WO2020239656A1 - Nouveaux composés et compositions pharmaceutiques de ceux-ci pour le traitement de l'hépatite b - Google Patents

Nouveaux composés et compositions pharmaceutiques de ceux-ci pour le traitement de l'hépatite b Download PDF

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Publication number
WO2020239656A1
WO2020239656A1 PCT/EP2020/064364 EP2020064364W WO2020239656A1 WO 2020239656 A1 WO2020239656 A1 WO 2020239656A1 EP 2020064364 W EP2020064364 W EP 2020064364W WO 2020239656 A1 WO2020239656 A1 WO 2020239656A1
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independently selected
substituted
compound
unsubstituted
alkyl
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PCT/EP2020/064364
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English (en)
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Jacques Huck
Oscar MAMMOLITI
Adeline Marie Elise PALISSE
Sébastien Richard
Pascal Pierre Alexandre Savy
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Galapagos Nv
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Publication of WO2020239656A1 publication Critical patent/WO2020239656A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to compounds useful in the prophylaxis and/or treatment of hepatitis B virus (HBV).
  • HBV hepatitis B virus
  • the present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of hepatitis B virus by administering the compound of the invention.
  • HBV-related end-stage complications including cirrhosis of the liver, liver failure, and hepatocellular carcinoma (HCC), which occur decades post-exposure and represent the second leading cause of cancer death worldwide.
  • the hepatitis B virus belongs to the hepadnaviridae family and is a small, enveloped partially double-stranded DNA virus, consisting of 4 overlapping open reading frames (ORF) encoding respectively for the core, polymerase, envelope and X-proteins. (Gómez-Moreno and Garaigorta 2017)
  • HBV chronic hepatitis B
  • the infection starts with the HBV virion interacting with the hepatocytes via initial interaction with proteoglycans followed by entry of the virus to the hepatocyte via the sodium taurocholate transporter peptide (NTCP), the established entry factor for HBV (Huan et al, 2012). Internalisation is then followed unmasking of the outer protein coat of the viral particle to reveal the inner capsid, which is then transported to and enters the nucleus of the hepatocyte. This capsid is then disassembled, allowing the released DNA to be converted initially to relaxed circular DNA (rcDNA), which is in turn converted into the highly stable closed circular DNA (cccDNA) minichromosomal form of the virus DNA. The cccDNA then serves as the template for production of all viral RNA transcripts, which are then translated to the different viral proteins required for assembly of new infectious viral particles.
  • NTCP sodium taurocholate transporter peptide
  • Pegylated interferon (Peg-IFN)-a is an approved therapy now in use for chronic hepatitis B (CHB) which is intended to boost immune response resulting in HBeAg and HBsAg seroconversion, meaning the virus is then under the control of the host immune system, reducing circulating HBV DNA to undetectable levels, and placing the virus under the control of the host immune system.
  • CHB chronic hepatitis B
  • Peg-IFN-a treatment shows limited rate of success even after years of treatment (van Zonneveld et al.2004), moreover since IFN is associated with substantial adverse effects in many patients it is only used temporarily in a limited number of patients.
  • the second treatment type are nucleos(t)ide analogue reverse transcriptase inhibitors (NUCs) which act to suppressing HBV DNA formation in new viral particles, but have no effect on the cccDNA population (Sussman 2009).
  • NUCs nucleos(t)ide analogue reverse transcriptase inhibitors
  • Treatment with NUCs is associated with reduced liver necroinflammation, increased liver fibrosis regression rate, normalization of alanine aminotransferase (ALT) levels, reduced risk of liver cirrhosis, decompensation and HCC, and increased survival (Ruan et al.2013).
  • HBsAg decrease is generally very low; even with long-term therapy (5–7 years) (Buti et al.2015). It has been shown that even when HBV replication is well-controlled, HBsAg clearance is unlikely to occur during a patient’s lifetime (Chevaliez et al.2013). With this very low rate of HBsAg loss and the high rate of viral rebound and biochemical relapse that commonly occurs with discontinuation, lifelong NUC therapy is generally recommended for the majority of patients.
  • the present invention is based on the identification of novel compounds, for the prophylaxis and/or treatment of HBV.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of HBV by administering the compounds of the invention.
  • G is -OH, or C1-4 alkoxy
  • R1 is:
  • Each R2a and R2b is independently selected from:
  • R2a and R2b together with the atom to which they are attached may form a spirocyclic C 3-7 cycloalkyl ring;
  • R3 is
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb1,
  • cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb2,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,
  • R5 is H, -CN, halo, or C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo; each R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h is independently H or C 1-4 alkyl;
  • each Ra1 and Ra2 is independently:
  • - phenyl - 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,
  • - monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9b
  • - fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c
  • R9a, R9b, and R9c is independently selected from:
  • Each Rb1 and Rb2 is independently selected from:
  • each R10a and R10b is independently H or C 1-4 alkyl.
  • G is -OH, or C1-4 alkoxy
  • R1 is: - monocyclic C3-6 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkyl, or
  • Each R2a and R2b is independently selected from:
  • R2a and R2b together with the atom to which they are attached may form a spirocyclic C 3-7 cycloalkyl ring;
  • R3 is
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb1,
  • cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb2,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,
  • R5 is H, -CN, halo, or C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo; each R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h is independently H or C 1-4 alkyl;
  • each Ra1 and Ra2 is independently:
  • - monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9b
  • - fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c
  • R9a, R9b, and R9c is independently selected from:
  • Each Rb1 and Rb2 is independently selected from:
  • each R10a and R10b is independently H or C 1-4 alkyl.
  • the compounds of the invention are provided for use in the prophylaxis and / or treatment of hepatitis B.
  • the compounds of the invention exhibit good potency and exposure in vivo. This may result in low dosages regimen, and suitability for use alone or in combination with other medicaments.
  • the compounds of the invention may show a good safety profile.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • the further therapeutically active ingredient is an agent for the treatment of HBV.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly HBV, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine.
  • the pharmaceutical composition is for use in the prophylaxis and/or treatment of HBV.
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • the articles‘a’ and‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
  • an analogue means one analogue or more than one analogue.
  • Alkyl means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • alkyl groups are methyl (-CH 3 ), ethyl (-CH 2 -CH 3 ), n-propyl (-CH 2 -CH 2 -CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (- CH 2 -CH 2 -CH 2 -CH 3 ), tert-butyl (-CH 2 -C(CH 3 ) 3 ), sec-butyl (-CH 2 -CH(CH 3 ) 2 ), n-pentyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), n-hexyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), and 1,2-dimethylbutyl (-CHCH 3 )-C(CH 3 )H 2 -CH 2 -CH 3 ).
  • Particular alkyl groups have between 1 and 4 carbon atoms.
  • Alkylene refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH 3 )- and the like.
  • Alkynylene refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CoC-, -CH2- CoC-, and -C(CH 3 )H-CoCH-.
  • Alkoxy refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C1-6 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Amino refers to the radical -NH2.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified.
  • the term includes groups that include from 6 to 10 ring members.
  • Particular aryl groups include phenyl, and naphthyl.
  • Cycloalkyl refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified.
  • a cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Halo or‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • polycyclic refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two (bicyclic) or three rings of atoms (tricyclic), most particularly two rings of atoms.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom.
  • hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • Heteroaryl means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the aromatic ring structure may have from 5 to 9 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.
  • Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  • Heterocycloalkyl means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g.1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g.
  • heterocycloalkenyl means a‘heterocycloalkyl’, which comprises at least one double bond.
  • heterocycloalkenyl groups are shown in the following illustrative examples:
  • each W and Y is independently selected from -CH2-, -NH-, -O- and–S-.
  • each W and Y is independently selected from -CH2-, -NH-, -O- and–S-.
  • each W and Y is independently selected from -CH2-, -NH-, -O- and–S- and each Z is selected from N or CH.
  • each Y is selected from -CH 2 -, -NH-, -O- and–S-.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • Thiol refers to the group -SH.
  • term‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
  • Thioalkoxy refers to the group–S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-C1-6 alkyl.
  • Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n- thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy.
  • Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • “Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • “Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvation reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, EtOH, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • ‘Solvate’ encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • Subject includes humans.
  • the terms‘human’,‘patient’ and‘subject’ are used interchangeably herein.
  • Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • The“effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Preventing refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop) in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • prophylactic measures is related to‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • ‘Treating’ or‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • ‘treating’ or‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • ‘treating’ or‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treating” or“treatment” relates to slowing the progression of the disease.
  • inflammatory disease(s) refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints.
  • allergic airway disease e.g. asthma, rhinitis
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • endotoxin-driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure
  • the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases
  • HBV Hepatitis B virus
  • hepatitis B virus refers to a species of viruses of the genus Orthohepadnavirus. This virus causes hepatitis B.
  • HBcAg refers to hepatitis B virus core antigen. It is an indicator of hepatitis B viral replication. This antigen forms the inner capsid of the hepatitis B virus. HBcAg may be secreted into blood as naked capsids.
  • HBeAg refers to a particular secreted hepatitis B viral protein and its presence in the serum of patients can serve as a marker of active replication of the hepatitis B virus in chronic hepatitis patients.
  • HBsAg refers to the hepatitis B viral surface antigen family of three proteins, which form the outer protein coat of the HBV virion. It is secreted into blood both as a part of viral particles, but also as non-infectious protein complexes containing only HBsAg, and can serve as a marker of active replication of the hepatitis B virus in chronic hepatitis patients.
  • HBV DNA refers to the DNA of HBV. This DNA is often found in the blood. It is secreted into the blood only inside viral particles, and can be used as a marker of active replication of hepatitis B virus in chronically infected patients.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the C1-8 alkyl, C2-8 alkenyl, C6-10 unsubstituted or substituted aryl, and (C6-10 aryl)-(C1-4 alkyl) esters of the compounds of the invention.
  • the present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the‘natural isotopic form’) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an‘unnatural variant isotopic form’). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • the term“unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an ‘uncommon isotope’) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an‘isotopically enriched variant form’).
  • the term‘unnatural variant isotopic form’ also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36Cl), chlorine-37 (37Cl), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e. 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11C, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Stereoisomers that are not mirror images of one another are termed‘diastereomers’ and those that are non-superimposable mirror images of each other are termed‘enantiomers’.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a‘racemic mixture’.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of p electrons and an atom (usually h). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • the present invention is based on the identification of novel compounds, for the prophylaxis and/or treatment of HBV.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of HBV by administering the compounds of the invention.
  • the compounds of the invention are provided having a Formula I:
  • G is -OH, or C1-4 alkoxy
  • R1 is:
  • Each R2a and R2b is independently selected from:
  • o C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo; and - 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected:
  • R2a and R2b together with the atom to which they are attached may form a spirocyclic C3-7 cycloalkyl ring;
  • R3 is
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb1,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb2,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,
  • R5 is H, -CN, halo, or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; each R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h is independently H or C1-4 alkyl;
  • each Ra1 and Ra2 is independently:
  • - monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9b
  • - fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c
  • R9a, R9b, and R9c is independently selected from:
  • Each Rb1 and Rb2 is independently selected from:
  • each R10a and R10b is independently H or C 1-4 alkyl.
  • G is -OH, or C1-4 alkoxy
  • Each R2a and R2b is independently selected from:
  • R2a and R2b together with the atom to which they are attached may form a spirocyclic C 3-7 cycloalkyl ring;
  • R3 is
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb1,
  • cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb2,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,
  • R5 is H, -CN, halo, or C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo; each R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h is independently H or C 1-4 alkyl;
  • each Ra1 and Ra2 is independently:
  • - phenyl - 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,
  • - monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9b
  • - fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c
  • R9a, R9b, and R9c is independently selected from:
  • Each Rb1 and Rb2 is independently selected from:
  • each R10a and R10b is independently H or C 1-4 alkyl.
  • the compound of the invention is according to Formula I, wherein R5 is -CN, halo, or C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo.
  • R5 is -CN, -CH 3 , -CF 3 , F, Cl or Br.
  • the compound of the invention is according to Formula I, wherein R5 is H.
  • the compound of the invention is according to Formula I, wherein G is OH.
  • the compound of the invention is according to Formula I, wherein G is C 1-4 alkoxy. In a particular embodiment, G is–OCH 3 , -OCH2CH 3 , -OCH(CH 3 ) 2 or -OC(CH 3 )3. In a more particular embodiment, G is -OCH(CH 3 ) 2 . [0096] In one embodiment, the compound of the invention is according to Formula II:
  • the compound of the invention is according to Formula I or II, wherein R1 is C3-6 cycloalkyl.
  • R1 is cyclopropyl.
  • R1 is cyclobutyl.
  • the compound of the invention is according to Formula I or II, wherein R1 is C3-6 cycloalkyl substituted with one or more independently selected halo, or C1-4 alkyl.
  • R1 is cyclopropyl, or cyclobutyl, each of which is substituted with one or more independently selected halo or C1-4 alkyl.
  • R1 is C3-6 cycloalkyl substituted with one or more independently selected F or–CH 3 .
  • R1 is cyclopropyl, or cyclobutyl, each of which is substituted with one, or two independently selected F or–CH 3 .
  • R1 is cyclopropyl substituted with one F or–CH 3 .
  • the compound of the invention is according to Formula I or II, wherein R1 is
  • the compound of the invention is according to Formula I or II, wherein R1 is spirocyclic C6-10 cycloalkyl.
  • R1 is spiro[3.3]heptane.
  • the compound of the invention is according to Formula III:
  • the compound of the invention is according to Formula I, II or III, wherein R2a is H.
  • the compound of the invention is according to Formula I, II or III, wherein R2a is C 1-4 alkyl.
  • R2a is aboutCH 3 , -CH 2 CH 3 ,–CH(CH 3 ) 2 or–C(CH 3 ) 3 .
  • R2a is–CH 3 .
  • the compound of the invention is according to Formula I, II or III, wherein R2a is C3-7 cycloalkyl.
  • R2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R2a is cyclopropyl or cyclobutyl.
  • the compound of the invention is according to Formula I, II or III, wherein R2a is C3-7 cycloalkyl substituted with one or more independently selected C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected -CH 3 , -CH2CH 3 , -CF3, -CHF2, -CH2CF3, -OCH 3 , -OCH2CH 3 , or -OCF3.
  • R2a is cyclopropyl substituted with one -CH 3 , -CH2CH 3 , -CF3, CHF2, -CH2CF3, -OCH 3 , -OCH2CH 3 , or -OCF3.
  • the compound of the invention is according to Formula I, II or III, wherein R2a is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms. In a particular embodiment, R2a is oxetanyl.
  • the compound of the invention is according to Formula I, II or III, wherein R2a is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms, substituted with one or more independently selected C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2a is oxetanyl substituted with one or more independently selected C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2a is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms, substituted with one or more independently selected -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , or -OCF 3 .
  • R2a is oxetanyl substituted with one or more independently selected -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , or -OCF 3 .
  • R2a is oxetanyl substituted with one -CH 3 .
  • the compound of the invention is according to Formula I, II, or III, wherein R2a and R2b together with the atom to which they are attached may form a spirocyclic C 3-7 cycloalkyl ring.
  • R2a and R2b together with the atom to which they are attached form a spirocyclic ring, which ring is selected from cyclopropyl, cyclobutyl, or cyclopentyl.
  • R2a and R2b together with the atom to which they are attached form a spirocyclic ring, which ring is cyclobutyl.
  • the compound of the invention is according to Formula IV:
  • the compound of the invention is according to Formula I, II, III or IV, wherein R2b is H.
  • the compound of the invention is according to Formula I, II, III or IV, wherein R2b is C 1-4 alkyl.
  • R2b is aboutCH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 or -C(CH 3 ) 3 .
  • R2b is–CH 3 , or -CH 2 CH 3 .
  • R2b is -CH 3 .
  • the compound of the invention is according to Formula I, II, III or IV, wherein R2b is C 3-7 cycloalkyl.
  • R2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R2b is cyclopropyl or cyclobutyl.
  • the compound of the invention is according to Formula I, II, III or IV, wherein R2b is C 3-7 cycloalkyl substituted with one or more independently selected C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected -CH 3 , -CH 2 CH 3 , -CF 3 , CHF 2 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , or -OCF 3 .
  • R2b is cyclopropyl substituted with one -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , or -OCF 3 .
  • the compound of the invention is according to Formula I, II, III or IV, wherein R2b is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms. In a particular embodiment, R2b is oxetanyl.
  • the compound of the invention is according to Formula I, II, III or IV, wherein R2b is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms, substituted with one or more independently selected C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is oxetanyl substituted with one or more independently selected C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms, substituted with one or more independently selected - CH 3 , -CH2CH 3 , -CF3, CHF2, -CH2CF3, -OCH 3 , -OCH2CH 3 , or -OCF3.
  • R2b is oxetanyl substituted with one or more independently selected -CH 3 , -CH2CH 3 , -CF3, -CHF2, -CH2CF3, -OCH 3 , -OCH2CH 3 , or -OCF3. In a most particular embodiment, R2b is oxetanyl substituted with one -CH 3 .
  • the compound of the invention is according to Formulae Va or Vb:
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is H
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is -SO 2 -C 1-4 alkyl. In a particular embodiment, R4 is–SO 2 CH 3 , or–SO 2 CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is halo.
  • R4 is F, Cl or Br.
  • R4 is F or Cl.
  • R4 is Cl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is–CN.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is C 1-4 alkyl.
  • R4 is aboutCH 3 , -CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is C 1-4 alkyl substituted with one or more independently selected Ra2 groups.
  • R4 is C 1-4 alkyl substituted with one, two or three independently selected Ra2 groups.
  • R4 is C1-4 alkyl substituted with one Ra2 group.
  • R4 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , or -CH(CH 3 ) 2 , each of which substituted with one, two or three independently selected Ra2 groups.
  • R4 is– CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , or -CH(CH 3 ) 2 , each of which substituted with one Ra2 group.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is halo. In a particular embodiment, one or more independently selected Ra2 is F or Cl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is–CN.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is–OH.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is -SO2-C1-4 alkyl. In a particular embodiment, one or more independently selected Ra2 is -SO2CH 3 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is C1-4 alkoxy.
  • Ra2 is -OCH 3 , -OCH2CH 3 , or–OCH(CH 3 ) 2 .
  • one or more independently selected Ra2 is -OCH 3 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is phenyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.
  • one or more independently selected Ra2 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is C 3-7 cycloalkyl.
  • Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is C 3-7 cycloalkyl substituted with one or more independently selected R9a.
  • Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R9a.
  • one or more independently selected Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two of three independently selected R9a.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one, or more independently selected R9b.
  • one or more independently selected Ra2 is monocyclic 4-7 membered heterocycloalkyl comprising one, two or three heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one, or more independently selected R9b.
  • one or more independently selected Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is unsubstituted or substituted with one or more independently selected R9b.
  • one or more independently selected Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is unsubstituted or substituted with one, two of three independently selected R9b.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is fused/spiro/bridged 4- 10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • one or more independently selected Ra2 is 2,6-diazaspiro[3.3]heptanyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is as previously defined and one or more independently selected Ra2 is fused/spiro/bridged 4- 10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c.
  • one or more independently selected Ra2 is fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one, two or three independently selected R9c.
  • one or more independently selected Ra2 is 2,6-diazaspiro[3.3]heptanyl each of which is unsubstituted or substituted with one or more independently selected R9c.
  • one or more independently selected Ra2 is 2,6- diazaspiro[3.3]heptanyl each of which is unsubstituted or substituted with one, two of three independently selected R9c.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , or–CH 2 OCH 3 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is phenyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is phenyl substituted with one more independently selected Rb2. In a further embodiment, R4 is phenyl substituted with one, two or three independently selected Rb2. In a particular embodiment, each Rb2 is independently selected from halo, C 1-4 alkyl unsubstituted or substituted with one C 1-4 alkoxy, and C 1-4 alkoxy. In a particular embodiment, each Rb2 is independently selected from F, Cl,–CH 3 , or -OCH 3 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.
  • R4 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl.
  • R4 is thiazolyl, thienyl, oxazolyl, or furanyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is substituted with one or more independently selected Rb2.
  • R4 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is substituted with one, two or three independently selected Rb2.
  • R4 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is substituted with one, two or three independently selected Rb2.
  • R4 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl, each of which is substituted with one, two or three independently selected Rb2.
  • each Rb2 is independently selected from halo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy.
  • each Rb2 is independently selected from F, Cl,–CH 3 , or -OCH 3 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is C3-7 cyclolalkyl.
  • R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R4 is cyclopropyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is C3-7 cyclolalkyl, which cycloalkyl is substituted with one or more independently selected Rb2.
  • R4 is C3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb2.
  • R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three independently selected Rb2.
  • each Rb2 is independently selected from halo, oxo, C 1-4 alkyl unsubstituted or substituted with one C 1-4 alkoxy, and C 1-4 alkoxy. In a further most particular embodiment, each Rb2 is independently selected from F, Cl, oxo,–CH 3 , or -OCH 3 .
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • R4 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one or more independently selected Rb2.
  • R4 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one, two or three independently selected Rb2.
  • R4 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one, two or three independently selected Rb2.
  • R4 is pyrolidinyl substituted with one, two or three independently selected Rb2.
  • each Rb2 is independently selected from halo, oxo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy.
  • each Rb2 is independently selected from F, Cl, oxo,–CH 3 , or -OCH 3 .
  • R 7f is selected from H, -CH 3 , or -CH2CH 3 .
  • R 4 is -NFh.
  • the compound of the invention is according to Formulae Via or VIb:
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is halo. In a particular embodiment, R 3 is F or Cl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is -OH.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is -CN.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is C 1-4 alkyl.
  • R 3 is -G3 ⁇ 4, -CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is C H alkyl substituted with one or more independently selected R al groups.
  • R 3 is C 1-4 alkyl substituted with one, two or three independently selected R al groups.
  • R 3 is C 1-4 alkyl substituted with one R al group.
  • R 3 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , or -CH(CH 3 ) 2 , each of which substituted with one, two or three independently selected R al groups.
  • R 3 is - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , or -CH(CH 3 ) 2 , each of which substituted with one R al group.
  • R 3 is -CH 2 -R 31 , -CH 2 CH 2 -R 31 , or -CH 2 CH 2 CH 2 -R 31 .
  • R 3 is -CH 2 CH 2 CH 2 -R 31 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is Ci- 6 alkoxy.
  • R 3 is -OCH 3 , -OCH 2 CH 3 ,
  • R 3 is -OCH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH(CH 3 ) 2 or -OCH(CH 2 CH 3 ) 2 .
  • R 3 is -OCH 3 .
  • R 3 is -OCH 2 CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is C 1-4 alkoxy.
  • R 3 is -OCH 3 , -OCH 2 CH 3 ,
  • R 3 is -OCH 3 . In another more particular embodiment, R 3 is -OCH2CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is Ci- 6 alkoxy substituted with one or more independently selected R al groups. In a particular embodiment, R 3 is Ci- 6 alkoxy substituted with one, two or three independently selected R al groups. In a more particular embodiment, R 3 is Ci- 6 alkoxy substituted with one R al group. In most particular embodiment, R 3 is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 or -OCH(CH 3 ) 2 , each of which substituted with one, two or three independently selected R al groups.
  • R 3 is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 or -OCH(CH 3 ) 2 , each of which substituted with one R al group.
  • R 3 is -OCH 2 -R 31 , -OCH 2 CH 2 -R 31 , -OCH(CH 3 )-R al , or -OCH 2 CH 2 CH 2 -R 31 .
  • R 3 is -OCFFCH 2 CH 2 -R 31 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is C 1-4 alkoxy substituted with one or more independently selected R al groups.
  • R 3 is C 1-4 alkoxy substituted with one, two or three independently selected R al groups.
  • R 3 is C 1-4 alkoxy substituted with one R al group.
  • R 3 is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 or -OCH(CH 3 ) 2 , each of which substituted with one, two or three independently selected R al groups.
  • R 3 is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 or -OCH(CH ,) 2 . each of which substituted with one R al group.
  • R 3 is -OCH 2 -R 31 , -OCH 2 CH 2 -R 31 , -OCH(CH 3 )-R al , or -OCFFCH 2 CH 2 -R 31 .
  • R 3 is -OCFFCH 2 CH 2 -R 31 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is as previously defined and one or more independently selected R al is halo. In a particular embodiment, one or more independently selected R al is F or Cl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is as previously defined and one or more independently selected R al is -CN.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R 3 is as previously defined and one or more independently selected R al is -OH.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is -SO2-C1-4 alkyl. In a particular embodiment, one or more independently selected Ra1 is -SO2CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is C1-4 alkoxy.
  • one or more independently selected Ra1 is -OCH 3 , -OCH2CH 3 , or–OCH(CH 3 ) 2 .
  • one or more independently selected Ra1 is -OCH 3 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is phenyl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.
  • one or more independently selected Ra1 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is C 3-7 cycloalkyl.
  • one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is C 3-7 cycloalkyl substituted with one or more independently selected R9a.
  • one or more independently selected Ra1 is C 3-7 cycloalkyl substituted with one, two or three independently selected R9a.
  • one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R9a.
  • one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two of three independently selected R9a.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is C 3-7 cycloalkyl substituted with one or more independently selected R9a.
  • one or more independently selected Ra1 is C3-7 cycloalkyl substituted with one, two or three independently selected R9a.
  • one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R9a.
  • one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two of three independently selected R9a.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • one or more independently selected Ra1 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9b.
  • one or more independently selected Ra1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one, two or three independently selected R9b.
  • one or more independently selected Ra1 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is unsubstituted or substituted with one or more independently selected R9b.
  • one or more independently selected Ra1 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is unsubstituted or substituted with one, two of three independently selected R9b.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is fused/spiro/bridged 4- 10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • one or more independently selected Ra1 is 2,6-diazaspiro[3.3]heptanyl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as previously defined and one or more independently selected Ra1 is fused/spiro/bridged 4- 10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c.
  • one or more independently selected Ra1 is fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one, two or three independently selected R9c.
  • one or more independently selected Ra1 is 2,6-diazaspiro[3.3]heptanyl each of which is unsubstituted or substituted with one or more independently selected R9c.
  • one or more independently selected Ra1 is 2,6- diazaspiro[3.3]heptanyl each of which is unsubstituted or substituted with one, two of three independently selected R9c.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is phenyl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is phenyl substituted with one more independently selected Rb1. In a particular embodiment, R3 is phenyl substituted with one, two or three independently selected Rb1. [0176] In one embodiment, the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.
  • R3 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, furanyl, pyridinyl, pyrimidinyl, or pyrazinyl.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is substituted with one or more independently selected Rb1.
  • R3 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is substituted with one, two or three independently selected Rb1.
  • R3 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, furanyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, two or three independently selected Rb1.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is C3-7 cyclolalkyl.
  • R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R3 is cyclopropyl.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is C 3-7 cyclolalkyl, which cycloalkyl is substituted with one or more independently selected Rb1.
  • R3 is C 3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb1.
  • R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three independently selected Rb1.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is–O-C 3-7 cyclolalkyl.
  • R3 is–O-cyclopropyl,–O-cyclobutyl, –O-cyclopentyl, or–O-cyclohexyl.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is–O-C 3-7 cyclolalkyl, which cycloalkyl is substituted with one or more independently selected Rb1.
  • R3 is–O-C 3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb1.
  • R3 is –O-cyclopropyl, –O-cyclobutyl,–O-cyclopentyl, or–O-cyclohexyl, each of which is substituted with one, two or three independently selected Rb1.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • R3 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one or more independently selected Rb1.
  • R3 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one, two or three independently selected Rb1.
  • R3 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one, two or three independently selected Rb1.
  • R3 is pyrolidinyl substituted with one, two or three independently selected Rb1.
  • the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is–O-heterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • R3 is -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-dioxanyl, -O-azetidinyl, -O-pyrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl, or -O-thiomorpholinyl.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is–O-heterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one or more independently selected Rb1.
  • R3 is– O-heterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one, two or three independently selected Rb1.
  • R3 is –O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-dioxanyl, -O-azetidinyl, -O-pyrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl, or -O-thiomorpholinyl, each of which is substituted with one, two or three independently selected Rb1.
  • R3 is -O-pyrolidinyl substituted with one, two or three independently selected Rb1.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as described previously, and Rb1 is halo.
  • Rb1 is F or Cl.
  • Rb1 is F.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as described previously, and Rb1 is oxo.
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as described previously, and Rb1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • Rb1 is azetidinyl, oxetanyl, pyrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, dioxanyl, or piperazinyl.
  • Rb1 is pyrolidinyl.
  • R6c is selected from H,–CH 3 , or–CH2CH 3 .
  • R6f is selected from H,–CH 3 , or–CH 2 CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is -NR6gR6h, wherein each R6g and R6h is independently selected from H, or C 1-4 alkyl. In a particular embodiment, each R6g and R6h is independently selected from H,–CH 3 , or–CH 2 CH 3 . In a more particular embodiment, R3 is–NH 2 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is–OCH 2 CH 2 CH 3 ,–OCH 2 CH 2 CH 2 -OCH 3 ,–O-cyclobutyl,–OCH 2 -cyclopropyl,–OCH(CH 3 )- cyclopropyl,–OCH 2 -cyclobutyl, or–OCH 2 C(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-VIb, wherein X is–S-.
  • the compound of the invention is selected from:
  • Cpd_002 9-chloro-1-cyclopropyl-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_003 5-tert-butyl-1-cyclopropyl-9-fluoro-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_004 1-cyclopropyl-9-fluoro-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_005 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_006 5-tert-butyl-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_007 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_008 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_009 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_010 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid
  • Cpd_011 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_012 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_013 9-chloro-1-cyclopropyl-8-methoxy-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_015 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_016 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_017 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_018 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_019 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_020 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_021 9-chloro-1-cyclopropyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_022 9-chloro-1-cyclopropyl-8-wasopropoxy-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_023 9-chloro-1-cyclopropyl-8-propoxy-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid
  • Cpd_024 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid
  • Cpd_025 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6-dioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_026 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_028 9-chloro-8-(3-methoxypropoxy)-1-(trans-2-methylcyclopropyl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_029 9-chloro-1-cyclopentyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_030 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2R)-2-methylcyclopropyl]-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_031 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2S)-2-methylcyclopropyl]-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_032 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_033 9-chloro-1-cyclopropyl-8-(3-methoxy-1-methyl-propoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_034 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_035 1-cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_036 isopropyl 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylate,
  • Cpd_037 isopropyl 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2-oxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylate,
  • Cpd_038 1-cyclobutyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_039 1-cyclopropyl-9-(methoxymethyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_040 7-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_041 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,
  • Cpd_042 isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_043 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyran-4-yloxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_044 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_045 9-chloro-8-(cyclobutoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_046 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_048 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_050 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_051 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_052 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_053 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_054 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-propoxy-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_055 1,9-dicyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_056 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-phenyl-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_058 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-thiazol-4-yl-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_059 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,
  • Cpd_060 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_061 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_062 9-chloro-8-(cyclohexoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_063 9-chloro-8-(cyclohexoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_065 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_066 (5R)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_068 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(2R)-tetrahydrofuran-2-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_069 9-chloro-1-(3,3-difluorocyclobutyl)-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_070 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_071 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(3S)-tetrahydrofuran-3-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_072 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(3R)-tetrahydrofuran-3-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_073 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_074 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_075 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-(2-thienyl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_076 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-oxazol-2-yl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_077 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,
  • Cpd_078 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_079 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-(tetrahydropyran-4-ylmethoxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_080 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid
  • Cpd_081 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-tetrahydropyran-4-yloxy-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_082 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(tetrahydropyran-4-ylmethoxy)-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_083 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_084 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,
  • Cpd_086 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_087 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_088 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_089 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-thiazol-2-yl-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_090 1-cyclopropyl-9-(2-furyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_091 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-thienyl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_092 9-chloro-1-cyclopropyl-5-methyl-8-(1-methylpyrazol-4-yl)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_093 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_094 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_096 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-(2-oxopyrrolidin-1-yl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_097 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_099 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyran-4-yloxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_100 9-chloro-1-cyclopropyl-8-[[(2S)-1,4-dioxan-2-yl]methoxy]-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_101 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_102 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_103 9-chloro-1-cyclopropyl-8-ethoxy-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_104 9-(2-carboxyethylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_105 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methylthiazol-2-yl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_106 9-cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_107 1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_108 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_109 1-cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_110 1-cyclopropyl-9-(dimethylcarbamoyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_111 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(methylcarbamoyl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_112 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_113 9-chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2-yl]methoxy]-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_114 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiochromeno[4,3- b]pyridine-3-carboxylic acid 6,6-dioxide,
  • Cpd_115 1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-9-(thiazol-4-yl)-1,5-dihydro-2H- thiochromeno[4,3-b]pyridine-3-carboxylic acid 6,6-dioxide,
  • Cpd_116 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_117 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,
  • Cpd_118 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_119 9-chloro-1,8-dicyclopropyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_120 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_121 9-chloro-1,8-dicyclopropyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_122 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid
  • Cpd_123 9'-chloro-1'-cyclopropyl-8'-(3-methoxypropoxy)-2',6',6'-trioxo-spiro[cyclobutane-1,5'- thiochromeno[4,3-b]pyridine]-3'-carboxylic acid,
  • the compound of the invention is selected from
  • Cpd_125 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-furyl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_126 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-thiazol-2-yl-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_127 1,9-dicyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_128 1-cyclopropyl-9-(difluoromethyl)-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_129 1-cyclopropyl-9-iodo-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_130 9-chloro-1-cyclopropyl-8-[(2-methyloxetan-2-yl)methoxy]-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_131 9-chloro-1-cyclopropyl-8-(oxetan-3-ylmethoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,
  • Cpd_132 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]methoxy]-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_133 9-chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid,
  • Cpd_134 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-(2-thienyl)-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_135 9-cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_136 1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid
  • Cpd_137 1-cyclopropyl-9-(dimethylcarbamoyl)-8-(3-methoxypropoxy)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • Cpd_138 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid
  • Cpd_139 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_140 1-cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_141 1-cyclopropyl-8-(3-methoxypropoxy)-9-(5-methyl-2-thienyl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_142 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-(3-thienyl)-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_143 1-cyclopropyl-8-(3-methoxypropoxy)-9-(1-methylpyrazol-3-yl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,
  • Cpd_144 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-(trifluoromethyl)-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,
  • Cpd_145 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2-oxo-5H-thiochromeno[4,3-b]pyridine-3- carboxylic acid, and
  • Cpd_146 9-chloro-8-isobutoxy-2,6,6-trioxo-1-(1,2,2,3,3-pentadeuteriocyclopropyl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid
  • the compound of the invention is 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid.
  • the compound of the invention is not 9-chloro-1-cyclopropyl-8-isobutoxy- 2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid.
  • the compounds of the invention are provided in a natural isotopic form.
  • the compounds of the invention are provided in an unnatural variant isotopic form.
  • the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention.
  • the atoms of the compounds of the invention are in an isotopic form which is not radioactive.
  • one or more atoms of the compounds of the invention are in an isotopic form which is radioactive.
  • radioactive isotopes are stable isotopes.
  • the unnatural variant isotopic form is a pharmaceutically acceptable form.
  • a compound of the invention whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples. [0207] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.
  • a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
  • G is -OH, or C 1-4 alkoxy
  • Each R2a and R2b is independently selected from:
  • R2a and R2b together with the atom to which they are attached may form a spirocyclic C3-7 cycloalkyl ring;
  • R3 is
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb1,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heterocycloalkyl comprises one or more heteroatoms independently selected from O, N, or S, and which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb2,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,
  • R5 is H, -CN, halo, or C1-4 alkyl unsubstituted or substituted with one or more independently selected halo; each R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h is independently H or C1-4 alkyl;
  • each Ra1 and Ra2 is independently: - halo
  • - monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9b
  • - fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c
  • R9a, R9b, and R9c is independently selected from:
  • Each Rb1 and Rb2 is independently selected from:
  • each R10a and R10b is independently H or C 1-4 alkyl
  • G is -OH, or C1-4 alkoxy
  • Each R2a and R2b is independently selected from:
  • R2a and R2b together with the atom to which they are attached may form a spirocyclic C3-7 cycloalkyl ring;
  • R3 is
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb1,
  • cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heterocycloalkyl comprises one or more heteroatoms independently selected from O, N, or S, and which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,
  • heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is unsubstituted or substituted with one or more independently selected Rb2,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,
  • R5 is H, -CN, halo, or C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo; each R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h is independently H or C 1-4 alkyl;
  • each Ra1 and Ra2 is independently:
  • - monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9b
  • - fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one or more independently selected R9c
  • R9a, R9b, and R9c is independently selected from:
  • Each Rb1 and Rb2 is independently selected from:
  • each R10a and R10b is independently H or C 1-4 alkyl
  • R2a is -CH 3 , CH2CH 3 ,–CH(CH 3 ) 2 or–C(CH 3 )3.
  • R2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected -CH 3 , -CH2CH 3 , -CF3, -CHF2, -CH2CF3, -OCH 3 , -OCH2CH 3 , or -OCF3.
  • R2a is cyclopropyl substituted with one -CH 3 , -CH2CH 3 , -CF3, -CHF2, -CH2CF3, -OCH 3 , -OCH2CH 3 , or -OCF3.
  • R2a is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms.
  • R2a is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms, substituted with one or more independently selected C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2a is oxetanyl substituted with one or more independently selected C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is C3-7 cycloalkyl substituted with one or more independently selected C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected -CH 3 , -CH 2 CH 3 , -CF 3 , CHF 2 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , or -OCF 3 .
  • R2b is cyclopropyl substituted with one -CH 3 , -CH 2 CH 3 , -CF 3 , CHF 2 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , or -OCF 3 .
  • R2b is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms.
  • R2b is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms, substituted with one or more independently selected C 1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C 1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is oxetanyl substituted with one or more independently selected C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo.
  • R2b is oxetanyl substituted with one or more independently selected -CH 3 , -CH2CH 3 , -CF3, CHF2, -CH2CF3, -OCH 3 , -OCH2CH 3 , or -OCF3.
  • Ra2 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.
  • Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is unsubstituted or substituted with one, two of three independently selected R9b.
  • Ra2 is 2,6- diazaspiro[3.3]heptanyl each of which is unsubstituted or substituted with one, two of three independently selected R9c.
  • each Rb2 is independently selected from halo, C 1-4 alkyl unsubstituted or substituted with one C 1-4 alkoxy, and C 1-4 alkoxy.
  • each Rb2 is independently selected from F, Cl,–CH 3 , or -OCH 3 .
  • R4 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S, which heteroaryl is substituted with one, two or three independently selected Rb2.
  • each Rb2 is independently selected from halo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy.
  • each Rb2 is independently selected from F, Cl,–CH 3 , or -OCH 3 .
  • each Rb2 is independently selected from halo, oxo, C 1-4 alkyl unsubstituted or substituted with one C 1-4 alkoxy, and C 1-4 alkoxy.
  • each Rb2 is independently selected from F, Cl, oxo,–CH 3 , or -OCH 3 .
  • R4 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one, two or three independently selected Rb2.
  • R4 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one, two or three independently selected Rb2.
  • each Rb2 is independently selected from halo, oxo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy.
  • each Rb2 is independently selected from F, Cl, oxo,–CH 3 , or -OCH 3 .
  • R3 is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 , or -OCH(CH 3 ) 2 , each of which substituted with one, two or three independently selected Ra1 groups.
  • Ra1 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.
  • Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two of three independently selected R9a.
  • Ra1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • Ra1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, unsubstituted or substituted with one, two or three independently selected R9b.
  • R3 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.
  • R3 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, furanyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, two or three independently selected Rb1.
  • R3 is–O-cyclopropyl,–O-cyclobutyl,–O-cyclopentyl, or–O-cyclohexyl, each of which is substituted with one, two or three independently selected Rb1.
  • R3 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.
  • R3 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.
  • R3 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one, two or three independently selected Rb1.
  • R3 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one, two or three independently selected Rb1.
  • R3 is–O-heterocycloalkyl, which heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S, which heterocycloalkyl is substituted with one, two or three independently selected Rb1.
  • a compound or pharmaceutically acceptable salt according to clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein Rb1 is–CH 3 ,–CH2CH 3 ,–CH2CH2CH 3 , each of which is unsubstituted or substituted with one C1-4 alkoxy, or–C( O)OH.
  • a compound or pharmaceutically acceptable salt according to clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein Rb1 is–CH 3 ,–CH 2 CH 3 ,–CH 2 CH 2 CH 3 , each of which is unsubstituted or substituted with one -OCH 3 , -OCH 2 CH 3 , or -C( O)OH.
  • each R6a and R6b is independently selected from H, or C 1-4 alkyl.
  • each R6a and R6b is independently selected from H,–CH 3 , or–CH 2 CH 3 .
  • a compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -C( O)NR6aR6b, wherein each R6a and R6b is independently selected from H,–CH 3 , and–CH 2 CH 3 .
  • a compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -S( O) 2 NR6dR6e, wherein, each R6d and R6e is independently selected from H,–CH 3 , or–CH2CH 3 . 194.
  • a compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -NR6f-C( O)O-C1-4 alkyl, wherein R6f is selected from H, or C1-4 alkyl. 195.
  • R3 is -NR6gR6h, wherein each R6g and R6h is independently selected from H, or C1-4 alkyl.
  • R3 is–OCH2CH2CH2-OCH 3 ,–O-cyclobutyl,–OCH2-cyclopropyl,–OCH(CH 3 )-cyclopropyl,–OCH2- cyclobutyl, or–OCH2C(CH 3 ) 2 .
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-201.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-201 and a further therapeutic agent.
  • a compound of the invention When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • a compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • a compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
  • a compound of the invention according to Formula I may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
  • a compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75oC and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • a compound of the invention according to Formula I 50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g)
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of hepatitis B.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of hepatitis B.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with hepatitis B, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a hepatitis B treatment agent.
  • Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compound of the invention When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

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Abstract

La présente invention concerne des composés selon la formule (I), dans laquelle X, G, R1, R2a, R2b, R3, R4, et R5 sont tels que définis dans la description. La présente invention concerne des composés, des procédés pour leur production, des compositions pharmaceutiques les comprenant, et des procédés de traitement faisant appel à ceux-ci, pour la prophylaxie et/ou le traitement de maladies impliquant l'hépatite B par l'administration du composé de l'invention.
PCT/EP2020/064364 2019-05-29 2020-05-25 Nouveaux composés et compositions pharmaceutiques de ceux-ci pour le traitement de l'hépatite b WO2020239656A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11964986B1 (en) 2023-07-03 2024-04-23 Rejuveron Telomere Therapeutics Ag 9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid derivatives

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