Cyclic compounds and methods of using same

Abstract

This application relates to compounds of formula (I) as defined herein and their pharmaceutically acceptable salts. This application also describes pharmaceutical compositions comprising compounds of formula (I) and their pharmaceutically acceptable salts, and methods of using such compounds and compositions to inhibit kinase activity and treat cancer.

Description

technical field

[0001] This application relates to tricyclic and other polycyclic compounds useful in the treatment of proliferative disorders, such as cancer. prior art

[0002] Cancer is characterized by abnormal cell growth and proliferation. Genome instability is a hallmark of cancer cells, with high mutation rates and gene rearrangements leading to aggressive and treatment-resistant tumors. See Hanahan and Weinberg, Cell, 144, pp. 646-674 (2011) and McGranahan and Swanton, Cell 168, pp. 613-628 (2017). Dysregulation of DNA replication leads to gene body instability and tumor formation. Eukaryotic cells divide by a directed, highly regulated stepwise process known as the cell cycle. DNA replication is an essential part of the highly regulated stepwise cell cycle, and this tight regulation ensures that DNA replication occurs only once during S phase, and with high fidelity.

[0003] During late G1 to S phase, CDC7 kinase (also known as DDK) is activated by binding to its regulatory protein DBF4 (ASK in eukaryotes), which subsequently phosphorylates chromatin-loaded minichromosomes at multiple phosphorylation sites Maintenance (MCM) 2, 4 and 6 proteins to initiate DNA synthesis. See Jiang et al., EMBO J., 18, pp. 5703-5713 (1999), Cho et al., Proc. Natl. Acad. Sci. U.S.A. ), 103, pp. 11521-11526 (2006) and Masai et al., J Biol Chem., 281, pp. 39249-39261 (2006). CDC7 kinase plays an important role in maintaining DNA replication forks and DNA damage response pathways. See Yamada et al., Cell Cycle 13, pp. 1859-1866 (2014).

[0004] CDC7 is a highly conserved serine / threonine kinase from yeast to humans. Attenuation of CDC7 has been shown to cause cell death in cancer cells but not in normal cells, where a p53-dependent pathway arrests the cell cycle in the G1 phase. The apoptotic response induced by CDC7 depletion in cancer cells is not mediated by p53 but by p38 MAPK. See Montagnoli et al., Cancer Research, 64, pp. 7110-7116 (2004) and Im and Lee, Journal of Biochemistry, 283, pp. 25171-25177 (2008). In addition, CDC7 upregulation is associated with poor prognosis in various cancer types. See eg Kulkarni et al., Clinical Cancer Research, 15, pp. 2417-2425 (2009); Choschzick et al., Hum. Pathol., 41, pp. 358-365 (2010); Datta et al., EMBO Rep., 18, pp. 2030-2050 (2017); Cheng et al., Cancer Lett., 337, 218-225 (2013 ). Contents of the invention

[0005] Certain fusion compounds have now been found to be CDC7 kinase inhibitors and are useful in the treatment of diseases, such as proliferative diseases, such as cancer.

[0006] Therefore, a kind of formula (I) compound is provided herein: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , ring A and m are as defined herein.

[0007] Also provided herein is a pharmaceutical composition, which includes a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0008] Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0009] Also provided herein is a method for inhibiting CDC7 kinase activity in vitro or in vivo, which includes allowing cells to react with an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof contact.

[0010] Also provided herein is a method of treating cancer in an individual in need of such treatment, comprising administering to the individual an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .

[0011] Also provided herein is a method of treating a CDC7-associated disease or disorder in an individual in need of such treatment, comprising administering to the individual an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof or Its pharmaceutical composition.

[0012] Also provided herein is a method of treating cancer in an individual in need thereof, comprising administering to an individual identified as having a cancer associated with CDC7 an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salts or pharmaceutical compositions thereof.

[0013] Also provided herein is a method of treating cancer and / or inhibiting metastasis associated with a particular cancer in an individual in need of such treatment, comprising administering to the individual an effective amount of a compound of formula (I) as defined herein or its pharmaceutical acceptable salts or pharmaceutical compositions thereof.

[0014] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of cancer.

[0015] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a CDC7-associated disease or disorder.

[0016] Also provided herein is a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in treating cancer and / or inhibiting metastasis associated with a specific cancer.

[0017] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting CDC7 kinase activity.

[0018] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a CDC7-associated disease or disorder.

[0019] Also provided herein is a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating cancer and / or inhibiting metastasis associated with a specific cancer.

[0020] Also provided herein is a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting CDC7 kinase activity.

[0021] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a CDC7-associated disease or disorder.

[0022] Also provided are methods of treating an individual with a CDC7-associated cancer comprising administering a compound of formula (I) or its compound before, during, or after administration of another anticancer drug (e.g., a first CDC7 kinase inhibitor or another kinase inhibitor). Pharmaceutically acceptable salts.

[0023] Also provided herein is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof obtained by a process for the preparation of a compound as defined herein.

[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Methods and materials are described herein for use in the present invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0026] Other features and advantages of the present invention will be apparent from the following embodiments and claims. Brief description of the diagram

[0027] none Implementation

[0028] definition

[0029] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopically enriched variants of the depicted structure. Unless otherwise stated, compounds identified herein by name or structure as one particular tautomeric form are intended to encompass the other tautomeric form.

[0030] As used herein, the term "tautomer" refers to compounds whose structures differ significantly due to the arrangement of atoms, but which equilibrate easily and rapidly, and it is understood that the compounds presented herein may be depicted as different tautomers , and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the compound nomenclature does not exclude any tautomer. Examples of tautomeric forms include the following: .

[0031] It is to be understood that certain compounds provided herein may contain one or more asymmetric centers and thus may be prepared and isolated as mixtures of isomers, such as racemic mixtures, or in enantiomerically pure form.

[0032] The term "halogen" refers to one of the halogens, group 17 of the periodic table of elements. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0033] The term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- Butyl, second butyl, tertiary butyl, n-pentyl and n-hexyl. Alkyl groups can be unsubstituted or substituted with one or more substituents as described herein.

[0034] The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted in each occurrence with at least one independently selected halogen atom, such as fluorine, chlorine, bromine and iodine. Halogen atoms can be present anywhere on the hydrocarbon chain. For example, C1-C6 haloalkyl can refer to chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl (for example, 1-chloroethyl and 2-chloroethyl), trifluoromethyl, Chloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoro Ethyl (eg, 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0035] The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group attached to a molecule through an oxygen. This includes alkyl moieties which may be straight or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tertiary-butoxy, n-pentyloxy and n-hexyloxy.

[0036] As used herein, the term "hydroxyl" refers to an -OH group.

[0037] The term "C1-C6 hydroxyalkyl" refers to a hydrocarbon chain substituted with one hydroxyl group. Hydroxyl groups can be present anywhere on the hydrocarbon chain. For example, C1-C6 hydroxyalkyl can refer to hydroxymethyl, hydroxyethyl (such as 1-hydroxyethyl and 2-hydroxyethyl) and 2-hydroxyisopropyl.

[0038] As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic ring system of 6-10 full carbons. Non-limiting examples of aryl include phenyl and naphthyl.

[0039] As used herein, the term "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic group, wherein each ring in the system is aromatic; wherein one or more carbons in at least one ring in the system Atoms are replaced with heteroatoms independently selected from N, O and S. Non-limiting examples of heteroaryl include pyridine, pyrimidine, pyrrole, imidazole, and indole.

[0040] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic carbon group having from 3 to 10 ring atoms; Alkyl") and bridged ring systems. Fused cycloalkyls may comprise one aromatic ring and another saturated or partially saturated ring, such as 1,2,3,4-tetrahydronaphthalene and 2,3-dihydro-1H-indene. Non-limiting examples of cycloalkyl include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl. As substituents, for example on alkyl, cycloalkyl may share carbon atoms with the alkyl chain.

[0041] The term "heterocyclyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or bicyclic ring system which is not fully aromatic, having at least one heteroatom selected from N, O and S within the ring. Bicyclic heterocyclyl includes fused, spiro (optionally referred to as a "spiroheterocyclyl" group) and bridged ring systems. Fused heterocyclyl groups can contain one aromatic ring and another saturated or partially saturated ring, such as 5,6,7,8-tetrahydroquinoline and indoline. A heterocyclyl may be represented as a "3 to 10 membered heterocyclyl", which is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2, present. A heterocyclyl group can be bonded to the rest of the molecule via any carbon atom or via a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperidine base, N-morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl and 2-azaspiro[3.3]heptyl. As a substituent, for example on an alkyl group, a heterocyclyl group may share a carbon atom with the alkyl chain.

[0042] As used herein, the term "twin" refers to substituent atoms or groups attached to the same atom in a molecule.

[0043] As used herein, the term "pendent oxy" refers to an "=0" group attached to a carbon atom.

[0044] As used in this article, the notation Depicts the point of attachment of an atom or moiety to a given atom or group in the rest of the molecule.

[0045] It is to be understood that the A ring in the included compounds of formula (I) does not contain two adjacent oxygen atoms or two adjacent S atoms.

[0046] The compounds of formula (I) include their pharmaceutically acceptable salts. In addition, the compound of formula (I) also includes other salts of such compounds, which may not be pharmaceutically acceptable salts and can be used for preparing and / or purifying the compound of formula (I) and / or isolating the compound of formula (I) Intermediates of enantiomers. Non-limiting examples of pharmaceutically acceptable salts of compounds of formula (I) include trifluoroacetic acid and hydrochloride.

[0047] It is further understood that compounds of formula (I) or salts thereof may be isolated in the form of solvates, and therefore, any such solvates are included within the scope of the present invention. For example, compounds of formula (I) and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.

[0048] In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-96 and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the compound of formula (I) is in free base form. In some embodiments, the compound of formula (I) is in the form of a salt (eg, a pharmaceutically acceptable salt).

[0049] In some embodiments, the compound of formula (I) includes its stereoisomers and pharmaceutically acceptable salts and solvates. In some embodiments, the compound of formula (I) is in free base form. In some embodiments, the compounds of formula (I) are in the form of salts.

[0050] The term "pharmaceutically acceptable" means that the compound or salt or composition thereof is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the individual being treated therewith.

[0051] A protecting group can be a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. The choice of the particular protecting group employed is well within the skill of one of ordinary skill in the art. Several considerations can determine the choice of protecting group, including but not limited to the functional group to be protected, other functional groups present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, the need for removal of protection. The functional group tolerance of the conditions required for the group, and the reaction conditions for the thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd Supplement; Wiley: New York, 1991).

[0052] The nitrogen protecting group can be any temporary substituent that protects the amine moiety from undesired chemical transformations. Examples of moieties formed when such protecting groups are bonded to amines include, but are not limited to, allylamine, benzylamine (e.g., benzylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine and tritylamine), acetamide, trichloroacetamide, trifluoroacetamide, pent-4-enamide, phthalimide, carbamates (such as methyl carbamate ester, tertiary butyl carbamate, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethyl carbamate and 9-fenylmethyl carbamate ), imines and sulfonamides (such as benzenesulfonamide, p-toluenesulfonamide and p-nitrobenzenesulfonamide).

[0053] The oxygen protecting group can be any temporary substituent that protects the hydroxyl moiety from undesired chemical transformations. Examples of moieties formed when such protecting groups are bonded to hydroxyl groups include, but are not limited to, esters (e.g., acetyl, tert-butylcarbonyl, and benzoyl), benzyl groups (e.g., benzyl, p-methoxy phenylmethyl and 2,4-dimethoxybenzyl and trityl), carbonates (such as methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate and carbonic acid Benzyl ester) ketal, and acetal, and ether.

[0054] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, especially when referred to with respect to compounds of formula (I), an atom includes all isotopes and mixtures of isotopes (naturally occurring or synthetically produced) of that atom in natural abundance or in isotopically enriched form. For example, when hydrogen is mentioned, it is understood to mean 1H, 2H, 3H or mixtures thereof; when carbon is mentioned, it is understood to mean 11C, 12C, 13C, 14C or mixtures thereof; when nitrogen is mentioned, It should be understood to mean 13N, 14N, 15N or a mixture thereof; when referring to oxygen, it should be understood to mean 14O, 15O, 16O, 17O, 18O or a mixture thereof; and when referring to fluorine, it should be understood to mean 18F, 19F or mixtures thereof; unless expressly stated otherwise. For example, in deuterated alkyl and deuterated alkoxy, one or more hydrogen atoms are specifically replaced by deuterium (2H). Since some of the aforementioned isotopes are radioactive, the compounds provided herein also include compounds having one or more isotopes of one or more atoms and mixtures thereof, including radioactive compounds in which one or more non-radioactive atoms have been It is replaced by one of its radioactive-rich isotopes. Radiolabeled compounds are useful as therapeutic agents, such as cancer therapeutics, research reagents (eg, assay reagents), and diagnostic agents (eg, in vivo imaging agents). All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0055] For illustrative purposes, general methods and key intermediates for the preparation of compounds are provided herein. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0056] The ability of test compounds to act as CDC7 inhibitors can be demonstrated by the biological and computational assays described herein. IC50 values ​​are shown in Tables 2 and 3.

[0057] Compounds of formula (I) (e.g. any one of formulas (I-A) to (I-P)) or pharmaceutically acceptable salts thereof are useful in the treatment of diseases and conditions treatable with CDC7 kinase inhibitors, such as CDC7-associated cancers, including Blood cancers and solid tumors.

[0058] As used herein, the term "treat / treatment" refers to curative or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial remission of symptoms associated with a disease or disorder or condition, reduction in extent of disease, stabilization of disease state (i.e., not worsening), delay or slowing of disease progression, disease state (e.g. one or more symptoms of a disease), improvement or alleviation, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0059] As used herein, the term "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the individual is a human. In some embodiments, the individual has experienced and / or exhibited at least one symptom of the disease or condition to be treated and / or prevented.

[0060] In some embodiments, the individual has been identified or diagnosed as having a cancer with dysregulation of the expression or activity or level of the CDC7 gene, CDC7 protein, or either (CDC7-associated cancer) (e.g., using a regulatory agency-approved (e.g., FDA Approved) analysis or set of assays). In some embodiments, the individual has a tumor that is positive for CDC7 gene, CDC7 protein, or dysregulation of the expression or activity or level of either (eg, as determined using a regulatory agency approved assay or panel). An individual can be an individual with a tumor positive for CDC7 gene, CDC7 protein, or dysregulation of the expression or activity or level of either (e.g., as identified using a regulatory agency-approved (e.g., FDA-approved) assay or panel) . An individual may have a tumor whose tumor has a dysregulation of the expression or activity or amount of the CDC7 gene, CDC7 protein, or either (e.g., where the tumor is identified as such using a regulatory agency-approved (e.g., FDA-approved) panel or assay) . In some embodiments, the individual is suspected of having a CDC7-associated cancer. In some embodiments, the individual's clinical records indicate that the individual has a tumor in which the expression or activity or amount of the CDC7 gene, CDC7 protein, or either is dysregulated (and optionally, the individual's clinical records indicate that the individual uses the any one of the provided compositions for treatment). In some embodiments, the individual is a pediatric individual. In some embodiments, the individual has been identified or diagnosed as having a cancer that, based on histological examination, is associated with dysregulation of the expression or activity or amount of the CDC7 gene, CDC7 protein, or either (CDC7-associated cancer) .

[0061] The term "pediatric subject" as used herein refers to a subject who is younger than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (birth to first month of life); infants (1 month to 2 years); children (2 years to 12 years); and adolescents (12 aged to 21 (up to but not including the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics 21st ed., New York: McGraw-Hill, 2002; and Avery MD, First LR, Pediatric Medicine 2nd Ed., Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or from 12 years of age to 21 years of age (up to but not including the twenty-second birthday). In some embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age Age to less than 1 year, from 1 to less than 2 years, from 2 to less than 3 years, from 2 to less than 7 years, from 3 to less than 5 years, from 5 to less than 10 years, from 6 to less than 3 years Less than 13 years old, from 10 years old to less than 15 years old, or from 15 years old to less than 22 years old.

[0062] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for preventing diseases and disorders as defined herein (eg autoimmune diseases, inflammatory diseases and cancer). The term "preventing" as used herein means preventing the onset, recurrence or spread, in whole or in part, of a disease or condition as described herein, or symptoms thereof.

[0063] As used herein, the term "CDC7-associated cancer" refers to a dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase (also referred to herein as CDC7 kinase protein), or any one (e.g., one or more) of them (e.g. Cancers associated with or having any type of dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase, CDC7 kinase domain, or any of them described herein. Non-limiting examples of CDC7-associated diseases or disorders include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).

[0064] As used herein, the term "CDC7-associated cancer" refers to a cancer associated with or having a dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase, or either. Non-limiting examples of CDC7-associated cancers are described herein.

[0065] The phrase "dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase, or either" refers to a genetic mutation (such as a chromosomal translocation resulting in the expression of a fusion protein comprising the CDC7 kinase domain and a fusion partner, resulting in a A mutation in the CDC7 gene that results in the expression of a CDC7 protein with one or more point mutations compared to a wild-type CDC7 protein compared to a CDC7 protein comprising at least one amino acid deletion A mutation, a mutation in the CDC7 gene that results in the expression of a CDC7 protein having at least one inserted amino acid compared to a wild-type CDC7 protein, a gene duplication that results in an increase in the amount of CDC7 protein in the cell, or a gene that results in an increase in the amount of the CDC7 protein in the cell regulatory sequences such as promoters and / or enhancers), alternative spliced ​​forms of CDC7 mRNA resulting in a CDC7 protein having at least one amino acid deletion in the CDC7 protein compared to wild-type CDC7 protein), Or increased expression (eg, increased levels) of wild-type CDC7 kinase in mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (eg, compared to control non-cancerous cells). As another example, dysregulation of the expression or activity or level of the CDC7 gene, CDC7 protein, or either may be a mutation in the CDC7 gene encoding a CDC7 protein that is comparable to a protein encoded by a CDC7 gene that does not contain the mutation. Than have constitutive activity or have increased activity. As another example, increased copy number of the CDC7 gene can lead to overexpression of the CDC7 kinase. For example, dysregulation of the expression or activity or level of the CDC7 gene, CDC7 protein, or either may be the result of a gene or chromosomal translocation that results in a first portion of CDC7 comprising a functional kinase domain Expression of fusion proteins with the second part of the partner protein (ie, not CDC7). In some instances, dysregulation of the expression or activity or level of a CDC7 gene, CDC7 protein, or either, may be the result of a genetic translocation of a CDC7 gene with another non-CDC7 gene.

[0066] The term "wild type" describes a nucleic acid (e.g., CDC7 gene or CDC7 mRNA) or protein (e.g., CDC7 protein) that is found in individuals who do not have a CDC7-associated disease (e.g., a CDC7-associated cancer) (and, optionally, do not suffer from a CDC7-associated disease). increased risk of CDC7-related disease and / or not suspected of having a CDC7-related disease), or in individuals who do not have a CDC7-related disease (such as CDC7-related cancer) (and, as the case may in cells or tissues of individuals who are not suspected of having a CDC7-associated disease).

[0067] The term "regulatory agency" refers to a national agency of a country that approves the medical use of a pharmaceutical agent. By way of example, a non-limiting example of a regulatory agency is the United States Food and Drug Administration (FDA).

[0068] Provided herein are compounds of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is hydrogen or halogen; R is a 5-6 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C1 to C6 alkyl; or optionally substituted with 1 or 2 substituents independently selected from halogen And a 5-6 membered heterocyclic group substituted by a substituent consisting of a group of C1 to C6 alkyl groups; R 3 is hydrogen or C1-C6 alkyl; Ring A is C6-C10 cycloalkyl or 6-10 membered heterocyclyl; Each R is independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxyl ( C1-C6 alkyl)-, -C(=O)C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -NR AR B and optionally substituted by 1 or 2 independently selected halogens The 4-6 membered heterocyclyl; each R A and R B independently hydrogen or C1-C6 alkyl; and m is 0, 1, 2, 3 or 4.

[0069] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0070] In some embodiments, R is a 5-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl. In some embodiments, R 2 is a 5-membered heteroaryl substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl.

[0071] In some embodiments, R is a 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, Azolyl, iso Azolyl, isothiazolyl, thiazolyl, furacryl, Diazolyl, thiadiazolyl, Triazolyl and thiatriazolyl. In some embodiments, the 5-membered heteroaryl of R is pyrazolyl or isothiazolyl. In some embodiments, R 2 is 4-pyrazolyl, 5-pyrazolyl or 5-isothiazolyl.

[0072] In some embodiments, R is a 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl. In some embodiments, R is a 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl.

[0073] In some embodiments, R is a 6-membered heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridyl base, click base and three base. In some embodiments, the 6-membered heteroaryl of R is pyridyl, pyrimidinyl or pyridyl base. In some embodiments, the 6-membered heteroaryl of R is pyridyl. In some embodiments, R 2 is 4-pyridyl. In some embodiments, R 2 is 4-pyrimidinyl. In some embodiments, R 2 is 4-D base.

[0074] In some embodiments, the heteroaryl of R is substituted with one substituent selected from halogen and C1-C6 alkyl. In some embodiments, the heteroaryl of R is substituted with one substituent selected from fluoro, chloro, and methyl. In some embodiments, the heteroaryl of R is substituted with two substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, the heteroaryl of R is substituted with two substituents independently selected from fluoro and methyl.

[0075] In some embodiments, the substituents on R are the same. In some embodiments, the substituents on R are different.

[0076] In some embodiments, R is unsubstituted 5-6 membered heteroaryl, such as unsubstituted pyrazolyl, isothiazolyl, pyridyl or pyridyl base.

[0077] In some embodiments, R is a 5-6 membered heterocyclyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl. In some embodiments, R 2 is an unsubstituted 5-6 membered heterocyclyl. In some embodiments, R 2 is morpholinyl, piperidinyl or piperidinyl base. In some embodiments, R 2 is morpholinyl. In some embodiments, R 2 is 4-morpholinyl.

[0078] In some embodiments, Ring A is C6-C10 cycloalkyl. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is bicyclo[2.2.2]octyl.

[0079] In some embodiments, Ring A is a 6-10 membered heterocyclyl. In some embodiments, Ring A is tetrahydropyranyl. In some embodiments, Ring A is piperidinyl.

[0080] In some embodiments, one or two R 4 are independently halogen. In some embodiments, one R4 is fluoro or chloro. In some embodiments, one R4 is fluoro. In some embodiments, one R 4 is chloro. In some embodiments, two R 4 are fluoro.

[0081] In some embodiments, one R4 is hydroxyl.

[0082] In some embodiments, one R 4 is independently C1-C6 alkyl. In some embodiments, one or two R 4 are independently selected C1-C6 alkyl. In some embodiments, one R 4 is independently selected from the group consisting of -CH 3 , -CH 2CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )CH 2CH 3 , -C(CH 3 ) 2CH 2CH 3 and -C(CH 3 ) 3.

[0083] In some embodiments, each R 4 is independently C1-C6 alkoxy. In some embodiments, one R 4 is C 1-C 6 alkoxy. In some embodiments, each R4 is independently methoxy, ethoxy, or isopropoxy. In some embodiments, one R4 is methoxy, ethoxy or isopropoxy. In some embodiments, each R 4 is methoxy. In some embodiments, one R 4 is methoxy.

[0084] In some embodiments, one R 4 is C1-C6 hydroxyalkyl. In some embodiments, one R 4 is C1-C6 hydroxyalkyl. In some embodiments, one R 4 is -CH 2OH or -C(CH 3 ) 2OH. In some embodiments, one R 4 is -CH 2OH or -C(CH 3 ) 2OH.

[0085] In some embodiments, one R 4 is C1-C6 haloalkyl. In some embodiments, one or two R 4 are independently selected from C1-C6 haloalkyl. In some embodiments, one R 4 is -CF 3 . In some embodiments, one R 4 is -CHF 2 . In some embodiments, one R 4 is -CF 3 . In some embodiments, one R 4 is -CHF 2 . In some embodiments, one R 4 is -CF 2CH 3 . In some embodiments, one R4 is CH2CF2CH3.

[0086] In some embodiments, one R4 is C1-C6 alkoxy(C1-C6 alkyl)-. In some embodiments, one R 4 is C1-C3 alkoxy(C1-C3 alkyl)-. In some embodiments, one R4 is independently methoxy(C1-C6 alkyl)-. In some embodiments, one R 4 is -CH 2 OCH 3 .

[0087] In some embodiments, one R 4 is -C(=0)C1-C6 alkyl. In some embodiments, R 4 is C(=O)CH 3 .

[0088] In some embodiments, one R 4 is C2-C6 alkynyl. In some embodiments, one R 4 is 1-propynyl.

[0089] In some embodiments, one R 4 is C3-C6 cycloalkyl. In some embodiments, R 4 is cyclopentyl.

[0090] In some embodiments, one R4 is -NRARB. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, R A and R B are both C1-C6 alkyl. In some embodiments, R 4 is -NH 2 .

[0091] In some embodiments, one R4 is a 4-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected halo. In some embodiments, one R4 is a 4-6 membered heterocyclyl substituted with 1 or 2 independently selected halo. In some embodiments, one R4 is a 4-6 membered heterocyclyl substituted with 1 or 2 fluorines. In some embodiments, one R 4 is a 4-6 membered heterocyclyl substituted with a geminal difluoro group.

[0092] In some embodiments, one R is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperidinyl , tetrahydrofuranyl, morpholinyl or dioxanyl; each optionally substituted with 1 or 2 independently selected halogens. In some embodiments, one R4 is pyrrolidinyl optionally substituted with 1 or 2 independently selected halo. In some embodiments, one R4 is pyrrolidinyl substituted with 1 or 2 independently selected halo. In some embodiments, one R4 is azetidinyl optionally substituted with 1 or 2 independently selected halo. In some embodiments, one R4 is azetidinyl substituted with 1 or 2 independently selected halo. In some embodiments, 1 or 2 independently selected halogens are fluorine. In some embodiments, two independently selected halogens are geminal difluoro groups.

[0093] In some embodiments, one R 4 is unsubstituted 4-6 membered heterocyclyl. In some embodiments, the unsubstituted 4-6 membered heterocyclic group of R is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperidinyl group, tetrahydrofuranyl, morpholinyl or dioxanyl. In some embodiments, one R 4 is unsubstituted pyrrolidinyl or unsubstituted azetidinyl.

[0094] In some embodiments, one R 4 is selected from , and composed of groups.

[0095] In some embodiments, m is 2, 3 or 4; and two of the 2, 3 or 4 R groups are geminal. In some embodiments, m is 2; and two (ie, two) R groups are geminal. In some embodiments, m is 3; and wherein two of the three R groups are geminal. In some embodiments, m is 4; and wherein each pair of R groups is geminal.

[0096] In some embodiments, R 1 is halogen. In some embodiments, R 1 is fluoro or chloro. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is hydrogen.

[0097] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is hydrogen.

[0098] In some embodiments, m is 2; one R is hydroxyl; and the other R is C1-C6 alkyl.

[0099] In some embodiments, m is 2 and each R is fluoro.

[0100] In some embodiments, m is 2; one R is hydroxyl; and the other R is C1-C6 haloalkyl.

[0101] In some embodiments, m is 2; one R 4 is hydroxyl; and the other R 4 is C2-C6 alkynyl.

[0102] In some embodiments, m is 2; one R 4 is hydroxyl; and the other R 4 is C3-C6 cycloalkyl.

[0103] In some embodiments, m is 2; one R 4 is hydroxyl; and the other R 4 is C1-C6 alkoxy(C1-C6 alkyl)-.

[0104] In some embodiments, m is 2; each R 4 is an independently selected C1-C6 alkyl.

[0105] In some embodiments, m is 2; one R 4 is C1-C6 alkyl; and the other R 4 is C1-C6 hydroxyalkyl.

[0106] In some embodiments, m is 2; one R 4 is C1-C6 alkyl; and the other R 4 is C1-C6 alkoxy.

[0107] In some embodiments, m is 2; one R 4 is C1-C6 alkyl; and the other R 4 is -NR AR B.

[0108] In some embodiments, m is 2; one R is C1-C6 alkyl; and the other R is 4-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected halogens.

[0109] In some embodiments, m is 4; two R 4 are fluoro; one R 4 is C1-C6 alkoxy; and one R 4 is C1-C6 alkyl.

[0110] In some embodiments, m is 4; two R 4 are fluoro; one R 4 is C1-C6 hydroxyalkyl; and one R 4 is C1-C6 alkyl.

[0111] In some embodiments, m is 4; two R 4 are fluoro; one R 4 is hydroxyl; and one R 4 is C1-C6 alkyl.

[0112] In some embodiments, m is 4; two R 4 are fluoro; one R 4 is hydroxyl; and one R 4 is C1-C6 alkoxy(C1-C6 alkyl)-.

[0113] In some embodiments, R1 is hydrogen; R2 is unsubstituted pyrazolyl; m is 2; one R4 is hydroxyl; and the other R4 is C1-C6 alkyl.

[0114] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted pyrazolyl; m is 2 and each R 4 is fluoro.

[0115] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted pyrazolyl; m is 2; one R 4 is hydroxyl; and the other R 4 is C1-C6 haloalkyl.

[0116] In some embodiments, R is hydrogen; R is unsubstituted pyrazolyl; m is 4; two R are fluoro; one R is C1-C6 alkoxy; -C6 alkyl.

[0117] In some embodiments, R is hydrogen; R is unsubstituted pyrazolyl; m is 4; two R are fluoro; one R is C1-C6 hydroxyalkyl; -C6 alkyl.

[0118] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted pyridyl; m is 2; one R 4 is hydroxyl;

[0119] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted pyridyl; m is 2 and each R 4 is fluoro.

[0120] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted pyridyl; m is 2; one R 4 is hydroxyl; and the other R 4 is C1-C6 haloalkyl.

[0121] In some embodiments, R is hydrogen; R is unsubstituted pyridyl; m is 4; two R are fluoro; one R is C1-C6 alkoxy; C6 alkyl.

[0122] In some embodiments, R is hydrogen; R is unsubstituted pyridyl; m is 4; two R are fluoro; one R is C1-C6 hydroxyalkyl; C6 alkyl.

[0123] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted isothiazolyl; m is 2; one R 4 is hydroxyl; and the other R 4 is C1-C6 alkyl.

[0124] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted isothiazolyl; m is 2 and each R 4 is fluoro.

[0125] In some embodiments, R 1 is hydrogen; R 2 is unsubstituted isothiazolyl; m is 2; one R 4 is hydroxyl; and the other R 4 is C1-C6 haloalkyl.

[0126] In some embodiments, R is hydrogen; R is unsubstituted isothiazolyl; m is 4; two R are fluoro; one R is C1-C6 alkoxy; -C6 alkyl.

[0127] In some embodiments, R is hydrogen; R is unsubstituted isothiazolyl; m is 4; two R are fluoro; one R is C1-C6 hydroxyalkyl; -C6 alkyl.

[0128] In some embodiments, Ring A is cyclohexyl; m is 2; one R4 is hydroxyl; and the other R4 is C1-C6 alkyl.

[0129] In some embodiments, Ring A is cyclohexyl; m is 2 and each R is fluoro.

[0130] In some embodiments, Ring A is cyclohexyl; m is 2; one R4 is hydroxyl; and the other R4 is C1-C6 haloalkyl.

[0131] In some embodiments, Ring A is cyclohexyl; m is 4; two R 4 are fluoro; one R 4 is C1-C6 alkoxy; and one R 4 is C1-C6 alkyl.

[0132] In some embodiments, Ring A is cyclohexyl; m is 4; two R 4 are fluoro; one R 4 is C1-C6 hydroxyalkyl; and one R 4 is C1-C6 alkyl.

[0133] In some embodiments, Ring A is bicyclo[2.2.2]octyl; m is 2; one R4 is hydroxyl; and the other R4 is C1-C6 alkyl.

[0134] In some embodiments, Ring A is bicyclo[2.2.2]octyl; m is 2 and each R is fluoro.

[0135] In some embodiments, Ring A is bicyclo[2.2.2]octyl; m is 2; one R4 is hydroxyl; and the other R4 is C1-C6 haloalkyl.

[0136] In some embodiments, Ring A is bicyclo[2.2.2]octyl; m is 4; two R4 are fluoro; one R4 is C1-C6 alkoxy; and one R4 is C1-C6 alkyl .

[0137] In some embodiments, Ring A is bicyclo[2.2.2]octyl; m is 4; two R4 are fluoro; one R4 is C1-C6 hydroxyalkyl; and one R4 is C1-C6 alkyl .

[0138] In some embodiments, Ring A is tetrahydropyranyl; m is 2; one R4 is hydroxyl; and the other R4 is C1-C6 alkyl.

[0139] In some embodiments, Ring A is tetrahydropyranyl; m is 2 and each R is fluoro.

[0140] In some embodiments, Ring A is tetrahydropyranyl; m is 2; one R4 is hydroxyl; and the other R4 is C1-C6 haloalkyl.

[0141] In some embodiments, Ring A is piperidinyl; m is 3; one R4 is hydroxyl; one R4 is C1-C6 alkyl; and one R4 is -C(=0)C1-C6 alkyl. In some embodiments, when ring A is piperidinyl, one R4 is attached to the piperidinyl nitrogen atom.

[0142] In some embodiments, Ring A is tetrahydropyranyl; m is 4; two R 4 are fluoro; one R 4 is C1-C6 alkoxy; and one R 4 is C1-C6 alkyl.

[0143] In some embodiments, Ring A is tetrahydropyranyl; m is 4; two R4 are fluoro; one R4 is C1-C6 hydroxyalkyl; and one R4 is C1-C6 alkyl.

[0144] In some embodiments, Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J) as described herein ), (I-K), (I-L), (I-M), (I-N), (I-O) and (I-P) compounds and pharmaceutically acceptable salts thereof, R 1 , R 2 , R 4 and m are as for formula ( I) or its pharmaceutically acceptable salt described.

[0145] In some embodiments, the compound of formula (I) is a compound of formula (I-A): Formula (I-A) or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the compound of formula (I) is a compound of formula (I-B): Formula (I-B) or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the compound of formula (I) is a compound of formula (I-C): Formula (I-C) or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the compound of formula (I) is a compound of formula (I-D): Formula (I-D) or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the compound of formula (I) is a compound of formula (I-E): Formula (I-E) or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound of formula (I) is a compound of formula I-F): Formula (I-F) or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the compound of formula (I) is a compound of formula I-G): Formula (I-G) or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound of formula (I) is a compound of formula I-H): Formula (I-H) or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the compound of formula (I) is a compound of formula I-I): Formula (I-I) or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the compound of formula (I) is a compound of formula I-J): Formula (I-J) or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the compound of formula (I) is a compound of formula I-K): Formula (I-K) or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the compound of formula (I) is a compound of formula I-L): Formula (I-L) or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the compound of formula (I) is a compound of formula I-M): Formula (I-M) or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the compound of formula (I) is a compound of formula I-N): Formula (I-N) or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the compound of formula (I) is a compound of formula I-O): Formula (I-O) or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the compound of formula (I) is a compound of formula I-P): Formula (I-P) or a pharmaceutically acceptable salt thereof.

[0161] Table 1 depicts compounds of formula (I). All stereochemistries in Table 1 are to be understood as arbitrary assignments unless otherwise specified.

[0162] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. Table 1: Exemplary compounds [] treatment method

[0163] Provided herein is a method of treating cancer (e.g., CDC7-associated cancer) in an individual in need of such treatment, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. combination. For example, provided herein are methods for treating a CDC7-associated cancer in an individual in need of such treatment comprising a) detecting the expression or activity or amount of the CDC7 gene, CDC7 kinase, or either of them in a sample from the individual and b) administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the CDC7 gene, CDC7 kinase, or dysregulation of the expression or activity or level of any of them comprises one or more fusion proteins.

[0164] In some embodiments of any of the methods or uses described herein, the cancer (eg, CDC7-related cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (eg, CDC7-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a CDC7-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer) carcinoma, medullary thyroid carcinoma (e.g., sporadic medullary thyroid carcinoma or hereditary medullary thyroid carcinoma), differentiated thyroid carcinoma, recurrent thyroid carcinoma, or refractory differentiated thyroid carcinoma), thyroid adenoma, endocrine gland neoplasm, pulmonary Adenocarcinoma, bronchiopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, breast neoplasm, breast neoplasm, colorectal Carcinoma (eg, metastatic colorectal cancer), papillary renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a CDC7-associated cancer) is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Juvenile cancer, adrenocortical cancer, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor , breast cancer, bronchial neoplasms, Burkitt lymphoma, carcinoid, unknown primary cancer, cardiac tumors, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid Leukemia (CML), chronic myeloproliferative neoplasm, neoplasm by site, neoplasm, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, breast ductal carcinoma in situ tumor, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, Eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hair cell tumor, Hairy cell leukemia, head and neck cancer, breast neoplasm, head and neck neoplasm, CNS tumor, primary CNS tumor, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, below Pharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, Lip and mouth cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, osteosarcoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic Squamous Neck Carcinoma, Midline Beam Carcinoma, Oral Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplasia / Myeloproliferative Neoplasm, Neoplasm by Site, Neoplasm myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasm, nasal and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-Hodgkin's lymphoma Cell lung cancer, lung neoplasm, lung cancer, lung neoplasm, respiratory neoplasm, bronchial carcinoma, bronchial neoplasm, mouth cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, nipple paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary gland cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy-related breast cancer, primary Primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colorectal cancer, colorectal neoplasia, renal cell carcinoma, CDC7 retinoblastoma (inoblastoma), rhabdomyosarcoma, salivary gland cancer, sarcoma, Seza Sezary syndrome, skin cancer, Spitz tumor, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T cell lymphoma, testicular cancer, Throat cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis and uCDC7er transitional cell carcinoma, unknown primary carcinoma, uCDC7hral carcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms' tumor (Wilms' tumor).

[0165] In some embodiments, the blood cancer (e.g., a blood cancer that is a CDC7-associated cancer) is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's disease) Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Acute Promyelocytic Leukemia (APL), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia ( CML), chronic myelomonocytic leukemia (CMML), chronic neutrophil leukemia (CNL), acute undifferentiated leukemia (AUL), pleomorphic large cell lymphoma (ALCL), prolymphocytic leukemia ( PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloid hyperplasia disease (MPD) and multiple myeloma (MM). Additional examples of hematological cancers include myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (eg, a hematological cancer that is a CDC7-associated cancer) is AML or CMML.

[0166] In some embodiments, the cancer (eg, CDC7-associated cancer) is a solid tumor. Examples of solid tumors (e.g., those that are CDC7-associated cancers) include, for example, thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal cancer , breast cancer, colorectal cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck cancer, neuroblastoma and melanoma. See eg Nature Reviews Cancer, 2014, 14, 173-186.

[0167] In some embodiments, the cancer line is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine carcinoma type 2A or 2B tumor (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, and cervical cancer.

[0168] In some embodiments, the individual is a human.

[0169] Compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also suitable for the treatment of CDC7-related cancers.

[0170] Accordingly, also provided herein is a method for treating an individual diagnosed with or identified as having a CDC7-associated cancer, such as any of the exemplary CDC7-associated cancers disclosed herein, comprising administering to the individual a therapeutically effective amount of A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from Examples 1-96, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof administered to an individual is of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (I-K), (I-L), (I-M), (I-N), (I-O) or (I-P) compounds or pharmaceutically acceptable compounds of any of the foregoing The salt of acceptance.

[0171] Dysregulation of the expression or activity or level of CDC7 kinase, CDC7 gene, or any one (eg, one or more) of them can lead to tumor formation. For example, fusion proteins may have increased kinase activity compared to wild-type CDC7 protein due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells), Wild-type CDC7 kinase expression is increased (eg, increased levels) in mammalian cells, and CDC7 mRNA splice variants can also lead to CDC7 dysregulation.

[0172] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds are able to cross the blood-brain barrier and inhibit CDC7 kinase in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in effective amounts. For example, treating an individual with cancer (eg, a CDC7-related cancer, such as a CDC7-related brain cancer or CNS cancer) can include administering (eg, orally administering) a compound to the individual. In some such embodiments, the compounds provided herein are useful in the treatment of primary brain tumors or metastatic brain tumors. For example, the compounds can be used to treat one or more of the following: gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglia Gliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (schwannomas), and craniopharyngiomas Tumors (see e.g. tumors listed in Louis, D.N. et al., Acta Neuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the individual has been previously treated with another anti-cancer agent, eg, another CDC7 inhibitor (eg, a compound other than a compound of formula (I)) or a multikinase inhibitor. In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the individual has been previously treated with another anticancer agent, such as another CDC7 inhibitor (eg, a compound other than a compound of formula (I)) or a multikinase inhibitor.

[0173] In some embodiments of any of the methods or uses described herein, the assay using a sample from an individual to determine whether the individual has a dysregulation of the expression or activity or amount of the CDC7 gene or the CDC7 kinase, or either, may include Examples include next-generation sequencing, immunohistochemistry, fluorescence microscopy, fractional FISH analysis, southern blotting, western blotting, FACS analysis, northern blotting, and PCR-based amplification (e.g., RT-PCR and Quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays Other detection methods known in the art may be used to detect dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase, or either. In some embodiments, the sample is a biological sample or biopsy sample (eg, a paraffin-embedded biopsy sample) from an individual. In some embodiments, the individual is an individual suspected of having a CDC7-associated cancer, an individual having one or more symptoms of a CDC7-associated cancer, and / or an individual having an increased risk of developing a CDC7-associated cancer).

[0174] In some embodiments, dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase, or either can be identified using a liquid biopsy (variously referred to as fluid biopsy or fluid phase biopsy). Liquid biopsy methods can be used to detect total tumor burden and / or dysregulation of the expression or activity or amount of the CDC7 gene, CDC7 kinase, or either. Liquid biopsies can be performed on biological samples that are relatively easier to obtain from an individual (e.g., via a simple blood draw) and can be used to detect tumor burden and / or expression or activity or levels of the CDC7 gene, CDC7 kinase, or either Traditional methods of treating the disorder are usually less invasive. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase, or either, at an earlier stage than conventional methods. In some embodiments, biological samples for liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage, bile, lymph, intracystic fluid, stool, ascites, and its combination. In some embodiments, liquid biopsies can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using the liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. ctDNA analysis (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify the expression or activity of the CDC7 gene, CDC7 kinase, or either or content imbalance.

[0175] In some embodiments, liquid biopsies can be used to detect ctDNA derived from a single gene. In some embodiments, liquid biopsies can be used to detect genes derived from multiple genes (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or more than 100, or any number of genes between these numbers) of ctDNA. In some embodiments, ctDNA derived from a plurality of genes can be obtained using a variety of commercially available test panels, such as commercially available tests designed to detect dysregulation of the expression or activity or levels of the CDC7 gene, CDC7 kinase, or either group) detected by any one. Liquid biopsy can be used to detect CDC7 gene, CDC7 kinase, or the expression or activity or content of any one of them, including but not limited to point mutations or single nucleotide variants (SNV), copy number variants (CNV), Gene fusions (such as translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, liquid biopsies can be used to detect germline mutations. In some embodiments, liquid biopsies can be used to detect somatic mutations. In some embodiments, liquid biopsies can be used to detect primary genetic mutations (eg, primary mutations or primary fusions associated with the initial development of a disease, such as cancer). In some embodiments, a dysregulation of the expression or activity or amount of the CDC7 gene, CDC7 kinase, or either identified using liquid biopsy is also present in cancer cells present in the individual (eg, in a tumor). In some embodiments, any type of dysregulation of the expression or activity or level of the CDC7 gene, CDC7 kinase, or either described herein can be detected using a liquid biopsy. In some embodiments, genetic mutations identified via liquid biopsies can be used to identify individuals as candidates for particular treatments. For example, detection of dysregulation in the expression or activity or level of the CDC7 gene, CDC7 kinase, or any of them in an individual may indicate that the individual will respond to a reaction comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof response to treatment.

[0176] Liquid biopsies can be taken multiple times during a diagnostic process, a monitoring process, and / or a therapeutic process to determine one or more clinically relevant parameters, including but not limited to disease progression and / or efficacy of treatment. For example, during a diagnostic procedure, a monitoring procedure, and / or a therapeutic procedure, a first liquid biopsy can be taken at a first time point and a second liquid biopsy can be taken at a second time point. In some embodiments, the first time point may be a time point before the individual is diagnosed with the disease (e.g., when the individual is healthy), and the second time point may be a time point after the individual has developed the disease (e.g., the second time point can be used to diagnose an individual with a disease). In some embodiments, the first time point may be a time point before the individual is diagnosed with a disease (eg, when the individual is healthy), after which the individual is monitored, and the second time point may be a time point after the individual is monitored. In some embodiments, the first time point may be the time point before the individual is diagnosed with the disease, after which the treatment is administered to the individual, and the second time point may be the time point after the administration of the treatment; in such cases, The second time point can be used to assess the efficacy of the treatment (eg, whether the gene mutation detected at the first time point is reduced in abundance or undetectable). In some embodiments, the treatment to be administered to an individual may comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be assessed by evaluating cfDNA obtained from an individual at different time points (eg, cfDNA obtained from an individual at a first time point and cfDNA obtained at a second time point). Two time points are determined from the dysregulated allele frequency of the CDC7 gene in cfDNA obtained from an individual, wherein at least one dose of a compound of formula (I) or its pharmaceutical agent is administered to the individual between the first time point and the second time point acceptable salt. Some embodiments of these methods can further comprise administering to the individual at least one dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, between the first time point and the second time point. For example, the dysregulated allele frequency (AF) of the CDC7 gene in cfDNA obtained from an individual at a second time point compared to the dysregulated allele frequency (AF) of the CDC7 gene in cfDNA obtained from the individual at a first time point ( AF) reduction (e.g., from 1% to about 99%, from 1% to about 95%, from 1% to about 90%, from 1% to about 85%, from 1% to about 80%, from 1% to About 75%, down 1% to about 70%, down 1% to about 65%, down 1% to about 60%, down 1% to about 55%, down 1% to about 50%, down 1% to about 45% less, 1% to about 40% less, 1% to about 35% less, 1% to about 30% less, 1% to about 25% less, 1% to about 25% less 20%, 1% to 15% reduction, 1% to 10% reduction, 1% to 5% reduction, 5% to 99% reduction, 10% to 99% reduction, 10% to 99% reduction, 15% to about 99%, about 20% to about 99% less, about 25% to about 99% less, about 30% to about 99% less, about 35% to about 99% less, about 40% to about 99% less %, about 45% to about 99% less, about 50% to about 99% less, about 55% to about 99% less, about 60% to about 99% less, about 65% to about 99% less, about 70% less % to about 99%, about 75% to about 95%, about 80% to about 99%, about 90% to about 99%, about 95% to about 99%, about 5% to about 10% %, about 5% to about 25% less, about 10% to about 30% less, about 20% to about 40% less, about 25% to about 50% less, about 35% to about 55% less, about 40% less % to about 60%, reduce about 50% to reduce about 75%, reduce about 60% to reduce about 80% or reduce about 65% to about 85%) indicating formula (I) compound or its pharmaceutically acceptable salt effective in individuals. In some embodiments, AF is reduced such that levels are below the detection limit of the instrument. Alternatively, the allele frequency (AF) of the dysregulation of the CDC7 gene in cfDNA obtained from the individual at the second time point compared to the allele frequency (AF) of the dysregulation of the CDC7 gene in the cfDNA obtained from the individual at the first time point An increase indicates that the compound of formula (I) or a pharmaceutically acceptable salt thereof is ineffective in the subject. Some embodiments of these methods can further comprise administering an additional dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual in whom the compound of formula (I) or a pharmaceutically acceptable salt thereof is determined to be effective. Some embodiments of these methods may further comprise administering a different treatment (e.g., not comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) to an individual in whom a compound of formula (I) or a pharmaceutically acceptable salt thereof is determined to be ineffective. administration of saline, as monotherapy).

[0178] In some embodiments, the CDC7-associated cancer is a microsatellite instability-high (MSI-H) cancer. In other embodiments, the CDC7-associated cancer is not a microsatellite instability-high (MSI-H) cancer. In some embodiments, MSIH status is determined by detecting repetitive DNA sequences selected from the group consisting of: mononucleotide repeat markers, dinucleotide repeat markers, monomorphic markers, or a combination of any of the foregoing .

[0179] In some embodiments, the cancer-associated tumor comprises a phenotype selected from the group consisting of chromosomal instability (CIN), spindle checkpoint assembly defect, mitotic defect, G1 / S checkpoint defect, and combinations thereof. In some embodiments, the cancer-associated tumor comprises a Wnt signaling pathway mutation. In some embodiments, the Wnt signaling pathway mutation is selected from the group consisting of adenomatous polyposis coli (APC) gene mutation, FAT1 mutation, FAT4 mutation, or a combination of any of the foregoing.

[0180] In some examples of these methods, the time difference between the first point in time and the second point in time can be from about 1 day to about 1 year, from about 1 day to about 11 months, from about 1 day to about 10 months, About 1 day to about 9 months, about 1 day to about 8 months, about 1 day to about 7 months, about 1 day to about 6 months, about 1 day to about 5 months, about 1 day to about 4 months, about 1 day to about 3 months, about 1 day to about 10 weeks, about 1 day to about 2 months, about 1 day to about 6 weeks, about 1 day to about 1 month, about 1 day to about 25 days, about 1 day to about 20 days, about 1 day to about 15 days, about 1 day to about 10 days, about 1 day to about 5 days, about 2 days to about 1 year, about 5 days to about 1 year, about 10 days to about 1 year, about 15 days to about 1 year, about 20 days to about 1 year, about 25 days to about 1 year, about 1 month to about 1 year, about 6 weeks to about 1 year , about 2 months to about 1 year, about 3 months to about 1 year, about 4 months to about 1 year, about 5 months to about 1 year, about 6 months to about 1 year, about 7 months to about 1 year, about 8 months to about 1 year, about 9 months to about 1 year, about 10 months to about 1 year, about 11 months to about 1 year, about 1 day to about 7 days, about 1 day to about 14 days, about 5 days to about 10 days, about 5 days to about 20 days, about 10 days to about 20 days, about 15 days to about 1 month, about 15 days to about 2 months, about 1 week to about 1 month, about 2 weeks to about 1 month, about 1 month to about 3 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to About 8 months, or about 7 months to about 9 months. In some embodiments of these methods, the individual can be previously identified as having a cancer with a dysregulated CDC7 gene, such as any of the examples of dysregulated CDC7 genes described herein. In some embodiments of these methods, the individual may have been pre-diagnosed with any of the types of cancer described herein. In some embodiments of these methods, the individual may have one or more metastases (eg, one or more brain metastases).

[0181] In some of the above embodiments, the cfDNA comprises ctDNA, such as CDC7-associated ctDNA. For example, the cfDNA is ctDNA, such as CDC7-associated ctDNA. In some embodiments, at least some portion of the cfDNA is determined to be CDC7-associated ctDNA, eg, sequenced and / or quantified amounts of total cfDNA are determined to have CDC7 fusions and / or overexpression of CDC7.

[0182] In the field of medical oncology, it is routine practice to use a combination of different treatment modalities to treat each individual with cancer. In medical oncology, other components of such combination therapy or therapy other than the compositions provided herein can be, for example, surgery, radiation therapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies. For example, surgery can be open surgery or minimally invasive surgery. Accordingly, the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be used as an adjuvant in cancer therapy, i.e. it may be used in combination with one or more additional therapies or therapeutic agents, e.g. by means of the same or different A chemotherapeutic agent with a functional mechanism of action. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be used prior to administration of the additional therapeutic agent or additional therapy. For example, one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to an individual in need thereof over a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (eg, tumor burden) prior to at least partial resection of the tumor. In some embodiments, one or more doses of a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered to an individual in need thereof over a period of time and under one or more rounds of radiation therapy. In some embodiments, treatment with one or more doses of a compound of formula (I), or a pharmaceutically acceptable salt thereof, reduces tumor size (eg, tumor burden) prior to one or more rounds of radiation therapy.

[0183] In some embodiments, the individual has cancer (e.g., locally advanced or metastatic tumors) that is refractory to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first CDC7 inhibitor or multiple kinase inhibitor, immunotherapy, or radiation ( Such as radioactive iodine)) treatment or intolerance to this standard therapy. In some embodiments, the individual has cancer (e.g., locally advanced or metastatic tumors) that has been refractory to previous therapy (e.g., administration of a chemotherapeutic agent, such as a first CDC7 inhibitor or multiple kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)) or intolerance to prior therapy. In some embodiments, the individual has cancer for which there is no standard therapy (eg, locally advanced or metastatic tumors). In some embodiments, the individual has not been treated with a CDC7 kinase inhibitor. For example, the individual has not been treated with a selective CDC7-kinase inhibitor. In some embodiments, the individual is not CDC7-kinase inhibitor naive.

[0184] In some embodiments, the individual has undergone prior therapy. In some embodiments, individuals with NSCLC (e.g., CDC7-associated NSCLS) have received platinum-based chemotherapy, PD-1 / PDL1 immunization prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof. therapy or both. In some embodiments, prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, individuals with thyroid cancer (such as CDC7-associated thyroid cancer) have received treatment with sorafenib, Leval Treatment with one or more of tinib and radioactive iodine. In some embodiments, prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, an individual with colorectal cancer (e.g., CDC7-associated colorectal cancer) has received fluoropyrimidine-based chemotherapy (Treatment with or without anti-VEGF-directed therapy or anti-EGFR-directed therapy). In some embodiments, prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, an individual with pancreatic cancer (e.g., CDC7-associated pancreatic cancer) has received fluoropyrimidine-based chemotherapy . Treatment by one or more of gemcitabine-based chemotherapy and S-1 chemotherapy. In some embodiments, prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, individuals with breast cancer (eg, CDC7-associated breast cancer) have received anthracyclines, taxanes, HER2 Treatment by one or more of targeted therapy and hormone therapy. In some embodiments, prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, individuals with MTC (eg, CDC7-associated MTC cancer) have received cabozantinib and vandetanib Treatment by one or more of them.

[0185] In some embodiments of any of the methods described herein, formula (I) is administered in combination with an effective amount of at least one additional therapeutic agent selected from one or more additional therapeutic or therapeutic (e.g., chemotherapy) agents A compound or a pharmaceutically acceptable salt thereof.

[0186] Non-limiting examples of additional therapeutic agents include: other CDC7-targeting therapeutics (i.e., first or second CDC7 kinase inhibitors), other kinase inhibitors (e.g., therapeutics targeting receptor tyrosine kinases (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators (eg obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies , immune targeting agents (including immunotherapy), and radiation therapy.

[0187] In some embodiments, the additional CDC7-targeting therapeutic agent is a multikinase inhibitor that exhibits CDC7 inhibitory activity. In some embodiments, another CDC7-targeted therapeutic inhibitor is selective for CDC7 kinase. Exemplary CDC7 kinase inhibitors can exhibit less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM against CDC7 Kinase inhibitory activity (IC50), as measured in the assay described herein. In some embodiments, the CDC7 kinase inhibitor can exhibit an inhibitory activity (IC50) against CDC7 kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as in the assays provided herein Measured.

[0188] Non-limiting examples of kinase-targeted therapeutics (eg, a first CDC7 inhibitor or a second CDC7 inhibitor) include TAK931, SRA141, and PHA-767491.

[0189] Non-limiting examples of multikinase inhibitors include alectinib (9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl ]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile); Amuvatinib (MP470, HPK56) (N-(1,3 -Benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piper -1-thiocarbamide; apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl-2-(4-pyridylmethyl)amino-3 - Nicotinamide mesylate); Cabozantinib (Cometriq XL-184) (N-(4-((6,7-dimethoxyquinolin-4-yl )oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dimethylamide); dovitinib (TKI258; GFKI-258; CHIR-258) ( (3Z)-4-Amino-5-fluoro-3-[5-(4-methylpiperene -1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one); Famitinib (5-[2-(diethylamino)ethyl ]-2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo [3,2-c]pyridin-4-one); fedratinib (SAR302503, TG101348) (N-(2-methyl-2-propionyl)-3-{[5-methyl -2-({4-[2-(1-Pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzenesulfonamide); foCDC7inib(XL880,EXEL-2880, GSK1363089, GSK089)(N1'-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolinyl]oxy]phenyl]-N1 -(4-fluorophenyl)cyclopropane-1,1-dimethylamide); Fumantinib (fostamantinib) (R788) (2H-pyrido[3,2-b]-1,4- -3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-di Methyl-4-[(phosphonoyloxy)methyl]-, sodium salt (1:2)); ilorasertib (ABT-348) (1-(4-(4-amino- 7-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl) urea); Lenvatinib (E7080, Lenvima) (4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6 -quinolineformamide); motesanib (AMG 706) (N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2- [(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide); nintedanib (3-Z-[1-(4-(N-((4-methyl- Piper -1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone); Ponatinib (ponatinib) (AP24534) (3-(2-imidazo[1,2-b]da -3-ylethynyl)-4-methyl-N-[4-[(4-methylpiper -1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide); PP242 (torkinib) (2-[4-amino-1-(1- Methyl ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol); quinzatinib (quizartinib) (1-(5-(tri grade butyl) iso Azol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)urea) ; Regorafenib (BAY 73-4506, Stivarga) (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] Carbamoyl}amino)-3-fluorophenoxy]-N-picoline-2-carboxamide hydrate); RXDX-105 (CEP-32496, agerafenib) (1- (3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropane-2 - base) iso oxazol-3-yl) urea); Semaxanib (SU5416) ((3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1, 3-dihydro-2H-indol-2-one); Sitravatinib (MGCD516, MG516) (N-(3-fluoro-4-{[2-(5-{[(2-methyl Oxyethyl)amino]methyl}-2-pyridyl)thieno[3,2-b]pyridin-7-yl]oxy}phenyl)-N'-(4-fluorophenyl)- 1,1-cyclopropanedimethylamide); sorafenib (Bey 43-9006) (4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl ]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide); vandetanib (N-(4-bromo-2-fluorophenyl)-6 -Methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine); Fantalanib (vatalanib) (PTK787, PTK / ZK, ZK222584) ( N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalein -1-amine); AD-57(N-[4-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl] Phenyl]-N'-[3-(trifluoromethyl)phenyl]-urea); AD-80(1-[4-(4-amino-1-prop-2-ylpyrazolo[3 ,4-d]pyrimidin-3-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea); AD-81(1-(4-(4-amino -1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea); ALW-II-41-27(N-(5-((4-((4-ethylpiper -1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide); BPR1K871( 1-(3-chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazole -2-yl)urea); CLM3(1-phenethyl-N-(1-phenethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); EBI-907(N -(2-chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinolin-7-yl)-4-fluorophenyl)-3 -Fluoropropane-1-sulfonamide); NVP-AST-487 (N-[4-[(4-ethyl-1-piper base)methyl]-3-(trifluoromethyl)phenyl]-N'-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]-urea); NVP -BBT594(BBT594)(5-((6-Acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiper -1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide); PD173955(6-(2,6-dichlorophenyl)-8-methyl -2-(3-Methanesulfonamide nitrogen (methylsulfonanilino))pyrido[2,3-d]pyrimidin-7-one); PP2(4-amino-5-(4-chloro Phenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine); PZ-1(N-(5-(tertiary butyl)iso Azol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H benzo[d]imidazol-1-yl)phenyl)acetamide) ;RPI-1(1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one;(3E)-3 -[(4-hydroxyphenyl)methylene]-5,6-dimethoxy-1H-indol-2-one); SGI-7079 (3-[2-[[3-fluoro-4- (4-Methyl-1-piper base)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenylacetonitrile); SPP86(1-isopropyl-3-(phenylacetylene base)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); SU4984(4-[4-[(E)-(2-oxo-1H-indol-3-ylidene )methyl]phenyl]piperene -1-formaldehyde); sunitinib (sunitinb) (SU11248) (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H- Indole-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide); TG101209(N-tertiary butyl-3-(5-methyl-2- (4-(4-Methylpiper -1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide); withaferin A ((4β,5β,6β,22R)-4,27-dihydroxy-5,6: 22,26-diethoxyergosta-2,24-diene-1,26-dione); XL-999((Z)-5-((1-ethylpiperidin-4-yl)amine Base)-3-((3-fluorophenyl)(5-methyl-1H-imidazol-2-yl)methylene)indolin-2-one); BPR1J373(5-phenylthiazole-2- amine-pyrimidine derivatives); CG-806 (CG'806); DCC-2157; GTX-186; HG-6-63-01 ((E)-3-(2-(4-chloro-1H-pyrrole And[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiper -1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide); SW-01(cyclobenzapine hydrochloride); XMD15-44(N-(4 -((4-Ethylpiper -1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide (generated from structure)); Y078- DM1 (an antibody drug conjugate consisting of an antibody to CDC7 (Y078) linked to a derivative of the cytotoxic agent maytansine); Y078-DM4 (an antibody to CDC7 (Y078) linked to a derivative of the cytotoxic agent maytansine Antibody Drug Conjugate); ITRI-305 (D0N5TB, DIB003599); BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazole-1 -yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine- 2-yl) cyclohexane-1-carboxamide); BLU6864; DS-5010; GSK3179106; GSK3352589; NMS-E668; TAS0286 / HM05; Ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2- Fluorophenyl) acetamide.

[0190] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeting therapeutics include afatinib, cabozantinib, cetuximab, crizotinib ), dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, Lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, Tocilizumab (trastuzumab), l-((3S,4R)-4-(3-fluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4 -Methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR - 618, AZ-23, AZ623, DS-6051, Gö6976, GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101, VM-902A, TPX-0005, TSR-011, GNF- 4256, N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]- 4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea, AZ623, AZ64, (S)-5-chloro-N2-(1-(5- Fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine, AZD7451, CEP-751, CT327, sunitinib Nil, GNF-8625, and (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridine -3-yl)-[2,4'-dipyridin]-2'-yl)hexahydropyridin-4-ol.

[0191] Non-limiting examples of BRAF inhibitors include dabrafenib, vemurafenib (also known as RG7204 or PLX4032), sorafenib tosylate, PLX-4720, GDC -0879, BMS-908662 (Bristol-Meyers Squibb), LGX818 (Novartis), PLX3603 (Hofmann-LaRoche), RAF265 (Novartis), RO5185426 (Hofmann-LaRoche), and GSK2118436 (GlaxoSmithKline). Additional examples of BRAF inhibitors are known in the art.

[0192] In some embodiments, the receptor tyrosine kinase inhibitor is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors may include osimertinib (meretinib, Tagrisso), erlotinib (Tarceva), gefitinib Gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (neratinib) (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib ) (Caprelsa).

[0193] In some embodiments, the signal transduction pathway inhibitor comprises a Ras-Raf-MEK-ERK pathway inhibitor (eg, binitinib, selumetinib, encorafinib, Sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (eg, everolimus, rapamycin ), perifosine, temsirolimus), and other kinase inhibitors such as baricitinib, brigatinib, capmatinib, Danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semazanib ( semaxanib), AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 ((R)-amino-N-[5,6-dihydro -2 -(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H pyrrolo[4,3,2-ef][2,3]benzodiazepine-8-yl] -cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108 and TG101209 (N-tertiary butyl-3-(5-methyl-2-(4-( 4-Methylpiperene -1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide).

[0194] Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS -936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.

[0195] In some embodiments, the cytotoxic chemotherapeutic agent is selected from arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin , cyclophosphamide, cytarabine, dacarba (dacarbazine), daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan , lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide (temozolomide) and vincristine (vincristine).

[0196] Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.

[0197] In some embodiments, the additional therapy or therapeutic agent may comprise a histididyl-tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding an HRS polypeptide.

[0198] The term "immunotherapy" refers to agents that modulate the immune system. In some embodiments, immunotherapy increases the expression and / or activity of regulatory factors of the immune system. In some embodiments, immunotherapy reduces the expression and / or activity of regulatory factors of the immune system. In some embodiments, immunotherapy recruits and / or enhances the activity of immune cells.

[0199] In some embodiments, the immunotherapy is cellular immunotherapy (eg, receptive T cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) "Drugs" 71(1):101-108). In some embodiments, the cellular immunotherapy comprises cells expressing a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah™).

[0200] In some embodiments, the immunotherapy is antibody therapy (eg, monoclonal antibody, conjugated antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), Rito rituximab (MabThera™), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™), atatumumab Ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda ®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza® ), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), evelumab (Bavencio® ), necitumumab (Portrazza™), cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984 ), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), Latuzumab (ficlatuzumab) (AV-299), denosumab (denosumab) (Xgeva®), ganitumab (ganitumab), urelumab (urelumab), pilizumab ( pidilizumab) or amatuximab.

[0201] In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), Berento Brentuximab vedotin (Adcetris®), trastuzumab-matansine conjugate (TDM-1; Kadcyla®), mirvetuximab soravtansine (IMGN853 ) or anetumab ravtansine

[0202] In some embodiments, the immunotherapy comprises blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).

[0203] In some embodiments, immunotherapy comprises toxins. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[0204] In some embodiments, the immunotherapy is cytokine therapy. In some embodiments, the interleukin therapy is interleukin 2 (IL-2) therapy, interferon alpha (IFN alpha), granulocyte colony stimulating factor (G-CSF) therapy, interleukin 12 (IL-12) therapy, interleukin 15 (IL-15) therapy, interleukin 7 (IL-7) therapy, or erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNα therapy is Intron A® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®).

[0205] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, immunotherapy comprises one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is palivizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), evelumab (Bavencio®), or durvalumab (Imfinzi™).

[0206] In some embodiments, the immunotherapy is mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, e.g., Rausch et al. (2014) Human Vaccin Immunother 10(11):3146-52; and Kubler et al. (2015) J. Immunother Cancer 3:26).

[0207] In some embodiments, the immunotherapy is Bacillus Calmette-Guerin (BCG) therapy.

[0208] In some embodiments, the immunotherapy is oncolytic virotherapy. In some embodiments, the oncolytic virotherapy is talimogene alherparepvec (T-VEC; Imlygic®).

[0209] In some embodiments, the immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9®, or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®, Recombivax HB®, or GI-13020 (Tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is BiovaxID®, Oncophage®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, Rindopepimut®, CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge ™), GRNVAC1, GRNVAC2, GRN-1201, Hepcortespenlisimut-L (Hepko-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac, or Viagen pumatucel-L (viagenpumatucel-L) (HS-110).

[0210] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax™), IMA901 or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic personal neoantigen vaccine (see, e.g., Ott et al. (2017) Nature 547:217-221; Sahin et al. (2017) Nature 547:222- 226). In some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a mammoglobulin-A DNA vaccine (see, eg, Kim et al. (2016) Onco Immunology 5(2):e1069940).

[0211] In some embodiments, the immune targeting agent is selected from the group consisting of aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, presone (prednisone) and Cypriency-T.

[0212] Non-limiting examples of radiation therapy include radioactive iodine therapy, external beam radiation, and radium-223 therapy.

[0213] Additional kinase inhibitors include those described, for example, in U.S. Patent No. 7,514,446; U.S. Patent No. 7,863,289; U.S. Patent No. 8,026,247; U.S. Patent No. 8,501,756; U.S. Patent No. 8,552,002; U.S. Patent No. 9,260,437; U.S. Patent No. 9,273,051; U.S. Publication No. US 2015 / 0018336; International Publication No. WO 2007 / 002325; International Publication No. WO 2007 / 002433; International Publication No. WO 2008 / 080001 International Publication No. WO 2008 / 079906; International Publication No. WO 2008 / 079903; International Publication No. WO 2008 / 079909; International Publication No. WO 2008 / 080015; International Publication No. WO 2009 / 007748 International Publication No. WO 2009 / 012283; International Publication No. WO 2009 / 143018; International Publication No. WO 2009 / 143024; International Publication No. WO 2009 / 014637; International Publication No. 2009 / 152083 ; International Publication No. WO 2010 / 111527; International Publication No. WO 2012 / 109075; International Publication No. WO 2014 / 194127; International Publication No. WO 2015 / 112806; International Publication No. WO 2007 / 110344 ; International Publication No. WO 2009 / 071480; International Publication No. WO 2009 / 118411; International Publication No. WO 2010 / 031816; International Publication No. WO 2010 / 145998; International Publication No. WO 2011 / 092120 ; International Publication No. WO 2012 / 101032; International Publication No. WO 2012 / 139930; International Publication No. WO 2012 / 143248; International Publication No. WO 2012 / 152763; International Publication No. WO 2013 / 014039 ; International Publication No. WO 2013 / 102059; International Publication No. WO 2013 / 050448; International Publication No. WO 2013 / 050446; International Publication No. WO 2014 / 019908; International Publication No. WO 2014 / 072220 ; International Publication No. WO 2014 / 184069; International Publication No. WO 2016 / 075224; International Publication No. WO 2016 / 081450; International Publication No. WO 2016 / 022569; International Publication No. WO 2016 / 011141 ; International Publication No. WO 2016 / 011144; International Publication No. WO 2016 / 011147; International Publication No. WO 2015 / 191667; International Publication No. WO 2012 / 101029; International Publication No. WO 2012 / 113774 ; International Publication No. WO 2015 / 191666; International Publication No. WO 2015 / 161277; International Publication No. WO 2015 / 161274; International Publication No. WO 2015 / 108992; International Publication No. WO 2015 / 061572 ; International Publication No. WO 2015 / 058129; International Publication No. WO 2015 / 057873; International Publication No. WO 2015 / 017528; International Publication No. WO / 2015 / 017533; International Publication No. WO 2014 / 160521 and Kinase Inhibitors in International Publication No. WO 2014 / 011900, each of which is hereby incorporated by reference in its entirety.

[0214] Although the genetic basis of tumorigenesis can vary across cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During the metastatic cascade, cancer cells lose their growth inhibitory response, undergo changes in cohesion and produce enzymes that degrade extracellular matrix components. This causes tumor cells to detach from the original tumor, infiltrate into the circulatory system via newly formed vessels, tumor cells migrate and extravasate to favorable distal sites where they can form colonies. Various genes have been identified as promoters or repressors of transfer. For example, overexpression of glial cell-derived neurotrophic factor (GDNF) and its CDC7 receptor tyrosine kinase has been associated with cancer proliferation and metastasis. See, eg, Zeng et al. J. Int. Med. Res. (2008) 36(4): 656-64.

[0215] Therefore, a method for inhibiting, preventing, assisting in preventing or reducing the symptoms of cancer metastasis in an individual in need thereof is also provided herein, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or Its pharmaceutical composition. Such methods can be used to treat one or more of the cancers described herein. See, eg, US Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and US Patent No. 8,568,998. See also eg Hezam K et al, Rev Neurosci 2018 Jan 26;29:93-98; L et al, Pancreas 2015 Jan;44:134- 143; Ding K et al., J Biol Chem 2014 Jun 6;289:16057-71; and Amit M et al, Oncogene 2017 Jun 8; 36:3232–3239. In some embodiments, the cancer is a CDC7-associated cancer. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in combination with an additional therapy or another therapeutic agent, including chemotherapeutic agents, such as kinase inhibitors. For example, the first or second CDC7 kinase inhibitor. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the additional therapeutic agent is osimertinib. In some embodiments, one or more doses of a compound of formula (I), or a pharmaceutically acceptable salt thereof, are administered to the subject prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, CDC7-associated lung cancer). In some embodiments, the additional therapeutic agent is a PARP inhibitor (eg, olaparib). In some embodiments, the additional therapeutic agent is an ATR inhibitor (eg, ceralasertib). In some embodiments, the additional therapeutic agent is a Weel inhibitor (eg, AZD-1775). In some embodiments, the additional therapeutic agent is an EGFR inhibitor (eg, lapatinib).

[0216] The term "metastasis" is a term known in the art and means the formation of an additional tumor (eg, a solid tumor) in an individual at a site remote from the primary tumor, wherein the additional tumor contains the same or similar cancer cells as the primary tumor.

[0217] Also provided is a method of reducing the risk of metastasis or additional metastasis in an individual having a CDC7-associated cancer, the method comprising: selecting, identifying, or diagnosing the individual as having a CDC7-associated cancer; The subject is administered an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method of reducing the risk of metastasis or additional metastasis in an individual having a CDC7-associated cancer comprising administering to an individual having a CDC7-associated cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in risk of developing metastases or additional metastases in an individual with a CDC7-associated cancer can be compared to the individual's risk of developing metastases or additional metastases prior to treatment, or to a similar or identical risk in individuals who have not received treatment or have received a different treatment Individuals or groups of individuals with CDC7-associated cancers are compared. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the additional therapeutic agent is osimertinib. In some embodiments, one or more doses of a compound of formula (I), or a pharmaceutically acceptable salt thereof, are administered to the subject prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, CDC7-associated lung cancer).

[0218] The phrase "risk of developing metastases" means the risk that an individual with a primary tumor will develop, during a set period of time, an additional tumor (e.g., a solid tumor) at a site distant from the individual's primary tumor, wherein the additional tumor Contains the same or similar cancer cells as the primary tumor. Described herein are methods of reducing the risk of developing metastasis in an individual with cancer.

[0219] The phrase "at risk of additional metastasis" means having a primary tumor and having one or more additional tumors at a site distant from the primary tumor (wherein the one or more additional tumors contain the same or Individuals with similar cancer cells) will be at risk of developing one or more other tumors distant from the primary tumor that contain the same or similar cancer cells as the primary tumor. Methods to reduce the risk of additional metastases are described herein.

[0220] Treatment with a multikinase inhibitor (MKI) or target-specific kinase inhibitor (eg, BRAF inhibitor, EGFR inhibitor, MEK inhibitor, ALK inhibitor, ROS1 inhibitor, MET inhibitor, aromatase inhibitor, RAF inhibitor, or RAS inhibitors) treatment of individuals with cancer can lead to dysregulation of CDC7 gene, CDC7 kinase or its expression or activity or level, and / or resistance to CDC7 inhibitors. See, eg, Bhinge et al., Oncotarget 8:27155-27165, 2017; Chang et al., Yonsei Med. J. 58:9-18, 2017; and Lopez-Delisle et al., doi: 10.1038 / s41388-017-0039-5, Oncogene 2018.

[0221] Compared to treating an individual with cancer with a CDC7 inhibitor as monotherapy or a multikinase inhibitor or a target-specific kinase inhibitor as monotherapy, combining a CDC7 inhibitor with a multikinase inhibitor or a target-specific kinase inhibitor (e.g., Combination treatment of BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors or RAS inhibitors) in the same individual or similar individuals may have enhanced treatment effect. See eg Tang et al., doi: 10.1038 / modpathol.2017.109, Mod. Pathol. 2017; Andreucci et al., Oncotarget 7:80543-80553, 2017; Nelson-Taylor et al., Mol. Cancer Ther. 16:1623-1633, 2017; and Kato et al., Clin. Cancer Res. 23:1988-1997, 2017.

[0222] Provided herein are methods for treating a patient with a cancer, such as any of the cancers described herein, who have previously been administered a multikinase inhibitor (MKI) or a target-specific kinase inhibitor (such as a BRAF inhibitor, EGFR inhibitor, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, or RAS inhibitors) (e.g., as monotherapy), comprising: administering to the individual (i) an effective A dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof in monotherapy, or (ii) an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an effective dose of a previously prescribed Administered MKI or previously administered target specific kinase inhibitor.

[0223] Provided herein are methods for the treatment of previously administered MKI or target-specific kinase inhibitors (e.g., BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors) or RAS inhibitor) (e.g., as monotherapy), a method for an individual with cancer (e.g., any of the cancers described herein), comprising: identifying an individual with a CDC7 gene, CDC7 kinase, or expression or activity or level thereof and administering to the identified individual (i) an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof in monotherapy, or (ii) an effective dose of a compound of formula (I) A compound or a pharmaceutically acceptable salt thereof, and an effective dose of a previously administered MKI or a previously administered target-specific kinase inhibitor.

[0224] Provided herein are methods for treating an individual with cancer, such as any of the cancers described herein, comprising: administering to the individual an effective amount of a MKI or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, or RAS inhibitors) (e.g., as monotherapy); after this period, individuals identified as having Cancer cells with dysregulated CDC7 gene, CDC7 kinase or expression or activity or content thereof; and administering (i) an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the form of monotherapy to the identified individual , or (ii) an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an effective dose of a previously administered MKI or a previously administered target specific kinase inhibitor.

[0225] Also provided is a method of inhibiting CDC7 kinase activity in a mammalian cell comprising contacting the mammalian cell with a compound of formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering to an individual having mammalian cells having CDC7 kinase activity an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cells are CDC7-related mammalian cancer cells.

[0226] Also provided is a method of inhibiting CDC7 kinase activity in a mammalian cell comprising contacting the mammalian cell with a compound of formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo contacting, wherein the method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal having mammalian cells having CDC7 kinase activity . In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cells are CDC7-related mammalian cancer cells. In some embodiments, the mammalian cells are gastrointestinal mammalian cells.

[0227] As used herein, the term "contacting" refers to bringing together the indicated moiety in an in vitro system or in an in vivo system. For example, "contacting" a "CDC7 kinase" with a compound provided herein includes administering a compound provided herein to an individual having CDC7 kinase, such as a human, and, for example, introducing a compound provided herein into a mammalian cell containing samples or purified preparations containing CDC7 kinase.

[0228] Also provided herein is a method for inhibiting the proliferation of mammalian cells in vitro or in vivo, the method comprising subjecting mammalian cells to an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or Pharmaceutical composition contacts.

[0229] A "CDC7 kinase inhibitor" as defined herein includes any compound exhibiting CDC7 inhibitory activity. In some embodiments, the CDC7 kinase inhibitor is selective for CDC7 kinase. Exemplary CDC7 kinase inhibitors can exhibit less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM against CDC7 Kinase inhibitory activity (IC50), as measured in the assay described herein. In some embodiments, the CDC7 kinase inhibitor can exhibit an inhibitory activity (IC50) against CDC7 kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as in the assays provided herein Measured.

[0230] As used herein, a "first CDC7 kinase inhibitor" or "first CDC7 inhibitor" is a CDC7 kinase inhibitor as defined herein, but it does not include a compound of formula (I) as defined herein or its pharmaceutical acceptable salt. As used herein, a "second CDC7 kinase inhibitor" or "second CDC7 inhibitor" is a CDC7 kinase inhibitor as defined herein, but it does not include a compound of formula (I) as defined herein or its pharmaceutical acceptable salt. When both the first and second CDC7 inhibitors are present in the methods provided herein, the first and second CDC7 kinase inhibitors are not the same.

[0231] Exemplary first and second CDC7 kinase inhibitors are described herein. In some embodiments, the first or second CDC7 kinase inhibitor can be selected from the group consisting of TAK931, SRA141 and PHA-767491.

[0232] The phrase "effective amount" means sufficient to (i) treat a CDC7-associated disease or disorder (such as a CDC7-associated cancer), (ii) attenuate, ameliorate, or eliminate one of the particular disease, condition, or disorder when administered to a subject in need of such treatment. or more of the symptoms, or (iii) delaying the onset of one or more of the symptoms of a particular disease, condition or disorder described herein. The amount corresponding to this amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof will vary depending on factors such as the particular compound, the disease condition and its severity, the identity (e.g. body weight) of the individual in need of treatment, However, it can still be routinely determined by those skilled in the art.

[0233] When used as a medicine, compounds of formula (I) (including pharmaceutically acceptable salts thereof) may be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the art of medicine and can be administered by various routes, depending upon the need for local or systemic treatment and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; tracheal intranasally), orally or parenterally. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial (eg, intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose, or can be by, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0234] Also provided herein are pharmaceutical compositions, which contain a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof present in the composition is of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F ), (I-G), (I-H), (I-I), (I-J), (I-K), (I-L), (I-M), (I-N), (I-O) or (I-P) compounds, or pharmaceuticals of any of the foregoing Scientifically acceptable salt.

[0235] For example, a pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions are suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by the excipient or enclosed within such a carrier which takes the form of, for example, a capsule, sachet, paper or other container. When the excipient acts as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be in the form of lozenges, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in solid form or in a liquid medium) medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile encapsulated powders containing, for example, up to 10% by weight of the active compound. In some embodiments, compositions are formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In one embodiment, the composition is formulated as a tablet or capsule.

[0236] Further provided herein is a pharmaceutical composition, which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutical compound according to known pharmaceutical compounding techniques. The carrier is prepared by uniform mixing. The carrier can take a variety of forms depending on the desired route of administration (eg, oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0237] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in "The Handbook of Pharmaceutical Excipients" published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Excipients)".

[0238] Methods of formulating pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, edited by Lieberman et al. , Vols 1-3; Pharmaceutical Dosage Forms: Parenteral Medications, eds., Avis et al., vols 1-2; and Pharmaceutical Dosage Forms: Dispersed Systems, eds., Lieberman et al. Pharmaceutical Dosage Forms: Disperse Systems) Volumes 1-2; Published by Marcel Dekker, Inc.

[0239] In preparing the composition in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, and the like ; For solid oral preparations (such as powders, capsules and lozenges), suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants and the like. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, stearin sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, sanxian gum, and the like. Solid oral preparations may also be coated with substances such as sugars or may be provided with an enteric coating in order to regulate the major site of absorption. For parenteral administration, the carrier usually consists of sterile water, and other ingredients may be added to enhance solubility or for preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous vehicles along with suitable additives. Each dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful, and the like) of the pharmaceutical compositions herein will contain the amount of active ingredient necessary to deliver an effective dosage as described herein. of.

[0240] Compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated in unit dosage form, each dosage containing from about 1 to about 1,000 mg (1 g) of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human and other individuals, each unit containing a predetermined quantity of active substance (i.e., a compound of formula (I) or its pharmaceutically acceptable salt) and suitable pharmaceutical excipients.

[0241] The active compounds are effective over a wide dosage range, and are generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will thus be understood that the actual amount of compound administered will generally be determined by a physician and will vary according to the relevant circumstances, including the mode of administration, the actual compound being administered, the strength of the preparation, the condition to be treated, and the progression of the disease condition. In addition, factors associated with the particular individual being treated, including individual response, age, body weight, diet, time of administration, and severity of individual symptoms, will result in the need for dosage adjustments.

[0242] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given condition.

[0243] Those skilled in the art will further appreciate that human clinical trials, including first-in-human dose-ranging and efficacy trials in healthy individuals and / or individuals with established conditions, can be performed according to methods well known in the clinical and medical arts .

[0244] Provided herein are pharmaceutical kits useful, for example, in the treatment of CDC7-associated diseases or conditions, such as cancer, comprising one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. If desired, such kits may further comprise one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., such as This is readily apparent to those skilled in the art. Instructions, either in the form of an insert or in the form of a label, may also be included in the kit, stating the amounts of the components to be administered, directions for administration, and / or directions for mixing the components. example Materials and methods

[0245] The compounds provided herein, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0246] The reactions used to prepare the compounds provided herein can be performed in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially nonreactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out (eg, may be at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by one skilled in the art.

[0247] The preparation of the compounds provided herein may involve the protection and removal of various chemical groups. Those skilled in the art can readily determine the need for protection and removal of protecting groups and the selection of appropriate protecting groups. Chemical substances of protecting groups can be found, for example, in "Protecting Group Chemistry" 1st edition, Oxford University Press, 2000; "March's Advanced Organic Chemistry: Reaction, Mechanism and Structure (March's Advanced Organic Chemistry) : Reactions, Mechanisms, and Structure), 5th ed., Wiley-Interscience Publishing, 2001; and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry", Chemical Education Journal (J.Chem.Educ.) "74(11), 1297(1997) found.

[0248] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be by spectroscopic means (such as nuclear magnetic resonance spectroscopy (for example, 1H or 13C), infrared spectroscopy, spectrophotometry (for example, UV-visible light), mass spectrometry or by chromatographic methods such as High-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin-layer chromatography (TLC)) to monitor. Compounds can be purified by a variety of methods by those skilled in the art, including high-efficiency Liquid Chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization”) K.F. Blom et al., J Combinatorial Chemistry ( J . Combi. Chem.)》6(6), 874 (2004), normal phase silica chromatography and supercritical fluid chromatography (SFC).

[0249] Unless otherwise specified, the stereochemistry of compounds 1-58 in the following examples should be understood as being arbitrarily assigned.

[0250] All solvents and reagents were obtained from commercial sources and used without further purification unless otherwise indicated. Purchase anhydrous solvents and use as supplied. The reaction was monitored by thin layer chromatography (TLC), observation with UV light (254 nm) and KMnO4 staining. NMR spectra were acquired on a Bruker Neo 400M spectrometer operating at 400 MHz. Chemical shifts are reported in parts per million (δ) from resonances of tetramethylsilane in the indicated solvents. LC-mass spectra were acquired with an Agilent 1260-6125B single quadrupole mass spectrometer using a Welch Biomate column (C18, 2.7 μm, 4.6*50 mm) or a waters H-Class SQD2 system. Detection was performed by DAD (254 nm and 210 nm and 280 nm). Daicel chiralpak AD-H (5 μm, 4.6*250 mm), Daicel chiralpak OD-H (5 μm, 4.6*250 mm), Daicel chiralpak IG-3 (3 μm, 4.6*150 mm), Chiral Technologies Europe AD-3 (3 μm, 3.0*150 mm) and Trefoil TM Technology Trefoil TM AMY1 (2.5 μm, 3.0*150 mm) for chiral HPLC. Detection was performed by DAD (254 nm). Preparative HPLC was performed on a GILSON Trilution LC system using a Welch XB-C18 column (5 μm, 21.2*150 mm). Flash chromatography was performed on a Biotage Isolera Prime system using a Welch WelFlash column (40-63 μm). Unless otherwise stated, the synthesized compounds had > 95% purity. abbreviation * = Indicates that the amount of solvent or reagent before the "*" was used in the technique equal to the number of times after the "*". ℃ = degrees Celsius 1H NMR = Proton Nuclear Magnetic Resonance Spectroscopy AcOH = acetic acid Boc2O = tertiary butoxycarbonyl anhydride con.= concentrate d = doublet DCM = dichloromethane DIAD = diisopropyl azodicarboxylate DIPEA = N,N-Diisopropylethylamine DMF = N,N-dimethylformamide EA = ethyl acetate ESI = electrospray ionization g = grams h = hours HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluoro Azabenzotriazole tetramethyl phosphate HPLC = high performance liquid chromatography LCMS = Liquid Chromatography-Mass Spectrometry M = mass m / z = mass-to-charge ratio MeCN = acetonitrile MeOH = Methanol MeONa = sodium methoxide mg = milligram mL = milliliter mmol = millimoles mol = Mole MS = mass spectrum NBS = N-Bromosuccinimide obsd.= Observation PCy 3=tricyclohexylphosphine Pd(AcO) 2 = palladium(II) acetate Pd(dppf)Cl 2 = (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride PE = petroleum ether ppm = parts per million PTSA = p-toluenesulfonic acid rt = room temperature SFC = Supercritical Fluid Chromatography s = single peak t = triplet TBAF = tetrabutylammonium fluoride TFA=trifluoroacetic acid THF=tetrahydrofuran TLC = Thin Layer Chromatography Trixiephos = rac-2-(two-tertiary butylphosphino)-1,1'-binaphthyl Example 1 - Compound 1: 2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one Compound 1 Step A : 6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: Methyl 3-bromothiophene-2-carboxylate (1.00 g, 4.52 mmol, 1.0 equiv), (5-diphenylphosphoryl-9,9-dimethyl-dibenzopyran-4 -yl)-diphenyl-phosphine (787 mg, 1.36 mmol, 0.3 equivalent), cesium carbonate (3.68 g, 11.30 mmol, 2.5 equivalent), sodium metabisulfite (172 mg, 0.90 mmol, 0.2 equivalent) and reference To a solution of (dibenzylideneacetone)dipalladium (824 mg, 0.90 mmol, 0.20 equiv) in toluene (40.0 mL) was added cyclohexanone (888 mg, 9.04 mmol, 2.0 equiv). The reaction mixture was stirred at 105 °C under N for 16 h. The solvent was concentrated to dryness and the residue was purified by flash chromatography (SiO 2 , 0-10% EtOAc / PE) to give 6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (600 mg, 64%). MS observation (ESI+): 207.0 [(M+H)+]. Step B : 2-iodo-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: 6,7,8,9-tetrahydro-4H-thieno[2,3-c] at -78°C To a solution of en-4-one (400 mg, 1.94 mmol, 1.0 equiv) in THF (15.0 mL) was added lithium (diisopropylamido) (2 M in THF, 1.1 mL, 2.2 mmol, 1.1 equiv). The mixture was stirred at -78 °C for 30 min, then I2 (492 mg, 1.94 mmol, 1.0 equiv) was added. The mixture was stirred at -78°C for 1 h, then quenched with aqueous Na 2 SO 3 (10 mL) at 0°C. The mixture was extracted with DCM (10 mL×3), and the combined organic phases were washed with water (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , 0-10% EtOAc / PE) to give 2-iodo-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (300 mg, 46%). MS observation (ESI+): 333.1 [(M+H)+]. Step C: 2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: At room temperature to 2-iodo-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (300 mg, 903 µmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)- 1H-pyrazole (175 mg, 900 µmol, 1.0 equiv), sodium carbonate (287.18 mg, 2.71 mmol, 3.0 equiv) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)benzene phosphine (129 mg, 270.96 µmol, 0.3 eq) in water (2.0 mL) and 1,4-bis To a solution in alkanes (10.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (132 mg, 181 µmol, 0.20 equiv). The mixture was stirred at 110 °C in a microwave reactor for 2 hours, then concentrated, and the residue was purified by flash column chromatography (SiO2, 0-50% EtOAc / PE) to give 2-(1H-pyrazole -4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (230 mg, 93%). MS observation (ESI +): 273.2 [(M+H) +]. Step D: 2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (Compound 1): Compound 1 To 2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] Aqueous ammonia (6.0 mL, 28% w / w) was added to a solution of en-4-one (230 mg, 844.59 µmol, 1.0 equiv) in methanol (2.0 mL). The mixture was stirred at 120° C. in a sealed tube for 16 hours. After cooling to room temperature, the mixture was concentrated to dryness. The residue was dissolved in DMF and purified by preparative HPLC to give 2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline -4(5H)-one (14 mg, 6.0%). MS observation (ESI +): 272.1 [(M+H) +]; 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.19 (s, 1H), 11.15 (s, 1H), 8.28 (brs, 1H) , 7.96 (brs, 1H), 7.42 (s, 1H), 2.67 - 2.62 (m, 2H), 2.53 - 2.50 (m, 2H), 1.75 (s, 4H). Example 2 - Compound 2: 1,8,8-Trifluoro-2-(1H-pyrazol-4-yl)-5,6,7,9-tetrahydrothieno[2,3-c]quinoline- 4-keto Compound 2 Step A : Methyl 3,5-dibromo-4-fluoro-thiophene-2-carboxylate: To a solution of methyl 4-fluorothiophene-2-carboxylate (1.00 g, 6.24 mmol, 1.0 equiv) in carbon tetrachloride (5.0 mL) was added FeBr3 (1.29 g, 4.37 mmol, 1.0 equiv) at 25 °C ) and bromine (39.9 g, 250 mmol, 20.0 mL, 40.0 equiv), and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated and purified by flash column chromatography (SiO 2 , 0-15% EtOAc / PE) to give methyl 3,5-dibromo-4-fluoro-thiophene-2-carboxylate (480 mg, 24.0% ). 1H NMR (400 MHz, CDCl 3 ) δppm: 3.91 (s, 3H). Step B: Methyl 3-bromo-4-fluoro-5-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]thiophene-2-carboxylate: Palladium(II) acetate (8 mg, 0.04 mmol, 0.05 equiv) and (5-diphenylphosphoryl-9,9-dimethyl-dibenzopyran-4-yl)-diphenyl- A solution of phosphine (22 mg, 0.04 mmol, 0.05 equiv) in THF (10.0 mL) was stirred at 25 °C under N2 for 5 min. To the mixture was added methyl 3,5-dibromo-4-fluoro-thiophene-2-carboxylate (240 mg, 0.75 mmol, 1.0 equiv), trimethyl-[2-[[4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (367 mg, 1.13 mmol, 1.5 equivalents) and tripotassium orthophosphate (481 mg, 2.26 mmol, 3.0 equiv), and the mixture was stirred at 60° C. under N 2 for 16 hours. The mixture was then concentrated in vacuo and purified by flash column chromatography (SiO2, 0-30% EtOAc / PE) to give 3-bromo-4-fluoro-5-[1-(2-trimethylsilyl ethoxymethyl)pyrazol-4-yl]thiophene-2-carboxylic acid methyl ester (168 mg, 51%). MS Observation (ESI+): 79Br / 81Br 435.3 / 437.3 [(M+H) +]. Step C: 1,8,8-Trifluoro-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-7,9-dihydro-6H-thieno [2,3-c] en-4-one To 3-bromo-4-fluoro-5-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]thiophene-2-carboxylic acid methyl ester (464 mg, 1.07 mmol, 1.0 equivalent) in toluene (100.0 mL) was added ginseng (dibenzylideneacetone) dipalladium (98 mg, 0.11 mmol, 0.10 equivalent), 4,5-bis(diphenylphosphino)-9,9 -Dimethyldibenzopyran (93 mg, 0.16 mmol, 0.15 equivalent), cesium carbonate (1.0 g, 3.20 mmol, 3.0 equivalent), sodium metabisulfite (20 mg, 0.11 mmol, 0.1 equivalent) and 4 , 4-Difluorocyclohexanone (429 mg, 3.20 mmol, 3.0 equiv). The mixture was purged with N2, then heated to 105 °C and stirred for 16 hours. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (SiO2, 0-30% EtOAc / PE) to give the product 1,8,8-trifluoro-2-[1-(2-trimethyl Silylethoxymethyl)pyrazol-4-yl]-7,9-dihydro-6H-thieno[2,3-c] En-4-one (217 mg, 44%). MS observation (ESI+): 457.3 [(M+H)+]. Step D : 1,8,8-Trifluoro-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-5,6,7,9-tetrahydrothiophene And[2,3-c]quinolin-4-one: 1,8,8-trifluoro-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-7,9-dihydro-6H- Thieno[2,3-c] To a solution of en-4-one (110 mg, 0.24 mmol, 1.0 equiv) in MeOH (5.0 mL) was added ammonium hydroxide (4.5 g, 128 mmol, 5.0 mL, 320 equiv), and the mixture was heated at 95 °C Stir under microwave irradiation for 8 hours. The solution was cooled and concentrated to give 1,8,8-trifluoro-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-5,6,7,9 - Tetrahydrothieno[2,3-c]quinolin-4-one (109 mg, crude material), which was used in the next step without further purification. MS observation (ESI +): 456.3 [(M+H) +]. Step E: 1,8,8-Trifluoro-2-(1H-pyrazol-4-yl)-5,6,7,9-tetrahydrothieno[2,3-c]quinolin-4-one (Compound 2): Compound 2 To 1,8,8-trifluoro-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-5,6,7,9-tetrahydrothieno[ To a solution of 2,3-c]quinolin-4-one (109 mg, 0.24 mmol, 1.0 equiv) in DCM (1.0 mL) was added 2,2,2-trifluoroacetic acid (5.9 g, 52 mmol, 4.0 mL, 220 equivalents), and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated to dryness, and the residue was purified by flash column chromatography (SiO 2 , 0-8% MeOH / DCM) to give impure product. The residue was further purified by reverse phase column chromatography (C18 SiO 2 , 0-40% MeCN, 0.1% FA in water) to give 1,8,8-trifluoro-2-(1H-pyrazole-4- base)-5,6,7,9-tetrahydrothieno[2,3-c]quinolin-4-one (22 mg, 28%). MS observation (ESI+): 326.2 [(M+H)+]. Examples 3 and 4 - Compounds 3 and 4: (S)-6-hydroxyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c] Quinolin-4(5H)-one (compound 3) and (R)-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2, 3-c] quinolin-4(5H)-one (compound 4 (the stereochemistry of compounds 3 and 4 is arbitrarily designated) Step A : 2-Benzyloxycyclohexanol: BnOH (910 mg, 20 mmol, 2.0 eq) was added dropwise to a stirred suspension of NaH (820 mg, 21.4 mmol, 60% in mineral oil, 2.0 eq) in anhydrous DMF (25 mL) at 0 °C in the liquid. The mixture was stirred at 0 °C for 1 h, then 7-oxabicyclo[4.1.0]heptane (1.0 g, 10 mmol, 1.0 equiv) was added. The mixture was heated to 60 °C for 2 hours, then cooled. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , 0-50% EtOAc / PE) to give 2-benzyloxycyclohexanol (1.0 g, 48%). MS observation (ESI+): 207.3 [(M+H)+]. Step B : 2-Benzyloxycyclohexanone: Acetyl chloride (738 mg, 5.82 mmol, 1.2 equiv) was dissolved in anhydrous DCM (5.0 mL) under nitrogen atmosphere and cooled to -78 °C. A solution of DMSO (909 mg, 11.6 mmol, 2.0 equiv) in anhydrous DCM (5.0 mL) was added dropwise, and the resulting mixture was stirred for 20 min. 2-Benzyloxycyclohexanol (1.0 g, 4.85 mmol, 1.0 equiv) in dry DCM (5.0 mL) was added dropwise to form a white precipitate. The mixture was stirred for 30 minutes, warmed to -60 °C, and anhydrous triethylamine (2.5 g, 24 mmol, 3.4 mL, 1.0 equiv) was added dropwise. The mixture was kept at -60°C for 5 minutes, then warmed to room temperature for 2 hours. The reaction was quenched with H2O and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , 0-50% EtOAc / PE) to give 2-benzyloxycyclohexanone (770 mg, 78%). MS observation (ESI+): 205.2 [(M+H)+]. Step C: 6-(Benzyloxy)-6,7,8,9-tetrahydrothieno[2,3-c] En-4-ones: To a solution of methyl 3-bromothiophene-2-carboxylate (1.0 g, 4.5 mmol, 1.0 equiv) in toluene (15 mL) was added 2-benzyloxycyclohexanone (1.4 g, 6.8 mmol, 1.5 equiv) , ginseng (dibenzylideneacetone) dipalladium (414 mg, 0.45 mmol, 0.1 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (785 mg , 1.36 mmol, 0.30 equivalent), cesium carbonate (3.0 g, 9.1 mmol, 2.0 equivalent) and sodium metabisulfite (170 mg, 0.90 mmol, 0.20 equivalent). The reaction was purged with nitrogen and stirred at 105°C for 3 hours. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (SiO2, 0-50% EtOAc / PE) to give 6-(benzyloxy)-6,7,8,9-tetrahydrothieno [2,3-c] En-4-one (450 mg, 32%). MS observation (ESI+): 313.3 [(M+H)+]. Step D: 6-(Benzyloxy)-2-iodo-6,7,8,9-tetrahydrothieno[2,3-c] en-4-one 6-benzyloxy-6,7,8,9-tetrahydrothieno[2,3-c] at -65°C To a solution of en-4-one (350 mg, 1.12 mmol, 1.0 equiv) and I2 (569 mg, 2.24 mmol, 2.0 equiv) in THF (5.0 mL) was added LDA (2 M in THF, 2.2 mL, 4.0 equiv). The mixture was stirred at -65°C for 1 h, then quenched with H 2 O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by flash column chromatography (Si0, 0-50% EtOAc / PE) to afford 6-( Benzyloxy)-2-iodo-6,7,8,9-tetrahydrothieno[2,3-c] En-4-one (300 mg, 61%). MS observation (ESI+): 439.3 [(M+H)+]. Step E: 6-(Benzyloxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8 ,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: Trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazol-1-yl] Methoxy]ethyl]silane (444 mg, 1.37 mmol, 1.2 equivalents), 6-(benzyloxy)-2-iodo-6,7,8,9-tetrahydrothieno[2,3-c] En-4-one (500 mg, 1.10 mmol, 1.0 equiv), Pd(dppf)Cl 2 (80 mg, 0.11 mmol, 0.1 equiv), X-phos (104 mg, 0.22 mmol, 0.2 equiv) and Cs 2CO 3 (1.08 g, 3.30 mmol, 3.0 equiv) in 1,4-di A suspension in a mixture of alkanes (15.0 mL) and H2O (5.0 mL) was irradiated in a microwave reactor at 110 °C for 2 h. The mixture was cooled and extracted with EtOAc. The organic layer was concentrated to dryness, and the residue was purified by flash column chromatography (Si0, 0-70% EtOAc / PE) to give 6-(benzyloxy)-2-(1-((2-( Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (450 mg, 80%). MS observation (ESI+): 509.7 [(M+H)+]. Step F: 6-(Benzyloxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8 ,9-Tetrahydrothieno[2,3-c]quinolin-4(5H)-one: 6-(Benzyloxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9 -Tetrahydro-4H-thieno[2,3-c] A suspension of en-4-one (500 mg, 1.32 mmol, 1.0 equiv) in a mixture of MeOH (7.0 mL) and 25% ammonia (7.0 mL) was irradiated in a microwave reactor at 100 °C for 3 hours. The resulting solid was filtered, washed with MeOH and dried to give 6-(benzyloxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4 -yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (250 mg, 50%). MS observation (ESI +): 508.7 [(M+H) +] Step G: (S)-6-Hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4(5H) - Ketone (Compound 3) and (R)-6-Hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline- 4(5H)-Kone (Compound 4): 6-Benzyloxy-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-6,7,8,9-tetrahydro-5H-thieno[ A solution of 2,3-c]quinolin-4-one (250 mg, 0.49 mmol, 1.0 equiv) in trifluoroacetic acid (10.0 mL) was heated at 70°C for 1 hour. The solvent was removed, and NH 3 (7 M in MeOH, 5.0 mL) was added to the residue. The mixture was stirred at room temperature for 5 minutes, concentrated and the residue was purified via preparative HPLC to give 6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[ 2,3-c]quinolin-4(5H)-one (60 mg, 40%). MS observation (ESI+): 288.4 [(M+H)+]. The racemic products were separated by chiral SFC to obtain the individual enantiomers. (S)-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one ( Compound 3): MS observation (ESI +): 288.2 [(M+H) +]. (R)-6-Hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one ( Compound 4): MS observation (ESI +): 288.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 13.20 (s, 1H), 10.82 (s, 1H), 8.30 (s , 1H), 7.96 (s, 1H), 7.47 (s, 1H), 5.22 (d, J= 5.6 Hz, 1H), 4.49 - 4.46 (m, 1H), 2.70 - 2.65 (m, 1H), 2.51 - 2.49 (m, 1H), 1.89 - 1.82 (m, 2H), 1.78 - 1.69 (m, 2H). Examples 5 and 6 - Compounds 5 and 6: (R)-6-(3,3-difluoropyrrolidin-1-yl)-2-(1H-pyrazol-4-yl)-6,7,8, 9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 5) and (S)-6-(3,3-difluoropyrrolidin-1-yl)-2- (1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (Compound 6). (The stereochemistry of compounds 5 and 6 is arbitrarily assigned) Step A : 6-Bromo-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: 6-Hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-5H-thieno[2,3-c]quinolin-4-one (120 mg, A suspension of 0.41 mmol, 1.0 equiv) in TMSBr (8.0 mL) was stirred in a sealed tube at 80 °C for 6 hours. The solvent was removed in vacuo, and the residue was used directly in the next step without further purification. MS observation (ESI +): 302.4 [(M-Br+OCH 3)+H) +]. Step B: (R)-6-(3,3-Difluoropyrrolidin-1-yl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[ 2,3-c] quinolin-4(5H)-one (compound 5) and (S)-6-(3,3-difluoropyrrolidin-1-yl)-2-(1H-pyrazole-4 -yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 6): 3,3-Difluoropyrrolidine hydrochloride (1.9 g, 14 mmol, 20 equiv) and N,N-diisopropylethylamine (1.8 g, 13.88 mmol, 20.0 equiv) were dissolved in MeCN (10.0 mL) The suspension was stirred at room temperature for 2 hours. The solid was filtered off, and the filtrate was added to a solution containing 6-bromo-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-5H-thieno[2,3-c]quinone Sealed vial of lin-4-one (200 mg, 0.69 mmol, 1.0 equiv). NaI (103 mg, 0.69 mmol, 1.0 equiv) was added to the vial. The mixture was stirred at room temperature for 16 hours, then concentrated in vacuo, and the residue was purified via flash column chromatography (SiO, 0-100% EtOAc / PE) to afford racemic 6-(3,3-di Fluoropyrrolidin-1-yl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (60 mg, 19%). MS observation (ESI+): 377.5 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (R)-6-(3,3-difluoropyrrolidin-1-yl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3 -c] Quinolin-4(5H)-one (compound 5): MS observation (ESI +): 377.3 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 13.20 (s, 1H), 10.53 (s, 1H), 8.30 (s, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 3.73 (t, J= 5.6 Hz, 1H), 3.06 - 2.93 (m, 2H ), 2.87 - 2.78 (m, 2H), 2.68 - 2.62 (m, 2H), 2.30 - 2.22 (m, 2H), 1.98 - 1.95 (m, 1H), 1.84 - 1.77 (m, 2H), 1.74 - 1.71 (m, 1H). (S)-6-(3,3-difluoropyrrolidin-1-yl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3 -c] Quinolin-4(5H)-one (compound 6): MS observation (ESI +): 377.3 [(M+H) +]. Example 7 and 8 - Compounds 7 and 8: 6-methoxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-, 9-ethionothieno[2, 3-c] Quinolin-4(5H)-one (compound 7) and 6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-6,9- Ethothieno[2,3-c]quinolin-4(5H)-one (Compound 8). Step A : 6-methoxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9 - Tetrahydro-4H-6,9-Ethothieno[2,3-c] En-4-ones: Cesium carbonate (230 mg, 720 µmol, 3.0 equiv) and Sphos-Pd-G 3 (37 mg, 48 µmol, 0.2 equiv) were added to 3-bromo-5-(1-((2-(trimethylsilyl yl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid methyl ester (100 mg, 240 µmol, 1.0 equiv) and 1-methoxybicyclo[2.2.2]octyl- 2-Kone (74 mg, 480 µmol, 2.0 equiv, synthesized according to the procedure described in WO2007070201) in solution in toluene (6.0 mL). The mixture was heated at 105 °C under nitrogen for 8 h, then concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO2, 0-25% EtOAc / PE) to give 6-methoxy-2-(1-((2-(trimethylsilyl)ethoxy )methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-6,9-ethionothieno[2,3-c] En-4-one (32 mg, 24%, 82% purity). MS observation (ESI+): 459.4 [(M+H)+]. Step B : 6-methoxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9 - Tetrahydro-6,9-ethidethieno[2,3-c]quinolin-4(5H)-one: To 6-methoxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetra Hydrogen-4H-6,9-Ethothieno[2,3-c] Aqueous ammonia (17% w / w, 12.0 mL) was added to a solution of en-4-one (20 mg, 44 µmol, 1.0 equiv) in isopropanol (3.0 mL). The mixture was stirred at 60 °C for 16 hours, then concentrated in vacuo and purified by flash column chromatography (SiO 20-5% MeOH / DCM) to give 6-methoxy-2-(1-((2-( Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-6,9-ethoxythieno[2,3-c] Quinolin-4(5H)-one (10 mg, 24%, 48% purity). MS observation (ESI +): 458.4 [(M+H) +]. Step C: 6-Methoxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-6,9-ethylodethieno[2,3-c]quinoline -4(5H)-one (Compound 7): 6-methoxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetra A solution of Hydrogen-6,9-Ethieno[2,3-c]quinolin-4(5H)-one (28 mg, about 50% purity, 29 µmol, 1.0 equiv) in DCM (4.0 mL) Cool to 0 °C, then add trifluoroacetic acid (1.0 mL). The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo and purified by preparative HPLC to afford 6-methoxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro -6,9-Ethothieno[2,3-c]quinolin-4(5H)-one (Compound 7, 5 mg, 51%). MS observation (ESI +): 328.1 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δ ppm: 13.16 (s, 1H), 10.52 (s, 1H), 8.10 (s, 2H) , 7.59 (s, 1H), 3.39 (s, 3H), 3.40 - 3.92 (m, 1H), 2.12 (t, J= 10.4 Hz, 2H), 1.88 (t, J= 10.4 Hz, 2H), 1.49 - 1.44 (m, 2H), 1.36 - 1.31 (m, 2H). Step D: 6-Hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-6,9-ethylodethieno[2,3-c]quinoline-4 (5H)-Kone (Compound 8): 6-Methoxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-6,9-ethenothieno[2,3-c]quinoline-4 A solution of (5H)-ketone (55 mg, 120 µmol, 1.0 equiv) in HBr (40% aqueous solution, 5.0 mL) was heated to 100°C for 8 hours. The mixture was concentrated in vacuo and purified by reverse phase column chromatography (C18 SiO2, 0-40% MeCN / water, 0.1% NH4HCO3 / water) to give 6-hydroxy-2-(1H-pyrazole-4 -yl)-6,7,8,9-tetrahydro-6,9-ethidethieno[2,3-c]quinolin-4(5H)-one (Example 8, 16.2 mg, 31%). MS observation (ESI +): 314.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 13.17 (s, 1H), 10.22 (s, 1H), 8.14 (brs, 2H), 7.58 (s, 1H), 5.72 (s, 1H), 3.30 (s, 1H), 1.84 - 1.80 (m, 4H), 1.43 (d, J= 6.4 Hz, 4H). Example 9 - Compound 9: 6-Hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-6,9-ethenothieno[2,3-c]quinoline-4 (5H)-Kone Step A: Methyl 3-bromo-5-(pyridin-4-yl)thiophene-2-carboxylate: Cesium carbonate (210 mg, 680 µmol, 2.0 equiv), Pd(dppf)Cl 2 (240 mg, 330 µmol, 1.0 equiv) and dicyclohexyl-[2-(2,4,6-triisopropylbenzene Base) phenyl]phosphine (160 mg, 330 µmol, 1.0 equiv) was added to 3,5-dibromothiophene-2-carboxylic acid methyl ester (100 mg, 330 µmol, 1.0 equiv) and 4-pyridyl acid (45 mg, 370 µmol, 1.1 eq) in 1,4-bis solution in alkanes (10.0 mL). The mixture was degassed twice with N 2 and then heated to 80 °C for 1 h. The mixture was concentrated in vacuo and purified by column chromatography (SiO2, 0-25% EtOAc / PE) to give methyl 3-bromo-5-(pyridin-4-yl)thiophene-2-carboxylate (65 mg ,56%). MS observation (ESI+): 298.0 [(M+H)+]. Step B : 6-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-6,9-ethionothieno[2,3-c] En-4-ones: Add cesium carbonate (330 mg, 1.0 mmol, 3.0 equiv) and Sphos-Pd-G3 (52 mg, 67 µmol, 0.2 equiv) to methyl 3-bromo-5-(4-pyridyl)thiophene-2-carboxylate (100 mg, 340 µmol, 1.0 equiv) and 1-methoxybicyclo[2.2.2]octan-2-one (100 mg, 670 µmol, 2.0 equiv) in toluene (4.0 mL). The mixture was stirred at 100 °C under nitrogen for 16 hours, concentrated in vacuo and purified by flash column chromatography (SiO2, 0-10% MeOH / DCM) to give 6-methoxy-2-(pyridine-4 -yl)-6,7,8,9-tetrahydro-4H-6,9-ethionothieno[2,3-c] En-4-one (21 mg, 16%, 82% purity). MS observation (ESI+): 340.4 [(M+H)+]. Step C: 6-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-6,9-ethionothieno[2,3-c] En-4-ones: To 6-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-6,9-ethylothieno[2,3-c] To a solution of en-4-one (15 mg, 44.19 µmol, 1.0 equiv) in isopropanol (4.0 mL) was added aqueous ammonia (25% w / w, 16.0 mL). The mixture was stirred at 60 °C for 16 hours, then concentrated in vacuo to give 6-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-6,9-ethano Thieno[2,3-c] En-4-one (15 mg, crude material) was used without further purification. MS observation (ESI+): 357.3 [(M+H)+]. Step D : 6-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-6,9-ethidethieno[2,3-c]quinoline-4( 5H)- Ketones: Crude 3-(4-methoxy-3-oxobicyclo[2.2.2]oct-2-yl)-5-(pyridin-4-yl)thiophene-2-carboxamide (30 mg) was dissolved In toluene (4.0 mL) and p-toluenesulfonic acid (3 mg, 17 µmol, 0.20 equiv). The mixture was stirred at 100 °C for 1 h, followed by the addition of NaHCO 3 (saturated aqueous solution, 10 mL). The mixture was extracted with EtOAc (3×15 mL), and the combined organic layers were dried over Na 2 SO 4 and filtered. Concentrated in vacuo to give 6-methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-6,9-ethionothieno[2,3-c]quinoline-4 (5H)-Kone (28 mg, crude material), which was used without further purification. MS observation (ESI+): 339.2 [(M+H)+]. Step E: 6-Hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-6,9-ethenothieno[2,3-c]quinoline-4(5H) - Ketone (compound 9): 6-Methoxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-6,9-ethenothieno[2,3-c]quinoline-4(5H) A solution of -ketone (30 mg, 89 µmol) in HBr (48% aqueous solution, 4.0 mL) was heated to 100 °C for 16 h, concentrated in vacuo, and purified by preparative HPLC to give 6-hydroxy-2-( Pyridin-4-yl)-6,7,8,9-tetrahydro-6,9-ethieno[2,3-c]quinolin-4(5H)-one (compound 9,11 mg,38 %). MS observation (ESI +): 325.1 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δ ppm: 10.59 (s, 1H), 8.68 - 8.67 (m, 2H), 8.23 ​​(s, 1H), 7.82 - 7.81 (m, 2H), 5.76 (s, 1H), 3.43 - 3.41 (m, 1H), 1.85 - 1.78 (m, 4H), 1.46 - 1.43 (m, 4H). Examples 10 and 11 - Compounds 10 and 11: (R)-4-methoxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[ 4,3-b]thieno[3,2-d]pyridin-6-one (compound 10) and (S)-4-methoxy-8-(1H-pyrazol-4-yl)-1, 3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 11) (stereochemistry is arbitrarily assigned) Step A : 4-methoxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro- 1H,6H-Pyrano[4,3-b]thieno[3,2-d]pyran-6-one To 3-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid methyl ester (300 mg, 0.72 mmol, 1.0 equivalents, prepared in a similar manner to compound 9 step A) and 3-methoxytetrahydropyran-4-one (190 mg, 1.4 mmol, 2.0 equivalents, synthesized as described in WO2005014537) in toluene ( 7.0 mL), sodium metabisulfite (14 mg, 72 µmol, 0.1 equiv), Cs 2CO 3 (700 mg, 2.2 mmol, 3.0 equiv), Pd 2(dba) 3 (130 mg, 0.14 mmol , 0.2 equiv) and Xantphos (170 mg, 0.29 mmol, 0.4 equiv). The mixture was stirred at 100 °C for 16 h, concentrated, and purified by column chromatography (SiO2, 0-25% EtOAc / PE) to give 4-methoxy-8-(1-((2-( Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3, 2-d]pyran-6-one (160 mg, 51%). MS observation (ESI+): 435.4 [(M+H)+]. Step B : 4-methoxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro- 1H,6H-Pyrano[4,3-b]thieno[3,2-d]pyran-6-one: 4-methoxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H, 6H-Pyrano[4,3-b]thieno[3,2-d]pyran-6-one (160 mg, 0.37 mmol, 1.0 equiv) in 1:4 trifluoroacetic acid / DCM (10 mL) The solution was stirred at room temperature for 2 hours. The mixture was concentrated to give 4-methoxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-di Hydrogen-1H,6H-pirano[4,3-b]thieno[3,2-d]pyran-6-one (112 mg, crude material) was used without further purification. MS observation (ESI+): 305.2 [(M+H)+]. Step C: (R)-4-methoxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thiophene And[3,2-d]pyridin-6-one (compound 10) and (S)-4-methoxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetra Hydrogen-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 11): 4-methoxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H, A solution of 6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (110 mg, 1.0 equivalent) in NH 4OH / MeOH=1 / 1 (10 mL) Stir in a microwave reactor at 100 °C for 6 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to afford racemic 4-methoxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyran and[4,3-b]thieno[3,2-d]pyridin-6-one (75 mg, 77%). MS observation (ESI+): 304.2 [(M+H)+]. Individual enantiomers were separated by chiral SFC. (R)-4-methoxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3 ,2-d]pyridin-6-one (compound 10): MS observation (ESI +): 304.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 13.23 (s, 1H) , 11.53 (s, 1H), 8.30 (brs, 2H), 7.44 (s, 1H), 4.88 - 4.69 (m, 1H), 4.64 - 4.46 (m, 1H), 4.18 (d, J= 12.0 Hz, 1H ), 4.01 (s, 1 H), 3.70 (d, J= 12.0 Hz, 1 H), 3.39 (s, 3 H). (S)-4-methoxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3 ,2-d]pyridin-6-one (compound 11): MS observation (ESI +): 304.2 [(M+H) +]. Examples 12 and 13 - Compounds 12 and 13: (S)-6-(azetidin-1-yl)-8,8-difluoro-2-(1H-pyrazol-4-yl)-6, 7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 12) and (R)-6-(azetidin-1-yl)-8 , 8-difluoro-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 13 ) (stereochemistry arbitrarily specified) Step A : 5,5-Difluoro-2,2-dimethoxy-cyclohexanol: 4,4-Difluorocyclohexanone (4.0 g, 30 mmol, 1.0 equiv) and KOH (4.0 g, 72 mmol, 3.0 equiv) were dissolved in MeOH (80.0 mL). The mixture was cooled to 0 °C, and a solution of I2 (8.3 g, 33 mmol, 1.1 equiv in 100.0 mL MeOH) was added dropwise over 1 h. The reaction was stirred at room temperature for 18 hours, concentrated in vacuo, and the oil was suspended in 80 mL of DCM. The precipitate was filtered off and the solution was concentrated to afford crude 5,5-difluoro-2,2-dimethoxy-cyclohexanol (4.2 g, crude). Step B: (((5,5-difluoro-2,2-dimethoxycyclohexyl)oxy)methyl)benzene Sodium hydride (610 mg, 15 mmol, 60% in mineral oil, 1.2 equiv) was added to a solution of BnBr (2.8 g, 17 mmol, 1.3 equiv) in DMF (30.0 mL) at 0 °C. After 30 minutes, 5,5-difluoro-2,2-dimethoxy-cyclohexanol (2.5 g crude material, 13 mmol, 1.0 equiv) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with EtOAc (15 mL×2). The organic layer was dried, filtered, concentrated and purified by column chromatography (SiO, 0-12% EtOAc / PE) to give (((5,5-difluoro-2,2-dimethoxycyclohexyl )oxy)methyl)benzene (3.2 g, 64%). 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.37 - 7.25 (m, 5H), 4.72 (d, J= 12.0 Hz, 1H), 4.56 (d, J= 12.0 Hz, 1H), 3.70 (t, J = 8.0 Hz, 1H), 3.24 (s, 3H), 3.22 (s, 3H), 2.38 - 2.35 (m, 1H), 2.11 - 1.74 (m, 5H). Step C: 2-(Benzyloxy)-4,4-difluorocyclohexan-1-one: To a solution of (((5,5-difluoro-2,2-dimethoxycyclohexyl)oxy)methyl)benzene (2.2 g, 7.7 mmol, 1.0 equiv) in acetone (60.0 mL) was added I 2 (195 mg, 768 µmol, 0.1 equiv). After 30 min, Na 2 S 2 O 3 (sat. aq.) was added, and the aqueous phase was extracted with DCM (15 mL×3). The combined org. phases were washed with Na 2 S 2 O 3 (sat. aq.), filtered and concentrated. Purification by column chromatography (SiO 2 , 0-8% EtOAc / PE) afforded 2-(benzyloxy)-4,4-difluorocyclohexan-1-one (1.3 g, 70%). 1H NMR (400 MHz, CDCl 3 ): δ ppm: 7.36 - 7.25 (m, 5H), 4.85 (d, J= 11.2 Hz, 1H), 4.51 (d, J= 11.2 Hz, 1H), 4.15 - 4.11 ( m, 1H), 2.75 - 2.14 (m, 6H). Step D: 6-(Benzyloxy)-8,8-difluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl )-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones : To 3-bromo-5-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]thiophene-2-carboxylic acid methyl ester (400 mg, 960 µmol, 1.0 equiv) and 2 To a solution of -(benzyloxy)-4,4-difluorocyclohexan-1-one (460 mg, 1.9 mmol, 2.0 eq) in toluene (80.0 mL) was added Cs 2 CO 3 (940 mg, 2.9 mmol, 3.0 equiv), Pd 2(dba) 3 (180 mg, 190 µmol, 0.2 equiv), Xantphos (170 mg, 270 µmol, 0.3 equiv), and Na 2S 2 O 5 (54 mg, 290 µmol, 0.3 equiv). The mixture was stirred and heated at 105°C for 16 hours. The mixture was cooled, filtered and concentrated, and the residue was purified by silica gel chromatography (Si0, 0-28% EtOAc / PE) to give 6-(benzyloxy)-8,8-difluoro-2-( 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3 -c] En-4-one (360 mg, 55%). MS observation (ESI+): 545.3 [(M+H)+]. Step E: 6-(Benzyloxy)-8,8-difluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl )-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: To 6-(benzyloxy)-8,8-difluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 6,7,8,9-tetrahydro-4H-thieno[2,3-c] Aqueous ammonia (30% w / w, 8.0 mL) was added to a solution of en-4-one (150 mg, 200 µmol, 1.0 equiv) in MeOH (8.0 mL). The mixture was heated at 95 °C in a microwave reactor for 8 h, followed by cooling. The mixture was extracted with DCM (10 mL x 3) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (SiO2, 0-4% MeOH / DCM) gave 6-(benzyloxy)-8,8-difluoro-2-(1-((2-(trimethylsilyl Base) ethoxy) methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (90 mg, 69%). MS observation (ESI+): 544.4 [(M+H)+]. Step F: 8,8-difluoro-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4 (5H)- Ketone: 6-(Benzyloxy)-8,8-difluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- A solution of 6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (200 mg, 367 µmol, 1.0 equiv) in DCM (12.0 mL) was cooled to 0 °C and BCl 3 (1 M in n-Hexane, 3.68 mL, 3.68 mmol, 10 equiv) was added. After 1 h at 0 °C, MeOH (3.0 mL) was added, and the solution was concentrated to give a solid. Wet trituration (1:1 hexane / MeOH) afforded 8,8-difluoro-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8, 9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (110 mg, 92% yield). MS observation (ESI+): 324.1 [(M+H)+]. Step G: (R)-6-(azetidin-1-yl)-8,8-difluoro-2-(1H-pyrazol-4-yl)-6,7,8,9-tetra Hydrothieno[2,3-c]quinolin-4(5H)-one (compound 12) and (S)-6-(azetidin-1-yl)-8,8-difluoro-2 -(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 13): At room temperature to 8,8-difluoro-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline- 4(5H)-Kone (70 mg, 190 µmol, 1.0 equiv) was slowly added SOCl 2 (2.5 g, 21 mmol, 1.5 mL, 11 equiv). After 4 h, the mixture was concentrated. Will contain 6-chloro-8,8-difluoro-2-(1H-pyrazol-4-yl)-5,6,7,9-tetrahydrothieno[2,3-c]quinoline-4- The ketone concentrate was dissolved in MeCN (3.0 mL), and KI (241 mg, 1.45 mmol, 10.0 equiv) and azetidine (170 mg, 2.9 mmol, 20.0 equiv) were added. The mixture was stirred at room temperature for 12 hours, then concentrated and purified via reverse phase chromatography to give 6-(azetidin-1-yl)-8,8-difluoro-2-(1H-pyrazole-4 -yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (34 mg, 55%, 85% purity). MS observation (ESI+): 363.3 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (R)-6-(azetidin-1-yl)-8,8-difluoro-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno [2,3-c]quinolin-4(5H)-one (compound 12): MS observation (ESI +): 363.4 [(M+H) +]. (S)-6-(azetidin-1-yl)-8,8-difluoro-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno [2,3-c]quinolin-4(5H)-one (compound 13): MS observation (ESI +): 363.3 [(M+H) +]. Examples 14 and 15 - Compounds 14 and 15: (S)-8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1H-pyrazol-4-yl)-6,7 ,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 14) and (R)-8,8-difluoro-6-(hydroxymethyl)-6 -Methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 15)( Stereochemistry arbitrarily designated) Step A : Methyl 5,5-difluoro-2-hydroxycyclohex-1-ene-1-carboxylate: A solution of 4,4-difluorocyclohexanone (2.0 g, 15 mmol, 1.0 equiv) in DMF (4.0 mL) was added to NaH (430 mg, 18 mmol, 60% in mineral oil, 1.2 equiv) in DMF (13.0 mL) in suspension at 0°C. After 30 min at 0 °C, a solution of dimethyl carbonate (1.6 g, 18 mmol, 1.5 mL, 1.2 equiv) in DMF (3.0 mL) was added and the mixture was stirred at room temperature for 16 h, followed by the addition of NH 4 Cl ( saturated aqueous solution). The mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried (Na 2 SO 4 ), concentrated in vacuo, and purified by column chromatography (SiO 2 , 0-8% EtOAc / PE) to give 5,5-difluoro-2-hydroxycyclohexyl- Methyl 1-ene-1-carboxylate (2.0 g, 70%). 1H NMR (400 MHz, CDCl 3 ) δppm: 12.17 (s, 1H), 3.78 (s, 3H), 2.74 (t, J= 14.4 Hz, 2H), 2.55 (t, J= 6.8 Hz, 2H), 2.17 - 2.07 (m, 2H). Step B : Methyl 5,5-difluoro-1-methyl-2-oxocyclohexane-1-carboxylate : To a flask containing methyl 5,5-difluoro-2-hydroxycyclohex-1-ene-1-carboxylate (1.0 g, 6.4 mmol, 1.0 equiv) in acetone (12.0 mL) was added KCO at room temperature 3 (2.7 g, 19 mmol, 3.0 equiv) and methyl iodide (2.7 g, 19 mmol, 3.0 equiv). The mixture was heated to 50 °C and stirred for 3 hours, then water was added. The mixture was extracted with tert-butyl methyl ether (30 mL×3), and the combined organic layers were washed with water, brine and dried (Na 2 SO 4 ). Filtration, concentration in vacuo, and purification by column chromatography (SiO 2 , 0-15% EtOAc / PE) afforded 5,5-difluoro-1-methyl-2-oxocyclohexane-1- Methyl formate (800 mg, 66%). 1H NMR (400 MHz, CDCl 3 ) δppm: 3.76 (s, 3H), 3.09 - 2.88 (m, 2H), 2.61 - 2.54 (m, 1H), 2.46 - 2.35 (m, 1H), 2.26 - 1.98 (m , 2H), 1.37 (d, J= 0.8 Hz, 3H). Step C: 8,8-Difluoro-6-methyl-4-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] Methyl ene-6-carboxylate : To 3-iodo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid methyl ester (200 mg, 430 µmol, 1.0 equivalent) and 5,5-difluoro-1-methyl-2-oxocyclohexane-1-carboxylic acid methyl ester (180 mg, 860 µmol, 2.0 equivalent) in toluene (12.0 mL) Add Cs 2CO 3 (420 mg, 1.3 mmol, 3.0 equiv), Pd 2(dba) 3 (79 mg, 86 µmol, 0.2 equiv), Xantphos (74 mg, 130 µmol, 0.30 equiv) and Na 2S 2O 5 into the solution (16 mg, 86 µmol, 0.2 equiv). The mixture was heated to 105 °C in a microwave reactor for 2 h, then cooled, concentrated and purified (SiO 2 , 0-32% EtOAc / PE). The material was further purified by reverse phase chromatography to give 8,8-difluoro-6-methyl-4-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] Methyl-ene-6-carboxylate (100 mg, 46%). MS observation (ESI+): 511.4 [(M+H)+]. Step D: 8,8-Difluoro-6-(hydroxymethyl)-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine Azol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: eq.) to 8,8-difluoro-6-methyl-4-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] To a cooled (0 °C) solution of methylene-6-carboxylate (100 mg, 200 µmol, 1.0 equiv) in EtOH (12.0 mL) was added CaCl 2 (45 mg, 410 µmol, 2.0 equiv). After 10 minutes, NaBH 4 (116 mg, 3.08 mmol, 15.0 equiv) was added, and the ice bath was removed. The mixture was stirred at room temperature for 20 min, then cooled to 0 °C and NH 4 Cl (sat. aq.) was added. The mixture was extracted with DCM (10 mL x 3) and the combined organic phases were dried (Na 2 SO 4 ), filtered, and concentrated. Purification by column chromatography (SiO 20-70% EtOAc / PE) gave 8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1-((2-(tri Methylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (55 mg, 48%). MS observation (ESI+): 483.4 [(M+H)+]. Step E: 8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine Azol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: To 8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] To a solution of en-4-one (98 mg, 200 µmol, 1.0 equiv) in MeOH (5.0 mL) was added ammonia (5.0 mL, 30% w / w). The mixture was heated to 95°C in a microwave reactor for 8 hours. The mixture was concentrated and purified by column chromatography (SiO 20-7% MeOH / DCM) to give 8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1-(( 2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4 (5H)-Kone (68 mg, 56%). MS observation (ESI+): 482.4 [(M+H)+]. Step F: (S)-8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro Thieno[2,3-c]quinolin-4(5H)-one (compound 14) and (R)-8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-( 1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 15): To 8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- Cooling of 4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (43 mg, 89 µmol) in DCM (4.0 mL) ( 0 °C) solution was added trifluoroacetic acid (2.0 mL). The mixture was warmed to room temperature and stirred for 2 hours, then concentrated in vacuo and purified by reverse phase chromatography to give 8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1H-pyrazole -4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (22 mg, 69%). MS observation (ESI +): 352.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6): δppm 13.22 (s, 1H), 10.86 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.53 (s, 1H), 5.23 (s, 1H), 3.84 (d, J= 10.8 Hz, 1H), 3.41 (d, J= 10.4 Hz, 1H), 3.29 - 3.13 (m , 2H), 2.58 - 2.46 (m, 1H), 2.03 - 1.94 (m, 1H), 1.30 (s, 3H). Individual enantiomers were separated via chiral SFC to obtain each enantiomer. (S)-8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[ 2,3-c] Quinolin-4(5H)-one (compound 14): MS observation (ESI +): 352.1 [(M+H) +]. (R)-8,8-difluoro-6-(hydroxymethyl)-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[ 2,3-c] Quinolin-4(5H)-one (compound 15): MS observation (ESI +): 352.1 [(M+H) +]. Examples 16 and 17 - Compounds 16 and 17: (S)-4-Hydroxy-4-isopropyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H- Pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 16) and (R)-4-hydroxy-4-isopropyl-8-(1H-pyrazole -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 17) Step A: 4-(Benzyloxy)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-di Hydrogen-1H,6H-pyrano\[4,3-b]thieno\[3,2-d]pyran-6-one: To 3-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid methyl ester (5.0 g, 12 mmol, 1.0 equivalent) and 3-(benzyloxy)tetrahydro-4H-pyran-4-one (4.9 g, 24 mmol, 2.0 equivalent) in 1,4-bis Add Na 2S 2O 5 (228 mg, 1.20 mmol, 0.1 equiv), Cs 2CO 3 (12 g, 36 mmol, 3.0 equiv), Pd 2(dba) 3 (2.19 g, 2.40 mmol, 0.20 equiv) and Xantphos (2.8 g, 4.8 mmol, 0.40 equiv). The mixture was degassed twice with N2, then stirred and heated at 100 °C for 16 h. The mixture was filtered and concentrated in vacuo, and purified by flash column chromatography (Si0, 0-60% EtOAc / PE) to give 4-(benzyloxy)-8-(1-((2-(trimethyl Silyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d ]pyran-6-one (3.5 g, 38% yield, 81% purity). MS observation (ESI+): 511.5 [(M+H)+]. Step B : 4-(Benzyloxy)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,3,4 ,5-Tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one: 4-(Benzyloxy)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro- 1H,6H-Pyrano[4,3-b]thieno[3,2-d]pyran-6-one (1.00 g, 1.6 mmol, 81% purity, 1.0 equivalent) and NH 4OH (6 mL) The solution in MeOH (6.0 mL) was stirred at 100 °C for 6 h under microwave heating. The mixture was concentrated in vacuo to give a residue, which was purified by flash column chromatography (SiO, 0-10% MeOH / DCM) to afford 4-(benzyloxy)-8-(1-((2-(tri Methylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3 , 2-d]pyridin-6-one (560 mg, 68%). MS observation (ESI+): 510.2 [(M+H)+]. Step C : 4-Hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2- d] pyridin-6-one: To 4-(benzyloxy)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,3,4,5 - Tetrahydro-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (300 mg, 590 µmol, 1.0 equiv) in DCM (2.0 mL) Add BCl 3 (1 M in hexanes, 5.9 mL, 10 equiv). The mixture was stirred at 0 °C for 15 minutes, then concentrated in vacuo to give 4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4 , 3-b]thieno[3,2-d]pyridin-6-one (170 mg, crude material), which was used in the next reaction without further purification. MS observation (ESI+): 290.0 [(M+H)+]. Step D : 4-(4-Hydroxy-6-oxo-3,4,5,6-tetrahydro-1H-pyrano[4,3-b]thieno[3,2-d]pyridine- 8-yl)-1H-pyrazole-1-carboxylic acid tertiary butyl ester: To 4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d] To a suspension of pyridin-6-one (170 mg, crude material) in DMF (2.0 mL) was added trimethylamine (119 mg, 1.18 mmol, 2.0 equiv), DMAP (36 mg, 290 µmol, 0.5 equiv) and ( Boc)2O (130 mg, 590 µmol, 1.0 equiv). The mixture was stirred at room temperature for 10 min, then poured into water and extracted with EtOAc / THF (10:1, 15 mL×2). The combined organic layers were dried, filtered, concentrated and purified by flash column chromatography (SiO 2 , 0-10% MeOH / DCM) to give 4-(4-hydroxy-6-oxo-3,4, tertiary butyl 5,6-tetrahydro-1H-piperano[4,3-b]thieno[3,2-d]pyridin-8-yl)-1H-pyrazole-1-carboxylate (130 mg , 56%, 2 steps). MS observation (ESI+): 390.0 [(M+H)+]. Step E : 4-(4,6-Dioxo-3,4,5,6-tetrahydro-1H-pyrano\[4,3-b]thieno\[3,2-d]pyridine -8-yl)-1H-pyrazole-1-carboxylic acid tertiary butyl ester: Add Dess-Martin periodinane (425 mg, 1.00 mmol, 3.0 equiv) to 4-(4-hydroxy-6-oxo-3,4,5,6-tetrahydro-1H- Pyrano[4,3-b]thieno[3,2-d]pyridin-8-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (130 mg, 334 µmol, 1.0 equiv) in DCM (3.0 mL) and DMF (3.0 mL). The mixture was stirred at room temperature for 2 h, then saturated Na 2 S 2 O 3 (aq) and NaHCO 3 (aq) and water (10 mL) were added. The mixture was extracted with DCM / MeOH (10:1, 20 mL×3), and the combined organic layers were dried, filtered, concentrated and purified by flash column chromatography (SiO 2 , 0-10% MeOH / DCM), Obtain 4-(4,6-dioxo-3,4,5,6-tetrahydro-1H-pyrano[4,3-b]thieno[3,2-d]pyridin-8-yl )-1H-pyrazole-1-carboxylic acid tertiary butyl ester (70 mg, 54%). MS observation (ESI+): 388.0 [(M+H)+]. Step F: (S)-4-Hydroxy-4-isopropyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b] Thieno[3,2-d]pyridin-6-one (compound 16) and (R)-4-hydroxy-4-isopropyl-8-(1H-pyrazol-4-yl)-1 ,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 17): To 4-(4,6-dioxo-3,4,5,6-tetrahydro-1H-pyrano[4,3-b]thieno[3,2-d]pyridin-8-yl )-1H-pyrazole-1-carboxylic acid tert-butyl ester (1.96 g, 5.06 mmol, 1.0 equiv) in anhydrous THF (6.0 mL) was added i-PrMgCl-LiCl (1.3 M in THF, 80 mL , 20 equivalents). The mixture was stirred at 0 °C for 30 min, then quenched with saturated aqueous NH 4 Cl and extracted with EtOAc / THF (10:1, 30 mL×2). The combined organic layers were dried, filtered, concentrated and purified by flash column chromatography (Si0, 0-10% MeOH / DCM) to give rac 4-hydroxy-4-isopropyl-8-(1H -pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (680 mg, 41%). MS observation (ESI+): 332.0 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-Hydroxy-4-isopropyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b] Thieno[3,2-d]pyridin-6-one (compound 16): MS observation (ESI +): 332.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6): δ ppm: 13.22 (s, 1H), 10.81 (s, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 7.41 (s, 1H), 5.25 (s, 1H), 4.67 (s, 2H), 3.96 (d, J= 11.6 Hz, 1H), 3.53 (d, J= 11.6 Hz, 1H), 2.41 - 2.34 (m, 1H), 1.00 (d, J= 6.8 Hz, 3H), 0.76 (d, J= 6.8 Hz, 3H). (R)-4-Hydroxy-4-isopropyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b] Thieno[3,2-d]pyridin-6-one (compound 17): MS observation (ESI +): 332.0 [(M+H) +]. Examples 18 and 19 - Compounds 18 and 19: (S)-4-Ethyl-4-hydroxyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-piper Furo[4,3-b]thieno[3,2-d]pyridin-6-one (compound 18) and (R)-4-ethyl-4-hydroxy-8-(1H-pyrazole-4 -yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 19) To 4-(4,6-dioxo-3,4,5,6-tetrahydro-1H-pyrano[4,3-b]thieno[3,2-d]pyridin-8-yl )-1H-pyrazole-1-carboxylic acid tert-butyl ester (180 mg, 460 µmol) in anhydrous THF (2.0 mL) was added EtMgCl (2 M in THF, 12.0 mL, 52 equiv), and The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with saturated NH 4 Cl(aq) and extracted with EtOAc:THF (10:1, 30 mL×2). The combined organic layers were dried, filtered, concentrated and purified by flash column chromatography (SiO 2 , 0-10% MeOH / DCM) to give rac 4-ethyl-4-hydroxy-8-(1H- Pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (60 mg, 41 %). MS observation (ESI+): 318.1 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-Ethyl-4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thiophene And[3,2-d]pyridin-6-one (compound 18): MS observation (ESI +): 318.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δ ppm: 13.22 ( s, 1H), 10.88 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.40 (s, 1H), 5.28 (s, 1H), 4.86 - 4.49 (m, 2H), 3.85 (d, J= 11.2 Hz, 1H), 3.54 (d, J= 11.2 Hz, 1H), 2.00 -1.79 (m, 2H), 0.85 (t, J= 7.6 Hz, 3H). (R)-4-Ethyl-4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thiophene De[3,2-d]pyridin-6-one (compound 19): MS observation (ESI +): 318.0 [(M+H) +]. Example 20 and 21 - Compounds 20 and 21: (S)-4-(tertiary butyl)-4-hydroxyl-8-(1H-pyrazol-4-yl)-3,4-dihydro-1H -Pyrano[4,3-b]thieno[3,2-d]pyridin-6(5H)-one (compound 20) and (R)-4-(tertiary butyl)-4-hydroxyl -8-(1 H-pyrazol-4-yl)-3,4-dihydro-1 H-pyrano[4,3-b]thieno[3,2-d]pyridine-6(5 H )-ketone (compound 21). (The stereochemistry of compounds 20 and 21 is arbitrarily assigned) 4-(4,6-dioxo-3,4,5,6-tetrahydro-1 H-pyrano[4,3-b]thieno[3,2-d] To a solution of pyridin-8-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol, 1.0 equiv) in anhydrous THF (4.0 mL) was added t-BuMgCl (1 M in in THF, 3.9 mL, 30 equiv). The mixture was stirred at 0°C for 0.5 hours. The mixture was quenched with saturated aqueous NH 4 Cl (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , 0-10% MeOH / DCM) to give racemic 4-(tertiary butyl)-4-hydroxy-8-(1 H-pyrazole-4 -yl)-3,4-dihydro-1H-pyrano[4,3-b]thieno[3,2-d]pyridin-6(5H)-one (10 mg, 23%). MS observation (ESI+): 346.5 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-(tertiary butyl)-4-hydroxy-8-(1 H-pyrazol-4-yl)-3,4-dihydro-1 H-pyrano[4,3-b ]thieno[3,2-d]pyridin-6(5 H)-one (compound 20): MS observation (ESI +): 346.1 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 13.23 (s, 1H), 10.02 (s, 1H), 8.29 (s, 1H), 7.97 (s, 1H), 7.40 (s, 1H), 5.32 (s, 1H), 4.80 (m, 2H), 4.14 (d, J= 11.6 Hz, 1H), 3.46 (d, J= 11.6 Hz, 1H), 1.03 (s, 9H). (R)-4-(tertiary butyl)-4-hydroxy-8-(1 H-pyrazol-4-yl)-3,4-dihydro-1 H-pyrano[4,3-b ] Thieno[3,2-d]pyridin-6(5H)-one (compound 21): MS observation (ESI+): 346.1 [(M+H)+]. Example 22 and 23-compounds 22 and 23: (S)-4-(tertiary butyl)-4-hydroxyl-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H- Pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 22) and (R)-4-(tertiary butyl)-4-hydroxy-8-(pyridine -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 23) (compound 22 and the stereochemistry of 23 are arbitrarily designated) Step A: 4-(Benzyloxy)-8-(pyridin-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d ] pyran-6-one: 3-Bromo-5-(4-pyridyl)thiophene-2-carboxylic acid methyl ester (1.0 g, 3.4 mmol, 1.0 equiv) and 3-benzyloxytetrahydropyran-4 -To a solution of ketone (1.4 g, 6.7 mmol, 2.0 equiv) in toluene (50.0 mL) was added Cs 2CO 3 (2.2 g, 6.71 mmol, 2.0 equiv), Pd 2(dba) 3 (614 mg, 0.67 mmol, 0.2 eq), Xantphos (582 mg, 1.01 mmol, 0.3 eq) and Na 2 S 2 O 5 (64 mg, 0.34 mmol, 0.1 eq). The mixture was stirred at 105°C for 16 hours, cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0-10% MeOH / DCM) to give 4-(benzyloxy)-8-(pyridin-4-yl)-3,4-dihydro-1H,6H -Pyrano[4,3-b]thieno[3,2-d]pyran-6-one (457 mg, 32%). MS observation (ESI+): 392.1 [(M+H)+]. Step B: 4-(Benzyloxy)-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2 -d] pyridin-6-one: To 4-(benzyloxy)-8-(pyridin-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]piper To a solution of pyran-6-one (1.0 g, 2.55 mmol, 1.0 equiv) in MeOH (9.0 mL) was added NH4OH (9.0 mL). The mixture was heated in a microwave reactor at 100 °C for 3 hours and monitored to completion by LCMS. The mixture was filtered, and the filter cake was washed with MeOH (50.0 mL) and dried in vacuo to give 4-(benzyloxy)-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-piper Furo[4,3-b]thieno[3,2-d]pyridin-6-one (512 mg, 50%). MS observation (ESI+): 391.2 [(M+H)+]. Step C: 4-Hydroxy-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine -6-ketone: To 4-(benzyloxy)-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d ] To a solution of pyridin-6-one (475 mg, 1.22 mmol, 1.0 equiv) in DCM (12.0 mL) was added BCl 3 (1 M in DCM, 12.2 mL, 10.0 equiv). The mixture was stirred at room temperature for 1 h, then quenched with aqueous NaHCO 3 (24.0 mL) and diluted with EtOAc (25.0 mL). The mixture was filtered and the filter cake was washed with EtOAc (25.0 mL) and dried in vacuo to give 4-hydroxy-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4 ,3-b]thieno[3,2-d]pyridin-6-one (360 mg, 92%). MS observation (ESI+): 301.0 [(M+H)+]. Step D: 8-(pyridin-4-yl)-1,5-dihydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine-4,6(3H)- Diketones: To 4-hydroxy-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine-6 - To a solution of the ketone (10 mg, 0.033 mmol, 1.0 equiv) in DCM (1.0 mL) and DMF (1.0 mL) was added Dess-Martin periodinane (140 mg, 0.333 mmol, 10 equiv). The mixture was stirred at room temperature for 2 h, then quenched with saturated aqueous NaHCO 3 (2.0 mL) and extracted with EtOAc (10 mL×2). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (SiO2, 1-30% MeOH / DCM) to give 8-(pyridin-4-yl)-1,5-dihydro-6H-pyrano[4,3- b] Thieno[3,2-d]pyridine-4,6(3H)-dione (6 mg, 60%). MS observation (ESI+): 299.3 [(M+H)+]. Step E: (S)-4-(tertiary butyl)-4-hydroxy-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b] Thieno[3,2-d]pyridin-6-one (compound 22) and (R)-4-(tertiary butyl)-4-hydroxyl-8-(pyridin-4-yl)-1 ,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 23): 8-(pyridin-4-yl)-1,5-dihydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine-4,6(3H )-diketone (25 mg, 0.08 mmol, 1.0 equiv) in anhydrous THF (1.5 mL) was added t-BuMgBr (1 M in THF, 1.7 mL, 20.0 equiv). The mixture was stirred at 0°C for 2 hours. The mixture was quenched with aqueous NH 4 Cl (2.0 mL), extracted with EtOAc (20.0 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , 0-10% MeOH / DCM) to give racemic 4-(tertiary butyl)-4-hydroxy-8-(pyridin-4-yl)- 1,3,4,5-Tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (5 mg, 17%). MS observation (ESI+): 357.1 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-(tertiary butyl)-4-hydroxy-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b] Thieno[3,2-d]pyridin-6-one (compound 22): MS observation (ESI +): 357.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 10.35 (s, 1H), 8.70 (d, J= 6.0 Hz, 2H), 8.03 (s, 1H), 7.82 (d, J= 6.0 Hz, 2H), 5.35 (s, 1H), 4.87 (m, 2H) , 4.15 (d, J= 11.2 Hz, 1H), 3.47 (d, J= 11.2 Hz, 1H), 1.03 (s, 9H). (R)-4-(tertiary butyl)-4-hydroxy-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b] Thieno[3,2-d]pyridin-6-one (compound 23): MS observation (ESI +): 357.2 [(M+H) +]. Examples 24 and 25 - Compounds 24 and 25: (S)-4-hydroxyl-4-isopropyl-8-(3-methyl-1H-pyrazol-4-yl)-1,3,4,5- Tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 24) and (R)-4-hydroxy-4-isopropyl-8- (3-Methyl-1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine- 6-keto (Compound 25) (The stereochemistry of Compounds 24 and 25 is arbitrarily assigned) The synthesis was carried out via a similar route to compounds 16 and 17. (S)-4-Hydroxy-4-isopropyl-8-(3-methyl-1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4 ,3-b]thieno[3,2-d]pyridin-6-one (compound 24). MS observation (ESI +): 346.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6 ) δppm: 12.94 (brs, 1H), 10.81 (brs, 1H), 7.96 (brs, 1H) , 7.29 (s, 1H), 5.27 (s, 1H), 4.69 (s, 2H), 3.96 (d, J= 11.8 Hz, 1H), 3.53 (d, J= 11.6 Hz, 1H), 2.48 (s, 3H), 2.40 - 2.34 (m, 1H), 1.00 (d, J= 6.8 Hz, 3H), 0.76 (d, J= 6.8 Hz, 3H).(R)-4-Hydroxy-4-isopropyl- 8-(3-Methyl-1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d] Pyridin-6-one (compound 25). MS observation (ESI+): 346.2 [(M+H)+]. Examples 26 and 27 - Compounds 26 and 27: (R)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-4-isopropyl-1,3,4,5-tetra Hydrogen-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 26) and (S)-8-(3-fluoro-1H-pyrazole-4 -yl)-4-hydroxy-4-isopropyl-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine-6- Ketone (Compound 27) (The stereochemistry of Compounds 26 and 27 is arbitrarily assigned) Step A: 4-Bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a solution of 4-bromo-3-fluoro-1H-pyrazole (1.5 g, 9.1 mmol, 1.0 equiv) in DMF (15 mL) was added sodium hydride (60% in mineral oil, 700 mg , 18 mmol, 2.0 equivalents). The mixture was stirred at 0 °C for 10 minutes, followed by the addition of 2-(chloromethoxy)ethyl-trimethyl-silane (2.27 g, 13.6 mmol, 2.41 mL, 1.5 equiv). The mixture was stirred at room temperature for 2 h, then quenched by the addition of saturated NH 4 Cl(aq), followed by water (200 mL). The mixture was extracted with EtOAc (50 mL×3) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was analyzed by flash column chromatography (SiO 2 , 0-4 % EtOAc / PE) to give 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.6 g, 96%); 1H NMR (400 MHz, CDCl 3 ) δppm: 7.45 (d, J= 2.0 Hz, 1H), 5.24 (d, J= 0.8 Hz, 2H), 3.58 (m, 2H), 0.92 (m, 2H), 0.00 ( s, 9H). Step B : 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1-((2-(trimethyl Silyl)ethoxy)methyl)-1H-pyrazole: 4-Bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (850 mg, 2.88 mmol, 1.0 equiv), 4,4,5 ,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (804 mg, 3.17 mmol, 1.1 equiv), Pd(dppf)Cl 2 (421 mg, 576 µmol, 0.2 equiv) and potassium acetate (848 mg, 8.64 mmol, 3.0 equiv) in 1,4-di The mixture in alkanes (17.0 mL) was heated at 100 °C under nitrogen for 16 hours. The mixture was cooled and concentrated in vacuo, then water (50 mL) was added and the mixture was extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (SiO2, 0-8% EtOAc / PE) to give 3 -Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-pyrazole (650 mg, 66%). 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.66 (d, J= 2.4 Hz, 1H), 5.26 (s, 2H), 3.59 (m, 2H), 1.34 (s, 12H), 0.92 (m, 2H ), 0.00 (s, 9H). Step C: 3-Bromo-5-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid Esters: Methyl 3,5-dibromothiophene-2-carboxylate (1.37 g, 4.56 mmol, 1.2 equivalents), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.3 g, 3.80 mmol, 1.0 equiv), Xantphos (440 mg, 760 µmol, 0.20 equiv), K 3PO 4 (2.4 g, 11 mmol, 3.0 equiv) and Pd(OAc) 2 (85 mg, 380 µmol, 0.10 equiv) in THF (60.0 mL) N2 was degassed, and the mixture was stirred at 60 °C for 16 h. The mixture was filtered and concentrated in vacuo, and the residue was purified by flash column chromatography (SiO 2 , 0-7% EtOAc / PE) to give 3-bromo-5-(3-fluoro-1-((2-( Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylate (810 mg, 49%). MS Observation (ESI+): 79Br / 81Br 435.2, 437.2 [(M+H)+]. Step D: 4-(Benzyloxy)-8-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4 - Isopropyl-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one: To 3-bromo-5-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylate ( 400 mg, 918.73 µmol, 1.0 equiv), 3-(benzyloxy)-3-isopropyltetrahydro-4H-pyran-4-one (462 mg, 1.86 mmol, 2.0 equiv, with compound 28 step B-C ) and cesium carbonate (909 mg, 2.79 mmol, 3.0 equiv) in toluene (20.0 mL) were added Pd 2(dba) 3 (170 mg, 186 µmol, 0.20 equiv) and Xantphos (215 mg , 372 µmol, 0.40 equiv). The mixture was degassed twice with N2 and stirred at 105 °C for 16 hours. The mixture was filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (SiO2, 0-16% EtOAc / PE) to give 4-(benzyloxy)-8-(3-fluoro-1 -((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-isopropyl-3,4-dihydro-1H,6H-pyrano [4,3-b]thieno[3,2-d]pyran-6-one (275 mg, 51%). MS observation (ESI+): 571.3 [(M+H)+]. Step E: 8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-4-isopropyl-3,4-dihydro-1H,6H-pyrano[4,3-b ] Thieno[3,2-d]pyran-6-one: To 4-(benzyloxy)-8-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl) at 0°C -4-Isopropyl-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (275 mg, 482 µmol, To a solution of 1.0 eq) in DCM (12.0 mL) was added BCl 3 (1 M, 1.93 mL, 4.0 eq) and the mixture was stirred at 0 °C for 40 min. The mixture was concentrated via nitrogen flow, and the pH was adjusted to ~9 by gradually adding NH4OH(aq) at 0 °C. The mixture was concentrated in vacuo to afford 8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-4-isopropyl-3,4-dihydro-1H,6H-pyrano[4,3 -b] Thieno[3,2-d]pyran-6-one (400 mg, crude material), which was used without further purification. MS observation (ESI+): 351.1 [(M+H)+]. Step F: (R)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-4-isopropyl-1,3,4,5-tetrahydro-6H-pyrano [4,3-b]thieno[3,2-d]pyridin-6-one (compound 26) and (S)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxyl -4-isopropyl-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 27): To 8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-4-isopropyl-3,4-dihydro-1H,6H-pyrano[4,3-b]thiophene To a solution of and[3,2-d]pyran-6-one (400 mg, crude material) in isopropanol (6.5 mL) was added aqueous NH4OH (6.5 mL). The mixture was stirred at 95 °C under microwave heating for 4 hours, then concentrated and purified by flash column chromatography (SiO2, 0-6% MeOH / DCM) to give 8-(3-fluoro-1H-pyridine Azol-4-yl)-4-hydroxy-4-isopropyl-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine -6-keto (75 mg, 31%, 2 steps). MS observation (ESI+): 350.1 [(M+H)+]. The racemic mixture was separated via chiral SFC to afford the individual enantiomers. (R)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-4-isopropyl-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b]Thieno[3,2-d]pyridin-6-one (compound 26): MS observation (ESI +): 350.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 12.89 (brs, 1H), 10 .90 (brs, 1H), 8.32 (d, J= 1.2 Hz, 1H), 7.35 (s, 1H), 5.27 (s, 1H), 4.68 (s, 2H) , 3.96 (d, J= 12.0 Hz, 1H), 3.53 (d, J= 12.0 Hz, 1H), 2.41 - 2.34 (m, 1H), 1.00 (d, J= 6.8 Hz, 3H), 0.76 (d, J= 6.8 Hz, 3H). (S)-8-(3-Fluoro-1H-pyrazol-4-yl)-4-hydroxy-4-isopropyl-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b] Thieno[3,2-d]pyridin-6-one (compound 27): MS observation (ESI +): 350.0 [(M+H) +]. Examples 28 and 29 - Compounds 28 and 29: (S)-4-Hydroxy-8-(1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro -6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 28) and (R)-4-hydroxy-8-(1H-pyrazole-4- Base)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one ( Compound 29) (The stereochemistry of Compounds 28 and 29 is arbitrarily assigned) Step A: 4,4-Dimethoxy-3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol: 4,4-Dimethoxydihydro-2H-pyran-3(4H)-one (500 mg, 3.12 mmol, 1.0 eq. synthesized according to the procedure described in WO2013152269) in THF (5.0 mL ) was added TBAF (81.6 mg, 312 µmol, 90.4 µL, 0.10 equiv). The mixture was stirred at 0 °C for 10 minutes, then trimethyl(trifluoromethyl)silane (666 mg, 4.68 mmol, 744 230 L, 1.5 equiv) was added dropwise. The mixture was warmed to room temperature and stirred at room temperature for 16 hours. The mixture was concentrated and purified by flash column chromatography (SiO2, 12-25% EtOAc / PE) to give 4,4-dimethoxy-3-(trifluoromethyl)tetrahydro-2H-pyran -3-ol (480 mg, 66%). 1H NMR (400 MHz, CDCl 3 ) δppm: 4.02 - 3.99 (m, 2H), 3.85 - 3.82 (m, 2H), 3.37 (s, 6H), 2.03 - 2.02 (m, 2H). Step B: 3-(Benzyloxy)-4,4-dimethoxy-3-(trifluoromethyl)tetrahydro-2H-pyran: To a solution of 4,4-dimethoxy-3-(trifluoromethyl)tetrahydropyran-3-ol (1 g, 4.34 mmol, 1.0 equivalent) in DMF (8.0 mL) at 0°C NaH (333 mg, 8.69 mmol, 60% in mineral oil, 2.0 equiv) was added. The mixture was stirred at 0 °C for 10 min, then bromomethylbenzene (1.49 g, 8.69 mmol, 1.03 mL, 2.0 equiv) was added dropwise. The mixture was stirred at room temperature for 3 h, then quenched with saturated NH 4 Cl(aq), diluted with water (120 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by flash column chromatography (SiO2, 0-7% EtOAc / PE) to give 3-(benzyloxy)- 4,4-Dimethoxy-3-(trifluoromethyl)tetrahydro-2H-pyran (690 mg, 49%). 1H NMR (400 MHz, CDCl 3 ) δppm: 7.38 - 7.20 (m, 5H), 4.87 (d, J= 10.5 Hz, 1H), 4.75 (d, J= 10.5 Hz, 1H), 4.13 - 4.06 (m, 2H), 3.77 - 3.70 (m, 2H), 3.39 (s, 3H), 3.37 (s, 3H), 2.22 - 2.16 (m, 1H), 1.99 - 1.93 (m, 1H). Step C: 3-(Benzyloxy)-3-(trifluoromethyl)tetrahydro-4H-pyran-4-one: To 3-(benzyloxy)-4,4-dimethoxy-3-(trifluoromethyl)tetrahydro-2H-pyran (690 mg, 2.15 mmol, 1.0 equiv) in acetone (15.0 mL) Iodine (54.68 mg, 215.42 µmol, 0.1 equiv) was added to the solution. The reaction mixture was stirred at room temperature for 1 h, then quenched with saturated Na 2 SO 3 (aq) (25 mL) and extracted into DCM (35 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 0-8% EtOAc / PE) to give 3-(benzyloxy)-3-(trifluoromethyl)tetrahydro-4H-pyran-4- Ketones (550 mg, 93%). 1H NMR (400 MHz, CDCl 3 ) δppm: 7.39 - 7.20 (m, 5H), 4.90 (d, J= 11.0 Hz, 1H), 4.62 (d, J= 11.0 Hz, 1H), 4.33 (d, J= 12.8 Hz, 1H), 4.23 - 4.17 (m, 1H), 3.90 (d, J= 12.8 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.02 - 2.94 (m, 1H), 2.54 - 2.48 (m , 1H). Step D: 4-(Benzyloxy)-4-(trifluoromethyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4 -yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one: To 3-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid methyl ester (200 mg, 480 µmol, 1.0 equiv), 3-benzyloxy-3-(trifluoromethyl)tetrahydropyran-4-one (263 mg, 958 µmol, 2.0 equiv) and cesium carbonate (468 mg, 1.44 mmol, 3.0 equiv ) in toluene (12.0 mL) were added Pd 2(dba) 3 (87.8 mg, 95.8 µmol, 0.2 equiv) and Xantphos (111 mg, 192 µmol, 0.4 equiv). The mixture was degassed with N2 and stirred at 105 °C for 16 hours. The mixture was filtered and concentrated in vacuo, followed by purification by flash column chromatography (Si0, 0-20% EtOAc / PE) to afford 4-(benzyloxy)-4-(trifluoromethyl)-8-( 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3- b] Thieno[3,2-d]pyran-6-one (185 mg, 66%). MS observation (ESI+): 579.5 [(M+H)+]. Step E: 4-(Benzyloxy)-4-(trifluoromethyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4 -yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one: To 4-(benzyloxy)-4-(trifluoromethyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl )-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (185 mg, 320 µmol) in MeOH (5.0 mL ) was added ammonium hydroxide (5.0 mL). The mixture was stirred at 100 °C in a microwave reactor for 6 hours, then concentrated in vacuo to give a residue, which was purified by flash column chromatography (SiO2, 0-4% MeOH / DCM) to give 4-(benzyl Oxy)-4-(trifluoromethyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,3 , 4,5-tetrahydro-6H-pirano[4,3-b]thieno[3,2-d]pyridin-6-one (105 mg, 57%). MS observation (ESI+): 578.3 [(M+H)+]. Step F: (S)-4-Hydroxy-8-(1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[ 4,3-b]thieno[3,2-d]pyridin-6-one (compound 28) and (R)-4-hydroxy-8-(1H-pyrazol-4-yl)-4-(tri Fluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 29): 4-(Benzyloxy)-4-(trifluoromethyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole at 0°C -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (105 mg, 181.76 µmol, 1.0 eq) was dissolved in trifluoroacetic acid (2.6 mL). The mixture was stirred at 60 °C for 2 h under microwave irradiation, then concentrated, and the pH was adjusted to about 9 by gradually adding NH 3 / MeOH (7 M). The mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 0-6% MeOH / DCM) to afford racemic 4-hydroxy-8-(1H-pyrazol-4-yl)-4-( Trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (54 mg, 83%) . MS observation (ESI+): 358.0 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-Hydroxy-8-(1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b]Thieno[3,2-d]pyridin-6-one (compound 28): MS observation (ESI +): 358.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm : 13.25 (s, 1H), 10.94 (s, 1H), 8.27 (brs, 2H), 7.48 (s, 1H), 7.13 (s, 1H), 4.89 - 4.77 (m, 2H), 4.23 (d, J = 12.4 Hz, 1H), 3.71 (m, 1H). (R)-4-Hydroxy-8-(1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b] Thieno[3,2-d]pyridin-6-one (compound 29): MS observation (ESI +): 358.0 [(M+H) +]. Examples 30 and 31 - Compounds 30 and 31: (S)-4-Hydroxy-8-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)-1,3,4 ,5-tetrahydro-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 30) and (R)-4-hydroxyl-8-(1- Methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3, 2-d] pyridin-6-one (compound 31) (the stereochemistry of compounds 30 and 31 is arbitrarily assigned) Synthesis was carried out by a similar route to compounds 28 and 29. (S)-4-Hydroxy-8-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyran and[4,3-b]thieno[3,2-d]pyridin-6-one (compound 30). MS observation (ESI +): 372.1 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 11.21 (brs, 1H), 7.65 (s, 1H), 7.54 (d, J= 2.0 Hz, 1H), 7.19 (brs, 1H), 6.72 (d, J= 2.0 Hz, 1H), 4.96 (d, J= 15.2 Hz, 1H), 4.81 (d, J= 15.2 Hz, 1H), 4.25 (d, J= 12.0 Hz, 1H), 4.05 (s, 3H), 3.71 (d, J= 12.0 Hz, 1H). (R)-4-Hydroxy-8-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyran and[4,3-b]thieno[3,2-d]pyridin-6-one (Compound 31). MS observation (ESI+): 372.1 [(M+H)+]. Examples 32 and 33 - Compounds 32 and 33: (S)-4-Hydroxy-8-(5-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4 ,5-tetrahydro-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 32) and (R)-4-hydroxyl-8-(5- Methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3, 2-d] Pyridin-6-one (Compound 33) (The stereochemistry of Compounds 32 and 33 is arbitrarily assigned). Synthesis was carried out by a similar route to compounds 28 and 29. (S)-4-Hydroxy-8-(5-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyran And[4,3-b]thieno[3,2-d]pyridin-6-one. MS observation (ESI +): 372.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6 ) δppm: 12.98 (brs, 1H), 10.90 (brs, 1H), 8.23 ​​- 7.86 (m, 1H), 7.35 (s, 1H), 7.14 (s, 1H), 4.92 (d, 15.02 Hz, 1H), 4.78 (d, 15.02 Hz, 1H), 4.24 (d, J= 12.0 Hz, 1H), 3.70 (d, J= 12.0 Hz, 1H), 2.43 (s, 3H). (R)-4-Hydroxy-8-(5-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)-1,3,4,5-tetrahydro-6H-pyran And[4,3-b]thieno[3,2-d]pyridin-6-one. MS observation (ESI+): 372.0 [(M+H)+]. Examples 34 and 35 - Compounds 34 and 35: (S)-4-(hydroxymethyl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-piper Furo[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (compound 34) and (R)-4-(hydroxymethyl)-4-methyl-8- (1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (compound 35 ) (The stereochemistry of compounds 34 and 35 is arbitrarily assigned) Step A: 2-(2-Hydroxytetrahydrofuran-2-yl)benzyl acetate: Benzyl 2-bromoacetate (19.2 g, 83.6 mmol, 1.2 equivalents), indium (9.60 g, 83.6 mmol, 1.2 equivalents), tetrahydrofuran-2-one (6.0 g, 69.7 mmol, 1.0 equivalents) and THF (21.0 mL ) mixture was stirred at 70°C for 16 hours. The reaction was quenched with saturated aqueous NaHCO 3 (20 mL) and extracted with EtOAc (60 mL×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash column chromatography (SiO 2 , 10-20% EtOAc / DCM) gave benzyl 2-(2-hydroxytetrahydrofuran-2-yl)acetate (4.0 g, 24%). MS Observation (ESI+): 219.2 [(M+H-H2O)+]. Step B : Benzyl 2-diazo-6-hydroxy-3-oxohexanoate: 2-(2-Hydroxytetrahydrofuran-2-yl) benzyl acetate (700 mg, 2.96 mmol, 1.0 equivalent) and N-diazo-2,4,6-triisopropyl-benzenesulfonyl To a solution of the amine (1.01 g, 3.26 mmol, 1.1 equiv) in THF (10.0 mL) was added N,N-diethylethylamine (900 mg, 8.9 mmol, 3.0 equiv). The mixture was stirred at room temperature for 16 hours, then concentrated. The residue was purified by flash column chromatography (Si02, 15-30% EtOAc / PE) to give benzyl 2-diazo-6-hydroxy-3-oxo-hexanoate (1.18 g, 81%). MS observation (ESI+): 263.2 [(M+H)+]. Step C: Benzyl 3-oxotetrahydro-2H-pyran-2-carboxylate: A solution of benzyl 2-diazo-6-hydroxy-3-oxo-hexanoate (1.0 g, 3.81 mmol, 1.0 equiv) in benzene (50.0 mL) was added dropwise to In a solution of Rh 2(OAc) 4 (50.0 mg, 113 µmol, 0.030 equiv) in benzene (50.0 mL). The mixture was stirred at 100 °C for 1 hour, then filtered and concentrated to give benzyl 3-oxotetrahydro-2H-pyran-2-carboxylate (180 mg, crude material), which was used without purification in the following in one step. MS observation (ESI+): 235.2 [(M+H)+]. Step D: Benzyl 2-methyl-3-oxotetrahydro-2H-pyran-2-carboxylate: Sodium hydride (247 mg , 5.70 mmol, 60% in mineral oil, 1.5 equivalents). The mixture was stirred for 10 minutes, then iodomethane (1.62 g, 11.40 mmol, 3.0 equiv) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by flash column chromatography (SiO2, 0-10% EtOAc / PE) to give 2-methyl- Benzyl 3-oxotetrahydro-2H-pyran-2-carboxylate (474 ​​mg, 50%). MS observation (ESI+): 271.0 [(M+Na)+]. Step E: 4-methyl-6-oxo-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1, Benzyl 2,4,6-tetrahydropyrano[3,4-b]thieno[3,2-d]pyran-4-carboxylate: 3-Bromo-5-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]thiophene-2-carboxylic acid methyl ester (84.1 mg, 201 µmol, 1.0 equiv), 2 -Methyl-3-oxotetrahydro-2H-pyran-2-carboxylic acid benzyl ester (100 mg, 403 µmol, 2.0 equiv), sodium metabisulfite (11.5 mg, 60.4 µmol, 0.3 equiv), Cs A mixture of 2CO 3 (197 mg, 604 µmol, 3.0 equiv), Sphos-Pd-G3 (31.4 mg, 40.3 µmol, 0.2 equiv) and toluene (15.0 mL) was stirred at 105°C for 16 hours. The mixture was poured into water and extracted with EtOAc (70 mL×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , 0-25% EtOAc / PE) to give 4-methyl-6-oxo-8-(1-((2-(trimethylsilyl )ethoxy)methyl)-1H-pyrazol-4-yl)-1,2,4,6-tetrahydropyrano[3,4-b]thieno[3,2-d]pyrano - Benzyl 4-carboxylate (78 mg, 70%). MS observation (ESI+): 553.5 [(M+H)+]. Step F: 4-(Hydroxymethyl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 1,4-Dihydropyrano[3,4-b]thieno[3,2-d]pyran-6(2H)-one: 4-Methyl-6-oxo-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2, Benzyl 4,6-tetrahydropyrano[3,4-b]thieno[3,2-d]pyran-4-carboxylate (50 mg, 90.5 µmol, 1.0 equiv), calcium dichloride (50.2 mg , 452 µmol, 5 eq) and EtOH (5.0 mL) were stirred at room temperature for 20 minutes, then sodium borohydride (51.3 mg, 1.36 mmol, 15.0 eq) was added to the mixture portionwise at 0 °C, followed by Stir for 20 minutes. The mixture was poured into water and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , 50% EtOAc / PE) to give 4-(hydroxymethyl)-4-methyl-8-(1-((2-(trimethylsilyl )ethoxy)methyl)-1H-pyrazol-4-yl)-1,4-dihydropyrano[3,4-b]thieno[3,2-d]pyran-6(2H )-ketone (20 mg, 49%). MS observation (ESI+): 449.2 [(M+H)+]. Step G: 4-(Hydroxymethyl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 1,5-Dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one: 4-(Hydroxymethyl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1, 4-dihydropyrano[3,4-b]thieno[3,2-d]pyran-6(2H)-one (60 mg, 134 µmol), ammonium hydroxide (3.5 mL) and MeOH ( 3.5 mL) of the mixture was stirred in a microwave reactor at 100 °C for 3 h. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (Si0, 15-35% EtOAc / PE) to give 4-(hydroxymethyl)-4-methyl-8-(1-((2- (Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2 -d] pyridin-6(4H)-one (20 mg, 33%). MS observation (ESI+): 448.5 [(M+H)+]. Step H: (S)-4-(Hydroxymethyl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4 -b] Thieno\[3,2-d]pyridin-6(4H)-one (compound 34) and (R)-4-(hydroxymethyl)-4-methyl-8-(1H-pyrazole -4-yl)-1,5-dihydro-2H-pyrano\[3,4-b]thieno\[3,2-d]pyridin-6(4H)-one (compound 35): Add trichloroborane (1 M, 890 µL, 5.0 equiv) to 4-(hydroxymethyl)-4-methyl-8-(1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridine-6( 4H)-Kone (80 mg, 180 µmol) in DCM (50.0 mL). The mixture was stirred at room temperature for 2 hours, then quenched with MeOH and concentrated in vacuo. The residue was basified with NaHCO 3 and purified by column chromatography (SiO 2 , 0-6% MeOH / DCM) to give racemic 4-(hydroxymethyl)-4-methyl-8-(1H- Pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (32 mg, 56% ). MS observation (ESI+): 318.5 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-(Hydroxymethyl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thiophene And[3,2-d]pyridin-6(4H)-one (compound 34): MS observation (ESI +): 318.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm : 13.22 (brs, 1H), 10.90 (brs, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.48 (s, 1H), 4.87 (s, 1H), 4.09 - 3.96 (m, 1H ), 3.93 - 3.72 (m, 2H), 3.51 (d, J= 11.6 Hz, 1H), 2.86 - 2.58 (m, 2H), 1.39 (s, 3H). (R)-4-(Hydroxymethyl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thiophene And[3,2-d]pyridin-6(4H)-one (compound 35): MS observation (ESI +): 318.0 [(M+H) +]. Examples 36 and 37 - Compounds 36 and 37: (S)-6-(difluoromethyl)-6-hydroxyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydro Thieno[2,3-c]quinolin-4(5H)-one (compound 36) and (R)-6-(difluoromethyl)-6-hydroxy-2-(1H-pyrazole-4- base)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 37) (the stereochemistry of compounds 36 and 37 is arbitrarily designated) Step A: 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-8,9-dihydro-4H-thieno[2 ,3-c] En-4,6(7H)-dione: Methyl 3-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylate (200 mg, 480 µmol, 1.0 eq) and cyclohexane-1,2-dione (1.1 g, 9.6 mmol, 20 eq) were dissolved in anhydrous toluene (40.0 mL), then Sphos-Pd-G3 (56 mg, 96 µmol 0.20 equiv), Cs 2CO 3 (470 mg, 1.40 mmol, 3.0 equiv) and Na 2S 2O 5 (18 mg, 0.096 mmol, 0.20 equiv). The mixture was degassed with N2 and heated to 105 °C for 16 h. The mixture was cooled, concentrated in vacuo, and purified by flash column chromatography (SiO 2 , 0-45% EtOAc / PE). Further purification (SiO2, 0-8% MeOH / DCM) gave 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-8 ,9-Dihydro-4H-thieno[2,3-c] ene-4,6(7H)-dione (20 mg, 10%). MS observation (ESI+): 417.5 [(M+H)+]. Step B: 6-(difluoromethyl)-6-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: Cesium fluoride (55 mg, 0.36 mmol, 2.5 equiv) was added to 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-8,9-dihydro-4H-thieno[2,3-c] To a solution of ene-4,6(7H)-dione (60 mg, 0.144 mmol, 1.0 equiv) in anhydrous DMF (4.0 mL), difluoromethyl(trimethyl)silane (90 mg, 0.72 mmol, 100 µL, 5.0 equiv). The mixture was stirred at room temperature for 24 h, then diluted with water (50 mL), and extracted with EtOAc (40 mL×4). The combined org. phases were dried (Na 2 SO 4 ), filtered and concentrated. Purification (SiO2, 0-39% EtOAc / PE) afforded 6-(difluoromethyl)-6-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl) -1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (23 mg, 34%). MS observation (ESI+): 469.4 [(M+H)+]. Step C: 6-(difluoromethyl)-6-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: 6-(difluoromethyl)-6-hydroxyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6, 7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (65 mg, 0.14 mmol) was added to NH4OH (5.0 mL, saturated aqueous solution) followed by MeOH (5.0 mL). The mixture was heated to 95 °C in a microwave reactor for 10 hours, then concentrated to give 6-(difluoromethyl)-6-hydroxy-2-(1-((2-(trimethylsilyl)ethyl) Oxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (65 mg, crude material). This material was used in the next step without further purification. MS observation (ESI+): 468.5 [(M+H)+]. Step D: (S)-6-(difluoromethyl)-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3- c] quinolin-4(5H)-one (compound 36) and (R)-6-(difluoromethyl)-6-hydroxyl-2-(1H-pyrazol-4-yl)-6,7, 8,9-Tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 37): 6-(difluoromethyl)-6-hydroxyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6, 7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (180 mg, 370 µmol) was dissolved in DCM (15.0 mL) and cooled to 0 °C, followed by addition of trifluoroacetic acid (3.0 mL). The reaction mixture was warmed to room temperature, and after 4 hours, the mixture was concentrated in vacuo. The residue was purified (C18 SiO 20-25% MeCN / water (0.1% NH4OH)) to give racemic 6-(difluoromethyl)-6-hydroxy-2-(1H-pyrazol-4-yl )-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (40 mg, 26%). MS observation (ESI+): 388.4 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-6-(Difluoromethyl)-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinone Lin-4(5H)-one (compound 36): MS observation (ESI +): 388.1 [(M+H) +]. (R)-6-(Difluoromethyl)-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinone Lin-4(5H)-one (compound 37): MS observation (ESI+): 388.1 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 13.22 (s, 1H), 10.68 (s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.54 (s, 1H), 6.52 (t, J= 55.6 Hz, 1H), 6.26 (s, 1H), 2.77 - 2.73 ( m, 1H), 2.68 - 2.61 (m, 1H), 2.10 - 2.04 (m, 1H), 1.87 - 1.85 (m, 3H). Examples 38 and 39 - Compounds 38 and 39: (S)-9-methoxy-9-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno [2,3-c]quinolin-4(5H)-one (compound 38) and (R)-9-methoxy-9-methyl-2-(1H-pyrazol-4-yl)-6 ,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 39) (the stereochemistry of compounds 38 and 39 is arbitrarily designated) Step A : 7,8-Dihydro-4H-thieno[2,3-c] En-4,9(6H)-dione: Dissolve methyl 3-bromothiophene-2-carboxylate (0.50 g, 2.3 mmol, 1.0 equiv) and cyclohexane-1,3-dione (1.5 g, 14 mmol, 6.0 equiv) in toluene (80.0 mL) , followed by addition of Cs 2 CO 3 (2.2 g, 6.8 mmol, 3.0 equiv) and SPhos-Pd-G3 (180 mg, 230 μmol, 0.10 equiv). The mixture was heated to 105 °C for 16 h, cooled, and diluted with H2O (50 mL). The mixture was extracted with EtOAc (50 mL×3), and the combined organic phases were washed with brine (50 mL), dried (Na 2 SO 4 ), filtered and concentrated. Purified by column chromatography (SiO 2 , 0-20% EtOAc / PE to give 7,8-dihydro-4H-thieno[2,3-c] En-4,9(6H)-dione (82 mg, 14%). MS observation (ESI+): 221.2 [(M+H)+]. Step B : 7,8-Dihydrothieno[2,3-c]quinoline-4,9(5H,6H)-dione : 7,8-Dihydro-4H-thieno[2,3-c] En-4,9(6H)-dione (550 mg, 2.50 mmol, 1.0 equiv) was dissolved in MeOH (8.0 mL), followed by the addition of NH4OH (8 mL, saturated aqueous solution). The reaction mixture was heated to 90 °C in a microwave reactor for 4 h, cooled, and concentrated in vacuo. Purified by column chromatography (SiO2, 0-25% MeOH / DCM) to give 7,8-dihydrothieno[2,3-c]quinoline-4,9(5H,6H)-dione (420 mg, 77%). MS observation (ESI+): 220.2 [(M+H)+]. Step C: 5-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydrothieno\[2,3-c]quinoline-4,9(5H,6H )- diketones: 7,8-Dihydrothieno[2,3-c]quinoline-4,9(5H,6H)-dione (1.3 g, 5.9 mol, 1.0 equiv) in anhydrous DMF (60.0 mL) The solution was cooled to 0 °C, then NaH (360 mg, 8.9 mmol, 60% in mineral oil, 1.5 equiv) was added. After 30 minutes, 2-(chloromethoxy)ethyl-trimethyl-silane (2.0 g, 12 mmol, 2.1 mL, 2.0 equiv) was added, and the mixture was allowed to warm to room temperature, where it was stirred for 2 hours. Water (150 mL) was added, and the mixture was extracted with EtOAc (100 mL×3). The combined organic phases were washed (brine, 100 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-30% EtOAc / PE) gave 5-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydrothieno [2,3-c]quinoline-4,9(5H,6H)-dione (1.0 g, 48%). MS observation (ESI+): 350.5 [(M+H)+]. Step D : 9-Hydroxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrothieno[2,3- c] Quinolin-4(5H)-one: 5-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydrothieno[2,3-c]quinoline-4,9(5H,6H)-di The ketone (1.0 g, 2.9 mmol, 1.0 equiv) was dissolved in THF (30.0 mL), and the solution was cooled to 0 °C, followed by the addition of methylmagnesium bromide (1 M, 57.0 mL, 57 mmol, 20 equiv). The reaction mixture was warmed to room temperature and stirred for 2 hours, then water (100 mL) was added. The mixture was extracted with EtOAc (100 mL×3), and the combined organic phases were washed with brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification by column chromatography (SiO 20-30% EtOAc / PE) afforded 9-hydroxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-6 , 7,8,9-Tetrahydrothieno[2,3-c]quinolin-4(5H)-one (320 mg, 27%). MS observation (ESI+): 366.5 [(M+H)+]. Step E: 9-methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrothieno[2, 3-c] quinolin-4(5H)-one: To 9-hydroxy-9-methyl-5-( (2-(Trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (330 mg, 0.90 mmol, 1.0 equiv) in anhydrous THF (15.0 mL). After 2 hours, water (50 mL) was added, and the mixture was extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (30 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification by column chromatography (SiO 2 , 0-15% EtOAc / PE) gave 9-methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy base)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (190 mg, 55%). MS observation (ESI+): 380.6 [(M+H)+]. Step F: 2-iodo-9-methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrothiophene And[2,3-c]quinolin-4(5H)-one: 9-methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrothieno[2,3- c] Quinolin-4(5H)-one (140 mg, 0.37 mmol, 1.0 equiv) was dissolved in THF (8.0 mL) and cooled to -65 °C. Lithium diisopropylamide (2 M, 0.7 mL, 1.5 mmol, 4.0 equiv) was added, followed by iodine (190 mg, 0.74 mmol, 2.0 equiv), and the mixture was stirred at -65°C for 2 hours. Water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification by column chromatography (SiO 2 , 0-15% EtOAc / PE) afforded 2-iodo-9-methoxy-9-methyl-5-((2-(trimethylsilyl)ethane oxy)methyl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (120 mg, 62%). MS observation (ESI+): 506.6 [(M+H)+]. Step G: 9-Methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-2-(1-((2-(trimethylsilyl) )ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: Pd(dppf)Cl 2 (32 mg, 40 µmol, 0.20 equiv), XPhos (42 mg, 90 µmol, 0.40 equiv) and Na 2CO 3 (70 mg, 0.65 mmol, 3.0 equiv) were added to 2-iodo-9 -Methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrothieno[2,3-c] Quinolin-4(5H)-one (110 mg, 0.22 mmol, 1.0 equiv) and trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (110 mg, 0.35 mmol, 1.6 equivalents) in H 2 O / 1,4-di Alkanes (8.0 mL, 1:3 mixture). The mixture was heated to 110 °C for 2 hours, then concentrated in vacuo. Purification by column chromatography (0-30% EtOAc / PE) gave 9-methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)- 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3 -c] Quinolin-4(5H)-one (110 mg, 88%). MS observation (ESI+): 576.9 [(M+H)+]. Step H: (9S)-9-methoxy-9-methyl-2-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydrothieno[2,3-c] Quinolin-4-one (compound 38) and (9R)-9-methoxy-9-methyl-2-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydrothiophene And[2,3-c]quinolin-4-one (compound 39): Add BCl3 (1.0 M, 1.1 mL, 1.1 mmol, 5.0 equiv) to 9-methoxy-9-methyl-5-((2-(trimethylsilyl)ethoxy) at 0 °C Methyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno A solution of [2,3-c]quinolin-4(5H)-one (130 mg, 0.22 mmol, 1.0 equiv) in DCM (13.0 mL). After 10 min, NH 3 / MeOH (to pH 9) was added, and the mixture was concentrated in vacuo. Purification by column chromatography (C18 SiO 2 , 0-20% MeCN / water (0.1% NH 4OH)) gave racemic 9-methoxy-9-methyl-2-(1H-pyrazole- 4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (24 mg, 34%). MS observation (ESI+): 316.2 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (9S)-9-methoxy-9-methyl-2-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydrothieno[2,3-c]quinoline- 4-Keto (compound 38): MS observation (ESI +): 316.2 [(M+H) +]. (9R)-9-methoxy-9-methyl-2-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydrothieno[2,3-c]quinoline- 4-Keto (compound 39) MS observation (ESI +): 316.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 13.21 (s, 1H), 11.29 (s, 1H), 8.32 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 2.94 (s, 3H), 2.70 - 2.52 (m, 2H), 2.15 - 2.01 (m, 1H), 1.95 - 1.87 ( m, 1H), 1.83 - 1.67 (m, 1H), 1.55 - 1.65 (m, 1H), 1.50 (m, 3H). Examples 40 and 41 - Compounds 40 and 41: (S)-6-hydroxyl-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2 ,3-c] quinolin-4(5H)-one (compound 40) and (R)-6-hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8 ,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 41) (the stereochemistry of compounds 40 and 41 is arbitrarily designated) Step A: 4-(6-Hydroxy-4-oxo-4,5,6,7,8,9-hexahydrothieno[2,3-c]quinolin-2-yl)-1H-pyridine Azole-1-carboxylic acid tertiary butyl ester: Triethylamine (280 mg, 2.8 mmol, 2.0 equiv), DMAP (85 mg, 70 µmol, 0.50 equiv) and (Boc)2O (300 mg, 1.40 mmol, 1.0 equiv) were added to 6-hydroxy-2-( 1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-5H-thieno[2,3-c]quinolin-4-one (400 mg, 1.40 mmol, 1.0 equiv) in DMF (20.0 mL) in suspension. The mixture was stirred at room temperature for 16 h, then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. Purification by column chromatography (SiO 2 , 0-100% EtOAc / PE) gave 4-(6-hydroxy-4-oxo-4,5,6,7,8,9-hexahydrothieno [2,3-c]quinolin-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (400 mg, 74%). MS observation (ESI+): 388.5 [(M+H)+]. Step B: 4-(4,6-Dioxo-5,7,8,9-tetrahydrothieno[2,3-c]quinolin-2-yl)pyrazole-1-carboxylic acid tertiary butyl Esters: 4-(6-Hydroxy-4-oxo-4,5,6,7,8,9-hexahydrothieno[2,3-c]quinolin-2-yl)-1H-pyrazole- 1-Tertiary butyl carboxylate (140 mg, 0.36 mmol, 1.0 equivalent) and (1,1-diacetyloxy-3-oxo-1,2-benzoiodooxol-1-yl ) acetate (110 mg, 3.6 mmol, 10 eq) in DCM (14.0 mL) was stirred at room temperature for 1 h. The mixture was concentrated and the residue was purified by column chromatography (SiO 2 , 0-10% MeOH / DCM) to give 4-(4,6-dioxo-5,7,8,9-tetrahydrothieno [2,3-c]quinolin-2-yl)pyrazole-1-carboxylic acid tert-butyl ester (120 mg, 87%). MS observation (ESI+): 386.5 [(M+H)+]. Step C: (S)-6-Hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline -4(5H)-one (compound 40) and (R)-6-hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno [2,3-c]quinolin-4(5H)-one (compound 41): Add methylmagnesium bromide (1.0 M, 4.8 mL, 4.8 mmol, 3.0 equiv) to 4-(6-hydroxy-4-oxo-4,5,6,7,8,9-hexahydrothieno A solution of [2,3-c]quinolin-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (60 mg, 0.16 mmol, 1.0 equiv) in THF (24.0 mL). The mixture was stirred at room temperature for 2 hours, then MeOH was added, and the resulting mixture was concentrated in vacuo and purified by column chromatography (Si0, 0-10% MeOH / DCM) to afford racemic 6-hydroxy-6- Methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (39 mg, 62 % ). Individual enantiomers were separated via chiral SFC. (S)-6-Hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4( 5H)-ketone (compound 40): MS observation (ESI +): 302.1 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 13.10 (s, 1H), 10.51 (s, 1H), 8.12 (s, 2H), 7.46 (s, 1H), 5.12 (s, 1H), 2.32 - 2.51 (m, 2H), 1.88 - 1.82 (m, 3H), 1.78 - 1.67 (m, 1H) , 1.46 (s, 3H). (R)-6-Hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4( 5H)-Kone (compound 41): MS observation (ESI +): 302.1 [(M+H) +]. Examples 42 and 43 - Compounds 42 and 43: (S)-4-(difluoromethyl)-4-hydroxyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro -6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 42) and (R)-4-(difluoromethyl)-4-hydroxyl-8 -(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one ( Compound 43) (The stereochemistry of Compounds 42 and 43 is arbitrarily assigned) Step A : 4-Hydroxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H, 6H-Pyrano[4,3-b]thieno[3,2-d]pyran-6-one: Sodium hydride (140 mg, 3.4 mmol, 60% in mineral oil, 2.0 equiv) was added to 4-hydroxy-8-(1H-pyrazol-4-yl)-3,4-dihydro-1H,6H- In a cooled (0°C) solution of pyrano[4,3-b]thieno[3,2-d]pyran-6-one (500 mg, 1.7 mmol, 1.0 equiv) in DMF (20.0 mL) . After 10 min at 0 °C, SEMCl (370 µL, 350 mg, 2.0 mmol, 1.2 equiv) was slowly added to the mixture. The mixture was stirred at room temperature for 2 h, then quenched with ammonium chloride (sat. aq.), followed by extraction with EtOAc (25 mL×3). The combined organic phases were treated with brine, dried (Na 2 SO 4 ), filtered and concentrated. Purification by column chromatography (SiO 2 , 0-40% EtOAc / DCM) afforded 4-hydroxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (400 mg, 52 %). MS observation (ESI+): 421.2 [(M+H)+]. Step B : 8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H,3H-pyrano[4,3-b ] Thieno[3,2-d]pyran-4,6-dione: 4-Hydroxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H,6H- Pirano[4,3-b]thieno[3,2-d]pyran-6-one (400 mg, 950 µmol, 1.0 equivalent) was dissolved in DCM (20.0 mL) and DMF (20.0 mL), And (1,1-diacetyloxy-3-oxo-1,2-benzoiodooxol-1-yl)acetate (1.2 g, 2.9 mmol, 3.0 equiv) was added. The mixture was stirred at room temperature for 16 h, then quenched with Na 2 S 2 O 3 (sat aq) and NaHCO 3 (sat aq). The mixture was extracted with EtOAc (30 mL x 3) and the combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated. Purification by column chromatography (SiO 2 , 0-30% EtOAc / DCM) gave 8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-1H,3H-pyrano[4,3-b]thieno[3,2-d]pyran-4,6-dione (270 mg, 63%). MS observations (ESI +): 419.2 [(M+H) +], 436.2 [(M+NH 4) +]. Step C: 4-(difluoromethyl)-4-hydroxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 3,4-Dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one: Cesium fluoride (210 mg, 1.4 mmol, 2.5 equiv) was added to 8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 1H,3H-Pyrano[4,3-b]thieno[3,2-d]pyran-4,6-dione (270 mg, 560 µmol, 1.0 equiv) in DMF (24.0 mL) solution, followed by the addition of TMSCF 2H (350 mg, 2.8 mmol, 400 µL, 5.0 equiv). The mixture was stirred for 16 hours. Water was added, and the mixture was extracted with EtOAc (25 mL×5). The combined organic phases were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. Purification by column chromatography (SiO2, 0-40% EtOAc / PE) gave 4-(difluoromethyl)-4-hydroxy-8-(1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran -6-keto (48 mg, 16%). MS observation (ESI+): 471.4 [(M+H)+]. Step D: 4-(difluoromethyl)-4-hydroxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one: Add ammonia (8.0 mL, 25% w / w) to 4-(difluoromethyl)-4-hydroxy-8-(1-((2-(trimethylsilyl)ethoxy)methyl) -1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (140 mg , 260 µmol, 1.0 equiv) in a solution in i-PrOH (8.0 mL). The mixture was heated to 100 °C in a microwave reactor for 6 h, then cooled and concentrated. Purification by column chromatography (SiO 2 , 0-8% MeOH / DCM) gave 4-(difluoromethyl)-4-hydroxy-8-(1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d] Pyridin-6-one (55 mg, 41%). MS observation (ESI+): 470.2 [(M+H)+]. Step E: (S)-4-(difluoromethyl)-4-hydroxyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano\ [4,3-b]thieno\[3,2-d]pyridin-6-one (compound 42) and (R)-4-(difluoromethyl)-4-hydroxyl-8-(1H-pyridine Azol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano\[4,3-b]thieno\[3,2-d]pyridin-6-one (compound 43) : 4-(difluoromethyl)-4-hydroxyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1, 3,4,5-Tetrahydro-6H-pirano[4,3-b]thieno[3,2-d]pyridin-6-one (10 mg, 21 µmol) was dissolved in DCM:trifluoroacetic acid ( 4.0 mL, 3:1). The mixture was stirred at room temperature for 1 h, then concentrated and purified by reverse phase HPLC (C18 Si02, 0-15% MeCN / water (0.1% NH4OH)). Further purification by column chromatography (SiO 2 , 0-8% MeOH / DCM) gave racemic 4-(difluoromethyl)-4-hydroxy-8-(1H-pyrazol-4-yl) - 1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (1.3 mg, 17%). MS observation (ESI+): 340.0 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-(Difluoromethyl)-4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b]Thieno[3,2-d]pyridin-6-one (compound 42): MS observation (ESI +): 340.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm : 13.24 (s, 1H), 11.04 (s, 1H), 8.29 (s, 1H), 7.99 (s, 1H), 7.47 (s, 1H), 6.57 (s, 1H), 6.44 (t, J= 55.0 Hz, 1H), 4.76 (s, 2H), 4.11 (d, J= 12.0 Hz, 1H), 3.72 (d, J= 12.0 Hz, 1H). (R)-4-(Difluoromethyl)-4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b] Thieno[3,2-d]pyridin-6-one (compound 43): MS observation (ESI +): 340.2 [(M+H) +]. Examples 44 and 45 - Compounds 44 and 45: (S)-4-Hydroxy-4-isopropyl-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano [4,3-b]thieno[3,2-d]pyridin-6-one (compound 44) ​​and (R)-4-hydroxy-4-isopropyl-8-(pyridin-4-yl)- 1,3,4,5-tetrahydro-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 45) (the stereochemistry of compounds 44 and 45 arbitrary designation) Step A: 4,4-Dimethoxy-3-(prop-1-en-2-yl)tetrahydro-2H-pyran-3-ol: To 4,4-dimethoxydihydro-2H-pyran-3(4H)-one (5.0 g, 31 mmol, 1.0 eq., synthesized according to the procedure described in WO2013152269) at 0 °C under N2 atmosphere ) in anhydrous THF (100 mL) was added bromo(isopropenyl)magnesium (1 M, 125.0 mL, 125 mmol, 4.0 equiv). After the addition, the mixture was stirred at 0 °C for 30 min, then warmed to 25 °C and stirred for an additional 2 h under N2. The mixture was cooled to 0 °C, then quenched with saturated NH 4 Cl(aq) (120 mL), diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. Purification by column chromatography (SiO 2 , 0-25% EtOAc / PE) gave 4,4-dimethoxy-3-(prop-1-en-2-yl)tetrahydro-2H-pyran -3-ol (3.5 g, 55%). 1H NMR (400 MHz, CDCl 3 ) δ ppm: 5.37 (m, 1H), 5.08 - 5.03 (m, 1H), 3.76 (d, J= 11.4 Hz, 1H), 3.72 - 3.60 (m, 2H), 3.36 (d, J= 11.4 Hz, 1H), 3.32 (d, J= 2.8 Hz, 6H), 2.08 - 1.99 (m, 1H), 1.98 - 1.95 (m, 3H), 1.94 - 1.87 (m, 1H). Step B : 3-Hydroxy-3-isopropyltetrahydro-4H-pyran-4-one: 4,4-Dimethoxy-3-(prop-1-en-2-yl)tetrahydro-2H-pyran-3-ol (17.5 g, 82.20 mmol ) was added to methanol (500.0 mL), 4 N aqueous HCl (20.0 mL) and Pd / C (998.34 mg, 8.22 mmol). The vessel was sealed and shaken under 20 atm hydrogen pressure at room temperature for 8 hours. After purging with nitrogen, the container was not sealed and the mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo to afford 3-hydroxy-3-isopropyltetrahydro-4H-pyran-4-one (10.9 g, 65.46 mmol, 79.63% yield, 95% purity) as a yellow liquid. MS observation (ESI+): 159.2 [(M+H)+]. Step C: 4-Hydroxy-4-isopropyl-8-(pyridin-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2 -d] pyran-6-one: 3-Bromo-5-(pyridine -4-yl)thiophene-2-carboxylic acid methyl ester (100 mg, 0.34 mmol, 1.0 equivalent), ginseng (dibenzylideneacetone) dipalladium (61 mg, 0.67 mmol, 0.20 equivalent), 4,5-bis (Diphenylphosphino)-9,9-dimethyldibenzopyran (116 mg, 0.20 mmol, 0.60 equiv), cesium carbonate (219 mg, 0.67 mmol, 2.0 equiv) and sodium metabisulfite (13 mg, 0.070 mmol, 0.20 equiv). The mixture was stirred at 105 °C for 16 h, then concentrated. The residue was diluted with water (20 mL), extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 1-50% EtOAc / PE) to give racemic 4-hydroxy-4-isopropyl-8-(pyridin-4-yl)-3,4- Dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one. MS observation (ESI+): 344.4 [(M+H)+]. Step D: (S)-4-Hydroxy-4-isopropyl-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b] Thieno[3,2-d]pyridin-6-one (compound 44) ​​and (R)-4-hydroxy-4-isopropyl-8-(pyridin-4-yl)-1,3,4,5 - Tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 45): 4-Hydroxy-4-isopropyl-8-(pyridin-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d A solution of ]pyran-6-one (62 mg, 0.18 mmol, 1.0 equiv) in a mixture of NH4OH (3.0 mL) and MeOH (3.0 mL) was heated at 100 °C for 3 h in a microwave reactor. The mixture was concentrated and the residue was purified by column chromatography (Si02, 1-5% EtOAc / PE) to afford racemic 4-hydroxy-4-isopropyl-8-(pyridin-4-yl)-1, 3,4,5-Tetrahydro-6H-pirano[4,3-b]thieno[3,2-d]pyridin-6-one (17 mg, 28%). MS observation (ESI+): 343.5 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-Hydroxy-4-isopropyl-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[ 3,2-d]pyridin-6-one (compound 44): MS observation (ESI +): 343.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6 ) δppm: 11.07 (s, 1H), 8.69 (d, J= 6.0 Hz, 2H), 8.04 (s, 1H), 7.81 (d, J= 6.0 Hz, 2H), 5.31 (s, 1H), 4.73 (s, 2H), 3.98 ( d, J= 12.0 Hz, 1H), 3.55 (d, J= 11.6 Hz, 1H), 2.39 - 2.25 (m, 1H), 1.00 (d, J= 6.8 Hz, 3H), 0.77 (d, J= 7.2 Hz, 3H). (R)-4-Hydroxy-4-isopropyl-8-(pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[ 3,2-d]pyridin-6-one (compound 45): MS observation (ESI +): 343.2 [(M+H) +]. Examples 46 and 47 - Compounds 46 and 47: (S)-4-Hydroxy-4-isopropyl-8-(isothiazol-5-yl)-1,3,4,5-tetrahydro-6H-pyran And[4,3-b]thieno[3,2-d]pyridin-6-one (compound 46) and (R)-4-hydroxy-4-isopropyl-8-(isothiazol-5-yl )-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 47) Racemic 4-Hydroxy-4-isopropyl-8-(isothiazol-5-yl)-3,4-dihydro-1H-pyrano[4,3-b]thieno[3,2- d] Pyridin-6(5H)-one was synthesized via a similar route to compounds 43 and 44). The enantiomers were obtained by separation via chiral SFC. (S)-4-Hydroxy-4-isopropyl-8-(isothiazol-5-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno [3,2-d]pyridin-6-one (compound 46): MS observation (ESI +): 349.0 [(M+H) +]. (R)-4-Hydroxy-4-isopropyl-8-(isothiazol-5-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno [3,2-d]pyridin-6-one (compound 47): MS observation (ESI +): 349.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6 ) δppm: 11.10 (s , 1H), 8.64 (d, J= 2.0 Hz, 1H), 7.84 (d, J= 2.0 Hz, 1H), 7.81 (s, 1H), 5.31 (s, 1H), 4.71 (s, 2H), 3.97 (d, J= 11.6 Hz, 1H), 3.54 (d, J= 11.6 Hz, 1H), 2.40 - 2.37 (m, 1H), 1.01 - 0.99 (d, J= 6.8 Hz, 3H), 0.77 - 0.75 ( d, J= 6.8 Hz, 3H). Examples 48 and 49 - Compounds 48 and 49: (S)-8,8-difluoro-6-hydroxy-6-(methoxymethyl)-2-(1H-pyrazol-4-yl)-6, 7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 48) and (R)-8,8-difluoro-6-hydroxyl-6-(methyl Oxymethyl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 49 ) Step A : 5,5-difluoro-2,2-dimethoxycyclohexan-1-one: To a solution of 5,5-difluoro-2,2-dimethoxy-cyclohexanol (29.4 g, 150 mmol, synthesized according to the procedure of Compound 12 Step A) in DCM (800.0 mL) was added gradually over 20 minutes. Dess-Martin periodinane (95.4 g, 225 mmol) was added in portions. The mixture was stirred for 2 hours, then concentrated. The residue was diluted with water, washed with petroleum ether:ethyl acetate (10:1,500 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , 12% EtOAc / PE) to give 5,5-difluoro-2,2-dimethoxycyclohexan-1-one (16.2 g, 55%). 1H NMR (400 MHz, CDCl 3 ): δppm: 3.27 (s, 6H), 3.04 (t, J= 14.4 Hz, 2H), 2.28 ppm (m, 2H), 2.02 (m, 2H). Step B : 5,5-Difluoro-2,2-dimethoxy-1-vinylcyclohexan-1-ol: To a solution of 5,5-difluoro-2,2-dimethoxycyclohexan-1-one (1.2 g, 6.2 mmol, 1.0 equiv) in anhydrous THF (30.0 mL) dropwise at 0°C Bromo(vinyl)magnesium (1 M, 18.5 mL, 3.0 equiv) was added. The mixture was stirred at room temperature for 1 h, then poured into saturated NH 4 Cl(aq) (10 mL) and extracted with ethyl acetate (40 mL×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , 0-10% EtOAc / PE) to give 5,5-difluoro-2,2-dimethoxy-1-vinylcyclohexan-1-ol ( 630 mg, 45%). 1H NMR (400 MHz, CDCl 3): δppm: 6.19 (dd, J= 17.2, 10.8 Hz, 1H), 5.47 (dd, J= 17.2, 1.6 Hz, 1H), 5.13 (dd, J= 10.8, 1.6 Hz , 1H), 3.24 (s, 3H), 3.23 (s, 3H), 2.54 (s, 1H), 2.16 - 1.74 (m, 6H). Step C: (((5,5-difluoro-2,2-dimethoxy-1-vinylcyclohexyl)oxy)methyl)benzene: Sodium hydride (305 mg, 7.63 mmol, 60% in mineral oil, 1.5 equiv) was added portionwise to 5,5-difluoro-2,2-dimethoxy-1-vinylcyclohexane at 0 °C In a solution of -1-ol (1.13 g, 5.08 mmol, 1.0 equiv) in anhydrous DMF (30.0 mL). The mixture was stirred at 0°C for 1 hour, then benzyl bromide (2.61 g, 15.2 mmol, 3.0 equiv) was added, and the mixture was stirred at room temperature for another 1 hour. The mixture was poured into ice water and extracted with DCM (30 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-10% EtOAc / PE) to give (((5,5-difluoro-2,2-dimethoxy-1-vinylcyclohexyl)oxy (yl)methyl)benzene (1.3 g, 81%). 1H NMR (400 MHz, CDCl 3): δppm: 7.38 - 7.28 (m, 5H), 6.13 - 6.04 (m, 1H), 5.44 (dd, J= 11.2, 0.8 Hz, 1H), 5.29 (d, J= 18.0 Hz, 1H), 4.44 (dd, J= 34.8, 11.2 Hz, 2H), 3.42 (s, 3H), 3.28 (s, 3H), 2.50 - 1.80 (m, 6H). Step D: (1-(Benzyloxy)-5,5-difluoro-2,2-dimethoxycyclohexyl)methanol: Ozone was bubbled through (((5,5-difluoro-2,2-dimethoxy-1-vinylcyclohexyl)oxy)methyl)benzene (650 mg, 2.08 mmol, 1.0 equiv) in DCM (20.0 mL). The mixture was stirred at -78 °C for 30 min, then allowed to warm to room temperature. MeOH (5.0 mL) and NaBH 4 (236 mg, 6.24 mmol, 3.0 equiv) were added, and the mixture was stirred for 5 minutes. The mixture was poured into water and extracted with ethyl acetate (70 mL×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO 215-30% EtOAc / PE) to give (1-(benzyloxy)-5,5-difluoro-2,2-dimethoxycyclohexyl)methanol ( 1.1 g, 83%). 1H NMR (400 MHz, CDCl 3 ): δppm: 7.36 - 7.19 (m, 5H), 4.53 (d, J= 1.6 Hz, 2H), 3.92 (d, J= 12.2 Hz, 1H), 3.69 - 3.57 (m , 1H), 3.38 (s, 3H), 3.25 (s, 3H), 2.35 (m, 2H), 2.08-1.85 (m, 4H). Step E: (((5,5-difluoro-2,2-dimethoxy-1-(methoxymethyl)cyclohexyl)oxy)methyl)benzene: Sodium hydride (265 mg, 6.64 mmol, 60% in mineral oil, 1.4 equiv) was added portionwise to (1-(benzyloxy)-5,5-difluoro-2,2-dimethyl A solution of oxycyclohexyl)methanol (1.5 g, 4.74 mmol, 1.0 equiv) in anhydrous DMF (30.0 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of iodomethane (6.73 g, 47.4 mmol, 10 equiv). The mixture was stirred for 2 hours, then poured into ice water and extracted with DCM (60 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , 0-10% EtOAc / PE) to give (((5,5-difluoro-2,2-dimethoxy-1-(methoxymethyl )cyclohexyl)oxy)methyl)benzene (1.2 g, 76%). 1H NMR (400 MHz, CDCl 3 ): δppm: 7.38 - 7.17 (m, 5H), 4.72 (s, 2H), 3.74 (s, 2H), 3.39 (s, 3H), 3.34 (s, 3H), 3.30 (s, 3H), 2.64 - 2.25 (m, 3H), 2.22 - 1.75 (m, 3H). Step F: 2-(Benzyloxy)-4,4-difluoro-2-(methoxymethyl)cyclohexan-1-one: (((5,5-difluoro-2,2-dimethoxy-1-(methoxymethyl)cyclohexyl)oxy)methyl)benzene (1.33 g, 4.03 mmol, 1.0 equiv), A mixture of I 2 (102 mg, 402 µmol, 0.1 equiv) and acetone (30.0 mL) was stirred at room temperature for 2 hours. The mixture was poured into water, quenched with saturated Na 2 S 2 O 3 (aq), and extracted with DCM (60 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 0-5% EtOAc / PE) to give 2-(benzyloxy)-4,4-difluoro-2-(methoxymethyl)cyclohexane -1-one (1.05 g, 91%). 1H NMR (400 MHz, CDCl 3): δppm: 7.42 - 7.26 (m, 5H), 4.60 (dd, J=11.4 Hz, 1H), 4.40 (dd, J=11.4 Hz, 1H), 3.68 (m, 2H ), 3.37 (s, 3H), 2.92 - 2.62 (m, 2H), 2.52 - 2.23 (m, 4H). Step G: 6-(Benzyloxy)-8,8-difluoro-6-(methoxymethyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: 3-Bromo-5-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]thiophene-2-carboxylic acid methyl ester (660 mg, 1.6 mmol, 1.8 equivalents), 2 -(Benzyloxy)-4,4-difluoro-2-(methoxymethyl)cyclohexan-1-one (250 mg, 880 µmol, 1.0 equiv), sodium metabisulfite (50 mg, 263 A mixture of µmol, 0.3 equiv), cesium carbonate (859 mg, 2.64 mmol, 3.0 equiv), Sphos-Pd-G3 (137 mg, 175 µmol, 0.20 equiv), and toluene (50.0 mL) was stirred at 105 °C under nitrogen 16 hours. The mixture was poured into water and extracted with EtOAc (60 mL×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 0-35% EtOAc / PE) to give 6-(benzyloxy)-8,8-difluoro-6-(methoxymethyl)-2 -(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2 ,3-c] En-4-one (360 mg, 69%). MS observation (ESI+): 589.5 [(M+H)+]. Step H: 6-(Benzyloxy)-8,8-difluoro-6-(methoxymethyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: 6-(benzyloxy)-8,8-difluoro-6-(methoxymethyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] A mixture of en-4-one (180 mg, 305 µmol, 1.0 equiv), ammonium hydroxide (8.0 mL) and 2-propanol (8.0 mL) was stirred at 100°C in a microwave reactor for 4 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (SiO, 0-1% MeOH / DCM) to give 6-(benzyloxy)-8,8-difluoro-6-(methoxymethyl Base)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[ 2,3-c]quinolin-4(5H)-one (80 mg, 44%). MS observation (ESI+): 588.5 [(M+H)+]. Step I: (S)-8,8-difluoro-6-hydroxy-6-(methoxymethyl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetra Hydrothieno[2,3-c]quinolin-4(5H)-one (compound 48) and (R)-8,8-difluoro-6-hydroxy-6-(methoxymethyl)-2 -(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 49): Boron trichloride (1 M, 4.7 mL, 15 equiv) was added to 6-(benzyloxy)-8,8-difluoro-6-(methoxymethyl)-2-(1 -((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinone A solution of olin-4(5H)-one (190 mg, 320 µmol, 1.0 equiv) in DCM (25.0 mL). The mixture was stirred at room temperature for 2 h, then quenched with MeOH, concentrated and neutralized with NH 3 / MeOH (7 M). The residue was purified by column chromatography (SiO2, 0-4% MeOH / DCM) to give racemic 8,8-difluoro-6-hydroxy-6-(methoxymethyl)-2-( 1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (64 mg, 53%). MS observation (ESI+): 368.0 [(M+H)+]. Separation via SFC afforded the individual enantiomers. (S)-8,8-Difluoro-6-hydroxy-6-(methoxymethyl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno [2,3-c]quinolin-4(5H)-one (compound 48): MS observation (ESI +): 368.0 [(M+H) +]. (R)-8,8-difluoro-6-hydroxy-6-(methoxymethyl)-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno [2,3-c]quinolin-4(5H)-one (compound 49): MS observation (ESI +): 368.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 13.23 (s, 1H), 10.70 (s, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 7.58 (s, 1H), 5.69 (s, 1H), 3.60 (dd, J= 45.2, 10.0 Hz, 2H), 3.29 (s, 3H), 3.21 - 3.10 (m, 2H), 2.77 - 2.61 (m, 1H), 2.38 - 2.19 (m, 1H). Examples 50 and 51 - Compounds 50 and 51: (S)-6-ethyl-8,8-difluoro-6-hydroxyl-2-(1H-pyrazol-4-yl)-6,7,8,9 -tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 50) and (R)-6-ethyl-8,8-difluoro-6-hydroxyl-2-(1H -pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 51) Step A : 1-Ethyl-5,5-difluoro-2,2-dimethoxycyclohexan-1-ol: To 5,5-difluoro-2,2-dimethoxy-1-vinylcyclohexan-1-ol (1.8 g, 8.1 mmol, 1.0 equiv) in MeOH (90 mL) and H 2 O (2.0 mL) Wetting Pd / C (10%, 540 mg) was added to the solution in . The mixture was purged with nitrogen, then stirred at 50 °C under hydrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated in vacuo and purified by flash column chromatography (SiO2, 10-50% EtOAc / PE) to give 1-ethyl-5,5-difluoro-2,2-dimethoxycyclohexane -1-ol (1.5 g, 82%). 1H NMR (400 MHz, CDCl 3 ) δppm: 3.39 (s, 3H), 3.33 (s, 3H), 1.99 - 1.62 (m, 8H), 0.99 (t, J= 7.6 Hz, 3H). Step B : 2-Ethyl-4,4-difluoro-2-hydroxycyclohexan-1-one: To a solution of 1-ethyl-5,5-difluoro-2,2-dimethoxycyclohexan-1-ol (1.8 g, 8.03 mmol, 1.0 equiv) in DCM (28.0 mL) was added water ( 7.0 mL) and trifluoroacetic acid (7.0 mL). The mixture was stirred at room temperature for 1 hour, then concentrated. Purification by column chromatography (SiO 2 , 10-50% EtOAc / PE) afforded 2-ethyl-4,4-difluoro-2-hydroxycyclohexan-1-one (1.2 g, 85%). 1H NMR (400 MHz, CDCl 3 ) δppm: 2.84 - 2.70 (m, 2H), 2.59 - 2.46 (m, 2H), 2.29 - 2.11 (m, 2H), 1.97 - 1.87 (m, 1H), 1.84 - 1.74 (m, 1H), 0.84 (t, J= 7.2 Hz, 3H). Step C: 6-Ethyl-8,8-difluoro-6-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- base)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: 2-Ethyl-4,4-difluoro-2-hydroxycyclohexan-1-one (205 mg, 1.15 mmol, 2.0 equivalents) and 3-bromo-5-[1-(2- To a solution of methyl trimethylsilylethoxymethyl)pyrazol-4-yl]thiophene-2-carboxylate (240 mg, 0.58 mmol, 1.0 equiv) in toluene (15.0 mL) was added metabisulfite Sodium (22 mg, 0.12 mmol, 0.2 equiv), Cs 2CO 3 (374 mg, 1.15 mmol, 2.0 equiv), Pd 2(dba) 3 (105 mg, 0.12 mmol, 0.2 equiv), Xantphos (100 mg, 0.17 mmol ,0.3 equivalent). The mixture was stirred at 105 °C for 16 hours, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , 0-100% EtOAc / PE) to give 6-ethyl-8,8-difluoro-6-hydroxy-2-(1-((2-( Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (224 mg, 80%). MS observation (ESI+): 483.7 [(M+H)+]. Step D: 6-Ethyl-8,8-difluoro-6-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- base)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: 6-Ethyl-8,8-difluoro-6-hydroxyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl) -6,7,8,9-tetrahydro-4H-thieno[2,3-c] A solution of en-4-one (595 mg, 1.23 mmol, 1.0 equiv) in a mixture of MeOH (9 mL) and NH4OH (9.0 mL) was heated at 100 °C for 3 h in a microwave reactor. The mixture was concentrated and the residue was purified by column chromatography (SiO 2 , 0-10% MeOH / DCM) to give 6-ethyl-8,8-difluoro-6-hydroxy-2-(1-(( 2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4 (5H)-Kone (360 mg, 60%). MS observation (ESI+): 482.7 [(M+H)+]. Step E: (S)-6-ethyl-8,8-difluoro-6-hydroxyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2 ,3-c] quinolin-4(5H)-one (compound 50) and (R)-6-ethyl-8,8-difluoro-6-hydroxyl-2-(1H-pyrazol-4-yl )-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 51): To 6-ethyl-8,8-difluoro-6-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl) - To a solution of 6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (357 mg, 0.74 mmol, 1.0 equiv) in DCM (5.0 mL) was added Trifluoroacetic acid (5.0 mL). The mixture was stirred at room temperature for 1 h, then concentrated in vacuo, and the residue was purified by column chromatography (SiO 2 , 0-10% MeOH / DCM) to give rac 6-ethyl-8,8-di Fluoro-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (140 mg ,54%). MS observation (ESI+): 352.4 [(M+H)+]. Individual isomers were separated by chiral SFC. (S)-6-Ethyl-8,8-difluoro-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3- c] Quinolin-4(5H)-one (compound 50): MS observation (ESI +): 352.2 [(M+H) +]. (R)-6-Ethyl-8,8-difluoro-6-hydroxy-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3- c] Quinolin-4(5H)-one (compound 51): MS observation (ESI +): 352.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 13.23 (s, 1H), 10.74 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 5.33 (s, 1H), 3.30 - 3.27 (m, 2H), 2.68 - 2.54 (m, 1H), 2.33 - 2.20 (m, 1H), 1.96 - 1.87 (m, 1H), 1.83 - 1.74 (m, 1H), 0.89 - 0.84 (m, 3H). Examples 52 and 53 - Compounds 52 and 53: (S)-8,8-difluoro-6-methoxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8 ,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 52) and (R)-8,8-difluoro-6-methoxy-6-methyl- 2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 53) (stereoisomer by arbitrary designation) Step A : 5,5-difluoro-2,2-dimethoxy-1-methylcyclohexan-1-ol: Add 5,5-difluoro-2,2-dimethoxycyclohexan-1-one (5.65 g, 29.1 mmol, 1.0 equiv) to a dry three-neck To the flask was added methylmagnesium bromide (3 M in diethyl ether, 29.1 mL, 87.4 mmol, 3.0 equiv). The mixture was stirred at room temperature under N2 atmosphere for 2 h and monitored by TLC to completion. The mixture was quenched with saturated NH 4 Cl(aq) at 0 °C, diluted with water (125 mL) and extracted with EtOAc (90 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the residue was purified by column chromatography (SiO2, 0-20% EtOAc / PE) to give 5,5-difluoro-2,2 - Dimethoxy-1-methylcyclohexan-1-ol (5.98 g, 97%). 1H NMR (400 MHz, CDCl 3 ) δppm: 3.41 (s, 3H), 3.32 (s, 3H), 2.69 (s, 1H), 2.20 - 2.06 (m, 2H), 2.03 - 1.90 (m, 2H), 1.85 - 1.68 (m, 2H), 1.32 (s, 3H). Step B : 4,4-difluoro-1,1,2-trimethoxy-2-methylcyclohexane: To a dry three-necked round bottom flask containing sodium hydride (2.28 g, 56.7 mmol, 60% in mineral oil, 2.0 equiv) at 0 °C was added anhydrous THF (170.0 mL) followed by 5,5-difluoro - A mixture of 2,2-dimethoxy-1-methylcyclohexan-1-ol (5.98 g, 28.5 mmol, 1.0 equiv) in THF (3.0 mL). The mixture was stirred at 0°C for 30 minutes, then iodomethane (40.4 g, 285 mmol, 10.0 equiv) was added, and the mixture was stirred for another 1.5 hours. Additional iodomethane (40.4 g, 285 mmol, 10.0 equiv) was added to the reaction mixture at 0 °C. The mixture was stirred for another 1.5 hours, then water was added at 0 °C. The mixture was extracted with EtOAc (160 mL×2), and the combined organic layers were washed with brine (150 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-10% EtOAc / PE) gave 4,4-difluoro-1,1,2-trimethoxy-2-methylcyclohexane (5.1 g, 80 %). 1H NMR (400 MHz, CDCl 3 ) δppm: 3.37 (s, 3H), 3.33 (s, 3H), 3.27 (s, 3H), 2.27 - 2.20 (m, 1H), 2.18 - 2.05 (m, 2H), 2.00 - 1.86 (m, 2H), 1.80 - 1.69 (m, 1H), 1.29 (s, 3H). Step C: 4,4-difluoro-2-methoxy-2-methylcyclohexan-1-one: To a flask containing 4,4-difluoro-1,1,2-trimethoxy-2-methylcyclohexane (2.58 g, 11.51 mmol) in DCM (28 mL) was added water ( 7 mL) and trifluoroacetic acid (7 mL). The mixture was stirred at room temperature for 5 h, followed by extraction with DCM (30 mL×2). The combined organic layers were concentrated in vacuo. The residue was diluted with DCM (20 mL), washed with aqueous NaHCO 3 (10 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo to give 4,4-difluoro-2-methoxy-2-methylcyclohexan-1-one (1.9 g, 10.1 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ ppm: 3.21 (s, 3H), 2.91 - 2.85 (m, 1H), 2.65 - 2.57 (m, 1H), 2.48 - 2.41 (m, 2H), 2.23 - 2.09 (m , 2H), 1.30 (s, 3H). Step D: 8,8-Difluoro-6-methoxy-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: To 3-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid methyl ester (1.0 g, 2.4 mmol) and 4,4-difluoro-2-methoxy-2-methylcyclohexan-1-one (598 mg, 3.35 mmol) in toluene (30.0 mL) were added Cs 2CO 3 (2.34 g ,7.19 mmol), Pd 2(dba) 3 (439 mg, 479 µmol) and Na 2S 2O 5 (91.1 mg, 479 µmol). The mixture was stirred at 105°C under nitrogen for 12 hours. The mixture was cooled to 0 °C, H 2 O (40 mL) was added, and the resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (SiO2, 0-10% EtOAc / PE) gave 8,8-difluoro-6-methoxy-6-methyl-2-(1-((2-(tri Methylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-one (385 mg, 33%). MS observation (ESI+): 483.4 [(M+H)+]. Step E: 8,8-Difluoro-6-methoxy-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: To 8,8-difluoro-6-methoxy-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- base)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] To a solution of en-4-one (0.70 g, 1.45 mmol) in MeOH (6.0 mL) was added ammonium hydroxide (6.0 mL). The mixture was stirred at 95 °C for 2 hours in a microwave reactor. The mixture was cooled to 0°C, and H 2 O (20 mL) was added. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (SiO2, 0-30% EtOAc / PE) to give 8,8-difluoro-6-methoxy-6-methyl-2-(1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4( 5H)-ketone (170 mg, 24%). MS observation (ESI+): 482.5 [(M+H)+]. Step F: (S)-8,8-difluoro-6-methoxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno [2,3-c] Quinolin-4(5H)-one (compound 52) and (R)-8,8-difluoro-6-methoxy-6-methyl-2-(1H-pyrazole -4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 53): To 8,8-difluoro-6-methoxy-6-methyl-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]- To a solution of 7,9-dihydro-5H-thieno[2,3-c]quinolin-4-one (170 mg, 353 µmol, 1.0 equiv) in DCM (5.0 mL) was added trifluoroacetic acid (402 mg, 3.53 mmol, 272 µL, 10.0 equiv). The mixture was stirred at 25°C for 15 hours. Then the mixture was cooled to 0°C and saturated aqueous NaHCO 3 (20 mL) was added dropwise at 0°C. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (SiO2, 0-10% MeOH / DCM) to give racemic 8,8-difluoro-6-methoxy-6-methyl-2-(1H- Pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (100 mg, 80%). Individual enantiomers were separated via chiral SFC. (S)-8,8-difluoro-6-methoxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2, 3-c] Quinolin-4(5H)-one (compound 52): MS observation (ESI +): 352.1 [M+H] +. (R)-8,8-difluoro-6-methoxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2, 3-c]quinolin-4(5H)-one (compound 53): MS observation (ESI +): 352.1 [M+H] +; 1H NMR (400 MHz, DMSO- d6) δppm: 13.23 (s, 1H ), 11.02 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.59 (s, 1H), 3.44 - 3.37 (m, 2H), 3.07 (s, 3H) 2.82 - 2.61 (m , 1H), 2.40 - 2.26 (m, 1H), 1.56 (s, 3H). Examples 54 and 55 - Compounds 54 and 55: (R)-8,8-difluoro-6-hydroxyl-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9 -Tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 54) and (S)-8,8-difluoro-6-hydroxy-6-methyl-2-(1H -pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 55) (stereoisomers are arbitrarily designated) Step A: (((5,5-difluoro-2,2-dimethoxy-1-methylcyclohexyl)oxy)methyl)benzene: Add 5,5-difluoro-2,2-dimethoxy-1-methylcyclohexan-1-ol (300 mg, 1.43 mmol, 1.0 equiv) in anhydrous DMF (3.0 mL) at 0°C To a solution of NaH (109 mg, 2.85 mmol, 60% in mineral oil, 2.0 equiv) was added. The mixture was stirred at 0 °C for 10 min, then benzyl bromide (488.16 mg, 2.85 mmol, 339 µL, 2.0 equiv) was added dropwise. The mixture was stirred at room temperature for 1 h, then quenched with saturated aqueous NH 4 Cl and diluted with water (60 mL). The mixture was extracted with EtOAc (40 mL×3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , 0-4% EtOAc / PE) to afford (((5,5-difluoro-2,2-dimethoxy-1-methylcyclohexyl) oxy)methyl)benzene (370 mg, 86%). 1H NMR (400 MHz, CDCl 3 ) δppm: 7.36 - 7.24 (m, 5H), 4.60 - 4.52 (m, 2H), 3.39 (s, 3H), 3.33 (s, 3H), 2.50 - 2.35 (m, 1H ), 2.26 - 2.22 (m, 1H), 2.15 - 2.07 (m, 1H), 2.05 - 1.89 (m, 2H), 1.83 - 1.77 (m, 1H), 1.38 (s, 3H). Step B: 2-(Benzyloxy)-4,4-difluoro-2-methylcyclohexan-1-one: To (((5,5-difluoro-2,2-dimethoxy-1-methylcyclohexyl)oxy)methyl)benzene (370 mg, 1.23 mmol, 1.0 equiv) in acetone (15.0 mL) Iodine (31.7 mg, 125 µmol, 0.10 equiv) was added to the solution in . The mixture was stirred at room temperature for 10 min, then quenched with saturated Na 2 SO 3 (aq) (20 mL) and extracted with DCM (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 0-10% EtOAc / PE) to give 2-(benzyloxy)-4,4-difluoro-2-methylcyclohexan-1-one ( 280 mg, 88%). 1H NMR (400 MHz, CDCl 3 ) δppm: 7.35 - 7.26 (m, 5H), 4.56 (d, J=11.6 Hz, 1H), 4.26 (d, J= 11.6 Hz, 1H), 2.94 - 2.91 (m, 1H), 2.79 - 2.74 (m, 1H), 2.48 - 2.42 (m, 2H), 2.25 - 2.18 (m, 2H), 1.41 (s, 3H). Step C: 6-(benzyloxy)-8,8-difluoro-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine Azol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] En-4-ones: To 3-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid methyl ester (240 mg, 575 µmol, 1.0 equiv) and 2-(benzyloxy)-4,4-difluoro-2-methylcyclohexan-1-one (292 mg, 1.15 mmol, 2.0 equiv) in toluene (18.0 mL) Pd 2(dba) 3 (105 mg, 115 µmol, 0.20 equiv), Xantphos (133 mg, 230 µmol, 0.40 equiv) and cesium carbonate (562 mg, 1.72 mmol, 3.0 equiv) were added. The mixture was stirred at 105 °C under nitrogen for 16 hours, then cooled and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, 0-16% EtOAc / PE) to give 6-(benzyloxy)-8,8-difluoro-6-methyl-2- (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydro-4H-thieno[2, 3-c] En-4-one (220 mg, 68%). MS observation (ESI+): 559.5 [(M+H)+]. Step D: 6-(benzyloxy)-8,8-difluoro-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine Azol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one: To 6-(benzyloxy)-8,8-difluoro-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-6,7,8,9-tetrahydro-4H-thieno[2,3-c] To a solution of en-4-one (220 mg, 394 µmol) in MeOH (7 mL) was added ammonia (7 M in MeOH, 7.0 mL). The mixture was stirred at 95 °C for 16 h, then cooled and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , 0-5% MeOH / DCM) to give 6-(benzyloxy)-8,8-difluoro-6-methyl-2-(1-(( 2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinoline-4 (5H)-Kone (180 mg, 77%). MS observation (ESI+): 558.6 [(M+H)+]. Step E: (R)-8,8-difluoro-6-hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2 ,3-c] quinolin-4(5H)-one (compound 54) and (S)-8,8-difluoro-6-hydroxyl-6-methyl-2-(1H-pyrazol-4-yl )-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (compound 55) (stereoisomers are arbitrarily designated): To 6-(benzyloxy)-8,8-difluoro-6-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (90 mg, 161 µmol, 1.0 equiv) in DCM (10.0 mL) was added boron trichloride (1 M, 2.0 mL, 12 equiv). The mixture was stirred at -5 °C for 1.5 h, quenched with MeOH, then concentrated under a stream of nitrogen. The pH was adjusted to ~9 by gradually adding NH3 / MeOH (7 M). The mixture was then concentrated in vacuo, and the residue was purified by flash column chromatography (SiO, 0-10% MeOH / DCM) to afford racemic 8,8-difluoro-6-hydroxy-6-methyl-2 -(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3-c]quinolin-4(5H)-one (23 mg, 42%). MS observation (ESI+): 338.3 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (R)-8,8-Difluoro-6-hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3- c] Quinolin-4(5H)-one (compound 54): MS observation (ESI +): 338.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm: 13.24 (s, 1H ), 10 .88 (s, 1H), 8.13 (s, 2H), 7.56 (s, 1H), 5.57 (s, 1H), 3.33 - 3.24 (m, 2H), 2.50 - 2.42 (m, 2H), 1.54 (s, 3H). (S)-8,8-difluoro-6-hydroxy-6-methyl-2-(1H-pyrazol-4-yl)-6,7,8,9-tetrahydrothieno[2,3- c] Quinolin-4(5H)-one (compound 55): MS observation (ESI +): 338.0 [(M+H) +]. Examples 56 and 57 - Compounds 56 and 57: (S)-4-(2-hydroxypropan-2-yl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-di Hydrogen-2H-piperano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (compound 56) and (R)-4-(2-hydroxypropan-2- Base)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridine -6(4H)-one (Compound 57) Step A: 4-methyl-6-oxo-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1, 4,5,6-Tetrahydro-2H-pyrano\[3,4-b]thieno\[3,2-d]pyridine-4-carbaldehyde: 4-(Hydroxymethyl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1, 5-Dihydro-2H-piperano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (100 mg, 223 µmol, 1.0 equiv. Synthesized by procedure), IBX (626 mg, 2.23 mmol, 10.0 eq) and DCM (12 mL) was stirred at 45 °C for 24 h. The mixture was quenched with saturated aqueous Na 2 SO 3 , extracted with DCM (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , 0-4% MeOH / DCM) to give 4-methyl-6-oxo-8-(1-((2-(trimethylsilyl) Ethoxy)methyl)-1H-pyrazol-4-yl)-1,4,5,6-tetrahydro-2H-pyrano[3,4-b]thieno[3,2-d] Pyridine-4-carbaldehyde (80 mg, 80%). MS observation (ESI+): 464.3 [(M+H2O+H)+]. Step B : 4-(1-Hydroxyethyl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl )-1,5-dihydro-2H-pyrano\[3,4-b]thieno\[3,2-d]pyridin-6(4H)-one: To 4-methyl-6-oxo-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,4, 5,6-tetrahydro-2H-pirano[3,4-b]thieno[3,2-d]pyridine-4-carbaldehyde (160 mg, 360 µmol, 1.0 equiv) in THF (7.5 mL) To the solution of Methylmagnesium bromide (3 M in diethyl ether, 23.3 mL, 195 eq) was added. The mixture was stirred at room temperature for 1.5 h, quenched with saturated NH 4 Cl(aq), then poured into water and extracted with DCM (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , 0-4% MeOH / DCM) to give 4-(1-hydroxyethyl)-4-methyl-8-(1-((2-(trimethyl Silyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridine -6(4H)-one (152 mg, 82%). MS observation (ESI+): 462.3 [(M+H)+]. Step C: 4-acetyl-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1, 5-Dihydro-2H-pyrano\[3,4-b]thieno\[3,2-d]pyridin-6(4H)-one: 4-(1-hydroxyethyl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4 -yl)-1,5-dihydro-2H-piperano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (126 mg, 273 µmol, 1.0 equiv) To a solution in DCM (40.0 mL) was added Dess-Martin periodinane (694 mg, 1.64 mmol, 6.0 equiv) in small portions. The mixture was stirred at room temperature for 1.5 h, then quenched with saturated Na 2 SO 3 (aq) and extracted with DCM (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , 0-3% MeOH / DCM) to give 4-acetyl-4-methyl-8-(1-((2-(trimethylsilyl )ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridine-6 (4H)-Kone (85 mg, 67%). MS observation (ESI+): 460.3 [(M+H)+]. Step D: 4-(2-Hydroxypropan-2-yl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)-1,5-dihydro-2H-pyrano\[3,4-b]thieno\[3,2-d]pyridin-6(4H)-one: To 4-acetyl-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5- Dihydro-2H-piperano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (85 mg, 185 µmol, 1.0 equiv) in THF (2.0 mL) To the solution was added methylmagnesium bromide (3 M in diethyl ether, 2.0 mL, 32.4 equiv). The mixture was stirred at room temperature for 2 h, quenched with saturated NH 4 Cl(aq), then poured into water and extracted with DCM (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO 2 , 0-4% MeOH / DCM) to give 4-(2-hydroxypropan-2-yl)-4-methyl-8-(1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3, 2-d]pyridin-6(4H)-one (50 mg, 56%). MS observation (ESI+): 476.3 [(M+H)+]. Step E: (S)-4-(2-hydroxypropan-2-yl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano [3,4-b]thieno[3,2-d]pyridin-6(4H)-one (compound 56) and (R)-4-(2-hydroxypropan-2-yl)-4-methyl -8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (compound 57): To 4-(2-hydroxypropan-2-yl)-4-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine at 0°C Azol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one (75 mg, 160 µmol, 1.0 equiv) in DCM (6.0 mL) was added trifluoroacetic acid (2.0 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was concentrated under nitrogen flow, and the pH was adjusted to ~9 by gradually adding NH 3 / MeOH (7 M) at 0 °C. The mixture was concentrated to give a residue, which was purified by column chromatography (SiO2, 0-7% MeOH / DCM) to give racemic 4-(2-hydroxypropan-2-yl)-4-methyl- 8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3,4-b]thieno[3,2-d]pyridin-6(4H)-one ( 48 mg, 85%). MS observation (ESI+): 346.0 [(M+H)+]. Individual enantiomers were separated via chiral SFC. (S)-4-(2-Hydroxypropan-2-yl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3, 4-b]thieno[3,2-d]pyridin-6(4H)-one (compound 56): MS observation (ESI +): 346.2 [(M+H) +]; 1H NMR (400 MHz, DMSO - d6) δppm: 13.22 (s, 1H), 10.21 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 5.98 (s, 1H), 4.02 - 3.89 (m, 2H), 2.76 - 2.60 (m, 2H), 1.53 (s, 3H), 1.27 (s, 3H), 1.00 (s, 3H). (R)-4-(2-Hydroxypropan-2-yl)-4-methyl-8-(1H-pyrazol-4-yl)-1,5-dihydro-2H-pyrano[3, 4-b] Thieno[3,2-d]pyridin-6(4H)-one (compound 57): MS observation (ESI +): 346.2 [(M+H) +]. Example 58 - Compound 58: 4,4-Dimethyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b] Thieno[3,2-d]pyridin-6-one Step A : 4,4-Dimethyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-di Hydrogen-1H,6H-pyrano\[4,3-b]thieno\[3,2-d]pyran-6-one: Methyl 3-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiophene-2-carboxylic acid (100 mg, 240 µmol, 1.0 eq) was dissolved in DMF (10.0 mL), followed by the addition of 3,3-dimethyltetrahydropyran-4-one (61 mg, 480 µmol, 2.0 eq), Na2S2O5 (9.0 mg, 48 µmol, 0.20 equiv), Cs 2CO 3 (230 mg, 720 µmol, 3.0 equiv) and BINAP-Pd-G3 (24 mg, 24 µmol, 0.10 equiv). The mixture was stirred at 105 °C for 16 hours, cooled, filtered and concentrated. Purification by column chromatography (SiO 20-4% MeOH / DCM) gave 4,4-dimethyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl) -1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (20 mg ,19%). MS observation (ESI+): 433.4 [(M+H)+]. Step B : 4,4-Dimethyl-8-(1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3, 2-d] pyran-6-one: 4,4-Dimethyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3,4-dihydro- 1H,6H-Pyrano[4,3-b]thieno[3,2-d]pyran-6-one (45 mg, 100 µmol), DCM (5.0 mL) and trifluoroacetic acid (1.5 mL) The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give 4,4-dimethyl-8-(1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[ 3,2-d]pyran-6-one (40 mg), which was used without further purification. MS observation (ESI+): 303.2 [(M+H)+]. Step C: 4,4-Dimethyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[ 3,2-d] pyridin-6-one: 4,4-Dimethyl-8-(1H-pyrazol-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2- d] A mixture of pyran-6-one (40 mg, crude material), NH4OH (5.0 mL) and MeOH (5.0 mL) was heated to 100 °C in a microwave reactor for 4 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (SiO, 0-5% MeOH / DCM) to give 4,4-dimethyl-8-(1H-pyrazol-4-yl)-1 , 3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (9.0 mg, 36%). MS observation (ESI +): 302.2 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 13.21 (brs, 1H), 11.20 (s, 1H), 8.29 (s, 1H) , 7.94 (s, 1H), 7.37 (s, 1H), 4.69 (s, 2H), 3.57 (s, 2H), 1.26 (s, 6H). Example 59 and 60-Compounds 59 and 60: (S)-4-(tertiary butyl)-8-(3-fluoropyridin-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro -6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 59) and (R)-4-(tertiary butyl)-8-(3- Fluoropyridin-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one ( Compound 60) (The stereochemistry of Compounds 59 and 60 is arbitrarily assigned) Step A : 4,4-Dimethoxytetrahydro-2H-pyran-3-ol: A solution of tetrahydropyran-4-one (40.0 g, 400 mmol, 1.0 equiv) and potassium hydroxide (67.3 g, 1.20 mol, 3.0 equiv) in MeOH (1.7 L) was cooled to 0 °C and slowly added I 2 (117 g, 459 mmol, 1.15 equiv). The reaction mixture was warmed to room temperature and after 4 hours, the mixture was concentrated. The crude product was triturated with EtOAc (300 mL) to give 4,4-dimethoxytetrahydro-2H-pyran-3-ol (50 g, used without further purification). 1H NMR (400 MHz, DMSO-d6) δ 4.75 (s, 1H), 3.68 - 3.54 (m, 2H), 3.52 - 3.41 (m, 2H), 3.32 - 3.25 (m, 1H), 3.12 (s, 3H ), 3.11 (s, 3H), 1.84 - 1.76 (m, 1H), 1.62 - 1.57 (m, 1H). Step B : 4,4-Dimethoxydihydro-2H-pyran-3(4H)-one: A solution of 4,4-dimethoxytetrahydropyran-3-ol (40.0 g, 247 mmol, 1.0 equiv) in DCM (900 mL) was cooled to 0 °C and DMP (157 g, 370 mmol, 1.5 equiv). The mixture was heated to 30 °C for 16 h, then a mixture of petroleum ether and EtOAc (8:1, 400 mL) was added. The filtrate was concentrated and purified (SiO 2 , 5% petroleum ether / EtOAc) to give 4,4-dimethoxydihydro-2H-pyran-3(4H)-one (23 g, 45%, 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 3.99 (s, 2H), 3.87 - 3.80 (m, 2H), 3.14 (s, 6H), 2.16 - 2.10 (m, 2H). Step C: 3-(tertiary butyl)-3-hydroxytetrahydro-4H-pyran-4-one: A solution of 4,4-dimethoxytetrahydropyran-3-one (10.0 g, 62.4 mmol, 1.0 equiv) in anhydrous THF (100 mL) was cooled to -78 °C and added dropwise over 30 minutes t-BuLi (1.3 M in THF, 62 mL, 1.3 equiv). The mixture was stirred at -78 °C for 2 h, then HCl (2 M aq, 94 mL) was added dropwise over 15 min. After the addition, the mixture was stirred at 0 °C for 2 hours. The mixture was extracted with EtOAc (3×100 mL), washed with brine (2×100 mL) and the combined organic layers were concentrated and purified (SiO 2 , 0-10% EtOAc / PE) to give 3-(tert-butyl )-3-Hydroxytetrahydro-4H-pyran-4-one (3.6 g, 33%). 1H NMR (400 MHz, DMSO-d6) δ 5.05 (s, 1H), 4.06 (dd, J= 12.0, 1.2 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.75 - 3.64 (m, 1H), 3.35 (d, J= 12.0 Hz, 1H), 2.60 - 2.52 (m, 2H), 0.95 (s, 9H). Step D: 4-(tertiary butyl)-4-hydroxy-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6 - Ketones: Add 3-bromothiophene-2-carboxylic acid methyl ester (2 g, 9.05 mmol, 1.0 equivalent) and 3-tertiary butyl-3-hydroxy-tetrahydropyran-4-one (1.56 g, 9.05 mmol, 1.0 equivalent) to a dry three-necked flask was added anhydrous toluene (50 mL). The mixture was degassed and purged with N 2 (3×), followed by addition of Pd 2(dba) 3 (414 mg, 452 μmol, 0.050 equiv), Xantphos (524 mg, 905 μmol, 0.10 equiv), K 3PO 4 ( 3.84 g, 18.1 mmol, 2.0 equiv). It was degassed and purged again with N 2 (3×), and stirred at 105° C. for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. Purified by column chromatography (SiO2, 0-30% EtOAc / PE) and further purified by reverse-phase column chromatography (C18 SiO2, 0-30% MeCN / water (0.1% NH4OH), 4-(tert-butyl)-4-hydroxy-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]piperene was obtained as a white solid Pyran-6-one (600 mg, 2.14 mmol, 24%). MS observation (ESI +): 281.2 [(M+H) +]. Step E: (4-(tertiary butyl)-4-hydroxy-6-oxo-4,6-dihydro-1H,3H-pyrano[4,3-b]thieno[3,2 -d] pyran-8-yl) Acid: 4-(tertiary butyl)-4-hydroxy-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (500 mg, 1.78 mmol, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaboron (1.37 g, 10.7 mmol, 1.55 mL, 6.0 equiv), (1,5-cyclooctadiene)(methoxy)iridium dimer (59.1 mg, 89.2 μmol, 0.050 equiv), 2,6-diiso A mixture of propyl-N-(pyridin-2-ylmethylene)aniline (47.5 mg, 178 μmol, 0.10 equiv) and anhydrous DME (10 mL) was stirred at 85°C for 24 hours. The mixture was cooled and concentrated in vacuo to afford (4-(tertiary butyl)-4-hydroxy-6-oxo-4,6-dihydro-1H,3H-pyrano[4,3-b]thiophene And[3,2-d]pyran-8-yl) Acid (2 g, crude material) was used without further purification. MS observation (ESI+): 325.5 [(M+H)+]. Step F: 10-tertiary butyl-4-(3-fluoro-4-pyridyl)-10-hydroxy-8,12-dioxa-5-thiatricyclo[7.4.0.0 2,6]tridecane Carbon-1(9),2(6),3-trien-7-one: To (10-tertiary butyl-10-hydroxyl-7-oxo-8,12-dioxa-5-thiatricyclo[7.4.0.0 2,6]trideca-1(9),2 (6),3-trien-4-yl) To a mixture of acid (130 mg, 401 μmol, 1.0 equiv), Na2CO3 (128 mg, 1.20 mmol, 3.0 equiv) in THF (12 mL) and H2O (1.2 mL) was added 3-fluoro-4-iodo - Pyridine (99 mg, 441 μmol, 1.1 equiv) and Sphos-Pd-G3 (32 mg, 40.1 μmol, 0.10 equiv). The mixture was degassed and purged with N 2 (2×), then stirred at 50° C. for 6 hours. The reaction mixture was concentrated and the residue was diluted with DCM / MeOH=10 / 1 (300 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO 20-5% MeOH / DCM) to give 10-tert-butyl-4-(3-fluoro-4-pyridyl)-10- as a yellow solid Hydroxy-8,12-dioxa-5-thiatricyclo[7.4.0.0 2,6]trideca-1(9),2(6),3-trien-7-one (280 mg,23 %). MS observation (ESI+): 376.4 [(M+H)+]. Step G: (S)-4-(tertiary butyl)-8-(3-fluoropyridin-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro-6H-pyrano[ 4,3-b]thieno[3,2-d]pyridin-6-one (compound 59) and (R)-4-(tertiary butyl)-8-(3-fluoropyridin-4-yl) -4-Hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (Compound 60): The 10-tertiary butyl-4-(3-fluoro-4-pyridyl)-10-hydroxy-8,12-dioxa-5-thiatricyclo[7.4.0.0 2,6]tridecyl- A solution of 1(9),2(6),3-trien-7-one (140 mg, 373 μmol, 1.0 equiv) in NH3 / MeOH (7.0 M, 10 mL) was stirred at 95 °C for 3 h . The reaction mixture was cooled and concentrated in vacuo to give a residue which was purified by flash column chromatography (SiO2 0-5% MeOH / DCM) to give 4-(tert-butyl)-8-(3-fluoropyridine- 4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (123 mg, 44%). MS observation (ESI+): 375.0 [(M+H)+]. The enantiomers were separated via chiral SFC. (S)-4-(tertiary butyl)-8-(3-fluoropyridin-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b]Thieno[3,2-d]pyridin-6-one (compound 59): MS observation (ESI +): 375.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δppm : 10.41 (s, 1H), 8.78 (d, J= 2.8 Hz, 1H), 8.57 (dd, J= 5.2, 0.8 Hz, 1H), 8.08 - 7.99 (m, 2H), 5.36 (s, 1H), 4.82 (dd, J= 44.0, 15.2 Hz, 2H), 4.14 (d, J= 11.2 Hz, 1H), 3.46 (d, J= 11.2 Hz, 1H), 1.04 (s, 10H). (R)-4-(tertiary butyl)-8-(3-fluoropyridin-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b] Thieno[3,2-d]pyridin-6-one (compound 60): MS observation (ESI +): 375.0 [(M+H) +]. Examples 61 and 62 - Compounds 61 and 62: (S)-4-(tertiary butyl)-4-hydroxy-8-(2-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b] Thieno[3,2-d]pyridin-6-one (compound 61) and (R)-4-(tertiary butyl)-4-hydroxyl-8-(2-methylpyridine-4 -yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 62) (compound 61 and 62 The stereochemistry is arbitrarily designated) Step A: 10-tertiary butyl-10-hydroxy-4-(2-methyl-4-pyridyl)-8,12-dioxa-5-thiatricyclo[7.4.0.0 2,6] ten Tricarbon-1(9),2(6),3-trien-7-one: Subjecting 4-iodo-2-methyl-pyridine to conditions similar to those described for compound 59, Step F afforded 10-tert-butyl-10-hydroxy-4-(2-methyl-4-pyridyl) -8,12-dioxa-5-thiatricyclo[7.4.0.0 2,6]trideca-1(9),2(6),3-trien-7-one (169 mg, 29% ). MS observation (ESI+): 372.2 [M+H]+. Step B: (S)-4-(tertiary butyl)-4-hydroxy-8-(2-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b] Thieno[3,2-d]pyridine-6-one (compound 61) and (R)-4-(tertiary butyl)-4-hydroxyl-8-(2-methylpyridine-4 -yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 62): Make 10-tertiary butyl-10-hydroxyl-4-(2-methyl-4-pyridyl)-8,12-dioxa-5-thiatricyclo[7.4.0.0 2,6]tridecyl -1(9),2(6),3-trien-7-ones were subjected to similar conditions as described for compound 59, Step G, to afford 4-(tertiary butyl)-4-hydroxy-8-( 2-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (200 mg, 78%). MS observation (ESI+): 371.1 [M+H]+. The enantiomers were separated via chiral SFC. (S)-4-(tertiary butyl)-4-hydroxy-8-(2-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b]Thieno[3,2-d]pyridin-6-one (compound 61): MS observation (ESI +): 371.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δ 10.32 (s, 1H), 8.55 (d, J= 5.2 Hz, 1H), 7.99 (s, 1H), 7.70 (s, 1H), 7.61 (dd, J= 5.2, 1.6 Hz, 1H), 5.35 ( s, 1H), 4.80 (dd, J= 38.8, 14.8 Hz, 2H), 4.14 (d, J= 11.2 Hz, 1H), 3.45 (d, J= 11.2 Hz, 1H), 2.55 (s, 3H), 1.03 (s, 9H). (R)-4-(tertiary butyl)-4-hydroxy-8-(2-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b] Thieno[3,2-d]pyridin-6-one (compound 62): MS observation (ESI +): 371.0 [(M+H) +]. Example 63 and 64-Compounds 63 and 64: (S)-4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro -6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 63) and (R)-4-(tertiary butyl)-8-(5- Chloropyrimidin-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one ( Compound 64) (The stereochemistry of Compounds 63 and 64 is arbitrarily assigned) Step A: 5-Chloro-4-iodopyrimidine: To a solution of 5-chloropyrimidin-4-amine (500 mg, 3.86 mmol, 1.0 equiv) and diiodomethane (2.07 g, 7.72 mmol, 622 μL, 2.0 equiv) in CH 3CN (20 mL) at 0°C Isoamyl nitrite (995 mg, 8.49 mmol, 1.14 mL, 2.2 equiv) in CH 3 CN (1 mL) was added dropwise in . The mixture was stirred at 0 °C for 30 min, then heated to 70 °C for 16 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (SiO 2 , 0-3% EtOAc / PE) to give 5-chloro-4-iodopyrimidine (410 mg, 44% yield). MS observation (ESI+): 241.1 [(M+H)+]. Step B : 4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl)-4-hydroxy-3,4-dihydro-1H,6H-pyrano[4,3-b] Thieno[3,2-d]pyran-6-one: Similar conditions to those described in Compound 59, Step F were used for (4-(tertiary-butyl)-4-hydroxy-6-oxo-4,6-dihydro-1H,3H-pyrano[4 ,3-b]thieno[3,2-d]pyran-8-yl) acid and 5-chloro-4-iodopyrimidine to give 4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl)-4-hydroxy-3,4-dihydro-1H,6H-piper Furano[4,3-b]thieno[3,2-d]pyran-6-one (76 mg, 31%). MS observation (ESI+): 393.4 [(M+H)+]. Step C: (S)-4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro-6H-pyrano[ 4,3-b]thieno[3,2-d]pyridin-6-one (compound 63) and (R)-4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl) -4-Hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 64): Similar conditions to those described in Compound 59, Step G were used for 4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl)-4-hydroxy-3,4-dihydro-1H,6H -pyrano[4,3-b]thieno[3,2-d]pyran-6-one to give 4-(tertiary butyl)-8-(5-chloropyrimidine- 4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (53 mg, 70%). MS observation (ESI+): 392.4 [(M+H)+]. Enantio-chiral SFC was used to separate the enantiomers. (S)-4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b]Thieno[3,2-d]pyridin-6-one (compound 63): MS observation (ESI +): 392.0 [(M+H) +] ; 1H NMR (400 MHz, DMSO- d6) δ ppm: 10.46 (s, 1H), 9.22 (s, 1H), 9.10 (s, 1H), 8.33 (s, 1H), 5.36 (s, 1H), 4.93 - 4.76 (m, 2H), 4.14 (d, J= 11.2 Hz, 1H), 3.46 (d, J= 11.6 Hz, 1H), 1.04 (s, 9H). (R)-4-(tertiary butyl)-8-(5-chloropyrimidin-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b] Thieno[3,2-d]pyridin-6-one (compound 64): MS observation (ESI +): 392.0 [(M+H) +]. Example 65 and 66 - Compounds 65 and 66: (R)-4-(tertiary butyl)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxyl-1,3,4, 5-tetrahydro-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 65) and (S)-4-(tertiary butyl)-8 -(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2- d] pyridin-6-one (compound 66) (the stereochemistry of compounds 65 and 66 is arbitrarily assigned) Step A: 4-(tertiary butyl)-8-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)- 4-Hydroxy-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one: Subjecting 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole to conditions similar to those described for compound 59, Step D afforded 4 -(tertiary butyl)-8-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-4-hydroxyl- 3,4-Dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (10 mg, 13%). MS observation (ESI+): 495.5 [(M+H)+]. Step B: 4-(tertiary butyl)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxyl-3,4-dihydro-1H,6H-pyrano\[4 ,3-b]thieno\[3,2-d]pyran-6-one: 4-(tertiary butyl)-8-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- base)-4-hydroxy-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (100 mg, 202 μmol, 1.0 equiv) in DCM (5 mL) was added boron trichloride (1.0 M, 1.0 mL, 5.0 equiv). The mixture was stirred at -78 °C for 2 h, then MeOH was added. The mixture was concentrated in vacuo to afford 4-(tert-butyl)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-3,4-dihydro-1H,6H-pyrano[ 4,3-b]thieno[3,2-d]pyran-6-one (75 mg, used without further purification). MS observation (ESI+): 365.5 [(M+H)+]. Step C: (R)-4-(tertiary butyl)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro-6H- Pyrano\[4,3-b]thieno\[3,2-d]pyridin-6-one (compound 65) and (S)-4-(tertiary butyl)-8-(3-fluoro -1H-pyrazol-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano\[4,3-b]thieno\[3,2-d]pyridine -6- Ketone (Compound 66): Make 4-(tertiary butyl)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxyl-3,4-dihydro-1H,6H-pyrano[4,3- b] Thieno[3,2-d]pyran-6-one is subjected to similar conditions as described for compound 59, step G, to give 4-(tertiary butyl)-8-(3-fluoro-1H- Pyrazol-4-yl)-4-hydroxyl-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one ( 40 mg, 110 μmol, 45%, 2 steps). MS observation (ESI+): 364.4 [(M+H)+]. The isomers were separated by chiral HPLC. (R)-4-(tertiary butyl)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano [4,3-b]thieno[3,2-d]pyridin-6-one (compound 65): MS observation (ESI +): 364.0 [(M+H) +]. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.83 (brs, 1H), 10.16 (brs, 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.33 (s, 1H), 5.33 (s, 1H), 4.75 (dd, J = 34.2, 14.8 Hz, 2H), 4.12 (d, J = 11.2 Hz, 1H), 3.44 (d, J = 11.2 Hz, 1H), 1.03 (s, 9H). (S)-4-(tertiary butyl)-8-(3-fluoro-1H-pyrazol-4-yl)-4-hydroxy-1,3,4,5-tetrahydro-6H-pyrano [4,3-b]thieno[3,2-d]pyridin-6-one (compound 66): MS observation (ESI +): 364.0 [(M+H) +]. Example 67 and 68-Compounds 67 and 68: (S)-4-(tertiary butyl)-4-hydroxyl-8-(diaphragm -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 67) and (R )-4-(tertiary butyl)-4-hydroxyl-8-( -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 68) (compound 67 and the stereochemistry of 68 are arbitrarily assigned) Step A: 4-(tertiary butyl)-4-hydroxy-8-( -4-yl)-3,4-dihydro-1H,6H-pyrano\[4,3-b]thieno\[3,2-d]pyran-6-one: Compound 59, similar conditions as described in step F were used for 4-bromopyridine Hydrobromide, get 4-(tertiary butyl)-4-hydroxyl-8-(diaphragm -4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (53 mg, 40%). MS observation (ESI+): 359.4 [(M+H)+]. Step B: (S)-4-(tertiary butyl)-4-hydroxy-8-( -4-yl)-1,3,4,5-tetrahydro-6H-pyrano\[4,3-b]thieno\[3,2-d]pyridin-6-one (compound 67) and (R)-4-(tertiary butyl)-4-hydroxy-8-( -4-yl)-1,3,4,5-tetrahydro-6H-pyrano\[4,3-b]thieno\[3,2-d]pyridin-6-one (compound 68): Compound 59, similar conditions described in step G were used for 4-(tertiary butyl)-4-hydroxy-8-(pyridine -4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one to give 4-(tertiary butane Base) -4-hydroxy-8-(A -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (37 mg, 66%) . MS observation (ESI+): 358.4 [(M+H)+]. The enantiomers were separated by chiral SFC. (S)-4-(tertiary butyl)-4-hydroxyl-8-(diaphragm -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 67): MS observation (ESI +): 358.0 [(M+H) +]; 1H NMR (400 MHz, DMSO- d6) δ ppm: 10.45 (s, 1H), 9.76 - 9.75 (m, 1H), 9.35 - 9.33 (m, 1H), 8.22 (s, 1H), 8.08 - 8.06 (m, 1H), 5.37 (s, 1H), 4.87 - 4.75 (m, 2H), 4.14 (d, J= 11.6 Hz, 1H), 3.46 (d , J= 11.2 Hz, 1H), 1.03 (s, 9H). (R)-4-(tertiary butyl)-4-hydroxyl-8-(diaphragm -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 68): MS observation (ESI+): 358.0 [(M+H)+]. Example 69 and 70 - Compounds 69 and 70: (S)-4-(tertiary butyl)-4-hydroxyl-8-(3-methylpyridin-4-yl)-1,3,4,5-tetra Hydrogen-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 69) and (R)-4-(tertiary butyl)-4-hydroxy- 8-(3-Methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine-6- Ketone (Compound 70) (The stereochemistry of Compounds 69 and 70 is arbitrarily assigned) Step A: 4-(tertiary butyl)-4-hydroxy-8-(3-methylpyridin-4-yl)-3,4-dihydro-1H,6H-pyrano\[4,3- b] Thieno\[3,2-d]pyran-6-one: Similar conditions to those described in Compound 59, Step F were applied to 4-bromo-3-methyl-pyridine hydrochloride to afford 4-(tertiary-butyl)-4-hydroxy-8-( 3-methylpyridin-4-yl)-3,4-dihydro-1H,6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one (87 mg ,63%). MS observation (ESI+): 372.4 [(M+H)+]. Step B: (S)-4-(tertiary butyl)-4-hydroxy-8-(3-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano [4,3-b]thieno[3,2-d]pyridin-6-one (compound 69) and (R)-4-(tertiary butyl)-4-hydroxyl-8-(3-methyl Pyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 70): Similar conditions to those described in Compound 59, Step G were used for 4-(tert-butyl)-4-hydroxy-8-(3-methylpyridin-4-yl)-3,4-dihydro-1H, 6H-pyrano[4,3-b]thieno[3,2-d]pyran-6-one to give 4-(tertiary butyl)-4-hydroxyl-8-(3-methylpyridine -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (36 mg, 41%) . MS observation (ESI+): 371.4 [(M+H)+]. The enantiomers were separated by chiral SFC. (S)-4-(tertiary butyl)-4-hydroxy-8-(3-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b] Thieno[3,2-d]pyridin-6-one (compound 69): MS observation (ESI +): 371.0 [(M+H) +]. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.30 (s, 1H), 8.60 (s, 1H), 8.52 (d, J= 4.8 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J= 4.8 Hz, 1H), 5.35 (s, 1H), 4.87 - 4.72 (m, 2H), 4.14 (d, J= 11.2 Hz, 1H), 3.45 (d, J= 11.2 Hz, 1H), 1.04 ( s, 9H). (R)-4-(tertiary butyl)-4-hydroxy-8-(3-methylpyridin-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4, 3-b] Thieno[3,2-d]pyridin-6-one (compound 70) (27.2 mg 29%). MS observation (ESI+): 371.0 [(M+H)+]. Example 71 - Compound 71: 4-methyl-8-(1H-pyrazol-4-yl)-4-(pyrrolidin-1-yl)-1,3,4,5-tetrahydro-6H-pyran And[4,3-b]thieno[3,2-d]pyridin-6-one Step A : 4-Hydroxy-4-methyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno [3,2-d]pyridin-6-one: To the 4-(4-hydroxy-4-methyl-6-oxo-3,4,5,6-tetrahydro-1H-pyrano[4,3-b]thieno[3,2- d] To a dry three-necked flask of pyridin-8-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (500 mg, 1.29 mmol, 1.0 equiv), THF (50 mL) was added, and the mixture was degassed and Sweep with N2 (3x). Methylmagnesium bromide (1 M, 25.8 mL, 20.0 equiv) was added at 0 °C, followed by warming to room temperature. After 2 h, NH 4 Cl solution (13 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated to give a residue which was purified by flash column chromatography (SiO 2 , 0-8% MeOH / DCM) to give 4-hydroxy-4-methyl -8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridine-6- Ketones (340 mg, 69%). MS observation (ESI+): 304.1 [(M+H)+]. Step B : 4-Chloro-4-methyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno [3,2-d]pyridin-6-one: Acetyl chloride (15 mL) and N,N-dimethylformamide (0.1 mL) were added to 4-hydroxy-4-methyl-8-(1H-pyrazol-4-yl)-1, 3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (340 mg, 1.12 mmol, 1.0 equiv) in DCM (50 mL ) in the solution. The reaction mixture was heated to 40 °C and stirred for 16 hours. The mixture was concentrated in vacuo to give 4-chloro-4-methyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b] Thieno[3,2-d]pyridin-6-one (280 mg, used without further purification). Step C: 4-methyl-8-(1H-pyrazol-4-yl)-4-(pyrrolidin-1-yl)-1,3,4,5-tetrahydro-6H-pyrano\[ 4,3-b]thieno\[3,2-d]pyridin-6-one (compound 71): 4-Chloro-4-methyl-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3 , 2-d] A solution of pyridin-6-one (280 mg, crude material) in acetonitrile (40 mL) was cooled to 0 °C, and then pyrrolidine (15 mL) was added dropwise. The reaction mixture was warmed to room temperature for 16 hours, then concentrated and purified by reverse phase column chromatography (0-20% MeCN / water (0.1% FA). By preparative TLC (SiO 2 , 0-10% MeOH / DCM) was further purified to give 4-methyl-8-(1H-pyrazol-4-yl)-4-(pyrrolidin-1-yl)-1,3,4,5-tetrahydro-6H- Pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 71) (2.2 mg, 17%). MS observation (ESI +): 357.2 [(M+H ) +].1H NMR (400 MHz, DMSO-d6) δ ppm: 8.11 (s, 2H), 7.40 (s, 1H), 4.74 (d, J= 14.2 Hz, 1H), 4.61 (d, J= 14.2 Hz , 1H), 4.12 (d, J= 11.6 Hz, 1H), 3.58 (d, J= 11.8 Hz, 1H), 2.80 (d, J= 6.4 Hz, 2H), 2.44 - 2.38 (m, 1H), 2.06 - 1.92 (m, 1H), 1.65 (s, 4H), 1.42 (s, 3H). Examples 72 and 73 - Compounds 72 and 73: (S)-4-hydroxyl-4-(prop-1-yn-1-yl)-8-(1H-pyrazol-4-yl)-1,3,4 ,5-tetrahydro-6H-piperano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 72) and (R)-4-hydroxyl-4-(propane- 1-alkyn-1-yl)-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3, 2-d] pyridin-6-one (compound 73) (the stereochemistry of compounds 72 and 73 is arbitrarily assigned) To 4-(7,10-dioxo-12-oxa-5-thia-8-azatricyclo[7.4.0.0 2,6]trideca-1(9) at 0°C, 2(6),3-trien-4-yl)pyrazole-1-carboxylic acid tertiary butyl ester (100 mg, 258 µmol, 1.0 equivalent) in 1,4-di To a solution in alkanes (20 mL) was added prop-1-yn-1-ylmagnesium bromide (0.5 M, 10 mL, 20 equiv). The mixture was stirred at 0 °C for 1 h, followed by the slow addition of HO (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 350 mL), and the combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (SiO2, 0-10% MeOH / DCM) to give 4-hydroxy-4-(prop-1-yn-1-yl)-8-(1H-pyrazole -4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (110 mg, 43%) . MS observation (ESI+): 328.0 [(M+H)+]. The enantiomers were separated by chiral SFC. (S)-4-Hydroxy-4-(prop-1-yn-1-yl)-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyran And[4,3-b]thieno[3,2-d]pyridin-6-one (compound 72): MS observation (ESI +): 328.1 [(M+H) +]; 1H NMR (400 MHz, DMSO- d 6) δppm: 13.23 (s, 1H), 10.90 (s, 1H), 8.29 (s, 1H), 7.97 (s, 1H), 7.43 (s, 1H), 6.20 (s, 1H), 4.74 (s, 2H), 3.94 (d, J= 11.2 Hz, 1H), 3.76 (d, J= 11.2 Hz, 1H), 1.86 (s, 3H). (R)-4-Hydroxy-4-(prop-1-yn-1-yl)-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyran And[4,3-b]thieno[3,2-d]pyridin-6-one (compound 73): MS observation (ESI +): 327.8 [(M+H) +]. Examples 74, 75, 76 and 77 - Compounds 74, 75, 76 and 77: (S)-4-((S)-secondary butyl)-4-hydroxyl-8-(1H-pyrazol-4-yl )-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 74), (R)-4- ((R)-Secondary butyl)-4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b ]thieno[3,2-d]pyridin-6-one (compound 75), (S)-4-((R)-secondary butyl)-4-hydroxyl-8-(1H-pyrazole-4 -yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (compound 76) and (R)- 4-((S)-Secondary butyl)-4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3 -b] Thieno[3,2-d]pyridin-6-one (compound 77) (the stereochemistry of compounds 74, 75, 76 and 77 is arbitrarily assigned) A procedure similar to that of compound 72, step A, using tert-amylmagnesium chloride (1 M in THF, 7.74 mL, 30 eq.) afforded 4-(secondary butyl)-4-hydroxy-8-(1H-pyridine Azol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-b]thieno[3,2-d]pyridin-6-one (35.2 mg, 39% ). MS observation (ESI+): 346.2 [(M+H)+]. The four diastereoisomers were separated by chiral SFC. (S)-4-((S)-Secondary butyl)-4-hydroxy-8-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydro-6H-pyrano [4,3-b]thieno[3,2-d]pyridin-6-one (compound 74): MS observation (ESI +): 346.2 [(M+H) +]. 1H NMR (400 MHz, DMSO-d6) δppm: 13.22 (s, 1H), 10.80 (s, 1H), 8.28 (brs, 1H), 7.96 (brs, 1H), 7.42 (s, 1H), 5.27 (s , 1H), 4.77 - 4.53 (m, 2H), 3.92 (d, J= 11.6 Hz, 1H), 3.56 (d, J= 11.6 Hz, 1H), 2.12-2.07 (m, 1H), 1.87 - 1.80 ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen or a halogen; R2 is a 5-6 member heteroaryl group containing one or more heteroatoms independently selected from N, O, and S and, where applicable, substituted with one or two substituents independently selected from the group consisting of halogens and C1 to C6 alkyl groups; or a 5-6 member heterocyclic group containing at least one heteroatom selected from N, O, and S and, where applicable, substituted with one or two substituents independently selected from the group consisting of halogens and C1 to C6 alkyl groups; R3 is hydrogen or a C1-C6 alkyl group; Ring A is a C6-C10 cycloalkyl group or a 6-10 member heterocyclic group containing at least one heteroatom selected from N, O, and S within the ring; Each R4 is independently selected from the group consisting of: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy(C1-C6 alkyl)-, -C(=O)C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -NRARB and 4-6 member heterocyclic groups containing at least one heteroatom selected from N, O and S in the ring and, where appropriate, substituted with one or two independently selected halogens; each RA and RB is independently hydrogen or C1-C6 alkyl; and m is 0, 1, 2, 3 or 4.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3 or 4.

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R2 is a 5-membered heteroaryl group containing one or more heteroatoms independently selected from N, O and S and, where appropriate, substituted by one or two substituents independently selected from the group consisting of halogens and C1-C6 alkyl groups.

4. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the 5-membered heteroaryl group of R2, which is independently selected from one or more heteroatoms of N, O and S, is pyrazolyl or isothiazolyl.

5. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the 5-membered heteroaryl group of R2, which is independently selected from one or more heteroatoms of N, O and S, is 4-pyrazolyl, 5-pyrazolyl or 5-isothiazolyl.

6. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R2 is a 6-membered heteroaryl group containing one or more heteroatoms independently selected from N, O and S and, where appropriate, substituted by one or two substituents independently selected from the group consisting of halogens and C1-C6 alkyl groups.

7. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the 6-membered heteroaryl group of R2, which is independently selected from one or more heteroatoms of N, O and S, is pyridyl, pyrimidinyl or pyridyl.

8. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the 6-membered heteroaryl group of R2, which is independently selected from one or more heteroatoms of N, O and S, is 4-pyridyl, 4-pyrimidinyl or 4-taldyl.

9. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the heteroaryl group containing one or more heteroatoms independently selected from N, O and S is substituted with a substituent selected from halogens and C1-C6 alkyl groups.

10. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the heteroaryl group containing one or more heteroatoms independently selected from N, O and S is substituted with a substituent selected from fluorine, chlorine and methyl.

11. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the heteroaryl group containing one or more heteroatoms independently selected from N, O and S is substituted by two substituents independently selected from halogens and C1-C6 alkyl groups.

12. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein the heteroaryl group containing one or more heteroatoms independently selected from N, O and S is substituted by two substituents independently selected from fluorine and methyl.

13. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R2 is an unsubstituted 5-6 heteroaryl group containing one or more heteroatoms independently selected from N, O and S.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of pyrazolyl, isothiazolyl, pyridyl and tertyl.

15. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R2 is 4-pyrazolyl, 5-isothiazolyl, 4-pyridyl or 4-tadyl.

16. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R2 is a 5-6 member heterocyclic group containing at least one heteroatom selected from N, O and S within the ring and, where applicable, substituted by one or two substituents independently selected from the group consisting of halogens and C1-C6 alkyl groups.

17. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R2 is a morpholino group.

18. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R2 is 4-morpholino.

19. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a C6-C10 cycloalkyl group.

20. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is cyclohexyl or bicyclic [2.2.2]octyl.

21. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-10 member heterocyclic group containing at least one heteroatom selected from N, O and S within the ring.

22. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is tetrahydropiperanyl or piperidinyl.

23. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein one of R4 is a halogen.

24. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is fluorine.

25. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a hydroxyl group.

26. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a C1-C6 alkyl group.

27. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein one of the R4s is selected from the group consisting of: -CH3, -CH2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)2CH2CH3 and -C(CH3)3.

28. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a C1-C6 alkoxy group.

29. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a methoxy group.

30. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a C1-C6 hydroxyalkyl group.

31. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of the R4 is -CH2OH or -C(CH3)2OH.

32. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a C1-C6 haloalkyl group.

33. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of the R4s is -CF3, -CHF2, -CF2CH3 or -CH2CF2CH3.

34. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is C1-C6 alkoxy (C1-C6 alkyl)-.

35. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of the R4 is -CH2OCH3.

36. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a -C(=O)C1-C6 alkyl group.

37. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of the R4 is -C(=O)CH3.

38. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a C2-C6 ynyl group.

39. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is 1-propynyl.

40. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a C3-C6 cycloalkyl group.

41. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is cyclopentyl.

42. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is -NRARB, wherein: One of RA and RB is hydrogen and the other of RA and RB is a C1-C6 alkyl group; RA and RB are both C1-C6 alkyl groups; or RA and RB are both hydrogen groups.

43. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is a 4-6 member heterocyclic group containing at least one heteroatom selected from N, O and S within the ring and, where applicable, substituted with one or two independently selected halogens.

44. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is pyrrolidone or aziridine, wherein the pyrrolidone or aziridine is substituted with one or two independently chosen halogens, as appropriate.

45. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein one of R4 is 1-pyrrolidyl or 1-azacyclobutyl.

46. ​​A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein m is 2, 3 or 4; and wherein the two R4 groups are in the homologous position.

47. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein m is 2; and wherein both R4 groups are in the homogeneous position; wherein: One R4 is hydroxyl, and the other R4 is C1-C6 alkyl; each R4 is fluorine; one R4 is hydroxyl, and the other R4 is C1-C6 haloalkyl; one R4 is hydroxyl, and the other R4 is C2-C6 alkynyl; one R4 is hydroxyl, and the other R4 is C3-C6 cycloalkyl; one R4 is hydroxyl, and the other R4 is C1-C6 alkoxy(C1-C6 alkyl)-; each R4 is an independently selected C1-C6 alkyl; one R4 is C1-C6 alkyl, and the other R4 is C1-C6 hydroxyalkyl; one R4 is C1-C6 alkyl, and the other R4 is C1-C6 alkoxy; One R4 is a C1-C6 alkyl group and the other R4 is -NRARB; or one R4 is a C1-C6 alkyl group and the other R4 is a 4-6 member heterocyclic group containing at least one heteroatom selected from N, O and S in the ring and, where appropriate, substituted with one or two independently selected halogens.

48. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein m is 4; and wherein the two R4 groups are in the homogeneous position; wherein: Two R4s are fluorine, one R4 is a C1-C6 alkoxy, and one R4 is a C1-C6 alkyl; two R4s are fluorine, one R4 is a C1-C6 hydroxyalkyl, and one R4 is a C1-C6 alkyl; two R4s are fluorine, one R4 is hydroxyl, and one R4 is a C1-C6 alkyl; or two R4s are fluorine, one R4 is hydroxyl, and one R4 is a C1-C6 alkoxy(C1-C6 alkyl)-.

49. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0.

50. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is a halogen.

51. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is fluorine.

52. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

53. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R3 is hydrogen.

54. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R3 is a C1-C6 alkyl group.

55. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IA): Formula (IA).

56. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IB): Formula (IB).

57. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IC): Formula (IC).

58. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (ID): Formula (ID).

59. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IP): Formula (IP).

60. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of:

61. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

62. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

63. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

64. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

65. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

66. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

67. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

68. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

69. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

70. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

71. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

72. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: .

73. A pharmaceutical composition comprising a compound of any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

74. Use of a compound of any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 73 in the preparation of a medicament for the treatment of cancer in an individual in need.

75. As claimed in claim 74, wherein the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid monocytic leukemia (CMML), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, Ewing sarcoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), head and neck cancer, head and neck vesicle, hepatocellular carcinoma, pancreatic neuroendocrine tumor, bone cancer, melanoma, non-small cell lung cancer, lung vesicle, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, uterine cancer, or uterine sarcoma.

76. As claimed in paragraphs 74 or 75, wherein the cancer is myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

77. As claimed in claim 74 or 75, wherein the cancer is prostate cancer or small cell lung cancer.