NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE

TREATMENT OF HEPATITIS B. FIELD OF THE INVENTION

[0001] The present invention relates to compounds useful in the prophylaxis and/or treatment of hepatitis B virus (HBV). 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. BACKGROUND OF THE INVENTION

[0002] It is estimated that 240 million people are chronically infected with HBV worldwide. More than 750,000 deaths annually worldwide are attributed to 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. (Dawood et al.2017)

[0003] The hepatitis B virus (HBV) 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)

[0004] The transmission of HBV occurs usually via exposure to body fluids, blood, skin lesions, sexual relationship, or passing from the mother to baby. Upon initial exposure to HBV, the failure to induce a significant innate immune response within hepatocytes and the immunosuppressive liver microenvironment can lead to incomplete clearance of infected hepatocytes and the establishment of a chronic hepatitis B (CHB) infection which can be categorised into five clinical phases: (1) immune tolerance characterised by high HBV serum titres (~2 × 109 IU/mL) and poorly-activated but not completely silent HBV-specific CD8+ T-cells; (2) immune reactive HBV e antigen (HBeAg)-positive characterised by observable flares of immune-mediated liver damage and fluctuations in HBV titres; (3) inactive HBV carrier characterized by low HBV titres and slower liver injury progression compared to the preceding immune reactive phase; (4) HBeAg-negative chronic hepatitis (or “functional cure”) wherein disease progression is halted characterized by greatly reduced HBV serum DNA and the presence of HBV HBe antigen recognizing antibodies; and (5) HBV surface antigen (HBsAg)-negative phases, wherein viral covalently closed circular DNA (cccDNA) remains present in the liver but is transcriptionally silent, and may be reactived, for example under immune suppressive therapy (Tu et al.2017).

[0005] 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.

[0006] 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. Unfortunately, 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.

[0007] 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). 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).

[0008] In patients receiving NUC therapy, 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.

[0009] Unfortunately, adverse effects associated to the use of certain NUCs in the treatment of HBV have been reported, in particular neuropathy, leading to a“black box” warning.(Kayaaslan and Guner 2017)

[0010] Thus, the current drugs are not satisfactory and there is strong interest in new therapies with novel mode of action for the treatment of HBV. For example, blocking viral replication in newly infected hepatocytes and preventing cccDNA production, suppressing cccDNA, and/or blocking cccDNA transcriptional activity. SUMMARY OF THE INVENTION

[0011] 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.

[0012] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:

wherein

X is–S-, -S(=O)-, or–S(=O) ₂ -;

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

- spirocyclic C6-10 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkyl;

Each R2a and R2b is independently selected from:

- H,

- C1-4 alkyl,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 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:

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; or R2a and R2b together with the atom to which they are attached may form a spirocyclic C _3-7 cycloalkyl ring; R3 is

- halo,

- -OH,

- –CN,

- C _1-4 alkyl unsubstituted or substituted with one or more independently selected Ra1 groups

- C _1-6 alkoxy unsubstituted or substituted with one or more independently selected Ra1 groups, - phenyl unsubstituted or substituted with one more independently selected Rb1,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- -O-C3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- 4-7 membered monocyclic 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, - -O-(4-7 membered monocyclic heterocycloalkyl), which 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, -C(=O)NR6aR6b,

- -NR6c-C(=O)-C1-4 alkyl,

- -S(=O) ₂ NR6dR6e,

- -NR6f-C(=O)O-C1-4 alkyl, or

- -NR6gR6h;

R4 is

- H,

- -SO2-C1-4 alkyl,

- halo,

- CN,

- C1-4 alkyl unsubstituted or substituted with one or more independently selected Ra2,

- phenyl unsubstituted or substituted with one more independently selected Rb2,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,

- 4-7 membered monocyclic 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,

- -C(=O)NR7aR7b,

- -NR7c-C(=O)-C _1-4 alkyl,

- -S(=O) ₂ NR7dR7e,

- -NR7f-C(=O)O-C _1-4 alkyl, or

- -NR7gR7h;

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 R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h is independently H or C _1-4 alkyl unsubstituted or substituted with one–C(=O)OH;

each Ra1 and Ra2 is independently:

- halo,

- –CN,

- -OH,

- -SO2-C1-4 alkyl,

- C1-4 alkoxy,

- phenyl, - 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected R9a,

- 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, and - 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;

Each R9a, R9b, and R9c is independently selected from:

- halo,

- -CN,

- -SO2-C1-4 alkyl,

- oxo,

- alkyl unsubstituted or substituted with one or more independently selected halo, -C1-4 alkoxy or -OH, - -C(=O)NR10aR10b,

- -C _1-4 alkoxy, or

- -C(=O)C _1-4 alkyl;

Each Rb1 and Rb2 is independently selected from:

- halo,

- oxo,

- C _1-4 alkyl unsubstituted or substituted with one C _1-4 alkoxy, or–C(=O)OH;

- C _1-4 alkoxy, and

- monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S; and

each R10a and R10b is independently H or C _1-4 alkyl.

[0013] In a second aspect of the invention, the compounds of the invention are provided having a Formula I:

wherein

X is–S-, -S(=O)-, or–S(=O) ₂ -;

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

- spirocyclic C6-10 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkyl;

Each R2a and R2b is independently selected from:

- H,

- C1-4 alkyl,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 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:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo; or R2a and R2b together with the atom to which they are attached may form a spirocyclic C _3-7 cycloalkyl ring; R3 is

- halo,

- -OH,

- –CN,

- C _1-4 alkyl unsubstituted or substituted with one or more independently selected Ra1 groups

- C _1-4 alkoxy unsubstituted or substituted with one or more independently selected Ra1 groups, - phenyl unsubstituted or substituted with one more independently selected Rb1,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- -O-C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- 4-7 membered monocyclic 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,

- -O-(4-7 membered monocyclic heterocycloalkyl), which 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, -C(=O)NR6aR6b,

- -NR6c-C(=O)-C1-4 alkyl,

- -S(=O) ₂ NR6dR6e,

- -NR6f-C(=O)O-C1-4 alkyl, or - -NR6gR6h;

R4 is

- H,

- -SO2-C1-4 alkyl,

- halo,

- CN,

- C1-4 alkyl unsubstituted or substituted with one or more independently selected Ra2,

- phenyl unsubstituted or substituted with one more independently selected Rb2,

- 5-6 membered monocyclic 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,

- C3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,

- 4-7 membered monocyclic 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,

- -C(=O)NR7aR7b,

- -NR7c-C(=O)-C _1-4 alkyl,

- -S(=O) ₂ NR7dR7e,

- -NR7f-C(=O)O-C _1-4 alkyl, or

- -NR7gR7h;

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 R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h is independently H or C _1-4 alkyl unsubstituted or substituted with one–C(=O)OH;

each Ra1 and Ra2 is independently:

- halo,

- –CN,

- -OH,

- -SO ₂ -C _1-4 alkyl,

- C _1-4 alkoxy,

- phenyl,

- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected R9a,

- 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, and - 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;

Each R9a, R9b, and R9c is independently selected from:

- halo,

- -CN,

- -SO2-C1-4 alkyl,

- oxo,

- alkyl unsubstituted or substituted with one or more independently selected halo, or -OH,

- -C(=O)NR10aR10b,

- -C1-4 alkoxy, or

- -C(=O)C1-4 alkyl;

Each Rb1 and Rb2 is independently selected from:

- halo,

- oxo,

- C _1-4 alkyl unsubstituted or substituted with one C _1-4 alkoxy, or–C(=O)OH;

- C _1-4 alkoxy, and

- monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S; and

each R10a and R10b is independently H or C _1-4 alkyl.

[0014] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of hepatitis B.

[0015] Furthermore, it has also been unexpectedly demonstrated that 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.

[0016] In yet another aspect, the compounds of the invention may show a good safety profile.

[0017] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of HBV.

[0018] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0019] In a further aspect of the invention, 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. [0020] 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. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and/or treatment of HBV.

[0021] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0022] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0023] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites. DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0024] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0025] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term“substituted” is to be defined as set out below. It should be further understood that the terms“groups” and“radicals” can be considered interchangeable when used herein.

[0026] 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. By way of example‘an analogue’ means one analogue or more than one analogue.

[0027]‘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. Particular 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.

[0028]‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH ₃ )=CH2) and the like. [0029]‘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.

[0030]‘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-.

[0031]‘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.

[0032]‘Amino’ refers to the radical -NH2.

[0033]‘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. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0034]‘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.

[0035]‘Cyano’ refers to the radical -CN.

[0036]‘Halo’ or‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0037] As used herein, term‘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.

[0038]‘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.

[0039]‘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. In particular, 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. Typically 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. In one embodiment, 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.

[0040] 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.

[0041] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0042] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0043] Particular examples of 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.

[0044] Particular examples of 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.

[0045] Examples of representative heteroaryls include the following:

wherein each Y is selected from >C=O, NH, O and S.

[0046]‘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. Typically 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. Examples of 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. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4- tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0047] As used herein, the term‘heterocycloalkenyl’ means a‘heterocycloalkyl’, which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples:

wherein each W is selected from CH ₂ , NH, O and S; each Y is selected from NH, O, C(=O),-SO ₂ , and S; and each Z is selected from N or CH.

[0048] Particular examples of monocyclic rings are shown in the following illustrative examples:

wherein each W and Y is independently selected from -CH2-, -NH-, -O- and–S-.

[0049] Particular examples of fused bicyclic rings are shown in the following illustrative examples:

wherein each W and Y is independently selected from -CH2-, -NH-, -O- and–S-.

[0050] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:

wherein each W and Y is independently selected from -CH2-, -NH-, -O- and–S- and each Z is selected from N or CH.

[0051] Particular examples of spirocyclic rings are shown in the following illustrative examples:

wherein each Y is selected from -CH ₂ -, -NH-, -O- and–S-.

[0052]‘Hydroxyl’ refers to the radical -OH. [0053]‘Oxo’ refers to the radical =O.

[0054]‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0055]‘Sulfo’ or‘sulfonic acid’ refers to a radical such as–SO3H.

[0056]‘Thiol’ refers to the group -SH.

[0057] As used herein, 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.

[0058]‘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.

[0059] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0060]‘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.

[0061]‘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. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, 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, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. 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. The term ‘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.

[0062]‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0063]‘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.

[0064]‘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.

[0065]‘Subject’ includes humans. The terms‘human’,‘patient’ and‘subject’ are used interchangeably herein.

[0066]‘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.

[0067]‘Preventing’ or‘prevention’ 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.

[0068] The term‘prophylaxis’ 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. Non-limiting examples of 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.

[0069]‘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). In another embodiment‘treating’ or‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘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. In a further embodiment,“treating” or“treatment” relates to slowing the progression of the disease.

[0070] As used herein the term‘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. Particularly 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

[0071] As used herein the term“HBV” or“Hepatitis B virus” refers to a species of viruses of the genus Orthohepadnavirus. This virus causes hepatitis B.

[0072] As used herein the term‘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.

[0073] As used herein the term‘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.

[0074] As used herein the term‘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.

[0075] As used herein the term‘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.

[0076]‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0077] When ranges are referred to herein, for example but without limitation, C1-8 alkyl, the citation of a range should be considered a representation of each member of said range.

[0078] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). 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. In some cases it is desirable to prepare 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.

[0079] 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.

[0080] 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.

[0081] 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. Further, 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. [0082] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed‘stereoisomers’.

[0083] 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’. When 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’.

[0084]‘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.

[0085] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0086] 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.

[0087] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0088] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites. THE INVENTION

[0089] 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. [0090] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:

wherein

X is–S-, -S(=O)-, or–S(=O) ₂ -;

G is -OH, or C1-4 alkoxy;

R1 is:

- monocyclic C _3-6 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C _1-4 alkyl, or

- spirocyclic C _6-10 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C _1-4 alkyl;

Each R2a and R2b is independently selected from:

- H,

- C _1-4 alkyl,

- C _3-7 cycloalkyl unsubstituted or substituted with one or more independently selected:

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:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo; or R2a and R2b together with the atom to which they are attached may form a spirocyclic C3-7 cycloalkyl ring; R3 is

- halo,

- -OH,

- –CN,

- C1-4 alkyl unsubstituted or substituted with one or more independently selected Ra1 groups

- C1-6 alkoxy unsubstituted or substituted with one or more independently selected Ra1 groups, - phenyl unsubstituted or substituted with one more independently selected Rb1,

- 5-6 membered monocyclic 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,

- C3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1, - -O-C3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- 4-7 membered monocyclic 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,

- -O-(4-7 membered monocyclic heterocycloalkyl), which 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, -C(=O)NR6aR6b,

- -NR6c-C(=O)-C1-4 alkyl,

- -S(=O) ₂ NR6dR6e,

- -NR6f-C(=O)O-C1-4 alkyl, or

- -NR6gR6h;

R4 is

- H,

- -SO ₂ -C _1-4 alkyl,

- halo,

- CN,

- C _1-4 alkyl unsubstituted or substituted with one or more independently selected Ra2,

- phenyl unsubstituted or substituted with one more independently selected Rb2,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,

- 4-7 membered monocyclic 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,

- -C(=O)NR7aR7b,

- -NR7c-C(=O)-C _1-4 alkyl,

- -S(=O) ₂ NR7dR7e,

- -NR7f-C(=O)O-C _1-4 alkyl, or

- -NR7gR7h;

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 R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h is independently H or C1-4 alkyl unsubstituted or substituted with one–C(=O)OH;

each Ra1 and Ra2 is independently:

- halo, - –CN,

- -OH,

- -SO2-C1-4 alkyl,

- C1-4 alkoxy,

- phenyl,

- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected R9a,

- 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, and - 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;

Each R9a, R9b, and R9c is independently selected from:

- halo,

- -CN,

- -SO ₂ -C _1-4 alkyl,

- oxo,

- alkyl unsubstituted or substituted with one or more independently selected halo, -C _1-4 alkoxy or -OH, - -C(=O)NR10aR10b,

- -C _1-4 alkoxy, or

- -C(=O)C _1-4 alkyl;

Each Rb1 and Rb2 is independently selected from:

- halo,

- oxo,

- C _1-4 alkyl unsubstituted or substituted with one C _1-4 alkoxy, or–C(=O)OH;

- C _1-4 alkoxy, and

- monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S; and

each R10a and R10b is independently H or C _1-4 alkyl.

[0091] In a second aspect of the invention the compounds of the invention are provided having a Formula I:

I wherein

X is–S-, -S(=O)-, or–S(=O) ₂ -;

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

- spirocyclic C6-10 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkyl;

Each R2a and R2b is independently selected from:

- H,

- C1-4 alkyl,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 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:

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; or R2a and R2b together with the atom to which they are attached may form a spirocyclic C _3-7 cycloalkyl ring; R3 is

- halo,

- -OH,

- –CN,

- C _1-4 alkyl unsubstituted or substituted with one or more independently selected Ra1 groups,

- C _1-4 alkoxy unsubstituted or substituted with one or more independently selected Ra1 groups, - phenyl unsubstituted or substituted with one more independently selected Rb1,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- -O-C3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- 4-7 membered monocyclic 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, - -O-(4-7 membered monocyclic heterocycloalkyl), which 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,-C(=O)NR6aR6b,

- -NR6c-C(=O)-C1-4 alkyl,

- -S(=O) ₂ NR6dR6e,

- -NR6f-C(=O)O-C1-4 alkyl, or

- -NR6gR6h;

R4 is

- H,

- -SO2-C1-4 alkyl,

- halo,

- CN,

- C1-4 alkyl unsubstituted or substituted with one or more independently selected Ra2,

- phenyl unsubstituted or substituted with one more independently selected Rb2,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,

- 4-7 membered monocyclic 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,

- -C(=O)NR7aR7b,

- -NR7c-C(=O)-C _1-4 alkyl,

- -S(=O) ₂ NR7dR7e,

- -NR7f-C(=O)O-C _1-4 alkyl, or

- -NR7gR7h;

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 R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h is independently H or C _1-4 alkyl unsubstituted or substituted with one–C(=O)OH;

each Ra1 and Ra2 is independently:

- halo,

- –CN,

- -OH,

- -SO2-C1-4 alkyl,

- C1-4 alkoxy,

- phenyl, - 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected R9a,

- 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, and - 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;

Each R9a, R9b, and R9c is independently selected from:

- halo,

- -CN,

- -SO2-C1-4 alkyl,

- oxo,

- alkyl unsubstituted or substituted with one or more independently selected halo, or -OH,

- -C(=O)NR10aR10b,

- -C _1-4 alkoxy, or

- -C(=O)C _1-4 alkyl;

Each Rb1 and Rb2 is independently selected from:

- halo,

- oxo,

- C _1-4 alkyl unsubstituted or substituted with one C _1-4 alkoxy, or–C(=O)OH;

- C _1-4 alkoxy, and

- monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S; and

each R10a and R10b is independently H or C _1-4 alkyl.

[0092] In one embodiment, 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. In a particular embodiment, R5 is -CN, -CH ₃ , -CF ₃ , F, Cl or Br.

[0093] In one embodiment, the compound of the invention is according to Formula I, wherein R5 is H.

[0094] In one embodiment, the compound of the invention is according to Formula I, wherein G is OH.

[0095] In one embodiment, 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:

II

wherein X, R1, R2a, R2b, R3and R4 are as described previously.

[0097] In one embodiment, the compound of the invention is according to Formula I or II, wherein R1 is C3-6 cycloalkyl. In a particular embodiment, R1 is cyclopropyl. In another embodiment, R1 is cyclobutyl.

[0098] In one embodiment, 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. In a particular embodiment, R1 is cyclopropyl, or cyclobutyl, each of which is substituted with one or more independently selected halo or C1-4 alkyl. In another embodiment, R1 is C3-6 cycloalkyl substituted with one or more independently selected F or–CH ₃ . In a particular embodiment, R1 is cyclopropyl, or cyclobutyl, each of which is substituted with one, or two independently selected F or–CH ₃ . In a more particular embodiment, R1 is cyclopropyl substituted with one F or–CH ₃ .

[0099] In one embodiment, the compound of the invention is according to Formula I or II, wherein R1 is

[0100] In one embodiment, the compound of the invention is according to Formula I or II, wherein R1 is spirocyclic C6-10 cycloalkyl. In a particular embodiment, R1 is spiro[3.3]heptane.

[0101] In one embodiment, the compound of the invention is according to Formula III:

III

wherein X, R2a, R2b, R3and R4 are as described previously.

[0102] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein R2a is H.

[0103] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein R2a is C _1-4 alkyl. In a particular embodiment, R2a is–CH ₃ , -CH ₂ CH ₃ ,–CH(CH ₃ ) ₂ or–C(CH ₃ ) ₃ . In a more particular embodiment, R2a is–CH ₃ .

[0104] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein R2a is C3-7 cycloalkyl. In a particular embodiment, R2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more particular embodiment, R2a is cyclopropyl or cyclobutyl. [0105] In one embodiment, 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. In a particular embodiment, 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. In another particular embodiment, 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. In a more particular embodiment, R2a is cyclopropyl substituted with one -CH ₃ , -CH2CH ₃ , -CF3, CHF2, -CH2CF3, -OCH ₃ , -OCH2CH ₃ , or -OCF3.

[0106] In one embodiment, 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.

[0107] In one embodiment, 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. In a particular embodiment, 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. In another particular embodiment, 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 . In a more particular embodiment, 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 . In a most particular embodiment, R2a is oxetanyl substituted with one -CH ₃ .

[0108] In one embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, R2a and R2b together with the atom to which they are attached form a spirocyclic ring, which ring is cyclobutyl. [0109] In one embodiment, the compound of the invention is according to Formula IV:

wherein X, R2b, R3 and R4 are as described previously.

[0110] In one embodiment, the compound of the invention is according to Formula I, II, III or IV, wherein R2b is H.

[0111] In one embodiment, the compound of the invention is according to Formula I, II, III or IV, wherein R2b is C _1-4 alkyl. In a particular embodiment, R2b is–CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ . In a more particular embodiment, R2b is–CH ₃ , or -CH ₂ CH ₃ . In a most particular embodiment, R2b is -CH ₃ .

[0112] In one embodiment, the compound of the invention is according to Formula I, II, III or IV, wherein R2b is C _3-7 cycloalkyl. In a particular embodiment, R2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more particular embodiment, R2b is cyclopropyl or cyclobutyl.

[0113] In one embodiment, 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. In a particular embodiment, 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. In another particular embodiment, 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 . In a more particular embodiment, 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 .

[0114] In one embodiment, 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.

[0115] In one embodiment, 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. In a particular embodiment, 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. In another particular embodiment, 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. In a more particular embodiment, 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 .

[0116] In one embodiment, the compound of the invention is according to Formulae Va or Vb:

wherein X, R3and R4 are as described previously.

[0117] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is H

[0118] In one embodiment, 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 .

[0119] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is halo. In a particular embodiment, R4 is F, Cl or Br. In a more particular embodiment, R4 is F or Cl. In a most particular embodiment, R4 is Cl.

[0120] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is–CN.

[0121] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is C _1-4 alkyl. In a particular embodiment, R4 is–CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH(CH ₃ ) ₂ .

[0122] In one embodiment, 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. In a particular embodiment, R4 is C _1-4 alkyl substituted with one, two or three independently selected Ra2 groups. In a more particular embodiment, R4 is C1-4 alkyl substituted with one Ra2 group. In most particular embodiment, 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. In a further most particular embodiment, 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. In another most particular embodiment, R4 -CH ₂ -Ra2, -CH ₂ CH ₂ -Ra2, or -CH ₂ CH ₂ CH ₂ -Ra2.

[0123] In one embodiment, 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.

[0124] In one embodiment, 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.

[0125] In one embodiment, 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. [0126] In one embodiment, 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 .

[0127] In one embodiment, 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. In a particular embodiment, Ra2 is -OCH ₃ , -OCH2CH ₃ , or–OCH(CH ₃ ) ₂ . In a more particular embodiment one or more independently selected Ra2 is -OCH ₃ .

[0128] In one embodiment, 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.

[0129] In one embodiment, 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. In a particular embodiment, one or more independently selected Ra2 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl.

[0130] In one embodiment, 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. In a particular embodiment, Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0131] In one embodiment, 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. In a particular embodiment, Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R9a. In a more particular embodiment, 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. In a most particular embodiment, each R9a is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ , or–C(=O)CH ₃ .

[0132] In one embodiment, 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. In a particular embodiment, Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0133] In one embodiment, 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. In a further embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a most particular embodiment, each R9b is independently selected from F, Cl, -SO2CH ₃ , oxo, -CH ₃ , -CF3, -CH2-OH, -C(=O)NH2, -OCH ₃ , or–C(=O)CH ₃ .

[0134] In one embodiment, 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. In a particular embodiment, one or more independently selected Ra2 is 2,6-diazaspiro[3.3]heptanyl.

[0135] In one embodiment, 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. In a further embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a most particular embodiment, each R9c is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ , or–C(=O)CH ₃ .

[0136] In a most particular embodiment, 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 .

[0137] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is phenyl.

[0138] In one embodiment, 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 .

[0139] In one embodiment, 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. In a particular embodiment, R4 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl. In a more particular embodiment, R4 is thiazolyl, thienyl, oxazolyl, or furanyl.

[0140] In one embodiment, 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. In a further embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, R4 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl, each of which is substituted with one, two or three independently selected Rb2. In a most particular embodiment, each Rb2 is independently selected from halo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy. In a further most particular embodiment, each Rb2 is independently selected from F, Cl,–CH ₃ , or -OCH ₃ .

[0141] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is C3-7 cyclolalkyl. In a particular embodiment, R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more particular embodiment, R4 is cyclopropyl.

[0142] In one embodiment, 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. In a particular embodiment, R4 is C3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb2. In a more particular embodiment, R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three independently selected Rb2. In a most particular embodiment, 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 .

[0143] In one embodiment, 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. In a particular embodiment, R4 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0144] In one embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a most particular embodiment, R4 is pyrolidinyl substituted with one, two or three independently selected Rb2. In a most particular embodiment, each Rb2 is independently selected from halo, oxo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy. In a further most particular embodiment, each Rb2 is independently selected from F, Cl, oxo,–CH ₃ , or -OCH ₃ .

[0145] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R4 is -C(=O)NR7aR7b, wherein each R7a and R7b is independently selected from H, or C1-4 alkyl. In a particular embodiment, each R7a and R7b is independently selected from H,–CH ₃ , or–CH2CH ₃ . [0146] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R ⁴ is -NR ^7C -C(=0)-C _I-4 alkyl, wherein R ^7c is selected from H, or Ci-4 alkyl. In a particular embodiment, R ⁴ is -NR ^7c -C(=0)-C]¾, or -NR ^7c -C(=0)-CH2CH ₃ , wherein R ^7c is selected from H, or Ci- ₄ alkyl. In a particular embodiment, R ^7c is selected from H, -C¾, or -CH2CH ₃ .

[0147] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R ⁴ is -S(=0) ₂ NR ^7d R ^7e , wherein each R ^7d and R ^7e is independently selected from H, or C _1-4 alkyl. In a particular embodiment, each R ^7d and R ^7e is independently selected from H, -CH ₃ , or -CH ₂ CH ₃ .

[0148] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R ⁴ is -NR ^7f -C(=0)0-Ci- ₄ alkyl, wherein R ^7f is selected from H, or C1-4 alkyl. In a particular embodiment, R ⁴ is -NR ^7f -C(=0)0-CH ₃ , -NR ^7f -C(=0)0-CH ₂ CH ₃ , or -NR ^7f -C(=0)0-C(CH ₃ ) ₃ , wherein R ^7f is selected from H, or C1-4 alkyl. In a particular embodiment, R ^7f is selected from H, -CH ₃ , or -CH2CH ₃ . In a more particular embodiment, R ⁴ is -NH-C(=0)0-C(CH ₃ )3.

[0149] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R ⁴ is -NR ^7g R ^7h , wherein each R ^7g and R ^7h is independently selected from H, or C _1-4 alkyl unsubstituted or substituted one -C(=0)OH. In a particular embodiment, each R ^7g and R ^7h is independently selected from H, -CH ₃ , or -CH ₂ CH ₃ , -CH ₂ CH ₂ -C(=0)0H. In a more particular embodiment, R ⁴ is -NFh.

[0150] In one embodiment, the compound of the invention is according to Formulae Via or VIb:

wherein X, and R ³ are as described previously.

[0151] In one embodiment, 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.

[0152] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R ³ is -OH.

[0153] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R ³ is -CN.

[0154] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R ³ is C _1-4 alkyl. In a particular embodiment, R ³ is -G¾, -CH ₂ CH ₃ , or -CH ₂ CH(CH ₃ ) ₂ .

[0155] In one embodiment, 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. In a particular embodiment, R ³ is C _1-4 alkyl substituted with one, two or three independently selected R ^al groups. In a more particular embodiment, R ³ is C _1-4 alkyl substituted with one R ^al group. In most particular embodiment, 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. In a further most particular embodiment, 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. In another most particular embodiment, R ³ is -CH ₂ -R ³¹ , -CH ₂ CH ₂ -R ³¹ , or -CH ₂ CH ₂ CH ₂ -R ³¹ . In another most particular embodiment, R ³ is -CH ₂ CH ₂ CH ₂ -R ³¹ .

[0156] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R ³ is Ci- ₆ alkoxy. In a particular embodiment, R ³ is -OCH ₃ , -OCH ₂ CH ₃ ,

-OCH ₂ CH ₂ CH ₃ , -OCCH ₂ CH(CH ₃ ) ₂ -OCH(CH ₃ ) ₂ , or -OCH(CH ₂ CH ₃ ) ₂ . In a more particular embodiment, R ³ is -OCH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CH(CH ₃ ) ₂ or -OCH(CH ₂ CH ₃ ) ₂ . In a more particular embodiment, R ³ is -OCH ₃ . In another more particular embodiment, R ³ is -OCH ₂ CH(CH ₃ ) ₂ .

[0157] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R ³ is C _1-4 alkoxy. In a 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 . In a more particular embodiment, R ³ is -OCH ₃ . In another more particular embodiment, R ³ is -OCH2CH(CH ₃ ) ₂ .

[0158] In one embodiment, 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. In a further 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 R ^al group. In another most particular embodiment, 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 . In another most particular embodiment, R ³ is -OCFFCH ₂ CH ₂ -R ³¹ .

[0159] In one embodiment, 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. In a particular embodiment, R ³ is C _1-4 alkoxy substituted with one, two or three independently selected R ^al groups. In a more particular embodiment, R ³ is C _1-4 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. In a further 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 ,) ₂ . each of which substituted with one R ^al group. In another most particular embodiment, 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 . In another most particular embodiment, R ³ is -OCFFCH ₂ CH ₂ -R ³¹ .

[0160] In one embodiment, 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.

[0161] In one embodiment, 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.

[0162] In one embodiment, 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. [0163] In one embodiment, 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 .

[0164] In one embodiment, 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. In a particular embodiment, one or more independently selected Ra1 is -OCH ₃ , -OCH2CH ₃ , or–OCH(CH ₃ ) ₂ . In a more particular embodiment, one or more independently selected Ra1 is -OCH ₃ .

[0165] In one embodiment, 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.

[0166] In one embodiment, 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. In a particular embodiment, one or more independently selected Ra1 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl.

[0167] In one embodiment, 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. In a particular embodiment, one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0168] In one embodiment, 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. In a further embodiment, one or more independently selected Ra1 is C _3-7 cycloalkyl substituted with one, two or three independently selected R9a. In a particular embodiment, one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R9a. In a more particular embodiment, 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. In a most particular embodiment, each R9a is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -CH ₂ -OCH ₃ , -C(=O)NH ₂ , -OCH ₃ , or–C(=O)CH ₃ .

[0169] In one embodiment, 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. In a further embodiment, one or more independently selected Ra1 is C3-7 cycloalkyl substituted with one, two or three independently selected R9a. In a particular embodiment, one or more independently selected Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R9a. In a more particular embodiment, 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. In a most particular embodiment, each R9a is independently selected from F, Cl, -SO2CH ₃ , oxo, -CH ₃ , -CF3, -CH2-OH, -C(=O)NH2, -OCH ₃ , or–C(=O)CH ₃ . [0170] In one embodiment, 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. In a particular embodiment, one or more independently selected Ra1 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0171] In one embodiment, 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. In a further embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a most particular embodiment, each R9b is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ , or–C(=O)CH ₃ .

[0172] In one embodiment, 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. In a particular embodiment, one or more independently selected Ra1 is 2,6-diazaspiro[3.3]heptanyl.

[0173] In one embodiment, 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. In a further embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a most particular embodiment, each R9c is independently selected from F, Cl, -SO2CH ₃ , oxo, -CH ₃ , -CF3, -CH2-OH, -C(=O)NH2, -OCH ₃ , or–C(=O)CH ₃ .

[0174] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is phenyl.

[0175] In one embodiment, 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. In a particular embodiment, R3 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, furanyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0177] 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, which heteroaryl is substituted with one or more independently selected Rb1. In a particular embodiment, 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. In a more particular embodiment, 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.

[0178] In one embodiment, the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is C3-7 cyclolalkyl. In a particular embodiment, R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more particular embodiment, R3 is cyclopropyl.

[0179] In one embodiment, 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. In a particular embodiment, R3 is C _3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb1. In a more particular embodiment, R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three independently selected Rb1.

[0180] In one embodiment, the compound of the invention is according to any one of Formulae I- VIb, wherein R3 is–O-C _3-7 cyclolalkyl. In a particular embodiment, R3 is–O-cyclopropyl,–O-cyclobutyl, –O-cyclopentyl, or–O-cyclohexyl.

[0181] In one embodiment, 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. In a particular embodiment, R3 is–O-C _3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb1. In a more particular embodiment, R3 is –O-cyclopropyl, –O-cyclobutyl,–O-cyclopentyl, or–O-cyclohexyl, each of which is substituted with one, two or three independently selected Rb1.

[0182] In one embodiment, 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. In a particular embodiment, R3 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0183] In one embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a most particular embodiment, R3 is pyrolidinyl substituted with one, two or three independently selected Rb1.

[0184] In one embodiment, 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. In a particular embodiment, R3 is -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-dioxanyl, -O-azetidinyl, -O-pyrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl, or -O-thiomorpholinyl.

[0185] In one embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a most particular embodiment, R3 is -O-pyrolidinyl substituted with one, two or three independently selected Rb1.

[0186] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as described previously, and Rb1 is halo. In a particular embodiment, Rb1 is F or Cl. In a more particular embodiment, Rb1 is F.

[0187] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as described previously, and Rb1 is oxo.

[0188] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is as described previously, and Rb1 is C _1-4 alkyl unsubstituted or substituted with one C _1-4 alkoxy or–C(=O)OH. In a particular embodiment, Rb1 is–CH ₃ ,–CH ₂ CH ₃ ,–CH ₂ CH ₂ CH ₃ , each of which is unsubstituted or substituted with one C _1-4 alkoxy, or–C(=O)OH. In another particular embodiment, Rb1 is C1-4 alkyl unsubstituted or substituted with one -OCH ₃ , -OCH2CH ₃ , or -C(=O)OH. In a more particular embodiment, Rb1 is–CH ₃ ,–CH2CH ₃ ,–CH2CH2CH ₃ , each of which is unsubstituted or substituted with one -OCH ₃ , -OCH2CH ₃ , or -C(=O)OH.

[0189] In one embodiment, 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. In a particular embodiment, Rb1 is azetidinyl, oxetanyl, pyrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, dioxanyl, or piperazinyl. In a more particular embodiment, Rb1 is pyrolidinyl.

[0190] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is -C(=O)NR6aR6b, wherein each R6a and R6b is independently selected from H, or C1-4 alkyl. In a particular embodiment, each R6a and R6b is independently selected from H,–CH ₃ , or–CH2CH ₃ .

[0191] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is -NR6c-C(=O)-C1-4 alkyl, wherein R6c is selected from H, or C1-4 alkyl. In a particular embodiment, R3 is -NR6c-C(=O)-CH ₃ , or -NR6c-C(=O)-CH2CH ₃ , wherein R6c is selected from H, or C1-4 alkyl. In a particular embodiment, R6c is selected from H,–CH ₃ , or–CH2CH ₃ .

[0192] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is -S(=O) ₂ NR6dR6e, wherein each R6d and R6e is independently selected from H, or C1-4 alkyl. In a particular embodiment, each R6d and R6e is independently selected from H,–CH ₃ , or–CH2CH ₃ .

[0193] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein R3 is -NR6f-C(=O)O-C1-4 alkyl, wherein R6f is selected from H, or C1-4 alkyl. In a particular embodiment, R3 is -NR6f-C(=O)O-CH ₃ , or -NR6f-C(=O)O-CH ₂ CH ₃ , wherein R6f is selected from H, or C _{1- 4} alkyl. In a particular embodiment, R6f is selected from H,–CH ₃ , or–CH ₂ CH ₃ .

[0194] In one embodiment, 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 .

[0195] In one embodiment, 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 .

[0196] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein X is–S-.

[0197] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein X is–S(=O)-.

[0198] In one embodiment, the compound of the invention is according to any one of Formulae I-VIb, wherein X is -S(=O) ₂ -.

[0199] In one embodiment, the compound of the invention is selected from:

Cpd_001: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-t rioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

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-5 H-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-thiochromen o[4,3-b]pyridine-3-carboxylic acid,

Cpd_008: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochr omeno[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-thiochrom eno[4,3-b]pyridine-3- carboxylic acid,

Cpd_012: 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_013: 9-chloro-1-cyclopropyl-8-methoxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3-carboxylic acid,

Cpd_014: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H -thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_015: 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trioxo-5H-thiochro meno[4,3-b]pyridine-3- carboxylic acid,

Cpd_016: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochro meno[4,3-b]pyridine-3- carboxylic acid,

Cpd_017: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_018: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiochrom eno[4,3-b]pyridine-3- carboxylic acid,

Cpd_019: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_020: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_021: 9-chloro-1-cyclopropyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_022: 9-chloro-1-cyclopropyl-8-wasopropoxy-5-methyl-2,6,6-trioxo-5 H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_023: 9-chloro-1-cyclopropyl-8-propoxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3-b]pyridine-3- carboxylic acid, Cpd_024: 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochr omeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_025: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6-dioxo-5H-thi ochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_026: 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-t rioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_027: 9-chloro-1-(2-fluorocyclopropyl)-8-(3-methoxypropoxy)-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-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_030: 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2R)-2-methylcyc lopropyl]-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-methylcyc lopropyl]-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-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_033: 9-chloro-1-cyclopropyl-8-(3-methoxy-1-methyl-propoxy)-5-meth yl-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-thiochrom eno[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-methy l-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-tr ioxo-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-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid, Cpd_043: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyr an-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-tr ioxo-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)-tetrah ydrofuran-2-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,

Cpd_047: 9-chloro-1-cyclobutyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-tri oxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_048: 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trioxo-5H-thi ochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_049: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-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-triox o-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_053: 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trioxo-5H-thiochro meno[4,3-b]pyridine-3- carboxylic acid,

Cpd_054: 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-propoxy-5H-thiochromen o[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-p henyl-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_057: 9-cyano-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_058: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-t hiazol-4-yl-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

Cpd_059: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trioxo-5 H-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_064: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-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_067: (5S)-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-thiochrom eno[4,3-b]pyridine-3- carboxylic acid,

Cpd_074: 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-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-5 H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,

Cpd_078: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-tri oxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_079: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-(tetrahydropy ran-4-ylmethoxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,

Cpd_080: 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-2,6,6-trioxo-5H-thio chromeno[4,3-b]pyridine-3- carboxylic acid, Cpd_081: 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-tetrahydropyran-4-ylox y-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_082: 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(tetrahydropyran-4-ylm ethoxy)-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_083: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trioxo-5H-th iochromeno[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_085: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-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-t hiochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_087: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trioxo-5H-th iochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_088: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_089: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-t hiazol-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-th ienyl)-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_095: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxeta n-3-yl)-2-oxo-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-methoxypropo xy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,

Cpd_098: 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_099: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyr an-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-ylpyri midin-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-methylthiaz ol-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-m ethyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,

Cpd_111: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(methylcarbamo yl)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid,

Cpd_112: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxeta n-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-tr ioxo-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-tr ioxo-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-thiochr omeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_123: 9'-chloro-1'-cyclopropyl-8'-(3-methoxypropoxy)-2',6',6'-trio xo-spiro[cyclobutane-1,5'- thiochromeno[4,3-b]pyridine]-3'-carboxylic acid,

Cpd_124: 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid

[0200] In another embodiment, the compound of the invention is selected from

Cpd_125: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-fu ryl)-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-thioc hromeno[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-tri oxo-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-5 H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid,

Cpd_132: 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]meth oxy]-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-th iochromeno[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-t hiochromeno[4,3-b]pyridine-3- carboxylic acid,

Cpd_139: 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropo xy)-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-(trifluoro methyl)-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid,

Cpd_145: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2-oxo-5H-thioc hromeno[4,3-b]pyridine-3- carboxylic acid, and

Cpd_146: 9-chloro-8-isobutoxy-2,6,6-trioxo-1-(1,2,2,3,3-pentadeuterio cyclopropyl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0201] In one embodiment, 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.

[0202] In another embodiment, 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.

[0203] In one embodiment, the compounds of the invention are provided in a natural isotopic form.

[0204] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, 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. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0205] In one embodiment, a compound of the invention is provided 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.

[0206] 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.

[0208] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0209] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0210] In one aspect 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.

[0211] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0212] While specified groups for each embodiment have generally been listed above separately, 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.

[0213] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0214] In certain aspects, 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.

[0215] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). 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. In some cases it is desirable to prepare 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. CLAUSES

1. A compound according to Formula I:

I

X is–S-, -S(=O)-, or–S(=O) ₂ -;

G is -OH, or C _1-4 alkoxy;

R1 is

- monocyclic C3-6 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkyl, or

- spirocyclic C6-10 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkyl;

Each R2a and R2b is independently selected from:

- H,

- C1-4 alkyl,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 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:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo;or R2a and R2b together with the atom to which they are attached may form a spirocyclic C3-7 cycloalkyl ring; R3 is

- halo,

- -OH,

- –CN,

- C _1-4 alkyl unsubstituted or substituted with one or more independently selected Ra1 groups

- C _1-6 alkoxy unsubstituted or substituted with one or more independently selected Ra1 groups, - phenyl unsubstituted or substituted with one more independently selected Rb1,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1, - -O-C3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- 4-7 membered monocyclic 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,

- -O-(4-7 membered monocyclic heterocycloalkyl), which 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,

- -C(=O)NR6aR6b,

- -NR6c-C(=O)-C1-4 alkyl,

- -S(=O) ₂ NR6dR6e,

- -NR6f-C(=O)O-C1-4 alkyl, or

- -NR6gR6h;

R4 is

- H,

- -SO ₂ -C _1-4 alkyl,

- halo,

- CN,

- C _1-4 alkyl unsubstituted or substituted with one or more independently selected Ra2,

- phenyl unsubstituted or substituted with one more independently selected Rb2,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,

- 4-7 membered monocyclic 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,

- -C(=O)NR7aR7b,

- -NR7c-C(=O)-C _1-4 alkyl,

- -S(=O) ₂ NR7dR7e,

- -NR7f-C(=O)O-C1-4 alkyl, or

- -NR7gR7h;

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 R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h is independently H or C1-4 alkyl unsubstituted or substituted with one–C(=O)OH;

each Ra1 and Ra2 is independently: - halo,

- –CN,

- -OH,

- -SO2-C1-4 alkyl,

- C1-4 alkoxy,

- phenyl,

- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected R9a,

- 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, and - 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;

Each R9a, R9b, and R9c is independently selected from:

- halo,

- -CN,

- -SO ₂ -C _1-4 alkyl,

- oxo,

- alkyl unsubstituted or substituted with one or more independently selected halo, -C _1-4 alkoxy or -OH, - -C(=O)NR10aR10b,

- -C _1-4 alkoxy, or

- -C(=O)C _1-4 alkyl;

Each Rb1 and Rb2 is independently selected from:

- halo,

- oxo,

- C _1-4 alkyl unsubstituted or substituted with one C _1-4 alkoxy, or–C(=O)OH;

- C _1-4 alkoxy, and

- monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S; and

each R10a and R10b is independently H or C _1-4 alkyl;

or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate. 2. A compound or pharmaceutically acceptable salt according to clause 1, wherein:

X is–S-, -S(=O)-, or–S(=O) ₂ -;

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 - spirocyclic C6-10 cycloalkyl unsubstituted or substituted with one or more independently selected halo, or C1-4 alkyl;

Each R2a and R2b is independently selected from:

- H,

- C1-4 alkyl,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 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:

o C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or o C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo;or R2a and R2b together with the atom to which they are attached may form a spirocyclic C3-7 cycloalkyl ring; R3 is

- halo,

- -OH,

- –CN,

- C _1-4 alkyl unsubstituted or substituted with one or more independently selected Ra1 groups

- C _1-4 alkoxy unsubstituted or substituted with one or more independently selected Ra1 groups, - phenyl unsubstituted or substituted with one more independently selected Rb1,

- 5-6 membered monocyclic 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,

- C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- -O-C _3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb1,

- 4-7 membered monocyclic 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,

- -O-(4-7 membered monocyclic heterocycloalkyl), which 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,

- -C(=O)NR6aR6b,

- -NR6c-C(=O)-C1-4 alkyl,

- -S(=O) ₂ NR6dR6e,

- -NR6f-C(=O)O-C1-4 alkyl, or

- -NR6gR6h; R4 is

- H,

- -SO2-C1-4 alkyl,

- halo,

- CN,

- C1-4 alkyl unsubstituted or substituted with one or more independently selected Ra2,

- phenyl unsubstituted or substituted with one more independently selected Rb2,

- 5-6 membered monocyclic 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,

- C3-7 cyclolalkyl, which cycloalkyl is unsubstituted or substituted with one or more independently selected Rb2,

- 4-7 membered monocyclic 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,

- -C(=O)NR7aR7b,

- -NR7c-C(=O)-C _1-4 alkyl,

- -S(=O) ₂ NR7dR7e,

- -NR7f-C(=O)O-C _1-4 alkyl, or

- -NR7gR7h;

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 R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h is independently H or C _1-4 alkyl unsubstituted or substituted with one–C(=O)OH;

each Ra1 and Ra2 is independently:

- halo,

- –CN,

- -OH,

- -SO ₂ -C _1-4 alkyl,

- C _1-4 alkoxy,

- phenyl,

- 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S,

- C3-7 cycloalkyl unsubstituted or substituted with one or more independently selected R9a,

- 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, and - 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;

Each R9a, R9b, and R9c is independently selected from:

- halo,

- -CN,

- -SO2-C1-4 alkyl,

- oxo,

- alkyl unsubstituted or substituted with one or more independently selected halo, or -OH,

- -C(=O)NR10aR10b,

- -C1-4 alkoxy, or

- -C(=O)C1-4 alkyl;

Each Rb1 and Rb2 is independently selected from:

- halo,

- oxo,

- C _1-4 alkyl unsubstituted or substituted with one C _1-4 alkoxy, or–C(=O)OH;

- C _1-4 alkoxy, and

- monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S; and

each R10a and R10b is independently H or C _1-4 alkyl;

or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate. 3. A compound or pharmaceutically acceptable salt according to clause 1 or 2, wherein R5 is -CN, -CH ₃ , -CF ₃ , F, Cl or Br.

4. A compound or pharmaceutically acceptable salt according to clause 1 or 2, wherein R5 is H.

5. A compound or pharmaceutically acceptable salt according to clause 1, 2, 3 or 4, wherein G is OH. 6. A compound or pharmaceutically acceptable salt according to clause 1, 2, 3 or 4, wherein G is C _1-4 alkoxy.

7. A compound or pharmaceutically acceptable salt according to clause 1, 2, 3 or 4, wherein G is–OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ or -OC(CH ₃ ) ₃ .

8. A compound or pharmaceutically acceptable salt according to clause 1, 2, 3 or 4, wherein G is -OCH(CH ₃ ) ₂ .

9. A compound or pharmaceutically acceptable salt according to clause 1 or 2, wherein the compound is according to Formula II:

II

10. A compound or pharmaceutically acceptable salt according to any one of clauses 1-9, wherein R1 is C3- 6 cycloalkyl.

11. A compound or pharmaceutically acceptable salt according to any one of clauses 1-9, wherein R1 is cyclopropyl, or cyclobutyl.

12. A compound or pharmaceutically acceptable salt according to any one of clauses 1-9, wherein R1 is cyclopropyl, or cyclobutyl, each of which is substituted with one or more independently selected halo or C1-4 alkyl.

13. A compound or pharmaceutically acceptable salt according to any one of clauses 1-9, wherein R1 is cyclopropyl, or cyclobutyl, each of which is substituted with one, or two independently selected F or– CH ₃ .

14. A compound or pharmaceutically acceptable salt according to any one of clauses 1-9, wherein R1 is spirocyclic C6-10 cycloalkyl.

15. A compound or pharmaceutically acceptable salt according to any one of clauses 1-9, wherein R1 is spiro[3.3]heptane.

16. A compound or pharmaceutically acceptable salt according to any one of clauses 1-9, wherein R1 is

17. A compound or pharmaceutically acceptable salt according to clause 1 or 2, wherein the compound of the invention is according to Formula II:

18. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is H.

19. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is -CH ₃ , CH2CH ₃ ,–CH(CH ₃ ) ₂ or–C(CH ₃ )3.

20. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is- CH ₃ .

21. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is C3-7 cycloalkyl.

22. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

23. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is cyclopropyl, or cyclobutyl. 24. .A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein 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.

25. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein 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.

26. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is cyclopropyl substituted with one -CH ₃ , -CH2CH ₃ , -CF3, -CHF2, -CH2CF3, -OCH ₃ , -OCH2CH ₃ , or -OCF3.

27. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms.

28. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is oxetanyl.

29. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, 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.

30. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein 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.

31. A compound or pharmaceutically acceptable salt according to any one of clauses 1-17, wherein R2a is oxetanyl substituted with one -CH ₃ .

32. A compound or pharmaceutically acceptable salt according to clause 1 or 2, wherein the compound is according to Formula III:

33. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is H.

34. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is C1-4 alkyl. 35. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is –CH ₃ , -CH2CH ₃ ,–CH(CH ₃ ) ₂ or–C(CH ₃ )3.

36. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is –CH ₃ , or -CH2CH ₃ .

37. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is –CH ₃ .

38. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is C3-7 cycloalkyl.

39. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

40. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein 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.

41. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein 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 .

42. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein 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 . 43. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected O, N, or S heteroatoms.

44. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is oxetanyl.

45. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, 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 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.

46. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein 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.

47. A compound or pharmaceutically acceptable salt according to any one of clauses 1-32, wherein R2b is oxetanyl substituted with one or more independently selected -CH ₃ , -CH2CH ₃ , -CF3, CHF2, -CH2CF3, -OCH ₃ , -OCH2CH ₃ , or -OCF3. 48. A compound or pharmaceutically acceptable salt according to clause 1 or 2, wherein the compound is according to Formulae Va or Vb:

49. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is H.

50. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -SO2-C1-4 alkyl.

51. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -SO2CH ₃ , or–SO2CH2CH ₃ .

52. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is halo.

53. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is F or Cl.

54. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is Cl.

55. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -CN.

56. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is C _1-4 alkyl.

57. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is– CH ₃ , -CH2CH ₃ , or -CH2CH(CH ₃ ) ₂ .

58. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is C _1-4 alkyl substituted with one, two or three independently selected Ra2 groups.

59. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein 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.

60. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -CH2-Ra2, -CH2CH2-Ra2, or -CH2CH2CH2-Ra2.

61. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is F or Cl.

62. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is -CN. 63. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is -OH. 64. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is -SO2- C1-4 alkyl. 65. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is -SO2CH ₃ .

66. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is C1-4 alkoxy.

67. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is -OCH ₃ , -OCH2CH ₃ , or–OCH(CH ₃ ) ₂ .

68. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is -OCH ₃ .

69. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is phenyl.

70. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.

71. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl.

72. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is C _3-7 cycloalkyl.

73. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

74. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is C _3-7 cycloalkyl substituted with one or more independently selected R9a.

75. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two of three independently selected R9a.

76. A compound or pharmaceutically acceptable salt according to clause 74 or 75, wherein R9a is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ , or –C(=O)CH ₃ .

77. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.

78. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

79. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 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. 80. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is unsubstituted or substituted with one, two of three independently selected R9b.

81. A compound or pharmaceutically acceptable salt according to clause 79 or 80, wherein R9b is independently selected from F, Cl, -SO2CH ₃ , oxo, -CH ₃ , -CF3, -CH2-OH, -C(=O)NH2, -OCH ₃ , or –C(=O)CH ₃ .

82. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.

83. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is 2,6- diazaspiro[3.3]heptanyl.

84. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein 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.

85. A compound or pharmaceutically acceptable salt according to clause 58, 59 or 60, wherein Ra2 is 2,6- diazaspiro[3.3]heptanyl each of which is unsubstituted or substituted with one, two of three independently selected R9c.

86. A compound or pharmaceutically acceptable salt according to clause 84 or 85, wherein R9c is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ , or –C(=O)CH ₃ .

87. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CF ₃ , or–CH ₂ OCH ₃ .

88. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 phenyl.

89. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 phenyl substituted with one, two or three independently selected Rb2.

90. A compound or pharmaceutically acceptable salt according to clause 89, wherein 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.

91. A compound or pharmaceutically acceptable salt according to clause 89, wherein each Rb2 is independently selected from F, Cl,–CH ₃ , or -OCH ₃ .

92. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.

93. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl. 94. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, 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, two or three independently selected Rb2.

95. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl, each of which is substituted with one, two or three independently selected Rb2.

96. A compound or pharmaceutically acceptable salt according to clause 94 or 95, wherein each Rb2 is independently selected from halo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy.

97. A compound or pharmaceutically acceptable salt according to clause 94 or 95, wherein each Rb2 is independently selected from F, Cl,–CH ₃ , or -OCH ₃ .

98. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is C3-7 cyclolalkyl.

99. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

100. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is C _3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb2. 101. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three independently selected Rb2.

102. A compound or pharmaceutically acceptable salt according to clause 100 or 101, wherein 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.

103. A compound or pharmaceutically acceptable salt according to clause 100 or 101, wherein each Rb2 is independently selected from F, Cl, oxo,–CH ₃ , or -OCH ₃ .

104. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.

105. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

106. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, 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, two or three independently selected Rb2.

107. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein 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.

108. A compound or pharmaceutically acceptable salt according to clause 106 or 107, wherein each Rb2 is independently selected from halo, oxo, C1-4 alkyl unsubstituted or substituted with one C1-4 alkoxy, and C1-4 alkoxy.

109. A compound or pharmaceutically acceptable salt according to clause 106 or 107, wherein each Rb2 is independently selected from F, Cl, oxo,–CH ₃ , or -OCH ₃ .

110. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -C(=O)NR7aR7b, wherein each R7a and R7b is independently selected from H, or C1-4 alkyl.

111. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -C(=O)NR7aR7b, wherein each R7a and R7b is independently selected from H,–CH ₃ , or–CH2CH ₃ . 112. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -S(=O) ₂ NR7dR7e, wherein each R7d and R7e is independently selected from H, or C1-4 alkyl.

113. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -S(=O) ₂ NR7dR7e, wherein each R7d and R7e is independently selected from H,–CH ₃ , or –CH ₂ CH ₃ .

114. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -NR7f-C(=O)O-C _1-4 alkyl, wherein R7f is selected from H, or C _1-4 alkyl.

115. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -NR7f-C(=O)O-CH ₃ , -NR7f-C(=O)O-CH ₂ CH ₃ , or -NR7f-C(=O)O-C(CH ₃ ) ₃ , wherein R7f is selected from H, or C _1-4 alkyl.

116. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -NR7f-C(=O)O-CH ₃ , -NR7f-C(=O)O-CH ₂ CH ₃ , or -NR7f-C(=O)O-C(CH ₃ ) ₃ , wherein R7f is selected from H,–CH ₃ , or–CH ₂ CH ₃ .

117. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -NR7gR7h, wherein each R7g and R7h is independently selected from H, or C _1-4 alkyl.

118. A compound or pharmaceutically acceptable salt according to any one of clauses 1-48, wherein R4 is -NR7gR7h, wherein each R7g and R7h is independently selected from H,–CH ₃ , or–CH ₂ CH ₃ .

119. A compound or pharmaceutically acceptable salt according to clause 1 or 2, wherein the compound is according to Formulae VIa or VIb:

120. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is F or Cl. 121. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–OH.

122. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–CN.

123. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is C1-4 alkyl.

124. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–CH ₃ , -CH2CH ₃ , or -CH2CH(CH ₃ ) ₂ .

125. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is C1-4 alkyl substituted with one, two or three independently selected Ra1 groups.

126. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -CH ₃ , -CH2CH ₃ , -CH2CH2CH ₃ , -CH2CH(CH ₃ ) ₂ , or -CH(CH ₃ ) ₂ , each of which substituted with one, two or three independently selected Ra1 groups.

127. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -CH ₂ -Ra1, -CH ₂ CH ₂ -Ra1, or -CH ₂ CH ₂ CH ₂ -Ra1.

128. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -CH ₂ CH ₂ CH ₂ -Ra1.

129. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is C _1-4 alkoxy.

130. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein 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 .

131. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is C _1-4 alkoxy substituted with one, two or three independently selected Ra1 groups.

132. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein 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.

133. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 -OCH ₂ -Ra1, -OCH ₂ CH ₂ -Ra1, -OCH(CH ₃ )-Ra1, or -OCH ₂ CH ₂ CH ₂ -Ra1. R3 is -OCH ₂ CH ₂ CH ₂ -Ra1. 134. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -OCH ₂ CH ₂ CH ₂ -Ra1.

135. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or131- 134, wherein Ra1 is F or Cl.

136. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is–CN.

137. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is–OH.

138. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is -SO2-C1-4 alkyl. 139. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is -SO2CH ₃ .

140. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is C1-4 alkoxy.

141. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is -OCH ₃ , -OCH2CH ₃ , or–OCH(CH ₃ ) ₂ .

142. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is phenyl.

143. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.

144. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, or furanyl.

145. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is C _3-7 cycloalkyl.

146. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

147. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is C _3-7 cycloalkyl substituted with one, two or three independently selected R9a. 148. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two of three independently selected R9a.

149. A compound or pharmaceutically acceptable salt according to clause 145 or 146, wherein R9a is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ , or– C(=O)CH ₃ .

150. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.

151. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

152. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein 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.

153. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is unsubstituted or substituted with one, two of three independently selected R9b. 154. A compound or pharmaceutically acceptable salt according to clause 152 or 153, wherein R9b is independently selected from F, Cl, -SO2CH ₃ , oxo, -CH ₃ , -CF3, -CH2-OH, -C(=O)NH2, -OCH ₃ , or– C(=O)CH ₃ .

155. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is fused/spiro/bridged 4-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.

156. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is 2,6-diazaspiro[3.3]heptanyl.

157. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein 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.

158. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein Ra1 is 2,6-diazaspiro[3.3]heptanyl each of which is unsubstituted or substituted with one, two of three independently selected R9c.

159. A compound or pharmaceutically acceptable salt according to clause 157 or 158, wherein R9c is independently selected from F, Cl, -SO ₂ CH ₃ , oxo, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ , or– C(=O)CH ₃ .

160. A compound or pharmaceutically acceptable salt according to any one of clauses 125-128 or 131- 134, wherein R3 is phenyl.

161. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is phenyl substituted with one, two or three independently selected Rb1.

162. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from O, N, or S.

163. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein thiazolyl, thienyl, oxazolyl, imidazolyl, pyrrazolyl, furanyl, pyridinyl, pyrimidinyl, or pyrazinyl. 164. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, 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, two or three independently selected Rb1. 165. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein 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.

166. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is C3-7 cyclolalkyl.

167. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 168. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is C3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb1. 169. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three independently selected Rb1.

170. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–O-C3-7 cyclolalkyl.

171. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–O-cyclopropyl,–O-cyclobutyl,–O-cyclopentyl, or–O-cyclohexyl.

172. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–O-C3-7 cyclolalkyl, which cycloalkyl is substituted with one, two or three independently selected Rb1.

173. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–O-cyclopropyl,–O-cyclobutyl,–O-cyclopentyl, or–O-cyclohexyl, each of which is substituted with one, two or three independently selected Rb1.

174. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.

175. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

176. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, 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, two or three independently selected Rb1.

177. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein 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.

178. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, 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.

179. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-dioxanyl, -O-azetidinyl, -O-pyrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl, or -O-thiomorpholinyl. 180. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, 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, two or three independently selected Rb1.

181. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein 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. 182. A compound or pharmaceutically acceptable salt according to clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein Rb1 is F or Cl.

183. A compound or pharmaceutically acceptable salt according to clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein Rb1 is oxo.

184. 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.

185. 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.

186. A compound or pharmaceutically acceptable salt according to clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein Rb1 is monocyclic 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, N, or S.

187. A compound or pharmaceutically acceptable salt according to clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein Rb1 is azetidinyl, oxetanyl, pyrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, dioxanyl, or piperazinyl.

188. 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, or C _1-4 alkyl. In a particular embodiment, each R6a and R6b is independently selected from H,–CH ₃ , or–CH ₂ CH ₃ .

189. 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 . 190. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -NR6c-C(=O)-C _1-4 alkyl, wherein R6c is selected from H, or C _1-4 alkyl.

191. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -NR6c-C(=O)-CH ₃ , or -NR6c-C(=O)-CH ₂ CH ₃ , wherein R6c is selected from H, or C _1-4 alkyl. 192. 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, or C1-4 alkyl.

193. 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. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -NR6f-C(=O)O-CH ₃ , or -NR6f-C(=O)O-CH2CH ₃ , wherein R6f is selected from H, or C1-4 alkyl. 196. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -NR6gR6h, wherein each R6g and R6h is independently selected from H, or C1-4 alkyl.

197. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is -NR6gR6h, wherein each R6g and R6h is independently selected from H,–CH ₃ , or–CH2CH ₃ . 198. A compound or pharmaceutically acceptable salt according to any one of clauses 1-119, wherein R3 is–OCH2CH2CH2-OCH ₃ ,–O-cyclobutyl,–OCH2-cyclopropyl,–OCH(CH ₃ )-cyclopropyl,–OCH2- cyclobutyl, or–OCH2C(CH ₃ ) ₂ .

199. A compound or pharmaceutically acceptable salt according to any one of clauses 1-198, wherein X is–S-.

200. A compound or pharmaceutically acceptable salt according to any one of clauses 1-198, wherein X is–S(=O)-.

201. A compound or pharmaceutically acceptable salt according to any one of clauses 1-198, wherein X is -S(=O) ₂ -.

202. 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.

203. 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.

204. A compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-201, or a pharmaceutically composition according to clauses 202 or 203, for use in medicine.

205. A compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-201, or a pharmaceutically composition according to clauses 202 or 203, for use in the prophylaxis and/or treatment of hepatitis B. PHARMACEUTICAL COMPOSITIONS

[0216] 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.

[0217] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, 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.

[0218] The 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. The term‘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. In such 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.

[0219] 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.

[0220] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, 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.

[0221] 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. 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.

[0222] 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.

[0223] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0224] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0225] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.

Formulation 1-Tablets

[0226] 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.

Formulation 2-Capsules

[0227] 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).

Formulation 3-Liquid

[0228] A compound of the invention according to Formula I (125 mg), 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.

Formulation 4-Tablets

[0229] 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.

Formulation 5-Injection

[0230] 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.

Formulation 6-Topical

[0231] 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. METHODS OF TREATMENT

[0232] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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.

[0233] In another embodiment, 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.

[0234] In additional method of treatment aspects, 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.

[0235] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a hepatitis B treatment agent.

[0236] 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.

[0237] For the prophylaxis and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, 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. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, 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.

[0238] Using these dosing patterns, 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.

[0239] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0240] 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. [0241] 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.

[0242] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0243] In one embodiment, a compound of the invention is co-administered with another therapeutic agent to stimulate immune response, particular agents include, but are not limited to PEG-IFN, TLR agonists, RIG-I agonists, therapeutic vaccine and immune checkpoint blockers.

[0244] In one embodiment, a compound of the invention is co-administered with another therapeutic agent to repress HBV DNA levels, particular agents include, but are not limited to nucleoside analogues like lamivudine, entecavir, tenofovir, tenofovir alafenamide

[0245] In one embodiment, a compound of the invention is co-administered with another therapeutic agent to block the HBV entry receptor NTCP, particular agents include, but are not limited to Myrcludex

[0246] In one embodiment, a compound of the invention is co-administered with another therapeutic agent preventing capsid assembly. Particular agent include but are not limited to AB-506, and/or AB-423.

[0247] In one embodiment, a compound of the invention is co-administered with another therapeutic agent to repress HBsAg levels. In particular embodiments, the HBsAg level repressing agent is a RNA interference agent, or is a Nucleic Acid Polymer (NAP). Particular agents include, but are not limited to RNAi agents such as ARO-HBV/ JNJ-3989 and ARB-1467, or NAPs such as REP-2139 and REP-2165.

[0248] In one embodiment, a compound of the invention is co-administered with another therapeutic agent targeted to modify the HBV genome to block HBV antigen production, such as CRISPR-Cas9.

[0249] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times. CHEMICAL SYNTHETIC PROCEDURES

General

[0250] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0251] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Greene, T W; Wuts, P G M;, 1991).

[0252] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0253] All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 µm). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm).1H NMR spectra were recorded on a Bruker DPX 400 NMR spectrometer (400 MHz or a Bruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (d) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (d 0.00) or the appropriate residual solvent peak, i.e. CHCl ₃ (d 7.26), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintuplet (quin), multiplet (m) and broad (br). Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C181.7µm, 2.1mm ID x 50mm L, Waters Acquity UPLC BEH C181.7 µm, 2.1mm ID x 30 mm L, or Waters Xterra MS 5µm C18, 100 x 4.6mm. The methods are using either ACN/H ₂ O gradients (H ₂ O contains either 0.1% TFA or 0.1% NH ₃ ) or MeOH /H ₂ O gradients (H ₂ O contains 0.05% TFA). Microwave heating was performed with a Biotage Initiator. HPLC preparative purifications were performed on Waters 2545 Pump (50 mL/min-1), Waters 2767 Sample Manager, Waters 2424 ELSD, Waters 2998 PDA, Waters 515 Pump (1 mL.min-1), X-Bridge C18 100x30mm, 5µm. Method A HPLC (acid method): ACN/H ₂ O gradients over 7 min (H ₂ O contains either 0.1 % of Formic Acid. Method B HPLC (basic method): ACN/H ₂ O gradients over 7 min (H ₂ O with 0.1 % Et ₂ NH).

Table I. List of abbreviations used in the experimental section:

SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION Int.011: 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene

[0254] 1-Bromo-3-methoxypropane (CAS: 36865-41-5, 13.0 mL, 116 mmol, 1.2 equiv.) was added to a mixture of stirred mixture of 5-bromo-2-chlorophenol (CAS: 183802-98-4, 20.0 g, 96.4 mmol, 1.0 equiv.) to K2CO3 (40.0 g, 289 mmol, 3.0 equiv.) in ACN (200 mL) under inert atmosphere at RT. The mixture was stirred to reflux for 3 h. The mixture was allowed to cool down to RT and concentrated. Water was added to the crude and was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product was used without purification.

[0255] Molecular weight: 332.8 ; LCMS, molecular weight observed: No ionization

Int.008: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylbutanoic acid

[0256] To a mixture of mixture of 4-bromo-1-chloro-2-(3-methoxypropoxy) benzene Int.011 (1.00 g, 3.58 mmo, 1.0 equiv.), 3-sulfanylbutanoic acid (CAS: 26473-49-4, 0.51 g, 4.29 mmol, 1.2 equiv.) and XantphosPd G3 (CAS: 1445085-97-1, 0.036 g, 0.357 mmol, 0.1 equiv.) in THF (10 mL) was added in one portion TEA (1.50 mL, 10.7 mmol, 3.0 equiv.). The mixture was stirred at 40°C for 40 min. The mixture was allowed to cool down to RT and was filtered through a pad of Celite ®, concentrated. To the residue EtOAc and 2 N aqueous HCl were added. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0257] Molecular weight: 318.8 ; LCMS, molecular weight observed: 317.2/319.1

Int.007: 6-chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one

[0258] H2SO4 (5 mL) was cooled down to 0°C, and was added dropwise 3-[4-chloro-3-(3- methoxypropoxy)phenyl]sulfanylbutanoic acid Int.008 (1.20 g, 3.80 mmol, 1.0 equiv.). The mixture was allowed to warm up to RT for 1 h. The reaction mixture was poured dropwise into ice-water. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0259] Molecular weight: 300.8 ; LCMS, molecular weight observed: 301.5/303.1 Int.006: 6-chloro-7-(3-methoxypropoxy)-2-methyl-1,1-dioxo-2,3-dihydro thiochromen-4-one:

[0260] 6-chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one Int 007 (1.0 g, 3.32 mmol, 1.0 equiv.) was charged in glacial acetic acid (2 mL, 34.9 mmol, 10.1 equiv.), and 30 %/w. aqueous H ₂ O ₂ (1 mL, 17.3 mmol, 5.2 equiv.) was added. The mixture was stirred at 100°C for 1 h . The mixture was allowed to cool down to RT and concentrated. To the mixture was added water and EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, DCM/MeOH 100:0 to 0:100) to afford the title product.

[0261] Molecular weight: 332.8 ; LCMS, molecular weight observed: 333.2/335.2

Synthesis of Cpd_001: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-t rioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid:

[0262] 6-chloro-7-(3-methoxypropoxy)-2-methyl-1,1-dioxo-2,3-dihydro thiochromen-4-one Int.006 (644 mg, 1.93 mmol, 1.0 equiv.) was dissolved in EtOH (3.2 mL). Glacial acetic acid (0.022 mL, 0.387 mmol, 0.2 equiv.) and cyclopropylamine (CAS: 765-30-0, 0.57 mL, 4.99 mmol, 4.0 equiv.) were added, and the mixture was stirred at reflux for 1 h. The mixture was allowed to cool down to RT. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The previous residue (719 mg, 1.93 mmol, 1.0 equiv.) and 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 468 mg, 2.51 mmol, 1.3 equiv.) were dissolved in DMSO (1 mL). The mixture was stirred at 50°C for 20 min. To the previous solution was added 2 N aqueous NaOH (1.90 mL, 3.86 mmol, 2.0 equiv.) and the mixture was stirred at 120°C for 30 min. The mixture was allowed to cool down to RT and 2 N aqueous HCl was added (1.90 mL, 3.86 mmol, 2.0 equiv.) a precipitate was formed and filtered. The precipitate was washed with water to afford the title product.

[0263] Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.2/470.2

[0264] 1H NMR (400 MHz, DMSO-d6) d 13.97 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 7.62 (s, 1H), 4.84 (d, 1H), 4.38 (tt, 2H), 3.82 (tt, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.10–1.99 (m, 2H), 1.31 (s, 3H), 1.20 (s, 1H), 0.95 (s, 1H), 0.58 (s, 1H). Synthesis of 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 & Synthesis of Cpd_067: (5S)-9-chloro-1-cyclopropyl-8- (3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3 -b]pyridine-3-carboxylic acid

[0265] 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-t rioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid Cpd_001 (100 mg, 0.203 mmol) undergoes a chiral separation (instrument: SFC Basic Sepiatec, columns: Chiralpak IG (10x250 mm, 5µm), detectors: UV (220 nm), solvent: 40 % MeOH in liquid CO2, gradient: isocratic over 18 min, flow: 10 mL.min-1) to afford (5R)-9-chloro-1- cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2-o xo-5H-chromeno[4,3-b]pyridine-3- carboxylic acid and (5S)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyl oxetan-3-yl)-2-oxo- 5H-chromeno[4,3-b]pyridine-3-carboxylic acid.

[0266] Cpd_066: Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.2/470.2

[0267] 1H NMR (400 MHz, Chloroform-d) d 13.97 (s, 1H), 8.42 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 4.44– 4.31 (m, 2H), 4.09 (q, J = 7.2 Hz, 1H), 3.65 (t, J = 5.9 Hz, 2H), 3.57–3.47 (m, 1H), 3.41 (s, 3H), 2.27–2.17 (m, 2H), 1.59–1.54 (m, 4H), 1.24–1.19 (m, 1H), 0.69–0.65 (m, 1H), 0.60–0.56 (m, 1H)

[0268] Cpd_067: Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.2/470.2

[0269] 1H NMR (400 MHz, Chloroform-d) d 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 4.41– 4.29 (m, 2H), 4.06 (q, J = 7.2 Hz, 1H), 3.62 (t, J = 5.9 Hz, 2H), 3.55–3.44 (m, 1H), 3.39 (s, 3H), 2.25–2.14 (m, 2H), 1.56–1.52 (m, 4H), 1.21–1.17 (m, 1H), 0.66–0.62 (m, 1H), 0.58–0.53 (m, 1H)

Synthesis of Cpd_014: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H - thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0270] 6-Chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one Int.007 (150 mg, 0.49 mmol, 1.0 equiv.) was dissolved in EtOH (0.75 mL). To the solution was added glacial acetic acid (0.057 mL, 0.099 mmol, 0.2 equiv.) and cyclobutylamine (CAS: 2516-34-9, 0.171 mL, 1.99 mmol, 4.0 equiv.). The mixture was stirred at 80°C for 16 h. The mixture was allowed to cool down to RT. Water and DCM were added, and the organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The previous mixture (246 mg, 0.49 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 117 mg, 0.63 mmol, 1.3 equiv.) were dissolved in DMSO (0.40 mL). The mixture was stirred at 50°C for 15 min. To the previous solution was added 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 0.8 equiv.) and the mixture was stirred at 120°C for 20 min. The mixture was allowed to cool down to RT and 2 N aqueous HCl was added (0.20 mL, 0.40 mmol, 0.8 equiv.). Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, column eluted with DCM/MeOH 100:0 to 0:100) to afford the title product.

[0271] Molecular weight: 450.0 ; LCMS, molecular weight observed: 450.3/452.2

[0272] 1H NMR (400 MHz, Chloroform-d) d 14.62 (s, 1H), 8.33 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 4.98– 4.89 (m, 1H), 4.28–4.13 (m, 2H), 3.94–3.88 (m, 1H), 3.62 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 2.93–2.79 (m, 1H), 2.36–2.09 (m, 4H), 2.01–1.93 (m, 1H), 1.89–1.76 (m, 1H), 1.30–1.17 (m, 4H)

Synthesis of Cpd_020: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0273] 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H -thiochromeno[4,3-b]pyridine- 3-carboxylic acid (20.0 mg, 0.04 mmol, 1.0 equiv.) was charged in glacial acetic acid (0.038 mL, 0.670 mmol, 15.0 equiv.), and was added 30 %/w. aqueous H ₂ O ₂ (0.020 mL, 0.210 mmol, 4.8 equiv.), the mixture was stirred at 100°C for 2 h . The mixture was allowed to cool down to RT and concentrated. The residue was purified by preparative HPLC (acid method) to afford the title product.

[0274] Molecular weight: 482.0 ; LCMS, molecular weight observed: 482.2/484.2

[0275] 1H NMR (400 MHz, Chloroform-d) d 14.13 (s, 1H), 8.54–8.25 (m, 1H), 7.73–7.52 (m, 2H), 5.01 (q, J = 8.1 Hz, 1H), 4.40–3.97 (m, 3H), 3.61 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 3.08–2.81 (m, 1H), 2.18 (q, J = 6.1 Hz, 3H), 2.06–1.65 (m, 6H), 1.36–1.25 (m, 1H)

Synthesis of Cpd_026: 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-t rioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0276] 6-chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one (150 mg, 0.49 mmol, 1.0 equiv.) was charged in glacial acetic acid (0.150 mL, 2.62 mmol, 5.2 equiv.) and cyclopentamine (CAS: 1003-03- 8, 425 mg, 4.99 mmol, 10.0 equiv.) was added. The mixture was stirred at 100°C for 20 h. The mixture was allowed to cool down to RT. Water and DCM were added, and the organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and concentrated. The previous mixture (183 mg, 0.50 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2 dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 120 mg, 0.65 mmol, 1.3 equiv.) were dissolved in DMSO (1.50 mL). The mixture was stirred at 50°C for 15 min and 2 N aqueous NaOH (0.500 mL, 0.99 mmol, 2.0 equiv.) was added and the mixture was stirred at 130°C for 30 min. The mixture was allowed to cool down to RT and 2 N aqueous HCl was added (0.50 mL, 0.99 mmol, 2.0 equiv.). Water and EtOAc were added. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The previous crude (247 mg, 0.53 mmol, 1.0 equiv.) was charged in glacial acetic acid (0.50 mL, 8.70 mmol, 16.0 equiv.), and 30 %/w. aqueous H2O2 (0.25 mL, 2.66 mmol, 5.0 equiv.) was added. The mixture was stirred at 100°C for 30 min. The mixture was allowed to cool down to RT and concentrated. The residue was purified by preparative HPLC (basic method) to afford the title product as a DEA salt.

[0277] Molecular weight: 496.0 ; LCMS, molecular weight observed: 496.2/498.2

[0278] 1H NMR (400 MHz, Chloroform-d) d 8.35 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 4.81 (p, J = 8.6 Hz, 1H), 4.41–4.24 (m, 2H), 4.05 (q, J = 7.2 Hz, 1H), 3.61 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 2.27–2.05 (m, 5H), 2.05–1.24 (m, 8H).

Int.010: 2-ethylhexyl 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoate

[0279] To a mixture of mixture of 4-bromo-1-chloro-2-(3-methoxypropoxy) benzene Int.011 (10.0 g, 35.8 mmol, 1.0 equiv.), 2-ethylhexyl 3-mercaptopropionate (CAS: 50448-95-8, 11.7 g, 53.7 mmol, 1.5 equiv.) and Xantphos Pd G3 (CAS: 1445085-97-1, 1.79 g, 1.79 mmol, 0.05 equiv.) were dissolved in THF (100 mL) and was added in one portion TEA (15.0 mL, 107 mmol, 3.0 equiv.). The mixture was stirred at 100°C for 16 h. The mixture was allowed to cool down to RT and was filtered through a pad of celite ®, concentrated. To the residue EtOAc and water were added. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , Heptane/EtOAc 100:0 to 0:100) to afford the desired compound.

[0280] Molecular weight: 417.0 ; LCMS, molecular weight observed: 417.5/419.1

Int.009: 4-chloro-3-(3-methoxypropoxy)benzenethiol

[0281] To a mixture of mixture of 2-ethylhexyl 3-[4-chloro-3-(3-methoxypropoxy)phenyl] sulfanylpropanoate (10.0 g, 24.0 mmol, 1.0 equiv.), EtONa (CAS: 141-52-6, 3.76 g, 48.0 mmol, 2.0 equiv.) were dissolved in EtOH (50 mL). The mixture was stirred at reflux for 15 min. The mixture was allowed to cool down to RT and was filtered through a pad of Celite ®, concentrated. To the residue EtOAc and water were added, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the title product. [0282] Molecular weight: 232.7 ; LCMS, molecular weight observed: 233.2/235.1

Synthesis of Cpd_005: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5 H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0283] 6-Chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one (50 mg, 0.166 mmol, 1.0 equiv.) and cyclopropylamine (CAS: 765-30-0, 19 mg, 0.332 mmol, 2.00 equiv.) were dissolved in DCE (2.0 mL) then titanium (IV) isopropoxide (0.0984 mL, 0.332 mmol, 2.0 equiv.) was added. The mixture was stirred at 60°C for 16 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and a solution of NaOH 1N was added and stirred vigorously for 5 min. The biphasic solvent was filtered through Celite ® and separated. The organic layer was dried over (Na ₂ SO ₄ ) and concentrated. This mixture and 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 164 mg, 0.883 mmol, 3.0 equiv.) were dissolved in fluorobenzene (1 mL) in microwave vial and degassed by argon bubbling for 5 min. The mixture was stirred at 180°C for 2 h under microwaves irradiation. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was taken up in THF (1 mL) and a solution of 1 N aqueous NaOH (1 mL) added. The mixture was stirred at RT for 1 h. The mixture was diluted with water and a solution of 1N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo to remove ACN before freeze-drying to afford the title product.

[0284] Molecular weight: 435.9 ; LCMS, molecular weight observed: 436.2/438.2 (MS+)

[0285] 1H NMR (400 MHz, DMSO-d ₆ ) d 8.29 (s, 1H), 8.23 (s, 1H), 7.36 (s, 1H), 4.35–4.15 (m, 3H), 3.73– 3.64 (m, 1H), 3.51 (t, 2H), 3.26 (s, 3H), 2.01 (p, 2H), 1.27 (d, 3H), 1.21–1.13 (m, 1H), 0.90–0.78 (m, 1H), 0.49 (s, 1H).

Int.015: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pen tanoic acid

[0286] 4-Chloro-3-(3-methoxypropoxy)benzenethiol (381 mg, 1.64 mmol, 1.5 equiv.) was dissolved in DMF (2.0 mL) and then 4-methyl-pent-2-enoic-acid (CAS: 1021-71-8, 125 mg, 1.09 mmol, 1.0 equiv.) and Bu ₄ NF.3H ₂ O (69 mg, 0.218 mmol, 0.20 equiv.) were added in a microwave vial. The mixture was degassed by argon bubbling for 10 min, and then stirred at 50°C for 3 h. The mixture was allowed to cool to RT. The solvent was removed in vacuo. The residue was purified by FLC (SiO ₂ , DCM/MeOH 100:00 to 95:05) to afford the title product. [0287] Molecular weight: 346.9 ; LCMS, molecular weight observed: 345.0/347.0 (MS-).

Int.014: 6-chloro-2-isopropyl-7-(3-methoxypropoxy)thiochroman-4-one

[0288] 3-[4-Chloro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pen tanoic acid (381 mg, 1.64 mmol, 1 equiv.) was cooled to 0°C, then H ₂ SO ₄ (3 mL) was added dropwise at 0°C. The mixture was allowed to warm up to RT for 1h. The reaction mixture was poured dropwise into ice-water. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 60:40) to afford the title product.

[0289] Molecular weight: 328.9 ; LCMS, molecular weight observed: 327.1/329.1 (MS-).

Int.013: 6-chloro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihy drothiochromen-4-one:

[0290] 6-Chloro-2-isopropyl-7-(3-methoxypropoxy)thiochroman-4-one (163 mg, 0.496 mmol, 1.0 equiv.) in DCM (10 mL) was cooled to 0°C, then MCPBA (CAS: 937-14-4, 342 mg, 1.98 mmol, 4.0 equiv.) was added at 0°C. The mixture was allowed to warm up to RT for 4h. The organics layer was washed (NaHCO ₃ , water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to afford the title product.

[0291] Molecular weight: 360.9 ; LCMS, molecular weight observed: 359.1/360.0 (MS).

Synthesis of Cpd_002: 9-chloro-1-cyclopropyl-5-isopropyl-8-(3-methoxypropoxy)-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0292] 6-Chloro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihy drothiochromen-4-one (80 mg, 0.222 mmol, 1.0 equiv.) was dissolved in DCE (3.0 mL) under argon then titanium (IV) isopropoxide (0.131 mL, 0.433 mmol, 2.0 equiv.) and cyclopropylamine (CAS: 765-30-0, 25 mg, 0.443 mmol, 2.0 equiv.) were added. The mixture was stirred at 60°C for 4 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and a solution of NaOH 1N was added and stirred vigorously for 10 min. The biphasic solvent is filtered through celite and separated. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. This mixture (90 mg, 0.225 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (CAS: 15568-85-1, 42 mg, 0.225 mmol, 1.0 equiv.) were dissolved in toluene. The mixture was stirred at 120°C for 3 h. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 50:50). The relevant fractions were concentrated in vacuo and ACN-water (1:1) was added before freeze-drying. This mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 27 mg, 0.144 mmol, 2.0 equiv.) was dissolved in DMSO (1.0 mL) in microwave vial and degassed by argon bubbling for 5 min. The mixture was stirred at 160°C for 1 h in microwave. After 1 h 1.0 equiv. of 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione was added again and degassed by argon bubbling for 5 min. The mixture was stirred at 160°C for 1 h under microwaves irradiation. The mixture was allowed to cool to RT and filtered through PTFE filter and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo and concentrated formic acid was added before freeze-drying to afford the title product.

[0293] Molecular weight: 496.0 ; LCMS, molecular weight observed: 496.2/498.2

[0294] 1H NMR (400 MHz, DMSO-d ₆ ) d 14.03 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.61 (s, 1H), 4.71 (d, 1H), 4.38 (tt, 2H), 3.82–3.72 (m, 1H), 3.52 (t, 2H), 3.27 (s, 3H), 2.10–1.92 (m, 3H), 1.35–1.21 (m, 1H), 1.03 (d, 3H), 0.90–0.71 (m, 2H), 0.42 (d, 3H).

Int.027: 2-tert-butyl-6-chloro-7-(3-methoxypropoxy)thiochroman-4-one

[0295] 4-Chloro-3-(3-methoxypropoxy)benzenethiol (440 mg, 1.89 mmol, 1.5 equiv.) was dissolved in DMF (3.00 mL) and then (E)4,4-dimethylpent-2-enoic-acid (CAS: 6945-35-3, 162 mg, 1.26 mmol, 1.00 equiv.) and Bu ₄ NF.3H ₂ O (CAS: 87749-50-6, 80 mg, 0.252mmol, 0.2 equiv.) and PPh ₃ (331mg, 1.26mmol, 1.00 equiv.) were added in a microwave vial. The mixture is degassed by argon bubbling for 10 min, and then stirred at 50°C for 72 h. The mixture was allowed to cool to RT. The solvent was removed in vacuo. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 60:40) to afford the title product. This acid compound is cooled to 0°C, and then H2SO4 (3 mL) was added dropwise at 0°C. The mixture was allowed to warm up to RT for 1 h. The reaction mixture was poured dropwise into ice- water. A solid started to form, this aqueous solution was stirred overnight at RT. The solid was filtered and dried overnight in desiccator at 50°C to afford the title product.

[0296] Molecular weight: 342.9 ; LCMS, molecular weight observed: 343.0/345.0 (MS+).

Int.026: 2-tert-butyl-6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dih ydrothiochromen-4-one

[0297] 2-tert-Butyl-6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (150 mg, 0.437 mmol, 1.0 equiv.) in DCM (10 mL) was cooled to 0°C, then MCPBA (CAS: 937-14-4, 302 mg, 1.75 mmol, 4.0 equiv.) was added at 0°C. The mixture was allowed to warm up to RT for 3h. The organics layer was washed (aqueous saturated NaHCO3, water and brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 60:40) to afford the title product.

[0298] Molecular weight: 374.9 ; LCMS, molecular weight observed: 373.1/375.0 (MS-)

Synthesis of 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

[0299] 2-tert-Butyl-6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dih ydrothiochromen-4-one (250 mg, 0.667 mmol, 1.0 equiv.) was dissolved in 1,2-dichloroethane (2.0 mL) under argon then titanium (IV) isopropoxide (0.395 mL, 1.33 mmol, 2.0 equiv.) and cyclopropylamine (CAS: 765-30-0, 76 mg, 1.33 mmol, 2.0 equiv.) were added. The mixture was stirred at 60°C for 4 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and 1 N aqueous NaOH was added and stirred vigorously for 10 min. The biphasic solvent was filtered through Celite ® and separated. The organic layer was dried (Na2SO4) and concentrated. The mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 308mg, 1.65 mmol, 3.0 equiv.) were dissolved in fluorobenzene (3 mL) in microwave vial and degassed by argon bubbling for 5 min. The mixture was stirred at 180°C for 2 h under microwaves irradiation. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was taken up in THF (3 mL) and 1 N aqueous NaOH (3 mL) was added. The mixture was stirred at RT for 1 h. The mixture was diluted with water 1 N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organics layer was washed (brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo to remove ACN before freeze- drying to afford the title product.

[0300] Molecular weight: 510.0 ; LCMS, molecular weight observed: 510.3/512.3 (MS+)

[0301] 1H NMR (400 MHz, DMSO-d ₆ ) d 8.45 (s, 1H), 8.40 (s, 1H), 7.61 (s, 1H), 4.76 (s, 1H), 4.37 (t, 2H), 3.81–3.71 (m, 1H), 3.52 (t, 2H), 3.27 (s, 3H), 2.04 (p, 2H), 1.35–1.18 (m, 1H), 0.80 (s, 11H), 0.77–0.69 (m, 1H), -0.03–-0.12 (m, 1H).

Int.021: Synthesis of intermediate 4-bromo-1-fluoro-2-(3-methoxypropoxy)benzene

[0302] 1-Bromo-3-methoxypropane (CAS: 36865-41-5, 4.42 mL, 39.27 mmol, 1.5 equiv.) was added to a stirred mixture of 5-bromo-2-fluorophenol (CAS: 147460-41-1, 5 g, 26.18 mmol, 1.0 equiv.) to K ₂ CO ₃ (4.34 g, 31.41 mmol, 1.2 equiv.) in DMF (120 mL) under air at RT. The mixture was stirred at 60°C for 18 h. The mixture was allowed to cool to RT and poured into water. The mixture was extracted with diethyl ether. The organic layer was washed (brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 60:40) to afford the title product.

[0303] Molecular weight: 263.1 ; LCMS, molecular weight observed: no ionization.

Int.020: 2-ethylhexyl 3-[4-fluoro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoate

[0304] A mixture of 4-bromo-1-fluoro-2-(3-methoxypropoxy)benzene (5 g, 19.0 mmol, 1.0 equiv.), Pd ₂ dba ₃ (CAS: 51364-51-3, 0.87g, 0.95mmol, 0.05 equiv.) and Xantphos (CAS: 161265-03-8, 1.10g, 1.90mmol, 0.1 equiv.) in 1,4 dioxane (140 mL) was degassed by argon bubbling for 10 min, then 2- ethylhexyl 3-mercaptopropionate (CAS: 50448-95-8, 5.18 mL, 22.8 mmol, 1.2 equiv.) and DIPEA (6.62 mL, 38.0 mmol, 2.0 equiv.) were added. The mixture was stirred at 100°C for 18 h under argon. The mixture was allowed to cool to RT and Et ₂ O added. The mixture was filtered through a pad Celite ®, concentrated and the residue was purified by FLC (SiO ₂ , cyclohexane/DCM 100:00 to 00:100) to afford the title product.

[0305] Molecular weight: 400.6 ; LCMS, molecular weight observed: 401.2

Int.019: Synthesis of intermediate 4-fluoro-3-(3-methoxypropoxy)benzenethiol

[0306] A mixture of 2-ethylhexyl 3-[4-fluoro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoate (3 g, 7.49 mmol, 1.0 equiv.) in ethanol (75 mL) was cooled to 0°C, then sodium ethoxide (21%, 5.59 mL, 14.98 mmol, 2.0 equiv.) was added dropwise. The mixture was allowed to warm up to RT for 2 h. The reaction mixture was concentrated to dryness and the residue was partitioned between water and EtOAc. The aqueous layer was acidified to pH 2 with 1N aqueous HCl and extracted with EtOAc. The organic layer was washed (brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 33:67) to afford the title product.

[0307] Molecular weight: 216.3 ; LCMS, molecular weight observed: no ionization

Int.018: 3-[4-fluoro-3-(3-methoxypropoxy)phenyl]sulfanyl-4,4-dimethyl -pentanoic acid

[0308] 4-Fluoro-3-(3-methoxypropoxy)benzenethiol (506 mg, 2.34 mmol, 1.5 equiv.) was dissolved in DMF (2.4 mL) and then (E) 4,4-dimethylpent-2-enoic-acid (CAS: 6945-35-3, 200 mg, 1.56 mmol, 1.0 equiv.) and Bu4NF.3H2O (CAS: 87749-50-6, 98 mg, 0.312 mmol, 0.2 equiv.) were added in a microwave vial. The mixture was degassed by argon bubbling for 10 min, and then stirred at 50°C for 24 h. The mixture was allowed to cool to RT. The solvent was removed in vacuo. The residue was purified by FLC (SiO2, DCM/MeOH 100:00 to 95:5) to afford the title product.

[0309] Molecular weight: 344.4 ; LCMS, molecular weight observed: 343.1 (MS-)

Int.017: 2-tert-butyl-6-fluoro-7-(3-methoxypropoxy)thiochroman-4-one

[0310] 3-[4-Fluoro-3-(3-methoxypropoxy)phenyl]sulfanyl-4,4-dimethyl -pentanoic acid (470 mg, 1.36 mmol, 1.0 equiv.) was cooled to 0°C, then H ₂ SO ₄ (10 mL) was added dropwise at 0°C. The mixture was allowed to warm up to RT for 1 h. The reaction mixture was poured dropwise into ice-water. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:0 to 60:40) to afford the title product.

[0311] Molecular weight: 326.4 ; LCMS, molecular weight observed: 327.0

Int.016: 2-tert-butyl-6-fluoro-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dih ydrothiochromen-4-one:

[0312] 2-tert-Butyl-6-fluoro-7-(3-methoxypropoxy)thiochroman-4-one (262 mg, 0.803 mmol, 1.0 equiv.) in DCM (8 mL) was cooled to 0°C, then MCPBA (CAS: 937-14-4, 416 mg, 2.41 mmol, 3.0 equiv.) is added at 0°C. The mixture was allowed to warm up to RT for 3 h. The organic layer was washed (saturated aqueous NaHCO3, water and brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 75:25). The relevant fractions were concentrated in vacuo to afford the title product.

[0313] Molecular weight: 358.4 ; LCMS, molecular weight observed: no ionization Synthesis of 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

[0314] 2-tert-Butyl-N-cyclopropyl-6-fluoro-7-(3-methoxypropoxy)-1,1 -dioxo-2H-thiochromen-4-amine (288 mg, 0.731 mmol, 1.0 equiv.) was dissolved in dichloromethane (5.0 mL) under argon then titanium (IV) isopropoxide (0.606 mL, 2.05mmol, 2.8 equiv.) and cyclopropylamine (CAS: 765-30-0, 0.203 mL, 2.92 mmol, 4.0 equiv.) were added. The mixture was stirred at 50°C for 40 min. The mixture was allowed to cool to RT. The mixture was diluted with DCM and 1 N aqueous NaOH was added and stirred vigorously for 5 min. The biphasic solvent was filtered through Celite® and separated. The organic layer was dried (Na2SO4) and concentrated. This mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 211 mg, 1.13 mmol, 3.0 equiv.) were dissolved in fluorobenzene (1 mL) in microwave vial and degassed by argon bubbling for 5 min. The mixture was stirred at 180°C for 6 h under microwaves irradiation. The solvent was removed in vacuo to afford the title product. The crude mixture was taken up in THF (1.0 mL) and 1 N aqueous NaOH (0.950 mL, 0.943 mmol, 2.5 equiv.) added. The mixture was stirred at RT for 2 h. The mixture was diluted with water and 1 N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo and concentrated formic acid was added before freeze-drying to afford the title product.

[0315] Molecular weight: 493.4 ; LCMS, molecular weight observed:: 494.3 (MS+)

[0316] 1H NMR (400 MHz, DMSO-d ₆ ) d 14.07 (s, 1H), 8.47 (s, 1H), 8.22 (d, 1H), 7.67 (d, 1H), 4.75 (s, 1H), 4.36 (t, 2H), 3.82–3.72 (m, 1H), 3.50 (t, 2H), 3.27 (s, 3H), 2.10–1.96 (m, 2H), 1.34–1.18 (m, 1H), 0.92–0.82 (m, 1H), 0.80 (s, 9H), 0.76–0.72 (m, 1H).

Int.025: 3-[4-fluoro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pen tanoic acid

[0317] 4-Fluoro-3-(3-methoxypropoxy)benzenethiol (500 mg, 2.31 mmol, 1.50 equiv.) was dissolved in DMF (2.40 mL) and then 4-methyl-pent-2-enoic-acid (CAS: 1021-71-8, 0.184 mL, 1.54 mmol, 1.0 equiv.) and Bu ₄ NF.3H ₂ O (CAS: 87749-50-6, 97 mg, 0.308 mmol, 0.2 equiv.) were added in a microwave vial. The mixture was degassed by argon bubbling for 10 min, and then stirred at 50°C for 18 h. The mixture was allowed to cool to RT. The solvent was removed in vacuo and azeotrope was done with toluene. The residue was purified by FLC (SiO ₂ , dichloromethane/Methanol 100:00 to 95:5) to afford the title product.

[0318] Molecular weight: 330.4 ; LCMS, molecular weight observed: 329.1 (MS-) Int.024: 6-fluoro-2-isopropyl-7-(3-methoxypropoxy)thiochroman-4-one

[0319] 3-[4-Fluoro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pen tanoic acid (460 mg, 1.39 mmol, 1 equiv.) was cooled to 0°C, then H ₂ SO ₄ (10 mL) was added dropwise at 0°C. The mixture was allowed to warm up to RT for 30 min. The reaction mixture was poured dropwise into ice-water. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to afford the title product.

[0320] Molecular weight: 312.4 ; LCMS, molecular weight observed: 313.0

Int.023: 6-fluoro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihy drothiochromen-4-one:

[0321] 6-Fluoro-2-isopropyl-7-(3-methoxypropoxy)thiochroman-4-one (315 mg, 1.01 mmol, 1.0 equiv.) in dichloromethane (8 mL) was cooled to 0°C, then MCPBA (CAS: 937-14-4, 522 mg, 3.02 mmol, 3.0 equiv.) was added at 0°C. The mixture was allowed to warm up to RT for 2.25 h. The organic layer was washed (saturated aqueous NaHCO3, water and brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 75:25) to afford the title product.

[0322] Molecular weight: 344.4 ; LCMS, molecular weight observed: no ionization

Synthesis of Cpd_004: 1-cyclopropyl-9-fluoro-5-isopropyl-8-(3-methoxypropoxy)-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0323] 6-fluoro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihy drothiochromen-4-one (299 mg, 0.868 mmol, 10.0 equiv.) was dissolved in dichloromethane (5 mL) under argon then titanium (IV) isopropoxide (CAS: 546-68-9, 0.720 mL, 2.43mmol, 2.8 equiv.) and cyclopropylamine (CAS: 765-30-0, 0.241 mL, 3.47 mmol, 4.0 equiv.) were added. The mixture was stirred at 50°C for 2 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and 1 N aqueous NaOH was added and stirred vigorously for 5 min. The biphasic solvent was filtered through Celite® and separated. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. This mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane- 4,6-dione (CAS: 15568-85-1, 218 mg, 1.17 mmol, 3.0 equiv.) were dissolved in fluorobenzene (1 mL) in microwave vial and degassed by argon bubbling for 5 min. The mixture was stirred at 180°C for 6 h under microwaves irradiation. The solvent was removed in vacuo to afford the title product. The crude mixture was taken up in THF (1 mL) and 1 N aqueous NaOH (0.978 mL, 0.978 mmol, 2.5 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was diluted with water and 1 N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo and concentrated formic acid was added before freeze-drying to afford the title product.

[0324] Molecular weight: 479.54 ; LCMS, molecular weight observed: 480.3 (MS+)

[0325] 1H NMR (400 MHz, DMSO-d6) d 8.38 (s, 1H), 8.22 (d, 1H), 7.68 (d, 1H), 4.70 (d, 1H), 4.43–4.29 (m, 2H), 3.84–3.74 (m, 1H), 3.50 (t, 2H), 3.27 (s, 3H), 2.09–1.94 (m, 3H), 1.34–1.21 (m, 1H), 1.02 (d, 3H), 0.95–0.83 (m, 1H), 0.82–0.70 (m, 1H), 0.40 (d, 3H).

Int.095: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylpentanoic acid

[0326] 4-Chloro-3-(3-methoxypropoxy)benzenethiol (0.5 g, 2.15 mmol, 1.5 equiv.) was dissolved in DMF (2 mL) and then 2-pentenoic acid (CAS: 13991-37-2, 143 mg, 1.43 mmol, 1.0 equiv.) and Bu ₄ NF.3H ₂ O (CAS: 87749-50-6, 90 mg, 0.29 mmol, 0.2 equiv.) were added. The mixture was degassed by bubbling argon for 10 min, and then stirred at 50°C for 18 h. The mixture was allowed to cool to RT and was partitioned between EtOAc and water. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FLC (SiO ₂ , DCM/MeOH 100:00 to 90:10) to afford the title product.

[0327] Molecular weight: 332.8 ; LCMS, molecular weight observed: LCMS: 331.1/333.1 (MS-)

Int.094: 6-chloro-2-ethyl-7-(3-methoxypropoxy)thiochroman-4-one

[0328] 3-[4-Chloro-3-(3-methoxypropoxy)phenyl]sulfanylpentanoic acid (640 mg, 1.92 mmol, 1.0 equiv.) in H2SO4 (5 mL) was stirred at 0°C for 10 min. The mixture was allowed to warm up to RT and stirred for 0.5 h. The reaction mixture was poured dropwise into ice-water. The aqueous layer was extracted with EtOAc. The organic layer was washed (saturated aqueous NaHCO3, water and brine), dried (Na2SO4) and concentrated to afford the title product.

[0329] Molecular weight: 314.8 ; LCMS, molecular weight observed: LCMS: 315.1/317.0 Int.093: 6-chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one:

[0330] 6-Chloro-2-ethyl-7-(3-methoxypropoxy)thiochroman-4-one (385 mg, 1.22 mmol, 1.0 equiv.) in DCM (25 mL) was cooled to 0°C, then MCPBA (CAS: 937-14-4, 822 mg, 3.67 mmol, 3.0 equiv.) was added at 0°C. The mixture was allowed to warm up to RT and stirred for 18 h. The mixture was poured into 10% sodium metabisulfite and the resulting mixture was stirred at RT for 15 min. The organic layer was washed (saturated aqueous NaHCO ₃ and brine), dried (Na ₂ SO ₄ ) and concentrated to afford the title product.

[0331] Molecular weight: 346.8 ; LCMS, molecular weight observed: LCMS: no ionization

Synthesis of Cpd_021: 9-chloro-1-cyclopropyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0332] 6-Chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one (107 mg, 0.31 mmol, 1.0 equiv.) was dissolved in DCM (2.0 mL) under argon then titanium (IV) isopropoxide (CAS: 546-68-9, 0.260 mL, 0.86 mmol, 2.8 equiv.) and cyclopropylamine (CAS: 765-30-0, 70 mg, 1.23 mmol, 2.0 equiv.) were added. The mixture was stirred at 50°C for 1.5 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and a solution of 1 N aqueous NaOH was added and stirred vigorously for 15 min. The biphasic solvent was filtered through Celite® and separated. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. This mixture (100 mg, 0.26 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2- dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 145 mg, 0.78 mmol, 3.0 equiv.) were dissolved in fluorobenzene (2 mL). The mixture was stirred at 160°C for 3 h and at 170°C for 1 h. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was dissolved in THF (5 mL) and 1 N aqueous NaOH (0.65 mL, 0.65 mmol, 2.5 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and aqueous 1 N HCl. The organics layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0333] Molecular weight: 482.0 ; LCMS, molecular weight observed: LCMS: 503.8/505.8 (M+Na+)

[0334] NMR: 1H NMR (400 MHz, DMSO-d6) d 14.31 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 7.61 (s, 1H), 4.79 (dd, 1H), 4.44-4.32 (m, 2H), 3.86-3.78 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.09-2.00 (m, 2H), 1.90- 1.79 (m, 1H), 1.34-1.26 (m, 1H), 1.24-1.13 (m, 1H), 0.92-0.85 (m, 1H), 0.82 (t, 3H), 0.78-0.70 (m, 1H), 0.08-0.01 (m, 1H) Synthesis of Cpd_047: 9-chloro-1-cyclobutyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-tri oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0335] 6-Chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one (100 mg, 0.29 mmol, 1.0 equiv.) was dissolved in DCE (5 mL) under argon then titanium (IV) isopropoxide (CAS: 546- 68-9, 0.171 mL, 0.58 mmol, 2.0 equiv.) and cyclobutylamine (CAS: 2516-34-9, 41 mg, 0.58 mmol, 2.0 equiv.) were added. The mixture was stirred at 60°C for 4 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and 1 N aqueous NaOH was added and stirred vigorously for 15 min. The biphasic solvent was filtered through Celite® and separated. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. This mixture (115 mg, 0.29 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (CAS: 15568-85-1, 209 mg, 1.13 mmol, 4.0 equiv.) were dissolved in fluorobenzene (2 mL). The mixture was stirred at 170°C for 6 h. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was dissolved in THF (5 mL) and 1 N aqueous NaOH (0.94 mL, 3.3 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and 1 N aqueous HCl. The organics layer was washed (water and brine), dried (Na2SO4) and concentrated.

[0336] The residue was purified by preparative HPLC. The relevant fractions were combined and freeze- dried to afford the title product.

[0337] Molecular weight: 496.0 ; LCMS, molecular weight observed: LCMS: 496.2/498.2

[0338] NMR: 1H NMR (400 MHz, DMSO-d6) d 14.14 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 5.28-5.19 (m, 1H), 4.78 (dd, 1H), 4.39-4.32 (m, 2H), 3.51 (dd, 2H), 3.26 (s, 3H), 2.80-2.70 (m, 1H), 2.11- 2.00 (m, 3H), 1.87-1.77 (m, 1H), 1.74-1.51 (m, 4H), 1.15-1.04 (m, 1H), 0.77 (t, 3H)

Synthesis of Cpd_029: 9-chloro-1-cyclopentyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0339] 6-Chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one (78 mg, 0.22 mmol, 1.0 equiv.) was dissolved in DCE (3 mL) under argon then titanium (IV) isopropoxide (CAS: 546- 68-9, 0.133 mL, 0.45 mmol, 2.0 equiv.) and cyclopentylamine (CAS: 1003-03-8, 38 mg, 0.45 mmol, 2.0 equiv.) were added. The mixture was stirred at 60°C for 18 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and 1 N aqueous NaOH was added and stirred vigorously for 15 min. The biphasic solvent was filtered through Celite® and separated. The organic layer was dried (Na2SO4) and concentrated. This mixture of 6-chloro-4-(cyclopentylamino)-2-ethyl-7-(3-methoxypropoxy)-2 H- thiochromene 1,1-dioxide (93 mg, 0.22 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (CAS: 15568-85-1, 155 mg, 0.83 mmol, 3.7 equiv.) were dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 4 h. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was dissolved in THF (2 mL) and 1 N aqueous NaOH (0.69 mL, 3.1 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and 1 N aqueous HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0340] Molecular weight: 510.0 ; LCMS, molecular weight observed: LCMS: 510.2/512.2

[0341] NMR: 1H NMR (400 MHz, DMSO-d6) d 14.32 (s, 1H), 8.32 (s, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 4.92-4.84 (m, 1H), 4.77 (dd, 1H), 4.37 (dd, 2H), 3.55-3.48 (m, 2H), 3.27 (s, 3H), 2.70-2.62 (m, 1H), 2.14- 1.97 (m, 5H), 1.92-1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.69-1.58 (m, 2H), 1.52-1.40 (m, 1H), 1.13-1.01 (m, 1H), 0.80 (dd, 3H)

Synthesis of compounds Cpd_030 & Cpd_031: 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2R)-2- methylcyclopropyl]-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridi ne-3-carboxylic acid & 9-chloro-5-ethyl- 8-(3-methoxypropoxy)-1-[(1S,2S)-2-methylcyclopropyl]-2,6,6-t rioxo-5H-thiochromeno[4,3-b]pyridine- 3-carboxylic acid

Cpd_030 Cpd_031

[0342] 6-Chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one (70 mg, 0.20 mmol, 1.0 equiv.) was dissolved in DCE (3.0 mL) under argon then titanium (IV) isopropoxide (CAS: 546- 68-9, 0.120 mL, 0.40 mmol, 2.0 equiv.) and 2-methylcyclopropan-1-amine (CAS: 68979-89-5, 29 mg, 0.40 mmol, 2.0 equiv.) were added. The mixture was stirred at 60°C for 3 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and 1 N aqueous NaOH was added and stirred vigorously for 15 min. The biphasic solvent was filtered through Celite® and separated. The organic layer was dried (Na2SO4) and concentrated. This mixture (75 mg, 0.19 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2-dimethyl- 1,3-dioxane-4,6-dione (CAS: 15568-85-1, 105 mg, 0.56 mmol, 3.0 equiv.) were dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 6 h. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was dissolved in THF (2.0 mL) and 1 N aqueous NaOH (0.47 mL, 2.5 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and 1 N aqueous HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title products as mixture of isomers. [0343] Cpd_030: Molecular weight: 496.0 ; LCMS, molecular weight observed: LCMS: 496.2/498.1

[0344] 1H NMR (400 MHz, DMSO-d6) d 14.25 (s, 1H), 8.41-8.23 (m, 2H), 7.64-7.59 (m, 1H), 4.81-4.73 (m, 1H), 4.44-4.32 (m, 2H), 3.59 (ddd, 1H), 3.55-3.49 (m, 2H), 3.28-3.25 (m, 3H), 2.04 (tt, 2H), 1.91-1.78 (m, 1H), 1.22-1.12 (m, 1H), 1.09-1.01 (m, 1H), 0.86-0.74 (m, 6H), 0.54-0.16 (m, 2H)

[0345] Cpd_031: Molecular weight: 496.0 ; LCMS, molecular weight observed: LCMS: 496.2/498.1

[0346] 1H NMR (400 MHz, DMSO-d6) d 14.25 (s, 1H), 8.37 (s, 1H), 8.32-8.28 (m, 1H), 7.62 (s, 0.3H), 7.59 (s, 0.7H), 4.74 (dd, 1H), 4.42-4.32 (m, 2H), 3.59-3.48 (m, 3H), 3.27 (s, 2H), 3.26 (s, 1H), 2.08-2.00 (m, 2H), 1.91-1.78 (m, 1H), 1.20 (t, 3H), 1.07-0.99 (m, 1H), 0.85-0.78 (m, 3H), 0.76 (d, 1H), 0.68 (dd, 1H), 0.49-0.42 (m, 0.3H), 0.20-0.15 (m, 0.7H)

Int.047: 2-ethylhexyl 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]sulfanylpropanoate

[0347] In a sealed tube, under nitrogen, to a stirred solution of 4-bromo-2-(3-methoxypropoxy)-1-methyl- benzene (CAS: 909406-81-1, 5.00 g, 19.3 mmol, 1.0 equiv,) in 1,4-dioxane (5 mL) were successively added 2-ethylhexyl 3-sulfanylpropanoate (5.30 mL, 23.2 mmol, 1.2 equiv), PdXantPhos G3 pre catalyst (CAS: 1445085-97-1, 0.913 g , 0.965 mmol, 0.05 equiv,) and TEA (8.07 mL, 57.9 mmol, 3.0 equiv,). The reaction mixture was stirred at 100°C for 16 h and then filtered through a pad of Celite ®, rinsed with EtOAc. The filtrate was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The crude product was submitted to FLC (SiO2, column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest were pooled, dried to afford the title product.

[0348] Molecular weight: 396.6 ; LCMS, molecular weight observed: LCMS: 397.6

Int.046: 3-(3-methoxypropoxy)-4-methyl-benzenethiol

[0349] To a solution of 2-ethylhexyl 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]sulfanylpropanoate Int.047 (0.750 mg, 1.91 mmol, 1.0 equiv) in EtOH (7.5 mL) was added EtONa (0.260 g, 3.82 mmol, 2.0 equiv.). The resulting mixture was stirred at 80°C for 1.5 h. The reaction mixture was evaporated to dryness and the residue was partitioned between water and EtOAc. The aqueous layer was acidified to pH 2 with 1 N aqueous HCl and extracted with EtOAc. The organic layer was then washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was submitted to FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest were pooled, dried to afford the title product.

[0350] Molecular weight: 212.3 ; LCMS, molecular weight observed: LCMS: 213.3 Int.132: 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]sulfanylbutanoic acid

[0351] To a solution of 3-(3-methoxypropoxy)-4-methyl-benzenethiol Int.046 (668 mg, 3.15 mmol, 1.0 equiv.) in THF (6.7 mL) were successively added CsF (1.43 g, 9.44 mmol, 3.0 equiv) and 4-methyloxetan- 2-one (271 mg, 3.15 mmol, 1.0 equiv.). The reaction was stirred at RT for 20 min and quenched with water. The aqueous layer was acidified to pH 2 with 1 N aqueous HCl and extracted with DCM (3 times). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude product was engaged in the next step without any further purification.

[0352] Molecular weight: 298.4 ; LCMS, molecular weight observed: LCMS: 299.2

Int.045: 7-(3-methoxypropoxy)-2,6-dimethyl-thiochroman-4-one

[0353] The crude product 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]sulfanylbutanoic acid Int.132 was slowly added at 0°C in H2SO4 (3.50 mL, 66.2 mmol, 21.0 equiv.) and stirred for 20 min. The reaction was carefully quenched with crushed iced water and extracted with DCM (3 times). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude product was submitted to FLC (SiO2, column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest were pooled, dried to afford the title product.

[0354] Molecular weight: 280.4 ; LCMS, molecular weight observed: LCMS: 281.3

Int.051: 7-(3-methoxypropoxy)-2,6-dimethyl-1,1-dioxo-2,3-dihydrothioc hromen-4-one

[0355] 7-(3-methoxypropoxy)-2,6-dimethyl-thiochroman-4-one Int.045 (166 mg, 0.531 mmol, 1.0 equiv.) was diluted in glacial acetic acid (0.308 mL, 5.38 mmol, 9.8 equiv.) and 30 %/w. aqueous H ₂ O ₂ (0.154 mL, 5.06 mmol, 9.2 equiv.). The resulting solution was heated at 100°C for 16 h. The reaction was diluted with water and extracted with DCM (3 times). The combined organic layers were dried over MgSO ₄ and evaporated under reduced pressure. The crude product was submitted to FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest were pooled, dried to afford the title product.

[0356] Molecular weight: 312.4 ; LCMS, molecular weight observed: LCMS: 313.2 Synthesis of Cpd_038: 1-cyclobutyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trioxo- 5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0357] In a sealed tube under inert atmosphere, 7-(3-methoxypropoxy)-2,6-dimethyl-1,1-dioxo-2,3- dihydrothiochromen-4-one Int.051 (83 mg, 0.266 mmol, 1.0 equiv.) was diluted in glacial acetic acid (0.083 mL, 1.40 mmol, 5.5 equiv.) and cyclobutylamine (CAS: 2516-34-9, 0.230 mL, 2.66 mmol, 10.0 equiv.). The suspension was heated at 60°C for 30 min. The reaction was then diluted with DCM and basified with 1 N aqueous NaOH and extracted with DCM (3 times). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was taken up in DMSO (1 mL) and mixed with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 59 mg, 0.319 mmol, 1.2 equiv.). The mixture was stirred 30 min at 50°C and diluted with DMSO (1 mL) and 2 N aqueous NaOH solution (0.266 mL, 0.532 mmol, 2.0 equiv.). The reaction was stirred at 120°C for 15 min. The reaction mixture was diluted with water and extracted with DCM (3 times). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was purified by HPLC (acid method) to afford the title product.

[0358] Molecular weight: 461.5 ; LCMS, molecular weight observed: LCMS: 462.3

[0359] 1H NMR (400 MHz, Chloroform-d) d 14.14 (s, 1H), 8.36 (s, 1H), 7.50 (s, 1H), 7.32 (s, 1H), 5.04– 4.97 (m, 1H), 4.31–4.19 (m, 2H), 4.07–3.99 (m, 1H), 3.59 (t, J = 6.0 Hz, 2H), 3.38 (s, 3H), 2.35 (s, 3H), 2.29–2.04 (m, 4H), 1.74–1.64 (m, 2H), 1.33–1.25 (m, 2H)

Int.044: 1-cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2-oxo-5H-thi ochromeno[4,3-b]pyridine-3- carboxylic acid

[0360] 7-(3-methoxypropoxy)-2,6-dimethyl-thiochroman-4-one Int.045 (100 mg, 0.357 mmol, 1.0 equiv.) was dissolved in DCE (1.0 mL) under inert atmosphere then titanium (IV) isopropoxide (CAS: 546-68-9, 0.137 mL, 0.464 mmol, 1.3 equiv) and cyclopropylamine (CAS: 765-30-0, 0.050 mL, 0.714 mmol, 2.0 equiv.) were added. The mixture was stirred at 50°C for 60 h. The mixture was allowed to cool to RT, diluted with DCM and an aqueous 1 N NaOH solution was added. After stirring vigorously for 5 min, the biphasic solvent was filtered through Celite ® and separated. The organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The residue was taken up in DMSO (1 mL) and mixed with 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 80 mg, 0.428 mmol, 1.2 equiv.). The mixture was stirred 30 min at 50°C and diluted with DMSO (1 mL) and 2 N aqueous NaOH solution (0.357 mL, 0.714 mmol, 2.0 equiv.). The reaction was stirred at 120°C for 15 min. The reaction mixture was acidified with 2 N aqueous HCl (0.357 mL, 0.714 mmol, 2.0 equiv.) and extracted with DCM (3 times). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC (acid method) to afford the title product.

[0361] Molecular weight: 415.5 ; LCMS, molecular weight observed: LCMS: 416.3

Synthesis of Cpd_035: 1-cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trioxo -5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0362] 1-cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2-oxo-5H-thi ochromeno[4,3-b]pyridine-3- carboxylic acid Int.044 (35 mg, 0.055 mmol, 1.0 equiv.) was diluted in glacial acetic acid (0.070 mL, 1.20 mmol, 21.8 equiv.) and 30 %/w. aqueous H2O2 (0.035 mL, 1.20 mmol, 21.8 equiv.). The resulting solution was heated at 100°C for 1 h. The reaction was diluted with water and extracted with DCM (3 times). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC (acid method) to afford the title product.

[0363] Molecular weight: 447.5 ; LCMS, molecular weight observed: LCMS: 448.3

[0364] 1H NMR (400 MHz, Chloroform-d) d 14.05 (s, 1H), 8.38 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 4.32– 4.24 (m, 2H), 4.03 (q, J = 7.1 Hz, 1H), 3.61 (t, J = 6.0 Hz, 2H), 3.53–3.48 (m, 1H), 3.39 (s, 3H), 2.37–2.34 (m, 3H), 2.16 (p, J = 6.2 Hz, 2H), 1.58–1.50 (m, 3H), 1.31–1.24 (m, 1H), 1.16–1.04 (m, 1H), 0.67–0.59 (m, 1H), 0.59–0.50 (m, 1H)

Int.053: isopropyl 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-t rioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0365] 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-t rioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid (150 mg, 0.32 mmol, 1.0 equiv.) was dissolved in DCM (1.5 mL), and was added two drops of DMF. The solution was cooled down to 0°C, and was added 2 N oxalyl chloride in DCM (CAS: 79-37-8, 0.24 mL, 0.48 mmol, 1.5 equiv.) the mixture was warmed to RT and stirred at RT for 45 min. The mixture was concentrated. The residue was taken up in 2-propanol (1.5 mL, 20.0 mmol, 61 equiv.). The mixture was stirred at reflux for 30 min. The mixture was concentrated and the crude was taken up with DCM. A precipitate was formed, filtered and washed with DCM to afford the title product.

[0366] Molecular weight: 510.0 ; LCMS, molecular weight observed: LCMS: 510.6/512.3 Int.052: isopropyl 1-cyclopropyl-9-(methoxymethyl)-8-(3-methoxypropoxy)-5-methy l-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate & Int.141: isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)- 5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carbo xylate

[0367] To a mixture of isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.058 g, 0.11 mmol, 1.0 equiv.), potassium methoxymethyltrifluoroborate (CAS: 910251-11-5, 0.055 g, 0.34 mmol, 3.0 equiv.) in toluene (0.75 mL) were charged in micro wave vial. To the previous mixture were added K2CO3 (185 mg, 0.57 mmol, 5.0 equiv.) and water (0.24 mL). The mixture was degassed under inert atmosphere at RT and RuPhos Pd G3 (CAS: 1445085-77-7, 0.015 g, 0.017 mmol, 0.15 equiv.) was added. The mixture was stirred at 100°C for 16 h. The mixture was allowed to cool down to RT and concentrated. To the mixture were added water and DCM, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, DCM/MeOH 100:0 to 0:100) to afford a mixture of the product Int.052 and the dechlorination product Int.141.

[0368] Int.052: Molecular weight: 519.6 ; LCMS, molecular weight observed: 520.3

[0369] Int.141: Molecular weight: 475.6 ; LCMS, molecular weight observed: 476.3

Synthesis of Cpd_039: 1-cyclopropyl-9-(methoxymethyl)-8-(3-methoxypropoxy)-5-methy l-2,6,6-trioxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid & Synthesis of Cpd_041: 1-cyclopropyl-8-(3-

Int052 Int141 Cpd_039 Cpd_041

[0370] The mixture of Int.052 and Int.141 (0.035 g, 0.067 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and was added 2 N aqueous NaOH (0.10 mL, 0.20 mmol, 2.9 equiv.). The mixture was stirred at RT for 1 h. To the previous solution were added 2 N aqueous HCl (0.10 mL, 0.20 mmol, 2.9 equiv and EtOAc. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by preparative HPLC (acid method) to afford the 2 products: Cpd_039 and Cpd_041.

[0371] Cpd_039: Molecular weight: 477.5 ; LCMS, molecular weight observed: 478.3

[0372] 1H NMR (400 MHz, Chloroform-d) d 8.39 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.28–7.22 (m, 1H), 4.32–4.22 (m, 2H), 4.11–4.01 (m, 1H), 3.59 (t, J = 5.9 Hz, 2H), 3.53–3.43 (m, 2H), 3.38 (s, 3H), 2.20–2.08 (m, 3H), 1.37–0.94 (m, 3H), 0.69–0.47 (m, 2H)

[0373] Cpd_041: Molecular weight: 433.5 ; LCMS, molecular weight observed: 434.3 [0374] 1H NMR (400 MHz, Chloroform-d) d 8.39 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.27–7.22 (m, 1H), 4.26 (td, J = 6.4, 1.2 Hz, 2H), 4.06 (q, J = 7.2 Hz, 1H), 3.59 (t, J = 5.9 Hz, 2H), 3.49 (t, J = 4.1 Hz, 1H), 3.38 (s, 3H), 2.18–2.08 (m, 2H), 1.67–1.41 (m, 3H), 1.35–1.22 (m, 1H), 1.22–1.05 (m, 1H), 0.69–0.47 (m, 2H)

Int.036: 3-(4-chloro-3-methoxy-phenyl)sulfanylbutanoic acid

[0375] In a round bottom flask under inert atmosphere, 4-bromo-1-chloro-2-methoxy-benzene (CAS: 16817-43-9, 7.37 g, 33.3 mmol, 1.0 equiv.) was stirred in 1,4-dioxane (100 mL). 3-sulfanylbutanoic acid (CAS: 26473-49-4, 4 g, 33.3 mmol, 1.0 equiv), XantPhos Pd G3 pre catalyst (CAS: 1445085-97-1, 3.51 g , 3.33 mmol, 0.10 equiv,) and TEA (9.76 mL, 66.6 mmol, 2.0 equiv,) were successively added. The reaction mixture was stirred at 100°C for 10 min, cooled down to RT and then filtered through a pad of Celite ®, rinsed with EtOAc and concentrated. The residue was taken up in EtOAc, washed with 1 N aqueous HCl, brine, dried over MgSO4 and evaporated under reduced pressure to afford the title product.

Molecular weight: 260.7 ; LCMS, molecular weight observed: 260.2/262.2

Int.035: 6-chloro-7-methoxy-2-methyl-thiochroman-4-one

[0376] To H ₂ SO ₄ (40 mL) cooled down to 0°C 3-(4-chloro-3-methoxy-phenyl)sulfanylbutanoic acid Int.036 (7.29 g, 28.0 mmol, 1.0 equiv.) was added portion wise. After 5 min, the mixture was then carefully poured into crushed ice water. The suspension was stirred at RT for 10 min. The precipitate was then filtered, washed with water and dried under suction to afford the title product.

[0377] Molecular weight: 242.7 ; LCMS, molecular weight observed: 243.2/245.1

Synthesis of Cpd_011: 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylic acid

[0378] In a sealed tube under inert atmosphere, 6-chloro-7-methoxy-2-methyl-thiochroman-4-one Int.035 (200 mg, 0.324 mmol, 1.0 equiv.) was diluted in EtOH (1 mL) in the presence of glacial acetic acid (0.010 mL, 0.162 mmol, 0.5 equiv.) and cyclopropylamine (CAS: 765-30-0, 0.228 mL, 3.30 mmol, 4.0 equiv.). The suspension was heated at reflux for 5 min. The reaction was then cooled down to RT, water was added (1 mL) and stirred vigorously for 5 min. The precipitate was filtered off, washed with cold water, dried under suction and engaged without any further purification. The residue was taken up in DMSO (1 mL) and mixed with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 79 mg, 0.424 mmol, 1.3 equiv.). The mixture was stirred 30 min at 50°C and diluted with DMSO (1 mL) and 2 N aqueous NaOH solution (0.324 mL, 0.648 mmol, 2.0 equiv.). The reaction was stirred at 120°C for 15 min. The reaction mixture was acidified with 2 N aqueous HCl (0.324 mL, 0.648 mmol, 2.0 equiv.) and MeOH was added (1 mL). The precipitate was washed with cold MeOH and collected by filtration to afford the title product.

[0379] Molecular weight: 377.8 ; LCMS, molecular weight observed: 376.2-378.2

[0380] 1H NMR (400 MHz, Chloroform-d) d 8.37 (s, 1H), 7.85 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 3.90 (q, J = 7.1 Hz, 1H), 3.47–3.40 (m, 1H), 1.41 (d, J = 7.1 Hz, 3H), 1.35–1.29 (m, 1H), 1.14–1.02 (m, 1H),0.58– 0.47 (m, 1H), 0.36–0.24 (m, 1H)

Synthesis of Cpd_012: 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid

[0381] In a sealed tube, 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylic acid Cpd_011 (40 mg, 0.106 mmol, 1.0 equiv.) was diluted in glacial acetic acid (0.200 mL, 3.49 mmol, 30.0 equiv.) and 30 %/w. aqueous H ₂ O ₂ (0.100 mL, 3.29 mmol, 32.0 equiv.). The resulting solution was heated at 100°C for 10 min. The reaction was cooled down to RT and the precipitate was filtered, washed with ACN and Et ₂ O to afford the title product.

[0382] Molecular weight: 409.8 ; LCMS, molecular weight observed: 410.3/412.6

[0383] 1H NMR (400 MHz, DMSO-d ₆ ) d 8.29 (s, 1H), 8.27 (s, 1H), 7.47 (s, 1H), 4.70 (q, J = 6.6 Hz, 1H), 3.94, (s, 3H), 3.75–3.55 (m, 1H), 1.33–0.91 (m, 4H), 0.87–0.68 (m, 1H), 0.58–0.31 (m, 1H), 0.13–-0.16, (m, 1H).

Synthesis of Cpd_018: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylic acid

[0384] In a sealed tube, 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylic acid Cpd_011 (689 mg, 1.82 mmol, 1.0 equiv.) was diluted in NMP (4 mL). LiCl (CAS: 7447-41-8, 0.387 g, 9.12 mmol, 5.0 equiv.) was added followed by Na2S.9H2O (CAS: 1313-84-4, 589 mg, 18.2 mmol, 10.0 equiv.). The slurry was stirred at 120°C for 14 h, cooled down to RT and diluted with ACN (20 mL). The solid material was removed by filtration and then carefully added to 2 N aqueous HCl (10 mL). The precipitate was filtered, washed with water, ACN, Et2O and dried to afford the title product.

[0385] Molecular weight: 363.8 ; LCMS, molecular weight observed: 364.2/366.2

[0386] 1H NMR (400 MHz, DMSO-d6) d 11.23 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.04 (s, 1H), 4.23 (q, J = 6.9, Hz, 1H), 3.71–3.48 (m, 1H), 1.20 (d, J = 6.9 Hz, 3H), 1.16–1.01 (m, 1H), 0.90–0.68 (m, 1H), 0.57– 0.29 (m, 1H), 0.14–-0.22 (m, 1H).

Synthesis of Cpd_019: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid

[0387] In a sealed tube, 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylic acid Cpd_018 (589 mg, 1.619 mmol, 1.0 equiv.) was diluted in glacial acetic acid 1.5 mL, 26.0 mmol, 16.0 equiv.) and 30 %/w. aqueous H ₂ O ₂ (0.750 mL, 27.6 mmol, 17.0 equiv.). The resulting solution was heated at 100°C for 10 min. The reaction was cooled down to RT and the precipitate was filtered, washed with ACN and Et ₂ O to afford the title product.

[0388] Molecular weight: 395.8 ; LCMS, molecular weight observed: 396.1/398.1

[0389] 1H NMR (400 MHz, DMSO-d ₆ ) d 8.25 (s, 1H), 8.17 (s, 1H), 7.35 (s, 1H), 4.74–4.54 (m, 1H), 3.74– 3.59 (m, 1H), 1.23–0.95 (m, 4H), 0.86–0.73 (m, 1H), 0.47–0.34 (m, 1H), 0.16–-0.21 (m, 1H).

Synthesis of Cpd_022: 9-chloro-1-cyclopropyl-8-wasopropoxy-5-methyl-2,6,6-trioxo-5 H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0390] In a 5 mL vial, 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid Cpd_019 (40 mg, 0.101 mmol, 1.0 equiv.) was diluted in DMF (0.4 mL) in the presence of 2-iodopropane (CAS: 75-30-9, 0.101 mL, 1.01 mmol, 10.0 equiv.) and K ₂ CO ₃ (0.140 g, 1.01 mmol, 10.0 equiv.) and heated at 80°C for 15 min. 4 N aqueous NaOH (0.4 mL, 1.00 mmol, 10.0 equiv.) was added and the mixture was stirred for 10 min at 80°C. After cooling down to 0°C, 2 N aqueous HCl was added to reach pH 2. The suspension was concentrated under reduced pressure, partitioned between DCM and water. The organic layer was dried over MgSO ₄ and evaporated to afford the title product. [0391] Molecular weight: 437.9 ; LCMS, molecular weight observed: 438.3/440.3

[0392] 1H NMR (400 MHz, Chloroform-d) d 8.39 (s, 1H), 7.94 (s, 1H), 7.58 (s, 1H), 4.95–4.78 (m, 1H), 4.14–3.93 (m, 1H), 3.68–3.30 (m, 1H), 2.08–1.90 (m, 3H), 1.53–1.48 (m, 6H), 1.39–1.27 (m, 1H), 1.24– 1.14 (m, 1H), 0.71–0.60 (m, 1H), 0.60–0.50 (m, 1H).

Synthesis of Cpd_023: 9-chloro-1-cyclopropyl-8-propoxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid

[0393] In a 5 mL vial, 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid Cpd_019 (40 mg, 0.101 mmol, 1.0 equiv.) was diluted in DMF (0.4 mL) in the presence of 1-iodopropane (CAS: 107-08-4, 0.101 mL, 1.01 mmol, 10.0 equiv.) and K ₂ CO ₃ (0.140 g, 1.01 mmol, 10.0 equiv.) and heated at 80°C for 15 min. 4 N aqueous NaOH (0.4 mL, 1.00 mmol, 10.0 equiv.) was added and the mixture was stirred for 10 min at 80°C. After cooling down to 0°C, 2 N aqueous HCl was added to reach pH 2. The suspension was concentrated under reduced pressure, partitioned between DCM and water. The organic layer was dried over MgSO ₄ and evaporated to afford the title product.

[0394] Molecular weight: 437.9 ; LCMS, molecular weight observed: 438.3/440.6

[0395] 1H NMR (400 MHz, Chloroform-d) d 13.98 (s, 1H), 8.41 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 4.29– 4.15, (m, 2H), 4.14–4.04 (m, 1H), 3.57–3.47 (m, 1H), 2.06–1.93 (m, 2H), 1.58–1.49 (m, 3H), 1.37–1.33 (m, 1H), 1.23–1.19 (m, 1H), 1.16 (t, J = 7.4 Hz, 3H), 0.69–0.64 (m, 1H), 0.59–0.55 (m, 1H).

Int.043: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylate

[0396] 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3-b]pyridine-3- carboxylic acid (3.14 g, 7.93 mmol, 1.0 equiv.) was dissolved in DCM (20 mL) and two drops of DMF were added ,the solution was cooled at 0°C. To the solution was added 2 N oxalyl chloride in DCM (CAS: 79-37-8, 6.0 mL, 11.9 mmol, 1.5 equiv.) the mixture was warmed to RT and stirred at RT for 1 h. After complete conversion the mixture was concentrated. The residue was taken up with 2-propanol (20 mL, 262 mmol, 33.0 equiv.), and stirred at reflux for 90 min. The solution was cooled down to RT and a precipitate was filtered washed with 2-propanol to afford the title product. [0397] Molecular weight: 437.9 ; LCMS, molecular weight observed: 438.2/440.2

Int.054: isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0398] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added 2- methoxyethanol (CAS: 109-86-4, 0.045 mL, 0.571 mmol, 2.5 equiv.) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16 h. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0399] Molecular weight: 496.0 ; LCMS, molecular weight observed: 496.2/498.2

Synthesis of Cpd_042: isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0400] Isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno [4,3-b]pyridine-3-carboxylate (0.17 g, 0.34 mmol, 1.0 equiv.) was dissolved in MeOH (0.1 mL) and 2 N aqueous NaOH (0.20 mL, 0.400 mmol, 1.17 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion water was added and extracted with EtOAc. To the aqueous layer 2 N aqueous HCl (0.20 mL, 0.400 mmol, 1.17 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0401] Molecular weight: 453.9 ; LCMS, molecular weight observed: 454.2/456.2

[0402] 1H NMR (400 MHz, Chloroform-d) d 13.94 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 4.47– 4.32 (m, 2H), 4.07 (q, J = 7.3 Hz, 1H), 3.92–3.85 (m, 2H), 3.54–3.45 (m, 4H), 1.63–1.45 (m, 3H), 1.39– 1.27 (m, 1H), 1.24–1.12 (m, 1H), 0.70–0.59 (m, 1H), 0.59–0.48 (m, 1H) Int.135: isopropyl 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6 -trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0403] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added cyclopropylmethanol (CAS: 2516-33-8, 0.041 g, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at 0°C for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at 0°C for 20 min. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0404] Molecular weight: 492.0 ; LCMS, molecular weight observed: 490.2/ 492.2

Synthesis of Cpd_034: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6 -trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0405] isopropyl 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6 -trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.072 g, 0.146 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 3.0 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 3.0 equiv.) was added and a precipitate was formed, filtered, and washed with water to afford the title product.

[0406] Molecular weight: 449.9 ; LCMS, molecular weight observed: 450.2/452.2

[0407] 1H NMR (400 MHz, Chloroform-d) d 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 4.17– 3.98 (m, 3H), 3.55–3.45 (m, 1H), 1.46–1.08 (m, 5H), 0.81–0.68 (m, 2H), 0.70–0.50 (m, 2H), 0.54–0.44 (m, 3H) Int.056: isopropyl 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0408] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added 3- ethoxypropan-1-ol (CAS: 111-35-3, 0.065 mL, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16h. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0409] Molecular weight: 524.0 ; LCMS, molecular weight observed: 524.6/526.2

Synthesis of Cpd_044: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0410] isopropyl 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.075 g, 0.144 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.8 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, a solution 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.8 equiv.) was added and a precipitate was formed, filtered and washed to afford the title product.

[0411] Molecular weight: 482.0 ; LCMS, molecular weight observed: 482.2/484.2

[0412] 1H NMR (400 MHz, Chloroform-d) d 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 4.36 (td, J = 6.3, 2.4 Hz, 2H), 4.07 (q, J = 7.2 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.53 (q, J = 7.0 Hz, 2H), 3.50– 3.45 (m, 1H), 2.20 (p, J = 6.1 Hz, 2H), 1.60 (d, J = 7.0 Hz, 6H), 1.61–1.46 (m, 3H), 1.39–1.27 (m, 1H), 1.27–1.11 (m, 4H), 0.71–0.59 (m, 1H), 0.59–0.46 (m, 1H) Int.057: isopropyl 9-chloro-8-(cyclobutoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo -5H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0413] isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added cyclobutanol (CAS: 2919-23-5, 0.041 mg, 0.571 mmol, 2.5 equiv.) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16 h. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0414] Molecular weight: 492.0 ; LCMS, molecular weight observed: 492.2/494.2

Synthesis of Cpd_045: 9-chloro-8-(cyclobutoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo -5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0415] isopropyl 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.075 g, 0.152 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.6 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.6 equiv.) was added and a precipitate was formed. The precipitate was purified by preparative HPLC (acid method) to afford the title product.

[0416] Molecular weight: 449.9 ; LCMS, molecular weight observed: 450.2/452.2

[0417] 1H NMR (400 MHz, Chloroform-d) d 13.95 (s, 1H), 8.39 (s, 1H), 7.93 (s, 1H), 7.44 (s, 1H), 4.89 (p, J = 7.1 Hz, 1H), 4.06 (q, J = 7.3 Hz, 1H), 3.55–3.43 (m, 1H), 2.68–2.51 (m, 2H), 2.43–2.25 (m, 2H), 2.06–1.94 (m, 1H), 1.90–1.75 (m, 1H), 1.41–1.12 (m, 5H), 0.70–0.51 (m, 2H) Int.058: isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-[[(2S)-tetrah ydrofuran-2- yl]methoxy]-5H-thiochromeno[4,3-b]pyridine-3-carboxylate

[0418] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added (S)-(tetrahydrofuran-2-yl)methanol (CAS: 57203-01-7, 0.059 mg, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16 h. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to afford the title product containing 10 % of oxide of PPh ₃ .

[0419] Molecular weight: 522.0 ; LCMS, molecular weight observed: 522.3/524.2

Synthesis of Cpd_046: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-[[(2S)-tetrah ydrofuran-2- yl]methoxy]-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0420] Isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-[[(2S)-tetrah ydrofuran-2-yl]methoxy]- 5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.094 g, 0.180 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.2 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.2 equiv.) was added. The precipitate was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) and (SiO2, DCM/MeOH 100:0 to 0:100) to afford the title product.

[0421] Molecular weight: 479.9 ; LCMS, molecular weight observed: 480.2/482.2

[0422] 1H NMR (400 MHz, Chloroform-d) d 13.94 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.63 (d, J = 1.5 Hz, 1H), OH 4.45–4.39 (m, 1H), 4.34–4.17 (m, 2H), 4.14–3.94 (m, 2H), 3.94–3.84 (m, 1H), 3.54–3.44 (m, 1H), 2.26–1.86 (m, 5H), 1.39–1.23 (m, 4H), 0.70–0.50 (m, 2H) Int.059 isopropyl 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trioxo-5H-thi ochromeno[4,3- b]pyridine-3-carboxylate

[0423] To a mixture of sopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) was added EtOH (0.026 mg, 0.571 mmol, 2.5 equiv.) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 48 h. The mixture was concentrated, and the residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0424] Molecular weight: 466.0 ; LCMS, molecular weight observed: 466.3/468.2

Synthesis of Cpd_048: 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trioxo-5H-thi ochromeno[4,3- b]pyridine-3-carboxylic acid

[0425] Isopropyl 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trioxo-5H-thi ochromeno[4,3- b]pyridine-3-carboxylate (0.072 g, 0.155 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.6 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.6 equiv.) was added and a precipitate was isolated corresponding to the title product.

[0426] Molecular weight: 423.9 ; LCMS, molecular weight observed: 424.3/426.3

[0427] 1H NMR (400 MHz, Chloroform-d) d 13.88 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 4.26 (qd, J = 7.0, 3.2 Hz, 2H), 4.00 (q, J = 7.2 Hz, 1H), 3.48–3.38 (m, 1H), 1.52 (t, J = 7.0 Hz, 5H), 1.34–1.07 (m, 3H), 0.59–0.55 (m, 1H), 0.50–0.46 (m, 1H)

Int.060 isopropyl 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0428] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added 2- cyclopropylethanol (CAS: 2566-44-1, 0.042 mg, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16 h. The mixture was concentrated. The residue was purified by FLC (SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the product contaminated by some impurities. The product was taken up with Et2O and the precipitate was filtered to afford the title product.

[0429] Molecular weight: 506.0 ; LCMS, molecular weight observed: 506.3/508.2

Synthesis of Cpd_049: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0430] Isopropyl 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.123 g, 0.243 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 1.6 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 1.6 equiv.) was added and a precipitate was isolated. The precipitate isolated corresponding to the title product.

[0431] Molecular weight: 463.9 ; LCMS, molecular weight observed: 464.2/466.2

[0432] 1H NMR (400 MHz, Chloroform-d) d 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 4.32 (td, J = 6.4, 3.1 Hz, 2H), 4.07 (q, J = 7.2 Hz, 1H), 3.55–3.45 (m, 1H), 1.84 (q, J = 6.6 Hz, 2H), 1.34–1.30 (m, 1H), 1.30–1.22 (m, 2H), 1.21–1.17 (m, 1H), 0.99–0.84 (m, 2H), 0.66–0.62 (m, 1H), 0.61–0.52 (m, 3H), 0.21 (dt, J = 5.8, 4.5 Hz, 2H)

Int.061: isopropyl 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3- b]pyridine-3-carboxylate

[0433] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added 2- methylpropan-1-ol (CAS: 78-83-1, 0.042 mg, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16 h. The mixture was concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the product contaminated by impurities. The product was taken up with Et2O and the precipitate was filtered to afford the title product.

[0434] Molecular weight: 494.0 ; LCMS, molecular weight observed: 494.3/496.2

Synthesis of Cpd_050: 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3- b]pyridine-3-carboxylic acid

[0435] Isopropyl 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3- b]pyridine-3-carboxylate (0.040 g, 0.081 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 4.9 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 4.9 equiv.) was added and a precipitate was isolated. The precipitate isolated corresponding to the title product.

[0436] Molecular weight: 451.9 ; LCMS, molecular weight observed: 452.2/454.2

[0437] 1H NMR (400 MHz, DMSO-d6) d 8.23 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 4.59–4.45 (m, 1H), 4.16– 3.99 (m, 2H), 3.63–3.46 (m, 1H), 2.18–2.04 (m, 1H), 1.34–1.17 (m, 3H), 1.15–0.92 (m, 7H), 0.91–0.77 (m, 1H), 0.39–0.24 (m, 1H), 0.15–-0.02 (m, 1H)

Int.062: isopropyl 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3- b]pyridine-3-carboxylate

[0438] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added cyclobutylmethanol (CAS: 4415-82-1, 0.049 g, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16 h. The mixture was concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0439] Molecular weight: 506.0 ; LCMS, molecular weight observed: 506.3/508.2 Synthesis of Cpd_051: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-5-methyl-2,6,6- trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0440] isopropyl 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3- b]pyridine-3-carboxylate (0.083 g, 0.164 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.4 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.4 equiv.) was added and a precipitate was isolated. The precipitate isolated corresponding to the title product.

[0441] Molecular weight: 463.9 ; LCMS, molecular weight observed: 464.2/466.2

[0442] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 4.19– 4.08 (m, 2H), 4.00 (q, J = 7.2 Hz, 1H), 3.43 (tt, J = 7.0, 4.3 Hz, 1H), 2.90–2.78 (m, 1H), 2.22–2.08 (m, 2H), 2.02–1.85 (m, 4H), 1.29–1.25 (m, 1H), 1.20 (d, J = 6.3 Hz, 3H), 1.15–1.10 (m, 1H), 0.60–0.55 (m, 1H), 0.51–0.46 (m, 1H)

Int.063: isopropyl 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-5-methyl-2,6,6-triox o-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0443] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added cyclopentanol (CAS: 96-41-3, 0.10 mL, 1.14 mmol, 5.0 equiv.) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 2 h. The mixture was concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0444] Molecular weight: 506.0 ; LCMS, molecular weight observed: 506.3/508.3 Synthesis of Cpd_052: 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-5-methyl-2,6,6-triox o-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0445] isopropyl 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-5-methyl-2,6,6-triox o-5H-thiochromeno[4,3- b]pyridine-3-carboxylate (115 mg, 0.23 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (0.20 mL, 0.80 mmol, 3.4 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.80 mmol, 3.4 equiv.) was added and a precipitate was isolated. The precipitate isolated corresponding to the title product.

[0446] Molecular weight: 463.9 ; LCMS, molecular weight observed: 464.2/466.2

[0447] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 4.96 (tt, J = 5.7, 2.6 Hz, 1H), 4.00 (q, J = 7.2 Hz, 1H), 3.72–3.63 (m, 2H), 3.42 (tt, J = 7.0, 4.3 Hz, 1H), 2.07– 1.89 (m, 3H), 1.88–1.73 (m, 4H), 1.73–1.60 (m, 2H), 1.35–1.08 (m, 2H), 0.57 (s, 1H), 0.49 (s, 1H)

Int.069: isopropyl 9-chloro-1-cyclopropyl-8-[(3,3-difluorocyclobutyl)methoxy]-5 -methyl-2,6,6-trioxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylate

[0448] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added (3,3-difluorocyclobutyl)methanol (CAS: 681128-39-2, 0.15 g, 1.14 mmol, 5.0 equiv.) and PPh3 (CAS: 603- 35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446- 83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 2 h and concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0449] Molecular weight: 542.0 ; LCMS, molecular weight observed: 542.2/544.1 Synthesis of Cpd_062: 9-chloro-8-(cyclohexoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo -5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0450] isopropyl 9-chloro-1-cyclopropyl-8-[(3,3-difluorocyclobutyl)methoxy]-5 -methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (120 mg, 0.22 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (0.40 mL, 0.80 mmol, 3.6 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.40 mL, 0.80 mmol, 3.6 equiv.) was added and a precipitate was isolated. The precipitate was purified preparative HPLC (acid method) to afford the title product.

[0451] Molecular weight: 499.9 ; LCMS, molecular weight observed: 500.1/502.1

[0452] 1H NMR (400 MHz, Chloroform-d) d 13.93 (bs, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 4.35– 4.23 (m, 2H), 4.08 (q, J = 7.2 Hz, 1H), 3.56–3.43 (m, 1H), 2.91–2.71 (m, 3H), 2.71–2.55 (m, 2H), 1.61– 1.44 (m, 3H), 1.43–1.29 (m, 1H), 1.26–1.12 (m, 1H), 0.74–0.59 (m, 1H), 0.59–0.46 (m, 1H)

Int.070: isopropyl 9-chloro-8-(cyclohexoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo -5H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0453] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added cyclohexanol (CAS: 108-93-0, 57.2 mg, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 2 h. The mixture was concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0454] Molecular weight: 520.0 ; LCMS, molecular weight observed: 520.3/522.2 Synthesis of Cpd_063: 9-chloro-8-(cyclohexoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo -5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0455] Isopropyl 9-chloro-8-(cyclohexoxy)-1-cyclopropyl-5-methyl-2,6,6-trioxo -5H-thiochromeno[4,3- b]pyridine-3-carboxylate (106 mg, 0.20 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.0 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.0 equiv.) was added and a precipitate was isolated. The precipitate was purified by preparative HPLC (acid method) to afford the title product.

[0456] Molecular weight: 478.0 ; LCMS, molecular weight observed: 478.2/480.2

[0457] 1H NMR (400 MHz, Chloroform-d) d 13.96 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.58 (d, J = 0.6 Hz, 1H), 4.67–4.56 (m, 1H), 4.07 (q, J = 7.2 Hz, 1H), 3.54–3.44 (m, 1H), 2.08–1.98 (m, 2H), 1.91–1.83 (m, 2H), 1.79–1.70 (m, 2H), 1.67–1.58 (m, 2H), 1.53–1.39 (m, 5H), 1.34–1.30 (m, 1H), 1.23–1.18 (m, 1H), 0.66–0.62 (m, 1H), 0.59–0.54 (m, 1H)

Int.071: isopropyl 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6 -trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0458] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added 2,2-difluoroethanol (CAS: 359-13-7, 0.047 mg, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 16 h. The mixture was concentrated. The residue was purified by FLC (SiO ₂ , Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0459] Molecular weight: 501.9 ; LCMS, molecular weight observed: 502.2/504.1 Synthesis of Cpd_064: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6 -trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0460] Isopropyl 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6 -trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.011 g, 0.022 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 18.1 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 18.1 equiv.) was added. The residue was precipitate by preparative HPLC (acid method) to afford the title product.

[0461] Molecular weight: 459.9 ; LCMS, molecular weight observed: 460.2/462.1

[0462] 1H NMR (400 MHz, Chloroform-d) d 13.90 (s, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 6.24 (tt, J = 54.4, 3.9 Hz, 2H), 4.53–4.44 (m, 1H), 4.09 (q, J = 7.3 Hz, 1H), 3.55–3.43 (m, 1H), 1.45–1.21 (m, 4H), 0.71–0.59 (m, 1H), 0.59–0.48 (m, 1H)

Int.072: isopropyl 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0463] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added 1- cyclopropylethanol (CAS: 765-42-4, 0.047 mg, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 1 h. The mixture was concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0464] Molecular weight: 506.0 ; LCMS, molecular weight observed: 506.2/508.2 Synthesis of Cpd_065: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0465] isopropyl 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.042 g, 0.083 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.40 mL, 0.80 mmol, 9.6 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.40 mL, 0.80 mmol, 9.6 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0466] Molecular weight: 463.9 ; LCMS, molecular weight observed: 464.2/466.2

[0467] 1H NMR (400 MHz, Chloroform-d) d 13.96 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 4.25– 4.15 (m, 1H), 4.13–4.02 (m, 1H), 1.53 (s, 3H), 1.38–1.15 (m, 3H), 1.03–0.85 (m, 3H), 0.73–0.60 (m, 3H), 0.60–0.52 (m, 1H), 0.52–0.43 (m, 1H), 0.43–0.34 (m, 1H)

Int.079: isopropyl 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-tri oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0468] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added 4- hydroxybutanenitrile (CAS: 628-22-8, 0.048 mg, 0.571 mmol, 2.5 equiv.) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 1 h. The mixture was concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0469] Molecular weight: 505.0 ; LCMS, molecular weight observed: 505.7/507.2 Synthesis of Cpd_078: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-tri oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0470] isopropyl 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-tri oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.058 g, 0.115 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 1.7 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 1.7 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0471] Molecular weight: 462.9 ; LCMS, molecular weight observed: 463.2/465.1

[0472] 1H NMR (400 MHz, Chloroform-d) d 8.40 (s, 1H), 7.97 (s, 1H), 7.61 (s, 1H), 4.38 (tq, J = 6.9, 3.8 Hz, 2H), 4.08 (q, J = 7.2 Hz, 1H), 3.50 (ddd, J = 11.2, 7.1, 4.2 Hz, 1H), 2.72 (t, J = 7.0 Hz, 2H), 2.32 (p, J = 6.6 Hz, 2H), 1.56–1.52 (m, 2H), 1.30–1.19 (m, 3H), 0.67–0.63 (m, 1H), 0.58–0.53 (m, 1H).

Int.080: isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-(tetrahydropy ran-4-ylmethoxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0473] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added tetrahydropyran-4-ylmethanol (CAS: 14774-37-9, 0.066 mg, 0.571 mmol, 2.5 equiv.) and PPh ₃ (CAS: 603- 35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446- 83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 1 h. The mixture was concentrated. The residue was purified by FLC (SiO ₂ , Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0474] Molecular weight: 536.0 ; LCMS, molecular weight observed: 536.3/538.3 Synthesis of Cpd_079: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-(tetrahydropy ran-4-ylmethoxy)- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0475] isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-(tetrahydropy ran-4-ylmethoxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.011 g, 0.205 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.0 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.0 equiv.) was added, a precipitate was formed, filtered and washed with water to afford the title product.

[0476] Molecular weight: 494.0 ; LCMS, molecular weight observed: 494.2/496.3

[0477] 1H NMR (400 MHz, Chloroform-d) d 13.94 (s, 1H), 8.39 (s, 1H), 7.95 (s, 1H), 7.58 (s, 1H), 4.14– 4.03 (m, 5H), 3.56–3.44 (m, 4H), 2.31–2.16 (m, 1H), 1.87–1.78 (m, 2H), 1.66–1.47 (m, 4H), 1.36–1.29 (m, 1H), 1.24–1.14 (m, 1H), 0.66–0.62 (m, 1H), 0.57–0.53 (m, 1H).

Int.149: isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyr an-4-yloxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0478] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (2 mL) were added tetrahydropyran-4-ol (CAS: 14774-37-9, 0.054 mL, 0.571 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 2 h. The mixture was concentrated and purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product contaminated by impurities The residue was taken up in EtOAc and was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated to afford the title product.

[0479] Molecular weight: 522.0 ; LCMS, molecular weight observed: 521.3/523.2 Synthesis of Cpd_099: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyr an-4-yloxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0480] Isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyr an-4-yloxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.015 g, 0.029 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 13.7 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 13.7 equiv.) was added. The precipitate isolated was purified by preparative HPLC (acid method) to afford the title product.

[0481] Molecular weight: 479.9 ; LCMS, molecular weight observed: 478.3/480.2

[0482] 1H NMR (400 MHz, Chloroform-d) d 8.39 (s, 1H), 7.97 (s, 1H), 7.58 (s, 1H), 4.84 (tt, J = 7.4, 3.7 Hz,1H), 4.17–3.98 (m, 4H), 3.75–3.64 (m, 2H), 3.55–3.45 (m, 1H), 2.20–2.10 (m, 2H), 1.98–1.93 (m,1H), 1.35–1.30 (m, 1H), 1.30–1.22 (m, 2H), 0.67–0.62 (m, 1H), 0.58–0.54 (m, 1H).

Int.050: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiochrom eno[4,3-b]pyridine- 3-carboxylate

[0483] To a mixture of 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylic acid (1.07 g, 2.94 mmol, 1.0 equiv.) in DCM (10 mL) were added two drops of DMF and the solution was cooled at 0°C. To the solution was added 2 N oxalyl chloride in DCM (CAS: 79-37-8, 2.20 mL, 4.41 mmol, 1.5 equiv.), and the mixture was warmed to RT and stirred for 30 min. After complete conversion the mixture was concentrated. The residue was taken up with 2-propanol (10 mL, 131 mmol, 44.5 equiv.). The mixture was stirred at reflux for 30 min. The mixture was concentrated and the crude was taken up with DCM. A precipitate was formed and filtered to afford the title product.

[0484] Molecular weight: 405.9 ; LCMS, molecular weight observed: 406.0/408.2

Synthesis of Cpd_037: isopropyl 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2-oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0485] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.246 mmol, 1.0 equiv.) in DMF (1 mL) was added K2CO3 (973 mg, 0.739 mmol, 3.0 equiv.). The mixture was stirred for 5 min at RT. To the previous solution was added 2-bromoethyl ethyl ether (CAS: 592-55-2, 0.040 mL, 0.369 mmol, 1.5 equiv.). The mixture was stirred at 60°C for 2 h. After complete conversion, EtOAc and water were added and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0486] Molecular weight: 478.0 ; LCMS, molecular weight observed: 478.0/480.2

[0487] 1H NMR (400 MHz, Chloroform-d) d 7.93 (s, 1H), 7.77 (s, 1H), 7.06 (s, 1H), 5.31–5.17 (m, 1H), 4.32–4.18 (m, 2H), 3.89 (t, J = 4.8 Hz, 2H), 3.80 (q, J = 7.1 Hz, 1H), 3.66 (q, J = 7.0 Hz, 2H), 3.38–3.27 (m, 1H), 1.37 (q, J = 6.6 Hz, 9H), 1.30–1.22 (m, 5H), 0.52–0.41 (m, 1H), 0.24–0.13 (m, 1H)

Int.055: isopropyl 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2,6,6-tri oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0488] To a mixture of isopropyl 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2,6,6-tri oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.070 g, 0.139 mmol, 1.0 equiv.) in glacial acetic acid (0.2 mL, 3.49 mmol, 25.1 equiv.), was added 30 %/w. aqueous H2O2 (0.1 mL, 1.06 mmol, 7.6 equiv.) the mixture was stirred at 100°C for 1 h . The mixture was allowed to cool down to RT and concentrated. To the mixture was added water and DCM, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was used without purification.

[0489] Molecular weight: 510.0 ; LCMS, molecular weight observed: 510.2/512.2

Synthesis of Cpd_043: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-tetrahydropyr an-4-yloxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0490] Isopropyl 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2,6,6-tri oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.046 g, 0.091 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (0.10 mL, 0.20 mmol, 2.2 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.10 mL, 0.20 mmol, 2.2 equiv.) was added. The precipitate isolated was purified by preparative HPLC (acid method) to afford the title product. [0491] Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.2/470.2

[0492] 1H NMR (400 MHz, Chloroform-d) d 8.39 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 4.48–4.34 (m, 3H), 4.06 (q, J = 7.2 Hz, 1H), 3.92 (t, J = 4.5 Hz, 2H), 3.65 (q, J = 7.0 Hz, 2H), 3.54–3.44 (m, 2H), 1.41–1.11 (m, 6H), 0.69–0.50 (m, 2H)

Synthesis of Cpd_033: 9-chloro-1-cyclopropyl-8-(3-methoxy-1-methyl-propoxy)-5-meth yl-2,6,6-trioxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0493] To a solution of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.050 g, 0.114 mmol, 1.0 equiv.) in DMF (1 mL) was added K2CO3 (450 mg, 0.342 mmol, 3.0 equiv.). The mixture was stirred for 5 min at RT. To the previous solution was added 3-bromo-1-methoxy-butane (CAS: 53424-50-3, 0.029 g, 0.171 mmol, 1.5 equiv.). The mixture was stirred at 60°C for 16 h. After complete conversion to the previous solution, 2 N aqueous NaOH (0.25 mL, 0.50 mmol, 4.4 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion, 2 N aqueous HCl (0.25 mL, 0.50 mmol, 4.4 equiv.) was added and the mixture was stirred at RT for 30 min. The crude was purified by preparative HPLC (acid method) to afford the title product.

[0494] Molecular weight: 482.0 ; LCMS, molecular weight observed: 482.2/484.4

[0495] 1H NMR (400 MHz, Chloroform-d) d 8.32 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 4.86– 4.75 (m, 1H), 4.00 (q, J = 7.2 Hz, 1H), 3.54–3.38 (m, 3H), 3.28 (d, J = 1.7 Hz, 3H), 2.29–1.72 (m, 3H), 1.42 (dd, J = 6.1, 3.6 Hz, 3H), 1.34–1.08 (m, 4H), 0.66–0.36 (m, 2H)

Int.112: isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-(trifluoromet hylsulfonyloxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0496] In a 25 mL round bottom flask under inert atmosphere, isopropyl 9-chloro-1-cyclopropyl-8- hydroxy-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine -3-carboxylate Int.043 (0.300 g, 0.685 mmol, 1.0 equiv.) was diluted in DCM (3 mL) in the presence of pyridine (0.111 mL, 1.37 mmol, 2.0 equiv.) and cooled down to 0°C. Tf2O (0.141 mL, 0.822 mmol, 1.2 equiv.) was added and the resulting mixture was stirred and warmed up to RT over 15 min. The reaction was quenched with saturated aqueous NaHCO3, extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by FLC (SiO2, column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0497] Molecular weight: 570.0 ; LCMS, molecular weight observed: 570.1/572.1

Int.090: isopropyl 9-chloro-1-cyclopropyl-5-methyl-8-(1-methylpyrazol-4-yl)-2,6 ,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0498] In a 25 mL round bottom flask under inert atmosphere, isopropyl 9-chloro-1-cyclopropyl-5- methyl-2,6,6-trioxo-8-(trifluoromethylsulfonyloxy)-5H-thioch romeno[4,3-b]pyridine-3-carboxylate Int.112 (110 mg, 0.193 mmol, 1.0 equiv.) was diluted in 1,4-dioxane (4 mL) and 1 M aqueous Na2CO3 (1 mL) in the presence of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyra zole (CAS: 761446-44-0, 0.048 g, 0.232 mmol, 1.2 equiv.). [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.019 mmol, 0.1 equiv.) was added and the mixture was heated at 50°C for 15 min. The reaction was filtered, evaporated under reduced pressure and the crude product was purified by FLC (SiO2, column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0499] Molecular weight: 502.0 ; LCMS, molecular weight observed: 502.2/504.1

Synthesis of 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

[0500] In a 25 mL round bottom flask charged with isopropyl 9-chloro-1-cyclopropyl-5-methyl-8-(1- methylpyrazol-4-yl)-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyrid ine-3-carboxylate Int.090 (0.080 g, 0.159 mmol, 1.0 equiv.) in MeOH (0.2 mL) was added 2 N aqueous NaOH (0.2 mL, 0.400 mmol, 2.5 equiv.). The reaction was stirred at RT for 30 min and then cooled down to 0°C.2 N aqueous HCl (0.2 mL, 0.400 mmol, 2.5 equiv.) was added. The precipitate was filtered off, rinsed with MeOH and dried under suction to afford the title product.

[0501] Molecular weight: 459.9 ; LCMS, molecular weight observed: 460.2/462.3

[0502] 1H NMR (400 MHz, Chloroform-d) d 13.93 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 8.04 (s, 2H), 7.99 (s, 1H), 4.09 (q, J = 7.2 Hz, 1H), 4.03 (s, 3H), 3.57–3.50 (m, 1H), 1.54 (s, 3H), 1.36 (s, 1H), 1.27–1.18 (m, 1H), 0.70–0.66 (m, 1H), 0.62–0.57 (m, 1H) Int.091: isopropyl 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5- methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0503] In a 25 mL round bottom flask under inert atmosphere, isopropyl 9-chloro-1-cyclopropyl-5- methyl-2,6,6-trioxo-8-(trifluoromethylsulfonyloxy)-5H-thioch romeno[4,3-b]pyridine-3-carboxylate Int.112 (110 mg, 0.193 mmol, 1.0 equiv.) was diluted in 1,4-dioxane (4 mL) and 1 M aqueous Na2CO3 (1 mL) in the presence of 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)-1h-pyrazole (CAS: 847818-71-7, 0.062 g, 0.232 mmol, 1.2 equiv.). [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.019 mmol, 0.1 equiv.) was added and the mixture was heated at 50°C for 15 min. The reaction was filtered, evaporated under reduced pressure and the crude product was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0504] Molecular weight: 546.0 ; LCMS, molecular weight observed: 546.2/548.2.

Synthesis of 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

[0505] In a 25 mL round bottom flask charged with isopropyl 9-chloro-1-cyclopropyl-8-[1-(2- methoxyethyl)pyrazol-4-yl]-5-methyl-2,6,6-trioxo-5H-thiochro meno[4,3-b]pyridine-3-carboxylate Int.091 (0.068 g, 0.125 mmol, 1.0 equiv.) in MeOH (2 mL) was added 2 N aqueous NaOH (0.2 mL, 0.400 mmol, 3.2 equiv.). The reaction was stirred at RT for 30 min and then cooled down to 0°C. 2 N aqueous HCl (0.2 mL, 0.400 mmol, 3.2 equiv.) was added. The precipitate was filtered off, rinsed with MeOH and dried under suction to afford the title product.

[0506] Molecular weight: 504.0 ; LCMS, molecular weight observed: 504.2/506.2

[0507] 1H NMR (400 MHz, Chloroform-d) d 13.93 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 8.14 (d, J = 0.8 Hz, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.99 (s, 1H), 4.39 (t, 2H), 4.09 (q, J = 7.2 Hz, 1H), 3.81 (t, 2H), 3.59–3.49 (m, 1H), 3.38 (s, 3H), 1.54 (s, 3H), 1.42–1.33 (m, 1H), 1.25–1.16 (m, 1H), 0.70–0.66 (m, 1H), 0.61–0.56 (m, 1H) Int.092: isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trioxo-8-(2-pyrrolidin -1-ylpyrimidin-5-yl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0508] In a 25 mL round bottom flask under inert atmosphere, isopropyl 9-chloro-1-cyclopropyl-5- methyl-2,6,6-trioxo-8-(trifluoromethylsulfonyloxy)-5H-thioch romeno[4,3-b]pyridine-3-carboxylate Int.112 (110 mg, 0.193 mmol, 1.0 equiv.) was diluted in 1,4-dioxane (4 mL) and 1 M aqueous Na2CO3 (1 mL) in the presence of 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester (CAS: 1015242-07-5, 0.065 g, 0.232 mmol, 1.2 equiv.). [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.019 mmol, 0.1 equiv.) was added and the mixture was heated at 50°C for 15 min. The reaction was filtered, evaporated under reduced pressure and the crude product was purified by FLC (SiO2, column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0509] Molecular weight: 569.1 ; LCMS, molecular weight observed: 569.2/571.2

Synthesis of 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

[0510] In a 25 mL round bottom flask charged with isopropyl 9-chloro-1-cyclopropyl-5-methyl-2,6,6- trioxo-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H-thiochromeno[4 ,3-b]pyridine-3-carboxylate Int.092 (0.095 g, 0.169 mmol, 1.0 equiv.) in MeOH (2 mL) was added 2 N aqueous NaOH (0.2 mL, 0.400 mmol, 2.4 equiv.). The reaction was stirred at RT for 30 min and then cooled down to 0°C.2 N aqueous HCl (0.2 mL, 0.400 mmol, 2.4 equiv.) was added. The precipitate was filtered off, rinsed with MeOH and dried under suction to afford the title product.

[0511] Molecular weight: 527.0 ; LCMS, molecular weight observed: 527.2/529.2

[0512] 1H NMR (400 MHz, Chloroform-d) d 13.91 (s, 1H), 8.58 (s, 2H), 8.43 (s, 1H), 8.05 (d, J = 13.4 Hz, 2H), 4.11 (q, J = 7.3 Hz, 1H), 3.71–3.63 (m, 4H), 3.60–3.51 (m, 1H), 2.10–2.02 (m, 4H), 1.55 (s, 3H), 1.39–1.35 (m, 1H), 1.28–1.23 (m, 1H), 0.71–0.66 (m, 1H), 0.65–0.61 (m, 1H) Int.034: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoic acid

[0513] To a stirred mixture of Int.011: 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene (10.0 g, 35.8 mmol, 1.0 equiv.), 3-mercaptopropionic acid (CAS 107-96-0, 3.46 mL, 39.3 mmol, 1.1 equiv.) and XantPhos Pd G3 (CAS 1445085-97-1, 3.77 g, 3.58 mmol, 0.1 equiv.) in THF (100 mL) at RT was added TEA (10.5 mL, 71.5 mmol, 2.0 equiv.) in one portion. The reaction mixture was heated to 70°C for 30 min and allowed to cool to RT. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with DCM/MeOH/0.1 % of AcOH: 100/0 to 97/3). The pure fractions were combined and evaporated to dryness to afford the title product.

[0514] Molecular weight: 304.8 ; LCMS, molecular weight observed: 303.2/305.2

Alternative route to Int.034: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoic acid

[0515] To a stirred mixture of Int.011: 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene (1100g, 4.17 moles, 1.0 equiv.), methyl 3-sulfanylpropanoate (CAS 2935-90-2, 508mL, 4.58 moles, 1.1 equiv.) and N,N- diisopropylethylamine (1.46L, 8.37 moles, 2.0 equiv.) in 1,4-dioxane (4.4L) was added Xantphos Pd G3 (CAS 1445085-97-1, 20.8g, 20.8 mmol, 0.5 mol%) in one portion. The reaction mixture was then heated at reflux for 1h and allowed to cool to RT. The reaction mixture was cooled to 10°C and HCl 1M (4L) was added in 30min followed by EtOAc (2L). The aqueous phase was extracted with EtOAc (2L). The combined organic phases were washed with 20% NaCl solution (1L) and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2.5L). LiOH.H2O (407g, 9.70 moles, 2.0 equiv.) suspended in water (2.5L) was added via an addition funnel over 1h. The reaction mixture was stirred at RT for a total of 1h40 and then carefully acidified with HCl 6M (1.6L, 2.0 equiv.) over 1h at RT. EtOAc (2L) was added for extraction. The aqueous phase was extracted with EtOAc (2L). The combined organic phases were washed with 20% NaCl solution (2L). The organic phase was concentrated and a solvent exchange with heptane was performed. Crystallization occurred at RT. The suspension was aged at RT for 10h. The suspension was then filtered and washed with heptane . The solid was dried at 45°C in a vacuum to afford the title product.

Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one

[0516] Int.034: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoic acid (11.0 g, 23.5 mmol, 1.0 equiv.) was slowly added toH2SO4 (40.0 mL, 709 mmol, 30.1 equiv.) cooled to 0°C. The thick solution was stirred at 0°C for 5 min. The reaction mixture was poured into ice (40 mL) and stirred for 5 min. The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0517] Molecular weight: 286.8 ; LCMS, molecular weight observed: 287.1/289.1 Alternative route to Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one

[0518] Trifluoroacetic anhydride (500mL, 3.56 moles, 1.1 equiv.) was added to a solution of Int.034: 3- [4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoic acid (1010g, 3.20 moles, 1.0 equiv.) in toluene (4L). The reaction mixture was stirred at 80°C for 1h followed by distillation of 630mL of a mixture toluene/tfa over 2h rising the temperature to 100°C. The reaction mixture was cooled to 15°C and NaOH 2M (2L) was carefully added, over 20 minutes, keeping the process temperature below 25°C. The aqueous phase was extracted with EtOAc (2L). The combined organic phases were washed with water (2L) and 20% NaCl solution (2L). The organic phase was concentrated and crystallization was induced by heptane addition. The suspension was aged at room temperature for 1h. The suspension was then filtered and washed with heptane. The solid was dried at 45°C in a vacuum oven to afford the title product.

Synthesis of Cpd_008: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochr omeno[4,3- b]pyridine-3-carboxylic acid

[0519] To a stirred solution of Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (0.50 g, 1.74 mmol, 1.0 equiv.) in EtOH (2.5 mL) at RT were added glacial acetic acid (0.10 mL, 1.74 mmol, 1.0 equiv.) and cyclopropylamine (CAS 765-30-0, 1.21 mL, 17.4 mmol, 10.0 equiv.). The reaction mixture was heated at reflux for 1.5 h and then allowed to cool to RT. Water was added (5 mL) and the resulting solid was filtered and dried under vacuo. To this crude mixture in DMSO (1 mL) at RT was added 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.33 g, 1.78 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 20 min.2 N aqueous NaOH (1.37 mL, 2.74 mmol, 2.0 equiv.) was added to the reaction mixture which was heated to 130°C for 20 min. The reaction mixture was allowed to cool to RT and MeOH was added (2 mL) followed by 2 N aqueous HCl (1.37 mL). The mixture was stirred for 16 h. The resulting solid was filtered, washed with Et ₂ O and dried under vacuo to afford the title product.

[0520] Molecular weight: 421.9 ; LCMS, molecular weight observed: 422.2/424.2

[0521] 1H NMR (400 MHz, DMSO-d6) d 8.42 (s, 1H), 8.23 (s, 1H), 7.39 (s, 1H), 4.23 (t, J = 6.3 Hz, 2H), 3.87 (s, 2H), 3.72 (td, J = 7.1, 3.6 Hz, 1H), 3.51 (t, J = 6.2 Hz, 2H), 3.26 (s, 3H), 2.55–2.51 (m, 7H), 2.01 (p, J = 6.3 Hz, 2H), 1.02 (d, J = 7.0 Hz, 2H), 0.30 (s, 2H) Synthesis of Cpd_010: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0522] To a stirred mixture of Cpd_008: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid (0.176 g, 0.39 mmol, 1.0 equiv.) in glacial acetic acid (0.35 mL, 6.11 mmol, 15.4 equiv.) at RT was added H2O230 % in water (0.17 mL, 1.86 mmol, 4.7 equiv.). The reaction mixture was heated to 100°C for 20 min and allowed to cool to RT. The precipitate was filtered, washed with Et2O and dried under vacuo to afford the title product.

[0523] Molecular weight: 453.9 ; LCMS, molecular weight observed: 454.2/456.2

[0524] 1H NMR (400 MHz, DMSO-d6) d 8.47 (d, J = 0.9 Hz, 2H), 7.64 (s, 1H), 4.83 (s, 2H), 4.38 (t, J = 6.3 Hz, 2H), 3.88 (tt, J = 7.2, 4.2 Hz, 1H), 3.53 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.06 (p, J = 6.3 Hz, 2H), 1.09 (d, J = 6.3 Hz, 2H), 0.40 (s, 2H).

Alternative synthesis of Cpd_010: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0525] Cyclopropylamine (3.0 eq., 456mL, 6.57 moles, 3.0 equiv.) and acetic acid (126mL, 2.2 moles, 1 equiv.) were successively added to a suspension of Int.042: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3- dihydrothiochromen-4-one (675g, 2.19 moles, 1.0 equiv.) in ethanol (4L). The reaction mixture was stirred at reflux for 1h30 and cooled to room temperature. Water (2L) was added over 30min to the suspension. The suspension was aged for 1h and then filtered. The cake was washed with EtOH/water 1:1 (2 V). The solid was dried to afford (Z)-6-chloro-N-cyclopropyl-7-(2-methylpropoxy)-1,1-dioxo-2,3 - dihydrothiochromen-4-imine.

[0526] 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 5568-85-1, 180.0g, 966.9 mmol, 1.1 equiv.) was added to a suspension of (Z)-6-chloro-N-cyclopropyl-7-isobutoxy-1,1-dioxo-2,3- dihydrothiochromen-4-imine (300.0g, 877.7 mmol, 1.0 equiv.) in DMSO (1000mL). The reaction mixture was heated at 54°C for 1h15. Methanol (1000mL) and NaOH (2N) (600mL, 1200 mmol, 1.4 equiv.) were successively added to the reaction mixture. The reaction mixture was stirred at 75°C for 2h. The reaction mixture was cooled to 30°C and HCl 2M (800mL) was slowly added over 30min, keeping the temperature around 30°C. The suspension was then cooled to RT and aged for 1h, filtered and the solid was washed with water/MeOH 1:1 (2*600mL). The solid was suspended in EtOH (2000mL) and the suspension was heated at reflux for 1h30. The suspension was cooled to room temperature over 1h30 and aged at room temperature for 1h. The suspension was filtered and the cake was washed with EtOH (2000mL). The solid was dried at 45°C in a vacuum oven to afford the title product. Synthesis of Cpd_016: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochro meno[4,3- b]pyridine-3-carboxylic acid

[0527] To a stirred solution of Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (0.20 g, 0.69 mmol, 1.0 equiv.) in EtOH (2.5 mL) at RT were added glacial acetic acid (0.139 mmol, 0.008 mL, 0.2 equiv.) and cyclobutylamine (CAS 2516-34-9, 0.239 mL, 2.79 mmol, 4.0 equiv.). The reaction mixture was heated at reflux for 1 h and then allowed to cool to RT. Water was added (1 mL) and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. To this crude mixture in DMSO (0.5 mL) at RT was added 5-(methoxymethylene)- 2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.168 g, 0.906 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 15 min. NaOH 2N (0.300 mL, 1.11 mmol, 1.6 equiv.) was added to the reaction mixture which was heated to 130°C for 25 min. The reaction mixture was allowed to cool to RT and MeOH was added (1 mL) followed by HCl 2N (0.300 mL). The mixture was stirred 1 h. The resulting solid was filtered, washed with cold MeOH (2 mL) and dried under vacuo. The residue was purified by preparative HPLC (basic method) to afford the title product as a DEA salt.

[0528] Molecular weight: 435.9 ; LCMS, molecular weight observed: 436.2/438.2

[0529] 1H NMR (400 MHz, Chloroform-d) d 10.53 (bs, 1H), 8.30 (s, 1H), 7.42 (s, 1H), 7.10 (s, 1H), 4.90 (p, J = 8.2 Hz, 1H), 4.29–4.12 (m, 2H), 3.87–3.44 (m, 4H), 3.40 (s, 3H), 2.59–1.78 (m, 6H), 1.76–1.61 (m, 2H)

Synthesis of Cpd_017: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3- b]pyridine-3-carboxylic acid

[0530] To a stirred mixture of Cpd_016: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid (0.090 g, 0.171 mmol, 1.0 equiv.) in glacial acetic acid (0.2 mL, 3.49 mmol, 20.3 equiv.) at RT was added H2O230 % in water (0.100 mL, 1.06 mmol, 6.2 equiv.). The reaction mixture was heated to 100°C for 30 min and allowed to cool to RT. The precipitate was filtered, washed with Et2O and dried under vacuo to afford the title product.

[0531] Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.2/470.2

[0532] 1H NMR (400 MHz, Chloroform-d) d 8.35 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 5.03 (p, J = 8.2 Hz, 1H), 4.38–4.24 (m, 2H), 4.21 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 3.37 (s, 3H), 3.06–2.84 (m, 1H), 2.28–2.09 (m, 3H), 2.08–1.78 (m, 2H), 1.78–1.63 (m, 2H) Int.042: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrothiochrom en-4-one

[0533] To a stirred mixture of Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (1.09 g, 3.80 mmol, 1.0 equiv.) in glacial acetic acid (4.40 mL, 77.0 mmol, 20.0 equiv.) at RT was added H2O230 % in water (2.20 mL, 23.0 mmol, 6.2 equiv.). The reaction mixture was heated to 100°C for 2 h and allowed to cool to RT. Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 96/4). The pure fractions were combined and evaporated to dryness to afford the title product.

[0534] Molecular weight: 318.8 ; LCMS, molecular weight observed: 319.1/321.1

Alternative route to Int.042: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrothiochrom en-4-one

[0535] Phthalic anhydride (899g, 5.88 moles, 2.2 equiv.) was added to a solution of Int.033: 6-chloro-7- (3-methoxypropoxy)thiochroman-4-one (725g, 2.67 moles, 1.0 equiv.) in EtOAc (4.35L). The reaction mixture was heated at 35-40°C.2 portions of Urea Hydrogen Peroxide (CAS: 124-43-6, 130g, 1.34 moles, 0.5 equiv.) were added over 1h30 keeping the process temperature below 50°C. 4 portions of Urea Hydrogen Peroxide (CAS: 124-43-6, 78g, 0.804 moles, 0.3 equiv.) were then added over 3h keeping the temperature below 50°C. The reaction mixture was stirred at 40°C till complete conversion. The reaction mixture was cooled to 10°C and quenched with 10% sodium sulfite solution (Na2SO3, 1.5L). The resulting suspension was filtered on cellulose and the cake washed with EtOAc (700mL). The organic phase of the filtrate was collected and the aqueous phase was extracted with EtOAc (1.4L). The combined organic phases were washed with NaOH 4M (2.4L). The organic phase was then washed with water (1.4L) and 20% NaCl solution (1.4L). The organic phase was concentrated and crystallization was induced by heptane addition. The suspension was aged at room temperature for 1h. The suspension was then filtered and washed with heptane. The solid was dried at 45°C in a vacuum oven to afford the title product.

Synthesis of Cpd_028: 9-chloro-8-(3-methoxypropoxy)-1-(trans-2-methylcyclopropyl)- 2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0536] To a stirred solution of Int.042: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3- dihydrothiochromen-4-one (0.100 g, 0.313 mmol, 1.0 equiv.) in DCE (2 mL) at RT were added trans-2- methylcyclopropanamine hydrochloride (CAS 97291-62-8, 0.069 g, 0.627 mmol, 2.0 equiv.) and titanium (IV) isopropoxide (0.110 mL, 0.376 mmol, 1.2 equiv.). The reaction mixture was heated to 60°C overnight and then allowed to cool to RT. The reaction mixture was diluted with DCM (1 mL), quenched with NaOH 2N (0.314 mL, 0.627 mmol, 2.0 equiv.) and stirred for 1 h. Salts were filtered over a pad of Celite ® and the filtrate was washed with water. The organic layer was collected on a phase separator and evaporated to dryness. To this crude mixture in DMSO (0.5 mL) at RT was added 5-(methoxymethylene)-2,2-dimethyl- 1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.080 g, 0.407 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 15 min. NaOH 2N (0.169 mL, 0.627 mmol, 2.0 equiv.) was added to the reaction mixture which was heated to 130°C for 25 min. The reaction mixture was allowed to cool to RT and MeOH was added (1 mL) followed by HCl 2N (0.170 mL). Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The residue was purified by preparative HPLC (basic method) to afford the title product as a DEA salt. (Mixture of the 2 trans compounds)

[0537] Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.2/470.2

[0538] 1H NMR (400 MHz, Chloroform-d) d 8.09 (s, 1H), 7.88 (s, 1H), 7.59 (s, 1H), 4.30 (t, J = 6.3 Hz, 2H), 4.09 (s, 2H), 3.60 (t, J = 6.0 Hz, 2H), 3.36 (s, 3H), 3.09–2.97 (m, 1H), 2.16 (p, J = 6.1 Hz, 2H), 1.06 (d, J = 5.2 Hz, 3H), 0.89–0.82 (m, 2H), 0.63–0.52 (m, 1H)

Synthesis of Cpd_027: 9-chloro-1-(2-fluorocyclopropyl)-8-(3-methoxypropoxy)-2,6,6- trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0539] To a stirred solution of Int.042: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3- dihydrothiochromen-4-one (0.100 g, 0.313 mmol, 1.0 equiv.) in DCE (2 mL) at RT were added (1R,2S)-2- fluorocyclopropanamine 4-methylbenzenesulfonate (CAS 143062-84-4, 0.158 g, 0.627 mmol, 2.0 equiv.) and titanium (IV) isopropoxide (0.110 mL, 0.376 mmol, 1.2 equiv.). The reaction mixture was heated to 60°C overnight and then allowed to cool to RT. The reaction mixture was diluted with DCM (1 mL), quenched with NaOH 2N (0.314 mL, 0.627 mmol, 2.0 equiv.) and stirred for 1 h. Salts were filtered over a pad of Celite ® and the filtrate was washed with water. The organic layer was collected on a phase separator and evaporated to dryness. To this crude mixture in DMSO (0.5 mL) at RT was added 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.080 g, 0.407 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 15 min. NaOH 2N (0.313 mL, 0.627 mmol, 2.0 equiv.) was added to the reaction mixture which was heated to 130°C for 25 min. The reaction mixture was allowed to cool to RT and MeOH was added (1 mL) followed by HCl 2N (0.313 mL). Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The residue was first purified by preparative HPLC (basic method) and then by FLC (SiO2, column eluted with DCM/MeOH/0.1 % of Glacial acetic acid: 100/0 to 95/5). The pure fractions were combined and evaporated to dryness to afford the title product.

[0540] Molecular weight: 471.9 ; LCMS, molecular weight observed: 472.2/474.2

[0541] 1H NMR (400 MHz, DMSO-d6) d 14.06 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 7.65 (s, 1H), 5.29–4.64 (m, 3H), 4.50–4.27 (m, 2H), 4.07–3.92 (m, 1H), 3.53 (t, J = 6.2 Hz, 2H), 3.27 (s, 3H), 2.05 (p, J = 6.3 Hz, 2H), 1.58–1.34 (m, 1H), 1.24 (s, 1H)

Synthesis of Cpd_069: 9-chloro-1-(3,3-difluorocyclobutyl)-8-(3-methoxypropoxy)-2,6 ,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0542] To a stirred solution of Int.042: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3- dihydrothiochromen-4-one (0.100 g, 0.313 mmol, 1.0 equiv.) in DCE (2 mL) at RT were added 3,3- difluorocyclobutanamine hydrochloride (CAS 637031-93-7, 0.270 g, 1.88 mmol, 6.0 equiv.) and titanium (IV) isopropoxide (0.110 mL, 0.376 mmol, 1.2 equiv.). The reaction mixture was heated to 60°C for 48 h and then allowed to cool to RT. The reaction mixture was diluted with DCM (2 mL), quenched with NaOH 2N (0.939 mL, 1.88 mmol, 6.0 equiv.) and stirred for 10 min. Salts were filtered over a pad of Celite ® and the filtrate was washed with water. The organic layer was collected on a phase separator and evaporated to dryness. To this crude mixture (0.127 g, 0.313 mmol, 1.0 equiv.) in DMSO (1 mL) at RT was added 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.058 g, 0.313 mmol, 1.0 equiv.). The reaction mixture was stirred at 50°C for 20 min. NaOH 2N (0.313 mL, 0.627 mmol, 2.0 equiv.) was added to the reaction mixture which was heated to 120°C for 10 min. The reaction mixture was allowed to cool to RT and MeOH was added (0.5 mL) followed by HCl 2N (0.314 mL). The mixture was stirred overnight. Water and DCM were added and the organic layer was collected on a phase separator and evaporated to dryness. The residue was purified by preparative HPLC (acid method) to afford the title product.

[0543] Molecular weight: 503.9 ; LCMS, molecular weight observed: 504.2/506.1

[0544] 1H NMR (400 MHz, Chloroform-d) d 13.51 (s, 1H), 8.39 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 4.98– 4.87 (m, 1H), 4.39–4.32 (m, 2H), 4.20 (s, 2H), 3.65–3.57 (m, 2H), 3.38 (s, 3H), 3.10–3.06 (m, 4H), 2.24– 2.13 (m, 2H)

Int.031: 3-(4-chloro-3-methoxy-phenyl)sulfanylpropanoic acid [0545] To a stirred mixture of Int.032: 4-bromo-1-chloro-2-methoxy-benzene (CAS 16817-43-9, 25.0 g, 113 mmol, 1.0 equiv.), 3-mercaptopropionic acid (CAS 107-96-0, 10.9 mL, 124 mmol, 1.1 equiv.) and XantPhos Pd G3 (CAS 1445085-97-1, 5.95 g, 5.64 mmol, 0.05 equiv.) in THF (150 mL) at RT was added TEA (33.1 mL, 226 mmol, 2.0 equiv.) in one portion. The reaction mixture was heated to 70°C for 40 min and allowed to cool to RT. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with DCM/MeOH/0.1 % of AcOH: 100/0 to 95/5). The pure fractions were combined and evaporated to dryness to afford the title product.

[0546] Molecular weight: 246.7 ; LCMS, molecular weight observed: 245.2/247.1

Int.030: 6-chloro-7-methoxy-thiochroman-4-one

[0547] Int.031: 3-(4-chloro-3-methoxy-phenyl)sulfanylpropanoic acid (17.7 g, 56.1 mmol, 1.0 equiv.) was slowly added toH ₂ SO ₄ (70.0 mL, 1.24 mol, 22.1 equiv.) cooled to 0°C. The thick solution was stirred at 0°C for 10 min. The reaction mixture was poured into ice (100 mL) and stirred for 45 min. The precipitate was filtered, washed with water, triturated with iPr2O and dried under vacuo. The obtained solid was diluted with DCM, washed with water and saturated NaHCO ₃ aqueous solution. The organic layer was collected on a phase separator and evaporated to dryness to afford the title product.

[0548] Molecular weight: 228.7 ; LCMS, molecular weight observed: 229.2/231.2

Synthesis of Cpd_009: 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiochromeno[4,3-b ]pyridine-3- carboxylic acid

[0549] To a stirred solution of Int.030: 6-chloro-7-methoxy-thiochroman-4-one (6.08 g, 26.6 mmol, 1.0 equiv.) in EtOH (30 mL) at RT were added glacial acetic acid (0.304 mL, 5.32 mmol, 0.2 equiv.) and cyclopropylamine (CAS 765-30-0, 7.38 mL, 106 mmol, 4.0 equiv.). The reaction mixture was heated at reflux for 1 h and then allowed to cool to RT. Water was added (30 mL) and the resulting solid was filtered, washed with cold water and dried under vacuo. To this crude mixture in DMSO (20 mL) at RT was added 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 6.43 g, 34.5 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 15 min. NaOH 2N (21.3 mL, 42.5 mmol, 1.6 equiv.) was added to the reaction mixture which was heated to 130°C for 30 min. The reaction mixture was allowed to cool to RT and MeOH was added (5 mL) followed by HCl 2N (21.3 mL). The mixture was stirred for 2 h. The resulting solid was filtered, washed with cold MeOH (10 mL) and dried under vacuo to afford the title product.

[0550] Molecular weight: 363.8 ; LCMS, molecular weight observed: 364.1/366.1 [0551] 1H NMR (400 MHz, Chloroform-d) d 8.38 (s, 1H), 7.83 (s, 1H), 7.08 (s, 1H), 4.00 (s, 3H), 3.66 (s, 2H), 3.47–3.36 (m, 1H), 1.27–1.15 (m, 2H), 0.48–0.37 (m, 2H)

Int.028: 9-chloro-1-cyclopropyl-8-hydroxy-2-oxo-5H-thiochromeno[4,3-b ]pyridine-3-carboxylic acid

[0552] To a stirred solution of Cpd_009 : 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid (3.95 g, 10.9 mmol, 1.0 equiv.) in NMP (105 mL) at RT were added sodiosulfanylsodium nonahydrate (CAS 1313-84-4, 26.1 g, 109 mmol, 10.0 equiv.) and lithium chloride (2.30 g, 54.3 mmol, 5.0 equiv.). The reaction mixture was heated to 120°C for 16 h before being cooled to RT and stirred for 1.5 h. The precipitate was filtered, washed with ACN and dried under vacuo. This solid was added portionwise to HCl 2N (50 mL) and stirred for 30 min at RT. The solid was filtered, washed with ACN and dried under vacuo to afford the title product.

[0553] Molecular weight: 349.8 ; LCMS, molecular weight observed: 350.1/352.1

Synthesis of Cpd_007: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine- 3-carboxylic acid

[0554] To a stirred mixture of Int.028: 9-chloro-1-cyclopropyl-8-hydroxy-2-oxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid (5.15 g, 14.7 mmol, 1.0 equiv.) in glacial acetic acid (20.6 mL, 359 mmol, 24.4 equiv.) at RT was added H2O2 30% in water (10.3 mL, 109 mmol, 7.4 equiv.). The reaction mixture was heated to 100°C for 3 h and allowed to cool to RT. The precipitate was filtered and dried under vacuo to afford the title product.

[0555] Molecular weight: 381.8 ; LCMS, molecular weight observed: 382.2/384.1

[0556] 1H NMR (400 MHz, DMSO-d ₆ ) d 7.63 (s, 1H), 7.45 (s, 1H), 6.75 (s, 1H), 3.72 (s, 2H), 2.99–2.88 (m, 1H), 0.45–0.39 (m, 2H), -0.24–-0.30 (m, 2H).

Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate

[0557] To a stirred mixture of Cpd_007: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid (3.75 g, 9.82 mmol, 1.0 equiv.) in DCM (20 mL) at 0°C were added DMF (0.100 mL, 1.00 mmol, 0.1 equiv.) and oxalyl dichloride (2.10 mL , 24.6 mmol, 2.5 equiv.). The solution was stirred for 4 h at RT. The reaction mixture was evaporated to dryness and 2- propanol (20 mL) was added to the crude. The reaction mixture was heated at reflux for 1 h. The precipitate was filtered, washed with iPr2O and dried under vacuo to afford the title product.

[0558] Molecular weight: 423.9 ; LCMS, molecular weight observed: 424.2/426.4

Int.065: isopropyl 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trioxo-5 H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0559] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and cyclopropylmethanol (CAS 2516-33-8, 0.040 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 16 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 30/70). The pure fractions were combined and evaporated to dryness to afford the title product.

[0560] Molecular weight: 478.0 ; LCMS, molecular weight observed: 478.2/480.2

Synthesis of Cpd_059: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trioxo-5 H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0561] To a stirred mixture of Int.065: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trioxo-5 H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.079 g, 0.165 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.330 mL, 0.661 mmol, 4.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.330 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0562] Molecular weight: 435.9 ; LCMS, molecular weight observed: 436.3/438.2 [0563] 1H NMR (400 MHz, Chloroform-d) d 13.91 (s, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 4.22 (s, 2H), 4.13 (d, J = 6.9 Hz, 2H), 3.53 (tq, J = 9.4, 5.2, 4.8 Hz, 1H), 1.47–1.34 (m, 0H), 1.31 (d, J = 7.3 Hz, 2H), 0.83–0.72 (m, 2H), 0.63 (d, J = 4.4 Hz, 2H), 0.54–0.46 (m, 2H)

Int.066: isopropyl 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6-trioxo- 5H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0564] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and 1-cyclopropylethanol (CAS 765-42-4, 0.046 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 16 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 30/70). The pure fractions were combined and evaporated to dryness to afford the title product.

[0565] Molecular weight: 492.0 ; LCMS, molecular weight observed: 492.2/494.2

Synthesis of Cpd_060: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6-trioxo- 5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0566] To a stirred mixture of Int.066: isopropyl 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.079 g, 0.143 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.286 mL, 0.572 mmol, 4.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.286 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0567] Molecular weight: 449.9 ; LCMS, molecular weight observed: 450.3/452.3

[0568] 1H NMR (400 MHz, Chloroform-d) d 13.91 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 4.22 (s, 3H), 4.27–4.16 (m, 0H), 3.53 (ddd, J = 11.4, 7.1, 4.3 Hz, 1H), 1.55 (d, J = 6.2 Hz, 3H), 1.30 (s, 3H), 1.34–1.19 (m, 1H), 0.75–0.61 (m, 4H), 0.56–0.46 (m, 1H), 0.49–0.37 (m, 1H) Int.073: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(2R)-tetrahydrofuran -2-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0569] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and [(3R)-tetrahydrofuran-3-yl]methanol (CAS 22415-59-4, 0.048 mg, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 3 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 20/80). The pure fractions were combined and evaporated to dryness to afford the title product.

[0570] Molecular weight: 508.0 ; LCMS, molecular weight observed: 508.3/510.2

Synthesis of 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

[0571] To a stirred mixture of Int.073: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(2R)- tetrahydrofuran-2-yl]methoxy]-5H-thiochromeno[4,3-b]pyridine -3-carboxylate (0.079 g, 0.150 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.150 mL, 0.300 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 2 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.150 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0572] Molecular weight: 465.9 ; LCMS, molecular weight observed: 466.3/468.3

[0573] 1H NMR (400 MHz, Chloroform-d) d 13.91 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 4.47– 4.38 (m, 1H), 4.31 (dd, J = 9.9, 3.5 Hz, 1H), 4.28–4.22 (m, 1H), 4.22 (s, 2H), 4.01 (dt, J = 8.4, 6.5 Hz, 1H), 3.91 (dt, J = 8.1, 6.5 Hz, 1H), 3.52 (ddd, J = 11.4, 7.2, 4.2 Hz, 1H), 2.18 (dtd, J = 12.6, 7.5, 5.2 Hz, 1H), 2.10 (s, 1H), 2.07–1.96 (m, 1H), 1.98–1.85 (m, 1H), 1.32–1.25 (m, 3H), 0.62 (d, J = 4.3 Hz, 2H) Int.074: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(2S)-tetrahydrofuran -2-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0574] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and [(2S)-tetrahydrofuran-2-yl]methanol (CAS 57203-01-7, 0.046 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 3 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 20/80). The pure fractions were combined and evaporated to dryness to afford the title product.

[0575] Molecular weight: 508.0 ; LCMS, molecular weight observed: 508.3/510.2

Synthesis of 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

[0576] To a stirred mixture of Int.074: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(2S)- tetrahydrofuran-2-yl]methoxy]-5H-thiochromeno[4,3-b]pyridine -3-carboxylate (0.070 g, 0.135 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.135 mL, 0.270 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 2 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.135 mL). The precipitate was filtered, washed with water and dried under vacuo. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 95/5). The pure fractions were combined and evaporated to dryness. The solid was triturated with MeOH, filtered and dried under vacuo to afford the title product.

[0577] Molecular weight: 465.9 ; LCMS, molecular weight observed: 466.3/468.2

[0578] 1H NMR (400 MHz, Chloroform-d) d 13.88 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 4.47– 4.36 (m, 1H), 4.33–4.18 (m, 2H), 4.20 (s, 2H), 4.04–3.94 (m, 1H), 3.94–3.84 (m, 1H), 3.56–3.45 (m, 1H), 2.23–2.10 (m, 1H), 2.10–2.06 (m, 1H), 2.06–1.97 (m, 1H), 2.00–1.83 (m, 1H), 1.30–1.24 (m, 2H), 0.63– 0.57 (m, 2H) Int.075: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(3S)-tetrahydrofuran -3-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0579] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and [(3R)-tetrahydrofuran-3-yl]methanol (CAS 124506-31-6, 0.048 mg, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 3 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 20/80). The pure fractions were combined and evaporated to dryness to afford the title product.

[0580] Molecular weight: 508.0 ; LCMS, molecular weight observed: 508.3/510.3

Synthesis of 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

[0581] To a stirred mixture of Int.075: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(3S)- tetrahydrofuran-3-yl]methoxy]-5H-thiochromeno[4,3-b]pyridine -3-carboxylate (0.087 g, 0.170 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.170 mL, 0.340 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 2 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.170 mL). The precipitate was filtered, washed with water and dried under vacuo. The solid was triturated with MeOH, filtered and dried under vacuo to afford the title product.

[0582] Molecular weight: 465.9 ; LCMS, molecular weight observed: 466.2/468.3

[0583] 1H NMR (400 MHz, Chloroform-d) d 13.87 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 4.25– 4.18 (m, 1H), 4.20 (s, 2H), 4.18–4.10 (m, 1H), 4.02–3.92 (m, 2H), 3.89–3.77 (m, 2H), 3.56–3.46 (m, 1H), 2.92–2.84 (m, 1H), 2.27–2.14 (m, 1H), 1.88–1.75 (m, 1H), 1.31–1.25 (m, 2H), 0.61 (d, J = 4.4 Hz, 2H) Int.076: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(3R)-tetrahydrofuran -3-yl]methoxy]-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0584] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and [(3S)-tetrahydrofuran-3-yl]methanol (CAS 124391-75-9, 0.048 mg, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 3 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 20/80). The pure fractions were combined and evaporated to dryness to afford the title product.

[0585] Molecular weight: 508.0 ; LCMS, molecular weight observed: 508.3/510.3

Synthesis of 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

[0586] To a stirred mixture of Int.076: isopropyl isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-[[(3R)- tetrahydrofuran-3-yl]methoxy]-5H-thiochromeno[4,3-b]pyridine -3-carboxylate (0.094 g, 0.170 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.170 mL, 0.340 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 2 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.170 mL). The precipitate was filtered, washed with water and dried under vacuo. The solid was triturated with MeOH, filtered and dried under vacuo to afford the title product.

[0587] Molecular weight: 465.9 ; LCMS, molecular weight observed: 466.2/468.3

[0588] 1H NMR (400 MHz, Chloroform-d) d 13.87 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 4.25– 4.18 (m, 1H), 4.20 (s, 2H), 4.18–4.10 (m, 1H), 4.02–3.92 (m, 2H), 3.89–3.77 (m, 2H), 3.56–3.46 (m, 1H), 2.92–2.84 (m, 1H), 2.27–2.14 (m, 1H), 1.88–1.75 (m, 1H), 1.31–1.25 (m, 2H), 0.64–0.58 (m, 2H) Synthesis of Cpd_036: isopropyl 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trioxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylate

[0589] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.100 g, 0.236 mmol, 1.0 equiv.) in DMF (1 mL) at RT were added K2CO3 (0.098 g, 0.707 mmol, 3.0 equiv.) and isobutyl iodide (CAS 513-38-2, 0.054 mL, 0.472 mmol, 2.0 equiv.). The reaction mixture was heated to 80°C for 4 h. Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 60/40). The pure fractions were combined and evaporated to dryness to afford the title product.

[0590] Molecular weight: 480.0 ; LCMS, molecular weight observed: 480.3/482.2

[0591] 1H NMR (400 MHz, Chloroform-d) d 7.96–7.82 (m, 2H), 7.55 (s, 1H), 5.25 (hept, J = 6.2 Hz, 1H), 4.12 (s, 2H), 3.97 (d, J = 6.5 Hz, 2H), 3.46–3.34 (m, 1H), 2.24 (hept, J = 6.6 Hz, 1H), 1.37 (d, J = 6.3 Hz, 6H), 1.22–1.14 (m, 2H), 1.11 (d, J = 6.7 Hz, 5H), 0.56–0.47 (m, 2H)

Synthesis of Cpd_073: 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trioxo-5H-thiochrom eno[4,3- b]pyridine-3-carboxylic acid

[0592] To a stirred mixture of Cpd_036: isopropyl 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.065 g, 0.122 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.122 mL, 0.240 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 2 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.170 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0593] Molecular weight: 437.9 ; LCMS, molecular weight observed: 438.3/440.2

[0594] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 4.20 (s, 2H), 4.03–3.97 (m, 2H), 3.56–3.46 (m, 1H), 2.33–2.18 (m, 1H), 1.31–1.22 (m, 2H), 1.15–1.09 (m, 6H), 0.64–0.58 (m, 2H) Synthesis of Int.171: 4-bromo-1-chloro-2-(2-methylpropoxy)benzene

[0595] In a 15L single jacketed process reactor equipped with a reflux condenser and baffles was added 5-bromo-2-chlorophenol (CAS 183802-98-4, 1205g, 5.81 mol, 1.00 equiv.) in ACN (4.8L). At RT, were successively added in one portion potassium carbonate (1632g, 11.7 mol, 2.00 equiv.) and 1-bromo-2- methylpropane (CAS 78-77-3, 1.32L, 12.2 mol, 2.10 equiv.). The reaction mixture was then heated at reflux for 29 h. The reaction mixture was cooled down to RT and left 26 h. The suspension was filtered and the solid was washed with EtOAc (4.8L). The filtrate was washed with NaOH 2N (2.5L). The aqueous phase was extracted with EtOAc (1.2L). The organic phases were combined and washed with 20% NaCl solution (2.4L) and concentrated under reduced pressure. Remaining water was removed by decantation and organic phase was filtered. Organic phase was concentrated under reduced pressure to afford the desired product.

[0596] Molecular weight: 263.5 ; LC-MS, molecular weight observed: -/- [0597] 1H NMR (400 MHz, DMSO-d6) d ppm 7.36 (d, 1H), 7.31 (d, 1H), 7.12 (dd, 1H), 3.85 (d, 2H), 2.03 (dt, 1H), 0.99 (d, 6H).

Synthesis of Int.172: 3-[4-chloro-3-(2-methylpropoxy)phenyl]sulfanylpropanoic acid

[0598] In a 15L single jacketed process reactor equipped with a reflux condenser and baffles were added Int.171 (1100g, 4.17 mol, 1.00 equiv.), methyl 3-sulfanylpropanoate (CAS 2935-90-2, 508mL, 4.58 mol, 1.10 equiv.) and N,N-diisopropylethylamine (1.46L, 8.37 mol, 2.00 equiv.) in 1,4-dioxane (4.4L). Xantphos Pd G3 (CAS 1445085-97-1, 20.8g, 20.8 mmol, 0.5 mol%) was added to the reaction mixture in one portion. The reaction mixture was then heated at reflux for 1 h. The reaction mixture was cooled to 10°C. HCl 1N (4L) was added in 30 min followed by EtOAc (2L). The organic phase was extracted. The aqueous phase was extracted one more time with EtOAc (2L). The combined organic phases were washed with 20% NaCl solution (1L) and concentrated under reduce pressure. The crude was dissolved in THF (2.5L). The mixture was maintained at 15-20°C. LiOH.H2O (407g, 9.70 mol, 2.00 equiv.) suspended in water (2.5L) was added via an addition funnel. Full conversion was reached after 1h40. The reaction mixture was cooled to 16°C and was carefully acidified with HCl 6N (1.6L, 9.70 mol, 2.00 equiv.) for 1 h. EtOAc (2L) was added for extraction. The aqueous phase was extracted with EtOAc (2L). The combined organic phases were washed with 20% NaCl solution (2L). A solvent exchange with heptane was performed (6L of heptane were added). Around 3L of solvent were evaporated at reflux. The reaction mixture was then stirred while cooling to 20°C for 2h30 and kept for 1 h at 20°C. The suspension was stirred furthr at RT for 10 h, then filtered and washed with heptane (2L). The solid was dried under vacuo to afford the desired product. [0599] Molecular weight: 288.8 ; LC-MS, molecular weight observed: 287.0-289.0/- [0600] 1H NMR (400 MHz, DMSO-d6) d ppm 12.34 (s, 1H), 7.35 (d, 1H), 7.05 (d, 1H), 6.90 (dd, 1H), 3.85 (d, 2H), 3.17 (t, 2H), 2.54 (t, 2H), 2.04 (hept, 1H), 1.00 (d, 6H).

Synthesis of Int.173: 6-chloro-7-(2-methylpropoxy)-2,3-dihydrothiochromen-4-one

[0601] In a 15L single jacketed process reactor equipped with a reflux condenser, trifluoroacetic anhydride (CAS 407-25-0, 490mL, 3.48 mol, 1.10 equiv.) was added to a solution of Int.172: 3-[4-chloro-3-(2- methylpropoxy)phenyl]sulfanylpropanoic acid (1000g, 3.17 mol, 1.00 equiv.) in toluene (4L). The jacket temperature was heated to 80°C in 45 min. Process temperature reached 81°C in 1 h. And was kept at that temperature for 30 min. The jacket temperature was raised to 120°C in 30 min. The process temperature reached 100°C and distillation of toluene/TFA was set up using a reflux divider head. 630mL of solvent was removed in 2 h. The reaction mixture was cooled to 15°C in 1 h and NaOH 2N (2L) was added over 20 min. The aqueous phase was extracted with EtOAc (2L). The combined organic phases were washed with water (2L). The organic phase was then washed with 20% NaCl solution (2L). The biphasic solution was filtered and transferred to the 15L reactor to be heated at 35°C. Heptane (5L) was added over 1 h while the reaction mixture was cooled over 1 h to 20°C. And stirred further at RT for 1 h. The suspension was then filtered and washed with heptane (2L). The solid was dried under vacuo to afford the desired product.

[0602] Molecular weight: 270.8 ; LC-MS, molecular weight observed: 269.0-271.0/271.0-273.0

[0603] 1H NMR (400 MHz, DMSO-d6) d ppm 7.91 (s, 1H), 7.09 (s, 1H), 3.92 (d, 2H), 3.35– 3.28 (m, 2H), 2.88– 2.80 (m, 2H), 2.13– 1.98 (m, 1H), 0.99 (d, 6H).

Synthesis of Int.174: 6-chloro-7-(2-methylpropoxy)-1,1-dioxo-2,3-dihydrothiochrome n-4-one

[0604] In a 15L single jacketed process reactor equipped with a reflux condenser, phthalic anhydride (899g, 5.88 mol, 2.20 equiv.) was added to a solution of Int.173 6-chloro-7-(2-methylpropoxy)-2,3- dihydrothiochromen-4-one (725g, 2.67 mol, 1.00 equiv.) in EtOAc (4.35L). Ground urea hydrogen peroxide (CAS 124-43-6, 130g, 1.34 mol, 0.50 equiv.) was added at 30°C. The process temperature reached 46°C in 40 min and kept further at 40°C for 1h10. Ground urea hydrogen peroxide (CAS 124-43-6, 130g, 1.34 mol, 0.50 equiv.) was further added and the jacket temperature was set to 35°C. Further to this addition, once the mixture temperature cooled back down to 37°C, additional ground urea hydrogen peroxide was added (CAS 124-43-6, 78.0g, 0.804 mol, 0.30 equiv.). After 3 h, another addition of ground urea hydrogen peroxide (CAS 124-43-6, 78.0g, 0.804 mol, 0.30 equiv.) was made. After 4h20, another addition of ground urea hydrogen peroxide (CAS 124-43-6, 78.0g, 0.804 mol, 0.30 equiv.) was made. After another 4h50, a last addition of ground urea hydrogen peroxide (CAS 124-43-6, 78.0g, 0.804 mol, 0.30 equiv.) was made and the resulting mixture was stirred for another 6h20. The reaction mixture was then cooled to 10°C and quenched with 10% sodium sulfite solution (1.5L). The biphasic suspension obtained was filtered on cellulose and washed with EtOAc (700mL). The organic phase of the filtrate was collected and the aqueous phase was extracted with EtOAc (1.4L). The combined organic phases were washed with NaOH 4N (2.4L) until pH 7. The organic phase was then washed with water (1.4L) and 20% NaCl solution (1.4L). Heptane (3.2L) was slowly added to the suspension over 1 h and the mixture stirred further at RT for 1 h. The suspension was filtered and was washed with heptane (1L). The solid was dried under vacuo to afford the desired product.

[0605] Molecular weight: 302.8 ; LC-MS, molecular weight observed: 301.0-303.0/- [0606] 1H NMR (400 MHz, DMSO-d6) d ppm 7.99 (s, 1H), 7.51 (s, 1H), 4.11 (d, 2H), 4.07– 3.99 (m, 2H), 3.27– 3.19 (m, 2H), 2.18– 2.03 (m, 1H), 1.02 (d, 6H).

Synthesis of Int.175: (Z)-6-chloro-N-cyclopropyl-7-(2-methylpropoxy)-1,1-dioxo-2,3 - dihydrothiochromen-4-imine

[0607] In a 15L single jacketed process reactor equipped with a reflux condenser and baffles, cyclopropylamine (CAS 765-30-0, 456mL, 6.57 mol, 3.00 equiv.) and acetic acid (126mL, 2.20 mol, 1.00 equiv.) were successively added to a suspension of Int.174 6-chloro-7-(2-methylpropoxy)-1,1-dioxo-2,3- dihydrothiochromen-4-one (675g, 2.19 mol, 1.00 equiv.) in EtOH (4L). The reaction was then heated at reflux for 1h30. The reaction mixture was then cooled to RT and water (2L) was added over 30 min. The suspension was stirred further for 1h and then filtered. The cake was washed with EtOH/water 1:1 (1.3L). The solid was dried under vacuo to afford the desired product.

[0608] Molecular weight: 341.8 ; LC-MS, molecular weight observed: -/342.0-344.0

[0609] 1H NMR (400 MHz, CDCl3) d 8.22 (s, 1H), 7.35 (s, 1H), 3.90 (d, 2H), 3.52– 3.40 (m, 4H), 3.15 – 3.06 (m, 1H), 2.21 (hept, 1H), 1.12– 0.98 (m, 10H).

Alternative synthesis of Cpd_073 (9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0610] In a 5L single jacketed process reactor equipped with a reflux condenser and baffles, 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 180g, 966 mmol, 1.10 equiv.) was added to a suspension of Int.175 (Z)-6-chloro-N-cyclopropyl-7-isobutoxy-1,1-dioxo-2,3- dihydrothiochromen-4-imine (300g, 877 mmol, 1.00 equiv.) in DMSO (1L). The reaction mixture was heated at 54°C for 1h15 and MeOH (1L) and NaOH 2N (600 mL, 1200 mmol, 1.36 equiv.) were added to the reaction mixture. The reaction mixture was stirred at 75°C for 2 h. The reaction mixture was allowed to cool down to RT. HCl 2N (800mL) was slowly added for 30 min and the reaction mixture was aged for 1 h at RT. The suspension was then filtered and the solid was washed with water/MeOH 1:1 ( 2*600mL). The solid was dried under vacuo. The wet solid was suspended in EtOH (2000mL) and the suspension was heated at reflux for 1h30. The suspension was then cooled to RT over 1h30 and aged at RT for 1 h. The suspension was filtered and the cake washed with EtOH (2000mL). The solid was then dried under vacuo to afford the desired product.

Int.078: isopropyl 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trioxo-5 H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0611] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at 0°C were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and 2,2-difluoroethanol (CAS 359-13-7, 0.030 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at 0°C and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 16 h at RT and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 60/40). The pure fractions were combined and evaporated to dryness to afford the title product.

[0612] Molecular weight: 487.9 ; LCMS, molecular weight observed: 488.3/489.9

Synthesis of Cpd_077: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trioxo-5 H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0613] To a stirred mixture of Int.078: isopropyl 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.041 g, 0.084 mmol, 1.0 equiv.) in MeOH (1 mL) at RT was added aqueous 2 N NaOH (0.084 mL, 0.240 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.084 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0614] Molecular weight: 445.8 ; LCMS, molecular weight observed: 446.2/448.1

[0615] 1H NMR (400 MHz, Chloroform-d) d 13.83 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 6.23 (tt, J = 54.4, 3.9 Hz, 1H), 4.46 (td, J = 12.5, 3.9 Hz, 2H), 4.22 (s, 2H), 3.64–3.38 (m, 1H), 1.32–1.22 (m, 2H), 0.63–0.58 (m, 2H)

Int.081: isopropyl 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-2,6,6-trioxo-5H-thio chromeno[4,3- b]pyridine-3-carboxylate

[0616] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at 0°C were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and cyclopentanol (CAS 96-41-3, 0.043 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at 0°C and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0617] Molecular weight: 492.0 ; LCMS, molecular weight observed: 492.3/494.4

Synthesis of Cpd_080: 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-2,6,6-trioxo-5H-thio chromeno[4,3- b]pyridine-3-carboxylic acid

[0618] To a stirred mixture Int.081: isopropyl 9-chloro-8-(cyclopentoxy)-1-cyclopropyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.078 g, 0.158 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.159 mL, 0.317 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.159 mL). DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness to afford the title product.

[0619] Molecular weight: 449.9 ; LCMS, molecular weight observed: 450.3/452.3 [0620] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 5.07– 4.98 (m, 1H), 4.20 (s, 2H), 3.55–3.45 (m, 1H), 2.14–1.82 (m, 5H), 1.80–1.67 (m, 1H), 1.76–1.71 (m, 2H), 1.31–1.20 (m, 2H), 0.64–0.58 (m, 2H).

Int.082: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-tetrahydropyran-4-ylox y-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0621] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at 0°C were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and tetrahydropyran-4-ol (CAS 2081-44-9, 0.045 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at 0°C and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 16 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 40/60). The pure fractions were combined and evaporated to dryness to afford the title product.

[0622] Molecular weight: 508.0 ; LCMS, molecular weight observed: 508.3/510.2

Synthesis of Cpd_081: 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-tetrahydropyran-4-ylox y-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0623] To a stirred mixture of Int.082: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-tetrahydropyran- 4-yloxy-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.046 g, 0.088 mmol, 1.0 equiv.) in MeOH (1 mL) at RT was added NaOH 2N (0.088 mL, 0.177 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before being acidified with HCl 2N (0.088 mL). DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness. The solid was triturated with MeOH, filtered and dried under vacuo to afford the title product.

[0624] Molecular weight: 465.9 ; LCMS, molecular weight observed: 466.2/468.2

[0625] 1H NMR (400 MHz, Chloroform-d) d 13.87 (s, 1H), 8.36 (s, 1H), 7.99 (s, 1H), 7.59 (s, 1H), 4.86– 4.82 (m, 1H), 4.20 (s, 2H), 4.03 (ddd, J = 11.3, 7.0, 3.8 Hz, 2H), 3.70 (ddd, J = 11.3, 7.3, 3.5 Hz, 2H), 3.56– 3.46 (m, 1H), 2.19–2.10 (m, 2H), 1.96–1.92 (m, 2H), 1.32–1.24 (m, 2H), 0.64–0.59 (m, 2H). Int.083: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(tetrahydropyran-4-ylm ethoxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0626] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at 0°C were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and tetrahydropyran-4-ylmethanol (CAS 14774-37-9, 0.055 g, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at 0°C and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 30/70). The pure fractions were combined and evaporated to dryness to afford the title product.

[0627] Molecular weight: 522.0 ; LCMS, molecular weight observed: 522.3/524.3

Synthesis of Cpd_082: 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(tetrahydropyran-4-ylm ethoxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0628] To a stirred mixture of Int.083: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(tetrahydropyran- 4-ylmethoxy)-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.077 g, 0.137 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.137 mL, 0.274 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before being acidified with HCl 2N (0.137 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0629] Molecular weight: 479.9 ; LCMS, molecular weight observed: 480.2/482.2

[0630] 1H NMR (400 MHz, Chloroform-d) d 13.85 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 4.18 (s, 2H), 4.15–4.00 (m, 4H), 3.54–3.37 (m, 4H), 2.31–2.12 (m, 1H), 1.84–1.76 (m, 2H), 1.62–1.52 (m, 1H), 1.29–1.20 (m, 2H), 0.61–0.56 (m, 2H) Int.084: isopropyl 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylate

[0631] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at 0°C were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and 4-hydroxybutanenitrile (CAS 628-22-8, 0.040 g, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at 0°C and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 30/70). The pure fractions were combined and evaporated to dryness to afford the title product.

[0632] Molecular weight: 491.0 ; LCMS, molecular weight observed: 491.2/493.2

Synthesis of Cpd_083: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid

[0633] To a stirred mixture of Int.084: isopropyl 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.069 g, 0.139 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.137 mL, 0.278 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before being acidified with HCl 2N (0.139 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0634] Molecular weight: 448.9 ; LCMS, molecular weight observed: 449.2/451.3

[0635] 1H NMR (400 MHz, Chloroform-d) d 13.85 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.62 (s, 1H), 4.42– 4.30 (m, 2H), 4.21 (s, 2H), 3.55–3.47 (m, 1H), 2.72 (t, J = 7.0 Hz, 2H), 2.37–2.27 (m, 2H), 1.32–1.22 (m, 2H), 0.64–0.59 (m, 2H) Int.085: isopropyl 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trioxo-5H -thiochromeno[4,3- b]pyridine-3-carboxylate

[0636] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at 0°C were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and cyclobutylmethanol (CAS 4415-82-1, 0.044 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at 0°C and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0637] Molecular weight: 492.0 ; LCMS, molecular weight observed: 492.2/494.2

Synthesis of Cpd_084: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trioxo-5H - thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0638] To a stirred mixture of Int.085: isopropyl 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.070 g, 0.142 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.142 mL, 0.284 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.142 mL). DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness to afford the title product.

[0639] Molecular weight: 449.9 ; LCMS, molecular weight observed: 450.2/452.2

[0640] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 4.23– 4.17 (m, 4H), 3.56–3.46 (m, 1H), 2.98–2.85 (m, 1H), 2.29–2.16 (m, 2H), 2.09–1.92 (m, 4H), 1.31–1.20 (m, 2H), 0.63–0.58 (m, 2H) Int.086: isopropyl 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6-trioxo- 5H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0641] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at 0°C were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and 2-cyclopropylethanol (CAS 2566-44-1, 0.040 g, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at 0°C and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0642] Molecular weight: 492.0 ; LCMS, molecular weight observed: 492.2/494.1

Synthesis of Cpd_085: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6-trioxo- 5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0643] To a stirred mixture of Int.086: isopropyl 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.166 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.166 mL, 0.332 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.166 mL). DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness to afford the title product.

[0644] Molecular weight: 449.9 ; LCMS, molecular weight observed: 450.3/452.2

[0645] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 4.32 (t, J = 6.4 Hz, 2H), 4.20 (s, 2H), 3.56–3.46 (m, 1H), 1.88–1.79 (m, 2H), 1.31–1.20 (m, 2H), 0.99–0.84 (m, 1H), 0.64–0.58 (m, 2H), 0.61–0.50 (m, 2H), 0.24–0.16 (m, 2H) Int.087: isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3- b]pyridine-3-carboxylate

[0646] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and 2-methoxyethanol (CAS 109-86-4, 0.037 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at RT and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0647] Molecular weight: 482.0 ; LCMS, molecular weight observed: 482.3/484.2

Synthesis of Cpd_086: 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3- b]pyridine-3-carboxylic acid

[0648] To a stirred mixture of Int.087: isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.082 g, 0.170 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.170 mL, 0.340 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.166 mL). DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness. The solid was triturated with MeOH, filtered and dried under vacuo to afford the title product.

[0649] Molecular weight: 439.9 ; LCMS, molecular weight observed: 440.3/442.2

[0650] 1H NMR (400 MHz, Chloroform-d) d 13.88 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 4.44– 4.37(m, 2H), 4.20 (s, 2H), 3.92–3.85 (m, 2H), 3.56–3.48 (m, 1H), 3.50 (s, 3H), 1.30–1.24 (m, 2H), 0.63– 0.57 (m, 2H) Int.088: isopropyl 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylate

[0651] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and 2-ethoxyethanol (CAS 110-80-5, 0.046 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at RT and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0652] Molecular weight: 496.0 ; LCMS, molecular weight observed: 496.3/498.3

Synthesis of Cpd_087: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid

[0653] To a stirred mixture of Int.088: isopropyl 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trioxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.090 g, 0.181 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.181 mL, 0.362 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.181 mL). DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness to afford the title product.

[0654] Molecular weight: 453.9 ; LCMS, molecular weight observed: 454.3/456.2

[0655] 1H NMR (400 MHz, Chloroform-d) d 13.88 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 4.44– 4.37 (m, 2H), 4.20 (s, 2H), 3.95–3.88 (m, 2H), 3.65 (q, J = 7.0 Hz, 2H), 3.56–3.46 (m, 1H), 1.29–1.25 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 0.63–0.57 (m, 2H) Int.089: isopropyl 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3- b]pyridine-3-carboxylate

[0656] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and 3-ethoxypropan-1-ol (CAS 111-35-3, 0.054 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at RT and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 2 h at RT and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0657] Molecular weight: 510.0 ; LCMS, molecular weight observed: 510.3/512.4

Synthesis of Cpd_088: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3- b]pyridine-3-carboxylic acid

[0658] To a stirred mixture of Int.089: of isopropyl 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.074 g, 0.145 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.145 mL, 0.290 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.145 mL). DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness to afford the title product.

[0659] Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.3/470.3

[0660] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 4.40– 4.32 (m, 2H), 4.20 (s, 2H), 3.69–3.62 (m, 1H), 3.54 (q, J = 7.0 Hz, 2H), 3.52–3.44 (m, 2H), 2.25–2.14 (m, 2H), 1.31–1.25 (m, 2H), 1.22 (t, J = 7.0 Hz, 3H), 0.64–0.58 (m, 2H) Int.134: isopropyl 9-chloro-1-cyclopropyl-8-[[(2S)-1,4-dioxan-2-yl]methoxy]-2,6 ,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0661] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and [(2R)-1,4-dioxan-2-yl]methanol (CAS 406913-88-0, 0.054 mL, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at RT and DIAD (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 16 h at RT and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 30/70). The pure fractions were combined and evaporated to dryness to afford the title product.

[0662] Molecular weight: 524.0 ; LCMS, molecular weight observed: 524.3/526.4

Synthesis of 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

[0663] To a stirred mixture of Int.134: isopropyl 9-chloro-1-cyclopropyl-8-[[(2S)-1,4-dioxan-2- yl]methoxy]-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-ca rboxylate (0.095 g, 0.181 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.452 mL, 0.905 mmol, 5.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before being acidified with HCl 2N (0.452 mL). EtOAc was added and the organic layer was evaporated to dryness. The residue was purified by preparative HPLC (acid method) to afford the title product.

[0664] Molecular weight: 481.9 ; LCMS, molecular weight observed: 482.2/484.1

[0665] 1H NMR (400 MHz, Chloroform-d) d 13.86 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 4.32– 4.19 (m, 2H), 4.20 (s, 2H), 4.15–4.05 (m, 1H), 4.01–3.93 (m, 1H), 3.93–3.79 (m, 2H), 3.83–3.75 (m, 1H), 3.75–3.60 (m, 2H), 3.56–3.45 (m, 1H), 1.30–1.24 (m, 2H), 0.63–0.57 (m, 2H) Int.136: isopropyl 9-chloro-1-cyclopropyl-8-ethoxy-2,6,6-trioxo-5H-thiochromeno [4,3-b]pyridine-3- carboxylate

[0666] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in ACN (2 mL) at RT were added K ₂ CO ₃ (0.078 g, 0.564 mmol, 3.0 equiv.) and iodoethane (CAS 75-03-6, 0.030 mL, 0.376 mmol, 2.0 equiv.). The reaction mixture was heated to 80°C for 2 h. The reaction mixture was evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0667] Molecular weight: 451.9 ; LCMS, molecular weight observed: 452.2/454.2

Synthesis of Cpd_103: 9-chloro-1-cyclopropyl-8-ethoxy-2,6,6-trioxo-5H-thiochromeno [4,3-b]pyridine- 3-carboxylic acid

[0668] To a stirred mixture of Int.136: isopropyl 9-chloro-1-cyclopropyl-8-ethoxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.045 g, 0.092 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.092 mL, 0.184 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.092 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0669] Molecular weight: 409.9 ; LCMS, molecular weight observed: 410.1/412.1

[0670] 1H NMR (400 MHz, Chloroform-d) d 13.88 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 4.33 (q, J = 7.0 Hz, 2H), 4.20 (s, 2H), 3.56–3.46 (m, 1H), 1.58 (t, J = 7.0 Hz, 3H), 1.31–1.24 (m, 2H), 0.63–0.58 (m, 2H)

Synthesis of Cpd_013: 9-chloro-1-cyclopropyl-8-methoxy-2,6,6-trioxo-5H-thiochromen o[4,3- b]pyridine-3-carboxylic acid

[0671] To a stirred mixture of Cpd_009: 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid (0.40 g, 0.110 mmol, 1.0 equiv.) in glacial acetic acid (0.040 mL) at RT was added H2O230 % in water (0.052 mL, 0.550 mmol, 5.0 equiv.). The reaction mixture was heated to 120°C for 10 min and allowed to cool to RT. The precipitate was filtered, washed successively with ACN and Et2O and dried under vacuo to afford the title product.

[0672] Molecular weight: 395.8 ; LCMS, molecular weight observed: 396.3/398.5

[0673] 1H NMR (400 MHz, DMSO-d6) d 8.47 (s, 1H), 8.47 (s, 1H), 7.64 (s, 1H), 4.83 (s, 2H), 4.11 (s, 3H), 3.95–3.79 (m, 1H), 1.26–1.00 (m, 2H), 0.52–0.20 (m, 2H)

Synthesis of Cpd_015: 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trioxo-5H-thiochro meno[4,3- b]pyridine-3-carboxylic acid

[0674] To a stirred mixture of Int.028: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid (0.038 g, 0.099 mmol, 1.0 equiv.) in DMF (0.25 mL) at RT were added K ₂ CO ₃ (0.137 g, 0.995 mmol, 10.0 equiv.) and 2-iodopropane (CAS 75-30-9, 0.040 mL, 0.398 mmol, 4.0 equiv.). The reaction mixture was heated to 80°C for 15 min. To the previous mixture was added NaOH 2N (0.543 mL, 1.086 mmol, 10.0 equiv.). The reaction mixture was heated to 80°C for 10 min and then allowed to cool to RT. The solution was acidified with HCl 2N (0.543 mL). Water and DCM were added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness to afford the title product.

[0675] Molecular weight: 423.9 ; LCMS, molecular weight observed: 424.3/426.7

[0676] 1H NMR (400 MHz, Methanol-d4) d 8.20 (s, 1H), 7.80 (s, 1H), 7.64 (s, 1H), 4.97–4.92 (m, 1H), 4.51–4.26 (m, 2H), 3.64–3.52 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H), 1.19–1.03 (m, 2H), 0.54–0.40 (m, 2H) Synthesis of Cpd_024: 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-2-oxo-5H-thiochr omeno[4,3- b]pyridine-3-carboxylic acid

[0677] To a stirred solution of Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (0.25 g, 0.871 mmol, 1.0 equiv.) in EtOH (1.25 mL) at RT were added glacial acetic acid (0.200 mL, 3.48 mmol, 4.0 equiv.) and cyclopentanamine (CAS 1003-03-8, 1.25 mL, 21.5 mmol, 20.0 equiv.). The reaction mixture was heated at reflux for 16 h and then allowed to cool to RT. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. To this crude mixture in DMSO (1 mL) at RT was added 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.211 g, 1.13 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 15 min. Aqueous 2 N NaOH (0.470 mL, 1.74 mmol, 2.0 equiv.) was added to the reaction mixture which was heated to 130°C for 25 min. The reaction mixture was allowed to cool to RT and MeOH was added (1 mL) followed by aqueous 2 N HCl (0.470 mL). Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by preparative HPLC (basic method) to afford the title product as a DEA salt.

[0678] Molecular weight: 450.0 ; LCMS, molecular weight observed: 452.2/454.2

[0679] 1H NMR (400 MHz, Chloroform-d) d 8.36 (s, 1H), 7.59 (s, 1H), 7.16 (s, 1H), 4.74 (p, J = 16.7, 9.5, 7.3 Hz, 1H), 4.23 (t, J = 6.2 Hz, 2H), 3.70–3.58 (m, 4H), 3.40 (s, 3H), 2.57–2.40 (m, 2H), 2.21–2.09 (m, 5H), 1.99–1.78 (m, 3H)

Synthesis of Cpd_025: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6-dioxo-5H-thi ochromeno[4,3- b]pyridine-3-carboxylic acid

[0680] To a stirred mixture of Cpd_008: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid (0.090 g, 0.213 mmol, 1.0 equiv.) in glacial acetic acid (0.18 mL) at RT was added H ₂ O ₂ 30 % in water (0.090 mL, 0.958 mmol, 4.5 equiv.). The reaction mixture was heated to 50°C for 4 h and allowed to cool to RT. Additional glacial acetic acid (0.18 mL) and H ₂ O ₂ 30 % in water (0.090 mL, 0.958 mmol, 4.5 equiv.) were added. The reaction mixture was heated to 50°C for 2 h and then allowed to cool to RT. Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by preparative HPLC (acid method) to afford the title product.

[0681] Molecular weight: 437.9 ; LCMS, molecular weight observed: 438.2/440.2

[0682] 1H NMR (400 MHz, Chloroform-d) d 14.00 (bs, 1H), 8.44 (s, 1H), 7.89 (s, 1H), 7.50 (s, 1H), 4.44– 4.29 (m, 2H), 4.22 (d, J = 14.0 Hz, 1H), 3.89 (d, J = 14.1 Hz, 1H), 3.70–3.58 (m, 2H), 3.54–3.45 (m, 1H), 3.40 (s, 3H), 2.20 (p, J = 6.1 Hz, 2H), 1.44–1.18 (m, 2H), 0.76–0.62 (m, 1H), 0.62–0.49 (m, 1H) Synthesis of Cpd_053: 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trioxo-5H-thiochro meno[4,3- b]pyridine-3-carboxylic acid

[0683] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.102 g, 0.192 mmol, 1.0 equiv.) in DMF (1 mL) at RT were added K ₂ CO ₃ (0.080 g, 0.577 mmol, 3.0 equiv.) and 3-bromo-1-methoxybutane (CAS 53424-50-3, 0.078 mL, 0.577 mmol, 3.0 equiv.). The reaction mixture was heated to 60°C for 16 h and allowed to cool to RT. Additional K ₂ CO ₃ (0.080 g, 0.577 mmol, 3.0 equiv.) and 3-bromo-1-methoxybutane (CAS 53424- 50-3, 0.078 mL, 0.577 mmol, 3.0 equiv.) were added. The reaction mixture was heated to 80°C for 2 h and allowed to cool to RT. To the previous mixture was added NaOH 2N (0.385 mL, 0.770 mmol, 4.0 equiv.). The reaction mixture was heated to 60°C for 3 h and then allowed to cool to RT. The crude was purified by preparative HPLC (acid method) followed by FLC (SiO ₂ , column eluted with DCM/MeOH/0.1 % of AcOH: 100/0 to 95/5). The pure fractions were combined and evaporated to dryness to afford the title product.

[0684] Molecular weight: 467.9 ; LCMS, molecular weight observed: 468.2/470.2

[0685] 1H NMR (400 MHz, Chloroform-d) d 13.90 (bs, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.72 (s, 1H), 4.93– 4.80 (m, 1H), 4.20 (s, 2H), 3.59–3.47 (m, 3H), 3.35 (s, 3H), 2.16–2.07 (m, 1H), 2.04–1.94 (m, 1H), 1.49 (d, J = 6.1 Hz, 3H), 1.31–1.23 (m, 2H), 0.66–0.57 (m, 2H)

Int.064: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-propoxy-5H-thiochromen o[4,3-b]pyridine-3- carboxylate

[0686] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.205 g, 0.483 mmol, 1.0 equiv.) in MEK (0.5 mL) at RT were added K2CO3 (0.200 g, 1.45 mmol, 3.0 equiv.) and 1-iodopropane (CAS 107-08-4, 0.094 mL, 0.967 mmol, 2.0 equiv.). The reaction mixture was heated to 80°C for 72 h. Water was added and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with Heptane/EtOAc: 100/0 to 40/60). The pure fractions were combined and evaporated to dryness to afford the title product.

[0687] Molecular weight: 466.0 ; LCMS, molecular weight observed: 466.3/468.2 Synthesis of Cpd_054: 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-propoxy-5H-thiochromen o[4,3-b]pyridine- 3-carboxylic acid

[0688] To a stirred mixture of Int.064: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-propoxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.017 g, 0.036 mmol, 1.0 equiv.) in THF/MeOH (0.2/0.2 mL) at RT was added NaOH 2N (0.073 mL, 0.146 mmol, 4.0 equiv.). The reaction mixture was heated to 60°C for 25 min and then allowed to cool to RT. The solution was acidified with HCl 2N (0.073 mL). The reaction mixture was evaporated to dryness. Water and DCM were added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness. The crude was purified by FLC (SiO ₂ , column eluted with DCM/MeOH/0.1 % of AcOH: 100/0 to 95/5). The pure fractions were combined and evaporated to dryness to afford the title product.

[0689] Molecular weight: 423.9 ; LCMS, molecular weight observed: 424.2/426.2

[0690] 1H NMR (400 MHz, Chloroform-d) d 13.87 (bs, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 4.30– 4.13 (m, 4H), 3.51 (tt, J = 7.1, 4.2 Hz, 1H), 1.97 (h, J = 7.1 Hz, 2H), 1.30–1.22 (m, 2H), 1.13 (t, J = 7.4 Hz, 3H), 0.66–0.52 (m, 2H)

Int.151: isopropyl 9-chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2-yl]methoxy]-2,6 ,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0691] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and [(2S)-1,4-dioxan-2-yl]methanol (CAS 406913-93-7, 0.055 g, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at RT and diisopropyl azodicarboxylate (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 16 h at RT and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 30/70). The pure fractions were combined and evaporated to dryness to afford the title product.

[0692] Molecular weight: 524.0 ; LCMS, molecular weight observed: 524.3/526.3 Synthesis of 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

[0693] To a stirred mixture of Int.151: isopropyl 9-chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2- yl]methoxy]-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-ca rboxylate (0.098 g, 0.188 mmol, 1.0 equiv.) in MeOH (2 mL) at RT was added NaOH 2N (0.188 mL, 0.376 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 2 h, allowed to cool to RT and then evaporated to dryness. Water was added, the solid was filtered and the aqueous layer was acidified with HCl 2N (0.188 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0694] Molecular weight: 481.9 ; LCMS, molecular weight observed: 482.2/484.3

[0695] 1H NMR (400 MHz, Chloroform-d) d 13.86 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 4.32– 4.25 (m, 1H), 4.25–4.19 (m, 1H), 4.20 (s, 2H), 4.15–4.05 (m, 1H), 4.01–3.93 (m, 1H), 3.92–3.75 (m, 3H), 3.75–3.60 (m, 2H), 3.55–3.45 (m, 1H), 1.30–1.24 (m, 2H), 0.63–0.57 (m, 2H)

Int.152: isopropyl 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0696] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.168 g, 0.376 mmol, 1.0 equiv.) in THF (2 mL) at RT were added triphenylphosphine (0.246 g, 0.941 mmol, 2.5 equiv.) and (1R)-1-cyclopropylethanol (CAS 6516- 09-2, 0.081 g, 0.941 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min and diisopropyl azodicarboxylate (0.097 mL, 0.489 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 3 h at RT and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0697] Molecular weight: 492.0 ; LCMS, molecular weight observed: 492.3/494.2 Synthesis of Cpd_116: 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0698] To a stirred mixture of Int.152: isopropyl 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]- 2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (0.181 g, 0.367 mmol, 1.0 equiv.) in MeOH (3 mL) at RT was added NaOH 2N (0.367 mL, 0.736 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.367 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0699] Molecular weight: 449.9 ; LCMS, molecular weight observed: 450.2/452.2

[0700] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 4.20 (s,2H), 4.25–4.14 (m, 1H), 3.56–3.46 (m, 1H), 1.55–1.51 (m, 3H), 1.31–1.25 (m, 1H), 1.25–1.19 (m, 2H), 0.71–0.64 (m, 2H), 0.64–0.59 (m, 2H), 0.53–0.34 (m, 2H)

Int.153: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-sec-butoxy-5H-thiochro meno[4,3-b]pyridine- 3-carboxylate

[0701] To a stirred mixture of Int.049: isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equiv.) in THF (1 mL) at RT were added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equiv.) and butan-2-ol (CAS 78-92-2, 0.055 g, 0.471 mmol, 2.5 equiv.). The reaction mixture was stirred for 5 min at RT and diisopropyl azodicarboxylate (0.051 mL, 0.257 mmol, 1.3 equiv.) was added. The reaction mixture was stirred for 1 h at RT and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 50/50). The pure fractions were combined and evaporated to dryness to afford the title product.

[0702] Molecular weight: 480.0 ; LCMS, molecular weight observed: 480.4/482.3 Synthesis of Cpd_118: 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0703] To a stirred mixture of Int.153: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-sec-butoxy-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.079 g, 0.164 mmol, 1.0 equiv.) in MeOH (1 mL) at RT was added NaOH 2N (0.165 mL, 0.329 mmol, 2.0 equiv.). The reaction mixture was heated to 65°C for 1 h, allowed to cool to RT and then evaporated to dryness. Water was added and the solution was acidified with HCl 2N (0.165 mL). The precipitate was filtered, washed with water and dried under vacuo to afford the title product.

[0704] Molecular weight: 437.9 ; LCMS, molecular weight observed: 438.3/440.3

[0705] 1H NMR (400 MHz, Chloroform-d) d 13.90 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 4.68– 4.56 (m, 1H), 4.21 (s, 2H), 3.56–3.46 (m, 1H), 1.97–1.74 (m, 2H), 1.48–1.43 (m, 3H), 1.32–1.24 (m, 2H), 1.10–1.01 (m, 3H), 0.62 (m, 2H)

Int.158: isopropyl 9-chloro-1-cyclopropyl-8-(oxetan-2-ylmethoxy)-2,6,6-trioxo-5 H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0706] Isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (1 mL) were added oxetan-2-ylmethanol (CAS: 61266-70-4, 0.047 mL, 0.578 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min, and diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.058 mL, 0.301 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 20 min. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , Heptane/EtOAc 100:0 to 0:100) to afford the title product containing trace of oxide of PPh _3.

[0707] Molecular weight: 494.0 ; LCMS, molecular weight observed: 493.3/ 495.4 Synthesis of Cpd_121: 9-chloro-1,8-dicyclopropyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3- carboxylic acid

[0708] Isopropyl 9-chloro-1-cyclopropyl-8-(oxetan-2-ylmethoxy)-2,6,6-trioxo-5 H-thiochromeno[4,3- b]pyridine-3-carboxylate (0.12 g, 0.24 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 1.6 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion a few water was added and trace of oxide of PPh ₃ was extracted with EtOAc. To the aqueous layer 2 N aqueous HCl (0.20 mL, 0.40 mmol, 1.6 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0709] Molecular weight: 451.9 ; LCMS, molecular weight observed: 450.2/452.2

[0710] 1H NMR (400 MHz, Chloroform-d) d 8.37 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 5.29–5.19 (m, 1H), 4.75 (dd, J = 8.5, 7.0 Hz, 2H), 4.46–4.33 (m, 2H), 4.21 (s, 2H), 3.57–3.47 (m, 1H), 2.96–2.77 (m, 2H),1.31– 1.22 (m, 2H), 0.63–0.58 (m, 2H).

Int.159: isopropyl 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0711] Isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (1 mL) were added (3-methyloxetan-3-yl)methanol (CAS: 3143-02-0, 0.057 mL, 0.578 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min at 0°C, and diisopropyl azodicarboxylate (CAS: 2446-83- 5, 0.058 mL, 0.301 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 5 h. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , Heptane/EtOAc 100:0 to 0:100) to afford the title product containing trace of oxide of PPh _3.

[0712] Molecular weight: 508.0 ; LCMS, molecular weight observed: 506.2/ 508.3 Synthesis of 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

[0713] Isopropyl 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.15 g, 0.29 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 1.3 equiv.) was added. The mixture was stirred at RT for 60 min. After complete conversion a few water was added and trace of oxide of PPh3 was extracted with EtOAc. To the aqueous layer 2 N aqueous HCl (0.20 mL, 0.40 mmol, 1.3 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0714] Molecular weight: 465.9 ; LCMS, molecular weight observed: 464.2/ 466.2

[0715] 1H NMR (400 MHz, Chloroform-d) d 13.86 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 4.68 (d, J =6.1 Hz, 2H), 4.54 (d, J = 6.1 Hz, 2H), 4.32 (s, 2H), 4.21 (s, 2H), 3.57–3.47 (m, 1H), 1.53 (s, 3H), 1.33–1.27 (m, 2H), 0.64–0.59 (m, 2H).

Int.160: isopropyl 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0716] Isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (1 mL) were added (1S)-1-cyclopropylethanol (CAS: 55637-37-1, 0.050 mL, 0.578 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equiv.). The mixture was stirred at RT for 5 min at 0°C, and diisopropyl azodicarboxylate (CAS: 2446-83- 5, 0.058 mL, 0.301 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 20 min. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0717] Molecular weight: 492.0 ; LCMS, molecular weight observed: 490.3/ 492.3 Synthesis of Cpd_124: 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0718] Isopropyl 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.17 g, 0.35 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.40 mL, 0.80 mmol, 2.3 equiv.) was added. The mixture was stirred at RT for 60 min. After complete conversion, 2 N aqueous HCl (0.40 mL, 0.80 mmol, 2.3 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0719] Molecular weight: 449.9 ; LCMS, molecular weight observed: 448.2/ 450.3

[0720] 1H NMR (400 MHz, Chloroform-d) d 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 4.25– 4.14 (m, 3H), 3.56–3.46 (m, 1H), 1.52 (d, J = 6.2 Hz, 3H), 1.30–1.21 (m, 3H), 0.71–0.65 (m, 2H), 0.65– 0.59 (m, 2H), 0.53–0.34 (m, 2H).

Int.068: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(trifluoromethylsulfon yloxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0721] To a stirred solution of isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate Int.049 (0.212 g, 0.4751 mmol,1.0 equiv.) in DCM (1 mL) at 0°C were added pyridine (0.077 mL, 0.950 mmol, 2.0 equiv.,) and Tf ₂ O (0.570 mL, 0.570 mmol, 1.2 equiv.,). The solution was stirred for 10 min at RT. Saturated aqueous NaHCO ₃ was added. The mixture was filtered over a phase separator. The organic layer was evaporated to dryness and the crude product was purified by FLC (SiO2, column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0722] Molecular weight: 555.9 ; LCMS, molecular weight observed: 556.1/558.0 Int.133: isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(2-pyrrolidin-1-ylpyri midin-5-yl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0723] To a stirred solution of isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8- (trifluoromethylsulfonyloxy)-5H-thiochromeno[4,3-b]pyridine- 3-carboxylate Int.068 (110 mg, 0.198 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) and 1 M aqueous Na ₂ CO ₃ (1 mL) in the presence of 2-(pyrrolidin- 1-yl)pyrimidine-5-boronic acid (CAS: 955374-13-7, 0.046 g, 0.237 mmol, 1.2 equiv.). [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.020 mmol, 0.1 equiv.) was added and the mixture was heated at 50°C for 15min. The reaction was filtered, evaporated under reduced pressure and the crude product was purified by FLC (SiO2, column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0724] Molecular weight: 555.1 ; LCMS, molecular weight observed: 555.3/557.3

Synthesis of Cpd_101: 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(2-pyrrolidin-1-ylpyri midin-5-yl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0725] To a stirred solution of isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(2-pyrrolidin-1- ylpyrimidin-5-yl)-5H-thiochromeno[4,3-b]pyridine-3-carboxyla te Int.133 (100 mg, 0.180 mmol, 1.0 equiv.) in MeOH (2 mL) was added 2 N aqueous NaOH (0.180 mL, 0.360 mmol, 2.0 equiv.). The reaction was stirred at 65°C for 1 h and then evaporated do dryness. DCM and 2 N aqueous HCl (0.180 mL, 0.360 mmol, 2.0 equiv.) were added. The organic layer was concentrated under reduced pressure to afford the desired compound.

[0726] Molecular weight: 513.0 ; LCMS, molecular weight observed: 513.3/515.3

[0727] 1H NMR (400 MHz, Chloroform-d) d 13.85 (s, 1H), 8.57 (s, 2H), 8.39 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 4.24 (s, 2H), 3.71–3.63 (m, 4H), 3.62–3.51 (m, 1H), 2.10–2.02 (m, 4H), 1.37–1.30 (m, 2H), 0.70– 0.64 (m, 2H). Int.150: isopropyl 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-2, 6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0728] To a stirred solution of isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8- (trifluoromethylsulfonyloxy)-5H-thiochromeno[4,3-b]pyridine- 3-carboxylate Int.068 (110 mg, 0.198 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) and 1 M aqueous Na2CO3 (1 mL) in the presence of 1-(2- methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1h-pyrazole (CAS: 847818-71-7, 0.060 g, 0.238 mmol, 1.2 equiv.). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.020 mmol, 0.1 equiv.) was added and the mixture was heated at 65°C for 45 min. The reaction was filtered, evaporated under reduced pressure and the crude product was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0729] Molecular weight: 532.0 ; LCMS, molecular weight observed: 532.4/534.3

Synthesis of 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

[0730] To a stirred solution of isopropyl 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]- 2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate Int.150 (103 mg, 0.194 mmol, 1.0 equiv.) in MeOH (2 mL) was added 2 N aqueous NaOH (0.194 mL, 0.388 mmol, 2.0 equiv.). The reaction was stirred at 65°C for 1 h and then evaporated do dryness. DCM and 2 N aqueous HCl (0.194 mL, 0.388 mmol, 2.0 equiv.) were added. The organic layer was concentrated under reduced pressure to afford the desired compound.

[0731] Molecular weight: 489.9 ; LCMS, molecular weight observed: 490.2/492.2

[0732] 1H NMR (400 MHz, Chloroform-d) d 8.38 (s, 1H), 8.22 (s, 1H), 8.13 (d, J = 0.8 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 4.43–4.36 (m, 2H), 4.23 (s, 2H), 3.84–3.77 (m, 2H), 3.60–3.50 (m, 1H), 3.38 (s, 3H), 1.34–1.20 (m, 2H), 0.67–0.62 (m, 2H) Int.067: isopropyl 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trioxo -5H-thiochromeno[4,3- b]pyridine-3-carboxylate

[0733] To a stirred solution of isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8- (trifluoromethylsulfonyloxy)-5H-thiochromeno[4,3-b]pyridine- 3-carboxylate Int.068 (113 mg, 0.203 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) and 1 M aqueous Na2CO3 (1 mL) in the presence of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS: 761446-44-0, 0.051 g, 0.243 mmol, 1.2 equiv.). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.020 mmol, 0.1 equiv.) was added and the mixture was heated at 90°C for 15 min. The reaction was filtered, evaporated under reduced pressure and the crude product was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 20:80) to afford the title product.

[0734] Molecular weight: 488.0 ; LCMS, molecular weight observed: 488.3/490.3

Synthesis of Cpd_061: 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trioxo -5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0735] To a stirred solution of isopropyl 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trioxo - 5H-thiochromeno[4,3-b]pyridine-3-carboxylate Int.068 (36 mg, 0.194 mmol, 1.0 equiv.) in MeOH (2 mL) was added 2 N aqueous NaOH (0.200 mL, 0.400 mmol, 5.4 equiv.). The reaction was stirred at 65°C for 1 h and then evaporated do dryness. DCM and 2 N aqueous HCl (0.200 mL, 0.400 mmol, 2.0 equiv.) were added. The organic layer was concentrated under reduced pressure to afford the desired compound.

[0736] Molecular weight: 445.9 ; LCMS, molecular weight observed: 446.2/448.2

[0737] 1H NMR (400 MHz, Chloroform-d) d 13.86 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 8.03 (s, 2H), 8.01 (s, 1H), 4.23 (s, 2H), 4.03 (s, 3H), 3.60–3.51 (m, 1H), 1.35–1.27 (m, 2H), 0.72–0.60 (m, 2H) Synthesis of Cpd_119: 9-chloro-1,8-dicyclopropyl-2,6,6-trioxo-5H-thiochromeno[4,3- b]pyridine-3- carboxylic acid

[0738] Isopropyl 9-chloro-1-cyclopropyl-2,6,6-trioxo-8-(trifluoromethylsulfon yloxy)-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.100 g, 0.180 mmol, 1.0 equiv.) and 2-cyclopropyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (CAS: 126689-01-8, 363 mg, 0.22 mmol, 1.2 equiv.) in 1,4-dioxane (4 mL) were charged in a sealed screw cap vial. The previous solution was degassed under inert atmosphere at RT. To the previous solution, 2 N aqueous of sodium carbonate (1 mL, 2 mmol, 11.1 equiv.) was added. The mixture was stirred to 70°C for 1h. To the mixture was added water and DCM, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was used without purification. The previous residue (84.0 mg, 0.19 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (0.20 mL, 0.40 mmol, 2.1 equiv.) was added. The mixture was stirred at RT for 60 min. After complete conversion, EtOAc and 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.1 equiv.) were added. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by preparative LC-MS (basic method) to afford the title product as a DEA salt.

[0739] Molecular weight: 405.9 ; LCMS, molecular weight observed: 404.2/ 406.2

[0740] 1H NMR (400 MHz, Chloroform-d) d 8.17 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 4.11 (s, 2H), 3.50– 3.40 (m, 1H), 2.40–2.29 (m, 1H), 1.25–1.21 (m, 2H), 1.19–1.12 (m, 2H), 0.94–0.88 (m, 2H), 0.55–0.49 (m, 2H).

Int.142: 1-[5-chloro-2-hydroxy-4-(3-methoxypropoxy)phenyl]ethanone

[0741] A mixture of 1-(5-chloro-2,4-dihydroxy-phenyl)ethanone (CAS: 90110-32-0, 1 g, 5.4 mmol, 1.0 equiv.), 1-bromo-3-methoxy-propane (CAS: 36865-41-5, 0.6 mL, 5.4 mmol, 1.0 equiv.) and K ₂ CO ₃ (0.74 g, 5.4 mmol, 1.0 equiv.) in DMF (8 mL) was stirred at RT for 24 h. A further 0.5 equiv. of 1-bromo- 3-methoxy-propane was added. The reaction mixture was stirred for a further 24 h. The mixture was diluted with water and DCM. The two layers are separated. The organic layer was dried (filtered through phase separator) and concentrated to afford the title product.

[0742] Molecular weight: 258.7 ; LCMS, molecular weight observed: 258.9 Int.145: [2-acetyl-4-chloro-5-(3-methoxypropoxy)phenyl] trifluoromethanesulfonate

[0743] To a mixture of 1-[5-chloro-2-hydroxy-4-(3-methoxypropoxy)phenyl]ethanone (10.0 g, 38.7 mmol, 1.0 equiv.), in pyridine (40 mL) was stirred to 0°C under inert atmosphere, and Tf ₂ O (CAS: 358-23- 6, 8.0 mL, 46.4 mmol, 1.2 equiv.) was added. The mixture was warmed up to RT and stirred for 48 h. After complete conversion pyridine was removed. To the residue were added EtOAc and water, organic layers were combined and washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford title product.

[0744] Molecular weight: 390.8 ; LCMS, molecular weight observed: 391.1/393.1

Int.146: 2-ethylhexyl 3-[2-acetyl-4-chloro-5-(3-methoxypropoxy)phenyl]sulfanylprop anoate

[0745] To a mixture of 1-[5-chloro-2-hydroxy-4-(3-methoxypropoxy)phenyl]ethanone (13.6 g, 34.7 mmol, 1.0 equiv.), 2-ethylhexyl 3-mercaptopropionate (CAS: 50448-95-8, 11.6 g, 52.0 mmol, 1.5 equiv.) and Xantphos Pd G3 (CAS: 1445085-97-1, 1.83 g, 1.73 mmol, 0.05 equiv.) were charged in THF (100 mL) and was added in one portion TEA (14.6 mL, 104 mmol, 3.0 equiv.). The mixture was stirred at 80°C for 30 min. The mixture was allowed to cool down to RT and was filtered through a pad of Celite ®, concentrated. To the residue EtOAc and water were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to afford title product.

[0746] Molecular weight: 445.0 ; LCMS, molecular weight observed: 459.4/461.3

Int.147: 1-[5-chloro-4-(3-methoxypropoxy)-2-sulfanyl-phenyl]ethanone

[0747] To a mixture of 2-ethylhexyl 3-[2-acetyl-4-chloro-5-(3- methoxypropoxy)phenyl]sulfanylpropanoate (15.4 g, 33.6 mmol, 1.0 equiv.), EtONa (CAS: 141-52-6, 4.81 g, 67.1 mmol, 2.0 equiv.) were charged in EtOH (100 mL). The mixture was stirred at reflux for 45 min. The mixture was allowed to cool down to RT and concentrated. To the residue EtOAc and water were added. The mixture was quenched with 2 N aqueous HCl to pH 1-2. The aqueous layer was extracted with EtOAc. Organics layers were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0748] Molecular weight: 274.8 ; LCMS, molecular weight observed: 275.2/277.2

Int.148: 6-chloro-7-(3-methoxypropoxy)-2-(3-methyloxetan-3-yl)thiochr oman-4-one

[0749] To a mixture of 1-[5-chloro-4-(3-methoxypropoxy)-2-sulfanyl-phenyl]ethanone (1.0 g, 3.60 mmol, 1.0 equiv.), in MeOH (5 mL) was added pyrrolidine (CAS: 123-75-1, 0.32 mL, 3.60 mmol, 1.0 equiv.) and was stirred at RT for 30 min in a sealed vial. In other sealed vial, a mixture of 3-methyloxetane-3- carbaldehyde (CAS: 99419-31-5, 580 mg, 5.50 mmol, 1.5 equiv.) in MeOH (0.5 mL) was added pyrrolidine (CAS: 123-75-1, 0.48 mL, 5.50 mmol, 1.5 equiv.) and was stirred at RT for 55 min. This previous solution was added dropwise on the first suspension, and the reaction mixture was stirred at RT for 1.5 h. 2 N aqueous HCl was added (1.8 mL, 3.60 mmol, 1.0 equiv.) and the mixture was stirred to RT for 2 h. a precipitate was formed and filtered. The precipitate containing pyrrolidine was taken up in DCM and washed with saturated aqueous NH ₄ Cl and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0750] Molecular weight: 356.9 ; LCMS, molecular weight observed: 357.1/359.2

Synthesis of Cpd_095: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxeta n-3-yl)-2-oxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0751] To a mixture of 6-chloro-7-(3-methoxypropoxy)-2-(3-methyloxetan-3-yl)thiochr oman-4-one (0.26 g, 0.73 mmol, 1.0 equiv.) in EtOH (1.25 mL) was added glacial acetic acid (0.008 mL, 0.145 mmol, 0.2 equiv.) and cyclopropylamine (CAS: 765-30-0, 0.21mL, 2.91 mmol, 4.0 equiv.) the mixture was stirred at reflux for 90 min. UPLC showed no complete conversion, cyclopropylamine (CAS: 765-30-0, 0.21mL, 2.91 mmol, 4.0 equiv.) was added and the mixture was stirred at reflux for 90 min. The mixture was allowed to cool down to RT. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The previous residue (0.24 g, 0.61 mmol, 1.0 equiv.) and 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 226 mg, 1.21 mmol, 2 equiv.) were dissolved in DMSO (1 mL). The mixture was stirred at 50°C for 25 min. To the previous solution was added 2 N aqueous NaOH (0.65 mL, 1.21 mmol, 2.0 equiv.) and the mixture was stirred at 120°C for 30 min. The mixture was allowed to cool down to RT and 2 N aqueous HCl was added (0.65 mL, 1.2 mmol, 2.0 equiv.). A precipitate was formed and filtered. The precipitate was purified by preparative HPLC (acid method) to afford the title product.

[0752] Molecular weight: 492.0 ; LCMS, molecular weight observed: 490.3-492.2

[0753] 1H NMR (400 MHz, Chloroform-d) d 14.19 (s, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.04 (s, 1H), 4.53 (dd, J = 13.9, 6.3 Hz, 2H), 4.30– 4.25 (m, 1H), 4.25– 4.20 (m, 1H), 4.20– 4.14 (m, 2H), 4.11 (s, 1H), 3.62 (t, J = 5.9 Hz, 2H), 3.50– 3.41 (m, 1H), 3.38 (s, 3H), 2.21– 2.09 (m, 2H), 1.46– 1.31 (m, 1H), 1.14 (s, 3H), 1.12– 1.00 (m, 1H), 0.63– 0.52 (m, 1H), 0.35– 0.23 (m, 1H).

Synthesis of Cpd_112: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxeta n-3-yl)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0754] To a mixture of 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxeta n-3-yl)-2-oxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid (0.087 g, 0.17 mmol, 1.0 equiv.) in glacial acetic acid (0.20 mL, 3.49 mmol, 20.9 equiv.), was added 30 %/w. aqueous H2O2 (0.10 mL, 1.06 mmol, 6.4 equiv.) the mixture was stirred at 100°C for 1 h . The mixture was allowed to cool down to RT and water and EtOAc were added. The aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by preparative HPLC (acid method) to afford the title product.

[0755] Molecular weight: 524.0 ; LCMS, molecular weight observed: 524.3-526.1

[0756] 1H NMR (400 MHz, Chloroform-d) d 13.79 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 5.05 (d, J =6.9 Hz, 1H), 4.79 (d, J = 6.3 Hz, 1H), 4.57 (s, 1H), 4.42–4.30 (m, 4H), 4.23–4.19 (m, 1H), 3.62 (t, J =5.9 Hz, 3H), 3.55–3.45 (m, 1H), 3.39 (s, 3H), 2.25–2.15 (m, 3H), 1.43–1.36 (m, 1H), 1.33–1.29 (m,1H), 0.72–0.65 (m, 1H), 0.49–0.44 (m, 1H).1H), 0.72–0.65 (m, 1H), 0.49–0.44 (m, 1H).

Int.100: 3-(3-hydroxyphenyl)sulfanylbutanoic acid

[0757] 3-sulfanylphenol (CAS: 40248-84-8, 2.4 g, 19.0 mmol, 1.0 equiv.) was dissolved in DMF (20 mL) and then crotonic acid (CAS: 107-93-7, 1.6 g, 19.0 mmol, 1.0 equiv.) and tetrabutylammonium fluoride trihydrate (CAS: 87749-50-6, 1.2 g, 3.8 mmol, 0.20 equiv.) were added. The mixture was degassed by argon bubbling for 10 min, and then stirred at 50°C for 18 h. The mixture was allowed to cool to RT and was partitioned between EtOAc and water. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated to afford the title product.

[0758] Molecular weight: 212.3 ; LCMS, molecular weight observed: 211.0 (MS-)_no MS+ m/z Int.099: 2-methyl-7-hydroxy-thiochroman-4-one

[0759] 3-(3-Hydroxyphenyl)sulfanylbutanoic acid (4.0 g, 19.0 mmol, 1.0 equiv.) was cooled to 0°C, thenH2SO4 (20 mL) was added dropwise at 0°C. The mixture was allowed to warm up to RT and stirred for 30 min. The reaction mixture was poured dropwise into ice-water. The aqueous layer was extracted with EtOAc. The organic layer was washed (sodium bicarbonate solution, water and brine), dried (Na2SO4) and concentrated to afford the title product.

[0760] Molecular weight: 194.3 ; LCMS, molecular weight observed: 195.1 (MS+)

Int.098: 2-methyl-7-(3-methoxypropoxy)thiochroman-4-one

[0761] 2-Methyl-7-hydroxy-thiochroman-4-one (1.85 g, 9.5 mmol, 1.0 equiv.) was dissolved in DMF (25 mL) and then 1-bromo-3-methoxypropane (CAS: 36865-41-5, 1.53 g, 10.0 mmol, 1.05 equiv.) and K2CO3 (CAS: 584-08-7, 1.45 g, 10.5 mmol, 1.1 equiv.) were added. The mixture was stirred at 50°C for 18 h. The mixture was allowed to cool to RT and was partitioned between EtOAc and water. The organic layer was washed (sodium bicarbonate solution, water and brine), dried (Na2SO4) and concentrated to afford the title product.

[0762] Molecular weight: 266.4 ; LCMS, molecular weight observed: 267.1.0 (MS+)

Int.103 & Int.097: 6-bromo-2-methyl-7-(3-methoxypropoxy)thiochroman-4-one and 8-bromo-2-methyl- 7-(3-methoxypropoxy)thiochroman-4-one

[0763] 2-Methyl-7-(3-methoxypropoxy)thiochroman-4-one (1.6 g, 6.2 mmol, 1.0 equiv.) was dissolved in ACN (50 mL) and the mixture was cooled to -10°C. N-Bromosuccinimide (CAS: 128-08-5, 1.1 g, 6.2 mmol, 1.0 equiv.) was added and the mixture was stirred at -10°C for 2 h. The mixture was allowed to warm to RT and was stirred for 18 h. The solvent was removed in vacuo. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to afford the title product.

[0764] Int.103 , First eluting compound: Molecular weight: 345.3 ; LCMS, molecular weight observed: 344.9/346.9 (MS+)

[0765] Int.097 , Second eluting compound: Molecular weight: 345.3; LCMS, molecular weight observed: 344.8/346.9 (MS+) Int.096: 6-Bromo-2-methyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one

[0766] 6-Bromo-2-methyl-7-(3-methoxypropoxy)thiochroman-4-one (1.5 g, 4.34 mmol, 1.0 equiv.) in DCM (50 mL) was cooled to 0°C, then MCPBA (CAS: 937-14-4, 2.9 g, 13.0 mmol, 3.0 equiv.) was added. The mixture was allowed to warm up to RT and stirred for 18 h. The mixture was poured into 10% aqueous sodium metabisulfite and the resulting mixture was stirred at RT for 15 min. The organic layer was washed (sodium bicarbonate solution and brine), dried (Na2SO4) and concentrated to afford the title product.

[0767] Molecular weight: 377.3 ; LCMS, molecular weight observed: LCMS: 377.0/378.9

Synthesis of Cpd_032: 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0768] 6-Bromo-2-methyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one (95 mg, 0.25 mmol, 1.0 equiv.) was dissolved in 1,2-dichloroethane (3.0 mL) under argon then titanium (IV) isopropoxide (CAS: 546-68-9, 0.15 mL, 0.50 mmol, 2.0 equiv.) and cyclopropylamine (CAS: 765-30-0, 29 mg, 0.50 mmol, 2.0 equiv.) were added. The mixture was stirred at 60°C for 18 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and a solution of NaOH 1N was added and stirred vigorously for 10 min. The biphasic solvent was filtered through Celite ® and separated. The organic layer was dried (Na2SO4) and concentrated. This residue and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane- 4,6-dione (CAS: 15568-85-1, 101 mg, 0.54 mmol, 3.0 equiv.) were dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 6 h under microwave irradiations. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was dissolved in THF (2.0 mL) and a 1N solution of NaOH (0.45 mL, 2.5 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0769] Molecular weight: 512.4 ; LCMS, molecular weight observed: 512.2/514.2

[0770] NMR: 1H NMR (400 MHz, DMSO-d ₆ ) d 14.24 (s, 1H), 8.55 (s, 1H), 8.42-8.37 (m, 1H), 7.56 (s, 1H), 4.87-4.81 (m, 1H), 4.37 (ddd, 2H), 3.84-3.79 (m, 1H), 3.54 (t, 2H), 3.27 (s, 3H), 2.04 (t, 2H), 1.36- 1.15 (m, 4H), 0.98-0.90 (m, 1H), 0.63-0.52 (m, 1H), 0.22-0.10 (m, 1H) Int.102: 8-Bromo-2-methyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one

[0771] 8-Bromo-2-methyl-7-(3-methoxypropoxy)thiochroman-4-one (103 mg, 0.30 mmol, 1.0 equiv.) in DCM (5.0 mL) was cooled to 0°C, then MCPBA (CAS: 937-14-4, 201 mg, 0.89 mmol, 3.0 equiv.) was added. The mixture was allowed to warm up to RT and stirred for 1 h. The mixture was poured into 10% aqueous sodium metabisulfite and the resulting mixture was stirred at RT for 15 min. The organic layer was washed (sodium bicarbonate solution and brine), dried (Na2SO4) and concentrated to afford the title product.

[0772] Molecular weight: 377.3 ; LCMS, molecular weight observed: LCMS: 377.0/378.9

Synthesis of Cpd_040: 7-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0773] 8-Bromo-2-methyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrot hiochromen-4-one (107 mg, 0.28 mmol, 1.0 equiv.) was dissolved in DCM (2.0 mL) under argon then titanium (IV) isopropoxide (CAS: 546-68-9, 0.24 mL, 0.79 mmol, 2.8 equiv.) and cyclopropylamine (CAS: 765-30-0, 65 mg, 1.13 mmol, 4.0 equiv.) were added. The mixture was stirred in at 50°C for 18 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and a solution of NaOH 1N was added and stirred vigorously for 10 min. The biphasic solvent was filtered through Celite ® and separated. The organic layer was dried (Na2SO4) and concentrated. This residue and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 158 mg, 0.85 mmol, 3.0 equiv.) were dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 6 h under microwave irradiations. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was dissolved in THF (5.0 mL) and a 1N solution of NaOH (0.71 mL, 2.5 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0774] Molecular weight: 512.4 ; LCMS, molecular weight observed: 512.2/514.1

[0775] 1H NMR (400 MHz, DMSO-d ₆ ) d 8.32 (s, 1H), 8.20 (d, 1H), 7.51 (d, 1H), 4.79 (q, 1H), 4.30 (ddt, 2H), 3.63 (ddd, 1H), 3.55 (dd, 2H), 3.27 (s, 3H), 2.08-2.01 (m, 2H), 1.43-1.34 (m, 3H), 1.15-1.04 (m, 1H), 0.91-0.80 (m, 1H), 0.60-0.36 (m, 1H), 0.21-0.00 (m, 1H) Int.104: isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0776] 9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylic acid (2.7 g, 5.25 mmol, 1.0 equiv.) was dissolved in DCM (50.0 mL) and the mixture was cooled to 0°C. Oxalyl chloride (CAS: 79-37-8, 0.54 mL, 6.3 mmol, 1.2 eq.) and then DMF (0.2 mL, 2.6 mmol, 0.5 eq.) were added. The mixture was stirred at RT for 30 min and was concentrated. The residue was dissolved in isopropyl alcohol (20.0 mL). The resulting solution was poured into a solution of TEA (CAS: 121-44-8, 1.5 mL, 2.0 equiv.) in isopropyl alcohol (10.0 mL). The mixture was stirred at RT for 18 h. The solvent was removed in vacuo. The residue was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (sodium bicarbonate solution, water and brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with DCM/MeOH 100:00 to 95:5) to afford the title product.

[0777] Molecular weight: 512.4 ; LCMS, molecular weight observed: 554.1/556.0

Synthesis of Cpd_055: 1,9-dicyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo -5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0778] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equiv.) was dissolved in dioxane (3.0 mL) and cyclopropylboronic acid (CAS: 411235-57-9, 23 mg, 0.27 mmol, 1.5 equiv.), potassium phosphate tribasic (CAS: 7778-53-2, 115 mg, 0.54 mmol, 3.0 equiv.) and [1,1¢- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 6.6 mg, 0.01 mmol, 0.05 equiv.) were added. The mixture was degassed and stirred at 90°C for 4 h. The mixture was cooled to RT and filtered through Celite ®. The filtrate was washed (brine), dried (Na2SO4) and concentrated. The residue was dissolved in THF (2.0 mL) and a 1N solution of NaOH (1.0 mL, 5.5 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0779] Molecular weight: 473.5 ; LCMS, molecular weight observed: 474.2 [0780] 1H NMR (400 MHz, DMSO-d6) d 14.20 (s, 1H), 8.32 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 4.76-4.68 (m, 1H), 4.31-4.26 (m, 2H), 3.77-3.70 (m, 1H), 3.54 (t, 2H), 3.27 (s, 3H), 2.31-2.23 (m, 1H), 2.09-2.02 (m, 2H), 1.33-1.22 (m, 3H), 1.19-1.11 (m, 1H), 1.09-1.01 (m, 2H), 0.96-0.90 (m, 1H), 0.85-0.78 (m, 2H), 0.57- 0.46 (m, 1H), 0.16-0.08 (m, 1H).

Int.106: Isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-p henyl-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0781] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) was dissolved in dimethoxyethane (3.0 mL) and phenylboronic acid pinacol ester (CAS: 24388-23-6, 37 mg, 0.18 mmol, 2.0 equiv.), and [1,1¢-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 3.3 mg, 0.005 mmol, 0.05 equiv.) were added. A solution of Cs2CO3 (CAS: 534-17-8, 65 mg, 0.20 mmol, 2.2 equiv.) in water (0.5 mL) was added. The mixture was degassed and stirred at 100°C for 1 h. The mixture was cooled to RT, diluted with DCM and filtered through Celite ®. The filtrate was washed (water and brine), dried (Na2SO4) and concentrated to afford the title product.

[0782] Molecular weight: 551.7 ; LCMS, molecular weight observed: 552.3

Synthesis of Cpd_056: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-p henyl-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0783] Isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-p henyl-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (65 mg, 0.12 mmol, 1.0 equiv.) was dissolved in THF (3.0 mL) and a 1N solution of NaOH (2.0 mL) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0784] Molecular weight: 509.6 ; LCMS, molecular weight observed: 510.2

[0785] 1H NMR (400 MHz, DMSO-d6) d 14.16 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.64-7.58 (m, 3H), 7.50- 7.41 (m, 3H), 4.81-4.76 (m, 1H), 4.29 (t, 2H), 3.80-3.73 (m, 1H), 3.42 (t, 2H), 3.23 (s, 3H), 1.95 (tt, 2H), 1.38-1.29 (m, 3H), 1.25-1.16 (m, 1H), 1.05-0.95 (m, 1H), 0.62-0.49 (m, 1H), 0.28-0.16 (m, 1H). Synthesis of Cpd_057: 9-cyano-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0786] 9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equiv.) was dissolved in DMF (3.0 mL) and zinc cyanide (CAS: 557-21-1, 21 mg, 0.18 mmol, 1.0 equiv.), zinc powder (CAS: 7440-66-6, 1.3 mg, 0.02 mmol, 0.11 equiv.), 1,1¢-ferrocenediyl-bis(diphenylphosphine (CAS: 12150-46-8, 11 mg, 0.02 mmol, 0.11 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 9.0 mg, 0.01 mmol, 0.05 equiv.) were added. The mixture was degassed and stirred at 100°C for 5 h. The mixture was cooled to RT and filtered through Celite ®. The filtrate was concentrated. The residue was dissolved in THF (3.0 mL) and a 1N solution of NaOH (1.0 mL, 5.5 equiv.) was added. The mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0787] Molecular weight: 458.5 ; LCMS, molecular weight observed: 459.2

[0788] 1H NMR (400 MHz, DMSO-d ₆ ) d 14.11 (s, 1H), 8.72 (s, 1H), 8.35 (s, 1H), 7.72 (s, 1H), 4.94-4.89 (m, 1H), 4.49-4.44 (m, 2H), 3.90-3.83 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.06 (tt, 2H), 1.37-1.27 (m, 3H), 1.25-1.19 (m, 1H), 1.03-0.93 (m, 1H), 0.63-0.51 (m, 1H), 0.18-0.05 (m, 1H).

Synthesis of Cpd_058: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-t hiazol-4-yl-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0789] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) and copper (I) iodide (CAS: 7681-65-4, 3.4 mg, 0.02 mmol, 0.2 equiv.) were dissolved in dioxane (0.6 mL), tetrakis(triphenylphospine)palladium(0) (CAS: 14221-01-3, 10 mg, 0.01 mmol 0.1 equiv.) and 4-(tri-n- butylstannyl)thiazole (CAS: 173979-01-6, 57 µL, 0.18 mmol, 2.0 equiv.) were added. The mixture was degassed and stirred at 100°C for 24 h. The mixture was cooled to RT, diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.9 mL, 0.9 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FLC (SiO2, column eluted with DCM/[10:1, MeOH:AcOH] 100:00 to 96:04) to afford the title product.

[0790] Molecular weight: 516.6 ; LCMS, molecular weight observed: 517.2

[0791] ¹H-NMR (400 MHz, DMSO-d6) d 14.36 (s, 1H), 9.26 (d, 1H), 9.04 (s, 1H), 8.45 (d, 1H), 8.44 (s, 1H), 7.67 (s, 1H), 4.84 (q, 1H), 4.46 (t, 2H), 3.60-3.54 (m, 3H), 3.28 (s, 3H), 2.18 (tt, 2H), 1.34 (d, 3H), 1.24 (s, 1H), 0.91 (s, 1H), 0.64 (s, 1H), 0.22 (s, 1H).

Int.109: isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-v inyl-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0792] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equiv.) was dissolved in dimethoxyethane (4.0 mL) and vinylboronic acid pinacol ester (CAS: 75927-49-0, 56 mg, 0.36 mmol, 2.0 equiv.) and [1,1¢-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 6.6 mg, 0.01 mmol, 0.05 equiv.) were added. A solution of Cs2CO3 (CAS:534-17-8, 129 mg, 0.40 mmol, 2.2 equiv.) in water (0.7 mL) was added. The mixture was degassed and stirred at 100°C for 1 h. The mixture was cooled to RT, diluted with DCM and filtered through Celite ®. The filtrate was washed (water and brine), dried (Na2SO4) and concentrated to afford the title product.

[0793] Molecular weight: 501.6 ; LCMS, molecular weight observed: 502.2

Synthesis of Cpd_074: 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0794] Isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-v inyl-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (175 mg, 0.35 mmol, 1 equiv.) was dissolved in EtOH (5.0 mL). Palladium on activated charcoal (CAS: 7440-05-3, 10 wt. % loading , 17.5 mg, 0.05 equiv.) was added and the mixture was degassed. The mixture was stirred at RT under a hydrogen atmosphere for 18 h and filtered through Celite ®. The filtrate was concentrated and the residue was dissolved in THF (3.0 mL). A 1N solution of NaOH (0.5 mL, 0.5 mmol, 1.4 equiv.) was added and the mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0795] Molecular weight: 501.6 ; LCMS, molecular weight observed: 462.2

[0796] 1H NMR (400 MHz, DMSO-d6) d 14.29 (s, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 7.45 (s, 1H), 4.80-4.74 (m, 1H), 4.30-4.24 (m, 2H), 3.88-3.81 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.82-2.64 (m, 2H), 2.04 (dd, 2H), 1.33-1.24 (m, 3H), 1.23-1.15 (m, 4H), 0.95-0.85 (m, 1H), 0.61-0.54 (m, 1H), 0.21-0.12 (m, 1H).

Synthesis of 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

[0797] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (CAS: 13965-03-2, 13 mg, 0.02 mmol, 0.2 equiv.) were dissolved in dioxane (0.6 mL) and 2-(tri-n-butylstannyl)thiophene (CAS: 54663-78-4, 57 µL, 0.18 mmol, 2.0 equiv.) was added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with MeOH and filtered through Celite ®. The filtrate was concentrated and the residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH 100:00 to 96:04). The relevant fractions were combined and concentrated. The residue was dissolved in THF (0.5 mL) and a 1N solution of NaOH (0.5 mL, 0.50 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was concentrated and the residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0798] Molecular weight: 515.6 ; LCMS, molecular weight observed: 516.2

[0799] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 14.26 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 7.95 (dd, 1H), 7.78 (dd, 1H), 7.61 (s, 1H), 7.21 (dd, 1H), 4.83-4.78 (m, 1H), 4.43 (t, 2H), 3.91-3.87 (m, 1H), 3.61 (t, 2H), 3.28 (3H, s), 2.19-2.12 (tt, 2H), 1.31 (s, 3H), 1.25-1.19 (m, 1H), 0.89 (s, 1H), 0.60 (s, 1H), 0.19 (s, 1H).

Synthesis of 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

[0800] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (CAS: 13965-03-2, 13 mg, 0.02 mmol, 0.2 equiv.) were dissolved in dioxane (0.5 mL) and 2-(tri-n-butylstannyl)oxazole (CAS: 145214-05-7, 57 µL, 0.18 mmol, 2.0 equiv.) was added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (1.0 mL, 0.98 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was acidified to pH 1 with a 1N solution of HCl, loaded onto an acid capture cartridge and washed (ACN and 1.25M HCl in MeOH). The relevant fraction was concentrated and the residue was purified by FLC (SiO2, column eluted with DCM/[10:1, MeOH:AcOH] 100:00 to 95:05). The relevant fractions were combined and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0801] Molecular weight: 500.5 ; LCMS, molecular weight observed: 501.2

[0802] ¹H-NMR (400 MHz, DMSO-d6) d 8.64 (s, 1H), 8.35 (d, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.49 (d, 1H), 4.77 (q, 1H), 4.40 (t, 2H), 3.59-3.53 (m, 3H), 3.26 (s, 3H), 2.04 (2H, tt), 1.32 (3H, d), 1.20 (1H, s), 0.93 (1H, s), 0.52 (1H, s), 0.17 (1H, s).

Synthesis of Cpd_089: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-t hiazol-2-yl-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0803] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (CAS: 13965-03-2, 13 mg, 0.02 mmol, 0.2 equiv.) were dissolved in dioxane (0.5 mL) and 2-(tri-n-butylstannyl)thiazole (CAS: 121359-48-6, 43 µL, 0.14 mmol, 1.5 equiv.) was added. The mixture was degassed and stirred at 110°C for 4 h. The mixture was cooled to RT, diluted with MeOH, filtered through Celite ® and concentrated. The residue was purified by FLC (SiO2, column eluted with DCM/MeOH 100:00 to 96:04). The relevant fractions were combined and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.2 mL, 0.20 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was acidified to pH 1 with a 1N solution of HCl, loaded onto an acid capture cartridge and washed (ACN followed by 1.25M HCl in MeOH). The relevant fraction was concentrated and the residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0804] Molecular weight: 516.6 ; LCMS, molecular weight observed: 517.2

[0805] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 9.05 (s, 1H), 8.08 (d, 1H), 8.05 (s, 1H), 8.01 (d, 1H), 7.71 (s, 1H), 4.75 (q, 1H), 4.55 (t, 2H), 3.64 (t, 2H), 3.47 (s, 1H), 3.29 (s, 3H), 2.21 (tt, 2H), 1.30 (d, 3H), 1.19 (s, 1H), 0.88 (s, 1H), 0.51 (s, 1H), 0.18 (s, 1H). Synthesis of 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

[0806] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) and copper (I) iodide (CAS: 7681-65-4, 3.4 mg, 0.02 mmol, 0.2 equiv.) were dissolved in dioxane (0.6 mL) and tetrakis(triphenylphospine)palladium(0) (CAS: 14221-01-3, 10 mg, 0.01 mmol 0.1 equiv.) and 2-(tri-n- butylstannyl)furan (CAS: 118486-94-5, 59 µL, 0.18 mmol, 2.0 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.9 mL, 0.91 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0807] Molecular weight: 499.5 ; LCMS, molecular weight observed: 500.2

[0808] ¹H-NMR (400 MHz, DMSO-d6) d 14.20 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.89 (d, 1H), 7.61 (s, 1H), 7.22 (d, 1H), 6.72 (dd, 1H), 4.81 (q, 1H), 4.43 (t, 2H), 3.71-3.65 (m, 1H), 3.57 (t, 2H), 3.28 (s, 3H), 2.20-2.12 (tt, 2H), 1.30 (s, 3H), 1.23 (s, 1H), 0.93 (s, 1H), 0.61 (s, 1H), 0.20 (s, 1H).

Synthesis of Cpd_091: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-th ienyl)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0809] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equiv.), K ₂ CO ₃ (CAS: 584-08-7, 45 mg, 0.33 mmol, 3.0 equiv.), XPhos (CAS: 564483-18-7, 3.1 mg, 0.006 mmol, 0.06 equiv.), 5- methylthiophene-2-boronic acid pinacol ester (CAS: 476004-80-5, 129 µL, 0.54 mmol, 5.0 equiv.) and XPhos Pd G2 (CAS: 1310584-14-5, 2.6 mg, 0.003 mmol, 0.003 equiv.) were dissolved in EtOH (0.6 mL). The mixture was degassed and stirred at 80°C for 18 h. K ₂ CO ₃ (CAS: 584-08-7, 105 mg, 0.76 mmol, 7.0 equiv.) and XPhos (CAS: 564483-18-7, 5.2 mg, 0.011 mmol, 0.1 equiv.) and XPhos Pd G2 (CAS: 1310584- 14-5, 4.3 mg, 0.005 mmol, 0.005 equiv.) were added. The mixture was degassed and stirred at 80°C for 18 h. The mixture was cooled to RT, diluted with EtOAc and filtered through Celite ®. The filtrate was concentrated and partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0810] Molecular weight: 529.6 ; LCMS, molecular weight observed: 530.2

[0811] ¹H-NMR (400 MHz, DMSO-d6) d 14.34 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 7.75 (d, 1H), 7.58 (s, 1H), 6.91 (dd, 1H), 4.81-4.77 (m, 1H), 4.41 (t, 2H), 3.91-3.84 (m, 1H), 3.60 (t, 2H), 3.28 (s, 3H), 2.15 (tt, 2H), 1.31 (s, 3H), 1.20 (s, 1H), 0.91 (s, 1H), 0.58 (s, 1H), 0.19 (s, 1H).3H under DMSO peak.

Int.117: isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-( 2-oxopyrrolidin-1-yl)- 5H-thiochromeno[4,3-b]pyridine-3-carboxylate

[0812] 9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylate (75 mg, 0.13 mmol, 1.0 equiv.) was dissolved in dioxane (3.0 mL) and 2- pyrrolidinone (CAS: 616-45-5, 14 mg, 0.16 mmol, 1.2 equiv.), Xantphos (CAS: 161265-03-8, 7.8 mg, 0.01 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 6.2 mg, 0.01 mmol, 0.05 equiv.) and Cs ₂ CO ₃ (CAS: 534-17-8, 66 mg, 0.20 mmol, 1.5 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with DCM and filtered through Celite ®. The filtrate was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated to afford the title product.

[0813] Molecular weight: 558.6 ; LCMS, molecular weight observed: 559.2

Synthesis of 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

[0814] Isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxo-9-( 2-oxopyrrolidin-1-yl)- 5H-thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equiv.) was dissolved in THF (3.0 mL) and a 1N solution of NaOH (1.0 mL, 1.0 mmol, 5.5 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product. [0815] Molecular weight: 516.6 ; LCMS, molecular weight observed: 517.2

[0816] 1H NMR (400 MHz, DMSO-d6) 14.23 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.60 (s, 1H), 4.84-4.78 (m, 1H), 4.30 (t, 2H), 3.89-3.82 (m, 1H), 3.73-3.62 (m, 2H), 3.49 (t, 2H), 3.26 (s, 3H), 2.43 (dd, 2H), 2.12 (tt, 2H), 2.02 (tt, 2H), 1.37-1.27 (m, 3H), 1.25-1.19 (m, 1H), 1.14-1.05 (m, 1H), 0.63-0.52 (m, 1H), 0.23- 0.13 (m, 1H).

Int.118: isopropyl 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropo xy)-5-methyl-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate

[0817] 9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) was dissolved in dioxane (3.0 mL) and tert-butyl carbamate (CAS: 4248-19-5, 13 mg, 0.11 mmol, 1.2 equiv.), Xantphos (CAS: 161265-03-8, 1.6 mg, 0.003 mmol, 0.03 equiv.), tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 0.8 mg, 0.001 mmol, 0.01 equiv.) and Cs2CO3 (CAS: 534-17-8, 44 mg, 0.13 mmol, 1.5 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT and filtered through Celite ®. The filtrate was concentrated to afford the title product.

[0818] Molecular weight: 590.7 ; LCMS, molecular weight observed: 591.3

Synthesis of Cpd_097: 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropo xy)-5-methyl- 2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0819] Isopropyl 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropo xy)-5-methyl-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (82 mg, mmol, 1 equiv.) was dissolved in THF (3.0 mL). A 1N solution of NaOH (1.0 mL, 1.0 mmol) was added and the mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0820] Molecular weight: 548.6 ; LCMS, molecular weight observed: 549.3

[0821] 1H NMR (400 MHz, DMSO-d6) d 14.24 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.28-8.22 (m, 1H), 7.48 (s, 1H), 4.73-4.67 (m, 1H), 4.33-4.25 (m, 2H), 3.53 (t, 2H), 3.50-3.45 (m, 1H), 3.28 (s, 3H), 2.06 (tt, 2H), 1.49 (s, 9H), 1.30-1.21 (m, 4H), 1.01-0.93 (m, 1H), 0.62-0.52 (m, 1H), 0.24-0.14 (m, 1H). Synthesis of Cpd_098: 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0822] Isopropyl 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (80 mg, 0.15 mmol, 1.0 equiv.) was dissolved in THF (3.0 mL) and a 1N solution of NaOH (1.0 mL, 1.0 mmol, 6.7 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organics layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0823] Molecular weight: 448.5 ; LCMS, molecular weight observed: 449.2

[0824] NMR: 1H NMR (400 MHz, DMSO-d ₆ ) d 14.34 (s, 1H), 8.39 (s, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 5.86 (s, 2H), 4.59 (dd, 1H), 4.24-4.15 (m, 2H), 3.55 (m, 3H), 3.27 (s, 3H), 2.02 (tt, 2H), 1.30-1.19 (m, 4H), 1.00-0.92 (m, 1H), 0.66-0.56 (m, 1H), 0.27-0.20 (m, 1H).

Synthesis of 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

[0825] 9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylate (75 mg, 0.13 mmol, 1.0 equiv.) was dissolved in dioxane (3.0 mL) and 2- azetidinone (CAS: 930-21-2, 12 mg, 0.16 mmol, 1.2 equiv.), Xantphos (CAS: 161265-03-8, 7.8 mg, 0.01 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 6.2 mg, 0.01 mmol, 0.05 equiv.) and Cs2CO3 (CAS: 534-17-8, 66 mg, 0.20 mmol, 1.5 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT and filtered through Celite ®. The filtrate was concentrated. The residue was dissolved in THF (3.0 mL) and a 1N solution of NaOH (1.0 mL, 1.0 mmol) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0826] Molecular weight: 520.6 ; LCMS, molecular weight observed: 521.3

[0827] NMR: 1H NMR (400 MHz, DMSO-d ₆ ) d 14.35 (s, 1H), 12.48 (s, 1H), 8.42 (s, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.07 (t, 1H), 4.64-4.58 (m, 1H), 4.25-4.18 (m, 2H), 3.87-3.81 (m, 1H), 3.54 (t, 2H), 3.48 (t, 2H), 3.27 (s, 3H), 2.54-2.49 (m, 2H), 2.03 (tt, 2H), 1.29-1.16 (m, 4H), 1.00-0.92 (m, 1H), 0.65-0.53 (m, 1H), 0.28-0.19 (m, 1H).

Synthesis of Cpd_105: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methylthiaz ol-2-yl)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0828] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) and copper (I) iodide (CAS: 7681-65-4, 3.4 mg, 0.02 mmol, 0.2 equiv.) were dissolved in dioxane (0.6 mL) and tetrakis(triphenylphospine)palladium(0) (CAS: 14221-01-3, 10 mg, 0.01 mmol 0.1 equiv.) and 5-methyl- 2-(tri-n-butylstannyl)thiazole (CAS: 848613-91-2, 65 µL, 0.18 mmol, 2.0 equiv.) were added. The mixture was degassed and stirred at 100°C for 24 h. The mixture was cooled to RT, diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.9 mL, 0.9 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. he residue was purified by FLC (SiO ₂ , column eluted with DCM/[10:1, MeOH:AcOH] 100:00 to 96:04). The relevant fractions were combined and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0829] Molecular weight: 530.6 ; LCMS, molecular weight observed: 531.2

[0830] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 8.88 (s, 1H), 7.75 (d, 1H), 7.65 (s, 2H), 4.61 (q, 1H), 4.50 (t, 2H), 3.62 (t, 2H), 3.49-3.49 (m, 1H), 3.29 (s, 3H), 2.54 (d, 3H), 2.19 (tt, 2H), 1.26 (d, 3H), 1.14 (s, 1H), 0.83 (s, 1H), 0.39 (s, 1H), 0.14 (s, 1H).

Synthesis of compound Cpd_106: 9-cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6 ,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0831] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equiv.), potassium phosphate tribasic (CAS: 7778-53-2, 74 mg, 0.35 mmol, 3.2 equiv.), cyclobutylboronic acid (CAS: 849052-26-2, 114 mg, 1.08 mmol, 10 equiv.), palladium(II) acetate (CAS: 3375-31-3, 9.7 mg, 0.04 mmol, 0.4 equiv.) and RuPhos (CAS: 787618-22-8, 40 mg, 0.09 mmol, 0.8 equiv.) were dissolved in toluene (0.9 mL) and water (0.2 mL). The mixture was degassed and stirred at 100°C for 1 h under microwave irradiations. The mixture was cooled to RT, diluted with MeOH and filtered through Celite ®. The filtrate was concentrated and the residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 00:100). The relevant fractions were combined and concentrated. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and a 1N solution of NaOH (0.9 mL, 0.90 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated to afford the title product.

[0832] Molecular weight: 487.6 ; LCMS, molecular weight observed: 488.2

[0833] ¹H-NMR (400 MHz, DMSO-d6) d 14.41 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.42 (s, 1H), 4.79 (q, 1H), 4.24 (dt, 2H), 3.86-3.80 (m, 1H), 3.80-3.71 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.37-2.09 (m, 4H), 2.06-1.98 (m, 3H), 1.85-1.77 (m, 1H), 1.28 (s, 3H), 1.21 (s, 1H), 0.94 (s, 1H), 0.58 (s, 1H), 0.17 (s, 1H). Int.123: isopropyl 1-cyclopropyl-9-isopropenyl-8-(3-methoxypropoxy)-5-methyl-2, 6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0834] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equiv.), Cs2CO3 (CAS: 534-17-8, 129 mg, 0.40 mmol, 2.2 equiv.) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II ) (CAS: 95464-05-4, 6.6 mg, 0.009 mmol, 0.05 equiv.) were dissolved in dimethoxyethane (1.5 mL) and water (0.3 mL) and isopropenylboronic acid pinacol ester (CAS: 126726-62-3, 72 µL, 0.36 mmol, 2.0 equiv.) was added. The mixture was degassed and stirred at 100°C for 1 h under microwave irradiation. The mixture was cooled to RT and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated to afford the title product.

[0835] Molecular weight: 515.6 ; LCMS, molecular weight observed: 516.2

Synthesis of compound Cpd_107: 1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-5-methyl-2,6, 6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0836] Isopropyl 1-cyclopropyl-9-isopropenyl-8-(3-methoxypropoxy)-5-methyl-2, 6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (60 mg, 0.116 mmol, 1.0 equiv.) was dissolved in EtOH (1.2 mL). Palladium on activated charcoal (CAS: 7440-05-3, 10 wt. % loading, 20 mg, 0.16 equiv.) was added and the mixture was degassed. The mixture was stirred at RT under a hydrogen atmosphere for 18 h. Palladium on activated charcoal (CAS: 7440-05-3, 10 wt. % loading, 20 mg, 0.16 equiv.) was added and the mixture was degassed. The mixture was stirred at RT under a hydrogen atmosphere for 72 h. The mixture was diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and a 1N solution of NaOH (1.16 mL, 1.16 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0837] Molecular weight: 475.6 ; LCMS, molecular weight observed: 476.3

[0838] ¹H-NMR (400 MHz, DMSO-d6) d 14.24 (s, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 7.45 (s, 1H), 4.74 (q, 1H), 4.26 (t, 2H), 3.81-3.75 (m, 1H), 3.54 (t, 2H), 3.39 (m, 1H), 3.27 (s, 3H), 2.05 (2H, tt), 1.27 (3H, s), 1.26-1.21 (7H, m), 0.89 (1H, s), 0.52 (1H, s), 0.16 (1H, s).

Int.137: isopropyl 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0839] 9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylate (200 mg, 0.36 mmol, 1.0 equiv.) was dissolved in dioxane (5.0 mL) and acetamide (CAS: 60-35-5, 32 mg, 0.54 mmol, 1.5 equiv.), Xantphos (CAS: 161265-03-8, 21 mg, 0.04 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 17 mg, 0.02 mmol, 0.05 equiv.) and Cs2CO3 (CAS: 534-17-8, 176 mg, 0.54 mmol, 1.5 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with EtOAc and filtered through Celite ®. The filtrate was washed (water and brine), dried (Na2SO4) and concentrated to afford the title product.

[0840] Molecular weight: 532.6 ; LCMS, molecular weight observed: 533.2 Synthesis of Cpd_108: 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0841] 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6, 6-trioxo-5H-thiochromeno[4,3- b]pyridine-3-carboxylate (100 mg, 0.19 mmol, 1.0 equiv.) was dissolved in THF (4.0 mL) and a 1N solution of NaOH (2.0 mL, 2.0 mmol, 10.5 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0842] Molecular weight: 490.5 ; LCMS, molecular weight observed: 491.2

[0843] NMR: 1H NMR (400 MHz, DMSO-d6) d 14.29 (s, 1H), 9.49 (s, 1H), 8.86 (s, 1H), 8.21-8.12 (m, 1H), 7.51 (s, 1H), 4.71-4.65 (m, 1H), 4.32 (t, 2H), 3.55 (t, 2H), 3.47-3.42 (m, 1H), 3.28 (s, 3H), 2.18 (s, 3H), 2.08 (tt, 2H), 1.32-1.18 (m, 4H), 1.00-0.93 (m, 1H), 0.59-0.50 (m, 1H), 0.22-0.14 (m, 1H).

Int.119: isopropyl 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0844] Isopropyl 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropo xy)-5-methyl-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylate (120 mg, 0.20 mmol, 1 equiv.) was dissolved in DCM (3.0 mL). TFA (3.0 mL) was added and the mixture was stirred at RT for 2 h. The mixture was concentrated to afford the title product.

[0845] Molecular weight: 490.6 ; LCMS, molecular weight observed: 492.3

Synthesis of Cpd_109: 1-cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-5 -methyl-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0846] Isopropyl 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (170 mg, 0.28 mmol, 1 equiv.) was dissolved in THF (5.0 mL). K2CO3 (CAS: 584-08-7, 117 mg, 0.84 mmol, 3.0 equiv.) and ethyl chloroformate (CAS: 541-41-3, 34 mg, 0.31 mmol, 1.1 equiv.) were added. The mixture was stirred at RT for 24 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organics layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was dissolved in THF (3.0 mL) and a 1N solution of NaOH (2.0 mL, 2.0 mmol) was added. The mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0847] Molecular weight: 520.6 ; LCMS, molecular weight observed: 521.2

[0848] 1H NMR (400 MHz, DMSO-d6) d 14.31 (s, 1H), 9.15 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 7.49 (s, 1H), 4.78-4.72 (m, 1H), 4.33-4.24 (m, 2H), 4.22-4.15 (m, 2H), 3.57-3.48 (m, 3H), 3.28 (s, 3H), 2.07 (tt, 2H 1.32-1.22 (m, 7H), 1.04-0.96 (m, 1H), 0.65-0.55 (m, 1H), 0.25-0.14 (m, 1H).

Synthesis of Cpd_110: 1-cyclopropyl-9-(dimethylcarbamoyl)-8-(3-methoxypropoxy)-5-m ethyl-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0849] 9-Methyl-9H-fluorene-9-carbonyl chloride (CAS: 82102-37-2, 29 mg, 0.12 mmol, 1.1 equiv.), tri- tert-butylphosphonium tetrafluoroborate (CAS: 131274-22-1, 1.6 mg, 0.005 mmol, 0.05 equiv.) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36-0, 3.1 mg, 0.005 mmol, 0.05 equiv.) were added to chamber A of a COware two-chamber reactor. Isopropyl 9-bromo-1-cyclopropyl-8-(3- methoxypropoxy)-5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b] pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equiv.), Na2CO3 (CAS: 497-19-8, 57 mg, 0.54 mmol, 5.0 equiv.), dimethylamine hydrochloride (CAS: 506-59-2, 18 mg, 0.22 mmol, 2.0 equiv.), di(1-adamantyl)-n-butylphosphine (CAS: 321921-71-5, 3.9 mg, 0.011 mmol, 0.1 equiv.) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36-0, 3.1 mg, 0.005 mmol, 0.05 equiv.) were added to chamber B of a COware two-chamber reactor. The system was sealed and placed under an atmosphere of argon. To chamber A a degassed solution of DIPEA (CAS: 7087- 68-5, 28 µL, 0.16 mmol, 1.5 equiv.) in toluene (0.7 mL) was added. To chamber B a degassed solution of toluene (0.7 mL) was added. The reactor was stirred at 80°C for 18 h. Dimethylamine (2M in MeOH, CAS: 124-40-3, 0.27 mL, 0.54 mmol, 5.0 equiv.) was added to chamber B. The reactor was stirred at 100°C for 18 h. A degassed solution of 9-Methyl-9H-fluorene-9-carbonyl chloride (CAS: 82102-37-2, 29 mg, 0.12 mmol, 1.1 equiv.) in toluene (0.3 mL) was added to chamber A. A degassed solution of dimethylamine (2M in MeOH, CAS: 124-40-3, 0.27 mL, 0.54 mmol, 5.0 equiv.), di(1-adamantyl)-n-butylphosphine (CAS: 321921-71-5, 3.9 mg, 0.011 mmol, 0.1 equiv.) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005- 36-0, 3.1 mg, 0.005 mmol, 0.05 equiv.) in toluene (0.3 mL) was added to chamber B. The reactor was stirred at 100°C for 18 h. The reaction was cooled to RT and the mixture in chamber A was removed. A degassed solution of tri-tert-butylphosphonium tetrafluoroborate (CAS: 131274-22-1, 3.2 mg, 0.01 mmol, 0.1 equiv.), bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36-0, 6.2 mg, 0.01 mmol, 0.1 equiv.) and DIPEA (CAS: 7087-68-5, 28 µL, 0.16 mmol, 1.5 equiv.) in toluene (0.3 mL) was added to chamber A. A degassed solution of 9-methyl-9H-fluorene-9-carbonyl chloride (CAS: 82102-37-2, 53 mg, 0.22 mmol, 2.0 equiv.) in toluene (0.3 mL) was then added to chamber A. Dimethylamine (2M in MeOH, CAS: 124-40-3, 0.27 mL, 0.54 mmol, 5.0 equiv.) was added to chamber B. The reactor was stirred at 100°C for 4 h. The mixture in chamber B was diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (1.08 mL, 1.08 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0850] Molecular weight: 504.6 ; LCMS, molecular weight observed: 505.3

[0851] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 8.34 (s, 1H), 8.14-8.08 (m, 1H), 7.59 (s, 1H), 4.83 (s, 1H), 4.32 (t, 2H), 3.79 (s, 1H), 3.46 (t, 2H), 3.25 (s, 3H), 3.01 (s, 3H), 2.86 (s, 2H), 2.79 (s, 1H), 1.98 (tt, 2H), 1.37- 1.28 (m, 3H), 1.17 (s, 1H), 0.87 (s, 1H), 0.58 (s, 1H), 0.16 (s, 1H).

Synthesis of Cpd_111: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(methylcarbamo yl)-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0852] 9-Methyl-9H-fluorene-9-carbonyl chloride (CAS: 82102-37-2, 79 mg, 0.33 mmol, 3.0 equiv.), tri- tert-butylphosphonium tetrafluoroborate (CAS: 131274-22-1, 3.1 mg, 0.011 mmol, 0.1 equiv.) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36-0, 6.2 mg, 0.011 mmol, 0.1 equiv.) were added to chamber A of a COware two-chamber reactor. Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)- 5-methyl-2,6,6-trioxo-5H-thiochromeno[4,3-b]pyridine-3-carbo xylate (60 mg, 0.11 mmol, 1.0 equiv.), Na2CO3 (CAS: 497-19-8, 57 mg, 0.54 mmol, 5.0 equiv.), 1-(2,4-dimethoxyphenyl)-N-methylmethanamine (CAS: 102503-23-1, 58 µL, 0.33 mmol, 3.0 equiv.), di(1-adamantyl)-n-butylphosphine (CAS: 321921-71- 5, 7.8 mg, 0.022 mmol, 0.2 equiv.) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36-0, 6.2 mg, 0.011 mmol, 0.1 equiv.) were added to chamber B of a COware two-chamber reactor. The system was sealed and placed under an atmosphere of argon. To chamber A, a degassed solution of DIPEA (CAS: 7087-68-5, 66 µL, 0.38 mmol, 3.5 equiv.) in toluene (0.7 mL) was added. To chamber B, a degassed solution of toluene (0.7 mL) was added. The reactor was stirred at 90°C for 18 h. A degassed solution of 9- methyl-9H-fluorene-9-carbonyl chloride (CAS: 82102-37-2, 53 mg, 0.22 mmol, 2.0 equiv.) in toluene (0.2 mL) was added to chamber A. The reactor was stirred at 90°C for 18 h. The mixture in chamber B was diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in DCM (0.4 mL) and TFA (0.8 mL) and stirred at RT for 18 h. The mixture was diluted with DCM, cooled to 0°C and partitioned between DCM and a saturated solution of NaHCO3. The organic layer was dried (brine and Na2SO4) and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (1.07 mL, 1.07 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0853] Molecular weight: 490.5 ; LCMS, molecular weight observed: 491.3

[0854] ¹H-NMR (400 MHz, DMSO-d6) d 14.29 (s, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 8.32 (q, 1H), 7.61 (s, 1H), 4.86 (q, 1H), 4.41-4.34 (m, 2H), 3.70-3.63 (m, 1H), 3.52 (t, 2H), 3.28 (s, 3H), 2.82 (d, 3H), 2.05 (tt, 2H), 1.30 (s, 3H), 1.22 (s, 1H), 0.94 (s, 1H), 0.59 (s, 1H), 0.13 (s, 1H).

Int.129: 3-(3-hydroxyphenyl)sulfanylpropanoic acid

[0855] 3-sulfanylphenol (CAS: 40248-84-8, 25 g, 198.1 mmol, 1.0 equiv.) was dissolved in DMF (100 mL) and then acrylic acid (CAS: 79-10-7, 15.7 g, 218.0 mmol, 1.1 equiv.) and tetrabutylammonium fluoride trihydrate (CAS: 87749-50-6, 12.5 g, 39.6 mmol, 0.20 equiv.) were added. The mixture was degassed by nitrogen bubbling for 10 min and then stirred at 50°C for 18 h. The mixture was allowed to cool to RT and was partitioned between EtOAc and water. The organic layer was washed (water,5 wt% aqueous LiCl solution and brine), dried (Na2SO4) and concentrated to afford the title product.

[0856] Molecular weight: 198.2 ; LCMS, molecular weight observed: 197.4 (MS-)

Int.128: 7-hydroxythiochroman-4-one

[0857] 3-(3-hydroxyphenyl)sulfanylpropanoic acid (11.5 g, 57.8 mmol, 1.0 equiv.) was cooled to 0°C, thenH ₂ SO ₄ (50 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 h. The reaction mixture was poured dropwise into ice-water. The aqueous layer was extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 70:30) to afford the title product.

[0858] Molecular weight: 180.2 ; LCMS, molecular weight observed: 181.0 Int.127: 7-(3-methoxypropoxy)thiochroman-4-one

[0859] 7-hydroxythiochroman-4-one (39.9 g, 130.7 mmol, 1.0 equiv.) was dissolved in DMF (130 mL) and 1-bromo-3-methoxypropane (CAS: 36865-41-5, 20.0 g, 130.7 mmol, 1.0 equiv.) and K ₂ CO ₃ (CAS: 584-08-7, 54.2 g, 392.1 mmol, 3.0 equiv.) were added. The mixture was stirred at RT for 24 h. The mixture was heated to 80°C for 72 h. The mixture was allowed to cool to RT and was partitioned between EtOAc and water. The organic layer was separated and washed (water, sodium bicarbonate solution, 5 wt% aqueous LiCl solution and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 50:50) to afford the title product.

[0860] Molecular weight: 252.3 ; LCMS, molecular weight observed: 253.0

Int.126: 6-bromo-7-(3-methoxypropoxy)thiochroman-4-one

[0861] 7-(3-methoxypropoxy)thiochroman-4-one (8.35 g, 33.1 mmol, 1.0 equiv.) was dissolved in ACN (50 mL) and the mixture was cooled to -10°C. N-Bromosuccinimide (CAS: 128-08-5, 5.89 g, 33.1 mmol, 1.0 equiv.) was added and the mixture was stirred at -10°C for 0.5 h. The mixture was allowed to warm to RT and was stirred for 18 h. The mixture was cooled to -10°C and N-bromosuccinimide (CAS: 128-08-5, 2.95 g, 16.1 mmol, 0.5 equiv.) was added. The mixture was stirred at -10°C for 0.5 h. The mixture was allowed to warm to RT and stirred for 1 h. The mixture was cooled to 0°C, diluted with DCM and filtered. The filtrate was concentrated and the residue was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 70:30) to afford the title product.

[0862] Molecular weight: 331.3 ; LCMS, molecular weight observed: 329.0/331.1 (MS-)

Int.125: 6-bromo-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrothiochrome n-4-one

[0863] 6-bromo-7-(3-methoxypropoxy)thiochroman-4-one (3.94 g, 11.9 mmol, 1.0 equiv.) was dissolved in DCM (50 mL) and cooled to 0°C, then MCPBA (CAS: 937-14-4, 6.16 g, 35.7 mmol, 3.0 equiv.) was added at 0°C. The mixture was allowed to warm to RT and stirred for 18 h. The mixture was poured onto a solution of saturated aqueous NaHCO ₃ and filtered. The filtrate was separated and the organic layer was washed (water and sodium bicarbonate solution), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FLC (SiO2, column eluted with cyclohexane/EtOAc 100:00 to 50:50) to afford the title product.

[0864] Molecular weight: 363.2 ; LCMS, molecular weight observed: 361.0/363.0 (MS-)

Synthesis of 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

[0865] 6-bromo-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrothiochrome n-4-one (1.88 g, 5.16 mmol, 1.0 equiv.) was dissolved in 1,2-dichloroethane (20 mL) under argon, titanium (IV) isopropoxide (CAS: 546- 68-9, 3.1 mL, 10.3 mmol, 2.0 equiv.) and cyclopropylamine (CAS: 765-30-0, 0.72 mL, 10.3 mmol, 2.0 equiv.) were then added. The mixture was stirred at 60°C for 4 h. The mixture was allowed to cool to RT. The mixture was diluted with DCM and a solution of NaOH 1N was added and stirred vigorously for 10 min. The biphasic mixture was filtered through Celite ® and separated. The organic layer was dried (Na2SO4) and concentrated. The residue and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 815 mg, 4.38 mmol, 3.0 equiv.) were dissolved in fluorobenzene (10 mL). The mixture was degassed and stirred at 170°C for 6 h under microwave irradiation. The mixture was allowed to cool to RT and the solvent was removed in vacuo. The residue was dissolved in THF (10 mL) and a 1N solution of NaOH (3.65 mL, 3.65 mmol, 2.5 equiv.) was added. The mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0866] Molecular weight: 498.3 ; LCMS, molecular weight observed: 498.2/500.1

[0867] ¹H-NMR (400 MHz, DMSO-d6) d 14.27 (s, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 7.57 (s, 1H), 4.78 (s, 2H), 4.36 (t, 2H), 3.85-3.81 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.04 (tt, 2H), 1.07 (s, 2H), 0.37 (s, 2H). Int.130: Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3- b]pyridine-3-carboxylate

[0868] 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H-thiochromeno[4,3- b]pyridine-3-carboxylic acid 6,6-dioxide (550 mg, 1.10 mmol, 1.0 equiv.) was dissolved in DCM (5.0 mL) and the mixture was cooled to 0°C. Oxalyl chloride (CAS: 79-37-8, 0.12 mL, 1.32 mmol, 1.2 equiv.) and then DMF (0.1 mL, 1.29 mmol, 1.2 equiv.) were added. The mixture was stirred at RT for 0.5 h and then concentrated. The residue was dissolved in isopropyl alcohol (2.5 mL) at 0°C. The solution was poured into a mixture of TEA (CAS: 121-44-8, 0.31 mL, 2.21 mmol, 2.0 equiv.) in isopropyl alcohol (2.5 mL) at 0°C. The mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and a 1N solution of HCl. The organic layer was separated and washed (sodium bicarbonate solution, water and brine), dried (Na2SO4) and concentrated. The residue was purified by FLC (KP-NH SiO2, column eluted with cyclohexane/EtOAc 100:00 to 50:50) to afford the title product.

[0869] Molecular weight: 540.4 ; LCMS, molecular weight observed: 540.2/542.2

Synthesis of 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

[0870] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno [4,3-b]pyridine-3-carboxylate (53 mg, 0.098 mmol, 1.0 equiv.) and copper (I) iodide (CAS: 7681-65-4, 3.7 mg, 0.020 mmol, 0.2 equiv.) were dissolved in dioxane (0.6 mL) and tetrakis(triphenylphospine)palladium(0) (CAS: 14221-01-3, 11 mg, 0.010 mmol 0.1 equiv.) and 4-(tri-n- butylstannyl)thiazole (CAS: 173979-01-6, 62 µL, 0.20 mmol, 2.0 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with methanol, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.79 mL, 0.79 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0871] Molecular weight: 502.6 ; LCMS, molecular weight observed: 503.3

[0872] ¹H-NMR (400 MHz, DMSO-d6) d 14.25 (s, 1H), 9.26 (d, 1H), 9.04 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 7.67 (s, 1H), 4.82 (s, 2H), 4.47 (t, 2H), 3.65-3.59 (m, 1H), 3.56 (t, 2H), 3.27 (s, 3H), 2.17 (tt, 2H), 1.09 (d, 2H), 0.44 (s, 2H).

Int.157: 6'-chloro-7'-(3-methoxypropoxy)spiro[cyclobutane-1,2'-thioch romane]-4'-one

[0873] To a mixture of 1-[5-chloro-4-(3-methoxypropoxy)-2-sulfanyl-phenyl]ethanone (1.0 g, 3.60 mmol, 1eq), in MeOH (5 mL) was added pyrrolidine (CAS: 123-75-1, 0.32 mL, 3.60 mmol, 1 equiv.) and was stirred at RT for 30 min in a sealed vial. In other sealed vial, a mixture of cyclobutanone (CAS: 1191-95- 3, 0.41 mL, 5.50 mmol, 1.5 equiv.) in MeOH (0.5 mL) was added pyrrolidine (CAS: 123-75-1, 0.48 mL, 5.50 mmol, 1.5 equiv.) and was stirred at RT for 55 min. This previous solution was added dropwise on the first suspension, and the reaction mixture was stirred at RT for 1.5 h.2 N aqueous HCl was added (1.8 mL, 3.60 mmol, 1.0 equiv.) and the mixture was stirred to RT for 2 h. The solvents were removed and the residue was taken up in DCM and washed with saturated aqueous NH4Cl and brine, dried over MgSO4 and concentrated. The residue was purified by FLC ((SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0874] Molecular weight: 326.8 ; LCMS, molecular weight observed: 327.2/329.2

Synthesis of Cpd_123: 9'-chloro-1'-cyclopropyl-8'-(3-methoxypropoxy)-2',6',6'-trio xo- spiro[cyclobutane-1,5'-thiochromeno[4,3-b]pyridine]-3'-carbo xylic acid

[0875] To a mixture of 6'-chloro-7'-(3-methoxypropoxy)spiro[cyclobutane-1,2'-thioch romane]-4'-one (200 mg, 0.61 mmol, 1.0 equiv.) in EtOH (1 mL) was added glacial acetic acid (0.007 mL, 0.122 mmol, 0.2 equiv.) and cyclopropylamine (CAS: 765-30-0, 0.17 mL, 2.45 mmol, 4.0 equiv.) the mixture was stirred at reflux for 2h . The mixture was allowed to cool down to RT. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The previous residue (224 mg, 0.61 mmol, 1.0 equiv.) and 5-(methoxymethylene)- 2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 148 mg, 0.79 mmol, 1.3 equiv.) were dissolved in DMSO (1 mL). The mixture was stirred at 50°C for 50 min. To the previous solution was added 2 N aqueous NaOH (0.61 mL, 1.22 mmol, 2.0 equiv.) and the mixture was stirred at 120°C for 30 min. The mixture was allowed to cool down to RT and 2 N aqueous HCl was added (0.61 mL, 1.22 mmol, 2.0 equiv.). Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The previous mixture (0.36 g, 0.78 mmol, 1.0 equiv. ) was charged in glacial acetic acid (0.8 mL, 14.0 mmol, 17.9 equiv. ), and was added 30 %/w. aqueous H2O2 (0.4 mL, 4.26 mmol, 5.5 equiv. ), the mixture was stirred at 100°C for 90 min. The mixture was allowed to cool down to RT and concentrated. The residue was purified by preparative LC-MS (basic method) to afford the title product.

[0876] Molecular weight: 493.9 ; LCMS, molecular weight observed: 448.2/ 450.3

[0877] 1H NMR (400 MHz, Chloroform-d) d 8.58 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 4.28 (t, J = 6.2 Hz, 2H), 3.56 (t, J = 5.9 Hz, 2H), 3.43–3.34 (m, 1H), 3.32 (s, 3H), 2.76–2.72 (m, 2H), 2.24–2.04 (m, 5H), 1.95– 1.35 (m, 2H), 1.21–1.16 (m, 1H), 0.57–0.39 (m, 2H). Int.154: 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]sulfanylpropanoic acid

[0878] To a stirred mixture of 4-bromo-2-(3-methoxypropoxy)-1-methyl-benzene (CAS 909406-81-1, 1.00 g, 3.85 mmol, 1.0 equiv.), 3-mercaptopropionic acid (CAS 107-96-0, 0.373 mL, 4.24 mmol, 1.1 equiv.) and XantPhos Pd G3 (CAS 1445085-97-1, 0.199 g, 0.192 mmol, 0.05 equiv.) in THF (6 mL) at RT was added TEA (1.13 mL, 7.71 mmol, 2.0 equiv.) in one portion. The reaction mixture was heated to 70°C for 2 h and allowed to cool to RT. The reaction mixture was evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with DCM/MeOH: 100/0 to 95/5). The pure fractions were combined and evaporated to dryness to afford the title product.

[0879] Molecular weight: 284.4 ; LCMS, molecular weight observed: 285.3

Int.155: 7-(3-methoxypropoxy)-6-methyl-thiochroman-4-one

[0880] Int.154: 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]sulfanylpropanoic acid (0.658 g, 2.31 mmol, 1.0 equiv.) was slowly added toH ₂ SO ₄ (3.92 mL, 69.4 mmol, 30.0 equiv.) cooled to 0°C. The thick solution was stirred at 0°C for 30 min. The reaction mixture was poured into ice and stirred for 30 min. DCM was added and the mixture was filtered over a phase separator. The organic layer was evaporated to dryness to afford the title product.

[0881] Molecular weight: 266.4 ; LCMS, molecular weight observed: 267.3

Synthesis of Cpd_122: 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-5H-thiochr omeno[4,3- b]pyridine-3-carboxylic acid

[0882] To a stirred solution of Int.155: 7-(3-methoxypropoxy)-6-methyl-thiochroman-4-one (0.40 g, 1.50 mmol, 1.0 equiv.) in EtOH (2 mL) at RT were added AcOH (0.086 mL, 1.50 mmol, 1.0 equiv.) and cyclopropylamine (CAS 765-30-0, 15.0 mL, 17.4 mmol, 10.0 equiv.). The reaction mixture was heated at reflux for 1.5 h and then allowed to cool to RT. Water was added (5 mL) and the resulting solid was filtered and dried under vacuo. To this crude mixture in DMSO (3 mL) at RT was added 5-(methoxymethylene)- 2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.36 g, 1.95 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 20 min. NaOH 2N (1.50 mL, 3.00 mmol, 2.0 equiv.) was added to the reaction mixture which was heated to 70°C for 16 h. The reaction mixture was allowed to cool to RT and MeOH was added (1 mL) followed by HCl 2N (1.50 mL). The mixture was stirred for 10 min. The resulting solid was filtered, washed with water and dried under vacuo to afford the crude title product. A part of this crude was purified by preparative LC-MS (basic method) to afford the title product as a DEA salt.

[0883] Molecular weight: 401.5 ; LCMS, molecular weight observed: 402.3

[0884] 1H NMR (400 MHz, Chloroform-d) d 8.35 (s, 1H), 7.56 (d, J = 1.0 Hz, 1H), 6.98 (s, 1H), 4.19– 4.11(m, 2H), 3.62 (s, 2H), 3.61–3.56 (m, 2H), 3.48–3.38 (m, 1H), 3.38 (s, 3H), 2.73–2.63 (m, 4H), 2.26– 2.21 (m, 3H), 2.18–2.07 (m, 2H), 1.16–1.12 (m, 6H), 1.11 (s, 2H), 0.45–0.39 (m, 2H)

Synthesis of Cpd_117: 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0885] To a stirred crude mixture of 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid (0.353 g, 0.88 mmol, 1.0 equiv.) in AcOH (0.70 mL, 8.80 mmol, 10.0 equiv.) at RT was added H ₂ O ₂ 30 % in water (0.41 mL, 4.40 mmol, 5.0 equiv.). The reaction mixture was heated to 100°C for 1 h and allowed to cool to RT. Water was added. The precipitate was filtered, washed with Et ₂ O and dried under vacuo. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 95/5). The pure fractions were combined and evaporated to dryness to afford the title product.

[0886] Molecular weight: 433.5 ; LCMS, molecular weight observed: 434.3

[0887] 1H NMR (400 MHz, Chloroform-d) d 8.35 (s, 1H), 7.69 (d, J = 0.9 Hz, 1H), 7.53 (s, 1H), 4.34– 4.24(m, 2H), 4.16 (s, 2H), 3.64–3.56 (m, 2H), 3.56–3.46 (m, 1H), 3.38 (s, 3H), 2.35 (s, 3H), 2.22–2.07 (m, 2H), 1.24–1.17 (m, 2H), 0.62–0.56 (m, 2H)

Synthesis of Cpd_125: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-fu ryl)-2,6,6-trioxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0888] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.) and copper (I) iodide (CAS: 7681-65-4, 3.4 mg, 0.02 mmol, 0.2 equiv.) were dissolved in dioxane (0.6 mL) and tetrakis(triphenylphospine)palladium(0) (CAS: 14221-01-3, 10 mg, 0.01 mmol 0.1 equiv.) and 5-methyl- 2-(tributylstannyl)furan (CAS: 118486-95-6, 60 µL, 0.18 mmol, 2.0 equiv.) were added. The mixture was degassed and stirred at 100°C for 24 h. The mixture was cooled to RT, diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.90 mL, 0.90 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0889] Molecular weight: 514.2 ; LCMS, molecular weight observed: 513.6

[0890] ¹H-NMR (400 MHz, DMSO-d6) d 14.38 (s, 1 H), 8.46 (s, 1 H), 8.45 (s, 1 H), 7.58 (s, 1 H), 7.11 (d, 1 H), 6.33 (dd, 1 H), 4.84 - 4.79 (m, 1 H), 4.43 - 4.39 (m, 2 H), 3.77 - 3.70 (m, 1 H), 3.56 (t, 2 H), 3.28 (s, 3 H), 2.38 (s, 3 H), 2.18 - 2.10 (m, 2 H), 1.34 - 1.26 (m, 3 H), 1.23 (s, 1 H), 0.97 - 0.89 (m, 1 H), 0.68 - 0.57 (m, 1 H), 0.26 - 0.15 (m, 1 H)

Synthesis of Cpd_126: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-thiazol-2- yl-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0891] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H-thiochromeno [4,3-b]pyridine-3-carboxylate 6,6-dioxide (53 mg, 0.098 mmol, 1.0 equiv.) and copper (I) iodide (CAS: 7681-65-4, 3.7 mg, 0.020 mmol, 0.2 equiv.) were dissolved in dioxane (0.6 mL) and tetrakis(triphenylphospine)palladium(0) (CAS: 14221-01-3, 11 mg, 0.010 mmol 0.1 equiv.) and 2-(tri-n- butylstannyl)thiazole (CAS: 121359-48-6, 62 µL, 0.20 mmol, 2.0 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with methanol, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.79 mL, 0.79 mmol, 10 equiv.) was added. The mixture was stirred at RT for 2 h. The mixture was cooled to RT, diluted with methanol, filtered through Celite ® and concentrated. The residue was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0892] Molecular weight: 502.6 ; LCMS, molecular weight observed: 503.2

[0893] ¹H-NMR (400 MHz, DMSO-d6) d 14.26 (s, 1H), 9.11 (s, 1H), 8.30 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.74 (s, 1H), 4.81 (s, 2H), 4.56 (t, 2H), 3.63 (t, 2H), 3.61-3.56 (m, 1H), 3.29 (s, 3H), 2.25-2.17 (m, 2H), 1.08 (d, 2H), 0.41 (s, 2H). Synthesis of compound Cpd_127: 1,9-dicyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0894] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H-thiochromeno [4,3-b]pyridine-3-carboxylate 6,6-dioxide (70 mg, 0.14 mmol, 1.0 equiv.), potassium phosphate tribasic (CAS: 7778-53-2, 89 mg, 0.42 mmol, 3.0 equiv.), cyclopropylboronic acid (CAS: 411235-57-9, 18 mg, 0.21 mmol, 1.5 equiv.) and [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II ) (CAS: 72287- 26-4, 5.1 mg, 0.007 mmol, 0.05 equiv.) were dissolved in 1,4-dioxane (1.5 mL). The mixture was degassed and stirred at 90°C for 4 h. The mixture was cooled to RT, diluted with dichloromethane, filtered through Celite ® and concentrated. The residue was dissolved in THF (2 mL) and a 1N solution of NaOH (5 mL, 2.79 mmol, 20 equiv.) added. The mixture was stirred at RT for 2 h. The mixture was acidified to pH 1 with a 1N solution of HCl and extracted into EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0895] Molecular weight: 459.5 ; LCMS, molecular weight observed: 460.2

[0896] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 14.38 (s, 1H), 8.33 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 4.71 (s, 2H), 4.28 (t, 2H), 3.81-3.73 (m, 1H), 3.54 (t, 2H), 3.27 (s, 3H), 2.30-2.22 (m, 1H), 2.10-2.02 (m, 2H), 1.07- 0.94 (m, 4H), 0.88-0.82(m, 2H), 0.32 (s, 2H)

Synthesis of compound Cpd_128: 1-cyclopropyl-9-(difluoromethyl)-8-(3-methoxypropoxy)-2,6,6- trioxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0897] Isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-vinyl-5H-t hiochromeno[4,3- b]pyridine-3-carboxylate (40 mg, 0.08 mmol, 1.0 equiv.) was dissolved in dioxane (1.0 mL) and water (0.25 mL) at 0°C. 2,6-lutidine (CAS: 108-48-5, 19 µL, 0.16 mmol, 2.0 equiv.) was added. Osmium tetroxide solution 2.5 wt. % in tert-butanol (CAS: 20816-12-0, 21 µL, 0.002 mmol, 0.02 equiv.) and sodium periodate (CAS: 7790-28-5, 70 mg, 0.33 mmol, 4.0 equiv.) were added. The mixture was allowed to warm to RT and stirred vigorously for 3 h. The mixture was diluted with EtOAc and filtered through Celite ®. The filtrate was partitioned between EtOAc and a 1 N solution of HCl and the organics separated. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was dissolved in DCM (1.0 mL) at 0°C and placed under inert atmosphere. [bis(2-methoxyethyl)amino]sulfur trifluoride, 2.7M (50 wt.%) solution in toluene (CAS: 202289-38-1, 121 µL, 0.33 mmol, 4.0 equiv.) was added. The mixture was allowed to warm to RT and stirred for 2 h. The mixture was diluted with 20% MeOH/DCM and filtered through a silica plug. The filtrate was washed with saturated Na2CO3 solution and concentrated. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and a 1N solution of NaOH (0.82 mL, 0.82 mmol, 10 equiv.) was added. The mixture was stirred at RT for 2 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed with pH1 brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0898] Molecular weight: 470.1 ; LCMS, molecular weight observed: 469.5

[0899] ¹H-NMR (400 MHz, DMSO-d6) d 14.33 (s, 1 H), 8.46 (s, 1 H), 8.43 (s, 1 H), 7.66 (s, 1 H), 7.23 (t, 1 H), 4.86 (s, 2 H), 4.38 (t, 2 H), 3.81 - 3.73 (m, 1 H), 3.51 (t, 2 H), 3.26 (s, 3 H), 2.06 - 2.00 (m, 2 H), 1.11 - 1.00 (m, 2 H), 0.42 - 0.33 (m, 2 H)

Synthesis of compound Cpd_129: 1-cyclopropyl-9-iodo-8-(3-methoxypropoxy)-5-methyl-2,6,6-tri oxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0900] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tr ioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equiv.), copper (I) iodide (CAS: 7681- 65-4, 0.9 mg, 0.005 mmol, 0.05 equiv.), sodium iodide (CAS: 7681-82-5, 27 mg, 0.18 mmol, 2.0 equiv.) and (R,R)-(-)-N,N¢-Dimethyl-1,2-cyclohexanediamine (CAS: 68737-65-5, 1.4 µL, 0.009 mmol, 0.1 equiv.) were placed under inert atmosphere. A degassed solution of dioxane (1.0 mL) was added and the mixture was stirred at 110°C for 72 h. Copper (I) iodide (CAS: 7681-65-4, 10.8 mg, 0.05 mmol, 0.6 equiv.), sodium iodide (CAS: 7681-82-5, 135 mg, 0.9 mmol, 10.0 equiv.) and (R,R)-(-)-N,N¢-Dimethyl-1,2- cyclohexanediamine (CAS: 68737-65-5, 16.8 µL, 0.11 mmol, 1.2 equiv.) were added and the mixture degassed before stirring at 110°C for 72 h. The mixture was cooled to RT, diluted with EtOAc and filtered through Celite ®. The filtrate was partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by FCC (SiO2, column eluted with DCM/MeOH 100:00 to 97:03). The relevant fractions were combined and concentrated. The residue was purified by SFC. The relevant fractions were combined and concentrated. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and a 1N solution of NaOH (0.47 mL, 0.47 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed with pH1 brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0901] Molecular weight: 560.2 ; LCMS, molecular weight observed: 559.4

[0902] ¹H-NMR (400 MHz, DMSO-d6) d 14.33 (s, 1 H), 8.68 (s, 1 H), 8.38 (s, 1 H), 7.41 (s, 1 H), 4.85 - 4.77 (m, 1 H), 4.36 - 4.31 (m, 2 H), 3.81 - 3.75 (m, 1 H), 3.57 (t, 2 H), 3.28 (s, 6 H), 2.08 - 2.00 (m, 2H), 1.34 - 1.26 (m, 3 H), 1.25 - 1.20 (m, 1 H), 0.97 - 0.87 (m, 1 H), 0.61 - 0.49 (m, 1 H), 0.21 - 0.10 (m, 1H) Int.161: isopropyl 9-chloro-1-cyclopropyl-8-[(2-methyloxetan-2-yl)methoxy]-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0903] Isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (1 mL) were added (3-methyloxetan-3-yl)methanol (CAS: 61266-71-5, 59.0 mg, 0.578 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equiv.). The mixture was stirred at RT for 15 min at 0°C, and di-tert-butyl azodicarboxylate (CAS: 870-50- 8, 69.2 mg, 0.301 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 5 days. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the title product containing trace of oxide of PPh3.

[0904] Molecular weight: 508.0 ; LCMS, molecular weight observed: 506.2/ 508.3

Synthesis of 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

[0905] isopropyl 9-chloro-1-cyclopropyl-8-[(2-methyloxetan-2-yl)methoxy]-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.22 g, 0.42 mmol, 1.0 equiv.) was dissolved in MeOH (0.5 mL) and 2 N aqueous NaOH (3 mL, 6.0 mmol, 14.0 equiv.) was added. The mixture was stirred at RT for 60 min. After complete conversion a few water was added and trace of oxide of PPh3 was extracted with EtOAc. To the aqueous layer 2 N aqueous HCl (3 mL, 6.0 mmol, 14 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0906] Molecular weight: 465.9 ; LCMS, molecular weight observed: 464.3/ 466.3 [0907] 1H NMR (400 MHz, Chloroform-d) d 8.37 (s, 1H), 7.99 (s, 1H), 7.72– 7.62 (m, 1H), 4.73– 4.63 (m,1H), 4.62– 4.52 (m, 1H), 4.21 (d, J = 1.4 Hz, 4H), 3.57– 3.47 (m, 1H), 2.97– 2.86 (m, 1H), 2.63– 2.52 (m, 1H), 2.10 (s, 3H), 1.32– 1.23 (m, 2H), 0.64– 0.58 (m, 2H).

Int.162: Isopropyl 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0908] Isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (1 mL) were added oxetan-3-ylmethanol (CAS: 6246- 06-6, 59.0 mg, 0.578 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equiv.). The mixture was stirred at RT for 15 min at 0°C, and di-tert-butyl azodicarboxylate (CAS: 870-50-8, 69.2 mg, 0.301 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 5 days. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the title product containing trace of oxide of PPh3.

[0909] Molecular weight: 494.0 ; LCMS, molecular weight observed: 492.3/494.3

Synthesis of Cpd_131: 9-chloro-1-cyclopropyl-8-(oxetan-3-ylmethoxy)-2,6,6-trioxo-5 H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0910] Isopropyl 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6, 6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.17 g, 0.35 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (1 mL, 2.0 mmol, 5.7 equiv.) was added. The mixture was stirred at RT for 60 min. After complete conversion a few water was added and trace of oxide of PPh3 was extracted with EtOAc. To the aqueous layer 2 N aqueous HCl (1 mL, 2.0 mmol, 5.7 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0911] Molecular weight: 451.9; LCMS, molecular weight observed: 450.3/452.3

[0912] 1H NMR (400 MHz, Chloroform-d) d 13.86 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.64 (s, 1H), 4.95 (dd, J= 7.8, 6.4 Hz, 2H), 4.65 (t, J = 6.1 Hz, 2H), 4.48 (d, J = 6.5 Hz, 2H), 4.22 (s, 2H), 3.66– 3.45 (m, 2H),1.34– 1.23 (m, 2H), 0.64– 0.58 (m, 2H). Int.163: isopropyl 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]meth oxy]-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate

[0913] Isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (1 mL) were added [1- (methoxymethyl)cyclopropyl]methanol (CAS: 338455-22-4, 70.7 mg, 0.578 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equiv.). The mixture was stirred at RT for 15 min at 0°C, and di-tert-butyl azodicarboxylate (CAS: 870-50-8, 69.2 mg, 0.301 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 5 days. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0914] Molecular weight: 522.0 ; LCMS, molecular weight observed: 520.4/522.4

Synthesis of Cpd_132: 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]meth oxy]-2,6,6- trioxo-5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0915] Isopropyl 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]meth oxy]-2,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylate (0.12 g, 0.23 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (1 mL, 2.0 mmol, 8.6 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion a few water was added and trace of oxide of PPh3 was extracted with EtOAc. To the aqueous layer 2 N aqueous HCl (1 mL, 2.0 mmol, 8.6 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0916] Molecular weight: 479.9 ; LCMS, molecular weight observed: 478.3/480.3

[0917] 1H NMR (400 MHz, Chloroform-d) d 13.90 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 4.20 (d, J =8.1 Hz, 4H), 3.58– 3.48 (m, 1H), 3.45 (s, 2H), 3.41 (s, 3H), 1.33– 1.25 (m, 2H), 0.81– 0.74 (m, 2H), 0.74– 0.69 (m, 2H), 0.66– 0.60 (m, 2H). Int.164: isopropyl 9-chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylate

[0918] Isopropyl 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trioxo-5H-thiochromen o[4,3-b]pyridine-3- carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) in THF (1 mL) were added pentan-3-ol (CAS: 584-02-1, 50.9 mg, 0.578 mmol, 2.5 equiv.) and PPh3 (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equiv.). The mixture was stirred at RT for 15 min at 0°C, and di-tert-butyl azodicarboxylate (CAS: 870-50-8, 69.2 mg, 0.301 mmol, 1.3 equiv.) was added to the previous solution. The mixture was stirred at RT for 5 days. To the mixture was added water and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO2, Heptane/EtOAc 100:0 to 0:100) to afford the title product.

[0919] Molecular weight: 494.0 ; LCMS, molecular weight observed: 492.3/494.4

Synthesis of Cpd_133: 9-chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylic acid

[0920] Isopropyl 9-chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trioxo-5H-th iochromeno[4,3- b]pyridine-3-carboxylate (0.92 g, 0.18 mmol, 1.0 equiv.) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH (1 mL, 2.0 mmol, 10.7 equiv.) was added. The mixture was stirred at RT for 30 min. After complete conversion a few water was added and trace of oxide of PPh ₃ was extracted with EtOAc. To the aqueous layer 2 N aqueous HCl (1 mL, 2.0 mmol, 10.7 equiv.) was added and a precipitate was formed, filtered and washed with water to afford the title product.

[0921] Molecular weight: 451.9 ; LCMS, molecular weight observed: 450.3/452.3

[0922] 1H NMR (400 MHz, Chloroform-d) d 13.90 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 4.50– 4.42 (m, 1H), 4.20 (s, 2H), 3.54– 3.47 (m, 1H), 1.83 (p, J = 7.3 Hz, 5H), 1.03 (t, J = 7.4 Hz, 6H), 0.92– 0.83 (m, 1H), 0.62 (d, J = 4.5 Hz, 2H).

Int.165: 4-bromo-1-chloro-2-(cyclopropylmethoxy)benzene [0923] (Bromomethyl)cyclopropane (CAS: 7051-34-5, 1.40 ml, 14.5 mmol, 1.0 equiv.) was added to a mixture of stirred mixture of 5-bromo-2-chloro-phenol (CAS: 183802-98-4, 2.0 g, 9.64 mmol, 1.0 equiv.) to K2CO3 (3.99 g, 28.9 mmol, 3.0 equiv.) in ACN (20 mL) under inert atmosphere at RT. The mixture was stirred to reflux for 16 h. The mixture was allowed to cool down to RT and concentrated. Water was added to the crude and was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product was used without purification.

[0924] Molecular weight: 261.5 ; LCMS, molecular weight observed: No ionization

Int.166: 3-[4-chloro-3-(cyclopropylmethoxy)phenyl]sulfanylpropanoic acid

[0925] To a stirred mixture of Int.165: 4-bromo-1-chloro-2-(cyclopropylmethoxy)benzene (2.98 g, 11.4 mmol, 1.0 equiv.), 3-mercaptopropionic acid (CAS 107-96-0, 1.20 mL, 13.7 mmol, 1.2 equiv.) and XantPhos Pd G3 (CAS 1445085-97-1, 1.14 g, 1.14 mmol, 0.1 equiv.) in THF (30 mL) at RT was added TEA (4.8 mL, 34.2 mmol, 3.0 equiv.) in one portion. The reaction mixture was heated to 70°C for 30 min and allowed to cool to RT. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was purified by FLC (SiO2, column eluted with DCM/MeOH: 100/0 to 0/100). The pure fractions were combined and evaporated to dryness to afford the title product.

[0926] Molecular weight: 286.8 ; LCMS, molecular weight observed: 285.3/287.3

Int.167: 6-chloro-7-(cyclopropylmethoxy)thiochroman-4-one

[0927] To a stirred mixture of Int 166: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanylpropanoic acid (500 mg, 1.74 mmol, 1.0 equiv.) in DCM (1 ml) was slowly added trifluoromethanesulfonic anhydride (CAS 358-23-6, 0.75 mL, 4.36 mmol, 2.5 equiv.) cooled to 0°C. The solution was stirred at 40 °C for 16 h. Saturated aqueous NaHCO3 and EtOAc were added, and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with Heptane/EtOAc: 100/0 to 0/100). The pure fractions were combined and evaporated to dryness to afford the title product.

[0928] Molecular weight: 268.8 ; LCMS, molecular weight observed: 269.2 Synthesis of Cpd_145: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2-oxo-5H-thioc hromeno[4,3- b]pyridine-3-carboxylic acid

[0929] To a stirred solution of Int.167: 6-chloro-7-(cyclopropylmethoxy)thiochroman-4-one (275 mg, 1.02 mmol, 1.0 equiv.) in EtOH (1.4 mL) at RT were added glacial acetic acid (12 µL, 0.20 mmol, 0.2 equiv.) and cyclopropylamine (CAS 765-30-0, 0.28 mL, 4.09 mmol, 4.0 equiv.). The reaction mixture was heated at reflux for 2 h and then allowed to cool to RT. Water and DCM were added, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was used without purification. To this crude mixture in DMSO (1 mL) at RT was added 5- (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.25 g, 1.33 mmol, 1.3 equiv.). The reaction mixture was stirred at 50°C for 30 min.2 N aqueous NaOH (1.0 mL, 2.04 mmol, 2.0 equiv.) was added to the reaction mixture which was heated to 130°C for 30 min. The reaction mixture was allowed to cool to RT and MeOH was added (2 mL) followed by 2 N aqueous HCl (1.0 mL). The resulting solid was filtered, washed with Et2O and dried under vacuo to afford the title product.

[0930] Molecular weight: 403.9 ; LCMS, molecular weight observed: 402.3/404.3

Synthesis of Cpd_134: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-(2-thienyl )-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0931] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (54 mg, 0.10 mmol, 1.0 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (CAS: 13965-03-2, 14 mg, 0.02 mmol, 0.2 equiv.) were dissolved in 1,4-dioxane (1.0 mL) and 2-(tri-n-butylstannyl)thiophene (CAS: 54663-78-4, 64 µL, 0.20 mmol, 2.0 equiv.) was added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (2.0 mL) and a 1N solution of NaOH (5 mL, 50 mmol, 100 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was cooled to RT, diluted with methanol, filtered through Celite ® and concentrated. The residue was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product. [0932] Molecular weight: 501.6 ; LCMS, molecular weight observed: 502.0

[0933] ¹H-NMR (400 MHz, DMSO-d6) d 14.31 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 7.94 (dd, 1H), 7.77 (dd, 1H), 7.62 (s, 1H), 7.21 (dd, 1H), 4.79 (s, 2H), 4.43 (t, 2H), 3.97-3.90 (m, 1H), 3.60 (t, 2H), 3.28 (3H, s), 2.20-2.10 (m, 2H), 1.06 (s, 2H), 0.39 (s, 2H).

Synthesis of compound Cpd_135: 9-cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo -5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0934] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (60 mg, 0.11 mmol, 1.0 equiv.), potassium phosphate tribasic (CAS: 7778-53-2, 75 mg, 0.36 mmol, 3.2 equiv.), cyclobutylboronic acid (CAS: 849052- 26-2, 117 mg, 1.11 mmol, 10 equiv.), palladium(II) acetate (CAS: 3375-31-3, 9.7 mg, 0.04 mmol, 0.4 equiv.) and RuPhos (CAS: 787618-22-8, 41 mg, 0.09 mmol, 0.8 equiv.) were dissolved in toluene (0.9 mL) and water (0.2 mL). The mixture was degassed and stirred at 100°C for 1 h under microwave irradiation. The mixture was cooled to RT, diluted with MeOH and filtered through Celite ®. The filtrate was concentrated and the residue was purified by FCC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 00:100). The relevant fractions were combined and concentrated. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and a 1N solution of NaOH (0.90 mL, 0.90 mmol, 10 equiv.) was added. The mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0935] Molecular weight: 474.3 ; LCMS, molecular weight observed: 473.5

[0936] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 14.33 (s, 1 H), 8.42 (s, 1 H), 8.06 (s, 1 H), 7.42 (s, 1 H), 4.75 (s, 2 H), 4.24 (t, 2 H), 3.88 - 3.81 (m, 1 H), 3.80 - 3.70 (m, 1 H), 3.52 (t, 2 H), 3.27 (s, 3 H), 2.34 - 2.27 (m, 2 H), 2.21 - 2.11 (m, 2 H), 2.07 - 1.97 (m, 3 H), 1.85 - 1.76 (m, 1 H), 1.12 - 1.03 (m, 2 H), 0.42 - 0.32 (m, 2 H).

Synthesis of compound Cpd_136: 1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo- 5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0937] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (100 mg, 0.19 mmol, 1.0 eq), cesium carbonate (CAS: 534-17-8, 133 mg, 0.37 mmol, 2.2 eq) and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 95464-05-4, 6.8 mg, 0.009 mmol, 0.05 eq) were dissolved in dimethoxyethane (1.5 mL) and water (0.3 mL) and isopropenylboronic acid pinacol ester (CAS: 126726-62-3, 70 µL, 0.37 mmol, 2.0 eq) was added. The mixture was degassed and stirred at 100°C for 1 h under microwave irradiation. The mixture was cooled to room temperature and partitioned between DCM and water. The organic layer was washed (NaHCO3, brine), dried (Na2SO4) and concentrated. The residue was dissolved in Ethanol (1.2 mL). Palladium on activated charcoal (CAS: 7440-05-3, 10 wt. % loading, 20 mg, 0.16 eq) was added and the mixture was degassed. The mixture was stirred at room temperature under a hydrogen atmosphere for 18 h. The mixture was diluted with methanol, filtered through celite ® and concentrated. The residue was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) and a 1N solution of NaOH (1.16 mL, 1.16 mmol, 10 equiv.) was added. The mixture was stirred at room temperature for 18 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (pH 1 brine and Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the desired product.

[0938] Molecular weight: 462.2 ; LCMS, molecular weight observed: 461.5

[0939] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 8.30 (s, 1 H), 8.06 (s, 1 H), 7.45 (s, 1 H), 4.73 (s, 2 H), 4.26 (t, 2 H), 3.85 - 3.78 (m, 1 H), 3.52 (t, 2 H), 3.42 - 3.35 (m, 1 H), 3.27 (s, 3 H), 2.08 - 2.02 (m, 2 H), 1.23 (d, 6 H), 1.07 - 1.00 (m, 2 H), 0.38 - 0.30 (m, 2 H)

Synthesis of Cpd_137: 1-cyclopropyl-9-(dimethylcarbamoyl)-8-(3-methoxypropoxy)-2,6 ,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0940] 9-Methyl-9H-fluorene-9-carbonyl chloride (CAS: 82102-37-2, 135 mg, 0.56 mmol, 5.0 equiv.), tri- tert-butylphosphonium tetrafluoroborate (CAS: 131274-22-1, 3.2 mg, 0.01 mmol, 0.1 equiv.) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36-0, 6.4 mg, 0.01 mmol, 0.1 equiv.) were added to chamber A of a COware two-chamber reactor. Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)- 2-oxo-1,5-dihydro-2H-thiochromeno[4,3-b]pyridine-3-carboxyla te 6,6-dioxide (60 mg, 0.11 mmol, 1.0 equiv.), Na ₂ CO ₃ (CAS: 497-19-8, 59 mg, 0.56 mmol, 5.0 equiv.), di(1-adamantyl)-n-butylphosphine (CAS: 321921-71-5, 8.0 mg, 0.02 mmol, 0.2 equiv.) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36- 0, 6.4 mg, 0.01 mmol, 0.1 equiv.) were added to chamber B of a COware two-chamber reactor. The system was sealed and placed under an atmosphere of argon. To chamber A a degassed solution of DIPEA (CAS: 7087-68-5, 106 µL, 0.61 mmol, 5.5 equiv.) in toluene (0.7 mL) was added. To chamber B a degassed solution of toluene (0.7 mL) was added followed by dimethylamine 2.0 M in THF (CAS: 124-40-3, 0.56 mL, 1.11 mmol, 10.0 equiv.). The reactor pwas stirred at 100°C for 48 h. The mixture in chamber B was cooled to RT, diluted with MeOH, filtered through Celite ® and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (1.11 mL, 1.11 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0941] Molecular weight: 491.3 ; LCMS, molecular weight observed: 490.5

[0942] ¹H-NMR (400 MHz, DMSO-d6) d 8.28 (s, 1 H), 8.10 (s, 1 H), 7.57 (s, 1 H), 4.83 - 4.73 (m, 2 H), 4.31 (t, 2 H), 3.81 - 3.73 (m, 1 H), 3.46 (t, 2 H), 3.25 (s, 3 H), 3.01 (s, 3 H), 2.82 (s, 3 H), 2.01 - 1.93 (m, 2 H), 1.11 - 0.93 (m, 2 H), 0.46 - 0.25 (m, 2 H)

Int.168: isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-vinyl-5H-t hiochromeno[4,3- b]pyridine-3-carboxylate

[0943] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (250 mg, 0.46 mmol, 1.0 equiv.) was dissolved in dimethoxyethane (3.5 mL). Vinylboronic acid pinacol ester (CAS: 75927-49-0, 142 mg, 0.93 mmol, 2.0 equiv.) and [1,1¢-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 17 mg, 0.02 mmol, 0.05 equiv.) were added. A solution of Cs2CO3 (CAS: 534-17-8, 332 mg, 1.02 mmol, 2.2 equiv.) in water (0.7 mL) was added. The mixture was degassed and stirred at 100°C for 1 h under microwave irradiation. The mixture was cooled to RT, diluted with DCM and filtered through Celite ®. The filtrate was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by FCC (SiO2, column eluted with DCM/MeOH 100:00 to 96:04). The relevant fractions were combined and concentrated to afford the title product.

[0944] Molecular weight: 488.2 ; LCMS, molecular weight observed: 487.6 Synthesis of Cpd_138: 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno[4,3- b]pyridine-3-carboxylic acid

[0945] Isopropyl 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-vinyl-5H-t hiochromeno[4,3- b]pyridine-3-carboxylate (32 mg, 0.07 mmol, 1.0 equiv.) was dissolved in EtOH (5.0 mL). Palladium on activated charcoal (CAS: 7440-05-3, 10 wt. % loading, 3.2 mg, 0.1 equiv.) was added and the mixture was degassed. The mixture was stirred at RT under a hydrogen atmosphere for 18 h and filtered through Celite ®. The filtrate was concentrated and the residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL). A 1N solution of NaOH (0.64 mL, 0.64 mmol, 10.0 equiv.) was added and the mixture was stirred at RT for 18 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0946] Molecular weight: 448.3 ; LCMS, molecular weight observed: 447.5

[0947] 1H NMR (400 MHz, DMSO-d ₆ ) d 8.14 (s, 1 H), 8.06 (s, 1 H), 7.43 (s, 1 H), 4.67 (s, 2 H), 4.25 (t, 2 H), 3.82 - 3.74 (m, 1 H), 3.52 (t, 2 H), 2.72 (q, 2 H), 2.07 - 1.99 (m, 2 H), 1.18 (t, 3 H), 1.05 - 0.99 (m, 2 H), 0.36 - 0.28 (m, 2 H)

Int.169: isopropyl 9-((tert-butoxycarbonyl)amino)-1-cyclopropyl-8-(3-methoxypro poxy)-2-oxo-1,5- dihydro-2H-thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide

[0948] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (120 mg, 0.22 mmol, 1.0 equiv.) was dissolved in dioxane (3.0 mL) and tert-butyl carbamate (CAS: 4248-19-5, 31 mg, 0.27 mmol, 1.2 equiv.), Xantphos (CAS: 161265-03-8, 3.9 mg, 0.007 mmol, 0.03 equiv.), tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 2.0 mg, 0.002 mmol, 0.01 equiv.) and Cs2CO3 (CAS: 534-17-8, 109 mg, 0.33 mmol, 1.5 equiv.) were added. The mixture was degassed and stirred at 100°C for 18 h. The mixture was cooled to RT, diluted with MeOH and filtered through Celite ®. The filtrate was concentrated, and residue partitioned between EtOAc and water. The organics were separated, washed (water, brine), dried (Na2SO4) and concentrated to afford the title product.

[0949] Molecular weight: 576.7; LCMS, molecular weight observed: 577.5 Synthesis of Cpd_139: 9-(tert-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropo xy)-2,6,6-trioxo- 5H-thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0950] Isopropyl 9-((tert-butoxycarbonyl)amino)-1-cyclopropyl-8-(3-methoxypro poxy)-2-oxo-1,5- dihydro-2H-thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (82 mg, mmol, 1 equiv.) was dissolved in THF (1.0 mL). A 1N solution of NaOH (1.7 mL, 1.7 mmol) was added and the mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0951] Molecular weight: 534.6 ; LCMS, molecular weight observed: 535.3

[0952] 1H NMR (400 MHz, DMSO-d6) d 14.28 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.49 (s, 1H), 4.69 (s, 2H), 4.29 (t, 2H), 3.54 (t, 2H), 3.53-3.47 (m, 1H), 3.28 (s, 3H), 2.09-2.01 (m, 2H), 1.48 (s, 9H), 1.12 (s, 2H), 0.39 (s, 2H).

Int.170: isopropyl 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide

[0953] Isopropyl 9-((tert-butoxycarbonyl)amino)-1-cyclopropyl-8-(3-methoxypro poxy)-2-oxo-1,5- dihydro-2H-thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (50 mg, 0.09 mmol, 1.0 equiv.) was dissolved in DCM (3.0 mL) and a TFA (3.0 mL) was added. The mixture was stirred at RT for 1 h. The mixture was concentrated, and residue partitioned between EtOAc and a solution of NaHCO3. The organic layer was washed (brine), dried (Na2SO4) and concentrated to afford the title product.

[0954] Molecular weight: 476.5 ; LCMS, molecular weight observed: 477.4

Synthesis of Cpd_140: 1-cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-2 ,6,6-trioxo-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0955] Isopropyl 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (62 mg, 0.13 mmol, 1 equiv.) was dissolved in THF (3.0 mL). K2CO3 (CAS: 584-08-7, 22 mg, 0.16 mmol, 1.2 equiv.) and ethyl chloroformate (CAS: 541- 41-3, 16 mg, 0.14 mmol, 1.1 equiv.) were added. The mixture was stirred at RT for 18 h. The mixture was concentrated, and residue partitioned between EtOAc and water. The organic layer was washed (water and brine), dried (Na2SO4), filtered and concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (2.3 mL, 2.0 mmol, 20 eq.) was added. The mixture was stirred at RT for 1.5 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was washed (water and brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0956] Molecular weight: 506.5 ; LCMS, molecular weight observed: 507.2

[0957] 1H NMR (400 MHz, DMSO-d6) d 14.07 (s, 1H), 9.09 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.48 (s, 1H), 4.66 (s, 2H), 4.27 (t, 2H), 4.17 (q, 2H), 3.54 (t, 2H), 3.50-3.43 (m, 1H), 3.28 (s, 3H) 2.10-2.02 (m, 2H), 1.26 (t, 3H), 1.01 (s, 2H), 0.36 (s, 2H).

Synthesis of 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

[0958] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (50 mg, 0.09 mmol, 1.0 equiv.), K ₂ CO ₃ (CAS: 584-08-7, 64 mg, 0.46 mmol, 5.0 equiv.), XPhos (CAS: 564483-18-7, 5.3 mg, 0.01 mmol, 0.12 equiv.), 5- methylthiophene-2-boronic acid pinacol ester (CAS: 476004-80-5, 66 µL, 0.28 mmol, 3.0 equiv.) and XPhos Pd G3 (CAS: 1445085-55-1, 4.7 mg, 0.006 mmol, 0.06 equiv.) were dissolved in EtOH (0.6 mL). The mixture was degassed and stirred at 80°C for 18 h. The mixture was cooled to RT, diluted with MeOH and filtered through Celite ®. The filtrate was concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.93 mL, 0.93 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0959] Molecular weight: 516.2 ; LCMS, molecular weight observed: 515.6

[0960] ¹H-NMR (400 MHz, DMSO-d6) d 8.53 (s, 1 H), 8.31 (s, 1 H), 7.73 (d, 1 H), 7.58 (s, 1 H), 6.90 (d, 1 H), 4.76 (s, 2 H), 4.41 (t, 2 H), 3.92 - 3.85 (m, 1 H), 3.60 (t, 2 H), 3.28 (s, 3 H), 2.17 - 2.10 (m, 2 H), 1.09 - 1.03 (m, 2 H), 0.42 - 0.35 (m, 2 H) Synthesis of Cpd_142: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-(3-thienyl )-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0961] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (50 mg, 0.09 mmol, 1.0 equiv.), K2CO3 (CAS: 584-08-7, 64 mg, 0.46 mmol, 5.0 equiv.), XPhos (CAS: 564483-18-7, 5.3 mg, 0.01 mmol, 0.12 equiv.), 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxaborolane (CAS: 214360-70-0, 58 mg, 0.28 mmol, 3.0 equiv.) and XPhos Pd G3 (CAS: 1445085-55-1, 4.7 mg, 0.006 mmol, 0.06 equiv.) were dissolved in EtOH (0.6 mL). The mixture was degassed and stirred at 80°C for 18 h. The mixture was cooled to RT, diluted with MeOH and filtered through Celite ®. The filtrate was concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.93 mL, 0.93 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0962] Molecular weight: 502.2 ; LCMS, molecular weight observed: 501.6

[0963] ¹H-NMR (400 MHz, DMSO-d6) d 8.42 (s, 1 H), 8.30 (s, 1 H), 8.10 - 8.08 (m, 1 H), 7.66 (s, 1 H), 7.65 (s, 1 H), 7.59 (s, 1 H), 4.77 (s, 2 H), 4.35 (t, 2 H), 3.90 - 3.83 (m, 1 H), 3.51 (t, 2 H), 3.26 (s, 3 H), 2.12 - 2.05 (m, 2 H), 1.10 - 1.03 (m, 2 H), 0.41 - 0.34 (m, 2 H)

Synthesis of 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

[0964] Isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro -2H- thiochromeno[4,3-b]pyridine-3-carboxylate 6,6-dioxide (50 mg, 0.09 mmol, 1.0 equiv.), K2CO3 (CAS: 584-08-7, 64 mg, 0.46 mmol, 5.0 equiv.), XPhos (CAS: 564483-18-7, 5.3 mg, 0.01 mmol, 0.12 equiv.), 1- methyl-1H-pyrazole-3-boronic acid pinacol ester (CAS: 1020174-04-2, 58 mg, 0.28 mmol, 3.0 equiv.) and XPhos Pd G3 (CAS: 1445085-55-1, 4.7 mg, 0.006 mmol, 0.06 equiv.) were dissolved in EtOH (0.6 mL). The mixture was degassed and stirred at 80°C for 18 h. The mixture was cooled to RT, diluted with MeOH and filtered through Celite ®. The filtrate was concentrated. The residue was dissolved in THF (1.0 mL) and a 1N solution of NaOH (0.93 mL, 0.93 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between 2-MeTHF and a 1N solution of NaOH. The aqueous layer was then separated and partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0965] Molecular weight: 500.2 ; LCMS, molecular weight observed: 499.5

[0966] ¹H-NMR (400 MHz, DMSO-d6) d 8.66 (s, 1 H), 8.19 (s, 1 H), 7.81 (d, 1 H), 7.57 (s, 1 H), 6.87 (d, 1 H), 4.72 (s, 2 H), 4.36 (t, 2 H), 3.92 (s, 3 H), 3.57 - 3.50 (m, 3 H), 3.26 (s, 3 H), 2.14 - 2.07 (m, 2 H), 1.09 - 1.03 (m, 2 H), 0.41 - 0.35 (m, 2 H)

Synthesis of Cpd_144: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-9-(trifluoro methyl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0967] Copper (I) bromide (CAS: 7787-70-4, 16 mg, 0.11 mmol, 1.0 equiv.) was dissolved in acetone (1.1 mL) and sonicated for 45 minutes. In a separate vial powdered Na2CO3 (CAS: 497-19-8, 48 mg, 0.44 mmol, 4.0 equiv.), mes-umemoto reagent (CAS: 1895006-01-5, 162 mg, 0.33 mmol, 3.0 equiv.) and isopropyl 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trioxo-5H-t hiochromeno

[4,3-b]pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equiv.) were placed under argon. To this vial the solution of copper (I) bromide was added. A solution of Ir[dFMeppy]2-(4,4¢-dCF3bpy)PF ₆ (CAS: 2229858- 26-6 PF ₆ salt, 0.2 mg, 0.0003 mmol, 0.0025 equiv.) in acetone (1.1 mL) was then added. Tris(trimethylsilyl)silanol (CAS: 7428-60-6, 58 mg, 0.22 mmol, 2.0 equiv.) was added and the mixture was degassed by argon bubbling at 0°C before sealing with Parafilm. The reaction was stirred and irradiated with a 34 W blue LED lamp (5 cm away, with cooling fan to keep the reaction temperature at 25 °C) for 18 hours. The reaction was quenched by exposure to air and concentrated. The residue was purified by FCC (SiO ₂ , column eluted with DCM/MeOH 100:00 to 97:03). The relevant fractions were combined and concentrated to afford a solid which was dissolved in THF (1.0 mL). A 1N solution of NaOH (1.1 mL, 1.1 mmol, 10 equiv.) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and a 1N solution of HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to afford the title product.

[0968] Molecular weight: 487.4 ; LCMS, molecular weight observed: 488.2

[0969] ¹H-NMR (400 MHz, DMSO-d ₆ ) d 8.52 (s, 1H), 7.73 (s, 1H), 6.62 (s, 1H), 4.83 (s, 2H), 4.42 (t, 2H), 3.74-3.67 (m, 1H), 3.50 (t, 2H), 3.25 (s, 3H), 2.05 - 1.99 (m, 2H), 1.04 (m, 2H) ), 0.39 (s, 2H). Synthesis of Cpd_146: 9-chloro-8-isobutoxy-2,6,6-trioxo-1-(1,2,2,3,3-pentadeuterio cyclopropyl)-5H- thiochromeno[4,3-b]pyridine-3-carboxylic acid

[0970] To a stirred solution of Int.1746-chloro-7-(2-methylpropoxy)-1,1-dioxo-2,3-dihydrothi ochromen- 4-one (3.05g, 10.1 mmol, 1.00 equiv.) in EtOH (15mL) at RT were added AcOH (0.57mL, 9.90 mmol, 0.99 equiv.) and 1,2,2,3,3-pentadeuteriocyclopropanamine (CAS 153557-95-0, 2.48g, 39.9 mmol, 3.96 equiv.). The reaction mixture was heated at reflux for 45 min and then allowed to cool to RT. Water was slowly added (15 mL) and the resulting solid was filtered and dried under vacuo. To this crude mixture in DMSO (10 mL) at RT was added 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 15568-85-1, 0.36 g, 1.95 mmol, 1.30 equiv.). The reaction mixture was stirred at 55 °C for 25 min. MeOH (10mL) and NaOH 2N (7 mL, 14.0 mmol, 1.45 equiv.) were added to the reaction mixture which was heated to 70 °C for 4H30. The reaction mixture was allowed to cool to RT and HCl 2N (7 mL) was slowly added. The suspension was aged for 15 min. The resulting solid was filtered, washed with water/MeOH and dried under vacuo. The solid was slurried in refluxing EtOH (20mL) for 1 h, then cool down to RT and aged for 1 h. The suspension was filtered, the solid was washed with EtOH (2*10mL) and dried under vacuo to afford the desired product.

[0971] Molecular weight: 443.1 ; LC-MS, molecular weight observed: 441.2-443.3/443.1-445.1

[0972] 1H NMR (400 MHz, CDCl3) d 13.90 (s, 1H), 8.35 (s, 1H), 7.97 (s, 1H), 7.58 (s, 1H), 4.21 (s, 2H), 4.00 (d, J = 6.4 Hz, 2H), 2.24 (dq, J = 13.3, 6.6 Hz, 1H), 1.12 (d, J = 6.7 Hz, 6H).

Table II. Illustrative compounds of the invention

BIOLOGICAL EXAMPLES Example 1. In vitro assays 1.1. PHH assay– version 1 1.1.1. Assay

[0973] This assay measures the effect of a test compound on the inhibition of the hepatitis virus B (HBV) replication compared to a reference compound after infection of primary human hepatocytes (PPH) with HBV. HBV surface antigen (HBsAg) is used as a marker for HBV infection. 1.1.2. Procedural Description

[0974] At day 0, PHH (CellzDirect, cat n° CZD-HMCPIS lot Hu8097) were seeded in pre-warmed collagen I coated 96well plates at 50000 cells/well in 125µL thawing/plating medium (William’s E medium with FBS, 1µM Dexamethasone and thawing/plating Cocktail A, CM3000). After 30 minutes incubation at room temperature, the plates were transferred to an incubator at 37°C, 5% CO ₂ . After 4-6 hours of incubation, the thawing/Plating medium was aspirated and refreshed with 100 µL/well Maintenance medium (William’s E Medium with 0.1µM Dexamethasone and Maintenance Cocktail B, CM4000). The assay plates were incubated overnight at 37°C, 5% CO ₂ .

[0975] On day 1, the medium was removed and 25 µL of fresh maintenance medium and 25 µL of HBV mix (final 1.5% DMSO) was added to the assay plates followed by test compound addition. The test compounds were added as a 6 point dose response starting from 1µM or 0.0625µM, 1/3 or 1/4 diluted with final 0.2% DMSO. The assay plates were incubated overnight at 37°C, 5% CO2.

[0976] On day 1 post infection, 50µL/well of HBV/cpd mix was removed from the assay plates and refreshed with 100µL of fresh maintenance medium followed by compound addition (final 0.2% DMSO). The assay plates were incubated for two days at 37°C, 5% CO ₂ .

[0977] On day 3 post infection the supernatant was harvested and frozen at -20°C. 100µL/well of fresh maintenance medium was added followed by test compound addition (final 0.2% DMSO). This harvesting and refreshment step was repeated after two or three days (day 5 or day 6 post infection).

[0978] Two days after the last refreshment step (day 7 or day 8 post infection), 100µL of supernatant was harvested. Harvested supernatant was then used for HBsAg ELISA.

[0979] HBsAg ELISA was performed according to the HBsAg ELISA kit (Diasource KAPG4SGE3). An HBsAg standard (active hepatitis B surface antigen (adw) full length protein, 4 mg/mL, Abcam, ab91276) 1/3 diluted in blocking buffer starting from 1.25 µg/mL and a no sample control were also included in the assay. Finally, absorbance read out (450nm) was measured. 1.1.3. Data Analysis

[0980] To normalize the results, negative controls (6 wells vehicle with no HBV infection at 0.2% DMSO) and positive (6 wells vehicle with HBV infection at 0.2% DMSO) controls are included in the experiments. [0981] Raw data were generated following read-out performed using an Envision machine and these were used to calculate percentage inhibition (PIN) using the control wells mentioned above, and to create Dose Response curves for individual compounds.

Table III. PHH assay IC50 for the illustrative compounds of the invention

1.2. PHH assay– version 1 1.2.1. Assay

[0982] The principle of the assay is to measure the effect of a test compound on the inhibition of the hepatitis virus B (HBV) replication compared to a reference compound after infection of primary human hepatocytes (PPH) with HBV. HBV surface antigen (HBsAg) is used as a marker for HBV infection. 1.2.2. Procedural Description

[0983] On day zero, PHH (BioIVT, cat n° F00995-P, lot n° SHW) were thawed and seeded in pre-warmed, collagen I coated 384 well plates at 12,500 cells in 50 µL per well in thawing/plating medium (InvitroGRO CP medium supplemented with 1% Penicillin/streptomycin (P/S)). After ten (10) minutes incubation at room temperature, the plates were transferred to an incubator at 37°C, 5% CO2 for four (4) to six (6) hours of incubation. Afterwards, 40 µL of the medium was removed from the cells with the plate washer and 40 µL new prewarmed thawing/plating medium was added. The plates were incubated at 37°C, 5% CO2 overnight. [0984] Eight (8) point serial dilutions were made using 1/4 dilution steps in 100% DMSO starting from 10 mM as highest concentration, unless otherwise requested.

[0985] Eight (8) identical compound plates (two (2) copies to use per compound refreshment, four (4) compound additions in total) were prepared consisting of:

[0986] On the second day, 40 µL of the medium was removed from the cells with the plate washer. Test compound series and negative control (vehicle with no HBV infection) wells (DMSO) were diluted 1/857 in 60 µL virus mix containing 0.25 µL of virus (stock 2018, Heidelberg, HBV genotype D) in maintenance medium supplemented with 1.5% DMSO and 4% polyethylene glycol. Positive control (vehicle with no HBV infection) wells (DMSO) were diluted 1/857 in 60 µL maintenance medium supplemented with 1.5% DMSO and 4% polyethylene glycol (no virus). 40 µL of diluted test compound series/controls was transferred to the assay plates (final 2% DMSO). Afterwards the assay plates were centrifuged for five (5) minutes at 1000 rpm. The assay plates were incubated at 37°C, 5% CO2 for 20-24 hours.

[0987] The next day, the virus was removed and the test compounds were re-added: 40 µL medium (containing compound and HBV virus) was removed from the assay plates with the plate washer and 40 µL of 1/857 diluted compound series (same compound series as used on day 2), diluted in 60 µL maintenance medium, was added to the cells. The assay plates were incubated at 37°C, 5% CO ₂ for 3 days.

[0988] On day 6, 4 days post infection, the compounds were re-added: 40 µL medium (containing compound) was removed from the assay plates with the plate washer and 40 µL of the compound series, (same compound series as used on day 2 and day 3) diluted 1/857 in 60 µL Maintenance medium, was added to the cells. The assay plates were incubated at 37°C, 5% CO ₂ for 2 days.

[0989] Six (6) days post infection, 35 µL supernatant was harvested from the assay plates and stored at - 80°C for HBsAg ELISA.

[0990] One day before the ELISA, the ELISA plates were coated with a 1 in 100 dilution of Anti-HBs capture antibody in a 0.1 M sodium carbonate pH 9.5 buffer and incubated overnight at room temperature.

[0991] On the day of the ELISA, an HBsAg standard (active hepatitis B surface antigen (adw) full length protein, 3.5 mg/mL, Abcam, ab91276) 1/3 diluted in Maintenance medium starting from 2.48 µg/mL was made (2X standard).

[0992] The remaining of the HBS ELISA can be performed either in an automated mode or semi- automated. 1.2.2.1. HBsAg ELISA

[0993] The ELISA plates were washed twice with 90 µL PBS-T with the plate washer.60 µL of blocking buffer (PBS + 1% BSA + 0.1% casein) was added to the plates and incubated for minimum 1 hour at room temperature in order to block the plates.

[0994] After blocking, the blocking buffer was removed from the ELISA plates using a Bluewasher machine, and 20 µL of Maintenance medium was added to the ELISA plates.

[0995] 5 µL of 5X standard or harvested supernatant was transferred to the ELISA plates with 1 in 5 dilution in PBS. [0996] 20 µL HRP labeled detection antibody (Anti-HBs Peroxidase solution, DIASource, cat n° 4B07CONSE8) was added to the plates. The plates were incubated for 80 minutes at 37°C after which they were washed twice with 50 µL PBS-T and once with 50 µL PBS.

[0997] 40 µL of 1-Step Ultra TMB (ThermoFisher, cat n° 34028) was dropped on the plates to start the detection reaction. The plate was covered with a black cover and incubated at room temperature for 30 minutes. The reaction was stopped by adding 40 µL of STOP solution (R&D Systems, cat n° 895032).

[0998] Within 30 minutes after dropping the STOP solution, the absorbance at 450 nm was measured. 1.2.2.2. HBsAg ELISA

[0999] The ELISA plates were washed twice with 90 µL PBS-T with the plate washer.60 µL of blocking buffer (PBS + 1% BSA + 0.1% casein) was added to the plates and incubated for minimum 1 hour at room temperature in order to block the plates.

[1000] After blocking, the blocking buffer was removed from the ELISA plates by tapping the plates on tissue and 40 µL of Maintenance medium was added to the ELISA plates.

[1001] 10 µL of 5X standard or harvested supernatant was transferred to the ELISA plates (1 in 5 dilution).

[1002] Dilution may be adapted (1 in 3 or 1 in 4) to fit samples in the linear range of the standard curve depending on the infection level obtained for the specific run.

[1003] 20 µL HRP labeled detection antibody (Anti-HBs Peroxidase solution, DIASource, cat n° 4B07CONSE8) was added to the plates.

[1004] The plates were incubated for 80 minutes at 37°C after which they were washed twice with 50 µL PBS-T. The plates were tapped to dry, washed once with 50 µL PBS and tapped to dry again.

[1005] 40 µL of 1-Step Ultra TMB (ThermoFisher, cat n° 34028) was dropped on the plates to start the detection reaction. The plate was covered with a black cover and incubated at room temperature for 30 minutes. The reaction was stopped by adding 40 µL of STOP solution (R&D Systems, cat n° 895032).

[1006] Within 30 minutes after dropping the STOP solution, the absorbance at 450 nm was measured. 1.2.3. Data Analysis

[1007] Raw data were generated using a Perkin Elmer Envision plate reader, dose response curved were plotted and percentage inhibition (PIN) calculation was calculated using the following Formula:

[1008] Wherein RLU = Relative Chemiluminescent Light Units (background subtracted) and p and n subscripts refer to each plate based average of positive and negative controls, respectively.

[1009] PIN values are plotted in concentration-response and IC50 values are derived applying 4-parameter nonlinear regression (sigmoidal) curve fitting. Table IV. PHH assay IC50 for the illustrative compounds of the invention

1.3. HepG2 NTCP assay 1.3.1. Assay

[1010] The principle of the HepG2-NTCP assay is to measure the effect of a test compound on the inhibition of the hepatitis virus B (HBV) infection compared to a reference compound. To be able to infect the hepatocellular carcinoma cells (HepG2) with HBV, HepG2 cells were stably transfected with the Na+- taurocholate co-transporting polypeptide (NTCP) receptor, also referred to as Sodium/bile acid cotransporter (SLC10A1), which is necessary for HBV infection. In this assay the HBV core antigen (HBcAg) is used as a marker of HBV infection. Nuclei count is used as an indication for compound toxicity. 1.3.2. Procedural Description

[1011] On day one, HepG2-NTCP cells ((Ni et al. 2014)) are seeded at 5000 cells in 50 µL per well in assay medium (DMEM high glucose supplemented with 10% non-heat inactivated (non HI) fetal bovine serum (FBS), 1% P/S, 1% L-glutamine and 1% MEM NEAA) in 384 well plate and incubated at 37°C, 5% CO2 overnight.

[1012] Compounds are prepared as 10 point serial dilutions using 1/3 dilution steps in 100% DMSO starting from 10 mM highest concentration, unless otherwise requested for very potent compounds, which started from 5mM or 1mM stock. Compounds are further diluted 1/500 in assay medium. [1013] A negative control (vehicle: 24 wells with 0.2% DMSO) and positive control (24 wells with 100nM Myrcludex B (Cas no.: 406461-66-3), 0.2% DMSO and in 10 point DR) are included in the experiments.

[1014] On the second day, 40µl medium is removed from the cells with the plate washer (Select 405 microplate washer, Biotek). 15 µL of diluted compound series is transferred to the assay plate and cells are infected with 15 µL of HBV mix (HBV virus, 4%PEG, 1%DMSO in assay medium). The infection is performed in assay medium containing final concentration of 1% DMSO. The assay plate is incubated at 37°C, 5% CO2 overnight.

[1015] The next day, 30µl compound and HBV mix are removed from the assay plate with the plate washer and 30 µL of compound series diluted 1/500 in assay medium containing final concentration of 2.5% DMSO is added to the cell assay plate. The assay plate is incubated at 37°C, 5% CO2 for 5 days.

[1016] After 5 days of incubation, supernatant is removed from the cells with the plate washer. Cells are fixed with 50 µL of 3.7% formaldehyde added with the Well mate (Matrix technologies) and incubated for 30 min at room temperature. After fixation, cells are washed four times with phosphate buffer saline (1xPBS, 137mM NaCl, 10mM na2HPO4, 2.7mM KCl, 1.8mM KH2PO4 at pH7.4). The cells are finally subjected to HBc staining.

[1017] First, the assay plate is blocked with blocking buffer (2%FBS, 3% BSA, 0.2% TritonX100 in PBS) for 1 h at room temperature (optional to block overnight at 4°C).

[1018] After 4 washes of PBST (1XPBS + 0.05% Tween) with the plate washer, the assay plate is incubated with 30 µL diluted primary antibody (1/700 Rabbit anti-HBV core antigen, Dako, B0586 or 1/350 Rabbit anti HBV core antigen, Invitrogen, PA516368) in blocking buffer and incubated for 90 min at room temperature.

[1019] After 4 washes of PBST with the plate washer, the assay plate is incubated with 50 µL of secondary antibody (Donkey-anti-rabbit Alexa 488 antibody, Lifetechnologies A21206) 1/500 diluted in blocking buffer and incubated for 60 min at room temperature and in the dark.

[1020] The assay plate is washed 4 times with PBST on the plate washer and incubated with 50µL of DAPI (Sigma D9542, stock 5mg/mL) 1/10000 diluted in PBS for 15-30 min at room temperature and in the dark. The assay plate is now ready for read out on the InCell Analyzer 2200 (GE Healthcare). 1.3.3. Data Analysis

[1021] Raw data are generated following read-out performed on InCell 2200 and are imported into the galapagos LIMS for automated calculation of percentage inhibition (PIN) and toxicity by nuclei count, using the control wells mentioned above, and creation of Dose Response curves.

Table V. Hepg2 NTCP assay activity of illustrative compounds of the invention

1.4. Neurite outgrowth assay 1.4.1. Principle of the assay

[1022] This assay evaluates the effect of the compounds of the invention on the survival and health of neurites in a co-culture of rat neuronal and glial cells derived from foetuses.

[1023] A neuronal marker (MAP2) present in the cell bodies and neurites is then used to study of neuron survival and the length of the neurite network. The total number of nuclei for all cell types is then determined using Hoescht staining providing a measure of the overall health of the co-culture. 1.4.2. Methods and experimental design 1.4.2.1. Primary culture of sensory neurons and Schwann cells

[1024] All experiments are carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and followed current European Union regulations (Directive 2010/63/EU). Primary sensory neurons and Schwann cells are cultured as previously described (Callizot et al.2011). Pregnant female rats of 15 days gestation (Rats Wistar; Janvier Labs France) are sacrificed and fetuses are collected and immediately placed in ice-cold L15 Leibovitz medium with a 2 % penicillin (10,000 U/mL) and streptomycin (10 mg/mL) solution (PS) and 1 % bovine serum albumin (BSA). Dorsal root ganglion (DRG) from spinal cord are treated for 20 min at 37 °C with a trypsin- EDTA solution at a final concentration of 0.05% trypsin and 0.02 % EDTA to dissociate sensory neurons from Schwann cells. The dissociation is stopped by addition of Dulbecco’s modified Eagle’s medium (DMEM) with 4.5 g/L of glucose, containing DNAse I grade II (final concentration 0.5 mg/mL) and 10 % fetal calf serum (FCS). Cells are mechanically dissociated through the tip of a 10 mL pipette. Cells are then centrifuged at 515 x g for 10 min at 4°C. DMEM F12 with a 1 % solution of N ₂ supplement, 2 mmol/L of L-glutamine, 2 % of PS solution, nerve growth factor (NGF) (5ng/mL, sigma aldrich) and neurotrophic factor 3 (NT3) (5ng/mL). Cells are seeded at a density of 15,000 per well in 96-well plates pre-coated with poly-L-lysine and are cultured at 37°C in an air (95%) - CO2 (5%) incubator. The medium is changed every 2 days. For 96 wells plates, only 60 wells are used. The wells of first and last lines and columns are not used (to avoid the edge effect) and are filled with sterile water. 1.4.2.2. Application of test compounds

[1025] On day 13 of culture, NGF (5 ng/mL) or the compounds (different concentrations) are incubated with primary sensory neurons for 96h (for the compounds).

[1026] On day 15, vincristine (10 ng/mL) which induces neuropathy, is incubated for 24 h a wash-out is done and the read-out is performed after 24 h (i.e.48 h after the vincristine application). 1.4.2.3. End point evaluation via immunostaining: MAP-2 (survival and neurite network)

[1027] On day 19 (96 h incubation of the compounds), the cell culture supernatant are discarded using automatic multichannel pipets. The sensory neurons are fixed by a cold solution of ethanol (95%) and acetic acid (5%) for 5 min at -20°C.

[1028] After permeabilization with 0.1 % of saponin, cells are incubated for 2 h with a mouse monoclonal antibody anti-microtubule-associated-protein 2 (MAP-2) (cat# M4403, Sigma), at a dilution of 1/400, in PBS containing 1 % fetal calf serum and 0.1 % saponin. This antibody are revealed with an Alexa Fluor 488 goat anti-mouse IgG (1/400 dilution) (cat# SAB4600042-250UL, Sigma) in PBS containing 1 % FCS, 0.1 % saponin, for 1 h at room temperature.

[1029] For each condition, 30 pictures per well are automatically taken using ImageXpress (Molecular Devices) at 20x magnification. All images are generated using the same acquisition parameters. From images, analyses are directly and automatically performed by Custom Module Editor (Molecular Devices). The following read-outs will be investigated:

- a. The total neuron survival (MAP-2 positive, number), (data is expressed into mean number of neurons of 30 pictures per well).

- b. The total neurite network (MAP-2 in mm), (data is expressed into total length of neurites).

[1030] These endpoints are automatically determined using Custom Module Editor (Molecular Devices). 1.4.3. Statistical analysis

[1031] All values are expressed as mean +/- SEM (standard error of the mean). Statistical analysis is performed by one-way ANOVA, followed by a Fisher’s LSD test.

Table VI. Neurite assay results

[1032] When submitted to this assay, the illustrative compounds of the invention tested according to this protocole show a good profile on the survival and health of neurites.

[1033] In particular at 1µM, all the illustrative compounds of the invention tested show a good profile on the survival and health of neurites (survival ³ 90%, lenght, ³ 91%, nuclei count ³ 88%) which in turn may result in a good safety profile.

[1034] At 3 µM, Cpd_001, Cpd_010, Cpd_028, Cpd_054, Cpd_059, Cpd_072, Cpd_073, Cpd_080, Cpd_082, Cpd_084, Cpd_085, Cpd_103, Cpd_114, Cpd_115, Cpd_116, Cpd_124, Cpd_126, Cpd_128, and Cpd_142 show ³ 90% survival in all end points.

[1035] At 10 µM, Cpd_001, Cpd_028, Cpd_054, Cpd_073, Cpd_080, Cpd_082, Cpd_084, Cpd_085, Cpd_103, and Cpd_126 show ³ 90% survival in all end points. Example 2. In vivo assays 2.1. Humanized Mouse model of HBV infection in human-murine liver chimeric mice 2.1.1. Animals

[1036] Six to ten weeks old male or female FRG KO mice (Fah-/-/Rag2-/-/Il2rg-/-triple knock-out- Yecuris Corporation P.O. Box 4645, Tualatin, OR 97062, USA) are used. They are provided with filtered tap water and standard chow ad libitum and maintained at 22 ± 2°C in 55 ± 10% humidity on a 12h light/dark cycle. 2.1.2. Humanisation process

[1037] Each mouse is repopulated by intra splenic injection of 1 to 2 106 human hepatocytes (Life Technologies ref HMCS2SA). To allow a progressive and efficacious repopulation, drinking water is regularly supplemented with Nitisinone (Yecuris, lot TNAK0002). The repopulation rate is controlled by hAlb dosage in serum (Euromedex ref E88-129). About 3 to 4 months after the human hepatocyte injection, mice for which repopulation is successful reach an hAlb level >1g/L and can be used for HBV infection. 2.1.3. Compounds preparation

[1038] The test compounds for p.o administration are formulated in Solutol at 2% (Sigma: Kolliphor hS15 12966-1kg lot BCBM0868V) and methylcellulose 0.5% at 98% 2.1.4. HBV infection

[1039] Each mouse is injected with HBV-2015 batch (6.6 106 copies/µL) with an inoculum of 1.38 108 GE HBV (0.2 mL) via tail vein.

[1040] Six to seven weeks after infection, blood is sampled under isoflurane anesthesia by retro-orbital puncture. HBsAg is dosed in serum by Elisa assay (Immunodiagnostic, ref HBSAG EIA). HBV DNA level is measured in the mice serum using qPCR (SYBR green). Only mice reaching HBsAg level above 1000UI/mL are kept and randomized.

[1041] Treatment is given for 5 weeks according to body weight.

[1042] Body weight is recorded every week.

[1043] Between Day 7 and Day 11, a steady state PK is performed with sampling of blood under isoflurane anesthesia by retro-orbital puncture at T=0, 1h, 3h, 6h post treatment. Plasma are frozen before decontamination with ethanol absolute 80% and transfer to bioanalysis laboratory for compound dosage by LCMS-MS.

[1044] At D8, D8, D15, D22 and D28, blood is sampled under isoflurane anesthesia by retro-orbital puncture. To follow compounds efficacy, HBsAg is dosed in serum by Elisa assay (Immunodiagnostic, ref HBSAG EIA) and HBV DNA level is measured in serum using qPCR (SYBR green).

[1045] After 5 weeks of treatment, mice are euthanized 2 hours after the last dosing for liver and blood collection or treatment is stopped and the mice monitored for a further 2 weeks to determine durability of treatment effect. [1046] In blood HBsAg is measured by Elisa assay, HBV DNA by qPCR and compound level by LCMS- MS.

[1047] In liver HBV DNA is measured by qPCR, compound level by LCMS-MS, pgRNA by RT-qPCR, HBcAg by immunohistochemistry (Dako ref B0586). Example 3. Pharmacokinetic, ADME and Toxicity Assays 3.1. Thermodynamic solubility

[1048] The test compound is added to 0.2M phosphate buffer pH 7.4 or 0.1M citrate buffer pH 3.0 at a concentration of 1 mg/mL in a glass vial.

[1049] In a 20 mL glass vial, 1-2 mg of dry matter of compound are added and stirred with the suitable buffer (Fed State Simulated Intestine Fluid FeSSIF, or Fasted State Simulated Intestine Fluid FaSSIF, or Fasted State Simulated gastric Fluid FaSSGF, or phosphate buffer pH7.4) for 24h at room temperature (for the buffer pH7.4) or 37°C (for the 3 physiological buffers) under magnetic stirring (200tr/min). The concentration of the mixture is 1mg/mL.

[1050] After 24 h, a volume of 500µL is sampled, centrifuged for 10 min at 10000 rpm and filtered. The samples are diluted in duplicates in DMSO (F100 and F10). Then, a final dilution (factor 100) in 80/20 water/acetonitrile containing the internal standard (warfarin) is used for LCMS-MS analysis.

[1051] A standard curve is made starting from a 200,000 ng/mL stock in DMSO, freshly prepared from dry matter. Then, successive concentrations at 15,000, 10,000, 2,500, 1,000, 200 and 75 ng/mL in DMSO are prepared by using the Tecan robot.

[1052] Two quality control samples are made: one of 10,000ng/mL and one of 500 ng/mL in DMSO, also starting from the DMSO working stock solution at 200,000 ng/mL.

[1053] The standard curve and quality controls are diluted a factor 100 in 80/20 water/acetonitrile (with internal standard) and analyzed on LC-MS/MS (API4000 or API5500).

[1054] The samples are analyzed on LC-MS with a flow rate of 0.6mL/min. The mobile phase A is 0.1% formic acid in water and the mobile phase B is 0.1% formic acid in acetonitrile. The sample is run under positive or negative ion spray on Pursuit C18-5µm (2.0 x 20mm) column, from Agilent.

[1055] The peak areas of the standard curve are plotted in a graph and a linear or polynomial of the second order equation is used to calculate the unknown concentrations of the test compound.

[1056] Solubility values are reported in µM and µg/mL. 3.2. Aqueous Solubility

[1057] Starting from a 10 mM stock solution of compound in DMSO, a second concentration in DMSO of 3mM is prepared.

[1058] Both DMSO concentrations will be diluted in 0.1 M phosphate buffer pH 7.4, by adding 200 µL of buffer to 2 µL stock solutions in DMSO. The final concentrations are 100 and 30 µM with a final DMSO concentration of 1%. Measurements are done in duplicate. [1059] As a positive control for precipitation, Pyrene is added to the corner points of each 96 well plate and serves as a reference point for calibration of Z-axis on the microscope. As a negative control, DMSO is added to the 12 wells on columns between positive control wells.

[1060] The assay plates are sealed and incubated for 1 h at 37°C while shaking at 230rpm.

[1061] The plates are then scanned under a white light microscope using a Nikon microscope, yielding individual pictures (20x) of the precipitate per concentration.

[1062] The precipitate is analyzed visually:

- If a precipitate is observed at 100µM and at 30µM, the data generated will be: <30µM

- If a precipitate is observed at 100µM but not at 30µM, the data generated will be: >30µM

- If no precipitate is observed (neither at 30 or at 100µM), the data generated will be: >100µM

[1063] Solubility values measured according to this protocol are reported in µM and in µg/mL. 3.3. Plasma Protein Binding PPB (Equilibrium Dialysis)

[1064] Prior to the start of the experiment, dialysis membranes (membrane strips, MW cut-off 12-14kDa, HTDialysis, Cat.No.#1101) are soaked in deionized water for 60 min, transferred and left overnight in 20% ethanol.

[1065] A 10mM stock solution of the compound in DMSO is diluted with a factor 10 in DMSO. This solution is further diluted in freshly thawed human, rat, mouse or dog plasma (BioReclamation INC) with a final concentration of 5 µM and final DMSO concentration of 0.5%.

[1066] Equilibrium Dialysis Device (96-well, model HTD96b, HTDialysis, Cat.No.#1006) is assembled according to manufacturer’s instructions. Immediately after assembly, a volume of 100µL of plasma (spiked with compound) is placed on one side of the well and another 100 µL of blank PBS buffer are added to the other side, respectively. Each compound is tested in duplicate.

[1067] Acebutolol and Nicardipine are used as low and very high binding controls.

[1068] The plate is incubated for 4 h at 37°C while shaking at 230 rpm.

[1069] Thereafter, an aliquot is taken from each side of the well and matrix matched (mix of equal volumes of spiked plasma with blank PBS buffer and samples from buffer compartment with blank plasma).

[1070] Matrix matched samples are further mixed with 4 volumes of STOP solution (acetonitrile with warfarin as internal standard). After brief mixing and centrifugation (at 2400 rpm for 15 min, at +4ºC), the supernatant is filtered and transferred into new 96-well plates for analysis on LC-MS/MS (systems API4000 or API5500).

[1071] The samples are analyzed on LC/MS-MS with a flow rate of 0.6mL/min. The mobile phase A is 0.1% formic acid in water and the mobile phase B is 0.1% formic acid in acetonitrile. The sample is run under positive or negative ion spray on Pursuit C18-5µm (2.0 x 20mm) column, from Agilent. The solvent gradient has a total run time of 1.2 min with a gradient profile as followed:

[1072] The percentage bound in plasma (PPB) is determined using the following equation:

C _plasma = compound concentration in plasma

Cbuffer = compound concentration in buffer

“Concentration” is the ratio between compound and internal standard peak areas.

[1073] The solubility of the compound in the final test concentration in PBS is checked by microscope to indicate whether precipitation is observed or not. If a precipitate is observed, no data of PPB is generated. 3.4. Liver microsomal stability

[1074] A 10 mM stock solution of compound in DMSO is diluted a factor 3 in DMSO. This pre-dilution in DMSO is further diluted to 2 µM in a 100 mM phosphate buffer pH 7.4 and pre-warmed at 37°C. This compound dilution is mixed factor 2 with microsomal/cofactor mix at 37°C under shaking at 300 rpm.

[1075] Each compound is tested in duplicate. Warfarin and Verapamil are included in the assay as reference molecules.

[1076] A glucose-6-phosphate-dehydrogenase (G6PDH, Sigma Aldrich) working stock solution of 700U/mL is diluted with a factor 1:700 in a 100mM phosphate buffer, pH7.4. A co-factor mix containing 0.528 M MgCl2.6H2O (Sigma, M2670), 0.528M glucose-6-phosphate (Sigma, G-7879) and 0.208M NADP+ (Sigma,N-0505) is diluted with a factor 1:8in a 100mM phosphate buffer, pH 7.4.

[1077] A working solution is made containing 1 mg/mL liver microsomes of the species of interest (human, mouse, rat, dog), 0.6U/mL G6PDH and co-factor mix (6.6mM MgCl2, 6.6 mM glucose-6- phosphate, 2.6mM NADP+). This mix is pre-incubated for 15 min, but never more than 20 min, at room temperature.

[1078] After pre-incubation, compound dilution and the mix containing the microsomes, are added together in equal amount and incubated for 30 min at 300 rpm and 37°C.

[1079] The final concentrations during incubation are: 1µM test compound or control compound, 0.5 mg/mL microsomes, 0.6U/mL G6PDH, 3.3mM MgCl2, 3.3mM glucose-6-phosphate and 1.3mM NaDP+.

[1080] After 30 min of incubation, the reaction is stopped with 2 volumes of stop solution (containing acetonitrile with Diclofenac as internal standard). For the time point of 0 min, two volumes of stop solution are added to the compound dilution before the microsome mix is added.

[1081] Samples of both time points are centrifuged, filtered and the supernatant is harvested for analysis on LC-MS/MS (API5500 system).

[1082] The samples are analyzed on LC/MS-MS with a flow rate of 0.6mL/min. The mobile phase A is 0.1% formic acid in water and the mobile phase B is 0.1% formic acid in acetonitrile. The sample is run under positive or negative ion spray on Pursuit C18-5µm (2.0 x 20mm) column, from Agilent. The solvent gradient has a total run time of 2.2 min with a gradient profile as followed: [1083] The instrument responses (peak areas/IS peak area) are referenced to the zero time-point samples (considered as 100%) in order to determine the percentage of compound remaining.

[1084] The data of microsomal stability are expressed as a percentage of the total amount of compound remaining after 30 min.

[1085] The solubility of the compound in the final test concentration in 100mM buffer pH 7.4 is checked by microscope to indicate whether precipitation is observed or not. If a precipitate is observed, no data of microsomal stability is generated. 3.5. Hepatocyte stability

[1086] A 10 mM DMSO stock solution is first diluted in DMSO (0.33 mM and 3.3 mM) and then in modified Krebs-Henseleit buffer (KHB, Sigma). In addition, third compound dilution was obtained by diluting 10 mM DMSO stock dilution directly in KHB. These compound dilutions in KHB (0.5 µM, 5 µM and 50 µM) were further added to a suspension of pooled cryopreserved hepatocytes (Bioreclamation IVT) at 37°C with gentle shaking.

[1087] Final reaction conditions were 0.1µM, 1 µM and 10 µM of compound (n=2 per concentration), 0.03% DMSO (0.1% for 10 µM concentration), 0.5 million viable hepatocytes/mL, 75 µL incubation volume.

[1088] Testosterone (1 µM) and 7-Hydroxycoumarin (1 µM) were used as Phase I and Phase II reaction controls, while caffeine was used as a negative control.

[1089] A full time curve (with: 0, 10, 20, 45, 90, 120 and 180 min of incubation) is done with hepatocytes from species of interest (mouse, rat, dog, minipig, monkey or human).

[1090] After the respective time of incubation, the reaction (75 µL) was terminated by adding 225 µL of acetonitrile:methanol (2:1) containing 100 ng/mL of diclofenac as analytical internal standard. Samples were mixed, centrifuged and the supernatant analyzed by LC-MS/MS.

[1091] The instrument responses (peak areas/IS peak area) are referenced to the zero time-point samples (considered as 100%) in order to determine the percentage of compound remaining. 3.6. MDCKII-MDR1 Permeability

[1092] MDCKII-MDR1 cells are Madin-Darby canine kidney epithelial cells, over-expressing human multi-drug resistance (MDR1) gene, coding for P-glycoprotein (P-gp). Cells are obtained from Netherlands Cancer Institute and used after a 3-4 day cell culture in 24-well Millicell cell culture insert plates (Millipore, PSRP010R5). Bi-directional MDCKII-MDR1 permeability assay is performed as described below. [1093] 3x105 cells/mL (1.2x105 cells/well) are seeded in plating medium consisting of DMEM + 1% glutamax-100 + 1% Antibiotic/Antimycotic + 10% FBS (Biowest, S1810). Cells are left in CO2 incubator for 3-4 days. The medium is changed 24h after seeding and on the day of experiment.

[1094] Test and reference compounds (amprenavir and propranolol) are prepared in Dulbecco’s phosphate buffer saline (D-PBS, pH 7.4) and added to either the apical (400 µL) or basolateral (800 µL) chambers of the Millicell cell culture insert plates assembly at a final concentration of 10 µM (0.5 µM in case of amprenavir) with a final DMSO concentration of 1%.

[1095] 100 µM Lucifer Yellow (Sigma) is added to the all donor buffer solutions, in order to assess integrity of the cell monolayers by monitoring Lucifer Yellow permeation. Lucifer yellow is a fluorescent marker for the paracellular pathway and it is used as an internal control in every monolayer to verify tight junction integrity during the assay.

[1096] After a 1 h incubation at 37°C while shaking at an orbital shaker at 150 rpm, 75 µL aliquots are taken from both apical (A) and basal (B) chambers and added to 225µL acetonitrile:water solution (2:1) containing analytical internal standard (10 ng/mL warfarin) in a 96 well plate. Aliquoting is also performed at the beginning of the experiment from donor solutions to obtain initial (Co) concentration.

[1097] Concentration of compound in the samples is measured by high performance liquid- chromatography/mass spectroscopy (LC-MS/MS).

[1098] Lucifer yellow is measured with a Fluoroscan Ascent FL Thermo Scientific (Ex 485nm and Em 530nm) in a 96 well plate containing 150 µL of liquid from all receiver wells (basolateral or apical side). 3.7. Pharmacokinetic study in rodents 3.7.1. Animals

[1099] Sprague-Dawley rats (male, 5-6 weeks old) and CD1(male, 18-20g) mice are obtained from Janvier (France). Rats are acclimatized for at least 4 days before treatment and are kept on a 12 h light/dark cycle (0700-1900). Temperature is maintained at approximately 22°C, and food and water are provided ad libitum. Rats and mice are deprived of food for at least 16 h before oral dosing and 4 h after. Water is provided ad libitum. 3.7.2. Pharmacokinetic study

[1100] Compounds are formulated in PEG200/water (60/40) or DMSO/PBS (1/99) +/-2eq NaOH for the intravenous route and in Solutol/0.5% methylcellulose (2/98) for the oral route. Test compounds are orally dosed as a single esophageal gavage at 5 mg/kg under a dosing volume of 5 mL/kg and intravenously dosed as a bolus via the caudal vein at 0.1 mg/kg under a dosing volume of 5 mL/kg. Each group consisted of 3 rats or 3 to 6 mice (if composite design). Blood samples are collected at the retro-orbital sinus under light anaesthesiausing lithium heparin as anti-coagulant at the following time points: 0.05, 0.25, 0.5, 1, 3, 6 and 24 h (intravenous route), and 0.25, 0.5, 1, 3, 5, 6 and 24 h (oral route). Alternatively, blood samples are collected at the retro-orbital sinus with lithium heparin as anti-coagulant at the following time points 0.25, 1, 3 and 6 h (oral route). Whole blood samples are centrifuged at 2,800 x g for 10 min and the resulting plasma samples are stored at -20°C pending analysis 3.7.3. Quantification of compound levels in plasma

[1101] Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive electrospray mode. 3.7.4. Determination of pharmacokinetic parameters

[1102] Pharmacokinetic parameters are calculated using Phoenix® (Certara®). 3.8. Liability for QT prolongation

[1103] Potential for QT prolongation is assessed in the hERG patch clamp assay.

[1104] The method used is the IonFlux HT automated whole cell patch-clamp instrument to record outward potassium currents.

[1105] HEK-293 cells stably transfected with human hERG cDNA are used. The cells are harvested by trypsinization and maintained in Serum Free Medium at room temperature before recording. The cells are washed and re-suspended in Extracellular Solution before being applied to the automated patch-clamp instrument.

[1106] The test solutions are prepared in the Extracellular Solution on the day of patch-clamp assay. The assay can tolerate up to 1% DMSO.

[1107] The intracellular Solution contained (in mM): 70 KF, 60 KCl, 15 NaCl, 5 HEPES, 5 EGTA, 4 MgATP (pH 7.3 by KOH)

[1108] The extracellular Solution contained (in mM): 137 NaCl, 4 KCl, 1 MgCl2, 1.8 CaCl2, 10 HEPES, 10 glucose (pH 7.35 by NaOH)

[1109] After whole cell configuration is achieved, the cell is held at -80 mV. A 50 ms pulse to -50 mV is delivered to measure the leaking current, which is subtracted from the tail current. Then the cell is depolarized to +30 mV for 800 ms, followed by a 1200 ms pulse to -50 mV to reveal the hERG tail current. This paradigm is delivered once every 5 s to monitor the current amplitude. The assay is conducted at room temperature. The Extracellular Solution (control) is applied first and the cell is stabilized in the solution for 3 min. Then the test compound is applied from low to high concentrations sequentially on the same cell, the cells are perfused with each test concentration for 3 min.

[1110] A reference compound (E-4031– CAS# 113559-13-0) is tested concurrently at multiple concentrations to obtain an IC ₅₀ value.

[1111] The percent inhibition of hERG channel is calculated by comparing the tail current amplitude before and after application of the compound (the current difference is normalized to control). FINAL REMARKS

[1112] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.

[1113] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[1114] It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.

[1115] At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control. REFERENCES

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