has Formula IA or Formula IB: or Formula IA Formula IB where C * is a carbon atom stereocenter that has a configuration that is (R) or (S) W and Y are independently C or N, with the proviso that W and Y are not equally C; where if W is C, then R1 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; and if Y is C, then R4 will be hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1- 6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; where if W is N, then R1 will be absent; and if Y is N, then R4 will be absent; R2 and R3 are independently selected from hydrogen, hydroxy, halogen, cyano, substituted amino or amino, substituted uncle or uncle, substituted alkyl or alkyl, substituted alkoxy or alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, pyrrolidinyl, –CxH2x – phenyl, –O – CxH2x – phenyl, or - (C1-6alkyl) N– CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5, 6; or –OR12; R5 and R6 are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, substituted alkoxy or alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; substituted aryl or aryl, heteroaryl or substituted aryl, - CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R7 and R8 are independently hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkylene; aryl or substituted aryl, heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, in whereas the 3- to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ; or R6 and R7 together form a 3- to 8-membered cycloalkyl ring or hetero-cycloalkyl ring comprising a heteroatom or two or more heteroatoms, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ, where the one heteroatom in the heteroalkyl ring is
NR20, and the two or more heteroatoms are selected from N, NR22, O, S, SR22 and SR22R22ꞌ; or R7 and R8 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with R17, R17ꞌ, R18 and / or R18ꞌ, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R9 is a bond, hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkenyl, substituted hetero-cycloalkyl or substituted hetero-cycloalkyl, aryl or substituted aryl , heteroaryl or substituted heteroaryl, –CxH2x – phenyl or - O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R10 is a substituent shown in Table 2 or a tautometer thereof; or R9 is a bond and R9 and R10 together form an oxaborol ring; R11 is hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; hetero-cycloalkyl or substituted hetero-cycloalkyl, aryl, heteroaryl, –CxH2x – phenyl or - O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R12 is hydrogen; substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted hetero-cycloalkyl or hetero-cycloalkyl, substituted aryl or aryl, heteroaryl or substituted heteroaryl; R13, R13ꞌ, R14 and R14ꞌ are independently hydrogen, hydroxy, halogen, amino, amino alkyl, cyano, C1-6 alkyl, C1-6 alkoxy, carbonyl, carboxamide, amide; or R13 and R13ꞌ or R14 and R14ꞌ together form a 3-8 membered cycloalkyl ring or 3-8 membered heterocycloalkyl ring, optionally substituted with oxygen.
nio, halogen, hydroxy, amino, cyano, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy, where the heteroatom in the heterocycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R15, R15ꞌ, R16 and R16ꞌ are independently hydrogen, hydroxy, halogen, amino, cyano, C1-6 alkyl, or C1-6 alkoxy; or R15 and R15ꞌ or R16 and R16ꞌ together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C1-6 alkyl, C3- 8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy, wherein the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R17, R17ꞌ, R18 and R18ꞌ are independently hydrogen, hydroxy, halogen, amino, cyano, C1-6 alkyl, or C1-6 alkoxy; or R17 and R18 or R17ꞌ and R18ꞌ together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C1-6 alkyl, C3 -8 cycloalkyl, C2-6 alkenyl or C1-6 alkoxy, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R19, R19ꞌ and R19ꞌꞌ are independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, phenyl, C1-6 alkylimidol, C1-6 alkyltriazole, C1-6 alkylthetrazole, C1-6 alkylthiazole, C1-6 alkyloxazole, C1-6 alkyldioxazole; C1-6 alkyloxazolidone; and R20 and R21 are independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, phenyl, C1-6 alkylimidizole, C1-6 alkyltriazole, C1-6 alkylthetrazole, C1-6 alkylthiazole, C1-6 alkyloxazole, C1-6 alkyldioxazole; C1-6 alkyloxazolidone, or R20 and R21 together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form carboxyl substituted pyrrolidinyl, carboxyl substituted piperidinyl or carboxyl substituted morpholinyl; and R22 and R22ꞌ are independently selected from hydrogen, oxygen, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C2 -6 alkenyl or C2-6 substituted alkenyl, aryl or substituted aryl, including substituted or unsubstituted C1-6 alkylimidizole, substituted or unsubstituted C1-6 alkylthiazole, C1-6 alkylthetrazole, C1-6 alkylthiazole, Substituted or unsubstituted C1-6 alkyloxazole, C1-6 alkyldioxazole; C1-6 alkyloxazolidone; -COR19, -COOR19ꞌ, -CSOR19ꞌꞌ, -CONR20R21, or a pharmaceutically acceptable salt thereof.
[6]
6. A compound of Formula I, Formula IA or Formula IB according to any of claims 1-5 or a pharmaceutically salt thereof, characterized by the fact that: R9 is a bond and R9 and R10 together form an oxaborol ring.
[7]
7. A compound of Formula I, Formula IA or Formula IB according to any one of claims 1-6 or a pharmaceutically salt thereof, characterized by the fact that: W is N; Y is C; R2 and R3 are independently selected from hydrogen, hydroxy, halogen, cyano, amino, uncle, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 alkoxy substituted; C3-8 cycloalkyl or substituted C3-8 cycloalkyl; C2-8 alkenyl or C2-8 substituted alkenyl; substituted 3- to 8-membered hetero-cycloalkyl or substituted 3- to 8-membered hetero-cycloalkyl, substituted aryl or aryl, substituted heteroaryl or heteroaryl, or –OR12; R5 and R6 are independently hydrogen, hydroxy, halogen, cyano, amino, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted ia, C2-8 alkenyl or substituted C2-8 alkenyl; aryl or substituted aryl
da, heteroaryl or substituted aryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R7 and R8 are independently hydrogen, hydroxy, halogen, cyano, amino, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted ia, C2-8 alkenyl or substituted C2-8 alkenyl; substituted aryl or aryl, heteroaryl or substituted aryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ, in whereas the 3- to 8-membered hetero-cycloalkyl ring is optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ; or R6 and R7 together form a 3- to 8-membered cycloalkyl ring or hetero-cycloalkyl ring comprising a heteroatom or two or more heteroatoms, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ, where the one heteroatom in the heteroalkyl ring is NR20, and the two or more heteroatoms are selected from N, NR22, O, S, SR22 and SR22R22ꞌ; or R7 and R8 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with R17, R17ꞌ, R18 and / or R18ꞌ, where the heteroatom in the hetero-cycloalkyl ring is O, N, NR22, S, SR22 or SR22R22ꞌ; R9 is a bond, hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkenyl, substituted hetero-cycloalkyl or substituted hetero-cycloalkyl, aryl or substituted aryl , heteroaryl or substituted heteroaryl, –CxH2x – phenyl or - O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R10 is a substituent shown in Table 2 or a tautomer.
the same; or R9 is a bond and R9 and R10 together form an oxaborol ring; R11 is hydrogen, hydroxy, halogen, cyano, amino, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C2-8 alkenyl or C2-8 substituted alkenyl; substituted aryl or aryl, heteroaryl or substituted aryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; R12 is hydrogen; C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 alkoxy substituted, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C3-8 hetero-cycloalkyl or C3-8 hetero-cycloalkyl substituted, aryl or substituted aryl, heteroaryl or substituted heteroaryl; and R22 and R22ꞌ are independently selected from hydrogen, oxygen, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 substituted alkoxy, C3-8 cycloalkyl or C3-8 cycloalkyl substituted, C2 -6 alkenyl or C2-6 substituted alkenyl, aryl or substituted aryl, -COR19, -COOR19ꞌ, -CSOR19ꞌꞌ, -CONR20R21.
[8]
A compound of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof according to any of claims 1-7, characterized by the fact that: W is N; Y is C; R1 is absent; R2 and R3 are independently selected from hydrogen, hydroxy, halogen,, C1-6 alkyl or substituted C1-6 alkyl, C1-6 alkoxy or C1-6 alkoxy substituted; C3-8 cycloalkyl or substituted C3-8 cycloalkyl; C2-8 alkenyl or C2-8 substituted alkenyl; or - OR12; R4 is H;
R6 and R7 together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ; R11 is H; and R15, R15ꞌ, R16 and / or R16ꞌ are independently hydrogen, hydroxy, halogen, amino, cyano, C1-6 alkyl, or C1-6 alkoxy.
[9]
9. Compound of Formula I, Formula IA or Formula IB or a pharmaceutically salt thereof according to any of claims 1-8, characterized by the fact that: W is N; Y is C: R1 is absent; R2 is halogen; R3 is OR12; and R4 is H.
[10]
10. A compound of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof according to any of claims 1-9, characterized by the fact that: W is N; Y is C; R1 is absent; R2 is halogen and R3 is –OR12; R4 is H; R6 and R7 together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ; R11 is H; and R15, R15ꞌ, R16 and / or R16ꞌ are independently C1-6 alkyl.
[11]
11. Formula I, Formula IA or Formula IB compound or pharmaceutically acceptable salt thereof according to any of claims 1-10,
characterized by the fact that: R6 and R7 together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ.
[12]
12. A compound of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof according to any of claims 1-11, characterized in that: R7 and R8 together form a 3- to 8-membered cycloalkyl ring or ring 3- to 8-membered hetero-cycloalkyl, optionally substituted with R17 and R18, where the heteroatom in the hetero-cycloalkyl ring is selected from O, N, NR22, S, SR22 or SR22R22ꞌ.
[13]
13. Compound, characterized by the fact that it is selected from the group: (4bR, 7aS) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6, 7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic; (4bS, 7aR) -2-chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1 , 2-h] [1,7] naphthyridine-10-carboxylic; (4bR, 7aS) -2-cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1 , 2 h] [1,7] naphthyridine-10-carboxylic; 2-Cyclopropyl-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [ 1.7] naphthyridine-10-carboxylic; (7aR) -2-cyclopropyl-4b-hydroxy-3- (3-methoxypropoxy) - 7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic; (7aR) -2-chloro-4b-hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-
h] [1,7] naphthyridine-10-carboxylic; (7aR) -2-chloro-4b-methoxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [1,7] naphthyridine-10-carboxylic; (4bR, 7aS) -2-Hydroxy-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo-4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1 , 2 h] [1,7] naphthyridine-10-carboxylic; (4bR, 7aS) -2-chloro-3-hydroxy-7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h ] [1,7] naphthyridine-10-carboxylic; 2-Chloro-6- (1-hydroxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -3- (3-methoxypropoxy) -2-methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-cyclopropyl-3- (cyclopropylmethoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-cyclopropyl-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylic; (R) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-methoxy-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-methoxy-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -3- (cyclopropylmethoxy) -2-hydroxy-10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-methoxy-3- (3-methoxypropoxy) -10-
oxo-6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-hydroxy-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -3- (3-methoxypropoxy) -10-oxo-2- (prop- 1-en-2-yl) -6,10-dihydro-5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-isopropyl-3- (3-methoxypropoxy) -10-oxo-6,10-dihydro-5H-pyrido [1,2-h] [1, 7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-chloro-3- (3-methoxypropoxy) -8-methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2- (hydroxymethyl) -3- (3-methoxypropoxy) - 10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [ 1.7] naphthyridine-9-carboxylic; (S) -6- (tert-Butyl) -2-cyclopropyl-11-hydroxy-3- (3-methoxypropoxy) -10-oxo-5,10-dihydro-6H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylic; (2-Chloro-3- (cyclopropylmethoxy) -6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9 acid -carboxylic; (2-Chloro-3- (cyclopropylmethoxy) -6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic acid; 2-Cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2-h] [ 1.7] naphthyridine-9-carboxylic acid; 2-Cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -6-methyl-10-oxo-5,10-dihydro-6H-pyrido [1,2 -h] [1,7] naphthyridine-9-carboxylic acid 6- (tert-butyl) -2-chloro-3- (cyclopropylmethoxy) -10-oxo- 6,10-dihydro-5H-pyrido [1 , 2-h] [1,7] naphthyridine-9-carboxylic acid; 2'-Chloro-3 '- (cyclopropylmethoxy) -10'-oxo-5', 10'-dihydrospiro [cyclobutane-1,6 ' -pyrido [1,2-h] [1,7] naphthyridine] -9'-carboxylic acid; 2 ', 3'-dimethoxy-10'-oxo-5', 10'-dihydrospiro [cyclobutane-1, 6'-pyrido [1,2-h] [1,7] naphthyridine] -9'-carboxylic acid; 6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido [2,1-f] [1,6] naphthyridine-9-carboxylic;
2-Chloro-3- (3-methoxypropoxy) -7,7-dimethyl-11-oxo- 4b, 5,6,7,7a, 11-hexahydrocyclopenta [f] pyrido [1,2-h] [ 1.7] naphthyridine-10-carboxylic; 3 '- (cyclopropylmethoxy) -2' - (difluoromethyl) -11'-fluoro-10'- oxo-5 ', 10'-dihydrospiro [cyclobutane-1,6'-pyrido [1,2-h] [1.7] naphthyridine] -9'-carboxylic; 2 '- (Difluoromethyl) -11'-fluoro-10'-oxo-3' - (((tetrahydrofuran-3-yl) methoxy) -5 ', 10'-dihydrospiro [cyclobutane-1,6' -pyrido [1,2-h] [1,7] naphthyridine] -9'-carboxylic; (S) -3- (Cyclopropylmethoxy) -2- (difluoromethyl) -11-fluoro-6-isopropyl-6-methyl-10-oxo-6,10-dihydro-5H-pyrido [1,2-h ] [1,7] naphthyridine-9-carboxylic; and (6S) -2- (difluoromethyl) -11-fluoro-6-isopropyl-6-methyl-10-oxo-3 - (((tetrahydrofuran-3-yl) methoxy) -6,10-dihydro -5H-pyrido [1,2-h] [1,7] naphthyridine-9-carboxylic; or a pharmaceutically acceptable salt or tautomer thereof.
[14]
14. Composed according to claim 1, characterized by the fact that it is selected from:,,,,,,,,,
,,,, or, or a pharmaceutically acceptable salt thereof.
[15]
A compound according to claim 1, characterized by the fact that the structure of which is: or a pharmaceutically acceptable salt thereof.
[16]
16. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[17]
17. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[18]
18. Composed according to claim 1, characterized by the fact that whose structure is:
, or a pharmaceutically acceptable salt thereof.
[19]
19. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[20]
20. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[21]
21. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[22]
22. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[23]
23. A compound according to claim 1, characterized
by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[24]
24. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[25]
25. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[26]
26. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[27]
27. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[28]
28. A compound according to claim 1, characterized by the fact that the structure of which is:, or a pharmaceutically acceptable salt thereof.
[29]
29. A Formula I, Formula IA or Formula IB compound according to any one of claims 1 - 28 or a pharmaceutically salt thereof, characterized by the fact that: (A) R5 and R6 are independently hydroxy, halogen, co - no, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, - CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R5 and R6 together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring, optionally substituted with R13, R13ꞌ, R14 and / or R14ꞌ, where the heteroatom in the hetero-cycloalkyl ring is selected from among O, N, NR22, S, SR22 or SR22R22ꞌ; and R7 and R8 are independently hydrogen, hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkylene; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or (B) R5 and R8 are independently hydrogen, hydroxy, halogen, cyano, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkylene; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; and
R6 and R7 together form a 3- to 8-membered cycloalkyl ring or 3- to 8-membered hetero-cycloalkyl ring comprising a heteroatom or two or more heteroatoms, optionally substituted with R15, R15ꞌ, R16 and / or R16ꞌ, where the one heteroatom in the heteroalkyl ring is NR20, and the two or more heteroatoms are selected from N, NR22, O, S, SR22 and SR22R22ꞌ; or (C) R5 and R6 are independently hydrogen, hydroxy, halogen, cyano, substituted alkyl or alkyl, substituted alkoxy or alkoxy, substituted cycloalkyl or cycloalkyl, substituted alkenyl or alkylene; aryl or substituted aryl, heteroaryl or substituted heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; and R7 and R8 are independently hydroxy, halogen, cyano, amino, substituted alkyl or alkyl, substituted alkoxy or alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl, –CxH2x – phenyl or –O – CxH2x – phenyl where x is 0, 1, 2, 3, 4, 5 or 6; or R7 and R8 together form a 3-8 membered cycloalkyl ring or 3-8 membered hetero-cycloalkyl ring, optionally substituted with R17, R18ꞌ, R17 and / or R18ꞌ, where the heteroatom in the hetero-cycloalkyl ring is selected among O, N, NR22, S, SR22 or SR22R22ꞌ.
[30]
30. A Formula I, Formula IA or Formula IB compound according to any one of claims 1-28, or a pharmaceutically salt thereof, the compound characterized by the fact that it is selected from the compounds in Table 1, and in which R10 is as described here or is a substituent shown in Table 2, or a tautomer thereof.
[31]
31. Method of treating or preventing a viral infection in an individual susceptible to or suffering from viral infection, characterized by the fact that it comprises administering to the individual an inhibitor of an HBe antigen or HBs in which the inhibitor is a compound of Formula I, Formula IA or Formula IB as defined in any of claims 1-30.
[32]
32. Method of treating or preventing hepatitis B virus infection in an individual susceptible to or suffering from hepatitis B virus infection, characterized by the fact that it comprises administering to the individual an inhibitor of an HBe antigen or HBs in which the inhibitor is a compound of Formula I, Formula IA or Formula IB as defined in any one of claims 1-30.
[33]
33. Method of treating or preventing hepatitis B virus infection in an individual susceptible to or suffering from hepatitis B virus infection, characterized by the fact that it comprises administering to the individual an inhibitor of an HBe antigen or HBs in which the inhibitor comprises a compound of Table 1 in which R10 is a substituent shown in Table 2 or tautomer thereof, or in which the inhibitor is a compound in Table IB.
[34]
34. Method of inhibiting the level of HBe or HBs antigen in a mammal, characterized by the fact that it comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt, solvate or hydrate thereof.
[35]
35. Method according to claim 34, characterized by the fact that the mammal is a human.
[36]
36. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I, Formula IA or Formula IB as defined in any of claims 1-30.
[37]
37. A Formula I, Formula IA or Formula IB compound according to any of claims 1-30, or a compound
pharmaceutical position according to claim 36, characterized by the fact that it is for use in therapy.
[38]
38. A Formula I, Formula IA or Formula IB compound according to any one of claims 1-30, or a pharmaceutical composition according to claim 36, characterized by the fact that it is for use in the treatment of a viral infection.
[39]
39. Compound according to claim 38, characterized by the fact that it is for use in the treatment of a viral infection, wherein the viral infection is an infection by the hepatitis B virus.
[40]
40. Use of a compound of Formula I, Formula IA or Formula IB as defined in any of claims 1-30, 38 or 39 or a pharmaceutical composition as defined in claim 36, characterized by the fact that it is for the manufacture of a medication for use in the treatment of an infection with hepatitis B virus in a human.
[41]
41. A pharmaceutically acceptable compound or salt according to any one of claims 1-30, characterized in that it is for use in medical therapy.
[42]
42. A pharmaceutically acceptable salt or compound according to any one of claims 1-30, characterized in that it is for use in the treatment of the prevention of a hepatitis B virus infection in a human.
[43]
43. A pharmaceutically acceptable salt or compound according to any one of claims 1-30, characterized in that it is for use in inhibiting the level of HBe or HBs antigen in a mammalian HBsAg in vitro.

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法律状态:
2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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US201762568633P| true| 2017-10-05|2017-10-05|

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US62/568,633|2017-10-05|

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US201762570509P| true| 2017-10-10|2017-10-10|

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US201862681146P| true| 2018-06-06|2018-06-06|

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