Dihydrothiopyranopyrimidine compound and use thereof

Abstract

The present invention relates to a dihydrothiopyranopyrimidine compound exhibiting phosphodiesterase-4 (PDE-4) inhibitory activity, and more specifically, to: a dihydrothiopyranopyrimidine compound exhibiting excellent PED-4B inhibitory activity, an optical isomer, stereoisomer, solvate, isotopic variant, or tautomer thereof, or a pharmaceutically acceptable salt thereof; and a use thereof in the prevention, amelioration, or treatment of diseases caused by PDE-4 activity.

Description

Dihydrothiopyranopyrimidine compounds and uses thereof

[0001] The present invention relates to a dihydrothiopyranopyrimidine compound exhibiting phosphodiesterase-4 (PDE-4) inhibitory activity, and more particularly, to a dihydrothiopyranopyrimidine compound exhibiting excellent PDE-4B inhibitory activity, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, and its use in the prevention, improvement or treatment of diseases caused by the activity of PDE-4.

[0002] Idiopathic pulmonary fibrosis (IPF), classified as a rare disease, is a type of interstitial lung disease in which fibrosis progresses chronically in the alveoli or the tips of the alveolar walls, preventing smooth gas exchange within the lungs, ultimately leading to respiratory failure and death.

[0003] The normal function of the inflammatory response is to suppress cell damage in the early stage, remove destroyed tissue and necrotic cells, and at the same time, aim for tissue regeneration. In contrast, inflammation that causes fibrosis is characterized by a predominance of fibrotic tissue remodeling, such as myofibroblasts that amplify fibrosis and promotion of angiogenesis, rather than normal tissue remodeling, leading to excessive accumulation of extracellular matrix (ECM) in organs, which progresses fibrosis. Damage to alveoli caused by inflammation is known to result in the influx of inflammatory cells (neutrophils, macrophages, and T cells), and the recruited cells induce the activation of proinflammatory cytokines (IL-1, TNF-α, IL-13) and TGF-β. Since the TGF-β pathway is the most important mechanism in fibrotic diseases, the development of drugs that can effectively inhibit the TGF-β pathway is necessary.

[0004] Cyclic adenosine monophosphate (cAMP) is a second messenger that mediates cellular biological responses to a wide range of extracellular stimuli. When an appropriate agonist binds to a specific cell surface receptor, adenylate cyclase (AC) is activated, converting adenosine triphosphate (ATP) to cAMP. Agonist-induced intracellular actions of cAMP are primarily mediated by cAMP-dependent protein kinases, enzymes implicated in many diseases and conditions, including asthma, psoriasis, atopic dermatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, and inflammation. Literature has shown that increased cAMP inhibits the subsequent release and activation of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), or relaxes airway smooth muscle.

[0005] Phosphodiesterases (PDEs) are a superfamily of enzyme systems that include 11 families, and each PDE can be further classified into four or more isotypes. The main role of PDEs is to hydrolyze the ester bond of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), thereby participating in various signal transductions and regulating physiological processes. The primary cellular mechanism of cAMP activation is known to be the degradation of cAMP by a family of isoenzymes called PDEs, and in particular, PDE-4 is an intracellular non-receptor enzyme that is mainly present in immune cells, epithelial cells, and brain cells and regulates inflammatory responses and the integrity of epithelial tissues. It plays a major regulatory role in the expression of inflammatory and anti-inflammatory mediators, and therefore PDE-4 inhibitors can suppress the release of harmful mediators derived from inflammatory cells. Indeed, inhibition of PDE-4 increases the concentration of cAMP in the body, thereby activating protein kinase A (PKA), which can inhibit inflammation and fibrosis through the regulation of a wide range of genes and proteins. Therefore, compounds that specifically inhibit PDE-4 could help suppress inflammation and relax airway smooth muscle while minimizing undesirable side effects such as cardiovascular or antithrombotic effects. The PDE-4 family is the most specific for selective cAMP activation and currently consists of at least four isoenzymes (a through d), with inhibition of PDE-4B being recognized as particularly effective in suppressing inflammation- and fibrosis-mediated release.

[0006] PDE-4 inhibitors such as Roflumilast, Apremilast, and Crisaborole have been approved for the treatment of inflammatory airway diseases, psoriasis, and atopic dermatitis, respectively. However, the major side effects of these approved drugs include vomiting, nausea, and gastrointestinal side effects, which have limited their use as second- or third-line treatments rather than first-line treatments. However, most of the known side effects are reported to be manageable. The main cause of side effects is known to be on-target side effects due to inhibition of PDE-4D among the PDE-4 subtypes. Therefore, securing selectivity for PDE-4D is necessary. However, various efforts to discover and optimize conjugates that selectively target the catalytic binding site of PDE-4B have not met expectations. Theoretically, various literature studies have confirmed that selective inhibition of PDE-4B alone significantly reduces known side effects. Therefore, securing novel derivatives with selectivity for PDE-4B / PDE-4D has the potential to reduce the risk of gastrointestinal toxicity.

[0007] The present invention aims to provide a dihydrothiopyranopyrimidine derivative compound having excellent PDE-4B inhibitory activity, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] In addition, another object of the present invention is to provide a pharmaceutical composition for preventing, improving or treating a disease caused by PDE-4 activity, comprising the dihydrothiopyranopyrimidine derivative compound as an active ingredient, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0009] In addition, another object of the present invention is to provide a use of the dihydrothiopyranopyrimidine derivative compound, or an optical isomer, stereoisomer, solvate, isotope variant or tautomer thereof, or a pharmaceutically acceptable salt thereof, in the prevention, improvement or treatment of a disease caused by the activity of PDE-4.

[0010] In addition, another object of the present invention is to provide a method for preventing, improving or treating a disease caused by the activity of PDE-4 by administering the dihydrothiopyranopyrimidine derivative compound, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0011] In one aspect of the present invention, a compound represented by the following chemical formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof may be provided:

[0012] [Chemical Formula 1]

[0013]

[0014] In the above chemical formula 1, X 1 , X 2 , X 3 , X 4 , A, L 1 , R 1 , L 2 , R 2 , n and R 3 is as defined herein.

[0015] In another aspect of the present invention, a pharmaceutical composition for preventing, improving or treating a disease caused by PDE-4 activity is provided, comprising a compound of the above chemical formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with a pharmaceutically acceptable carrier.

[0016] In another aspect of the present invention, the compound of formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, is provided for use in the prevention, improvement or treatment of a disease caused by the activity of PDE-4.

[0017] According to the present invention, a dihydrothiopyranopyrimidine derivative compound exhibiting an excellent PDE-4B inhibitory effect, or an optical isomer, stereoisomer, solvate, isotopic variant, or tautomer thereof, or a pharmaceutically acceptable salt thereof, can be provided. Therefore, the dihydrothiopyranopyrimidine derivative compound, or an optical isomer, stereoisomer, solvate, isotopic variant, or tautomer thereof, or a pharmaceutically acceptable salt thereof, can be effectively used for the prevention, improvement, or treatment of diseases caused by the activity of PDE-4.

[0018] Hereinafter, the present invention will be described in detail.

[0019]

[0020] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, numerical values ​​described herein are considered to include the meaning of "about" unless explicitly stated otherwise. All publications and other references mentioned herein are incorporated herein by reference in their entirety.

[0021]

[0022] According to one aspect of the present invention, a compound represented by the following chemical formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0023] [Chemical Formula 1]

[0024]

[0025] In the above chemical formula 1,

[0026] X 1 is S(=O) or S(=O)2;

[0027] X 2 , X 3 and X 4 are each independently CH, C-halo or N;

[0028] A is a saturated or partially unsaturated heterocyclylene;

[0029] L 1 is a direct bond, -C(=O)-, -NR 4 C(=O)-, -C(=O)NR 4 - or -NR 4 - and here R 4 is -H or alkyl;

[0030] R 1 is halo, alkyl, partially unsaturated carbocyclyl, aryl, saturated or partially unsaturated heterocyclyl or heteroaryl; wherein said saturated or partially unsaturated heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halo, oxo (=O), alkyl, cycloalkyl and alkoxy; wherein said aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, cyano (-CN), alkyl, haloalkyl and alkoxy;

[0031] L 2 is a direct bond, -CHR5 -, -CHR 5 C(=O)-, -C(=O)-, or -CR 6 R 7 - and here R 5 is -H, hydroxy or alkyl; R 6 and R 7 are linked to each other by carbon atoms to form cycloalkyl;

[0032] R 2 is hydroxy, halo, carboxy(-COOH), amino, alkyl, alkoxy, cycloalkyl, hydroxyalkyl, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkylamino, haloalkylamino, cycloalkyl-alkylamino, heterocycloalkyl or heteroaryl; wherein said heterocycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, alkyl, alkoxy and hydroxyalkyl;

[0033] n is 1 or 2;

[0034] R 3 is -H or alkyl;

[0035] The above heterocycloalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylene and heteroaryl have one or more heteroatoms selected from N, O and S,

[0036] Only R 1 If A is a heteroaryl having these two N atoms, it is not a partially unsaturated heterocyclene.

[0037]

[0038] Unless otherwise specified, the following terms used in the present invention have the meanings set forth below. Any undefined term has the meaning understood in the art.

[0039] The term “halo” or “halogen” as used herein, either alone or in combination with other additional terms (e.g., haloalkyl), means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0040] The term “hydroxy” as used herein, alone or in combination with other terms (e.g., hydroxyalkyl), means -OH.

[0041] The term “cyano” as used herein means -CN.

[0042] The term “carboxy” as used herein means -COOH.

[0043] The term “oxo” as used herein means =O.

[0044] The term “amino” group as used herein may mean a primary, secondary or tertiary amino group bonded through a nitrogen atom, either alone or in combination.

[0045] As used herein, the term “alkyl,” either alone or in combination with additional terms (e.g., haloalkyl or hydroxyalkyl), means a radical of a straight or branched saturated aliphatic hydrocarbon group having, for example, 1 to 7 or 1 to 5 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0046] The term “alkoxy” as used herein means an alkyloxy (-O-alkyl group), for example, an alkyloxy having 1 to 7 or 1 to 5 carbon atoms.

[0047] The term "cycloalkyl" as used herein refers to a saturated aliphatic hydrocarbon radical having, for example, 3 to 12 carbon atoms or 3 to 10 carbon atoms in a ring shape. Typical examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0048] The term “heterocycloalkyl” as used herein means a radical of a saturated aliphatic hydrocarbon group containing one or more heteroatoms selected from N, O and S as a reducing group, for example, 4 to 10 membered or 4 to 8 membered.

[0049] As used herein, the term “partially unsaturated carbocyclyl” means a radical of a hydrocarbon group forming a single or fused ring having, for example, 5 to 12 or 5 to 10 carbon atoms, which is partially unsaturated.

[0050] The term “aryl” as used herein means an aromatic hydrocarbon having, for example, 6 to 10 carbon atoms, specific examples of which include, but are not limited to, phenyl and naphthyl.

[0051] The term “heteroaryl” as used herein means an aromatic hydrocarbon having 5 to 10 membered atoms, which contains one or more heteroatoms selected from N, O and S as a reducing agent. For example, the heteroaryl may be pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, Including, but not limited to, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

[0052] The term “saturated or partially unsaturated heterocyclyl” as used herein means a saturated or partially unsaturated cyclic hydrocarbon group, for example, having 4 to 12 or 4 to 10 membered members, containing one or more heteroatoms selected from N, O and S as a reducing group. The saturated or partially unsaturated heterocyclyl may include a bridged structure, a fused structure or a spiro structure.

[0053] The term “saturated or partially unsaturated heterocyclylene” as used herein means a saturated or partially unsaturated cyclic hydrocarbon, for example, having 4 to 15 or 4 to 12 membered members, containing one or more heteroatoms selected from divalent N, O and S as a reducing group. The saturated or partially unsaturated heterocyclylene may include a bridged structure, a fused structure or a spiro structure.

[0054] The term “independently” as used herein means that when more than one substituent is selected from a plurality of possible substituents, these substituents may be the same or different from each other.

[0055]

[0056] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of this disclosure, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. A solvate in which water is the solvent molecule is referred to as a hydrate. Hydrates include compositions containing a stoichiometric amount of water as well as compositions containing variable amounts of water.

[0057] The term "isomers" refers to compounds having identical composition and molecular weight but different physical and / or chemical properties. Structural differences may arise in their configuration (geometric isomerism) or in their ability to rotate the plane of polarized light (stereoisomerism). With respect to stereoisomers, the compounds herein may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0058] The term "stereoisomers" refers to a group of compounds that have the same atomic number and type and the same bonding connections between their atoms, but differ in three-dimensional structure. The term "stereoisomer" refers to any member of this group. For example, a stereoisomer may be an enantiomer or a diastereoisomer.

[0059] The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "enantiomer" refers to a single member of such a pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers.

[0060] The term "diastereoisomer" refers to the set of stereoisomers that cannot be made superimposable by rotation about a single bond. For example, compounds containing cis- and trans- double bonds on a bicyclic ring system, endo- and exo- substitutions, and multiple stereogenic centers with different relative stereoconfigurations are considered to be diastereoisomers. The term "diastereoisomer" refers to any member of this set of compounds. In some of the examples presented, the synthetic routes may produce a single diastereoisomer or a mixture of diastereoisomers.

[0061] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. Some non-limiting examples of proton tautomers (also known as prototypic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions due to rearrangement of some of the bonding electrons.

[0062] The term “isotopic variant” means a compound in which at least one atom of any compound has been exchanged for another atom having the same atomic number but a different atomic mass than the atomic mass that usually or predominantly occurs in nature.

[0063] When used in connection with a compound, “effective amount” is an amount effective to treat or prevent a disease in a subject as described herein.

[0064]

[0065] According to one specific example of the present invention, in the chemical formula 1

[0066] X 1 is S(=O) or S(=O)2,

[0067] X 2 , X 3 and X 4 are each independently CH, C-halo or N;

[0068] A is a saturated or partially unsaturated 4 to 15 membered heterocyclylene;

[0069] L 1 is a direct bond, -C(=O)-, -NR 4 C(=O)-, -C(=O)NR 4 - or -NR 4 - and here R 4 is -H or C1-C7alkyl;

[0070] R 1 Silver halo, C1-C7 alkyl, partially unsaturated C5-C12 Carbocyclyl, C6-C 10 Aryl, saturated or partially unsaturated 4 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl; wherein said saturated or partially unsaturated heterocyclyl is halo, oxo, C1-C7 alkyl, C3-C 12 cycloalkyl and C1-C7alkoxy, which may be optionally substituted with 1 to 3 substituents selected from the group consisting of; and wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano, C1-C7alkyl, halo-C1-C7alkyl and C1-C7alkoxy;

[0071] L 2 is a direct bond, -CHR 5 -, -CHR 5 C(=O)-, -C(=O)-, or -CR 6 R 7 - and here R 5 is -H, hydroxy or C1-C7 alkyl; R 6 and R 7 C3-C is connected to the carbon atoms that bind to each other. 10 Forming a cycloalkyl;

[0072] R 2 is hydroxy, halo, carboxy, amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 12 Cycloalkyl, hydroxy-C1-C7 alkyl, C1-C7 alkylamino, di(C1-C7 alkyl)amino, C3-C 12 Cycloalkylamino, hydroxy-C1-C7 alkylamino, halo-C1-C7 alkylamino, C3-C 12 Cycloalkyl-C1-C7 alkylamino, 4 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said heterocycloalkyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halo, C1-C7 alkyl, C1-C7 alkoxy and hydroxy-C1-C7 alkyl;

[0073] n is 1 or 2;

[0074] R 3 is -H or C1-C7alkyl;

[0075] The above heterocycloalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylene and heteroaryl have 1 to 4 heteroatoms selected from N, O and S,

[0076] Only R 1 When A is a heteroaryl having two N atoms, it is not a partially unsaturated 4 to 15 membered heterocycle.

[0077] According to another specific embodiment of the present invention,

[0078] X 2 is CH or C-halo,

[0079] X 3 is CH or N,

[0080] X 4 can be CH, C-halo or N.

[0081] According to another embodiment of the present invention, A may be a saturated 4 to 12 membered heterocyclylene having 1 to 3 heteroatoms selected from N and O.

[0082] According to another specific embodiment of the present invention, A It could be.

[0083] According to another embodiment of the present invention, A may be a partially unsaturated 4 to 12 membered heterocyclylene having 1 to 3 heteroatoms selected from N and O.

[0084] According to another specific embodiment of the present invention, A , , , or It could be.

[0085] According to another embodiment of the present invention, A may be a saturated or partially unsaturated, bridged 4 to 12 membered heterocyclylene having 1 to 3 heteroatoms selected from N, O and S.

[0086] According to another specific embodiment of the present invention, A It could be.

[0087] According to another specific embodiment of the present invention, A or It could be.

[0088] According to another specific embodiment of the present invention, the bonding direction of A may be opposite. For example, if A If A is and may include, and A If A is and may include.

[0089] According to another specific embodiment of the present invention,

[0090] L 1 is a direct bond, -C(=O)-, -NR 4 C(=O)-, -C(=O)NR 4 - or -NR 4 - and here R 4 is -H or C1-C5 alkyl;

[0091] R 1 is C1-C5 alkyl, partially unsaturated C5-C 10 Carbocyclyl, C6-C 10 Aryl, saturated or partially unsaturated 4 to 10 membered heterocyclyl or 5 to 10 membered heteroaryl; wherein said saturated or partially unsaturated heterocyclyl is oxo, C1-C5 alkyl, C3-C 10which may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl and C1-C5alkoxy; wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano, C1-C5alkyl, halo-C1-C5alkyl and C1-C5alkoxy;

[0092] The above saturated or partially unsaturated heterocyclyl and heteroaryl may have 1 to 3 heteroatoms selected from N and O.

[0093] According to another specific embodiment of the present invention,

[0094] L 2 is a direct bond, -CHR 5 -, -CHR 5 C(=O)-, -C(=O)-, or -CR 6 R 7 - and here R 5 is -H, hydroxy or C1-C5 alkyl; R 6 and R 7 are connected to each other by the carbon atoms to which they are bonded to form C3 or C4 cycloalkyl;

[0095] R 2 is hydroxy, halo, carboxy, amino, C1-C5 alkyl, C1-C5 alkoxy, C3-C 10 Cycloalkyl, hydroxy-C1-C5 alkyl, C1-C5 alkylamino, di(C1-C5 alkyl)amino, C3-C 10 Cycloalkylamino, hydroxy-C1-C5 alkylamino, halo-C1-C5 alkylamino, C3-C 10 Cycloalkyl-C1-C5 alkylamino, 4 to 8 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said heterocycloalkyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halo, C1-C5 alkyl and hydroxy-C1-C5 alkyl;

[0096] The above heterocycloalkyl and heteroaryl may have 1 to 4 heteroatoms selected from N and O.

[0097]

[0098] According to another specific example of the present invention, representative examples of the compound of the above chemical formula 1 may include, but are not limited to, the compounds of Table 1 below.

[0099] [Table 1]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] Unless otherwise specified, the chemical formulas or names given herein and in the claims encompass tautomers and all stereoisomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the above in which isomers and enantiomers are present, and pharmaceutically acceptable salts thereof and salts thereof, including solvates and hydrates of the free compounds or hydrates including solvates and hydrates of salts of the compounds.

[0156] In one embodiment of the present invention, the compound of the present invention may exist in the form of a pharmaceutically acceptable salt. Useful salts include acid addition salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound, which is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects caused by the salt do not diminish the beneficial effects of the compound of the present invention.

[0157] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.

[0158] At this time, organic acids and inorganic acids can be used as free acids, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid can be used, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid can be used, but are not limited thereto.

[0159] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable for pharmaceutical purposes, but are not limited thereto. Furthermore, the corresponding silver salt can be prepared by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0160] Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, and may be prepared by methods for preparing salts known in the art. In one specific embodiment, the pharmaceutically acceptable salt of the compounds of the present invention may be hydrochloride.

[0161] As a salt of the compound of the above chemical formula 1 of the present invention, any salt of the compound of the above chemical formula 1 that is pharmaceutically acceptable and exhibits pharmacological activity equivalent to that of the compound described in Table 1 may be used without limitation.

[0162] Furthermore, the compound of formula 1 according to the present invention includes, without limitation, not only its pharmaceutically acceptable salts but also solvates, such as possible hydrates, and all possible stereoisomers that can be prepared therefrom. All stereoisomers of the present invention, including enantiomeric forms and diastereomeric forms (e.g., those that can exist due to the asymmetric carbons in various substituents), are included within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers (e.g., as pure or substantially pure optical isomers having a particular activity), or may be, for example, racemates or mixed with all other or other selected stereoisomers. The chiral center of the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendation. The racemic forms may be analyzed by physical methods such as separation by chiral column chromatography or separation or crystallization of diastereomeric derivatives, fractional shape crystallization. Individual optical isomers can be obtained from the racemate by any suitable method, including, but not limited to, salt formation with an optically active acid followed by crystallization.

[0163] Solvates and stereoisomers of the compound of the above formula 1 can be prepared from the compound using methods known in the art.

[0164] Furthermore, the compound of formula 1 according to the present invention can be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, can be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound of formula 1 but also compounds containing various amounts of water. The solvates of the compound of formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0165] The manufacturing method of the present invention can be used by purchasing a commercially available compound and using it as is, or by synthesizing it by performing one or more reactions known in the art, either as is or with appropriate modifications. For example, the compound can be synthesized by performing one or more reactions in a sequential order, taking into account the presence, type, and / or position of reactive functional groups and / or heteroatoms contained in the skeletal structure, but is not limited thereto.

[0166] In another specific embodiment according to the present invention, the compound of formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, is characterized in that it inhibits the interaction between PDE-4 and cAMP.

[0167]

[0168] According to another aspect of the present invention, a pharmaceutical composition for preventing, improving or treating a disease caused by the activity of phosphodiesterase-4 (PDE-4) is provided, comprising a compound of the above chemical formula 1 as an active ingredient, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0169]

[0170] In another specific embodiment according to the present invention, the disease caused by the activity of PDE-4 may be, for example, a lung disease; an inflammatory disease of the skin, gastrointestinal tract, joints, nose or eyes; or a peripheral nervous system or central nervous system disease.

[0171] In other embodiments according to the present invention, examples of the lung disease may include, but are not limited to, idiopathic pulmonary fibrosis (IPF), acute, allergic or chronic bronchitis, chronic obstructive bronchitis (COPD), cough, emphysema, progressive fibrosing interstitial lung disease (PF-ILD), asthma, alveolitis, infectious bronchitis or pneumonia, childhood asthma, bronchiectasis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), bronchial edema, pulmonary edema, bronchitis, viral pneumonia, cystic fibrosis, mucoviscidosis and alpha-1-antitrypsin deficiency.

[0172] In another embodiment according to the present invention, examples of inflammatory diseases of the skin, gastrointestinal tract, joints, nose or eyes may include, but are not limited to, rheumatoid arthritis, acne, acne vulgaris, atopic dermatitis, bacterial skin infections, macular degeneration, bullous pemphigoid, mycoses, hidradenitis suppurativa, seborrheic dermatitis, Crohn's disease, cystic fibrosis, diabetic kidney disease, interstitial cystitis, psoriasis, psoriatic arthritis, renal fibrosis, systemic sclerosis, ulcerative colitis, inflammatory pseudoaneurysm, cystic colitis profunda, uterine fibrosis, allergic or non-allergic rhinitis, sinusitis, chronic rhinitis, conjunctivitis and keratitis.

[0173] In other embodiments according to the present invention, examples of the central nervous system disorders may include, but are not limited to, depression, bipolar or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis, acute and chronic pain and seizures, and brain damage due to hypoxia or brain trauma.

[0174] In another specific embodiment according to the present invention, the disease caused by the activity of PDE-4 may be, for example, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, hepatic fibrosis, liver damage, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or diabetes.

[0175]

[0176] In another specific embodiment according to the present invention, the pharmaceutical composition according to the present invention may further comprise an additional active substance together with the compound of the above formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0177] In another specific embodiment according to the present invention, the additional active substance may be at least one selected from the group consisting of beta-agonists, anticholinergics, adrenocortical hormones, other PDE-4 inhibitors, LTD-4 (leukotriene D4) antagonists, EGFR (epidermal growth factor receptor) inhibitors, dopamine agonists, H1 antihistamines, adenyl cyclase agonists, LPAR (lysophosphatidic acid receptor) antagonists, JAK (Janus kinase) inhibitors, JNK (C-Jun N-terminal kinase) inhibitors, and autotaxin inhibitors, but is not limited thereto.

[0178]

[0179] The pharmaceutical composition according to the present invention can be administered to mammals such as rats, mice, livestock, and humans via various routes. In the present invention, the routes of administration of the pharmaceutical composition include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal.

[0180] Additionally, oral and parenteral administration are preferred methods of administering the pharmaceutical composition. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0181] The pharmaceutical composition according to the present invention may additionally comprise one or more pharmaceutically acceptable carriers, one or more excipients and / or diluents.

[0182] Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids, such as ethanol, glycerol, water, and the like. The amount of carrier in the therapeutic composition can range from about 5 to about 99 weight percent, based on the total weight of the therapeutic composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and diluents include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, wetting agents, bulking agents, antioxidants, lubricants, flavoring agents, thickening agents, coloring agents, surfactants, emulsifiers, suspending agents, and the like. Such excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and it will be apparent to those skilled in the art that any other pharmaceutically acceptable carrier, excipient and diluent may be used.

[0183] The pharmaceutical composition according to the present invention can be formulated and used in the form of oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, liquids, emulsions, syrups, external preparations, suppositories, or sterile injection solutions, each according to a conventional method.

[0184] The pharmaceutical composition according to the present invention may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Acceptable vehicles and solvents include mannitol, water, Ringer's solution, or isotonic sodium chloride solution. In addition, a sterile fixed oil is typically used as a solvent or suspending medium. For this purpose, any fixed oil with minimal irritation, including synthetic mono- or diglycerides, may be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in injectable preparations, as are pharmaceutically acceptable natural oils (e.g., olive oil or castor oil), especially their polyoxyethylated forms.

[0185] The pharmaceutical composition according to the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.

[0186] The pharmaceutical compositions of the present invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0187] Oral administration of the pharmaceutical composition according to the present invention is particularly useful when the desired treatment involves a site or organ easily accessible by topical application. When applied topically to the skin, the pharmaceutical composition should be formulated as a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present invention may also be applied topically to the lower intestinal tract by rectal suppository or as a suitable enema. Topically applied transdermal patches are also encompassed by the present invention.

[0188] The pharmaceutical composition according to the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical field and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0189]

[0190] The compound of formula 1 is contained in the pharmaceutical composition according to the present invention in a therapeutically effective amount or a prophylactically effective amount. The preferred dosage of the compound of formula 1 according to the present invention varies depending on the patient's condition and weight, the degree of the disease, the drug form, the route and period of administration, and can be appropriately selected by those skilled in the art. However, for a desirable effect, the compound of formula 1 according to the present invention can be administered once or several times a day in an amount of 0.0001 to 1,000 mg / kg, preferably 0.01 to 500 mg / kg.

[0191] In the composition of the present invention, the compound of the above chemical formula 1 can be blended in an amount of 0.0001 to 50 wt% based on the total weight of the entire composition.

[0192]

[0193] According to another aspect of the present invention, a method for preventing, improving or treating a disease caused by the activity of PDE-4 is provided by administering a compound of the above chemical formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0194] At this time, the compound of chemical formula 1 of the present invention, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount. The term "therapeutically effective amount" of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined according to the patient's health condition, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the excretion rate, the duration of treatment, the drug used in combination or simultaneously, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. Taking all of the above factors into account, it is important to administer the dose that achieves maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art. For example, the dosage may vary depending on the route of administration, severity of the disease, gender, body weight, age, etc., and thus the above dosage does not limit the scope of the present invention in any way. The preferred dosage of the compound of the present invention may vary depending on the patient's condition and body weight, the extent of the disease, the form of the drug, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art.

[0195]

[0196] [Example]

[0197] Hereinafter, the present invention will be described in more detail through examples. However, the following examples are provided merely to aid understanding of the present invention and are not intended to limit the scope of the present invention.

[0198]

[0199] chemical synthesis

[0200] <Synthesis Method A>

[0201]

[0202]

[0203] The general synthesis of compound A-6 is illustrated in Synthetic Method A. Compound A-2 is obtained by coupling ethyl-4-bromobutyrate and ethyl mercaptoacetate. Compound A-3 is obtained using potassium tert-butoxide, and a cyclization reaction is performed using S-ethylisothiourea hydrobromide to obtain compound A-4. Compound A-4 is reacted under acidic conditions to obtain compound A-5, and then intermediate compound A-6 with chloride introduced is obtained using phosphoryl trichloride.

[0204]

[0205] Step 1: Ethyl 4-((2-ethoxy-2-oxoethyl)thio)butanoate

[0206]

[0207]

[0208] Ethyl-4-bromobutyrate (20 g, 102.53 mmol) and ethyl mercaptoacetate (11.3 ml, 102.53 mmol) were dissolved in ethanol (40 ml), and then sodium ethoxide (7 g, 102.53 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethanol, water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate and washed with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound A-2 (28.24 g). Compound A-2 was used in the next reaction without any separate purification.

[0209]

[0210] Step 2: Ethyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate

[0211]

[0212]

[0213] Compound A-2 (28 g, 120.5 mmol) was dissolved in THF (450 ml), potassium tert-butoxide (27 g, 241.0 mmol) was added, and the mixture was heated to 70°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5 with 2 N HCl (aq.), extracted three times with ethyl acetate, and washed with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound A-3 (9.65 g). Compound A-3 was used in the next reaction without further purification.

[0214]

[0215] Step 3: 2-(Ethylthio)-7,8-dihydro-1H-thiopyrano[3,2-d]pyrimidin-4(6H)-one

[0216]

[0217]

[0218] After wrapping with foil to block light, water (170 ml) was added to compound A-3 (9.6 g, 51.29 mmol), S-ethylisothiourea hydrobromide (10.4 g, 56.42 mmol), and sodium chloride (6 g, 56.42 mmol), heated at 60°C, and stirred for 16 hours. The resulting solid was filtered to obtain compound A-4 (8.09 g, 69%) as an ivory-colored solid.

[0219]

[0220] Step 4: 7,8-Dihydro-1H-thiopyrano[3,2-d]pyrimidine-2,4(3H,6H)-dione

[0221]

[0222]

[0223] Compound A-4 (10.7 g, 46.95 mmol) was mixed with water (53 ml), followed by the addition of acetic acid (16 ml, 281.7 mmol) and hydrogen chloride (8 ml, 140.85 mmol), heated at 100°C, and stirred for 16 hours. The resulting solid was washed with water and methanol and filtered to obtain compound A-5 (7.1 g, 82%) as a white solid.

[0224]

[0225] Step 5: 2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine

[0226]

[0227]

[0228] To compound A-5 (5 g, 27.14 mmol) was added phosphoryl trichloride (30 ml), heated at 130°C, and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound A-6 (5.52 g, 92%) as a brown solid.

[0229]

[0230] <Synthesis Method B>

[0231]

[0232]

[0233] The general synthesis of compound B-3 is illustrated in Scheme B. Intermediate B-1 is obtained by Bkwald-Atwig coupling using tris(dibenzylideneacetone)dipalladium(0) and Xantphos. Subsequently, B-3 is obtained by chiral oxidation using (S,S)-(-)-diethyl tartrate and titanium(IV)-isopropoxide to generate the asymmetric sulfoxide, followed by SNAr reaction using DIPEA.

[0234]

[0235] Example 1: Synthesis of (R)-methyl (4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0236] Step 1: Methyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0237]

[0238]

[0239] Compound A-6 (540 mg, 2.44 mmol), methyl 2-(4-aminophenyl)acetate (166 mg, 2.68 mmol), and triethylamine (1 ml, 7.32 mmol) were added to acetonitrile (10 ml), heated to 75°C, and stirred for 16 hours. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B1-1 (540 mg, 64%).

[0240]

[0241] Step 2: (R)-Methyl 2-(4-((2-chloro-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0242]

[0243]

[0244] Intermediate B1-1 (277 mg, 0.8 mmol), S-(-)-1,1'-bi-2-naphthol (S-(-)-BINOL) (46 mg, 0.16 mmol), dichloromethane (2 ml), Ti(OiPr)4 (13 μl, 0.04 mmol), and water (14 μl, 0.8 mmol) were stirred at 0°C under nitrogen for 1 h. tert-Butyl hydroperoxide (70% in water, 76 μl, 0.8 mmol) was added at 0°C, the mixture was allowed to warm to room temperature, and stirred for 1 h. The reaction mixture was filtered to remove impurities, extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B1-2 (340 mg, 58%).

[0245]

[0246] Step 3: (R)-Methyl (4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0247]

[0248]

[0249] Intermediate B1-2 (50 mg, 0.137 mmol), 4-(4-chlorophenyl)piperidine (40 mg, 0.205 mmol), and N,N-diisopropylethylamine (71 μl, 0.411 mmol) were added to 1,4-dioxane (5 ml), heated to 70°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (15 mg, 21%).

[0250] 1H NMR (400 MHz, CDCl3); δ7.91 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.28-7.23 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 4.90 (d, J = 12.8 Hz, 2H), 3.70 (s, 3H), 3.68 (s, 2H), 3.49-3.22 (m, 1H), 3.08-3.01 (m, 1H), 2.95-2.85 (m, 3H), 2.79-2.52 (m, 3H), 2.18-2.09 (m, 1H), 1.91-1.66(m, 2H), 1.66-1.51 (m, 2H); LC / MS: m / z 525.1 (M+H)+(ES).

[0251]

[0252] Example 2: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0253]

[0254]

[0255] The compound obtained in Example 1 (47.6 mg, 0.090 mmol) and sodium hydroxide (5.4 mg, 0.136 mmol) were added to tetrahydrofuran (0.45 ml) and methanol (0.045 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH=5 using 2N HCl, and the resulting solid was filtered to obtain the title compound (32.2 mg, 69%).

[0256] 1H NMR (400 MHz, CD3OD); δ7.49 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8 Hz, 2H), 7.30 (dd, J = 6.8 Hz, 2.4 Hz, 2H), 7.24 (dd, J = 6.8 Hz, 2 Hz, 2H), 4.61 (brs, 1H), 3.45 (s, 2H), 3.42-3.39 (m, 2H), 3.16-3.03 (m, 5H), 2.91-2.88 (m, 2H), 2.65-2.62 (m, 1H), 2.28-2.24 (m, 1H), 1.96-1.93 (m, 2H), 1.72-1.68 (m, 2H); LC / MS: m / z 511.1 (M+H)+(ES).

[0257]

[0258] Example 3: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0259] Step 1: Methyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0260]

[0261]

[0262] Intermediate B1-1 (60 mg, 0.172 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (60 mg, 0.344 mmol), and dichloromethane (1 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B3-2 (55 mg, 84%) as a yellow solid.

[0263]

[0264] Step 2: Methyl 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0265]

[0266]

[0267] Intermediate B3-2 (50 mg, 0.131 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (37 mg, 0.183 mmol), and N,N-diisopropylethylamine (68 μl, 0.393 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B3-3 (50 mg, 74%).

[0268]

[0269] Step 3: 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0270]

[0271]

[0272] Intermediate B3-3 (24 mg, 0.047 mmol) was dissolved in methanol (0.2 mL) and dichloromethane (1 mL), and sodium hydroxide (11 mg, 0.282 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (14 mg, 60%) as a white solid.

[0273] 1H NMR (400 MHz, CDCl3); δ8.63 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 4.54 (t, J = 9 Hz, 2H), 4.13 (t, J = 7.6 Hz, 2H), 3.91-3.83 (m, 1H), 3.57 (s, 2H), 3.42-3.36 (m, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.49-2.43 (m, 2H); LC / MS: m / z 499.0 (M+H)+(ES).

[0274]

[0275] Example 4: Synthesis of 2-(3-(4-chlorophenyl)azetidin-1-yl)-4-((4-(hydroxymethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0276] Step 1: (4-(2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)methanol

[0277]

[0278]

[0279] Compound A-6 (100 mg, 0.452 mmol), 4-aminobenzyl alcohol (83 mg, 0.678 mmol), and triethylamine (125 μl, 0.904 mmol) were added to acetonitrile (2 ml), heated to 80°C, and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B4-1 (53 mg, 38%) as a white solid.

[0280]

[0281] Step 2: 2-chloro-4-((4-(hydroxymethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0282]

[0283]

[0284] Intermediate B4-1 (53 mg, 0.171 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (133 mg, 0.77 mmol), and dichloromethane (2 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B4-2 (33 mg, 57%) as a white solid.

[0285]

[0286] Step 3: 2-(3-(4-chlorophenyl)azetidin-1-yl)-4-((4-(hydroxymethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0287]

[0288]

[0289] Intermediate B4-2 (33 mg, 0.0971 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (31 mg, 0.15 mmol), and N,N-diisopropylethylamine (70 μl, 0.324 mmol) were added to 1,4-dioxane (1 ml) and heated in a microwave at 110°C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the title compound (35 mg, 77%) as a white solid.

[0290] 1H NMR (400 MHz, CDCl3); 8.66 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.35-7.27 (m, 6H), 4.65 (d, J = 6.0 Hz, 2H), 4.54 (t, J = 9.0 Hz, 2H), 4.13 (t, J = 7.4, 2H), 3.90-3.82 (m, 1H), 3.40-3.36 (m, 2H), 2.89-2.84 (m, 2H), 2.50-2.43 (m, 2H); LC / MS: m / z 472.1 (M+H)+(ES).

[0291]

[0292] Example 5: Synthesis of 2-(3-(4-chlorophenyl)azetidin-1-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0293] Step 1: 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)ethanol

[0294]

[0295]

[0296] Compound A-6 (100 mg, 0.452 mmol), 2-(4-aminophenyl)ethanol (93 mg, 0.678 mmol), and triethylamine (125 μl, 0.904 mmol) were added to acetonitrile (2 ml), heated to 80°C, and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B5-1 (64 mg, 44%) as a white solid.

[0297]

[0298] Step 2: 2-chloro-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0299]

[0300]

[0301] Intermediate B5-1 (64 mg, 0.02 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (123 mg, 0.5 mmol), and dichloromethane (1 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B5-2 (35 mg, 50%) as a white solid.

[0302]

[0303] Step 3: 2-(3-(4-chlorophenyl)azetidin-1-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0304]

[0305]

[0306] Intermediate B5-2 (35 mg, 0.099 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (24 mg, 0.119 mmol), and N,N-diisopropylethylamine (35 μl, 0.198 mmol) were added to 1,4-dioxane (1 ml) and heated in a microwave at 110°C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the title compound (14 mg, 21%) as a white solid.

[0307] 1H NMR (400 MHz, CDCl3); 8.62 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.54 (t, J = 9.0 Hz, 2H), 4.15-4.10 (m, 2H), 3.89-3.81 (m, 3H), 3.40-3.35 (m, 2H), 2.89-2.80 (m, 4H), 2.50-2.43 (m, 2H) ; m / z 486.1 (M+H)+(ES).

[0308]

[0309] Example 6: Synthesis of 4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)benzoic acid

[0310] Step 1: Ethyl 4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)benzoate

[0311]

[0312]

[0313] Compound A-6 (50 mg, 0.224 mmol), benzocaine (44 mg, 0.269 mmol), and N,N-diisopropylethylamine (390 μl, 2.24 mmol) were added to ethanol (3 ml), heated to 110°C, and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B6-1 (17 mg, 22%) as a white solid.

[0314]

[0315] Step 2: Ethyl 4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)benzoate

[0316]

[0317]

[0318] Intermediate B6-1 (17 mg, 0.048 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (17 mg, 0.096 mmol), and dichloromethane (1 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B6-2 (10 mg, 54%) as a white solid.

[0319]

[0320] Step 3: Ethyl 4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)benzoate

[0321]

[0322]

[0323] Intermediate B6-2 (10 mg, 0.0262 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (11 mg, 0.0524 mmol), and N,N-diisopropylethylamine (46 μl, 0.262 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B6-3 (12 mg, 89%) as an ivory solid.

[0324]

[0325] Step 4: 4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)benzoic acid

[0326]

[0327]

[0328] Intermediate B6-3 (12 mg, 0.023 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and sodium hydroxide (6 mg, 0.138 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and filtered with dichloromethane to obtain the title compound (10 mg, 88%) as a white solid.

[0329] 1H NMR (400 MHz, CDCl3); δ8.95 (s, 1H), 8.05-8.02 (m, 2H), 7.77-7.74 (m, 2H), 7.35-7.28 (m, 4H), 4.58 (t, J = 9 Hz, 2H), 4.19-4.15 (m, 2H), 3.94-3.86 (m, 1H), 3.41-3.38 (m, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.51-2.44; LC / MS: m / z 485.1 (M+H)+(ES).

[0330]

[0331] Example 7: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide

[0332]

[0333]

[0334] Methylamine (33% EtOH Solution, 1.5 ml) was added to intermediate B6-3 (20 mg, 0.095 mmol), heated to 55°C, and stirred for 1 day. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the title compound (20 mg, 99%) as a white solid.

[0335] 1H NMR (400 MHz, CDCl3); 8.68 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.34 (d, J =8.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.34 (br s, 1H), 4.55 (t, J=9.0 Hz, 2H), 4.14 (t, J = 7.4 Hz, 2H), 3.90-3.83 (m, 1H), 3.54 (s, 2H), 3.40-3.35 (m, 2H), 2.87 (t, J = 8.4 Hz, 2H), 2.75 (d, J = 4.8 Hz, 3H), 2.50-2.42 (m, 2H); LC / MS: m / z 513.1 (M+H)+(ES).

[0336]

[0337] Example 8: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

[0338]

[0339]

[0340] Ammonia (7N in methanol, 1.5 ml) was added to intermediate B6-3 (45 mg, 0.085 mmol), heated to 55°C, and stirred for 1 day. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the title compound (10 mg, 22%) as a white solid.

[0341] 1H NMR (400 MHz, CDCl3); 8.68 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.33 (d, J =8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 5.37 (br s, 2H), 4.55 (t, J=9.0 Hz, 2H), 4.13 (t, J = 7.4 Hz, 2H), 3.90-3.83 (m, 1H), 3.55 (s, 2H), 3.40-3.36 (m, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.50-2.42 (m, 2H); LC / MS: m / z 499.1 (M+H)+(ES).

[0342]

[0343] Example 9: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid

[0344] Step 1: Methyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate

[0345]

[0346]

[0347] Compound A-6 (20 mg, 0.090 mmol), methyl 2-(4-amino-2-fluorophenyl)acetate (20 mg, 0.108 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.6 mg, 0.004 mmol), xantphos (4.6 mg, 0.008 mmol), and sodium carbonate (30 mg, 0.27 mmol) were added to 1,4-dioxane (2 ml), and the mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B9-1 (20 mg, 61%).

[0348]

[0349] Step 2: Methyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate

[0350]

[0351]

[0352] Intermediate B9-1 (20 mg, 0.054 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (24 mg, 0.108 mmol), and dichloromethane (2 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B9-2 (20 mg, 92%) as an ivory-colored solid.

[0353]

[0354] Step 3: Methyl 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate

[0355]

[0356]

[0357] Intermediate B9-2 (20 mg, 0.050 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (15 mg, 0.075 mmol) and N,N-diisopropylethylamine (87 μl, 0.50 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B9-3 (9 mg, 34%) as a white solid.

[0358]

[0359] Step 4: 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid

[0360]

[0361]

[0362] Intermediate B9-3 (9 mg, 0.017 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and sodium hydroxide (4 mg, 0.102 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (1.6 mg, 18%) as a white solid.

[0363] 1H NMR (400 MHz, CDCl3); δ8.74 (s, 1H), 7.78 (dd, J = 12.2 Hz, 1.8 Hz, 1H), 7.35-7.29 (m, 4H), 7.18-7.10 (m, 2H), 4.56 (t, J = 9 Hz, 2H), 4.16-4.12 (m, 2H), 3.91-3.83 (m, 1H), 3.63 (s, 2H), 3.39-3.35 (m, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.49-2.42 (m, 2H); LC / MS: m / z 517.0 (M+H)+(ES).

[0364]

[0365] Example 10: Synthesis of 4-((4-(1H-tetrazol-5-yl)phenyl)amino)-2-(3-(4-chlorophenyl)azetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0366] Step 1: N-(4-(1H-tetrazol-5-yl)phenyl)-2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-amine

[0367]

[0368]

[0369] Compound A-6 (50 mg, 0.226 mmol), 4-(1H-tetrazol-5-yl)aniline (44 mg, 0.271 mmol), and N,N-diisopropylethylamine (197 μl, 1.13 mmol) were added to 1,4-dioxane (2 ml), heated to 90°C, and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B10-1 (46 mg, 59%) as a white solid.

[0370]

[0371] Step 2: 4-((4-(1H-tetrazol-5-yl)phenyl)amino)-2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0372]

[0373]

[0374] Intermediate B10-1 (30 mg, 0.087 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (39 mg, 0.173 mmol), and dichloromethane (2 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B10-2 (23 mg, 71%) as a white solid.

[0375]

[0376] Step 3: 4-((4-(1H-tetrazol-5-yl)phenyl)amino)-2-(3-(4-chlorophenyl)azetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0377]

[0378]

[0379] Intermediate B10-2 (20 mg, 0.053 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (16 mg, 0.079 mmol), and N,N-diisopropylethylamine (92 μl, 0.53 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound (7 mg, 26%) as a white solid.

[0380] 1H NMR (400 MHz, DMSO-d6); δ8.82 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.47-7.41 (m, 4H), 4.52 (brs, 2H), 4.11 (brs, 2H), 4.03-3.98 (m, 1H), 3.62-3.59 (m, 2H), 2.84 (d, J = 6.4 Hz, 2H), 2.34-2.28 (m, 2H); LC / MS: m / z 509.1 (M+H)+(ES).

[0381]

[0382] Example 11: Synthesis of (R)-2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0383] Step 1: (R)-Methyl 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0384]

[0385]

[0386] Intermediate B1-2 (30 mg, 0.082 mmol), 4-(4-chlorophenyl)azatidine hydrochloride (27.49 mg, 0.164 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B11-3 (43.6 mg, 99%).

[0387]

[0388] Step 2: (R)-2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0389]

[0390]

[0391] Intermediate B11-3 (43.6 mg, 0.087 mmol) and sodium hydroxide (5.26 mg, 0.131 mmol) were added to tetrahydrofuran (0.44 ml) and methanol (0.05 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (21.2 mg, 50%).

[0392] 1H NMR (400 MHz, CDCl3); δ8.59 (brs, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.30 (d J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 4H), 7.12 (d, J = 8.4 Hz, 2H), 4.94 (t, J = 8.8 Hz, 2H), 4.08-4.06 (m, 2H), 3.83-3.79 (m, 1H), 3.61 (s, 2H), 3.31-3.26 (m, 1H), 2.95-2.66 (m, 5H); LC / MS: m / z 433.1 (M+H)+(ES).

[0393]

[0394] Example 12: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(cyclopropylmethyl)acetamide

[0395]

[0396]

[0397] Compound obtained in Example 3 (6.2 mg, 0.012 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC . HCl) (7.2 mg, 0.036 mmol) and hydroxybenzotriazole (3.4 mg, 0.024 mmol) were dissolved in anhydrous dimethylformamide (1 ml) and stirred at room temperature for 10 minutes. Cyclopropylmethanamine (2.9 μl, 0.032 mmol) and triethylamine (7 μl, 0.048 mmol) were added and stirred at room temperature for 16 hours. After completion of the reaction, water was added and the precipitated solid was filtered to obtain the title compound (3.8 mg, 57%) as a white solid.

[0398] 1H NMR (400 MHz, CDCl3); δ8.68 (s, 1H), 7.63 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.35-7.28 (m, 4H), 7.20 (d, J = 8.8 Hz, 2H), 5.45 (brs, 1H), 4.55 (t, J = 9 Hz, 2H), 4.14 (brs, 2H), 3.90-3.83 (m, 1H), 3.53 (s, 2H), 3.40-3.37 (m, 2H), 3.08-3.05 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.50-2.44 (m, 2H), 0.89-0.81 (m, 1H), 0.45-0.40 (m, 2H), 0.13-0.09 (m, 2H); LC / MS: m / z 553.0 (M+H)+(ES).

[0399]

[0400] Example 13: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-cyclopropylacetamide

[0401]

[0402]

[0403] Compound obtained in Example 3 (6 mg, 0.012 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC . HCl) (7.2 mg, 0.036 mmol) and hydroxybenzotriazole (3.4 mg, 0.024 mmol) were dissolved in anhydrous dimethylformamide (1 ml) and stirred at room temperature for 10 minutes. Cyclopropylamine (2.2 μl, 0.032 mmol) and triethylamine (7 μl, 0.048 mmol) were added and stirred at room temperature for 16 hours. After completion of the reaction, water was added and the precipitated solid was filtered to obtain the title compound (1.9 mg, 29%) as a white solid.

[0404] 1H NMR (400 MHz, CDCl3); δ8.68 (s, 1H), 7.62 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.35-7.28 (m, 4H), 7.16 (d, J = 8.8 Hz, 2H), 5.43 (brs, 1H), 4.55 (t, J = 9 Hz, 2H), 4.13 (brs, 2H), 3.91-3.85 (m, 1H), 3.50 (s, 2H), 3.40-3.37 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.67-2.63 (m, 1H), 2.50-2.44 (m, 2H), 0.74-0.70 (m, 2H), 0.41-0.37 (m, 2H); LC / MS: m / z 538.1 (M+H)+(ES).

[0405]

[0406] Example 14: Synthesis of (S)-2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0407] Step 1: (S)-Methyl 2-(4-((2-chloro-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0408]

[0409]

[0410] Intermediate B1-1 (100 mg, 0.285 mmol), L-(+)-diethyl tartrate (190 μl, 1.143 mmol), chloroform (2 ml), and Ti(OiPr)4 (25.12 μl, 0.0857 mmol) were stirred at 0°C under nitrogen for 5 min, then at -20°C for 30 min. Cumyl hydroperoxide (80%, 52.28 μl, 0.285 mmol) was added at -20°C and stirred for 23 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B14-2 (112.2 mg, 99%).

[0411]

[0412] Step 2: (S)-Methyl 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0413]

[0414]

[0415] Intermediate B14-2 (112.2 mg, 0.306 mmol), 4-(4-chlorophenyl)azatidine hydrochloride (102.8 mg, 0.613 mmol), and N,N-diisopropylethylamine (0.26 ml, 1.533 mmol) were added to 1,4-dioxane (2 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B14-3 (116.7 mg, 76%).

[0416]

[0417] Step 3: (S)-2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0418]

[0419]

[0420] Intermediate B14-3 (116.7 mg, 0.234 mmol) and sodium hydroxide (14 mg, 0.352 mmol) were added to tetrahydrofuran (1.2 ml) and methanol (0.05 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (75.5 mg, 66%).

[0421] 1H NMR (400 MHz, CDCl3); δ8.59 (brs, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 4H), 7.12 (d, J = 8.4 Hz, 2H), 4.94 (t, J = 8.8 Hz, 2H), 4.08-4.06 (m, 2H), 3.83-3.79 (m, 1H), 3.61 (s, 2H), 3.31-3.26 (m, 1H), 2.95-2.66 (m, 5H); LC / MS: m / z 433.1 (M+H)+(ES).

[0422]

[0423] Example 15: Synthesis of 2-(5-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2-yl)acetic acid

[0424] Step 1: Methyl 2-(5-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2-yl)acetate

[0425]

[0426]

[0427] Compound A-6 (100 mg, 0.45 mmol), methyl 5-amino-2-pyridine acetate (90 mg, 0.542 mmol), and N,N-diisopropylethylamine (390 μl, 2.24 mmol) were added to 1,4-dioxane (3 ml), heated to 110°C, and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B15-1 (40 mg, 25%) as a white solid.

[0428]

[0429] Step 2: Methyl 2-(5-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2-yl)acetate

[0430]

[0431]

[0432] Intermediate B15-1 (40 mg, 0.114 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (49 mg, 0.285 mmol), and dichloromethane (2 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B15-2 (24 mg, 54%) as a white solid.

[0433]

[0434] Step 3: 2-(5-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2-yl)acetic acid

[0435]

[0436]

[0437] Intermediate B15-2 (9 mg, 0.017 mmol) was dissolved in methanol (1 mL), 1 N sodium hydroxide solution (175 μl, 0.175 mmol) was added, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and filtered with dichloromethane to obtain the title compound (1.77 mg, 20%) as a white solid.

[0438] 1H NMR (400 MHz, MeOD); δ8.88 (d, J = 2.4 Hz, 1H), 8.08 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 7.43-7.35 (m, 5H), 4.58 (t, J = 8.8 Hz, 2H), 4.15 (t, J = 4.6 Hz, 2H), 4.02-3.92 (m, 1H), 3.81 (s, 2H), 3.53-3.50 (m, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.47-2.43 (m, 2H) ; LC / MS: m / z 501.1 (M+H)+(ES).

[0439]

[0440] Example 16: Synthesis of methyl 2-(5-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2-yl)acetate

[0441]

[0442]

[0443] Intermediate B15-2 (24 mg, 0.062 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (15 mg, 0.0744 mmol), and N,N-diisopropylethylamine (32 μl, 0.186 mmol) were added to 1,4-dioxane (1 ml) and heated in a microwave at 110°C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the title compound (9 mg, 28%) as an ivory solid.

[0444] 1H NMR (400 MHz, CDCl3); δ8.89 (d, J = 2.4 Hz, 1H), 8.65 (s, 1H), 7.91 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 4.55 (t, J = 9.0 Hz, 2H), 4.16-4.12 (m, 2H), 3.90-3.85 (m, 1H), 3.82 (s, 2H), 3.71 (s, 3H), 3.41-3.36 (m, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.51-2.42 (m, 2H) ; LC / MS: m / z 515.1 (M+H)+(ES).

[0445]

[0446] Example 17: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide

[0447]

[0448]

[0449] The compound obtained in Example 1 (47.1 mg, 0.0897 mmol) and methylamine (in MeOH, 2 ml) were added and stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (39.3 mg, 83%).

[0450] 1H NMR (400 MHz, MeOD); δ7.52 (d, J = 8.8 Hz, 2H), 7.27-7.23 (m, 4H), 7.19 (d, J = 8.8 Hz, 2H), 4.60 (s, 2H), 3.46 (s, 2H), 3.28-3.26 (m, 1H), 3.02-2.73 (m, 7H), 2.71 (s, 3H), 2.69-2.58 (m, 2H), 2.18-2.13 (m, 1H), 1.87-1.84 (m, 2H), 1.60-1.57 (m, 2H); LC / MS: m / z 524.1 (M+H)+(ES).

[0451]

[0452] Example 18: Synthesis of (R)-2-(4-((2-(6-(4-chlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0453] Step 1: (R)-Methyl 2-(4-((2-(6-(4-chlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0454]

[0455]

[0456] Intermediate B1-2 (39.7 mg, 0.108 mmol), 2-(4-chlorophenyl)-2,6-diazaspiro[3.3]heptane (34 mg, 0.162 mmol), and N,N-diisopropylethylamine (94.51 μl, 0.542 mmol) were added to 1,4-dioxane (0.7 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B18-3 (45.2 mg, 77%).

[0457]

[0458] Step 2: (R)-2-(4-((2-(6-(4-chlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0459]

[0460]

[0461] Intermediate B18-3 (45 mg, 0.0836 mmol) and sodium hydroxide (5 mg, 0.125 mmol) were added to tetrahydrofuran (0.4 ml) and methanol (0.04 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (38.3 mg, 87%).

[0462] 1H NMR (400 MHz, MeOD); δ7.56 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 9.2 Hz, 2H), 6.48 (d, J = 9.2 Hz, 2H), 4.39 (m, 2H), 4.02 (s, 4H), 3.64 (s, 2H), 3.50-3.3.36 (m, 2H), 3.15-2.83 (m, 4H), 2.64-2.60 (m, 1H), 2.28-2.23 (m, 1H); LC / MS: m / z 524.1 (M+H)+(ES).

[0463]

[0464] Example 19: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0465] Step 1: (R)-Methyl 2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3, 2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0466]

[0467]

[0468] Intermediate B1-2 (30 mg, 0.082 mmol), 1-(4-chlorophenyl)-1,4-diazepane (26 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B19-3 (37 mg, 83%).

[0469]

[0470] Step 2: (R)-2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0471]

[0472]

[0473] Intermediate B19-3 (37 mg, 0.0685 mmol) and sodium hydroxide (4.11 mg, 0.102 mmol) were added to tetrahydrofuran (0.35 ml) and methanol (0.03 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (32.6 mg, 90%).

[0474] 1H NMR (400 MHz, MeOD); δ7.40-7.38 (m, 4H), 7.16-7.07 (m, 2H), 6.75-6.65 (m, 2H), 3.93-3.49 (m, 11H), 3.43-3.39 (m, 1H), 3.09-3.01 (m, 2H), 2.93-2.81 (m, 1H), 2.65-2.54 (m, 1H), 2.29-2.22 (m, 1H), 2.01-1.98 (m, 1H), 1.87-1.83 (m, 1H); LC / MS: m / z 526.1 (M+H)+(ES).

[0475]

[0476] Example 20: 2-(4-((2-(3-(5-chloropyrimidin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0477] Step 1: Methyl 2-(4-((2-(3-(5-chloropyrimidin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0478]

[0479]

[0480] Intermediate B3-2 (20 mg, 0.052 mmol), 2-(azetidin-3-yl)-5-chloropyrimidine trifluoroacetate (40 mg, 0.104 mmol), and N,N-diisopropylethylamine (27 μl, 0.156 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give a white solid compound B20-3 (18 mg, 67%).

[0481]

[0482] Step 2: 2-(4-((2-(3-(5-chloropyrimidin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0483]

[0484]

[0485] Intermediate B20-3 (10 mg, 0.019 mmol) was dissolved in methanol (0.2 mL) and dichloromethane (1 mL), and sodium hydroxide (5 mg, 0.114 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (6 mg, 63%) as a white solid.

[0486] 1H NMR (400 MHz, CDCl3); δ8.69 (s, 2H), 8.64 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.22 d, J = 8.4 Hz, 2H), 4.54 (t, J = 9 Hz, 2H), 4.43 (brs, 2H), 4.21-4.13 (m, 1H), 3.61 (s, 2H), 3.38-3.35 (m, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.48-2.42 (m, 2H); LC / MS: m / z 501.0 (M+H)+(ES).

[0487]

[0488] Example 21: Synthesis of 2-(4-((2-(3-(5-chloropyridin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0489] Step 1: Methyl 2-(4-((2-(3-(5-chloropyridin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0490]

[0491]

[0492] Intermediate B3-2 (20 mg, 0.052 mmol), 2-(azetidin-3-yl)-5-chloropyridine trifluoroacetate (41 mg, 0.104 mmol), and N,N-diisopropylethylamine (27 μl, 0.156 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give an ivory solid compound B21-3 (18 mg, 67%).

[0493]

[0494] Step 2: 2-(4-((2-(3-(5-chloropyridin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0495]

[0496]

[0497] Intermediate B21-3 (10 mg, 0.019 mmol) was dissolved in methanol (0.2 mL) and dichloromethane (1 mL), and sodium hydroxide (5 mg, 0.114 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (5 mg, 53%) as a white solid.

[0498] 1H NMR (400 MHz, CDCl3); δ8.68 (s, 2H), 8.57 (s, 1H), 7.64 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.23-7.20 (m, 3H), 4.52 (brs, 2H), 4.35 (brs, 2H), 4.03-3.98 (m, 1H), 3.60 (s, 2H), 3.39-3.36 (m, 2H), 2.92 (brs, 2H), 2.49-2.43 (m, 2H); LC / MS: m / z 500.1 (M+H)+(ES).

[0499]

[0500] Example 22: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0501] Step 1: Methyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0502]

[0503]

[0504] Compound A-6 (861 mg, 3.89 mmol), methyl 2-(4-amino-3-fluorophenyl)acetate (785 mg, 4.28 mmol), tris(dibenzylideneacetone)dipalladium(0) (71 mg, 0.078 mmol), xantphos (225 mg, 0.389 mmol), and sodium carbonate (1.2 g, 11.7 mmol) were added to 1,4-dioxane (15 ml), and the mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B22-1 (870 mg, 61%).

[0505]

[0506] Step 2: Methyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0507]

[0508]

[0509] Intermediate B22-1 (800 mg, 2.17 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (972 mg, 4.34 mmol), and dichloromethane (10 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B22-2 (798 mg, 92%) as an ivory-colored solid.

[0510]

[0511] Step 3: Methyl 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0512]

[0513]

[0514] Intermediate B22-2 (17 mg, 0.042 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (17 mg, 0.084 mmol), and N,N-diisopropylethylamine (37 μl, 0.21 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B22-3 (18 mg, 81%) as a white solid.

[0515]

[0516] Step 4: 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0517]

[0518]

[0519] Intermediate B22-3 (10 mg, 0.019 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (8 mg, 0.188 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (7 mg, 71%) as a white solid.

[0520] 1H NMR (400 MHz, CDCl3); δ8.86 (s, 1H), 8.26-8.21 (m, 1H), 7.35-7.28 (m, 4H), 7.09 (dd, J = 11.6 Hz, 2 Hz, 1H), 7.00 (d, J = 8 Hz, 1H), 4.55 (t, J = 9 Hz, 2H), 4.12 (brs, 2H), 3.90-3.86 (m, 1H), 3.56 (s, 2H), 3.41-3.38 (m, 3H), 2.92-2.89 (m, 2H), 2.48-2.45 (m, 2H); LC / MS: m / z 517.1 (M+H)+(ES).

[0521]

[0522] Example 23: Synthesis of 2-(4-(((R)-2-((3aR,6aS)-5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0523] Step 1: Methyl 2-(4-(((R)-2-((3aR,6aS)-5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0524]

[0525]

[0526] Intermediate B1-2 (30 mg, 0.082 mmol), (3aR,6aS)-2-(4-chlorophenyl)octahydropyrrolo[3,4-c]pyrrole (36 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B23-3 (38.4 mg, 84%).

[0527]

[0528] Step 2: 2-(4-(((R)-2-((3aR,6aS)-5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0529]

[0530]

[0531] Intermediate B23-3 (38.4 mg, 0.0695 mmol) and sodium hydroxide (4.17 mg, 0.104 mmol) were added to tetrahydrofuran (0.35 ml) and methanol (0.035 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (38 mg, 99%).

[0532] 1H NMR (400 MHz, DMSO-d6+MeOD); δ7.67 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 9.2 Hz, 2H), 3.91 (m, 2H), 3.24 (s, 2H), 3.57-3.45 (m, 4H), 3.26-3.14 (m, 5H), 3.10-3.02 (m, 1H), 2.29-2.70 (m, 3H), 2.19-2.15 (m, 1H); LC / MS: m / z 538.1 (M+H)+(ES).

[0533]

[0534] Example 24: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)propanoic acid

[0535] Step 1: Methyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)propanoate

[0536]

[0537]

[0538] Compound A-6 (30 mg, 0.136 mmol), methyl 2-(4-aminophenyl)propanoate (30 mg, 0.145 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.2 mg, 0.007 mmol), xantphos (7.9 mg, 0.014 mmol), and sodium carbonate (43 mg, 0.408 mmol) were added to 1,4-dioxane (2 ml), and stirred at 90°C for 16 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B24-1 (21 mg, 42%).

[0539]

[0540] Step 2: Methyl 2-(4-((2-chloro-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)propanoate

[0541]

[0542]

[0543] Intermediate B24-1 (21 mg, 0.057 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (26 mg, 0.114 mmol), and dichloromethane (1 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B24-2 (21 mg, 93%) as an ivory-colored solid.

[0544]

[0545] Step 3: Methyl 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)propanoate

[0546]

[0547]

[0548] Intermediate B24-2 (21 mg, 0.053 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (22 mg, 0.106 mmol), and N,N-diisopropylethylamine (46 μl, 0.265 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B24-3 (26 mg, 93%) as a white solid.

[0549]

[0550] Step 4: 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)propanoic acid

[0551]

[0552]

[0553] Intermediate B24-3 (10 mg, 0.019 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and then sodium hydroxide (8 mg, 0.190 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (8 mg, 82%) as a white solid.

[0554] 1H NMR (400 MHz, CDCl3); δ8.86 (s, 1H), 7.57 (dd, J = 8.4 Hz, 2 Hz, 2H), 7.35-7.28 (m, 6H), 4.59 (brs, 2H), 4.16 (brs, 2H), 3.93-3.90 (m, 1H), 3.69-3.67 (m, 1H), 3.43-3.40 (m, 3H), 3.00 (brs, 2H), 2.51-2.48 (m, 2H), 1.48 (d, J = 7.2 Hz, 3H); LC / MS: m / z 513.1 (M+H)+(ES).

[0555]

[0556] Example 25: 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0557] Step 1: Methyl 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0558]

[0559]

[0560] Intermediate B3-2 (22 mg, 0.058 mmol), 4-(4-chlorophenyl)piperidine (22 mg, 0.115 mmol), and N,N-diisopropylethylamine (50 μl, 0.29 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B25-3 (26 mg, 83%) as a white solid.

[0561]

[0562] Step 2: 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0563]

[0564]

[0565] Intermediate B25-3 (25 mg, 0.046 mmol) was dissolved in methanol (0.2 mL) and dichloromethane (1 mL), and sodium hydroxide (21 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (22 mg, 97%) as a white solid.

[0566] 1H NMR (400 MHz, CDCl3); δ8.53 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 8.2 Hz, 4H), 7.14 (d, J = 8.4 Hz, 2H), 4.90 (brs, 2H), 3.58 (s, 2H), 3.42-3.37 (m, 3H), 2.96-2.89 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.78-2.76 (m, 1H), 2.48-2.42 (m, 2H), 1.90 (d, J = 12.4 Hz, 2H), 1.66-1.56 (m, 2H); LC / MS: m / z 528.1 (M+H)+(ES).

[0567]

[0568] Example 26: Synthesis of 2-(4-(((5R)-2-(3-(4-chlorophenyl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0569] Step 1: Methyl 2-(4-(((5R)-2-(3-(4-chlorophenyl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0570]

[0571]

[0572] Intermediate B1-2 (20 mg, 0.0546 mmol), 3-(4-chlorophenyl)pyrrolidine (14.3 mg, 0.0656 mmol), and N,N-diisopropylethylamine (47.6 μl, 0.273 mmol) were added to 1,4-dioxane (0.36 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B26-3 (30 mg, 99%).

[0573]

[0574] Step 2: 2-(4-(((5R)-2-(3-(4-chlorophenyl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0575]

[0576]

[0577] Intermediate B26-3 (30 mg, 0.058 mmol) and sodium hydroxide (3.5 mg, 0.088 mmol) were added to tetrahydrofuran (0.3 ml) and methanol (0.03 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (14.9 mg, 51%).

[0578] 1H NMR (400 MHz, MeOD); δ7.59-7.53 (m, 2H), 7.39-7.29 (m, 6H), 4.13-1.07 (m, 1H), 3.99-3.87 (m, 1H), 3.76 (m, 7H), 3.16-3.09 (m, 2H), 2.99-2.91 (m, 1H), 2.67-2.51 (m, 1H), 2.40-2.10 (m, 2H); LC / MS: m / z 497.1 (M+H)+(ES).

[0579]

[0580] Example 27: Synthesis of (R)-2-(4-((2-(8-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0581] Step 1: (R)-Methyl 2-(4-((2-(8-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0582]

[0583]

[0584] Intermediate B1-2 (24 mg, 0.065 mmol), 8-(4-chlorophenyl)-2,8-diazaspiro[4.5]decane hydrochloride (19.7 mg, 0.065 mmol), and N,N-diisopropylethylamine (0.11 ml, 0.656 mmol) were added to 1,4-dioxane (0.43 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B27-3 (36 mg, 94%).

[0585]

[0586] Step 2: (R)-2-(4-((2-(8-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0587]

[0588]

[0589] Intermediate B27-3 (36 mg, 0.0620 mmol) and sodium hydroxide (3.7 mg, 0.0930 mmol) were added to tetrahydrofuran (0.3 ml) and methanol (0.03 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (29.3 mg, 82%).

[0590] 1H NMR (400 MHz, MeOD); δ7.67-7.56 (m, 6H), 7.41-7.37 (m, 2H), 3.81-3.42 (m, 11H), 3.20-3.09 (m, 2H), 3.00-2.97 (m, 1H), 2.68-2.59 (m, 1H), 2.31-2.01 (m, 7H); LC / MS: m / z 566.2 (M+H)+(ES).

[0591]

[0592] Example 28: Synthesis of 4-((4-((1H-tetrazol-5-yl)methyl)phenyl)amino)-2-(3-(4-chlorophenyl)azetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0593] Step 1: N-(4-((1H-tetrazol-5-yl)methyl)phenyl)-2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-amine

[0594]

[0595]

[0596] Compound A-6 (50 mg, 0.226 mmol), 4-((1H-tetrazol-5-yl)methyl)aniline (48 mg, 0.271 mmol), and N,N-diisopropylethylamine (197 μl, 1.13 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B28-1 (26 mg, 32%) as a white solid.

[0597]

[0598] Step 2: 4-((4-((1H-tetrazol-5-yl)methyl)phenyl)amino)-2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0599]

[0600]

[0601] Intermediate B28-1 (20 mg, 0.056 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (25 mg, 0.111 mmol), and dichloromethane (2 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain compound B28-2 (15 mg, 68%) as an ivory-colored solid.

[0602]

[0603] Step 3: 4-((4-((1H-tetrazol-5-yl)methyl)phenyl)amino)-2-(3-(4-chlorophenyl)azetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0604]

[0605]

[0606] Intermediate B28-2 (15 mg, 0.038 mmol), 3-(4-chlorophenyl)azetidine hydrochloride (12 mg, 0.057 mmol), and N,N-diisopropylethylamine (33 μl, 0.19 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound (7 mg, 35%) as a white solid.

[0607] 1H NMR (400 MHz, CDCl3); δ8.64 (s, 1H), 7.57 (d, J = 6.4 Hz, 2H), 7.34-7.31 (m, 4H), 7.18 (d, J = 8.8 Hz, 2H), 4.52 (t, J = 9 Hz, 2H), 4.26 (s, 2H), 4.11 (brs, 2H), 3.89-3.84 (m, 1H), 3.44-3.37 (m, 2H), 2.86 (t, J = 6.6 Hz, 2H), 2.50-2.43 (m, 2H); LC / MS: m / z 523.0 (M+H)+(ES).

[0608]

[0609] Example 29: Synthesis of (R)-2-(4-((2-(7-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0610] Step 1: (R)-Methyl 2-(4-((2-(7-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0611]

[0612]

[0613] Intermediate B1-2 (30 mg, 0.0820 mmol), 7-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonane hydrochloride (38 mg, 0.123 mmol), and N,N-diisopropylethylamine (150 μl, 0.820 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B29-3 (35 mg, 75%).

[0614]

[0615] Step 2: (R)-2-(4-((2-(7-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0616]

[0617]

[0618] Intermediate B29-3 (35 mg, 0.0618 mmol) and sodium hydroxide (3.7 mg, 0.0927 mmol) were added to tetrahydrofuran (0.3 ml) and methanol (0.03 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH=5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (12.5 mg, 36%).

[0619] 1H NMR (400 MHz, CDCl3+MeOD); δ7.61 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.89 (s, 2H), 3.59 (s, 2H), 3.40 (s, 2H), 3.31-3.26 (m, 1H), 3.14 (m, 4H), 3.02-2.88 (m, 2H), 2.71-2.56 (m, 2H), 2.19-2.14 (m, 1H), 1.96-1.93 (m, 4H); LC / MS: m / z 552.1 (M+H)+(ES).

[0620]

[0621] Example 30: Synthesis of (R)-2-(4-((2-(2-(4-chlorophenyl)-2,6-diazaspiro[3.4]octan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0622] Step 1: (R)-Methyl 2-(4-((2-(2-(4-chlorophenyl)-2,6-diazaspiro[3.4]octan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0623]

[0624]

[0625] Intermediate B1-2 (30 mg, 0.0820 mmol), 2-(4-chlorophenyl)-2,6-diazaspiro[3.4]octane hydrochloride (36.36 mg, 0.123 mmol), and N,N-diisopropylethylamine (150 μl, 0.820 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B30-3 (37 mg, 81%).

[0626]

[0627] Step 2: (R)-2-(4-((2-(2-(4-chlorophenyl)-2,6-diazaspiro[3.4]octan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0628]

[0629]

[0630] Intermediate B30-3 (35 mg, 0.067 mmol) and sodium hydroxide (4 mg, 0.067 mmol) were added to tetrahydrofuran (0.33 ml) and methanol (0.033 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH=5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (7.6 mg, 21%).

[0631] 1H NMR (400 MHz, CDCl3); δ8.57 (m, 1H), 7.52-7.48 (m, 2H), 7.17-7.08 (m, 4H), 6.57-6.54 (m, 2H), 3.70-3.49 (m, 8H), 3.34-3.29 (m, 3H), 2.96-2.64 (m, 4H), 2.17-2.14 (m, 1H), 2.02-1.96 (m, 2H); LC / MS: m / z 538.0 (M+H)+(ES).

[0632]

[0633] Example 31: Synthesis of methyl 2-(4-(((R)-2-((R)-3-acetamidopyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0634]

[0635]

[0636] Intermediate B1-2 (30 mg, 0.0820 mmol), (R)-N-(pyrrolidin-3-yl)acetamide (16.2 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (9.7 mg, 26%).

[0637] 1H NMR (400 MHz, CDCl3); δ7.94 (s, 1H), 7.59 (d, J = 8 H< 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.63 (br d, J = 6.8 Hz, 1H), 4.58 (m, 1H), 3.82-3.47 (m, 9H), 3.27-3.23 (m, 1H), 3.07-3.00 (m, 1H), 2.90-2.86 (m, 1H), 2.67-2.52 (m, 2H), 2.29-2.21 (m, 1H), 2.15-2.09 (m, 1H), 1.98 (m, 4H); LC / MS: m / z 458.1 (M+H)+(ES).

[0638]

[0639] Example 32: Synthesis of methyl 2-(4-(((R)-2-((S)-3-acetamidopyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0640]

[0641]

[0642] Intermediate B1-2 (30 mg, 0.0820 mmol), (S)-N-(pyrrolidin-3-yl)acetamide (16.2 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (8.4 mg, 22%).

[0643] 1H NMR (400 MHz, CDCl3); δ7.98 (s, 1H), 7.58 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.69 (br s, 1H), 4.58 (m, 1H), 3.79-3.47 (m, 8H), 3.49 (dd, J = 12 Hz, 4 Hz, 1H), 3.27-3.22 (m, 1H), 3.07-3.00 (m, 1H), 2.91-2.84 (m, 1H), 2.65-2.51 (m, 2H), 2.27-2.20 (m, 1H), 2.14-2.11 (m, 1H), 1.98-1.92 (m, 4H); LC / MS: m / z 458.1 (M+H)+(ES).

[0644]

[0645] Example 33: Synthesis of (R)-methyl 2-(4-((2-(4-acetamidopiperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0646]

[0647]

[0648] Intermediate B1-2 (49.5 mg, 0.135 mmol), (S)-N-(piperidin-3-yl)acetamide (29 mg, 0.162 mmol), and N,N-diisopropylethylamine (0.12 ml, 0.676 mmol) were added to 1,4-dioxane (0.9 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (12.7 mg, 20%).

[0649] 1H NMR (400 MHz, CDCl3); δ7.89 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.34 (br d, J = 8.4 Hz, 1H), 4.67-4.64 (m, 2H), 4.06-4.01 (m, 1H), 3.70 (s, 3H), 3.61 (s, 2H), 3.27-3.22 (m, 1H), 3.06-2.97 (m, 3H), 2.90-2.84 (m, 1H), 2.65-2.52 (m, 2H), 2.14-2.08 (m, 1H), 2.01-1.98 (m, 5H), 1.36-1.32 (m, 3H); LC / MS: m / z 472.1 (M+H)+(ES).

[0650]

[0651] Example 34: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

[0652]

[0653]

[0654] The compound obtained in Example 1 (30 mg, 0.0571 mmol) and ammonia (in MeOH, 1.5 ml) were added and stirred at 50°C for 16 hours. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (13 mg, 44%).

[0655] 1H NMR (400 MHz, CDCl3+MeOD); δ7.53 (d, J = 8.8 Hz, 2H), 7.29-7.25 (m, 4H), 7.18 (d, J = 8.4 Hz, 2H), 4.56 (s, 4H), 3.50 (s, 2H), 3.36 (s, 1H), 3.28-3.27 (m, 1H), 3.05-2.59 (m, 7H), 2.20-2.15 (m, 1H), 1.88-1.85 (m, 2H), 1.65-1.55 (m, 2H); LC / MS: m / z 510.1 (M+H)+(ES).

[0656]

[0657] Example 35: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0658] Step 1: Methyl 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0659]

[0660]

[0661] Intermediate B22-2 (25 mg, 0.062 mmol), 4-(4-chlorophenyl)piperidine (25 mg, 0.124 mmol), and N,N-diisopropylethylamine (54 μl, 0.31 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B35-3 (34 mg, 98%) as a white solid.

[0662]

[0663] Step 2: 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0664]

[0665]

[0666] Intermediate B35-3 (34 mg, 0.061 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (24 mg, 0.608 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (23 mg, 69%) as a white solid.

[0667] 1H NMR (400 MHz, CDCl3); δ8.72 (d, J = 2.4 Hz, 1H), 8.04 (t, J = 8.2, 1H), 7.28 (dd, J = 8.6 Hz, 2.2 Hz, 2H), 7.15 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.11 (dd, J = 11.4 Hz, 1.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.32 (brs, 2H), 3.57 (s, 2H), 3.42-3.38 (m, 2H), 2.98-2.91 (m, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.84-2.78 (m, 1H), 2.50-2.45 (m, 2H), 1.90 (d, J = 12 Hz, 2H), 1.65-1.59 (m, 2H); LC / MS: m / z 545.0 (M+H)+(ES).

[0668]

[0669] Example 36: Synthesis of 2-(4-(((R)-5-oxido-2-((S)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0670] Step 1: Methyl 2-(4-(((R)-5-oxido-2-((S)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0671]

[0672]

[0673] Intermediate B1-2 (30 mg, 0.0820 mmol), (S)-N-phenylpyrrolidine-3-kiboxamide hydrochloride (18.7 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B36-3 (34.7 mg, 81%).

[0674]

[0675] Step 2: 2-(4-(((R)-5-oxido-2-((S)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0676]

[0677]

[0678] Intermediate B36-3 (34.7 mg, 0.066 mmol) and sodium hydroxide (4 mg, 0.100 mmol) were added to tetrahydrofuran (0.33 ml) and methanol (0.033 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (32.1 mg, 95%).

[0679] 1H NMR (400 MHz, MeOD); δ7.57-7.56 (m, 4H), 7.39-7.31 (m, 4H), 7.12 (t, J = 7.2 Hz, 1H), 3.39-3.65 (m, 7H), 3.54-3.42 (m, 2H), 3.36 (s, 2H), 3.16-3.08 (m, 2H), 2.99-2.90 (m, 1H), 2.67-2.2.58 (m, 1H), 2.48-2.20 (m, 3H); LC / MS: m / z 506.1 (M+H)+(ES).

[0680]

[0681] Example 37: Synthesis of 2-(4-(((R)-5-oxido-2-((R)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0682] Step 1: Methyl 2-(4-(((R)-5-oxido-2-((R)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0683]

[0684]

[0685] Intermediate B1-2 (30 mg, 0.0820 mmol), (S)-N-phenylpyrrolidine-3-kiboxamide hydrochloride (18.7 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B37-3 (35.4 mg, 83%).

[0686]

[0687] Step 2: 2-(4-(((R)-5-oxido-2-((R)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0688]

[0689]

[0690] Intermediate B37-3 (35.4 mg, 0.068 mmol) and sodium hydroxide (4 mg, 0.102 mmol) were added to tetrahydrofuran (0.34 ml) and methanol (0.034 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (20.8 mg, 60%).

[0691] 1H NMR (400 MHz, MeOD); δ7.64-7.56 (m, 4H), 7.34-7.27 (m, 4H), 7.11 (t, J = 7.2 Hz, 1H), 3.94-3.74 (m, 4H), 3.61-3.49 (m, 4H), 3.36 (m, 3H), 3.15-3.02 (m, 1H), 2.93-2.59 (m, 3H), 2.32-2.15 (m, 3H); LC / MS: m / z 506.1 (M+H)+(ES).

[0692]

[0693] Example 38: 2-(4-(((R)-2-((R)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0694] Step 1: Methyl 2-(4-(((R)-2-((R)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0695]

[0696]

[0697] Intermediate B1-2 (30 mg, 0.0820 mmol), (R)-N-methyl-N-phenylpyrrolidin-3-amine hydrochloride (24.5 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B38-3 (32.5 mg, 78%).

[0698]

[0699] Step 2: 2-(4-(((R)-2-((R)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0700]

[0701]

[0702] Intermediate B38-3 (32.5 mg, 0.064 mmol) and sodium hydroxide (3.85 mg, 0.0964 mmol) were added to tetrahydrofuran (0.32 ml) and methanol (0.032 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (28.3 mg, 89%).

[0703] 1H NMR (400 MHz, MeOD); δ7.63-7.22 (m, 9H), 4.73-4.61 (m, 1H), 3.99-3.61 (m, 6H), 3.50-3.40 (m, 2H), 3.29-3.23 (m, 3H), 3.15-3.09 (m, 2H), 3.06-2.96 (m, 1H), 2.95-2.62 (m, 2H), 2.35-2.29 (m, 1H); LC / MS: m / z 492.2 (M+H)+(ES).

[0704]

[0705] Example 39: 2-(4-(((R)-2-((S)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0706] Step 1: Methyl 2-(4-(((R)-2-((S)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0707]

[0708]

[0709] Intermediate B1-2 (30 mg, 0.0820 mmol), (S)-N-methyl-N-phenylpyrrolidin-3-amine hydrochloride (24.5 mg, 0.123 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B39-3 (32.8 mg, 79%).

[0710]

[0711] Step 2: 2-(4-(((R)-2-((S)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0712]

[0713]

[0714] Intermediate B39-3 (32.8 mg, 0.064 mmol) and sodium hydroxide (3.89 mg, 0.097 mmol) were added to tetrahydrofuran (0.32 ml) and methanol (0.032 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (8.7 mg, 17%).

[0715] 1H NMR (400 MHz, MeOD); δ7.59 (m, 2H), 7.27-7.23 (m, 4H), 6.98 (d, J = 8 Hz, 2H), 6.83-6.82 (m, 1H), 4.66 (br s, 2H), 4.44-4.43 (m, 1H), 3.80 (m, 2H), 3.57-3.51 (m, 4H), 3.07-3.00 (m, 1H), 2.92-2.75 (m, 5H), 2.62-2.59 (m, 1H), 2.20-2.11 (m, 2H); LC / MS: m / z 492.3 (M+H)+(ES).

[0716]

[0717] Example 40: (R)-2-(4-((2-(2-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0718] Step 1: (R)-Methyl 2-(4-((2-(2-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0719]

[0720]

[0721] Intermediate B1-2 (30 mg, 0.0820 mmol), 2-(4-chlorophenyl)-2,8-diazaspiro[4.5]decane hydrochloride (24.67 mg, 0.123 mmol), and N,N-diisopropylethylamine (0.15 ml, 0.82 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B40-3 (46.4 mg, 97%).

[0722]

[0723] Step 2: (R)-2-(4-((2-(2-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0724]

[0725]

[0726] Intermediate B40-3 (46.4 mg, 0.080 mmol) and sodium hydroxide (4.8 mg, 0.119 mmol) were added to tetrahydrofuran (0.4 ml) and methanol (0.04 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (7.1 mg, 15%).

[0727] 1H NMR (400 MHz, MeOD+DMSO-d6); δ7.46 (d, J = 8.4 Hz, 2H), 7.15 (t, J = 8.8 Hz, 4H), 6.50 (d, J = 9.2 Hz, 2H), 3.79-3.54 (m, 4H), 3.36 (s, 2H), 3.30-3.26 (m, 2H), 3.17-3.16 (m, 1H), 2.98-2.91 (m, 1H), 2.78-2.60 (m, 4H), 2.33-2.32 (m, 1H), 2.01-1.85 (m, 3H), 1.53-1.48 (m, 4H); LC / MS: m / z 566.3 (M+H)+(ES).

[0728]

[0729] Example 41: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0730] Step 1: Methyl 2-(4-((2-(4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0731]

[0732]

[0733] Intermediate B22-2 (25 mg, 0.062 mmol), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (22 mg, 0.093 mmol), and N,N-diisopropylethylamine (54 μl, 0.31 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B41-3 (32 mg, 93%) as a white solid.

[0734]

[0735] Step 2: 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0736]

[0737]

[0738] Intermediate B41-3 (15 mg, 0.027 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (6 mg, 0.162 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (11 mg, 75%) as a white solid.

[0739] 1H NMR (400 MHz, CDCl3); δ8.75 (s, 1H), 8.10 (t, J = 8.2, 1H), 7.31-7.30 (m, 4H), 7.14-7.08 (m, 2H), 6.11 (t, J = 5.0 Hz, 1H), 4.38 (brs, 2H), 4.03 (brs, 2H), 3.60 (s, 2H), 3.41-3.38 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.50-2.44 (m, 2H); LC / MS: m / z 545.0 (M+H)+(ES).

[0740]

[0741] Example 42: 2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0742] Step 1: Methyl 2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0743]

[0744]

[0745] Intermediate B22-2 (15 mg, 0.038 mmol), 1-(4-chlorophenyl)-1,4-diazepane (12 mg, 0.056 mmol), and N,N-diisopropylethylamine (33 μl, 0.188 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B42-3 (21 mg, 98%) as a colorless liquid.

[0746]

[0747] Step 2: 2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0748]

[0749]

[0750] Intermediate B42-3 (21 mg, 0.036 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (9 mg, 0.219 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (16 mg, 79%) as a white solid.

[0751] 1H NMR (400 MHz, CDCl3); δ8.73 (d, J = 24.8 Hz, 1H), 8.02 (td, J = 51 Hz, 7.3 Hz, 1H), 7.16-7.00 (m, 4H), 6.62 (d, J = 8.8 Hz, 2H), 3.91 (td, J = 55 Hz, 4.8 Hz, 2H), 3.64-3.44 (m, 8H), 3.39-3.36 (m, 2H), 2.84-2.51 (m, 2H), 2.49-2.42 (m, 2H), 2.04-1.99 (m, 2H); LC / MS: m / z 560.0 (M+H)+(ES).

[0752]

[0753] Example 43: Synthesis of (R)-methyl 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0754] Step 1: (R)-Methyl 2-(4-((2-chloro-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0755]

[0756]

[0757] Intermediate B22-1 (242.5 mg, 0.659 mmol), L-(+)-diethyl tartrate (0.45 ml, 2.637 mmol), and chloroform (4.7 ml), Ti(OiPr)4 (57.95 μl, 0.197 mmol) were stirred at 0°C under nitrogen for 5 min and then at -40°C for 30 min. Cumyl hydroperoxide (80%, 0.12 ml, 0.659 mmol) was added at -40°C and stirred for 36 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B43-2 (142.1 mg, 56%).

[0758]

[0759] Step 2: (R)-Methyl 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0760]

[0761]

[0762] Intermediate B43-2 (79 mg, 0.20 mmol), 4-(4-chlorophenyl)piperidine (48.33 mg, 0.246 mmol), and N,N-diisopropylethylamine (0.18 ml, 1.02 mmol) were added to 1,4-dioxane (1.3 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (93.3 mg, 83%).

[0763] 1H NMR (400 MHz, MeOD); δ8.06-8.02 (m, 2H), 7.28-7.26 (m, 2H), 7.15-7.12 (m, 2H), 7.09-7.01 (m. 2H), 4.87 (br d, J = 12.4 Hz, 2H), 3.70 (s, 3H), 3.58 (s, 2H), 3.28-3.23 (m, 1H), 3.08-3.01 (m, 1H), 2.96-2.86 (m, 3H), 2.79-2.72 (m, 1H), 2.68-2.54 (m, 2H), 2.14-2.09 (m, 1H), 1.89-1.86 (m, 2H), 1.67-1.57 (m, 2H); LC / MS: m / z 543.2 (M+H)+(ES).

[0764]

[0765] Example 44: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0766] Step 1: Methyl 2-(4-((2-chloro-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0767]

[0768]

[0769] Intermediate B22-1 (50 mg, 0.136 mmol), S-(-)-1,1'-bi-2-naphthol (S-(-)-BINOL) (3.89 mg, 0.013 mmol), dichloromethane (0.8 ml), Ti(OiPr)4 (5.9 μl, 0.0086 mmol), and water (0.2 ml) were stirred at 0 °C under nitrogen for 1 h. tert-Butyl hydroperoxide (70% in water, 55.62 μl, 0.136 mmol) was added at 0 °C, the mixture was allowed to warm to room temperature, and stirred for 1 h. The reaction mixture was filtered to remove impurities, extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B44-2 (30 mg, 57%).

[0770]

[0771] Step 2: Methyl 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0772]

[0773]

[0774] Intermediate B44-2 (30 mg, 0.078 mmol), 2-(4-chlorophenyl)piperidine (18.35 mg, 0.093 mmol), and N,N-diisopropylethylamine (68 μl, 0.39 mmol) were added to 1,4-dioxane (0.52 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B44-3 (38.2 mg, 90%).

[0775]

[0776] Step 3: 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0777]

[0778]

[0779] Intermediate B44-3 (38.2 mg, 0.07 mmol) and sodium hydroxide (4.22 mg, 0.105 mmol) were added to tetrahydrofuran (0.35 ml) and methanol (0.035 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (25.6 mg, 68%).

[0780] 1H NMR (400 MHz, MeOD); δ7.48-7.29 (m, 4H), 7.25-7.19 (m, 3H), 4.49-4.45 (m, 2H), 3.74-3.69 (m, 3H), 3.46-3.41 (m, 1H), 3.16-3.3.08 (m, 4H), 2.97-2.88 (m, 2H), 3.65-3.61 (m, 1H), 2.23-2.01 (m, 1H), 1.90-1.87 (m, 2H), 1.70-1.64 (m, 2H); LC / MS: m / z 529.0 (M+H)+(ES).

[0781]

[0782] Example 45: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0783] Step 1: (R)-Methyl 2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0784]

[0785]

[0786] Intermediate B43-2 (30 mg, 0.078 mmol), 1-(4-chlorophenyl)-1,4-diazepane hydrochloride (23.18 mg, 0.093 mmol), and N,N-diisopropylethylamine (68 μl, 0.39 mmol) were added to 1,4-dioxane (0.52 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B45-3 (40.1 mg, 92%).

[0787]

[0788] Step 2: (R)-2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0789]

[0790]

[0791] Intermediate B45-3 (40.1 mg, 0.071 mmol) and sodium hydroxide (4.3 mg, 0.107 mmol) were added to tetrahydrofuran (0.36 ml) and methanol (0.036 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (15.3 mg, 39%).

[0792] 1H NMR (400 MHz, MeOD); δ7.97-7.78 (m, 1H), 7.13-7.10 (m, 4H), 6.64-6.62 (m, 2H), 4.19-4.06 (m, 5H), 3.93-3.66 (m, 2H), 3.62-3.51 (m, 9H), 3.39 (s, 2H), 3.29-3.25 (m, 1H), 3.06-2.87 (m, 2H), 2.66-2.53 (m, 2H), 2.20-2.15 (m, 1H), 2.03-1.97 (m, 2H); LC / MS: m / z 544.1 (M+H)+(ES).

[0793]

[0794] Example 46: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0795] Step 1: (R)-Methyl 2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0796]

[0797]

[0798] Intermediate B1-2 (30 mg, 0.082 mmol), 1-(4-chlorophenyl)piperazine hydrochloride (19.35 mg, 0.098 mmol), and N,N-diisopropylethylamine (0.15 ml, 0.82 mmol) were added to 1,4-dioxane (0.55 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B46-3 (33.2 mg, 77%).

[0799]

[0800] Step 2: (R)-2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0801]

[0802]

[0803] Intermediate B46-3 (33.2 mg, 0.063 mmol) and sodium hydroxide (3.78 mg, 0.094 mmol) were added to tetrahydrofuran (0.3 ml) and methanol (0.03 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (13.5 mg, 41%).

[0804] 1H NMR (400 MHz, DMSO-d6); δ8.94 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.25-7.20 (m, 4H), 6.99 (d, J = 9.2 Hz, 2H), 3.82 (br s, 4H), 3.53 (s, 2H), 3.17-3.15 (m, 5H), 2.99-2.92 (m, 1H), 2.78-2.64 (m, 3H), 2.02-1.99 (m, 2H); LC / MS: m / z 512.0 (M+H)+(ES).

[0805]

[0806] Example 47: Synthesis of (R)-2-(4-((2-(4-(N-methylacetamido)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0807] Step 1: (R)-Methyl 2-(4-((2-(4-(N-methylacetamido)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0808]

[0809]

[0810] Intermediate B1-2 (30 mg, 0.082 mmol), N-methyl-N-(piperidin-4-yl)acetamide hydrochloride (18.96 mg, 0.098 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.54 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B47-3 (33.4 mg, 83%).

[0811]

[0812] Step 2: (R)-2-(4-((2-(4-(N-methylacetamido)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0813]

[0814]

[0815] Intermediate B47-3 (33.4 mg, 0.068 mmol) and sodium hydroxide (4.12 mg, 0.103 mmol) were added to tetrahydrofuran (0.34 ml) and methanol (0.034 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (17.4 mg, 53%).

[0816] 1H NMR (400 MHz, MeOD); δ7.49-7.48 (m, 2H), 7.35-7.34 (m, 2H), 4.65 (m, 4H), 3.65 (s, 2H), 3.09-3.00 (m, 4H), 2.90-2.77 (m, 4H), 2.64-2.61 (m, 1H), 2.26-2.11 (m, 4H), 1.81-1.70 (m, 4H); LC / MS: m / z 472.1 (M+H)+(ES).

[0817]

[0818] Example 48: Synthesis of (R)-2-(4-((2-(4-acetylpiperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0819] Step 1: (R)-Methyl 2-(4-((2-(4-acetylpiperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0820]

[0821]

[0822] Intermediate B1-2 (45.7 mg, 0.125 mmol), 1-(piperidin-4-yl)ethan-1-one hydrochloride (24.53 mg, 0.149 mmol), and N,N-diisopropylethylamine (0.11 ml, 0.624 mmol) were added to 1,4-dioxane (0.83 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B48-3 (51 mg, 89%).

[0823]

[0824] Step 2: (R)-2-(4-((2-(4-acetylpiperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0825]

[0826]

[0827] Intermediate B48-3 (51 mg, 0.11 mmol) and sodium hydroxide (6.7 mg, 0.167 mmol) were added to tetrahydrofuran (0.55 ml) and methanol (0.055 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (30.3 mg, 61%).

[0828] 1H NMR (400 MHz, MeOD); δ7.46 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 4.38-4.35 (m, 2H), 3.67 (s, 2H), 3.43-3.40 (m, 1H), 3.26-3.05 (m, 4H), 2.94-2.78 (m, 2H), 2.63-2.60 (m, 1H), 2.28-2.25 (m, 1H), 2.11 (s, 3H). 2.02-1.99 (m, 2H), 1.61-1.58 (m, 2H); LC / MS: m / z 443.1 (M+H)+(ES).

[0829]

[0830] Example 49: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-(cyclopropylmethyl)acetamide

[0831]

[0832]

[0833] The compound obtained in Example 43 (15 mg, 0.028 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (16.3 mg, 0.085 mmol), and hydroxybenzotriazole (7.66 mg, 0.0567 mmol) were added to anhydrous dimethylformamide (2 ml) and stirred at room temperature for 10 minutes. Then, cyclopropylmethamine (6.5 μl, 0.076 mmol) and triethylamine (15.8 μl, 0.113 mmol) were added to the reaction mixture and stirred at room temperature for 16 hours. The solid formed after the reaction was washed with water and filtered to obtain the title compound (7.6 mg, 46%).

[0834] 1H NMR (400 MHz, MeOD); δ8.11-8.01 (m, 2H), 7.28 (m, 1H), 7.15-7.12 (m, 2H), 7.08-7.02 (m, 2H), 5.50 (s, 1H), 4.89-4.86 (m, 2H), 3.52 (s, 2H), 3.29-3.24 (m, 1H), 3.10-3.02 (m, 3H), 2.95-2.86 (m, 4H), 2.79-2.73 (m, 1H). 2.68-2.55 (m, 2H), 2.15-2.10 (m, 1H), 1.90-1.86 (m, 2H), 1.67-1.58 (m, 2H), 0.90-0.86 (m, 1H), 0.47-0.43 (m, 2H), 0.16-0.12 (m, 2H); LC / MS: m / z 581.9 (M+H)+(ES).

[0835]

[0836] Example 50: Synthesis of (R)-2-(4-((2-(2-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0837] Step 1: (R)-Methyl 2-(4-((2-(2-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0838]

[0839]

[0840] Intermediate B1-2 (30 mg, 0.082 mmol), 2-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonane hydrochloride (30.47 mg, 0.098 mmol), and N,N-diisopropylethylamine (71.42 μl, 0.41 mmol) were added to 1,4-dioxane (0.54 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B50-3 (35.2 mg, 75%).

[0841]

[0842] Step 2: (R)-2-(4-((2-(2-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0843]

[0844]

[0845] Intermediate B50-3 (35.2 mg, 0.062 mmol) and sodium hydroxide (3.73 mg, 0.093 mmol) were added to tetrahydrofuran (0.31 ml) and methanol (0.03 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (3.7 mg, 10%).

[0846] 1H NMR (400 MHz, MeOD); δ7.53-7.50 (m, 2H), 7.28-7.26 (m, 2H), 7.14-7.13 (m, 2H), 6.42-6.40 (m, 2H), 3.96 (m, 1H), 3.80 (m, 2H), 3.73-3.60 (m, 6H), 3.44-3.40 (m, 1H), 3.31-3.25 (m, 2H), 3.03-2.87 (m, 2H), 2.72-2.55 (m, 2H). 2.19-2.03 (m, 3H), 1.85-1.83 (m, 2H), 1.67-1.64 (m, 2H); LC / MS: m / z 552.1 (M+H)+(ES).

[0847]

[0848] Example 51: Synthesis of 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0849] Step 1: Methyl 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0850]

[0851]

[0852] Intermediate B22-2 (50 mg, 0.125 mmol), 5-chloro-2-(piperidin-4-yl)pyrimidine (49 mg, 0.250 mmol), and N,N-diisopropylethylamine (109 μl, 0.625 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B51-3 (60 mg, 86%) as a white solid.

[0853]

[0854] Step 2: 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0855]

[0856]

[0857] Intermediate B51-3 (60 mg, 0.107 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (43 mg, 1.07 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (34 mg, 59%) as a white solid.

[0858] 1H NMR (400 MHz, CDCl3); δ8.76 (s, 1H), 8.65 (s 2H), 8.08 (t, J = 8.2, 1H), 7.11-7.10 (dd, J = 11.4 Hz, 1.8 Hz, 1H), 7.04 (d, J = 8.4 Hz), 4.75 (brs, 2H), 3.64 (s, 2H), 3.37-3.36 (m, 2H), 3.20-3.14 (m, 1H), 3.08-3.01 (m, 2H), 2.85 (t, J = 6.6, 2H) 2.49-2.42 (m, 2H), 2.10-2.05 (m, 2H), 1.88-1.78 (m, 2H); LC / MS: m / z 547.0 (M+H)+(ES).

[0859]

[0860] Example 52: Synthesis of (R)-2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0861] Step 1: (R)-Methyl 2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0862]

[0863]

[0864] Intermediate B1-2 (45 mg, 0.123 mmol), 3-(4-chlorophenyl)-3,6-diazabischloro[3.1.1]heptane hydrochloride (41.56 mg, 0.147 mmol), and N,N-diisopropylethylamine (0.21 ml, 1.23 mmol) were added to 1,4-dioxane (1.5 ml), heated in a microwave at 120°C, and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B52-3 (64.3 mg, 97%).

[0865]

[0866] Step 2: (R)-2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0867]

[0868]

[0869] Intermediate B52-3 (64.32 mg, 0.11 mmol) and sodium hydroxide (7.13 mg, 0.179 mmol) were added to tetrahydrofuran (0.6 ml) and methanol (0.06 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (21 mg, 33%).

[0870] 1H NMR (400 MHz, MeOD); δ8.93 (brs, 1H), 7.55 (d, J = 8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz., 2H), 6.63-6.61 (m, 2H), 4.52-4.43 (m, 2H), 3.85-3.68 (m, 2H), 3.51 (s, 2H), 3.13-3.10 (m, 2H), 3.00-2.93 (m, 1H), 2.75-2.60 (m, 4H), 2.43-2.32 (m, 1H). 1.97-1.91 (m, 1H), 1.62 (d, J = 8.4 Hz, 1H); LC / MS: m / z 524.1 (M+H)+(ES).

[0871]

[0872] Example 53: Synthesis of 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(1,2-dihydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0873] Step 1: 1-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)ethane-1,2-diol

[0874]

[0875]

[0876] Compound A-6 (62 mg, 0.280 mmol), 1-(4-aminophenyl)-2-hydroxyethane-1-one (51 mg, 0.336 mmol), tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol), 1,1'-bis(diphenylphosphino)ferrocene (16 mg, 0.028 mmol), and potassium carbonate (77 mg, 0.560 mmol) were added to 1,4-dioxane (2 ml), and the mixture was stirred at 80°C for 2 hours using a microwave. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B53-1 (71 mg, 75%) as a brown solid.

[0877]

[0878] Step 2: 2-Chloro-4-((4-(1,2-dihydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0879]

[0880]

[0881] Intermediate B53-1 (30 mg, 0.089 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (40 mg, 0.178 mmol), and dichloromethane (2 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B53-2 (20 mg, 61%) as an ivory-colored solid.

[0882]

[0883] Step 3: 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(1,2-dihydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[0884]

[0885]

[0886] Intermediate B53-2 (20 mg, 0.054 mmol), 4-(4-chlorophenyl)piperidine (21 mg, 0.108 mmol), and N,N-diisopropylethylamine (47 μl, 0.270 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound (21 mg, 74%) as a white solid.

[0887] 1H NMR (400 MHz, CDCl3); δ8.58 (s, 1 H), 7.55 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.55 (dd, J = 16.4 Hz, 5.2 Hz, 2H), 7.27-7.26 (m, 2H), 7.14 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 4.89 (brs, 2H), 4.81 (dd, J = 8 Hz, 3.6 Hz, 1H), 3.78-3.64 (m, 2H), 3.39-3.36 (m, 2H), 2.96-2.89 (m, 2H), 2.84 (t, J = 6.4, 2H), 2.81-2.73 (m, 1H), 2.49-2.42 (m, 2H), 1.91-1.88 (m, 2H), 1.66-1.55 (m, 2H); LC / MS: m / z 529.0 (M+H)+(ES).

[0888]

[0889] Example 54: Synthesis of (R)-2-(4-(((5R)-2-(6-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0890] Step 1: (R)-Methyl 2-(4-(((5R)-2-(6-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0891]

[0892]

[0893] Intermediate B1-2 (45 mg, 0.123 mmol), 6-(4-chlorophenyl)-3,6-diazabischloro[3.1.1]heptane hydrochloride (41.56 mg, 0.147 mmol), and N,N-diisopropylethylamine (0.21 ml, 1.23 mmol) were added to 1,4-dioxane (1.5 ml), heated in a microwave at 120°C, and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B54-3 (73.7 mg, 99%).

[0894]

[0895] Step 2: (R)-2-(4-(((5R)-2-(6-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0896]

[0897]

[0898] Intermediate B54-3 (73.7 mg, 0.136 mmol) and sodium hydroxide (8.21 mg, 0.2 mmol) were added to tetrahydrofuran (0.68 ml) and methanol (0.068 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (14.9 mg, 20%).

[0899] 1H NMR (400 MHz, MeOD); δ 7.58 (dd, J = 8.4 Hz, 3.2 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.15-7.11 (m, 2H), 6.62 (d, J = 8.8 Hz., 2H), 4.20-4.06 (m, 2H), 3.64-3.53 (m, 4H), 3.29-2.23 (m, 1H), 3.07-2.95 (m, 1H), 2.88-2.52 (m, 5H), 2.29-2.09 (m, 2H), 1.68 (m, 1H); LC / MS: m / z 524.1 (M+H)+(ES).

[0900]

[0901] Example 55: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0902] Step 1: (R)-Methyl 2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0903]

[0904]

[0905] Intermediate B43-2 (30 mg, 0.078 mmol), 1-(4-chlorophenyl)piperazine hydrochloride (18.44 mg, 0.093 mmol), and N,N-diisopropylethylamine (68 μl, 0.39 mmol) were added to 1,4-dioxane (0.52 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B55-3 (36.2 mg, 85%).

[0906]

[0907] Step 2: (R)-2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0908]

[0909]

[0910] Intermediate B55-3 (36 mg, 0.066 mmol) and sodium hydroxide (3.97 mg, 0.099 mmol) were added to tetrahydrofuran (0.33 ml) and methanol (0.033 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (18.7 mg, 53%).

[0911] 1H NMR (400 MHz, MeOD); δ8.95 (s, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.24-7.08 (m, 4H), 6.97 (d, J = 8.8 Hz., 2H), 3.74 (brs, 3H), 3.62 (s, 2H), 3.19-3.00 (m, 6H), 2.80-2.63 (m, 4H), 2.03-2.00 (m, 1H); LC / MS: m / z 530.1 (M+H)+(ES).

[0912]

[0913] Example 56: Synthesis of (R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0914] Step 1: (R)-Methyl 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0915]

[0916]

[0917] Intermediate B43-2 (30 mg, 0.078 mmol), 5-chloro-2-(piperidin-4-yl)pyrimidine hydrochloride (21.96 mg, 0.093 mmol), and N,N-diisopropylethylamine (68 μl, 0.39 mmol) were added to 1,4-dioxane (0.52 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B56-3 (37.4 mg, 87%).

[0918]

[0919] Step 2: (R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0920]

[0921]

[0922] Intermediate B56-3 (37 mg, 0.068 mmol) and sodium hydroxide (4.07 mg, 0.101 mmol) were added to tetrahydrofuran (0.34 ml) and methanol (0.034 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (30.7 mg, 85%).

[0923] 1H NMR (400 MHz, MeOD); δ8.90-8.88 (m, 2H), 7.54 (t, J = 8 Hz, 1H), 7.16 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.07 (dd, J = 8.4 Hz., 1.6 Hz, 1H), 3.59 (s, 2H), 3.18-2.96 (m, 6H), 2.78-2.63 (m, 3H), 2.45-2.32 (m, 1H), 2.03-1.91 (m, 3H), 1.65-1.57 (m, 2H); LC / MS: m / z 531.1 (M+H)+(ES).

[0924]

[0925] Example 57: Synthesis of 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0926] Step 1: Methyl 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0927]

[0928]

[0929] Intermediate B3-2 (100 mg, 0.262 mmol), 1-(4-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (100 mg, 0.314 mmol), bis(diphenylphosphino)ferrocene dichloropalladium(II) (20 mg, 0.026 mmol), and potassium carbonate (110 mg, 0.786 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml), and stirred at 120°C for 1 h using a microwave. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound B57-3 (94 mg, 67%) as an ivory solid.

[0930]

[0931] Step 2: 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0932]

[0933]

[0934] Intermediate B57-3 (15 mg, 0.037 mmol) was dissolved in tetrahydrofuran (2 mL), sodium hydroxide (3 mg, 0.074 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, 4N hydrochloric acid (in dioxane) was added to adjust the pH to 6. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (5 mg, 26%) as a white solid.

[0935] H NMR (400 MHz, DMSO-d6); δ7.60-7.57 (m, 2H), 7.30-7.21 (m, 5H), 6.99 (dd, J = 7.0 Hz, 2.2 Hz, 2H), 3.95-3.94 (m, 2H), 3.71-3.68 (m, 2H), 3.56 (s, 2H), 2.99 (t, J = 6.4, 2H), 2.68-2.66 (m, 2H), 2.39-2.33 (m, 2H); LC / MS: m / z 526.0 (M+H)+(ES).

[0936]

[0937] Example 58: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide

[0938]

[0939]

[0940] After adding methylamine (40% in methanol, 2 mL) to intermediate B25-3 (50 mg, 0.092 mmol), the mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (47 mg, 95%) as a white solid.

[0941] 1H NMR (400 MHz, CDCl3); δ8.59 (s, 1H), 8.55 (dd, J = 6.4 Hz, 2.0 Hz, 2H), 7.29-7.26 (m, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.14 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 4.90 (brs, 2H), 3.55 (s, 2H), 3.40-3.74 (m, 2H), 2.97-2.90 (m, 2H), 2.84 (t, J = 10.6, 2H), 2.81-2.75 (m, 4H), 2.49-2.43 (m, 2H), 1.91-1.88 (m, 2H), 1.66-1.55 (m, 2H); LC / MS: m / z 540.0 (M+H)+(ES).

[0942]

[0943] Example 59: Synthesis of 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0944] Step 1: Methyl 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0945]

[0946]

[0947] Intermediate B22-2 (40 mg, 0.100 mmol), 5-chloro-2-(piperidin-4-yl)pyridine (30 mg, 0.150 mmol), and N,N-diisopropylethylamine (87 μl, 0.500 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B59-3 (6 mg, 11%) as a colorless liquid.

[0948]

[0949] Step 2: 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0950]

[0951]

[0952] Intermediate B59-3 (6 mg, 0.011 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (3 mg, 0.054 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to give the title compound (4 mg, 67%) as an ivory-colored solid.

[0953] 1H NMR (400 MHz, CDCl3); δ8.72 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.02 (t, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.15-7.02 (m, 3H), 4.87 (brs, 2H), 3.58 (s, 2H), 3.43-3.37 (m, 2H), 3.02-2.96 (m, 2H), 2.86 (t, J = 6.4, 2H), 2.49-2.43 (m, 2H), 1.91-1.88 (m, 2H), 1.76-1.66 (m, 2H); LC / MS: m / z 547.0 (M+H)+(ES).

[0954]

[0955] Example 60: Synthesis of methyl 2-(4-((2-(5-chloro-5',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0956]

[0957]

[0958] Intermediate B22-2 (34 mg, 0.085 mmol), 5-chloro-1',2',3',6'-tetrahydro-2,4'-bipyridine (20 mg, 0.102 mmol), and N,N-diisopropylethylamine (74 μl, 0.425 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (25 mg, 53%) as a white solid.

[0959] 1H NMR (400 MHz, CDCl3); δ8.78 (s, 1H), 8.51 (d, J = 2 Hz, 1H), 8.11 (t, J = 8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.12-7.06 (m, 2H), 6.69-6.67 (m, 1H), 4.44 (brs, 2H), 4.04 (s, 2H), 3.72 (s, 3H), 3.62 (s, 2H), 3.39-3.36 (m, 2H), 2.88 (t, J = 6.6, 2H), 2.69-2.68 (m, 2H), 2.48-2.445 (m, 2H); LC / MS: m / z 558.0 (M+H)+(ES).

[0960]

[0961] Example 61: Synthesis of 2-(4-((2-(5-chloro-5',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0962]

[0963]

[0964] The compound obtained in Example 60 (23 mg, 0.412 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (10 mg, 2.47 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (12 mg, 54%) as a white solid.

[0965] 1H NMR (400 MHz, CDCl3); δ8.78 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.12 (t, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.14-7.08 (m, 2H), 6.67 (brs, 1H), 4.44 (brs, 2H), 4.03 (brs, 2H), 3.62 (s, 2H), 3.38 (q, J = 4.13 Hz, 2H), 2.89-2.86 (m, 2H), 2.68 (brs, 2H), 2.50-2.45 (m, 2H); LC / MS: m / z 544.0 (M+H)+(ES).

[0966]

[0967] Example 62: Synthesis of 2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0968] Step 1: Methyl 2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[0969]

[0970]

[0971] Intermediate B1-2 (36 mg, 0.098 mmol), 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (34.91 mg, 0.118 mmol), and N,N-diisopropylethylamine (0.17 ml, 0.984 mmol) were added to 1,4-dioxane (0.65 ml), heated in a microwave at 120°C, and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B62-3 (53.8 mg, 99%).

[0972]

[0973] Step 2: 2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[0974]

[0975]

[0976] Intermediate B62-3 (53.8 mg, 0.097 mmol) and sodium hydroxide (5.84 mg, 0.146 mmol) were added to tetrahydrofuran (0.48 ml) and methanol (0.04 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (33.2 mg, 63%).

[0977] 1H NMR (400 MHz, MeOD); δ7.49 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 9.2 Hz. 2H), 4.87 (s, 2H), 3.73 (s, 2H), 3.69-3.59 (m, 2H), 3.50-3.41 (m, 2H), 3.16-2.89 (m, 5H), 2.68-2.58 (m, 1H), 2.32-2.25 (m, 1H), 2.07 (brs, 3H); LC / MS: m / z 538.1 (M+H)+(ES).

[0978]

[0979] Example 63: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-methylacetamide

[0980]

[0981]

[0982] The compound obtained in Example 43 (30 mg, 0.055 mmol) was added to methylamine (in MeOH, 1.5 ml) and stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was filtered to obtain the title compound (22.2 mg, 74%).

[0983] 1H NMR (400 MHz, MeOD); δ8.10 (t, J = 8 Hz, 2H), 7.28-7.26 (m, 1H), 7.14-7.12 (m, 2H), 7.06-6.99 (m. 2H), 5.37 (brs, 1H), 4.88 (d, J = 10.58 Hz, 2H), 3.52 (s, 2H), 3.29-3.24 (m, 1H), 3.10-3.03 (m, 1H), 2.96-2.87 (m, 3H), 2.77 (d, J = 4.8 Hz, 4H), 2.69-2.55 (m, 2H), 2.17-2.09 (m, 2H), 1.91-1.87 (m, 2H), 1.67-1.57 (m, 2H); LC / MS: m / z 542.1 (M+H)+(ES).

[0984]

[0985] Example 64: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0986]

[0987]

[0988] The compound obtained in Example 43 (38.2 mg, 0.07 mmol) and sodium hydroxide (4.22 mg, 0.105 mmol) were added to tetrahydrofuran (0.35 ml) and methanol (0.035 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH=5 using 2N HCl, and the resulting solid was filtered to obtain the title compound (25.6 mg, 68%).

[0989] 1H NMR (400 MHz, MeOD); δ7.48-7.29 (m, 4H), 7.25-7.19 (m, 3H), 4.49-4.45 (m, 2H), 3.74-3.69 (m, 3H), 3.46-3.41 (m, 1H), 3.16-3.3.08 (m, 4H), 2.97-2.88 (m, 2H), 3.65-3.61 (m, 1H), 2.23-2.01 (m, 1H), 1.90-1.87 (m, 2H), 1.70-1.64 (m, 2H); LC / MS: m / z 529.0 (M+H)+(ES).

[0990]

[0991] Example 65: Synthesis of 2-(4-((5,5-deoxido-2-(4-(pyridin-2-yl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0992] Step 1: Methyl 2-(4-((5,5-deoxido-2-(4-(pyridin-2-yl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[0993]

[0994]

[0995] Intermediate B22-2 (40 mg, 0.100 mmol), 2-(piperidin-4-yl)pyridine (24 mg, 0.150 mmol), and N,N-diisopropylethylamine (130 μl, 0.750 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B65-3 (45 mg, 86%) as a white solid.

[0996]

[0997] Step 2: 2-(4-((5,5-deoxido-2-(4-(pyridin-2-yl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[0998]

[0999]

[1000] Intermediate B65-3 (45 mg, 0.086 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (21 mg, 0.516 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (9 mg, 20%) as a white solid.

[1001] 1H NMR (400 MHz, CDCl3); δ8.56 (s, 1H), 8.36-8.34 (m, 1H), 7.95-7.89 (m, 1H), 7.59-7.54 (m, 1H), 7.23-6.91 (m, 4H), 4.75 (brs, 2H), 3.56 (s, 2H), 3.28-3.24 (m, 2H), 2.91-2.84 (m, 3H), 2.74 (t, J = 6.6 Hz, 2H), 2.37-2.30 (m, 2H), 1.91-1.87 (m, 2H), 1.64-1.55 (m, 2H); LC / MS: m / z 511.0 (M+H)+(ES).

[1002]

[1003] Example 66: Synthesis of 2-(4-(((5R)-2-(8-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1004] Step 1: Methyl 2-(4-(((5R)-2-(8-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1005]

[1006]

[1007] Intermediate B1-2 (30 mg, 0.082 mmol), 8-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (21.91 mg, 0.098 mmol), and N,N-diisopropylethylamine (0.15 ml, 0.82 mmol) were added to 1,4-dioxane (0.54 ml), heated in a microwave at 120°C, and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B66-3 (45.7 mg, 99%).

[1008]

[1009] Step 2: 2-(4-(((5R)-2-(8-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1010]

[1011]

[1012] Intermediate B66-3 (45 mg, 0.081 mmol) and sodium hydroxide (4.89 mg, 0.122 mmol) were added to tetrahydrofuran (0.4 ml) and methanol (0.04 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (35.4 mg, 80%).

[1013] 1H NMR (400 MHz, MeOD); δ7.51 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 9.2 Hz, 2H), 6.91 (d, J = 8.8 Hz. 2H), 4.31 (m, 4H), 3.62 (s, 2H), 3.27-3.24 (m, 3H), 3.07-3.00 (m, 1H), 2.90-2.84 (m, 1H), 2.77-2.55 (m, 2H), 2.18-2.13 (m, 1H), 2.00-1.98 (m, 2H), 1.76-1.74 (m, 2H); LC / MS: m / z 538.1 (M+H)+(ES).

[1014]

[1015] Example 67: Synthesis of (R)-2-(6-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-3-yl)acetic acid

[1016] Step 1: Methyl 2-(6-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-3-yl)acetate

[1017]

[1018]

[1019] Compound A-6 (50 mg, 0.226 mmol), methyl 2-(6-aminopyridin-3-yl)acetate (39.45 mg, 0.215 mmol), tris(dibenzylideneacetone)dipalladium(0) (10.35 mg, 0.0113 mmol), xantphos (13 mg, 0.022 mmol), and sodium carbonate (71.9 mg, 0.678 mmol) were added to 1,4-dioxane (0.9 ml) and stirred at 90°C for 16 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B67-1 (28.5 mg, 36%).

[1020]

[1021] Step 2: Methyl (R)-2-(6-((2-chloro-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-3-yl)acetate

[1022]

[1023]

[1024] Intermediate B67-1 (28 mg, 0.079 mmol), L-(+)-diethyl tartrate (54.4 μl, 0.319 mmol), chloroform (0.57 ml), and Ti(OiPr)4 (7.01 μl, 0.023 mmol) were stirred at 0°C under nitrogen for 5 min, then at -40°C for 30 min. Cumyl hydroperoxide (80%, 23 μl, 0.119 mmol) was added at -40°C and stirred for 36 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B67-2 (19.8 mg, 67%).

[1025]

[1026] Step 3: Methyl (R)-2-(6-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-3-yl)acetate

[1027]

[1028]

[1029] Intermediate B67-2 (19 mg, 0.051 mmol), 2-(4-chlorophenyl)piperidine (12.16 mg, 0.062 mmol), and N,N-diisopropylethylamine (45 μl, 0.25 mmol) were added to 1,4-dioxane (0.34 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B67-3 (24.4 mg, 93%).

[1030]

[1031] Step 4: (R)-2-(6-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-3-yl)acetic acid

[1032]

[1033]

[1034] Intermediate B67-3 (24 mg, 0.045 mmol) and sodium hydroxide (2.73 mg, 0.068 mmol) were added to tetrahydrofuran (0.23 ml) and methanol (0.023 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (14 mg, 60%).

[1035] 1H NMR (400 MHz, MeOD); δ8.51 (s, 1H), 8.35 (dd, J = 8.8 Hz 2 Hz,, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.32-7.25 (m. 4H), 4.70 (br d, J = 12.8 Hz,, 2H), 3.86 (s, 2H), 3.44-3.39 (m, 1H), 3.29-3.23 (m, 2H), 3.17-3.08 (m, 2H), 3.00-2.92 (m, 2H), 2.70-2.59 (m, 1H), 2.30-2.24 (m, 1H), 2.04-1.98 (m, 2H), 1.82-1.76 (m, 2H); LC / MS: m / z 529.2 (M+H)+(ES).

[1036]

[1037] Example 68: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1038] Step 1: Methyl 2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1039]

[1040]

[1041] Intermediate B3-2 (50 mg, 0.131 mmol), 1-(4-chlorophenyl)piperazine hydrochloride (53 mg, 0.196 mmol), and N,N-diisopropylethylamine (114 μl, 0.655 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B68-3 (70 mg, 98%) as an ivory solid.

[1042]

[1043] Step 2: 2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1044]

[1045]

[1046] Intermediate B68-3 (70 mg, 0.129 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (52 mg, 1.29 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (18 mg, 26%) as a white solid.

[1047] 1H NMR (400 MHz, CDCl3); δ8.57 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.29-7.21 (m, 4H), 6.86 (d, J = 9.2 Hz, 2H), 3.95 (brs, 4H), 3.66 (s, 2H), 3.39-3.35 (m, 2H), 3.16 (t, J = 5.2 Hz, 4H), 2.85 (t, J = 6.6 Hz, 2H), 2.47-2.44 (m, 2H); LC / MS: m / z 528.0 (M+H)+(ES).

[1048]

[1049] Example 69: Synthesis of (R)-2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1050] Step 1: Methyl (R)-2-(4-((2-(4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1051]

[1052]

[1053] Intermediate B43-2 (30 mg, 0.078 mmol), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (21.58 mg, 0.093 mmol), and N,N-diisopropylethylamine (68 μl, 0.39 mmol) were added to 1,4-dioxane (0.52 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B69-3 (38.8 mg, 90%).

[1054]

[1055] Step 2: (R)-2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1056]

[1057]

[1058] Intermediate B69-3 (38.3 mg, 0.070 mmol) and sodium hydroxide (4.24 mg, 0.10 mmol) were added to tetrahydrofuran (0.35 ml) and methanol (0.035 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (24.5 mg, 65%).

[1059] 1H NMR (400 MHz, MeOD); δ7.50 (t, J = 8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.29-7.22 (m. 2H), 6.16 (s, 1H), 4.29 (brs, 2H), 3.93-3.91 (m, 2H), 3.72 (s, 2H), .3.56-3.41 (m, 1H), 3.16-3.09 (m, 2H), 2.99-2.90 (m, 1H), 2.69-2.60 (m, 3H), 2.32-2.26 (m, 1H); LC / MS: m / z 527.2 (M+H)+(ES).

[1060]

[1061] Example 70: Synthesis of methyl 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1062]

[1063]

[1064] Intermediate B22-2 (30 mg, 0.075 mmol), 1-(4-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (29 mg, 0.090 mmol), bis(diphenylphosphino)ferrocene dichloropalladium(II) (6 mg, 0.007 mmol), and potassium carbonate (31 mg, 0.225 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml), and stirred at 90°C for 1 h using a microwave. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (37 mg, 88%) as a yellow solid.

[1065] 1H NMR (400 MHz, CDCl3); δ8.88 (s, 1H), 8.21 (t, J = 8.4 Hz, 1H), 7.29-7.26 (m, 3H), 7.22 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.14-7.09 (m, 2H), 6.88 (dd, J = 6.8 Hz, 2 Hz, 2H), 3.94 (q, J = 2.9 Hz, 2H), 3.72 (s, 3H), 3.63 (s, 2H), 3.47-3.43 (m, 4H), 3.04 (t, J = 6.3 Hz, 2H), 2.76 (brs, 2H), 2.58-2.53 (m, 2H); LC / MS: m / z 557.0 (M+H)+(ES).

[1066]

[1067] Example 71: Synthesis of 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1068]

[1069]

[1070] The compound obtained in Example 70 (14 mg, 0.025 mmol) was dissolved in tetrahydrofuran (2 mL), sodium hydroxide (2 mg, 0.050 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, 4N hydrochloric acid (in dioxane) was added to adjust the pH to 6. The reactant was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (3 mg, 22%) as a yellow solid.

[1071] 1H NMR (400 MHz, CDCl3); δ8.88 (s, 1H), 8.21 (t, J = 8.4 Hz, 1H), 7.29-7.26 (m, 3H), 7.22 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.14-7.09 (m, 2H), 6.88 (dd, J = 6.8 Hz, 2 Hz, 2H), 3.94 (q, J = 2.9 Hz, 2H), 3.63 (s, 2H), 3.47-3.43 (m, 4H), 3.04 (t, J = 6.3 Hz, 2H), 2.76 (brs, 2H), 2.58-2.53 (m, 2H); LC / MS: m / z 543.0 (M+H)+(ES).

[1072]

[1073] Example 72: Synthesis of (R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-cyclopropylacetamide

[1074] Step 1: Methyl (R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1075]

[1076]

[1077] Intermediate B43-2 (19.4 mg, 0.050 mmol), 5-chloro-2-(piperidin-4-yl)pyrimidine (14.2 mg, 0.060 mmol), and N,N-diisopropylethylamine (44 μl, 0.25 mmol) were added to 1,4-dioxane (0.33 ml), heated in a microwave at 120°C, and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B72-3 (17.4 mg, 63%).

[1078]

[1079] Step 2: (R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-cyclopropylacetamide

[1080]

[1081]

[1082] Intermediate B72-3 (25.4 mg, 0.046 mmol) was added to cyclopropyl amine (1.3 ml) and stirred at 70°C for 24 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (1.6 mg, 6%).

[1083] 1H NMR (400 MHz, CDCl3); δ8.62 (s, 2H), 8.11-8.07 (m, 2H), 7.03-6.98 (m, 2H), 5.47 (s. 1H), 4.80 (m, 2H), 3.49 (s, 2H), 3.28-3.12 (m, 2H), 3.08-3.02 (m, 3H), 2.92-2.86 (m, 1H), 2.71-2.58 (m, 3H), 2.14-2.05 (m, 3H), 1.88-1.79 (m, 2H), 0.76-0.72 (m, 2H), 0.44-0.40 (m, 2H); LC / MS: m / z 570.2 (M+H)+(ES).

[1084]

[1085] Example 73: Synthesis of (R)-2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1086] Step 1: Methyl (R)-2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1087]

[1088]

[1089] Intermediate B43-2 (40 mg, 0.10 mmol), 1-(4-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (39.97 mg, 0.125 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (7.62 mg, 0.010 mmol), and potassium carbonate (43.2 mg, 0.312 mmol) were added to water (0.7 ml) and 1,4-dioxane (1.4 ml), heated in a microwave at 120°C, and stirred for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B73-3 (34.8 mg, 61%).

[1090]

[1091] Step 2: (R)-2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1092]

[1093]

[1094] Intermediate B73-3 (34.8 mg, 0.0643 mmol) and sodium hydroxide (2.47 mg, 0.096 mmol) were added to tetrahydrofuran (0.3 ml) and methanol (0.03 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the solvent was removed. The residue was purified by silica gel column chromatography to obtain the title compound (3.7 mg, 11%).

[1095] 1H NMR (400 MHz, MeOD); δ9.25 (s, 1H), 7.67-7.63 (m, 1H), 7.23-7.19 (m, 3H), 7.13-7.10 (m, 1H), 6.97-6.95 (m. 2H), 3.89 (s, 2H), 3.88 (s, 3H), 3.61-3.08 (m, 3H), 2.98-2.77 (m, 4H), 2.60-2.56 (m, 1H), 2.42-2.40 (m, 1H); LC / MS: m / z 527.1 (M+H)+(ES).

[1096]

[1097] Example 74: Synthesis of (R)-2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1098] Step 1: Methyl (R)-2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1099]

[1100]

[1101] Intermediate B43-2 (50 mg, 0.13 mmol), 5-chloro-2-(piperidin-4-yl)pyridine hydrochloride (60 mg, 0.26 mmol), and N,N-diisopropylethylamine (0.2 ml, 1.30 mmol) were added to 1,4-dioxane (0.86 ml), heated in a microwave at 120°C, and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound B74-3 (72.7 mg, 99%).

[1102]

[1103] Step 2: (R)-2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1104]

[1105]

[1106] Intermediate B74-3 (72 mg, 0.132 mmol) and sodium hydroxide (7.94 mg, 0.198 mmol) were added to tetrahydrofuran (0.66 ml) and methanol (0.066 ml) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the solvent was removed. The residue was purified by silica gel column chromatography to obtain the title compound (25.2 mg, 36%).

[1107] 1H NMR (400 MHz, MeOD); δ8.47 (d, J = 2 Hz, 1H), 7.80 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 7.58 (t, J = 8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22-7.15 (m, 2H), 4.63-4.30 (m, 2H), 3.66 (s, 2H), 3.40-3.34 (m, 1H), 3.16-2.99 (m, 5H), 2.90-2.81 (m, 1H), 2.67-2.57 (m, 1H), 2.26-2.21 (m, 1H), 1.97-1.94 (m, 2H), 1.80-1.71 (m, 2H); LC / MS: m / z 530.1 (M+H)+(ES).

[1108]

[1109] Example 75: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-methylacetamide

[1110]

[1111]

[1112] Methylamine (40% in methanol, 2 mL) was added to intermediate B35-3 (77 mg, 0.138 mmol) and stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (60 mg, 78%) as a white solid.

[1113] 1H NMR (400 MHz, CDCl3); δ8.81 (s, 1H), 8.10 (t, J = 8 Hz, 1H), 7.28 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.13 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.06-7.00 (m, 2H), 5.37 (brs, 2H), 4.88 (brs, 2H), 3.53 (s, 2H), 3.39 (q, J = 4.1 Hz, 2H), 2.98-2.91 (m, 2H), 2.86 (t, J = 6.6 Hz, 2H), 2.78 (d, J = 5.2 Hz, 4H), 2.48-2.45 (m, 2H), 1.90 (d, J = 12 Hz), 1.66-1.59 (m, 2H); LC / MS: m / z 558.0 (M+H)+(ES).

[1114]

[1115] Example 76: Synthesis of 2-(3-fluoro-4-((2-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1116] Step 1: Methyl 2-(3-fluoro-4-((2-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1117]

[1118]

[1119] Intermediate B22-2 (50 mg, 0.125 mmol), 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (44 mg, 0.250 mmol), and N,N-diisopropylethylamine (217 μl, 1.25 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B76-3 (62 mg, 92%) as a white solid.

[1120]

[1121] Step 2: 2-(3-Fluoro-4-((2-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1122]

[1123]

[1124] Intermediate B76-3 (58 mg, 0.107 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (43 mg, 1.07 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (38 mg, 68%) as a white solid.

[1125] 1H NMR (400 MHz, CDCl3); δ8.77 (s, 1H), 8.12 (t, J = 8.2 Hz, 1H), 7.37-7.33 (m, 2H), 7.14-7.07 (m, 2H), 7.05-7.00 (m, 2H), 6.05 (brs, 1H), 4.37 (brs, 2H), 4.03 (brs, 2H), 3.40-3.37 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.56 (brs, 2H), 2.50-2.43 (m, 2H); LC / MS: m / z 526.0 (M+H)+(ES).

[1126]

[1127] Example 77: Synthesis of 2-(3-fluoro-4-((2-(4-(4-methoxyphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1128] Step 1: Methyl 2-(3-fluoro-4-((2-(4-(4-methoxyphenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1129]

[1130]

[1131] Intermediate B22-2 (50 mg, 0.125 mmol), 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (47 mg, 0.250 mmol), and N,N-diisopropylethylamine (217 μl, 1.25 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B77-3 (44 mg, 64%) as a colorless liquid.

[1132]

[1133] Step 2: 2-(3-Fluoro-4-((2-(4-(4-methoxyphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1134]

[1135]

[1136] Intermediate B77-3 (20 mg, 0.036 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (14 mg, 0.360 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to give the title compound (8 mg, 41%) as a yellow solid.

[1137] 1H NMR (400 MHz, CDCl3); δ8.80 (s, 1H), 8.16 (t, J = 8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.10 (t, J = 9.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.02 (brs, 1H), 4.37 (brs, 2H), 4.02 (brs, 2H), 3.81 (s, 3H), 3.65 (s, 2H), 3.40-3.36 (m, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.56 (brs, 2H), 2.53-2.43 (m, 2H); LC / MS: m / z 538.0 (M+H)+(ES).

[1138]

[1139] Example 78: Synthesis of 2-(4-((2-(4-(4-cyanophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1140] Step 1: Methyl 2-(4-((2-(4-(4-cyanophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1141]

[1142]

[1143] Intermediate B22-2 (50 mg, 0.125 mmol), 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (46 mg, 0.250 mmol), and N,N-diisopropylethylamine (217 μl, 1.25 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B78-3 (68 mg, 99%) as a white solid.

[1144]

[1145] Step 2: 2-(4-((2-(4-(4-cyanophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1146]

[1147]

[1148] Intermediate B78-3 (60 mg, 0.110 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (44 mg, 1.10 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (38 mg, 65%) as a white solid.

[1149] 1H NMR (400 MHz, CDCl3); δ8.74 (s, 1H), 8.09-8.04 (m, 1H), 7.63 (dd, J = 8.4 Hz, 2.4 Hz, 2H), 7.49 (dd, J = 8.4 Hz, 2 Hz, 2H), 7.14-7.07 (m, 2H), 6.27 (brs, 1H), 4.42 (brs, 2H), 4.04 (brs, 2H), 3.60 (s, 2H), 3.41-3.38 (m, 3H), 2.88 (t, J = 6.4 Hz, 2H), 2.59 (brs, 2H), 2.48-2.45 (m, 2H); LC / MS: m / z 538.0 (M+H)+(ES).

[1150]

[1151] Example 79: Synthesis of 2-(3-fluoro-4-((2-(4-(3-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1152] Step 1: Methyl 2-(3-fluoro-4-((2-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1153]

[1154]

[1155] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (64 mg, 0.300 mmol), and N,N-diisopropylethylamine (261 μl, 1.50 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B79-3 (68 mg, 84%) as a white solid.

[1156]

[1157] Step 2: 2-(3-Fluoro-4-((2-(4-(3-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1158]

[1159]

[1160] Intermediate B79-3 (50 mg, 0.092 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (37 mg, 0.920 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (38 mg, 78%) as a white solid.

[1161] 1H NMR (400 MHz, CDCl3); δ8.80 (s, 1H), 8.13 (t, J = 8.2 Hz, 1H), 7.32-7.28 (m, 1H), 7.17-7.06 (m, 4H), 7.00-6.93 (m, 1H), 6.15 (brs, 1H), 4.38 (brs, 2H), 4.03 (brs, 2H), 3.66 (s, 2H), 3.40-3.36 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.57 (brs, 2H), 2.48-2.45 (m, 2H); LC / MS: m / z 526.0 (M+H)+(ES).

[1162]

[1163] Example 80: Synthesis of 2-(4-((2-(4-(3,5-difluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1164] Step 1: Methyl 2-(4-((2-(4-(3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1165]

[1166]

[1167] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(3,5-difluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (69 mg, 0.300 mmol), and N,N-diisopropylethylamine (261 μl, 1.50 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B80-3 (80 mg, 96%) as a white solid.

[1168]

[1169] Step 2: 2-(4-((2-(4-(3,5-difluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1170]

[1171]

[1172] Intermediate B80-3 (60 mg, 0.107 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (43 mg, 1.07 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to give the title compound (44 mg, 76%) as an ivory-colored solid.

[1173] 1H NMR (400 MHz, CDCl3); δ8.77 (s, 1H), 8.08 (t, J = 8.2 Hz, 1H), 7.14-7.08 (m, 1H), 6.90 (dd, J = 9 Hz, 2.2 Hz, 2H), 6.73-6.68 (m, 1H), 6.18 (brs, 1H), 4.39 (brs, 2H), 4.02 (brs, 2H), 3.62 (s, 2H), 3.40-3.37 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.53 (brs, 2H), 2.48-2.45 (m, 2H); LC / MS: m / z 544.0 (M+H)+(ES).

[1174]

[1175] Example 81: Synthesis of 2-(4-((2-(4-(3-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1176] Step 1: Methyl 2-(4-((2-(4-(3-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1177]

[1178]

[1179] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (69 mg, 0.300 mmol), and N,N-diisopropylethylamine (261 μl, 1.50 mmol) were added to 1,4-dioxane (2 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B81-3 (80 mg, 96%) as a white solid.

[1180]

[1181] Step 2: 2-(4-((2-(4-(3-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1182]

[1183]

[1184] Intermediate B81-3 (60 mg, 0.108 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (43 mg, 1.08 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (46 mg, 78%) as a white solid.

[1185] 1H NMR (400 MHz, CDCl3); δ8.77 (s, 1H), 8.10 (t, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.25-7.23 (m, 3H), 7.14-7.08 (m, 2H), 6.14 (t, J = 3.4 Hz, 1H), 4.38 (brs, 2H), 4.03 (brs, 2H), 3.61 (s, 2H), 3.40-3.37 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.56 (brs, 2H), 2.50-2.44 (m, 2H); LC / MS: m / z 543.0 (M+H)+(ES).

[1186]

[1187] Example 82: Synthesis of 2-(4-((2-(4-(4-chloro-2-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1188] Step 1: Methyl 2-(4-((2-(4-(4-chloro-2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1189]

[1190]

[1191] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (56 mg, 0.225 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B82-3 (71 mg, 82%) as a white solid.

[1192]

[1193] Step 2: 2-(4-((2-(4-(4-chloro-2-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1194]

[1195]

[1196] Intermediate B82-3 (71 mg, 0.123 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 ml), and sodium hydroxide (98 mg, 2.46 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (51 mg, 74%) as a white solid.

[1197] 1H NMR (400 MHz, CDCl3); δ8.77 (s, 1H), 8.10 (t, J = 8.2 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 7.13-7.06 (m, 4H), 6.02 (s, 1H), 4.37 (brs, 2H), 4.01 (brs, 2H), 3.60 (s, 2H), 3.40-3.37 (m, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.54 (brs, 2H), 2.50-2.43 (m, 2H); LC / MS: m / z 561.0 (M+H)+(ES).

[1198]

[1199] Example 83: Synthesis of 2-(4-((2-(4-(4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1200] Step 1: Methyl 2-(4-((2-(4-(4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1201]

[1202]

[1203] Intermediate B3-2 (60 mg, 0.157 mmol), 1-(4-chlorophenyl)piperazine hydrochloride (53 mg, 0.196 mmol), and N,N-diisopropylethylamine (114 μL, 0.655 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B83-3 (70 mg, 98%) as an ivory solid.

[1204]

[1205] Step 2: 2-(4-((2-(4-(4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1206]

[1207]

[1208] Intermediate B83-3 (53.8 mg, 0.097 mmol) and sodium hydroxide (5.84 mg, 0.146 mmol) were added to tetrahydrofuran (0.48 mL) and methanol (0.04 mL) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (33.2 mg, 63%).

[1209] 1H NMR (400 MHz, MeOD); δ 7.49 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 9.2 Hz. 2H), 4.87 (s, 2H), 3.73 (s, 2H), 3.69-3.59 (m, 2H), 3.50-3.41 (m, 2H), 3.16-2.89 (m, 5H), 2.68-2.58 (m, 1H), 2.32-2.25 (m, 1H), 2.07 (brs, 3H); LC / MS: m / z 538.1 (M+H)+(ES).

[1210]

[1211] Example 84: Synthesis of 2-(4-((2-(4-(4-methoxyphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1212] Step 1: Methyl 2-(4-((2-(4-(4-methoxyphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1213]

[1214]

[1215] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(4-methoxyphenyl)piperidine trifluoroacetate (54.36 mg, 0.188 mmol), and N,N-diisopropylethylamine (0.13 ml, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B84-3 (75.5 mg, 89%) as an ivory solid.

[1216]

[1217] Step 2: 2-(4-((2-(4-(4-methoxyphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1218]

[1219]

[1220] Intermediate B84-3 (75.5 mg, 0.140 mmol) and sodium hydroxide (6.75 mg, 0.211 mmol) were added to tetrahydrofuran (0.7 mL) and methanol (0.07 mL) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (46.4 mg, 63%).

[1221] 1H NMR (400 MHz, MeOD); δ 8.61 (s, 1H), 7.54 (d, J = 8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.93-4.91 (m, 2H), 3.78 (s, 3H), 3.60 (s, 2H), 3.51-3.48 (m, 2H), 3.03-2.97 (m, 2H), 2.90-2.78 (m, 3H), 2.46-2.40 (m, 2H), 1.90-1.87 (m, 2H), 1.67-1.56 (m, 2H); LC / MS: m / z 523.2 (M+H)+(ES).

[1222]

[1223] Example 85: Synthesis of 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1224] Step 1: Methyl 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1225]

[1226]

[1227] Intermediate B3-2 (60 mg, 0.157 mmol), 5-chloro-2-(piperidin-4-yl)pyridine hydrochloride (73.2 mg, 0.314 mmol), and N,N-diisopropylethylamine (0.27 mL, 1.571 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B85-3 (82.3 mg, 99%) as an ivory solid.

[1228]

[1229] Step 2: 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1230]

[1231]

[1232] Intermediate B85-3 (82.3 mg, 0.155 mmol) and sodium hydroxide (9.35 mg, 0.233 mmol) were added to tetrahydrofuran (0.78 mL) and methanol (0.07 mL) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (46.8 mg, 58%).

[1233] 1H NMR (400 MHz, MeOD); δ 8.62 (s, 1H), 8.19 (s, 1H), 7.82-7.79 (m, 1H), 7.56-7.54 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 4.93-4.91 (m, 2H), 3.60 (s, 2H), 3.53-3.50 (m, 2H), 3.15-3.04 (m, 3H), 2.91-2.88 (m, 2H), 2.47-2.40 (m, 2H), 2.01-1.96 (m, 2H), 1.79-1.73 (m, 2H); LC / MS: m / z 528.1 (M+H)+(ES).

[1234]

[1235] Example 86: Synthesis of 2-(4-((5,5-dioxido-2-(4-(p-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1236] Step 1: Methyl 2-(4-((5,5-dioxido-2-(4-(p-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1237]

[1238]

[1239] Intermediate B3-2 (57 mg, 0.149 mmol), 4-p-tolylpiperidine trifluoroacetate (81.3 mg, 0.298 mmol), and N,N-diisopropylethylamine (0.27 mL, 1.49 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B86-3 (73.1 mg, 94%) as an ivory solid.

[1240]

[1241] Step 2: 2-(4-((5,5-deoxido-2-(4-(p-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1242]

[1243]

[1244] Intermediate B86-3 (73.1 mg, 0.140 mmol) and sodium hydroxide (8.42 mg, 0.210 mmol) were added to tetrahydrofuran (0.7 mL) and methanol (0.07 mL) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with 2 N HCl, and the resulting solid was filtered to obtain the title compound (60.9 mg, 85%).

[1245] 1H NMR (400 MHz, MeOD); δ 8.61 (s, 1H), 7.56-7.53 (m, 2H), 7.31-7.27 (m, 3H), 7.15-7.10 (m, 3H), 4.93-4.91 (m, 2H), 3.60 (s, 2H), 3.51-3.48 (m, 2H), 3.04-2.97 (m, 2H), 2.90-2.79 (m, 3H), 2.46-2.40 (m, 2H), 2.31 (s, 3H), 1.98-1.87 (m, 2H), 1.68-1.61 (m, 2H); LC / MS: m / z 507.2 (M+H)+(ES).

[1246]

[1247] Example 87: Synthesis of 2-(4-((2-(4-(2,4-difluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1248] Step 1: Methyl 2-(4-((2-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1249]

[1250]

[1251] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(2,4-difluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (79 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound B87-3 (82 mg, 92%) as an ivory solid.

[1252]

[1253] Step 2: 2-(4-((2-(4-(2,4-difluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1254]

[1255]

[1256] Intermediate B87-3 (61 mg, 0.109 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (87 mg, 2.18 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (51 mg, 86%) as a white solid.

[1257] 1H NMR (400 MHz, CDCl3); δ 8.80 (s, 1H), 8.14 (t, J = 8.4 Hz, 1H), 7.23-7.18 (m, 1H), 7.13-7.06 (m, 2H), 6.87-6.77 (m, 2H), 5.97 (s, 1H), 4.37 (brs, 2H), 4.01 (brs, 2H), 3.65 (s, 2H), 3.40-3.37 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.54 (brs, 2H), 2.50-2.44 (m, 2H); LC / MS: m / z 544.0 (M+H)+(ES).

[1258]

[1259] Example 88: Synthesis of 2-(3-fluoro-4-((2-(4-(2-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1260] Step 1: Methyl 2-(3-fluoro-4-((2-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1261]

[1262]

[1263] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (64 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B88-3 (68 mg, 84%) as a white solid.

[1264]

[1265] Step 2: 2-(3-Fluoro-4-((2-(4-(2-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1266]

[1267]

[1268] Intermediate B88-3 (53 mg, 0.098 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (78 mg, 1.96 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (43 mg, 83%) as a white solid.

[1269] 1H NMR (400 MHz, CDCl3); δ 8.81 (s, 1H), 8.14 (t, J = 8 Hz, 1H), 7.27-7.20 (m, 2H), 7.12-7.02 (m, 4H), 6.02 (t, J = 3.2 Hz, 1H), 4.38 (brs, 2H), 4.03 (brs, 2H), 3.64 (s, 2H), 3.40-3.37 (m, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.58 (brs, 2H), 2.50-2.44 (m, 2H); LC / MS: m / z 526.0 (M+H)+(ES).

[1270]

[1271] Example 89: Synthesis of 2-(4-((2-(4-(3,5-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1272] Step 1: Methyl 2-(4-((2-(4-(3,5-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1273]

[1274]

[1275] Intermediate B22-2 (50 mg, 0.150 mmol), 4-(3,5-dichlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (79 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B89-3 (66 mg, 74%) as an ivory solid.

[1276]

[1277] Step 2: 2-(4-((2-(4-(3,5-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1278]

[1279]

[1280] Intermediate B89-3 (67 mg, 0.113 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (90 mg, 2.26 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (55 mg, 84%) as a white solid.

[1281] 1H NMR (400 MHz, CDCl3); δ 8.74 (s, 1H), 8.06 (q, J = 7.7 Hz, 1H), 7.26 (s, 3H), 7.14-7.08 (m, 2H), 6.18 (s, 1H), 4.39 (brs, 2H), 4.03 (brs, 2H), 3.60 (s, 2H), 3.40-3.38 (m, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.54 (brs, 2H), 2.51-2.44 (m, 2H); LC / MS: m / z 577.0 (M+H)+(ES).

[1282]

[1283] Example 90: Synthesis of 2-(4-((2-(4-(3,4-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1284] Step 1: Methyl 2-(4-((2-(4-(3,4-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1285]

[1286]

[1287] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(3,4-dichlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (79 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B90-3 (66 mg, 74%) as an ivory solid.

[1288]

[1289] Step 2: 2-(4-((2-(4-(3,4-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1290]

[1291]

[1292] Intermediate B90-3 (57 mg, 0.096 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (77 mg, 1.92 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (42 mg, 76%) as a white solid.

[1293] 1H NMR (400 MHz, CDCl3); δ 8.75 (s, 1H), 8.08 (t, J = 8.2 Hz, 1H), 7.46 (d, J = 2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.4 Hz, 2 Hz, 1H), 7.14-7.07 (m, 2H), 6.15 (brs, 1H), 4.38 (brs, 2H), 4.02 (brs, 2H), 3.61 (s, 2H), 3.44-3.37 (m, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.54 (brs, 2H), 2.48-2.45 (m, 2H); LC / MS: m / z 577.0 (M+H)+(ES).

[1294]

[1295] Example 91: Synthesis of 2-(4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1296] Step 1: Methyl 2-(4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1297]

[1298]

[1299] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(4-chloro-2-fluorophenyl)piperidine hydrochloride (78 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μL, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B91-3 (22 mg, 24%) as a white solid.

[1300]

[1301] Step 2: 2-(4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1302]

[1303]

[1304] Intermediate B91-3 (22 mg, 0.038 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (31 mg, 0.760 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (13 mg, 63%) as a white solid.

[1305] 1H NMR (400 MHz, CDCl3); δ 8.58 (s, 1H), 7.53-7.50 (m, 2H), 7.27-7.23 (m, 2H), 7.11-7.05 (m, 3H), 4.91 (brs, 1H), 3.63 (s, 2H), 3.39-3.36 (m, 2H), 3.14-3.08 (m, 1H), 2.95 (t, J = 11.8 Hz, 2H), 2.86-2.85 (m, 1H), 2.49-2.42 (m, 2H); LC / MS: m / z 545.0 (M+H)+(ES).

[1306]

[1307] Example 92: Synthesis of 2-(4-((2-(4-(4-chloro-3-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1308] Step 1: Methyl 2-(4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1309]

[1310]

[1311] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (74 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B92-3 (77 mg, 89%) as a white solid.

[1312]

[1313] Step 2: 2-(4-((2-(4-(4-chloro-3-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1314]

[1315]

[1316] Intermediate B92-3 (62 mg, 0.108 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (86 mg, 2.16 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (46 mg, 76%) as a white solid.

[1317] 1H NMR (400 MHz, CDCl3); δ 8.81 (s, 1H), 8.05 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.17-7.10 (m, 4H), 6.15 (brs, 1H), 4.40 (brs, 2H), 4.05 (brs, 2H), 3.62 (s, 2H), 3.44-3.37 (m, 2H), 2.94 (brs, 2H), 2.55 (brs, 2H), 2.51-2.44 (m, 2H); LC / MS: m / z 561.0 (M+H)+(ES).

[1318]

[1319] Example 93: Synthesis of 2-(4-((2-(4-(2,4-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1320] Step 1: Methyl 2-(4-((2-(4-(2,4-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1321]

[1322]

[1323] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(2,4-dichlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (79 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B93-3 (54 mg, 61%) as a white solid.

[1324]

[1325] Step 2: 2-(4-((2-(4-(2,4-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1326]

[1327]

[1328] Intermediate B93-3 (54 mg, 0.091 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (73 mg, 1.82 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (44 mg, 84%) as a white solid.

[1329] 1H NMR (400 MHz, CDCl3); δ 8.81 (s, 1H), 8.12 (t, J = 8.2 Hz, 1H), 7.39 (d, J = 2 Hz, 1H), 7.21 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 7.12-7.05 (m, 3H), 5.76 (brs, 1H), 4.35 (brs, 2H), 4.03 (brs, 2H), 3.64 (s, 2H), 3.40-3.37 (m, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.49-2.44 (m, 2H); LC / MS: m / z 577.0 (M+H)+(ES).

[1330]

[1331] Example 94: Synthesis of 2-(4-((2-(4-(4-chloro-2-methylphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1332] Step 1: Methyl 2-(4-((2-(4-(4-chloro-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1333]

[1334]

[1335] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(4-chloro-2-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (73 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound B94-3 (83 mg, 97%) as an ivory solid.

[1336]

[1337] Step 2: 2-(4-((2-(4-(4-chloro-2-methylphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1338]

[1339]

[1340] Intermediate B94-3 (63 mg, 0.110 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (88 mg, 2.20 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (30 mg, 49%) as a white solid.

[1341] 1H NMR (400 MHz, CDCl3); δ 8.85 (s, 1H), 8.10 (t, J = 8.2 Hz, 1H), 7.17-7.01 (m, 4H), 6.99 (d, J = 2.4 Hz, 1H), 5.63 (brs, 1H), 4.36 (brs, 2H), 4.03 (brs, 2H), 3.64 (s, 2H), 3.41-3.38 (m, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.50-2.47 (m, 2H), 2.39 (brs, 2H), 2.26 (s, 3H); LC / MS: m / z 557.0 (M+H)+(ES).

[1342]

[1343] Example 95: Synthesis of 2-(4-((2-(4-(3-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1344] Step 1: Methyl 2-(4-((2-(4-(3-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1345]

[1346]

[1347] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(3-chlorophenyl)piperidine hydrochloride (72 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μL, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B95-3 (41 mg, 48%) as an ivory solid.

[1348]

[1349] Step 2: 2-(4-((2-(4-(3-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1350]

[1351]

[1352] Intermediate B95-3 (41 mg, 0.076 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (61 mg, 1.52 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (26 mg, 65%) as a white solid.

[1353] 1H NMR (400 MHz, CDCl3); δ 8.58 (s, 1H), 7.24-7.51 (m, 2H), 7.31-7.18 (m, 4H), 7.09-7.07 (m, 1H), 4.89 (brs, 2H), 3.63 (s, 2H), 3.39-3.36 (m, 2H), 2.96-2.87 (m, 4H), 2.81-2.74 (m, 1H), 2.49-2.43 (m, 2H), 1.91 (d, J = 11.2 Hz, 2H), 1.70-1.57 (m, 2H); LC / MS: m / z 527.0 (M+H)+(ES).

[1354]

[1355] Example 96: Synthesis of 2-(4-((2-(4-(3-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1356] Step 1: Methyl 2-(4-((2-(4-(3-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1357]

[1358]

[1359] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(3-fluorophenyl)piperidine hydrochloride (68 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μL, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B96-3 (81 mg, 98%) as a white solid.

[1360]

[1361] Step 2: 2-(4-((2-(4-(3-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1362]

[1363]

[1364] Intermediate B96-3 (60 mg, 0.114 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (91 mg, 2.28 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (47 mg, 81%) as a white solid.

[1365] 1H NMR (400 MHz, CDCl3); δ 8.62 (s, 1H), 7.52-7.49 (m, 2H), 7.29-7.23 (m, 3H), 6.98 (d, J = 8 Hz, 1H), 6.92-6.88 (m, 2H), 4.90 (brs, 2H), 3.62 (s, 2H), 3.39-3.36 (m, 2H), 2.98-2.90 (m, 4H), 2.82-2.76 (m, 1H), 2.49-2.43 (m, 2H), 1.93 (d, J = 11.2 Hz, 2H), 1.68-1.58 (m, 2H); LC / MS: m / z 510.0 (M+H)+(ES).

[1366]

[1367] Example 97: Synthesis of 2-(4-((2-(4-(3,5-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1368] Step 1: Methyl 2-(4-((2-(4-(3,5-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1369]

[1370]

[1371] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(3,5-difluorophenyl)piperidine hydrochloride (72 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μL, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B97-3 (81 mg, 95%) as a white solid.

[1372]

[1373] Step 2: 2-(4-((2-(4-(3,5-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1374]

[1375]

[1376] Intermediate B97-3 (60 mg, 0.110 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (88 mg, 2.20 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (51 mg, 88%) as a white solid.

[1377] 1H NMR (400 MHz, CDCl3); δ 8.56 (s, 1H), 7.53-7.50 (m, 2H), 7.27-7.23 (m, 2H), 6.74-6.71 (m, 12H), 6.68-6.63 (m, 1H), 4.89 (brs, 2H), 3.63 (s, 2H), 3.39-3.36 (m, 2H), 2.95-2.88 (m, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.81-2.74 (m, 1H), 2.49-2.42 (m, 2H), 1.91 (d, J = 11.2 Hz, 2H), 1.64-1.53 ​​(m, 2H); LC / MS: m / z 528.0 (M+H)+(ES).

[1378]

[1379] Example 98: Synthesis of 2-(4-((5,5-dioxido-2-(4-(p-tolyl)-5,6-dihydropyridin-1(2H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1380] Step 1: Methyl 2-(4-((5,5-dioxido-2-(4-(p-tolyl)-3,6-dihydropyridin-1(2H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1381]

[1382]

[1383] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(p-tolyl)-1,2,3,6-tetrahydropyridine hydrochloride (86 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B98-3 (69 mg, 86%) as an ivory solid.

[1384]

[1385] Step 2: 2-(4-((5,5-dioxido-2-(4-(p-tolyl)-5,6-dihydropyridin-1(2H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1386]

[1387]

[1388] Intermediate B98-3 (67 mg, 0.125 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (100 mg, 2.50 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (9 mg, 14%) as a white solid.

[1389] 1H NMR (400 MHz, CDCl3); δ 8.76 (s, 1H), 8.16-8.12 (m, 1H), 7.39-7.28 (m, 2H), 7.16-7.08 (m, 4H), 6.08 (s, 1H), 4.38 (brs, 2H), 4.03 (brs, 2H), 3.60 (s, 2H), 3.41-3.37 (m, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.59 (brs, 2H), 2.51-2.43 (m, 4H), 2.35 (s, 3H); LC / MS: m / z 522.0 (M+H)+(ES).

[1390]

[1391] Example 99: Synthesis of 2-(4-((2-(4-(3-chloro-4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1392] Step 1: Methyl 2-(4-((2-(4-(3-chloro-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1393]

[1394]

[1395] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (74 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B99-3 (86 mg, 96%) as a white solid.

[1396]

[1397] Step 2: 2-(4-((2-(4-(3-chloro-4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1398]

[1399]

[1400] Intermediate B99-3 (66 mg, 0.115 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (92 mg, 2.30 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (50 mg, 78%) as a white solid.

[1401] 1H NMR (400 MHz, CDCl3); δ 8.76 (s, 1H), 8.09 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 7 Hz, 2.2 Hz, 1H), 7.26-7.22 (m, 1H), 7.14-7.07 (m, 3H), 6.09 (brs, 1H), 4.38 (brs, 2H), 4.02 (brs, 2H), 3.61 (s, 2H), 3.44-3.37 (m, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.53 (brs, 2H), 2.50-2.45 (m, 2H); LC / MS: m / z 561.0 (M+H)+(ES).

[1402]

[1403] Example 100: Synthesis of 2-(4-((2-(4-(4-bromophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1404] Step 1: Methyl 2-(4-((2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1405]

[1406]

[1407] Intermediate B22-2 (60 mg, 0.150 mmol), 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (82 mg, 0.300 mmol), and N,N-diisopropylethylamine (130 μL, 0.750 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B100-3 (90 mg, 99%) as a white solid.

[1408]

[1409] Step 2: 2-(4-((2-(4-(4-bromophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1410]

[1411]

[1412] Intermediate B100-3 (57 mg, 0.095 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (76 mg, 1.90 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (37 mg, 66%) as a white solid.

[1413] 1H NMR (400 MHz, CDCl3); δ 8.77 (s, 1H), 8.09 (t, J = 8.2 Hz, 1H), 7.47-7.44 (m, 2H), 7.27-7.24 (m, 2H), 7.14-7.07 (m, 2H), 6.12 (brs, 1H), 4.37 (brs, 2H), 4.03 (brs, 2H), 3.60 (s, 2H), 3.43-3.37 (m, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.56 (brs, 2H), 2.50-2.44 (m, 2H); LC / MS: m / z 587.0 (M+H)+(ES).

[1414]

[1415] Example 101: Synthesis of 2-(4-((2-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1416] Step 1: Methyl 2-(4-((2-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1417]

[1418]

[1419] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(3-chloro-4-fluorophenyl)piperidine hydrochloride (78 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μL, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B101-3 (82 mg, 93%) as a white solid.

[1420]

[1421] Step 2: 2-(4-((2-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1422]

[1423]

[1424] Intermediate B101-3 (61 mg, 0.109 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (87 mg, 2.18 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (42 mg, 71%) as a white solid.

[1425] 1H NMR (400 MHz, CDCl3); δ 8.62 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.25-7.22 (m, 3H), 7.08-7.06 (m, 2H), 4.92 (brs, 2H), 3.60 (s, 2H), 3.43-3.37 (m, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.80-2.74 (m, 1H), 2.50-2.44 (m, 2H), 1.91 (d, J = 12.4 Hz, 2H), 1.65-1.59 (m, 2H); LC / MS: m / z 545.0 (M+H)+(ES).

[1426]

[1427] Example 102: Synthesis of 2-(4-((2-(4-(2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1428] Step 1: Methyl 2-(4-((2-(4-(2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1429]

[1430]

[1431] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(2-fluorophenyl)piperidine hydrochloride (68 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μL, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound B102-3 (79 mg, 96%) as an ivory solid.

[1432]

[1433] Step 2: 2-(4-((2-(4-(2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1434]

[1435]

[1436] Intermediate B102-3 (60 mg, 0.114 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (91 mg, 2.28 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (39 mg, 67%) as a white solid.

[1437] 1H NMR (400 MHz, CDCl3); δ 8.57 (s, 1H), 7.52 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.25-7.00 (m, 6H), 4.91 (brs, 2H), 3.62 (s, 2H), 3.39-3.36 (m, 2H), 3.19-3.12 (m, 1H), 3.00-2.93 (m, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.49-2.42 (m, 2H), 1.91 (d, J = 12.4 Hz, 2H), 1.72-1.62 (m, 2H); LC / MS: m / z 510.0 (M+H)+(ES).

[1438]

[1439] Example 103: Synthesis of 2-(4-((2-(4-(2,4-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1440] Step 1: Methyl 2-(4-((2-(4-(2,4-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1441]

[1442]

[1443] Intermediate B3-2 (63 mg, 0.165 mmol), 4-(2,4-difluorophenyl)piperidine hydrochloride (65 mg, 0.330 mmol), and N,N-diisopropylethylamine (143 μL, 0.825 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B103-3 (85 mg, 95%) as a white solid.

[1444]

[1445] Step 2: 2-(4-((2-(4-(2,4-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1446]

[1447]

[1448] Intermediate B103-3 (60 mg, 0.110 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (88 mg, 2.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (42 mg, 72%) as a white solid.

[1449] 1H NMR (400 MHz, CDCl3); δ 8.57 (s, 1H), 7.52 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.25-7.23 (m, 2H), 7.16-7.10 (m, 1H), 6.85-6.76 (m, 2H), 4.90 (brs, 2H), 3.63 (s, 2H), 3.39-3.36 (m, 2H), 3.13-3.07 (m, 1H), 2.98-2.91 (m, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.49-2.42 (m, 2H), 1.88 (d, J = 12.4) Hz, 2H), 1.68-1.58 (m, 2H); LC / MS: m / z 528.0 (M+H)+(ES).

[1450]

[1451] Example 104: Synthesis of 2-(4-((2-(4-(4-bromophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1452] Step 1: Methyl 2-(4-((2-(4-(4-bromophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1453]

[1454]

[1455] Intermediate B3-2 (60 mg, 0.157 mmol), 4-(4-bromophenyl)piperidine hydrochloride (86 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μL, 0.785 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound B104-3 (62 mg, 68%) as an ivory solid.

[1456]

[1457] Step 2: 2-(4-((2-(4-(4-bromophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1458]

[1459]

[1460] Intermediate B104-3 (15 mg, 0.027 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (22 mg, 0.54 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (3 mg, 20%) as a white solid.

[1461] 1H NMR (400 MHz, CDCl3); δ 8.55 (s, 1H), 7.51 (d, J = 8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.89 (brs, 2H), 3.59 (s, 2H), 3.43-3.36 (m, 2H), 2.96-2.76 (m, 5H), 2.47-2.44 (m, 2H), 1.91-1.82 (m, 2H), 1.65-1.59 (m, 2H); LC / MS: m / z 571.0 (M+H)+(ES).

[1462]

[1463] Example 105: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide

[1464] Step 1: Methyl 2-(4-((2-(4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1465]

[1466]

[1467] Intermediate B3-2 (50 mg, 0.131 mmol), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (70 mg, 0.262 mmol), and N,N-diisopropylethylamine (114 μL, 0.655 mmol) were added to 1,4-dioxane (1 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B105-3 (55 mg, 78%) as a white solid.

[1468]

[1469] Step 2: 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide

[1470]

[1471]

[1472] After adding methylamine (40% in methanol, 2 mL) to intermediate B105-3 (30 mg, 0.056 mmol), the mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (30 mg, 99%) as a white solid.

[1473] 1H NMR (400 MHz, CDCl3); δ 8.61 (s, 1H), 7.59 (dd, J = 6.4 Hz, 2 Hz, 2H), 7.31 (s, 4H), 7.24 (d, J = 8.4 Hz, 2H), 6.13-6.11 (m, 1H), 5.38 (brs, 1H), 4.40 (brs, 2H), 4.05 (brs, 2H), 3.57 (s, 2H), 3.39-3.36 (m, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.78 (d, J = 5.2 Hz, 3H), 2.57 (brs, 2H), 2.50-2.43 (m, 2H); LC / MS: m / z 538.0 (M+H)+(ES).

[1474]

[1475] Example 106: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-ethylacetamide

[1476]

[1477]

[1478] After adding ethylamine (40% in methanol, 2 mL) to intermediate B25-3 (25 mg, 0.046 mmol), the mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (23 mg, 90%) as a white solid.

[1479] 1H NMR (400 MHz, CDCl3); δ 8.59 (s, 1H), 7.56-7.52 (m, 2H), 7.29-7.27 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.15-7.12 (m, 2H), 5.31 (brs, 1H), 4.89 (brs, 2H), 3.53 (s, 2H), 3.40-3.36 (m, 2H), 3.28-3.21 (m, 2H), 2.97-2.90 (m, 2H), 2.86-2.81 (m, 2H), 2.78-2.74 (m, 1H), 2.49-2.43 (m, 2H), 1.90 (d, J = 12.8 Hz, 2H), 1.69-1.55 (m, 2H), 1.18-1.02 (m, 3H); LC / MS: m / z 554.0 (M+H)+(ES).

[1480]

[1481] Example 107: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-1-(3-fluoroazetidin-1-yl)ethanone

[1482]

[1483]

[1484] The compound obtained in Example 25 (30 mg, 0.057 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (33 mg, 0.171 mmol), and hydroxybenzotriazole (15 mg, 0.113 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. 3-Fluorazetidine hydrochloride (17 mg, 0.153 mmol) and triethylamine (32 μl, 0.228 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (30 mg, 90%) as a white solid.

[1485] 1H NMR (400 MHz, CDCl3); δ 8.55 (s, 1H), 7.51 (d, J = 8 Hz, 2H), 7.29-7.26 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 5.34-5.16 (m, 1H), 4.89 (brs, 2H), 4.35-4.08 (m, 4H), 3.51 (s, 2H), 3.47-3.36 (m, 2H), 2.96-2.74 (m, 5H), 2.49-2.42 (m, 2H), 1.89 (d, J = 11.2 Hz, 2H), 1.65-1.59 (m, 2H); LC / MS: m / z 584.0 (M+H)+(ES).

[1486]

[1487] Example 108: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-1-(3-hydroxyazetidin-1-yl)ethanone

[1488]

[1489]

[1490] The compound obtained in Example 25 (30 mg, 0.057 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (33 mg, 0.171 mmol), and hydroxybenzotriazole (15 mg, 0.113 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. Azetidin-3-ol hydrochloride (17 mg, 0.153 mmol) and triethylamine (32 μl, 0.228 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (30 mg, 90%) as a white solid.

[1491] 1H NMR (400 MHz, CDCl3); δ 8.54 (s, 1H), 7.51 (d, J = 8 Hz, 2H), 7.29-7.21 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 4.90 (brs, 2H), 4.65-4.60 (m, 1H), 4.31-4.23 (m, 2H), 3.96-3.84 (m, 2H), 3.45 (s, 2H), 3.39-3.35 (m, 2H), 2.96-2.74 (m, 5H), 2.49-2.42 (m, 2H), 2.08 (d, J = 5.6 Hz, 1H), 1.89 (d, J = 11.2 Hz, 2H), 1.65-1.59 (m, 2H); LC / MS: m / z 582.0 (M+H)+(ES).

[1492]

[1493] Example 109: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(2-fluoroethyl)acetamide

[1494]

[1495]

[1496] The compound obtained in Example 25 (30 mg, 0.057 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (33 mg, 0.171 mmol), and hydroxybenzotriazole (15 mg, 0.113 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. 2-Fluoroethane-1-amine hydrochloride (15 mg, 0.153 mmol) and triethylamine (32 μl, 0.228 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (30 mg, 92%) as a white solid.

[1497] 1H NMR (400 MHz, CDCl3); δ 8.58 (s, 1H), 7.56-7.53 (m, 2H), 7.28-7.21 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 5.74 (s, 1H), 4.90 (brs, 2H), 4.50 (t, J = 4.8 Hz, 1H), 4.38 (t, J = 4.8 Hz, 1H), 3.58 (s, 2H), 3.58-3.47 (m, 2H), 3.39-3.36 (m, 2H), 2.97-2.74 (m, 5H), 2.49-2.43 (m, 2H), 1.89 (d, J = 11.2 Hz, 2H), 1.65-1.59 (m, 2H); LC / MS: m / z 572.0 (M+H)+(ES).

[1498]

[1499] Example 110: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-ethylacetamide

[1500]

[1501]

[1502] Ethylamine (40% in methanol, 2 mL) was added to intermediate B105-3 (26 mg, 0.048 mmol), and the mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (20 mg, 75%) as a white solid.

[1503] 1H NMR (400 MHz, CDCl3); δ 8.61 (s, 1H), 7.59-7.52 (m, 2H), 7.28 (s, 4H), 7.28-7.23 (m, 2H), 6.12 (t, J = 3.2 Hz, 1H), 5.35 (brs, 1H), 4.40 (brs, 2H), 4.04 (brs, 2H), 3.56 (s, 2H), 3.40-3.36 (m, 2H), 3.28-3.23 (m, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.56 (brs, 2H), 2.50-2.45 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H); LC / MS: m / z 552.0 (M+H)+(ES).

[1504]

[1505] Example 111: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1506]

[1507]

[1508] Intermediate B105-3 (158 mg, 0.293 mmol) was dissolved in methanol (3 mL) and dichloromethane (3 mL), and sodium hydroxide (234 mg, 5.86 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to give the title compound (146 mg, 95%) as an ivory-colored solid.

[1509] 1H NMR (400 MHz, CDCl3); δ 8.56 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.33-7.28 (m, 6H), 6.12 (brs, 1H), 4.39 (brs, 2H), 4.04 (brs, 2H), 3.61 (s, 2H), 3.42-3.36 (m, 2H), 2.88 (t, J = 6.2 Hz, 2H), 2.56 (brs, 2H), 2.49-2.43 (m, 2H); LC / MS: m / z 525.0 (M+H)+(ES).

[1510]

[1511] Example 112: Synthesis of 2-(4-((2-(4-(4-bromophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1512] Step 1: Methyl 2-(4-((2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1513]

[1514]

[1515] Intermediate B3-2 (50 mg, 0.131 mmol), 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (71 mg, 0.262 mmol), and N,N-diisopropylethylamine (114 μL, 0.655 mmol) were added to 1,4-dioxane (2 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B112-3 (64 mg, 84%) as a white solid.

[1516]

[1517] Step 2: 2-(4-((2-(4-(4-bromophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1518]

[1519]

[1520] Intermediate B112-3 (64 mg, 0.110 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (88 mg, 2.20 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to give the title compound (58 mg, 93%) as an ivory-colored solid.

[1521] 1H NMR (400 MHz, CDCl3); δ 8.57 (s, 1H), 7.54 (dd, J = 4.6 Hz, 3.8 Hz, 2H), 7.48-7.44 (m, 2H), 7.30-7.24 (m, 4H), 6.12 (t, J = 3.2 Hz, 1H), 4.39 (brs, 2H), 4.04 (brs, 2H), 3.61 (s, 2H), 3.43-3.36 (m, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.56 (brs, 2H), 2.49-2.43 (m, 2H); LC / MS: m / z 569.0 (M+H)+(ES).

[1522]

[1523] Example 113: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(cyclopropylmethyl)acetamide

[1524]

[1525]

[1526] The compound obtained in Example 111 (60 mg, 0.114 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (66 mg, 0.342 mmol), and hydroxybenzotriazole (31 mg, 0.228 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. Cyclopropylmethanamine (26 μL, 0.308 mmol) and triethylamine (64 μL, 0.456 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (63 mg, 96%) as a white solid.

[1527] 1H NMR (400 MHz, CDCl3); δ 8.60 (s, 1H), 7.58 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.33 (s, 4H), 7.27-7.25 (m, 2H), 6.12 (t, J = 6.4 Hz, 1H), 5.52 (brs, 1H), 4.39 (brs, 2H), 4.04 (brs, 2H), 3.57 (s, 2H), 3.39-3.36 (m, 2H), 3.11-3.08 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.56 (brs, 2H), 2.48-2.45 (m, 2H), 0.92-0.84 (m, 1H), 0.48-0.43 (m, 2H), 0.16-0.01 (m, 2H); LC / MS: m / z 578.0 (M+H)+(ES).

[1528]

[1529] Example 114: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(cyclopropylmethyl)acetamide

[1530]

[1531]

[1532] The compound obtained in Example 25 (50 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (55 mg, 0.285 mmol), and hydroxybenzotriazole (26 mg, 0.190 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. Cyclopropylmethanamine (22 μL, 0.256 mmol) and triethylamine (53 μL, 0.380 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (54 mg, 99%) as a white solid.

[1533] 1H NMR (400 MHz, CDCl3); δ 8.59 (s, 1H), 7.55 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.29-7.21 (m, 4H), 7.15-7.12 (m, 2H), 5.45 (brs, 1H), 4.89 (brs, 2H), 3.54 (s, 2H), 3.39-3.36 (m, 2H), 3.09-3.06 (m, 2H), 2.97-2.93 (m, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.78-2.76 (m, 1H), 2.49-2.43 (m, 2H), 1.89 (d, J = 13.2 Hz, 2H), 1.63-1.59 (m, 2H), 0.88-0.84 (m, 1H), 0.46-0.41 (m, 2H), 0.14-0.11 (m, 2H); LC / MS: m / z 580.0 (M+H)+(ES).

[1534]

[1535] Example 115: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-cyclopropylacetamide

[1536]

[1537]

[1538] The compound obtained in Example 25 (50 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (55 mg, 0.285 mmol), and hydroxybenzotriazole (26 mg, 0.190 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. Cyclopropanamine (18 μL, 0.256 mmol) and triethylamine (53 μL, 0.380 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (49 mg, 91%) as a white solid.

[1539] 1H NMR (400 MHz, CDCl3); δ 8.58 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.29-7.26 (m, 2H), 7.19-7.12 (m, 4H), 5.43 (brs, 1H), 4.90 (brs, 2H), 3.51 (s, 2H), 3.39-3.36 (m, 2H), 2.97-2.90 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.81-2.74 (m, 1H), 2.68-2.64 (m, 1H), 2.49-2.43 (m, 2H), 1.89 (d, J = 13.2 Hz, 2H), 1.66-1.59 (m, 2H), 0.75-0.70 (m, 2H), 0.41-0.37 (m, 2H); LC / MS: m / z 566.0 (M+H)+(ES).

[1540]

[1541] Example 116: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone

[1542]

[1543]

[1544] The compound obtained in Example 25 (50 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (55 mg, 0.285 mmol), and hydroxybenzotriazole (26 mg, 0.190 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. Azetidin-3-ylmethanol hydrochloride (32 mg, 0.256 mmol) and triethylamine (53 μL, 0.380 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (49 mg, 86%) as a white solid.

[1545] 1H NMR (400 MHz, CDCl3); δ 8.53 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.29-7.26 (m, 2H), 7.26-7.13 (m, 4H), 4.89 (brs, 2H), 4.14 (t, J = 8.4 Hz, 1H), 4.04 (t, J = 8.4 Hz, 1H), 3.92-3.88 (m, 1H), 3.79-3.75 (m, 1H), 3.70 (d, J = 6 Hz, 2H), 3.43 (s, 2H), 3.39-3.36 (m, 2H), 2.96-2.89 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.78-2.71 (m, 1H), 2.48-2.42 (m, 2H), 1.89 (d, J = 13.2 Hz, 2H), 1.66-1.59 (m, 2H); LC / MS: m / z 596.0 (M+H)+(ES).

[1546]

[1547] Example 117: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-N-methylacetamide

[1548]

[1549]

[1550] The compound obtained in Example 25 (50 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl), (55 mg, 0.285 mmol), and hydroxybenzotriazole (26 mg, 0.190 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. N-Methylethanamine (22 μL, 0.256 mmol) and triethylamine (53 μL, 0.380 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (41 mg, 76%) as a white solid.

[1551] 1H NMR (400 MHz, CDCl3); δ 8.53 (s, 1H), 7.52-7.48 (m, 2H), 7.29-7.20 (m, 4H), 7.15-7.12 (m, 2H), 4.89 (brs, 2H), 3.68 (d, J = 7.6 Hz, 2H), 3.45-3.31 (m, 4H), 2.93 (d, J = 4.8 Hz, 5H), 2.85 (t, J = 6.6 Hz, 2H), 2.82-2.73 (m, 1H), 2.48-2.42 (m, 2H), 1.89 (d, J = 13.2 Hz, 2H), 1.66-1.55 (m, 2H), 1.11-1.02 (m, 3H); LC / MS: m / z 568.0 (M+H)+(ES).

[1552]

[1553] Example 118: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-ethylacetamide

[1554]

[1555]

[1556] Ethylamine (40% in methanol, 2 mL) was added to intermediate B41-3 (68 mg, 0.122 mmol) and stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (58 mg, 83%) as a white solid.

[1557] 1H NMR (400 MHz, CDCl3); δ 8.82 (s, 1H), 8.16 (t, J = 8 Hz, 1H), 7.31 (s, 4H), 7.06 (d, J = 9.2 Hz, 2H), 6.12-6.10 (m, 1H), 5.36 (brs, 1H), 4.38 (brs, 2H), 4.03 (brs, 2H), 3.54 (s, 2H), 3.40-3.37 (m, 2H), 3.32-3.25 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.56 (brs, 2H), 2.50-2.44 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H); LC / MS: m / z 570.0 (M+H)+(ES).

[1558]

[1559] Example 119: Synthesis of 2-(4-((5,5-dioxido-2-(4-(p-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide

[1560]

[1561]

[1562] After adding methylamine (40% in methanol, 2 mL) to intermediate B86-3 (59 mg, 0.113 mmol), the mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (50 mg, 85%) as a white solid.

[1563] 1H NMR (400 MHz, CDCl3); δ 8.59 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.22-7.19 (m, 2H), 7.14-7.09 (m, 4H), 5.35 (brs, 1H), 4.90 (brs, 2H), 3.55 (s, 2H), 3.39-3.36 (m, 2H), 2.98-2.91 (m, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.80-2.72 (m, 4H), 2.49-2.43 (m, 2H), 2.32 (s, 3H), 1.91 (d, J = 10.8 Hz, 2H), 1.69-1.60 (m, 2H); LC / MS: m / z 519.0 (M+H)+(ES).

[1564]

[1565] Example 120: Synthesis of 2-(4-((5,5-dioxido-2-(4-(m-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1566] Step 1: Methyl 2-(4-((5,5-dioxido-2-(4-(m-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1567]

[1568]

[1569] Intermediate B3-2 (55 mg, 0.144 mmol), 4-(m-tolyl)piperidine (61 mg, 0.288 mmol), and N,N-diisopropylethylamine (125 μL, 0.720 mmol) were added to 1,4-dioxane (2 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B120-3 (70 mg, 93%) as an ivory solid.

[1570]

[1571] Step 2: 2-(4-((5,5-deoxido-2-(4-(m-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1572]

[1573]

[1574] Intermediate B120-3 (70 mg, 0.134 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (107 mg, 2.68 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (49 mg, 72%) as a white solid.

[1575] 1H NMR (400 MHz, CDCl3); δ 8.66 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.31-7.18 (m, 3H), 7.04-6.99 (m, 3H), 4.90 (brs, 2H), 3.60 (s, 2H), 3.43-3.37 (m, 2H), 2.98-2.91 (m, 4H), 2.80-2.74 (m, 1H), 2.49-2.46 (m, 2H), 2.34 (s, 3H), 1.93 (d, J = 10.8 Hz, 2H), 1.69-1.60 (m, 2H); LC / MS: m / z 506.0 (M+H)+(ES).

[1576]

[1577] Example 121: Synthesis of 2-(4-((5,5-dioxido-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1578] Step 1: Methyl 2-(4-((5,5-dioxido-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1579]

[1580]

[1581] Intermediate B3-2 (50 mg, 0.131 mmol), 4-(4-(trifluoromethyl)phenyl)piperidine hydrochloride (69 mg, 0.266 mmol), and N,N-diisopropylethylamine (114 μL, 0.655 mmol) were added to 1,4-dioxane (2 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B121-3 (65 mg, 86%) as a white solid.

[1582]

[1583] Step 2: 2-(4-((5,5-deoxido-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1584]

[1585]

[1586] Intermediate B121-3 (65 mg, 0.113 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (90 mg, 2.26 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (49 mg, 77%) as a white solid.

[1587] 1H NMR (400 MHz, CDCl3); δ 8.58 (s, 1H), 7.57-7.50 (m, 4H), 7.32 (d, J = 8 Hz, 2H), 7.25-7.23 (m, 2H), 4.92 (brs, 1H), 3.62 (s, 2H), 3.39-3.36 (m, 2H), 2.98-2.91 (m, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.49-2.44 (m, 2H), 1.91 (d, J = 10.8 Hz, 2H), 1.69-1.60 (m, 2H); LC / MS: m / z 560.0 (M+H)+(ES).

[1588]

[1589] Example 122: Synthesis of 2-(4-((2-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1590] Step 1: Methyl 2-(4-((2-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1591]

[1592]

[1593] Intermediate B3-2 (50 mg, 0.131 mmol), 4-(4-chloro-2-methylphenyl)piperidine hydrochloride (64 mg, 0.262 mmol), and N,N-diisopropylethylamine (114 μL, 0.655 mmol) were added to 1,4-dioxane (2 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B122-3 (65 mg, 87%) as a white solid.

[1594]

[1595] Step 2: 2-(4-((2-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1596]

[1597]

[1598] Intermediate B122-3 (45 mg, 0.081 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and then sodium hydroxide (65 mg, 1.62 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, and the mixture was extracted three times with dichloromethane and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (15 mg, 34%) as a white solid.

[1599] 1H NMR (400 MHz, CDCl3); δ 8.56 (s, 1H), 7.52-7.50 (m, 2H), 7.26-7.23 (m, 2H), 7.14-7.06 (m, 3H), 4.92 (brs, 2H), 3.61 (s, 2H), 3.39-3.36 (m, 2H), 2.97-2.89 (m, 3H), 2.84 (t, J = 6.6 Hz, 2H), 2.49-2.42 (m, 2H), 2.35 (s, 3H), 1.82-1.70 (m, 2H), 1.65-1.54 (m, 2H); LC / MS: m / z 541.0 (M+H)+(ES).

[1600]

[1601] Example 123: Synthesis of 2-(4-((2-(4-(4-(difluoromethyl)phenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1602] Step 1: Methyl 2-(4-((2-(4-(4-(difluoromethyl)phenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1603]

[1604]

[1605] Intermediate B3-2 (55 mg, 0.144 mmol), 4-(4-(difluoromethyl)phenyl)piperidine hydrochloride (71 mg, 0.288 mmol), and N,N-diisopropylethylamine (125 μL, 0.720 mmol) were added to 1,4-dioxane (2 mL), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B123-3 (53 mg, 66%) as a white solid.

[1606]

[1607] Step 2: 2-(4-((2-(4-(4-(difluoromethyl)phenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1608]

[1609]

[1610] Intermediate B123-3 (53 mg, 0.095 mmol) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and sodium hydroxide (76 mg, 1.90 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (21 mg, 41%) as a white solid.

[1611] 1H NMR (400 MHz, CDCl3); δ 8.61 (s, 1H), 7.52 (t, J = 4.2 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.30-7.24 (m, 4H), 6.62 (t, J = 56.4 Hz, 1H), 4.91 (brs, 2H), 3.63 (s, 2H), 3.39-3.36 (m, 2H), 2.99-2.81 (m, 5H), 2.49-2.45 (m, 2H), 1.93 (d, J = 12.8 Hz, 2H), 1.71-1.55 (m, 2H); LC / MS: m / z 542.0 (M+H)+(ES).

[1612]

[1613] Example 124: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(2-hydroxyethyl)acetamide

[1614]

[1615]

[1616] The compound obtained in Example 25 (12 mg, 0.023 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl) (13 mg, 0.069 mmol), and hydroxybenzotriazole (7 mg, 0.046 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. 2-Aminoethanol-1-ol (4 μL, 0.062 mmol) and triethylamine (13 μL, 0.092 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (8 mg, 61%) as a white solid.

[1617] 1H NMR (400 MHz, CDCl3); δ 8.59 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.28-7.21 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 5.83 (brs, 1H), 4.89 (brs, 2H), 3.67-3.66 (m, 2H), 3.57 (s, 2H), 3.39-3.36 (m, 4H), 2.97-2.90 (m, 2H), 2.85 (t, J = 6.4Hz, 2H), 2.81-2.74 (m, 1H), 2.49-2.43 (m, 3H), 1.89 (d, J = 12.8 Hz, 2H), 1.63-1.56 (m, 2H); LC / MS: m / z 570.0 (M+H)+(ES).

[1618]

[1619] Example 125: Synthesis of 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(3-hydroxypropyl)acetamide

[1620]

[1621]

[1622] The compound obtained in Example 25 (12 mg, 0.023 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HCl) (13 mg, 0.069 mmol), and hydroxybenzotriazole (7 mg, 0.046 mmol) were dissolved in anhydrous dimethylformamide (1 mL), and stirred at room temperature for 10 minutes. 3-Aminepropan-1-ol (5 μL, 0.062 mmol) and triethylamine (13 μL, 0.092 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added, and the precipitated solid was filtered to obtain the title compound (8 mg, 60%) as a white solid.

[1623] 1H NMR (400 MHz, CDCl3); δ 8.59 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.28-7.26 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.75 (brs, 1H), 4.89 (brs, 2H), 3.56 (s, 4H), 3.39-3.36 (m, 4H), 2.99-2.90 (m, 2H), 2.84 (t, J = 6.4Hz, 2H), 2.81-2.74 (m, 1H), 2.49-2.43 (m, 2H), 1.89 (d, J = 12.8 Hz, 2H), 1.63-1.56 (m, 6H); LC / MS: m / z 584.0 (M+H)+(ES).

[1624]

[1625] Example 126: Synthesis of 2-(4-((2-(4-(4-chloro-2-methylphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1626] Step 1: Methyl 2-(4-((2-(4-(4-chloro-2-methylphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1627]

[1628]

[1629] Intermediate B3-2 (59 mg, 0.149 mmol), 4-(4-chloro-2-methylphenyl)-1,2,3,6-tetrahydropyridine (54 mg, 0.224 mmol), and N,N-diisopropylethylamine (130 μl, 0.745 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B126-3 (78 mg, 92%) as a white solid.

[1630]

[1631] Step 2: 2-(4-((2-(4-(4-chloro-2-methylphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1632]

[1633]

[1634] Intermediate B126-3 (78 mg, 0.138 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (110 mg, 2.75 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (60 mg, 76%) as a white solid.

[1635] 1H NMR (400 MHz, CDCl3); δ 8.61 (s, 1H), 7.56-7.52 (m, 2H), 7.27-7.25 (m, 2H), 7.16 (d, J = 2 Hz, 1H), 7.14-6.99 (m, 2H), 5.64-5.62 (m, 1H), 4.35 (brs, 2H), 4.02 (brs, 2H), 3.64 (s, 2H), 3.39-3.36 (m, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.50-2.43 (m, 2H), 2.38 (brs, 2H), 2.26 (s, 3H); LC / MS: m / z 539.0 (M+H)+(ES).

[1636]

[1637] Example 127: Synthesis of 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[1638] Step 1: (1-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)cyclobutyl)methanol

[1639]

[1640]

[1641] Compound A-6 (30 mg, 0.136 mmol), (1-(4-aminophenyl)cyclobutyl)methanol (36 mg, 0.204 mmol), tris(dibenzylideneacetone)dipalladium(0) (7.0 mg, 0.007 mmol), xantphos (8.0 mg, 0.014 mmol), and sodium carbonate (43 mg, 0.408 mmol) were added to 1,4-dioxane (2 ml), and the mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B127-1 (32 mg, 64%).

[1642]

[1643] Step 2: 2-chloro-4-((4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[1644]

[1645]

[1646] Intermediate B127-1 (32 mg, 0.088 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (40 mg, 0.177 mmol), and dichloromethane (2 ml) were stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B127-2 (31 mg, 89%) as an ivory-colored solid.

[1647]

[1648] Step 3: 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[1649]

[1650]

[1651] Intermediate B127-2 (7 mg, 0.018 mmol), 4-(4-chlorophenyl)piperidine (5.2 mg, 0.027 mmol), and N,N-diisopropylethylamine (16 μl, 0.09 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound (9 mg, 87%) as an ivory solid.

[1652] 1H NMR (400 MHz, CDCl3); δ 8.55 (s, 1H), 7.54-7.51 (m, 2H), 7.29-7.26 (m, 2H), 7.16-7.09 (m, 4H), 4.92 (brs, 2H), 3.74 (d, J = 6.8 Hz, 2H), 3.39-3.36 (m, 2H), 2.96-2.86 (m, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.78-2.74 (m, 2H), 2.48-2.42 (m, 1H), 2.36-2.29 (m, 4H), 2.25-2.19 (m, 3H), 2.11-2.04 (m, 3H), 1.92-1.88 (m, 2H); LC / MS: m / z 553.0 (M+H)+(ES).

[1653]

[1654] Example 128: Synthesis of 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((2-fluoro-4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[1655] Step 1: (1-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)cyclobutyl)methanol

[1656]

[1657]

[1658] Compound A-6 (30 mg, 0.136 mmol), (1-(4-amino-3-fluorophenyl)cyclobutyl)methanol (40 mg, 0.204 mmol), tris(dibenzylideneacetone)dipalladium(0) (7 mg, 0.007 mmol), xantphos (8 mg, 0.014 mmol), and sodium carbonate (43 mg, 0.408 mmol) were added to 1,4-dioxane (2 ml), and the mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B128-1 (35 mg, 68%).

[1659]

[1660] Step 2: 2-chloro-4-((2-fluoro-4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[1661]

[1662]

[1663] Intermediate B128-1 (15 mg, 0.039 mmol), meta-chloroperoxybenzoic acid (m-CPBA) (18 mg, 0.078 mmol), and dichloromethane (2 ml) were stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound B128-2 (15 mg, 92%) as an ivory-colored solid.

[1664]

[1665] Step 3: 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((2-fluoro-4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[1666]

[1667]

[1668] Intermediate B128-2 (7 mg, 0.018 mmol), 4-(4-chlorophenyl)piperidine (5 mg, 0.027 mmol), and N,N-diisopropylethylamine (16 μl, 0.090 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound (9 mg, 85%) as an ivory solid.

[1669] 1H NMR (400 MHz, CDCl3); δ 8.75 (s, 1H), 8.06 (t, J = 8.2 Hz, 1H), 7.29-7.28 (m, 2H), 7.16-7.13 (m, 2H), 6.94-6.88 (m, 2H), 4.90 (brs, 2H), 3.73 (d, J = 6.8 Hz, 2H), 3.40-3.37 (m, 2H), 2.97-2.74 (m, 5H), 2.50-2.43 (m, 2H), 2.34-2.18 (m, 4H), 2.17-2.03 (m, 1H), 1.93-1.88 (m, 2H), 1.69-1.67 (m, 2H); LC / MS: m / z 571.0 (M+H)+(ES).

[1670]

[1671] Example 129: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1672] Step 1: Methyl 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1673]

[1674]

[1675] Intermediate B3-2 (30 mg, 0.078 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene (26 mg, 0.118 mmol), and N,N-diisopropylethylamine (68 μl, 0.39 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B129-3 (55 mg, 82%) as a white solid.

[1676]

[1677] Step 2: 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1678]

[1679]

[1680] Intermediate B129-3 (55 mg, 0.097 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (78 mg, 1.95 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (34 mg, 64%) as a white solid.

[1681] 1H NMR (400 MHz, CDCl3); δ 8.57 (d, J = 18 Hz, 1H), 7.59-7.53 (m, 2H), 7.29-7.23 (m, 6H), 6.50 (d, J = 5.6 Hz, 1H), 5.06-4.85 (m, 2H), 3.65 (s, 2H), 3.35 (t, J = 6.2 Hz, 2H), 3.12 (d, J = 16 Hz, 1H), 2.84-2.82 (m, 2H), 2.44-2.43 (m, 2H), 2.34-2.23 (m, 2H), 2.06 (t, J = 5.4 Hz, 2H), 1.85-1.78 (m, 1H); LC / MS: m / z 551.0 (M+H)+(ES).

[1682]

[1683] Example 130: Synthesis of 2-(4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1684] Step 1: Methyl 2-(4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1685]

[1686]

[1687] Intermediate B3-2 (50 mg, 0.131 mmol), 4-(piperidin-4-yl)morpholine (33 mg, 0.196 mmol), and N,N-diisopropylethylamine (114 μl, 0.655 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B130-3 (53 mg, 79%) as a white solid.

[1688]

[1689] Step 2: 2-(4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1690]

[1691]

[1692] Intermediate B130-3 (53 mg, 0.103 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (82 mg, 2.06 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (21 mg, 41%) as a white solid.

[1693] 1H NMR (400 MHz, DMSO-d6); δ 10.28 (s, 1H), 8.58 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 3.98 (d, J = 10.8 Hz, 2H), 3.74 (t, J = 12.2 Hz, 2H), 3.13-3.08 (m, 3H), 2.95-2.80 (m, 4H), 2.34-2.15 (m, 4H), 2.09-1.91 (m, 2H), 1.57-1.54 (m, 2H); LC / MS: m / z 501.0 (M+H)+(ES).

[1694]

[1695] Example 131: Synthesis of 2-(3-fluoro-4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1696] Step 1: Methyl 2-(3-fluoro-4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1697]

[1698]

[1699] Intermediate B22-2 (50 mg, 0.125 mmol), 4-(piperidin-4-yl)morpholine (32 mg, 0.188 mmol), and N,N-diisopropylethylamine (109 μl, 0.625 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B131-3 (57 mg, 86%) as a white solid.

[1700]

[1701] Step 2: 2-(3-Fluoro-4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1702]

[1703]

[1704] Intermediate B131-3 (52 mg, 0.097 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (78 mg, 1.95 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (9 mg, 43%) as a white solid.

[1705] 1H NMR (400 MHz, DMSO-d6); δ 10.28 (s, 1H), 8.68 (s, 1H), 8.03-7.96 (m, 1H), 7.23 (d, J = 12 Hz, 2H), 7.11 (d, J = 12 Hz, 2H), 4.64-4.47 (m, 2H), 3.89 (s, 2H), 2.92 (t, J = 12.4 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.34-2.26 (m, 2H), 1.84 (d, J = 11.6 Hz, 2H), 1.31-1.24 (m, 2H); LC / MS: m / z 519.0 (M+H)+(ES).

[1706]

[1707] Example 132: Synthesis of 2-(4-((2-(4-(4-(difluoromethyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1708] Step 1: Methyl 2-(4-((2-(4-(4-(difluoromethyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1709]

[1710]

[1711] Intermediate B22-2 (50 mg, 0.125 mmol), 4-(4-(difluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (46 mg, 0.188 mmol), and N,N-diisopropylethylamine (109 μl, 0.625 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B132-3 (65 mg, 91%) as a white solid.

[1712]

[1713] Step 2: 2-(4-((2-(4-(4-(difluoromethyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1714]

[1715]

[1716] Intermediate B132-3 (23 mg, 0.114 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (91 mg, 2.27 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (52 mg, 81%) as an ivory-colored solid.

[1717] 1H NMR (400 MHz, CDCl3); δ 8.72 (s, 1H), 8.09-8.07 (m, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.24-6.85 (m, 3H), 6.35 (s, 1H), 3.89 (s, 2H), 2.89-2.82 (m, 2H), 2.44-2.43 (m, 2H), 2.34-2.23 (m, 2H); LC / MS: m / z 558.0 (M+H)+(ES).

[1718]

[1719] Example 133: Synthesis of 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide

[1720]

[1721]

[1722] Intermediate B5-2 (59 mg, 0.167 mmol), 4-(4-chlorophenyl)piperidine (49 mg, 0.250 mmol), and N,N-diisopropylethylamine (145 μl, 0.835 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (68 mg, 80%) as a white solid.

[1723] 1H NMR (400 MHz, CDCl3); δ 8.53 (s, 1H), 7.52-7.17 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 4.89 (brs, 2H), 3.85 (q, J = 6.4 Hz, 2H), 3.39-3.36 (m, 2H), 2.96-2.7 (m, 7H), 2.48-2.42 (m, 2H), 1.91-1.88 (m, 2H), 1.65-1.58 (m, 2H); LC / MS: m / z 513.0 (M+H)+(ES).

[1724]

[1725] Example 134: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1726] Step 1: Methyl 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1727]

[1728]

[1729] Intermediate B22-2 (59 mg, 0.125 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene (55 mg, 0.250 mmol), and N,N-diisopropylethylamine (109 μl, 0.625 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B134-3 (66 mg, 90%) as a white solid.

[1730]

[1731] Step 2: 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1732]

[1733]

[1734] Intermediate B134-3 (66 mg, 0.112 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (45 mg, 1.12 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (43 mg, 68%) as an ivory solid.

[1735] 1H NMR (400 MHz, CDCl3); δ 8.80 (d, J = 12 Hz, 1H), 8.21 (brs, 1H), 7.29-7.26 (m, 4H), 7.12-7.06 (m, 2H), 6.49 (brs, 1H), 5.06-4.82 (m, 2H) 3.65 (s, 2H), 3.36 (t, J = 6.2 Hz, 2H), 3.12 (d, J = 17.2 Hz, 2H), 2.85-2.84 (m, 2H), 2.44-2.04 (m, 6H); LC / MS: m / z 569.0 (M+H)+(ES).

[1736]

[1737] Example 135: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1738] Step 1: Methyl 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1739]

[1740]

[1741] Intermediate B3-2 (60 mg, 0.157 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octane (70 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μl, 0.785 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B135-3 (70 mg, 79%) as a white solid.

[1742]

[1743] Step 2: 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1744]

[1745]

[1746] Intermediate B135-3 (70 mg, 0.123 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (49 mg, 1.23 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (46 mg, 68%) as a white solid.

[1747] 1H NMR (400 MHz, CDCl3); δ 8.60 (s, 1H), 7.59-7.52 (m, 2H), 7.25-7.00 (m, 6H), 4.85-4.70 (m, 2H) 3.62 (s, 2H), 3.38 (t, J = 6.4 Hz, 2H), 2.88-2.82 (m, 2H), 2.59-2.43 (m, 4H), 2.18-1.64 (m, 7H); LC / MS: m / z 553.0 (M+H)+(ES).

[1748]

[1749] Example 136: Synthesis of 2-(4-((5,5-dioxido-2-(3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1750] Step 1: Methyl 2-(4-((5,5-dioxido-2-(3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1751]

[1752]

[1753] Intermediate B3-2 (60 mg, 0.157 mmol), 3-phenyl-8-azabicyclo[3.2.1]octane (59 mg, 0.314 mmol), and N,N-diisopropylethylamine (136 μl, 0.785 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B136-3 (67 mg, 80%) as a white solid.

[1754]

[1755] Step 2: 2-(4-((5,5-deoxido-2-(3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1756]

[1757]

[1758] Intermediate B136-3 (67 mg, 0.126 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (50 mg, 1.26 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (52 mg, 79%) as a white solid.

[1759] 1H NMR (400 MHz, CDCl3); δ 8.60 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.31-7.17 (m, 7H), 4.83-4.69 (m, 2H) 3.62 (s, 2H), 3.38 (t, J = 6.4 Hz, 2H), 2.88-2.82 (m, 2H), 2.64-2.42 (m, 5H), 2.18-1.64 (m, 6H); LC / MS: m / z 518.0 (M+H)+(ES).

[1760]

[1761] Example 137: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1762] Step 1: Methyl 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1763]

[1764]

[1765] Intermediate B3-2 (50 mg, 0.131 mmol), 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane (58 mg, 0.262 mmol), and N,N-diisopropylethylamine (114 μl, 0.655 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B137-3 (71 mg, 95%) as a white solid.

[1766]

[1767] Step 2: 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1768]

[1769]

[1770] Intermediate B137-3 (71 mg, 0.125 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (40 mg, 1.25 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (64 mg, 93%) as a white solid.

[1771] 1H NMR (400 MHz, CDCl3); δ 8.60 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.29-7.16 (m, 4H), 6.74 (dd, J = 6.8 Hz, 2.4 Hz, 2H), 4.93-4.78 (m, 2H), 3.67 (s, 2H), 3.42-3.35 (m, 4H), 3.04 (d, J = 9.6 Hz, 2H), 2.84 (brs, 2H), 2.46 (t, J = 6.4 Hz, 2H), 2.00-1.95 (m, 4H); LC / MS: m / z 554.1 (M+H)+(ES).

[1772]

[1773] Example 138: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1774] Step 1: Methyl 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1775]

[1776]

[1777] Intermediate B22-2 (50 mg, 0.125 mmol), 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane (56 mg, 0.250 mmol), and N,N-diisopropylethylamine (109 μl, 0.625 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B138-3 (72 mg, 98%) as a white solid.

[1778]

[1779] Step 2: 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1780]

[1781]

[1782] Intermediate B138-3 (72 mg, 0.123 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (49 mg, 1.23 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (65 mg, 93%) as a white solid.

[1783] 1H NMR (400 MHz, CDCl3); δ 8.81 (s, 1H), 8.08 (t, J = 8.4 Hz, 2H), 7.18 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.13-7.07 (m, 2H), 6.74 (dd, J = 6.8 Hz, 2.4 Hz, 2H), 4.93-4.73 (m, 2H), 3.66 (s, 2H), 3.42-3.36 (m, 4H), 3.04 (d, J = 9.6 Hz, 2H), 2.85 (brs, 2H), 2.46 (t, J = 6.4 Hz, 2H), 2.03-1.95 (m, 4H); LC / MS: m / z 572.1 (M+H)+(ES).

[1784]

[1785] Example 139: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1786] Step 1: Methyl 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

[1787]

[1788]

[1789] Intermediate B3-2 (50 mg, 0.131 mmol), 3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptane (55 mg, 0.262 mmol), and N,N-diisopropylethylamine (114 μl, 0.655 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B139-3 (64 mg, 88%) as a white solid.

[1790]

[1791] Step 2: 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid

[1792]

[1793]

[1794] Intermediate B139-3 (64 mg, 0.116 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (46 mg, 1.16 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (60 mg, 97%) as a white solid.

[1795] 1H NMR (400 MHz, CDCl3); δ 8.60 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.28-7.15 (m, 4H), 6.55 (d, J = 8.4 Hz, 2H), 4.62-4.58 (m, 2H), 3.89-3.86 (m, 2H), 3.67 (s, 2H), 3.35-3.32 (m, 4H), 2.81-2.78 (m, 2H), 2.43 (q, J = 6.3 Hz, 2H), 1.70-1.68 (m, 2H); LC / MS: m / z 540.1 (M+H)+(ES).

[1796]

[1797] Example 140: Synthesis of 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1798] Step 1: Methyl 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate

[1799]

[1800]

[1801] Intermediate B22-2 (50 mg, 0.125 mmol), 3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptane (52 mg, 0.250 mmol), and N,N-diisopropylethylamine (109 μl, 0.625 mmol) were added to 1,4-dioxane (1 ml), heated to 120°C, and stirred for 16 h. Water was added to the reaction mixture, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound B140-3 (64 mg, 90%) as a white solid.

[1802]

[1803] Step 2: 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid

[1804]

[1805]

[1806] Intermediate B140-3 (64 mg, 0.112 mmol) was dissolved in methanol (1 ml) and dichloromethane (1 ml), and sodium hydroxide (45 mg, 1.12 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 1 N hydrochloric acid was added to adjust the pH to 2. Water was added, the mixture was extracted three times with dichloromethane, and washed twice with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloromethane and hexane to obtain the title compound (57 mg, 92%) as a white solid.

[1807] 1H NMR (400 MHz, CDCl3); δ 8.83 (s, 1H), 8.15 (t, J = 7.4 Hz, 2H), 7.19-7.00 (m, 4H), 6.56 (d, J = 8.4 Hz, 2H), 4.65-4.56 (m, 2H), 3.92-3.85 (m, 2H), 3.66 (s, 2H), 3.36-3.32 (m, 4H), 2.83-2.78 (m, 2H), 2.45 (q, J = 6.3 Hz, 2H), 1.81-1.78 (m, 2H); LC / MS: m / z 558.0 (M+H)+(ES).

[1808]

[1809] Example 141: Synthesis of ...

Claims

1. A compound represented by the following chemical formula 1, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X 1 is S(=O) or S(=O)2, X 2 , X 3 and X 4 are each independently CH, C-halo or N; A is a saturated or partially unsaturated heterocyclylene; L 1 is a direct bond, -C(=O)-, -NR 4 C(=O)-, -C(=O)NR 4 - or -NR 4 - and here R 4 is -H or alkyl; R 1 is halo, alkyl, partially unsaturated carbocyclyl, aryl, saturated or partially unsaturated heterocyclyl or heteroaryl; wherein said saturated or partially unsaturated heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halo, oxo (=O), alkyl, cycloalkyl and alkoxy; wherein said aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, cyano (-CN), alkyl, haloalkyl and alkoxy; L 2 is a direct bond, -CHR 5 -, -CHR 5 C(=O)-, -C(=O)-, or -CR 6 R 7 - and here R 5 is -H, hydroxy or alkyl; R 6 and R 7 are linked to each other by carbon atoms to form cycloalkyl; R 2 is hydroxy, halo, carboxy(-COOH), amino, alkyl, alkoxy, cycloalkyl, hydroxyalkyl, alkylamino, dialkylamino, cycloalkylamino, hydroxyalkylamino, haloalkylamino, cycloalkyl-alkylamino, heterocycloalkyl or heteroaryl; wherein said heterocycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, alkyl, alkoxy and hydroxyalkyl; n is 1 or 2; R 3 is -H or alkyl; The above heterocycloalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylene and heteroaryl have one or more heteroatoms selected from N, O and S; Only R 1 If A is a heteroaryl having these two N atoms, it is not a partially unsaturated heterocyclene.

2. In paragraph 1, X 1 is S(=O) or S(=O)2, X 2 , X 3 and X 4 are each independently CH, C-halo or N; A is a saturated or partially unsaturated 4 to 15 membered heterocyclylene; L 1 is a direct bond, -C(=O)-, -NR 4 C(=O)-, -C(=O)NR 4 - or -NR 4 - and here R 4 is -H or C1-C7alkyl; R 1 Silver halo, C1-C7 alkyl, partially unsaturated C5-C 12 Carbocyclyl, C6-C 10 Aryl, saturated or partially unsaturated 4 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl; wherein said saturated or partially unsaturated heterocyclyl is halo, oxo, C1-C7 alkyl, C3-C 12 cycloalkyl and C1-C7alkoxy, which may be optionally substituted with 1 to 3 substituents selected from the group consisting of; and wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano, C1-C7alkyl, halo-C1-C7alkyl and C1-C7alkoxy; L 2 is a direct bond, -CHR 5 -, -CHR 5 C(=O)-, -C(=O)-, or -CR 6 R 7 - and here R 5 is -H, hydroxy or C1-C7 alkyl; R 6 and R 7 C3-C is connected to the carbon atoms that bind to each other. 10 Forming a cycloalkyl; R 2 is hydroxy, halo, carboxy, amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 12 Cycloalkyl, hydroxy-C1-C7 alkyl, C1-C7 alkylamino, di(C1-C7 alkyl)amino, C3-C 12 Cycloalkylamino, hydroxy-C1-C7 alkylamino, halo-C1-C7 alkylamino, C3-C 12 Cycloalkyl-C1-C7 alkylamino, 4 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said heterocycloalkyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halo, C1-C7 alkyl, C1-C7 alkoxy and hydroxy-C1-C7 alkyl; n is 1 or 2; R 3 is -H or C1-C7alkyl; The above heterocycloalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylene and heteroaryl have 1 to 4 heteroatoms selected from N, O and S; Only R 1 A compound characterized in that when A is a heteroaryl having two N atoms, it is not a partially unsaturated 4 to 15 membered heterocyclene, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, X 2 is CH or C-halo, X 3 is CH or N, X 4 A compound characterized by being CH, C-halo or N, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, characterized in that A is a saturated 4 to 12-membered heterocyclylene having 1 to 3 heteroatoms selected from N and O, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

5. In paragraph 4, A A compound characterized by being, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1, characterized in that A is a partially unsaturated 4 to 12-membered heterocyclylene having 1 to 3 heteroatoms selected from N and O, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

7. In paragraph 6, A , , , or A compound characterized by being, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1, characterized in that A is a saturated or partially unsaturated, bridged 4- to 12-membered heterocyclylene having 1 to 3 heteroatoms selected from N, O, and S, or an optical isomer, stereoisomer, solvate, isotope, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

9. In paragraph 8, A A compound characterized by being, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

10. In paragraph 8, A or A compound characterized by being, or a solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

11. In paragraph 1, L 1 is a direct bond, -C(=O)-, -NR 4 C(=O)-, -C(=O)NR 4 - or -NR 4 - and here R 4 is -H or C1-C5 alkyl; R 1 is C1-C5 alkyl, partially unsaturated C5-C 10 Carbocyclyl, C6-C 10 Aryl, saturated or partially unsaturated 4 to 10 membered heterocyclyl or 5 to 10 membered heteroaryl; wherein said saturated or partially unsaturated heterocyclyl is oxo, C1-C5 alkyl, C3-C 10 which may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl and C1-C5alkoxy; wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano, C1-C5alkyl, halo-C1-C5alkyl and C1-C5alkoxy; A compound characterized in that the above saturated or partially unsaturated heterocyclyl and heteroaryl have 1 to 3 heteroatoms selected from N and O, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

12. In paragraph 1, L 2 is a direct bond, -CHR 5 -, -CHR 5 C(=O)-, -C(=O)-, or -CR 6 R 7 - and here R 5 is -H, hydroxy or C1-C5 alkyl; R 6 and R 7 are connected to each other by the carbon atoms to which they are bonded to form C3 or C4 cycloalkyl; R 2 is hydroxy, halo, carboxy, amino, C1-C5 alkyl, C1-C5 alkoxy, C3-C 10 Cycloalkyl, hydroxy-C1-C5 alkyl, C1-C5 alkylamino, di(C1-C5 alkyl)amino, C3-C 10 Cycloalkylamino, hydroxy-C1-C5 alkylamino, halo-C1-C5 alkylamino, C3-C 10 Cycloalkyl-C1-C5 alkylamino, 4 to 8 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said heterocycloalkyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halo, C1-C5 alkyl and hydroxy-C1-C5 alkyl; A compound characterized in that the above heterocycloalkyl and heteroaryl have 1 to 4 heteroatoms selected from N and O, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof.

13. In the first paragraph, a compound characterized in that the compound of the chemical formula 1 is selected from the following group, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof: (R)-Methyl (4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 1); (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 2); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 3); 2-(3-(4-chlorophenyl)azetidin-1-yl)-4-((4-(hydroxymethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 4); 2-(3-(4-chlorophenyl)azetidin-1-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 5); 4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)benzoic acid (Compound 6); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide (Compound 7); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide (Compound 8); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (Compound 9); 4-((4-(1H-tetrazol-5-yl)phenyl)amino)-2-(3-(4-chlorophenyl)azetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 10); (R)-2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 11); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(cyclopropylmethyl)acetamide (Compound 12); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-cyclopropylacetamide (Compound 13); (S)-2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 14); 2-(5-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2-yl)acetic acid (Compound 15); Methyl 2-(5-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-2-yl)acetate (Compound 16); (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide (Compound 17); (R)-2-(4-((2-(6-(4-chlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 18); (R)-2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 19); 2-(4-((2-(3-(5-chloropyrimidin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 20); 2-(4-((2-(3-(5-chloropyridin-2-yl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 21); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 22); 2-(4-(((R)-2-((3aR,6aS)-5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 23); 2-(4-((2-(3-(4-chlorophenyl)azetidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)propanoic acid (Compound 24); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 25); 2-(4-(((5R)-2-(3-(4-chlorophenyl)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 26); (R)-2-(4-((2-(8-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 27); 4-((4-((1H-tetrazol-5-yl)methyl)phenyl)amino)-2-(3-(4-chlorophenyl)azetidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 28); (R)-2-(4-((2-(7-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 29); (R)-2-(4-((2-(2-(4-chlorophenyl)-2,6-diazaspiro[3.4]octan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 30); Methyl 2-(4-(((R)-2-((R)-3-acetamidopyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 31); Methyl 2-(4-(((R)-2-((S)-3-acetamidopyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 32); (R)-Methyl 2-(4-((2-(4-acetamidopiperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 33); (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide (Compound 34); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 35); 2-(4-(((R)-5-oxido-2-((S)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 36); 2-(4-(((R)-5-oxido-2-((R)-3-(phenylcarbamoyl)pyrrolidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 37); 2-(4-(((R)-2-((R)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 38); 2-(4-(((R)-2-((S)-3-(methyl(phenyl)amino)pyrrolidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 39); (R)-2-(4-((2-(2-(4-chlorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 40); 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 41); 2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 42); (R)-Methyl 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate (Compound 43); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 44); (R)-2-(4-((2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 45); (R)-2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 46); (R)-2-(4-((2-(4-(N-methylacetamido)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 47); (R)-2-(4-((2-(4-Acetylpiperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 48); (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-(cyclopropylmethyl)acetamide (Compound 49); (R)-2-(4-((2-(2-(4-chlorophenyl)-2,7-diazaspiro[3.5]nonan-7-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 50); 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 51); (R)-2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-6-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 52); 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(1,2-dihydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 53); (R)-2-(4-(((5R)-2-(6-(4-chlorophenyl)-3,6-diazabicycloro[3.1.1]heptan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 54); (R)-2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 55); (R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 56); 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 57); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide (Compound 58); 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 59); Methyl 2-(4-((2-(5-chloro-5',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate (Compound 60); 2-(4-((2-(5-Chloro-5',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 61); 2-(4-(((5R)-2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 62); (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-methylacetamide (Compound 63); (R)-2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 64); 2-(4-((5,5-deoxido-2-(4-(pyridin-2-yl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 65); 2-(4-(((5R)-2-(8-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 66); (R)-2-(6-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)pyridin-3-yl)acetic acid (Compound 67); 2-(4-((2-(4-(4-chlorophenyl)piperazin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 68); (R)-2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 69); Methyl 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetate (Compound 70); 2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 71); (R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-cyclopropylacetamide (Compound 72); (R)-2-(4-((2-(1-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 73); (R)-2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5-oxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 74); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-methylacetamide (Compound 75); 2-(3-Fluoro-4-((2-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 76); 2-(3-Fluoro-4-((2-(4-(4-methoxyphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 77); 2-(4-((2-(4-(4-cyanophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 78); 2-(3-Fluoro-4-((2-(4-(3-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 79); 2-(4-((2-(4-(3,5-difluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 80); 2-(4-((2-(4-(3-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 81); 2-(4-((2-(4-(4-chloro-2-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 82); 2-(4-((2-(4-(4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 83); 2-(4-((2-(4-(4-methoxyphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 84); 2-(4-((2-(4-(5-chloropyridin-2-yl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 85); 2-(4-((5,5-deoxido-2-(4-(p-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 86); 2-(4-((2-(4-(2,4-difluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 87); 2-(3-Fluoro-4-((2-(4-(2-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 88); 2-(4-((2-(4-(3,5-Dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 89); 2-(4-((2-(4-(3,4-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 90); 2-(4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 91); 2-(4-((2-(4-(4-chloro-3-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 92); 2-(4-((2-(4-(2,4-dichlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 93); 2-(4-((2-(4-(4-chloro-2-methylphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 94); 2-(4-((2-(4-(3-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 95); 2-(4-((2-(4-(3-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 96); 2-(4-((2-(4-(3,5-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 97); 2-(4-((5,5-Dioxido-2-(4-(p-tolyl)-5,6-dihydropyridin-1(2H)-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 98); 2-(4-((2-(4-(3-Chloro-4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 99); 2-(4-((2-(4-(4-bromophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 100); 2-(4-((2-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 101); 2-(4-((2-(4-(2-fluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 102); 2-(4-((2-(4-(2,4-difluorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 103); 2-(4-((2-(4-(4-bromophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 104); 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide (Compound 105); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-ethylacetamide (Compound 106); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-1-(3-fluoroazetidin-1-yl)ethanone (Compound 107); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-1-(3-hydroxyazetidin-1-yl)ethanone (Compound 108); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(2-fluoroethyl)acetamide (Compound 109); 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-ethylacetamide (Compound 110); 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 111); 2-(4-((2-(4-(4-bromophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 112); 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(cyclopropylmethyl)acetamide (Compound 113); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(cyclopropylmethyl)acetamide (Compound 114); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-cyclopropylacetamide (Compound 115); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone (Compound 116); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-ethyl-N-methylacetamide (Compound 117); 2-(4-((2-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)-N-ethylacetamide (Compound 118); 2-(4-((5,5-Dioxido-2-(4-(p-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide (Compound 119); 2-(4-((5,5-deoxido-2-(4-(m-tolyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 120); 2-(4-((5,5-Dioxido-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 121); 2-(4-((2-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 122); 2-(4-((2-(4-(4-(difluoromethyl)phenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 123); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(2-hydroxyethyl)acetamide (Compound 124); 2-(4-((2-(4-(4-chlorophenyl)piperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(3-hydroxypropyl)acetamide (Compound 125); 2-(4-((2-(4-(4-chloro-2-methylphenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 126); 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 127); 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((2-fluoro-4-(1-(hydroxymethyl)cyclobutyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 128); 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 129); 2-(4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 130); 2-(3-Fluoro-4-((2-(4-morpholinopiperidin-1-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 131); 2-(4-((2-(4-(4-(difluoromethyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 132); 2-(4-(4-chlorophenyl)piperidin-1-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (Compound 133); 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 134); 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 135); 2-(4-((5,5-Dioxido-2-(3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 136); 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 137); 2-(4-((2-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 138); 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 139); 2-(4-((2-(3-(4-chlorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 140); 2-(4-((5,5-Dioxido-2-(3-phenyl-8-azabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 141); 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 142); 2-(4-((2-(8-(4-chlorophenyl)-3-azabicyclo[3.2.1]octan-3-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 143); 2-(4-((2-(8-(4-chlorophenyl)-3-azabicyclo[3.2.1]octan-3-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 144); 2-(4-((2-(5-(4-chlorophenyl)-2-azabicyclo[2.2.2]octan-2-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 145); 2-(4-((2-(5-(4-chlorophenyl)-2-azabicyclo[2.2.2]octan-2-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid (Compound 146); 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-3-fluorophenyl)acetic acid, salt (Compound 147); 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (Compound 148); and 2-(4-((2-(3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2,5-difluorophenyl)acetic acid (Compound 149).

14. A pharmaceutical composition for preventing, improving or treating a disease caused by the activity of phosphodiesterase-4 (PDE-4), comprising a compound of formula 1 defined in any one of claims 1 to 13 as an active ingredient, or an optical isomer, stereoisomer, solvate, isotope or tautomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

15. A pharmaceutical composition according to claim 14, characterized in that the disease caused by the activity of PDE-4 is a lung disease; an inflammatory disease of the skin, gastrointestinal tract, joints, nose, or eyes; or a peripheral nervous system or central nervous system disease.

16. A pharmaceutical composition according to claim 15, wherein the lung disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), acute, allergic or chronic bronchitis, chronic obstructive bronchitis (COPD), cough, emphysema, progressive fibrosing interstitial lung disease (PF-ILD), asthma, alveolitis, infectious bronchitis or pneumonia, childhood asthma, bronchiectasis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), bronchial edema, pulmonary edema, bronchitis, viral pneumonia, cystic fibrosis, mucoviscidosis, and alpha-1-antitrypsin deficiency.

17. A pharmaceutical composition according to claim 15, wherein the inflammatory disease of the skin, gastrointestinal tract, joints, nose or eyes is selected from the group consisting of rheumatoid arthritis, acne, acne vulgaris, atopic dermatitis, bacterial skin infection, macular degeneration, bullous pemphigoid, mycosis, hidradenitis suppurativa, seborrheic dermatitis, Crohn's disease, cystic fibrosis, diabetic kidney disease, interstitial cystitis, psoriasis, psoriatic arthritis, renal fibrosis, systemic sclerosis, ulcerative colitis, inflammatory pseudoaneurysm, cystic colitis profunda, uterine fibrosis, allergic or non-allergic rhinitis, sinusitis, chronic rhinitis, conjunctivitis and keratitis.

18. A pharmaceutical composition according to claim 15, wherein the central nervous system disease is selected from the group consisting of depression, bipolar or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis, acute and chronic pain and seizures, and brain damage due to hypoxia or brain trauma.

19. A pharmaceutical composition according to claim 14, characterized in that the disease caused by the activity of PDE-4 is hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, hepatic fibrosis, liver damage, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or diabetes.

20. A pharmaceutical composition according to claim 14, characterized in that it further comprises an additional active substance as an effective ingredient.

21. A pharmaceutical composition according to claim 20, characterized in that the active substance is at least one selected from the group consisting of a beta-agonist, an anticholinergic, an adrenal cortical hormone, another PDE-4 inhibitor, an LTD-4 (leukotriene D4) antagonist, an EGFR (epidermal growth factor receptor) inhibitor, a dopamine agonist, an H1 antihistamine, an adenyl cyclase agonist, an LPAR (lysophosphatidic acid receptor) antagonist, a JAK (Janus kinase) inhibitor, a JNK (C-Jun N-terminal kinase) inhibitor, and an autotaxin inhibitor.

Images