1,6-naphthiridine compounds as SMARCA2 inhibitors useful in the treatment of SMARCA4-deficient cancers

Abstract

The present invention relates to pharmaceutical compounds and pharmaceutical compositions containing said compounds, processes for preparing said compounds, the use of said compounds as inhibitors of the SMARCA2 protein, and the use thereof in the treatment of SMARCA4-deficient cancers, such as SMARCA4-deficient non-small cell lung cancer (NSCLC). [Formula 1] TIFF2026523246000557.tif21128

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compounds and pharmaceutical compositions containing said compounds, processes for preparing said compounds, the use of said compounds as inhibitors of the SMARCA2 protein, and the use thereof in the treatment of SMARCA4-deficient cancers, such as SMARCA4-deficient non-small cell lung cancer (NSCLC). [Background technology]

[0002] The Switch / Sucrose Non-Fermenting (SWI / SNF) complex, also known as the BAF complex, is a multi-subunit complex that regulates chromatin structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits: SWI / SNF-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2, BRAHMA, or BRM) and SWI / SNF-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4, or BRG1). The core and regulatory subunits link ATP hydrolysis to histone-DNA contact perturbations, thereby providing access points to transcription factors and congeneral DNA elements that promote gene activation and repression.

[0003] Mutations in the genes encoding 20 standard SWI / SNF subunits are observed in nearly 20% of all cancers, with the highest frequency mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, and clear cell carcinomas of the esophagus and kidney. Despite having a high degree of homology and presumed overlapping functions, SMARCA2 and SMARCA4 have been reported to have different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is rare in tumorigenesis. Indeed, numerous types of cancer, including lung cancer (non-small cell lung cancer or NSCLC, etc.), have been shown to be SMARCA4-related (e.g., cancers with SMARCA4 mutations or SMARCA4 deficiencies, e.g., lack of expression).

[0004] SMARCA2 has been demonstrated as one of the most important genes in SMARCA4-related or mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells are exclusively dependent on SMARCA2 activity; that is, there is greater uptake of SMARCA2 into the complex to compensate for the SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The simultaneous occurrence of deficiencies in the expression of two (or more) genes that lead to cell death is known as synthetic lethality. Therefore, synthetic lethality can be utilized in the treatment of certain SMARCA2 / SMARCA4-related cancers.

[0005] There is a continuing need for effective treatments for diseases treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecific effects and the inability to selectively target and modulate SMARCA2 remain obstacles to the development of effective therapies. Therefore, small molecule therapies targeting SMARCA2 are highly valuable.

[0006] The object of the present invention is to provide a compound that is more selective to SMARCA2 than to SMARCA4.

[0007] The objective of the present invention is to provide a SMARCA2 inhibitor that is effective in treating SMARCA4-deficient cancer.

[0008] The object of the present invention is to provide a SMARCA2 inhibitor compound that is effective in treating SMARCA4-deficient NSCLC. [Overview of the project] [Means for solving the problem]

[0009] Embodiments of the present invention relate to 1,6-naphthyrizine chemicals having SMARCA2 regulatory properties, as described in the claims, specific uses and methods of use of pharmaceutical compositions containing these chemicals, the use of these chemicals as inhibitors of the SMARCA2 protein, and methods for treating or use in the treatment of SMARCA4-deficient cancer.

[0010] Additional embodiments, features, and advantages of the present invention will become apparent from the following "Modes for Carrying Out the Invention" and through the practice of the present invention.

[0011] Embodiments of the present invention are given by formula (I)

[0012] [ka] The use and method of treatment involving the compounds thereof, or pharmaceutically acceptable salts or stereoisomers thereof, During the ceremony, R 1 but, (a)

[0013] [ka] A five-membered heteroaryl selected from; or (b)

[0014] [ka] Here, each R a is independently selected from halo, C 1~4 alkyl, C 1~4 alkyl substituted with OH, C 1~4 haloalkyl, and (C=O)CH3; R b is C 1~4 alkyl substituted with OH; OC 1~4 alkyl; OCH2CH2OH; and OCHF2; or (c)

[0015] [Chemical formula] a 6-member heteroaryl selected from Here, each R d is independently C 1~4 alkyl, C 1~4 haloalkyl, and OC 1~4 alkyl; R e is C 1~4 alkyl substituted with alkyl, OH or OCH3, and C 1~4 haloalkyl; 1~4 selected from X is NH or O and is an optionally substituted heteroaryl selected from R 5 is such that (i) <00ff00299> [Chemical formula] [[ID=ff0069]] Here, ring A is

[0017] [Chemical formula]

[0018] [Chemical formula] A nitrogen-linked monocyclic, polycyclic, crosslinked, spirocyclic, or condensed heterocycloalkyl selected from the following, each R c is independently a halo or CH3; or (ii)

[0019] [ka] Here, ring B is,

[0020] [ka] It is a nitrogen-linked monocyclic, polycyclic, or spirocyclic heterocycloalkyl selected from; or (iii) Phenyl,

[0021] [ka] Here, R k (CH)(CH3)2, oxetane-3-yl,

[0022] [ka] Selected from; R f is either H or CH3; R g teeth,

[0023] [ka] Selected from; R h C 1~4 It is alkyl, R j teeth,

[0024] [ka] Selected from; n is 0, 1, or 2. is; This also includes pharmaceutically acceptable salts or stereoisomers thereof.

[0025] Built-in by reference All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referenced herein are incorporated by reference to the same extent that each individual publication, patent, patent application, or published nucleotide and amino acid sequence is specifically and individually indicated as being incorporated by reference. [Modes for carrying out the invention]

[0026] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood in relation to the subject matter claimed. Where URLs or other such identifiers or addresses are referenced, it is understood that such identifiers may change, and certain information on the Internet may shift, but equivalent information can be found by searching the Internet. References to these are evidence of the existence and public dissemination of such information.

[0027] Please understand that the general description above and the detailed description below are illustrative and descriptive only and do not limit any subject matter claimed.

[0028] In this application, unless otherwise specifically stated, the use of the singular form includes the plural. Note that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple objects unless otherwise clearly indicated by the surrounding context. In this application, unless otherwise specifically stated, the use of "or" means "and / or."

[0029] When a value is expressed as an approximation using the antecedent “about,” it should be understood that the particular value forms another embodiment. As used herein, “about X” (where X is a number) preferably encompasses ±10% of the stated value. For example, the phrase “about 8” encompasses values ​​from 7.2 to 8.8, and as another example, the phrase “about 8%” encompasses values ​​from 7.2% to 8.8%. All ranges, where present, are inclusive and combinable. For example, when listing the range “1 to 5,” the listed range should be interpreted as including ranges such as “1 to 4,” “1 to 3,” “1 to 2,” “1 to 2 and 4 to 5,” and “1 to 3 and 5.” Furthermore, where a list of substitutes is explicitly provided, such a list may also include embodiments in which any of the substitutes may be excluded. For example, when describing the range “1 to 5,” such description may support situations in which 1, 2, 3, 4, or 5 is excluded. Therefore, the statement "1-5" may support the interpretation of "1 and 3-5, but not 2" or simply "2 is not included."

[0030] Some of the quantitative expressions given herein are not modified by the term “approximately.” Whether or not the term “approximately” is explicitly used, all quantities shown herein mean the actual values ​​shown, and are understood to also mean approximations of such shown values ​​that can be reasonably estimated based on the ordinary skill in the art, including approximations of such shown values ​​based on experimental and / or measurement conditions and permissible errors.

[0031] As used herein, the expression "one or more" means, whenever possible, at least one, for example, one, two, three, four, five or more, depending on the context.

[0032] Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limited to these.

[0033] The chapter headings used herein are for structural purposes only and should not be interpreted as limiting the subjects described.

[0034] The standard definitions of chemical terms are found in Carey and Sundberg's "Advanced Organic Chemistry 4". th This can be found in references including, but not limited to, "Ed." Vols. A (2000) and B (2001), Plenum Press, New York.

[0035] Unless otherwise specified, the nomenclature, experimental procedures, and techniques used in relation to analytical chemistry, synthetic organic chemistry, and pharmaceutical and pharmaceutical chemistry described herein are recognized in the art. Standard methods can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and for the treatment of patients. Standard methods can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques can be performed, for example, using kits specified by the manufacturer, or as commonly achieved in the art or as described herein. The aforementioned techniques and procedures can generally be performed by conventional methods, as described in the various general and more specific references cited and discussed throughout this specification.

[0036] The methods and compositions described herein are not limited to the specific methodologies, protocols, cell lines, constructs, and reagents described herein, and should therefore be understood to be subject to change. Furthermore, the terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit the scope of the methods, compounds, and compositions described herein.

[0037] In the above and below, the term "compound of formula (I)" means including its addition salts and stereoisomers.

[0038] When used in this specification, "C x~y (where x and y are integers) refers to the number of carbon atoms that make up the part it specifies (excluding any optional substituent). Therefore, C 1~6 Alkyl groups contain 1 to 6 carbon atoms, C 3~6 Cycloalkyl groups contain 3 to 6 carbon atoms, for example.

[0039] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodine.

[0040] Alkyl groups may have 1 to 6 carbon atoms (wherein it appears herein, numerical ranges such as "1 to 6" refer to each integer within the given range; for example, "1 to 6 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and up to 6 carbon atoms; however, this definition also includes the case where the term "alkyl" does not specify a numerical range). The alkyl groups of the compounds described herein are "C 1~6 It may be designated as "alkyl" or a similar designation.

[0041] For example, "C" as used herein as a base or as part of a base. 1~4 "Alkyl" or "C 1~6 The term "alkyl" refers to a linear or branched saturated hydrocarbon group containing 1 to 4 or 1 to 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and hexyl.

[0042] The term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced by one or more halogens.1~4 Alkyl," "Halo C" 1~6 Alkyl, Monohalo C 1~4 Alkyl, Monohalo C 1~6 Alkyl, polyhalo C 1~4 alkyl and polyhalogen C 1~6 Contains alkyl. Halo C 1~4 Alkyl or Halo C 1~6 One, two, or three or more hydrogen atoms may be replaced by halogens so that the alkyl group may have one, two, or three or more halogens. Examples of "haloalkyl" groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and any group that is considered equivalent to any one of the above examples in light of the usual skills in the art and the teachings provided herein.

[0043] "Amino" refers to the -NH2 group.

[0044] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or 10 or more atoms. Aromatics may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0045] The term "non-aromatic group" encompasses unsaturated, partially saturated, and fully saturated heterocyclyl ring systems that do not possess aromatic properties, unless otherwise intended by context.

[0046] The terms "unsaturated" and "partially saturated" refer to ring structures containing atoms that share two or more valence bonds, i.e., rings with at least one multiple bond, for example,

[0047] [ka] It refers to a ring containing a bond.

[0048] The term "fully saturated" refers to a ring in which there are no multiple bonds between ring atoms. Examples of saturated heterocyclyl groups include piperidine, morpholine, thiomorpholine, and piperazine. Examples of partially saturated heterocyclyl groups include pyrazolines, such as 2-pyrazoline and 3-pyrazoline.

[0049] The term "aryl" refers to a monocyclic aromatic carbocyclic ring (a ring structure with all carbon atoms) that has six atoms per ring (the carbon atoms in the aryl group are sp2 hybridized).

[0050] The term "phenyl" refers to the following part:

[0051] [ka]

[0052] The term "cycloalkyl" refers to monocyclic or polycyclic non-aromatic radicals in which each of the atoms constituting the ring (i.e., the skeletal atoms) is a carbon atom. Cycloalkyls may be saturated or partially unsaturated. An example of a "cycloalkyl" is "C 3~6 This refers to a "cycloalkyl" group. A cycloalkyl group may be condensed with an aromatic ring (in this case, the cycloalkyl group is bonded via a non-aromatic ring carbon atom). Examples of cycloalkyl groups include those having 3 to 10 ring atoms. Typical examples of cycloalkyl groups, though not limited to these, include the following: namely,

[0053] [ka] These are some examples, but the list is not limited to these.

[0054] The terms “heterocyclyl” or “heterocycloalkyl,” as defined herein, typically contain at least one heteroatom selected from nitrogen, oxygen, or sulfur, and in particular, up to five, four, three, two, or a single heteroatom. Where a heterocyclyl or heterocycloalkyl ring system is referred to herein, the heterocyclyl or heterocycloalkyl ring may be optionally substituted (i.e., unsubstituted or substituted) with one or more substituents considered herein, unless the context indicates otherwise. It is understood that the heterocyclyl or heterocycloalkyl group may be bonded, where chemically possible, via heteroatoms in the ring or via one of the carbon atoms constituting the heterocycloalkyl ring. These radicals may be condensed with aryl or heteroaryl groups. Specific examples of heterocycloalkyl groups, also called non-aromatic heterocycles, include:

[0055] [ka] These are some examples.

[0056] A heterocyclyl ring system or heterocycloalkyl ring system may be a heteroaryl ring system having 5 to 12 ring members, more generally 5 to 10 ring members.

[0057] Heterocyclyl rings also include bridging ring systems, such as bridging cycloalkanes, e.g., norbornane (1,4-endo-methylene-cyclohexane), adamantane, oxa-adamantane; bridging morpholine rings, e.g., 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane; bridging piperazine rings, e.g., 3,6-diazabicyclo[3.1.1]heptane; and bridging piperidine rings, e.g., 1,4-ethylenepiperidine. For an explanation of the distinction between condensed ring systems and bridging ring systems, see Advanced Organic Chemistry, by Jerry March, 4 thSee Edition, Wiley Interscience, pages 131–133, 1992.

[0058] The term "heteroaryl" is used herein to describe a heterocyclyl ring system having aromatic properties. The term "heteroaryl" encompasses polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be bonded to the remainder of the compound by aromatic or non-aromatic rings.

[0059] Examples of heteroaryl groups include monocyclic and bicyclic groups containing 5 to 12 ring members, more commonly 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings, or bicyclic structures formed from fused 5- and 6-membered rings, two fused 6-membered rings, or two fused 5-membered rings. Heteroaryl ring systems can typically contain up to about 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Typically, heteroaryl rings contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more commonly up to 2, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or it may be essentially non-basic, as in the case of indole or pyrrole nitrogen. It is understood that heteroaryl groups can be bonded, where chemically possible, via heteroatoms in the ring or via one of the carbon atoms constituting the heteroaryl ring. Generally, the number of basic nitrogen atoms present in a heteroaryl group is less than five, including any amino group substituents in the ring. Examples of heteroaryl groups include: These are some examples.

[0060] [ka] These are some examples, but are not limited to these.

[0061] A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Each ring may further contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to three heteroatoms, e.g., one, two, or three, and more generally up to two nitrogen atoms, e.g., a single nitrogen atom. The nitrogen atoms in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or they may be essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than five.

[0062] Examples of non-aromatic heterocyclyl groups are those having 3 to 12 ring members, more commonly 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example, and typically have 1 to 5 heteroatom ring members (more commonly 1, 2, 3, or 4 heteroatom ring members), usually selected from nitrogen, oxygen, and sulfur. Heterocyclyl groups may contain, for example, cyclic ether moieties (such as those in tetrahydrofuran and dioxane), cyclic thioether moieties (such as those in tetrahydrothiophene and dithiane), cyclic amine moieties (such as those in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0063] Heterocyclyl rings and cycloalkyl rings also include cross-linked ring systems, such as cross-linked cycloalkanes, e.g., norbornane (1,4-endo-methylene-cyclohexane), adamantane, oxa-adamantane; cross-linked morpholine rings, e.g., 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane; cross-linked piperazine rings, e.g., 3,6-diazabicyclo[3.1.1]heptane; and cross-linked piperidine rings, e.g., 1,4-ethylenepiperidine. For an explanation of the distinction between condensed ring systems and cross-linked ring systems, see Advanced Organic Chemistry, by Jerry March, 4th See Edition, Wiley Interscience, pages 131–133, 1992.

[0064] The lines drawn within the ring system indicate that a bond can be attached to any of the appropriate and available ring atoms. The term "variable bond point" means that a group is bonded at two or more alternative positions within the structure. This bond always substitutes a hydrogen atom for one of the ring atoms. In other words, all permutations of bonding are represented by a single diagram, as shown in the diagram below.

[0065] [ka]

[0066] The terms "optional" or "optionally" mean that the event described after them may or may not occur. This term encompasses both cases where the event occurs and cases where it does not.

[0067] In the compounds disclosed herein, in the depicted formula, * The carbon atom indicated by " is a chiral center. * When a carbon atom is indicated as "(S)", it means it is a pure enantiomer, but it is unclear whether it is an R enantiomer or an S enantiomer. Similarly, when a carbon atom is indicated as "(S * When indicated by )", it means that it is a pure enantiomer, but it is unclear whether it is an R enantiomer or an S enantiomer.

[0068] The terms "bond" or "single bond" refer to a chemical bond between two atoms, or a chemical bond between two parts when the atoms linked by the bond are considered part of a larger substructure.

[0069] The term "part" refers to a specific segment or functional group of a molecule. Chemical parts are often perceived as chemical entities embedded within or attached to a molecule.

[0070] As used herein, the term “therapeutic dose” means the amount of active compound or medicinal product that, when administered to a mammal in need, is effective in at least partially improving or at least partially preventing the disease, disorder, or condition described herein.

[0071] As used herein, the term “composition” is intended to encompass products containing a particular component in a specific amount, as well as any products resulting directly or indirectly from a combination of a particular amount of a particular component.

[0072] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0073] As used herein, the term “antagonist” refers to a small molecule drug that binds to a receptor and subsequently reduces the receptor’s agonist-induced transcriptional activity.

[0074] As used herein, the term “agonist” refers to a small molecule drug that binds to a receptor and subsequently increases receptor transcriptional activity in the absence of a known agonist.

[0075] As used herein, the term “inverse agonist” refers to a small molecule drug that binds to a receptor and subsequently reduces the baseline level of receptor transcriptional activity present in the absence of a known agonist.

[0076] As used herein, the term “modulate” means to interact with a target directly or indirectly in such a way as to alter its activity, including, for example, enhancing, inhibiting, limiting, or prolonging the activity of the target.

[0077] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human. Those skilled in the art will recognize that a therapy that reduces the severity of a condition in one species of mammal may predict the effect of that therapy in another species of mammal.

[0078] When used herein, the terms “treat,” “treating,” or “treatment” include, for example, alleviating, reducing or improving at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, for example, stopping the onset of a disease or condition, reducing a disease or condition, causing a regression of a disease or condition, reducing a condition caused by a disease or condition, or preventing and / or therapeutically cessating the symptoms of a disease or condition.

[0079] "Proliferative disorders" refer to diseases resulting from abnormal growth or expansion due to cell proliferation. Proliferative disorders may be associated with: 1) pathological proliferation of cells that are normally quiescent; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0080] The terms “neoplasm” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue whose growth exceeds and does not coordinate with the growth of normal tissue. Neoplasms or tumors may be “benign” or “malignant” depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign neoplasms” are generally highly differentiated, grow more slowly than malignant neoplasms, and remain localized to the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromes, adenomas, filamentous fibromas, senile angiomas, seborrheic keratosis, lentigo, and sebaceous gland hyperplasia. In some cases, certain “benign” tumors may later develop into malignant neoplasms, which may be due to additional genetic changes in a subpopulation of neoplastic cells in the tumor; these tumors are called “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characterized by rapid growth accompanied by progressive invasion, infiltration, and destruction of surrounding tissues. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites.

[0081] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a healthy body for wound healing and restoring blood flow to damaged tissue. A healthy body controls angiogenesis through several means, such as angiogenic growth factors and angiogenic inhibitors. Many pathological conditions, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal angiogenesis (i.e., increased or excessive). Abnormal angiogenesis refers to angiogenesis that is greater than that in a normal body, especially in adults unrelated to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that nourish diseased tissue and / or destroy normal tissue, and in the case of cancer, new blood vessels can allow tumor cells to escape into the circulatory system and remain in other organs (tumor metastasis).

[0082] The term “biological specimen” refers to any specimen containing tissue specimens (such as tissue sections and needle biopsies); cell specimens (e.g., cytological smears (e.g., Pap or blood smears) or cell specimens obtained by microdissection); whole organism specimens (e.g., yeast or bacterial specimens); or cell fractions, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological specimens include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., cheek swabs), or any substance containing biomolecules derived from the first biological specimen. Biological specimens also include transgenic biological specimens such as transgenic oocytes, spermatids, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0083] Isomers, salts, N-oxides, isotope-labeled derivatives In the above and below, “compound of formula (I),” “compound of the present disclosure or the present invention,” “compound presented herein,” or similar terms mean including its addition salts and stereoisomers.

[0084] In certain embodiments, the compounds presented herein have one or more stereocenters, each independently existing in either an R or S configuration. The compounds presented herein include all diastereomers, enantiomers, atropisomers, and epimer forms, as well as suitable mixtures thereof. Stereoiomers are obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography column. In some embodiments, the compounds of the disclosure are used as single enantiomers. In some embodiments, the compounds of the disclosure are used as racemic mixtures. In some embodiments, the compounds of the disclosure have rotational hindrance around a single bond resulting in atropisomers.

[0085] Under certain circumstances, compounds may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0086] To avoid misunderstanding, a compound may exist in one of several geometric isomers or tautomers, and if only one is specifically described or shown, all others are nevertheless encompassed. Examples of tautomers include, for example, the following tautomer pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / endiamine, nitroso / oxime, thioketone / enthiol, and nitro / ac-nitro, such as the keto, enol, and enolate forms.

[0087] [ka]

[0088] Such forms are intended to be included within the range of compounds presented herein, to the extent that they exist. Thus, a single compound may exist in both stereoisomer and tautomer forms.

[0089] If a compound described herein contains one or more chiral centers and may exist in the form of two or more optical isomers, references to such compounds herein include all optical isomeric forms (e.g., enantiomers, epimers, and diastereoisomers) either as individual optical isomers or as a mixture of two or more optical isomers (e.g., a racemic mixture), unless the context requires otherwise. If a compound has two or more chiral centers and one chiral center is indicated to have absolute configuration, the other chiral centers include all optical isomeric forms either as individual optical isomers or as a mixture of two or more optical isomers (e.g., a racemic mixture), unless the context requires otherwise. Optical isomers may be characterized and identified by their optical activity (i.e., as + and - isomers or as d and l isomers depending on the direction in which they rotate plane-polarized light), or they may be characterized in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog (Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415). For example, decomposed enantiomers whose absolute configuration is unknown may be designated as (+) or (-) depending on the direction in which they rotate plane-polarized light.

[0090] Optical isomers can be separated by many techniques, including chiral chromatography (chromatography on a chiral support), and such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomer salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-ditoluyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential crystallization, and then dissociating the salts to obtain individual enantiomers of the free bases.

[0091] When a compound exists in two or more isomeric forms, one isomeric form, for example, one enantiomer in a pair of enantiomers, may exhibit superiority over the other isomeric form, for example, in terms of biological activity. Therefore, in certain situations, it may be desirable to use only one of a pair of enantiomers, or only one of multiple diastereoisomers, as a therapeutic agent.

[0092] When a particular stereoisomer is identified, this means that the stereoisomer is substantially free from other stereoisomers, i.e., it is associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other stereoisomers. Therefore, when a compound described herein is identified, for example, as (S), this means that the compound is substantially free from the (R) isomer; when a compound described herein is identified, for example, as E, this means that the compound is substantially free from the Z isomer; and when a compound described herein is identified, for example, as cis, this means that the compound is substantially free from the trans isomer.

[0093] When used herein, any chemical formula having a bond that is shown only as a solid line and not as a solid wedge bond or hashed wedge bond, or otherwise shown as having a specific arrangement (e.g., R, S) around one or more atoms, is intended to represent each possible stereoisomer or a mixture of two or more stereoisomers.

[0094] The terms "stereoisomer," "stereoisomeric form," and "stereochemical isomer form" used above and below are interchangeable.

[0095] Enantiomers are stereoisomers that are mirror images of each other but cannot be superimposed.

[0096] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers; that is, they are not related as mirror images. If a compound contains a double bond, the substituent may be in an E or Z configuration. Substituents on a divalent cyclic (partially) saturated radical may have either a cis or trans configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituent may be in a cis or trans configuration. Thus, this disclosure always includes, chemically possible, enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof.

[0097] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers may be designated by nomenclature prefixes such as cis and trans. Cis and trans isomers are also called "geometric isomers." When a compound described herein is identified, for example, as "cis," this means that the two groups point in the same direction with respect to the plane of the ring. In the "trans" isomer, they point in opposite directions. The "cis" and "trans" isomers of 2,6-dimethylmorpholine are illustrated below. Two possible relative configurations exist, based on the relative positions of the two substituents and whether they are on the same side or opposite side of the cyclic structure.

[0098] [ka]

[0099] for example,

[0100] [ka]

[0101] In the present invention, the trisubstituted piperidine moiety having a stereocenter is defined as (3α, 4α, 5α) or (3α, 4β, 5α). For example,

[0102] [ka]

[0103] The meanings of all terms, namely enantiomer, atropisomer, diastereomer, racemate, E isomer, Z isomer, cis isomer, trans isomer, and mixtures thereof, are known to those skilled in the art.

[0104] The methods and formulations described herein involve the use of N-oxides (where appropriate), pharmaceutically acceptable salts, and combinations thereof of compounds having the structure and the same type of activity as presented herein.

[0105] The salt forms of the compounds presented herein are typically pharmaceutically acceptable salts, examples of which are discussed in Berge et al. (1977), "Pharmaceutically Acceptable Salts," J.Pharm.Sci, Vol. 66, pp. 1-19. However, pharmaceutically unacceptable salts may also be prepared as intermediate forms and subsequently converted to pharmaceutically acceptable salts. For example, such non-pharmaceutically acceptable salt forms, which may be useful in the purification or separation of the compounds of the present invention, also form part of the present invention.

[0106] A pharmaceutically acceptable salt means that it includes pharmaceutically acceptable acids and base addition salts, and includes therapeutically active, non-toxic acid and base addition salt forms that the compounds described herein can form.

[0107] The salts of this disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use," edited by P. Heinrich Stahl and Camille G. Wermuth, ISBN: 3-90639-026-8, hardcover, page 388, August 2002. Generally, such salts can be prepared by reacting the free acid or base of these compounds with a suitable base or acid in water, an organic solvent, or a mixture thereof, typically using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. The compounds of the present invention may exist as monosaltes or disaltes, depending on the pKa of the acid in which the salt is formed.

[0108] Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the salt form with a suitable inorganic acid in an anionic form (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or an organic acid (e.g., acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.).

[0109] Suitable anions include, for example, acetate, 2,2-dichloroacetate, adipine, alginate, ascorbate (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetamidebenzoate, butanoate, bicarbonate, bicarbonate, bromide, (+)camphorate, camphor sulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, and camphor. Salts, caprinates, caproates, caprylates, carbonates, chlorides, cinnamic acid, citrates, cyclamates, dihydrochlorides, dodecyl sulfates, edetates, estates, esylates, ethane-1,2-disulfonates, ethanesulfonates, formate, fumarates, galactarates, gentisinates, glucoheptones, gluceptates, gluconates, D-gluconates, glucuronates (e.g., D-glucuronic acid), g Glutamate (e.g., L-glutamate), α-oxoglutarate, glycolate, glycolylarsanilate, hexylresorcinate, hippurate, hydravamin, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isethionate, lactate (e.g., (+)-L-lactate, (±)-DL-lactate), lactobionate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL-mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, naphthalene sulfonate (e.g., naphthalene-2-sulfonate), naphthalene-1,This includes 5-disulfonates, 1-hydroxy-2-naphthoates, napsylates, nicotinates, nitrates, oleates, orotates, oxalates, palmitates, pamoates (embonates), pantothenates, phosphates / diphosphates, propionates, polygalacturonic acids, L-pyroglutamates, pyruvates, salicylates, 4-aminosalicylates, sebacinates, stearates, diacetates, succinates, sulfates, tannates, tartrates, (+)-L-tartrates, theoclates, thiocyans, toluenesulfonates (e.g., p-toluenesulfonates), tosylates, triethiozides, undecylenates, valeric acid, as well as acylated amino acids and cation exchange resins. Conversely, the above salt forms can be converted to free salt forms by treatment with a suitable base.

[0110] Compounds of the present disclosure containing acidic protons may be converted to non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases in cationic form. Suitable basic salts are those formed with organic cations such as arginine, benzathine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, and tromethamine, and ammonium ions (i.e., NH4) + ), quaternary ammonium ion N(CH3)4 + , and substituted ammonium ions (e.g., NH3R + NH2R2 + NHR3 + NR4 +This includes compounds formed from ) and compounds formed from metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. If the compounds described herein contain amine functional groups, they can form quaternary ammonium salts by reaction with alkylating agents, for example, according to methods known to those skilled in the art. Such quaternary ammonium compounds are within the range of compounds presented herein.

[0111] Conversely, the salt form can be converted back to the free form by treatment with an appropriate acid.

[0112] In some embodiments, the sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporating appropriate substituents at the sites of metabolic reactions reduces, minimizes, or eliminates metabolic pathways. In certain embodiments, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions are, to name just a few, halogens, deuterium, or alkyl groups.

[0113] The compounds of this disclosure include isotope-labeled compounds, i.e., compounds having one or more isotopic substitutions. These compounds are identical to those enumerated in the various formulas and structures presented herein, but in practice, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. References to specific elements include, within their scope, all isotopes of the element that exist naturally or are synthetically produced, either in natural abundance or in isotopic enrichment forms. For example, references to hydrogen include, within their scope... 1 H, 2 H(D), and 3 H(T) is included. Similarly, references to carbon and oxygen are within their respective ranges. 12 C, 13 C and 14 C, and 16 O and 18Each contains O. These isotopes may be radioactive or non-radioactive. In one embodiment, the compound does not contain radioactive isotopes. In another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes may be useful in diagnostic settings. The radiolabeled compounds described herein are 2 H, 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 It may contain radioactive isotopes selected from the group including Br. Preferably, the radioactive isotopes are 2 H, 3 H, 11 C, and 18 Selected from the group F. More preferably, the radioactive isotope is 2 It is H. In particular, deuterium compounds are intended to be included within the scope of the present invention. In some embodiments, the metabolic sites on the compounds described herein are deuterated.

[0114] Throughout this specification, groups and their substituents can be selected to provide stable moieties and compounds.

[0115] The embodiments of the 1,6-naphthyridine compounds for use described herein are those of formula (I):

[0116] [ka] Compounds thereof, or pharmaceutically acceptable salts or stereoisomers thereof, During the ceremony, R 1 teeth, (a)

[0117] [ka] a 5-member heteroaryl selected from; or (b)

[0118] [Chemical formula] wherein each R a is independently selected from halo, C 1~4 alkyl, C 1~4 alkyl substituted with OH, C 1~4 haloalkyl, and (C=O)CH3; R b is C 1~4 alkyl substituted with OH; OC 1~4 alkyl; OCH2CH2OH; and OCHF2; or (c)

[0119] [Chemical formula] a 6-member heteroaryl selected from; wherein <着 each R d is independently C 1~4 alkyl, C<00000 (87>haloalkyl, and OC 1~4 alkyl; R e is C 1~4 alkyl substituted with alkyl, OH or OCH3, and C 1~4 haloalkyl; 1~4 selected from; X is N or O is an optionally substituted heteroaryl selected from; R 5 is (i)

[0120] [Chemical formula] wherein ring A is

[0121] [Chemical]

[0122] [Chemical] is a nitrogen-linked monocyclic, polycyclic, bridged, spirocyclic or fused heterocycloalkyl selected from the group consisting of, each R c is independently halo or CH3; or (ii)

[0123] [Chemical] where ring B is

[0124] [Chemical] is a nitrogen-linked monocyclic, polycyclic, spirocyclic heterocycloalkyl selected from the group consisting of; or (iii) phenyl,

[0125] [Chemical] where R k is (CH)(CH3)2, oxetan-3-yl,

[0126] [Chemical] is selected from the group consisting of; R f is H or CH3; R g is

[0127] [Chemical] is selected from the group consisting of; R h is C 1~4 alkyl, R j is

[0128] [ka] Selected from; n is 0, 1, or 2. is; This also includes pharmaceutically acceptable salts or stereoisomers thereof.

[0129] In some embodiments, R 1 teeth,

[0130] [ka] That is the case.

[0131] In some embodiments, R 1 teeth,

[0132] [ka] That is the case.

[0133] In some embodiments, R 1 teeth,

[0134] [ka] That is the case.

[0135] In some embodiments, R 1 teeth,

[0136] [ka] That is the case.

[0137] In some embodiments, X is N. In some embodiments, X is O.

[0138] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0139] In some embodiments, R 5 is

[0140]

Chemical Formula

[0141] In some embodiments, R 5 is

[0142]

Chemical Formula

[0143]

Chemical Formula

[0144] In some embodiments, the compound of formula (I) is the compound shown in Table 1 below.​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0149] Table 1-5

[0150] Table 1-6

[0151] Table 1-7

[0152] Table 1-8

[0153] Table 1-9

[0154] Table 1-10

[0155] Table 1-11

[0156] Table 1-12

[0157] Table 1-13

[0158] Table 1-14

[0159] Table 1-15

[0160] Table 1-16

[0161] Table 1-17

[0162] Table 1-18

[0163] Table 1-19

[0164] Table 1-20

[0165] Table 1-21

[0166] Table 1-22

[0167] Table 1-23

[0168] Table 1-24

[0169] Table 1-25

[0170] Table 1-26

[0171] Table 1-27

[0172] Table 1-28

[0173] Table 1-29

[0174] Table 1-30

[0175] Table 1-31

[0176] Table 1-32

[0177] Table 1-33

[0178] Table 1-34

[0179] Table 1-35

[0180] Table 1-36

[0181] Table 1-37

[0182] Table 1-38

[0183] Table 1-39

[0184] Table 1-40

[0185] Table 1-41

[0186] Table 1-42

[0187] Table 1-43

[0188] Table 1-44

[0189] Table 1-45

[0190] [Table 1-46] and their pharmaceutically acceptable salts or stereoisomers.

[0191] In some embodiments, the 1,6-naphthyridine compound is N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(( * S)-S-methylsulfonimidoyl)nicotinamide; and Selected from the group consisting of 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyrizin-7-yl)methyl)-6-methylnicotinamide; and pharmaceutically acceptable salts and stereoisomers thereof.

[0192] Compound Synthesis In this section, unless otherwise indicated by context, references to formula (I) in all other sections of this application include all other subgroups and their embodiments as defined herein.

[0193] The synthesis of the compounds described herein is achieved by means of the chemical literature, by the methods described herein, or by a combination thereof. In addition, the solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the art include, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4. th Ed.,(Wiley 1992);Carey and Sundberg,Advanced Organic Chemistry 4 th Ed.,Vols.A and B(Plenum 2000,2001), and Green and Wuts,Protective Groups in Organic Synthesis 3 rd The details are described in Ed., (Wiley 1999) (both of these documents are incorporated by reference to their disclosures). General methods for preparing the compounds disclosed herein may be derived from reactions to introduce the various parts found in the formulas provided herein, and the reactions may be modified using appropriate reagents and conditions.

[0194] The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources, including but not limited to Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0195] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxyl groups, amino groups, imino groups, thio groups, or carboxyl groups, if desired in the final product, to avoid their undesirable involvement in the reaction. Protecting groups are used to block some or all of the reactive moieties, preventing such groups from participating in the chemical reaction until the protecting group is removed. Preferably, each protecting group can be removed by different means. Protecting groups that are cleaved under completely different reaction conditions satisfy different removal requirements.

[0196] Protecting groups can be removed by acids, bases, reducing conditions (e.g., hydrolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl can be used to protect carboxy and hydroxy-reactive moieties in the presence of amino groups protected by acid-unstable and hydrolytically removable Cbz groups and base-unstable Fmoc groups. Carboxylic acid and hydroxy-reactive moieties can be blocked by acid-unstable groups such as t-butyl carbamate, or by base-unstable groups such as methyl, ethyl, and acetyl, in the presence of amines blocked by carbamates that are stable to both acids and bases but hydrolytically removable.

[0197] The carboxylic acid and hydroxyl-reactive moieties may also be blocked with hydrolytically removable protecting groups, such as benzyl groups, while amine groups that can hydrogenate with acids may be blocked with base-unstable groups, such as acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethylene-oxycarbonyl (Fmoc). The carboxylic acid-reactive moieties may be protected by conversion to simple ester compounds, such as those exemplified herein, including conversion to alkyl esters, or they may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride-unstable silylcarbamates.

[0198] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups because the former are stable and can then be removed with a metal or π-acid catalyst. For example, allyl-blocked carboxylic acids can be protected in the presence of acid-unstable t-butyl carbamate or base-unstable amine acetate protecting groups, and Pd 0 Deprotection can be achieved using catalytic reactions. Another form of protecting group is a resin to which a compound or intermediate can be bound. As long as the residue is bound to the resin, its functional group is blocked and cannot react. Once released from the resin, the functional group becomes available for reaction.

[0199] Typically, blocking / protecting groups can be selected from the following:

[0200] [ka]

[0201] A detailed description of other protecting groups, as well as techniques applicable to the fabrication and removal of protecting groups, is provided in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosures.

[0202] General synthesis route Scheme 1

[0203] [ka]

[0204] Appropriately substituted ester compounds of formula (II) are commercially available or obtainable by synthesis. A heteroaryl halide compound of formula (II), such as methyl 5-bromo-6-methyl-3-pyridinecarboxylate, can be reacted with tert-butylammonium bromide and a palladium catalyst, such as palladium acetate, in the presence of K2S2O5 and sodium formate in a palladium-catalyzed sulfinization using triphenylphosphine and 1,10-phenanthroline, followed by in situ alkylation with, for example, 2-(2-bromoethoxy)tetrahydro-2H-pyran in a suitable solvent such as DMSO or ACN at a temperature ranging from room temperature to 100°C, to obtain methyl 6-methyl-5-((3-((tetrahydro-2H-pyran-2-yl)oxypropyl)sulfonyl)nicotinate. Deprotection of pyrane can be achieved under acidic conditions known to those skilled in the art, such as HCl / MeOH, to obtain methyl 5-((3-hydroxypropyl)sulfonyl)-6-methylnicotinate.

[0205] Formula (II) (wherein, R 1Further functionalization of ester compounds of halides such as Br (e.g., those having 5-bromonicotinic acid) can be obtained by reacting them with n-butyllithium and acetone in a suitable solvent such as THF at a temperature ranging from -78°C to room temperature to obtain the compound of formula (II) (wherein Br is replaced by C(OH)(CH3)2).

[0206] A commercially available or synthetically obtained ester compound of formula (II) (wherein ring B is a appropriately substituted heteroaryl) can be reacted under basic conditions such as NaOH, LiOH, or KOH in a suitable solvent such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O, or a mixture thereof, at a temperature of approximately 60°C to 80°C for 1 to 6 hours to obtain an acid compound of formula (III).

[0207] Formula (III) (wherein, R 1 Further functionalization can be obtained by reacting an acid compound of a halogen (such as Br (bromide)), for example 5-bromonicotinic acid, with BuLi in a suitable solvent such as THF and an aldehyde at a temperature of approximately -78°C for 1 hour to obtain a compound of formula (III) (wherein Br is replaced by CH(OH)CH3).

[0208] A commercially available or synthetically obtainable ester compound of formula (II) (wherein ring B is a suitably substituted halogeno-heteroaryl) can be reacted in two steps: firstly, it is reacted with a suitable alkyl thiolate, such as sodium methyl thiolate, in a suitable solvent, such as DMF, at a suitable temperature, such as room temperature; and secondly, the intermediate alkyl sulfide is oxidized using a suitable oxidizing agent, such as mCPBA, in a suitable solvent, such as DCM, at a suitable temperature, such as 0°C or room temperature.

[0209] A commercially available or synthetically obtainable ester compound of formula (II) (wherein ring B has a thiol) can be difluoromethylsulfonylated in three steps: firstly, sodium 2-chloro-2,2-difluoroacetate is reacted with a suitable solvent such as DMF at a suitable temperature such as 100°C; secondly, the intermediate ester is hydrolyzed under conditions known in the art, such as LiOH, in a suitable solvent such as a mixture of THF and water at a suitable temperature such as room temperature; and thirdly, the intermediate is reacted with a suitable oxidizing agent such as NaIO4 and a suitable catalyst such as RuCl3 in a suitable solvent such as DCM, ACN, water, or a mixture thereof at a suitable temperature such as room temperature. Alternatively, commercially available or synthetically obtainable ester compounds of formula (II) (wherein ring B is methylsulfonyl heteroaryl) can be difluoromethylsulfonylated in three steps: firstly, 2,2,2-trifluoroethyltrifluoroacetate is reacted with a suitable solvent such as THF in the presence of a suitable base such as LiHMDS at a suitable temperature such as -78°C; then, in the second step, the intermediate 3,3,3-trifluoro-2-oxopropylsulfone is reacted with a suitable solvent such as 1-chloromethyl-4-fluoropropylsulfone. In the third step, the intermediate 1,1,3,3,3-pentafluoro-2-oxopropylsulfone can be difluoromethylsulfonylated by reacting it with a suitable fluorinating agent such as 4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (CAS[140681-55-6]) in a suitable solvent such as ACN at a suitable temperature such as room temperature to 60°C.

[0210] A commercially available or synthetically obtainable ester compound of formula (II) (wherein ring B is a heteroaryl substituted with an alkylthiolate) can be reacted with a suitable oxidizing agent, such as oxone, in a suitable solvent, such as MeOH, at a suitable temperature, such as room temperature, to obtain the corresponding alkylsulfonylated heteroaryl compound.

[0211] Scheme 2

[0212] [ka]

[0213] According to Scheme 2, equation (IV) (wherein Hal is Br or Cl, and R 5 Compounds of formula (wherein H is a appropriately substituted heteroaryl) can be borantized using conditions known to those skilled in the art, such as Miyaura borylation conditions. For example, a compound of formula (IV) (wherein Hal is Br or Cl) can be treated with a transition metal catalyst such as 1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) in a suitable solvent such as dimethyl sulfoxide (DMSO) or 1,4-dioxane, a base such as potassium acetate, and a boron source such as bis(pinacolato)diboron or pinacolborane, at a temperature in the range of 80°C to 100°C for 2 to 8 hours to obtain a compound of formula (V).

[0214] Scheme 3

[0215] [ka]

[0216] According to Scheme 3, the compound of formula (VI) can be prepared by reacting a commercially available or synthetically obtainable compound of formula (VII) (wherein Hal is a suitable halogen such as Br (bromine)) with a boronic acid or boronic acid ester, such as potassium trifluoro(vinyl)borate, in a suitable solvent such as THF, 1,4-dioxane, toluene, water, or a mixture thereof, in the presence of a catalyst such as bis(triphenylphosphine)palladium(II) dichloride and a base such as Cs2CO3, at a temperature range of 70°C to 100°C for 12 to 18 hours using a metal-mediated coupling reaction.

[0217] For example, the compound of formula (VI) can be obtained by halogenating the compound of formula (VI) using a chlorinating agent such as POCl3 in a suitable solvent such as 1,2-dichloroethane or chloroform at a temperature in the range of 70-90°C. The compound of formula (VIII) can be oxidized to the compound of formula (IX) by treatment with osmium tetroxide and NaIO4 in a suitable solvent such as 1,4-dioxane, THF, water, or a mixture thereof. The compound of formula (IX) (wherein Hal is Cl) can be subjected to a metal-mediated cross-coupling reaction using a method known in the art, resulting in the compound of formula R 5 -B(OH)2 (wherein, R 5 The compound of formula (IX) can be reacted with a commercially available or synthetically available boronic acid or boronate derivative thereof (where R is an optionally substituted heteroaryl as described in claim 1). For example, the compound of formula (IX) can be reacted with a palladium catalyst, such as bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of a suitable base such as 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine, Cs2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3, NaHCO3, in a suitable solvent such as 1,4-dioxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof, at a temperature in the range of 50-100°C for about 16-24 hours to obtain formula (X) (where R is an optionally substituted heteroaryl as described in claim 1). 5Compound (X) can be obtained (3-(pyridine-4-yl)phenyl). Compound (XI) can be obtained by reacting compound (X) with hydroxylamine in a suitable solvent, such as MeOH, in the presence of a base, such as NaHCO3, at a suitable temperature, such as room temperature. Reduction of compound (XI) can be achieved, for example, using hydrogen gas, in the presence of a catalyst such as Raney Ni, in a suitable solvent such as MeOH, THF, or a mixture thereof, at a suitable temperature, such as room temperature, to obtain compound (XII).

[0218] Scheme 4

[0219] [ka]

[0220] According to Scheme 4, the compound of formula (VII) (wherein Hal is Cl) can be subjected to palladium-catalyzed cyanation using conditions known to those skilled in the art. For example, the compound of formula (VII) can be reacted with a palladium catalyst such as Pd(dppf)Cl2CH2Cl2 and zinc cyanide as a nucleophile in a suitable solvent such as DMA or N,N-dimethylformamide (DMF) at a temperature of about 100°C for 2 to 6 hours to obtain the cyano compound of formula (XIII).

[0221] The halogenation of the compound of formula (XIII) can be achieved using previously described methods, such as using POCl3, to obtain the compound of formula (XIV). The compound of formula (XIV) can be reduced in a suitable solvent such as DCM or toluene at temperatures from -78°C to room temperature using a suitable reducing agent such as DIBAL-H, and then reacted with a suitable protecting group precursor, such as Boc anhydride, in a suitable solvent such as DCM at a suitable temperature such as room temperature, to obtain the compound of formula (XV).

[0222] Scheme 5

[0223] [ka]

[0224] According to Scheme 5, the compound of formula (XV) (wherein PG is Boc and Hal is Cl) is subjected to a metal-mediated cross-coupling reaction with a commercially available or synthetically obtained compound of formula R 5’ -B(OH)2 (wherein, R 5’ A boronic acid of formula (Va) (wherein R is an optionally substituted heteroaryl as described in claim 1) or a boronate derivative of formula (Va) can be reacted using methods known in the art. For example, a compound of formula (XV) can be reacted with a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride in the presence of a suitable base such as 6-fluoropyridine-2-boronic acid or 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, Cs2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3, NaHCO3, in a suitable solvent such as 1,4-dioxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof, at a temperature in the range of 50 to 100°C for about 16 to 24 hours to obtain formula (XVI) (wherein R is an optionally substituted heteroaryl as described in claim 1). 5’ This allows us to obtain compounds of 6-fluoropyridyl.

[0225] Formula (XVI) (where R 5’ The compound is a suitable heteroaryl compound (e.g., substituted with a suitable halogen leaving group such as F (fluorine), e.g., 2-pyridyl) reacted with a base such as a optionally substituted heterocycloalkyl (4-8 membered heterocycloalkyl, condensed, spiro, and bridged 8-10 membered heterocycloalkyl, each containing one or two heteroatoms optionally independently selected from N, S, and O), e.g., cis-2,6-dimethylmorpholine, e.g., DIPEA, in a suitable solvent such as DMSO or ACN, at a temperature in the range of 50-130°C for 12-24 hours to produce formula (XVII) (wherein R 5Compounds can be obtained that are suitable heteroaryls substituted with nitrogen-linked heterocycloalkyls.

[0226] The compound of formula (XVII) is prepared in two steps R 5 The compound can be alkylated on the group, that is, firstly, the compound of formula (XVII) is halogenated with a suitable halogenating agent such as N-iodosuccinimide in a suitable solvent such as hexafluoroisopropanol at a suitable temperature such as 0°C to room temperature, and secondly, the intermediate halogen is alkylated by reacting it with a suitable methylborone derivative such as trimethylboroxine in the presence of a suitable base such as K2CO3, in the presence of a suitable catalyst such as xanthophos PdG3 (CAS[1445085-97-1]), in a suitable solvent such as 1,4-dioxane or water, or a mixture thereof, at a suitable temperature such as 80°C.

[0227] Deprotection of the compound of formula (XVII) (wherein PG is Boc) can be achieved using established methodologies, such as those described by TW Greene and PGMWuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999, pgs 518-525, according to procedures known to those skilled in the art. For example, deprotection of the compound of formula (XII) can be obtained by deprotecting it at room temperature for 2 hours under acidic conditions such as trifluoroacetic acid (TFA) / CH2Cl2 or HCl / dioxane.

[0228] Scheme 6

[0229] [ka]

[0230] According to Scheme 6, the compound of formula (XV) (wherein Hal is Cl and PG is Boc) can be reacted with a suitable sulfinate, such as sodium 1-methyl-3-sulfinopropanoate (CAS[90030-48-1]), in the presence of a suitable catalyst, such as CuI, in a suitable solvent, such as DMSO; at a suitable temperature, such as 110°C, to obtain the compound of formula (XVIII). The compound of formula (XVIII) can be obtained from commercially available or synthetically available appropriately substituted 2-halogeno-R 5 For example, (cis)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine can be reacted with a suitable phosphonium salt, such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3]), in the presence of a suitable base such as K2CO3, in the presence of a suitable catalyst such as Pd(OAc)2, in a suitable solvent such as 1,4-dioxane, at a suitable temperature such as 150°C to obtain the compound of formula (XVII). Deprotection of the Boc protecting group on the compound of formula (XVII) can be achieved using acidic conditions known to those skilled in the art or the aforementioned acidic conditions to obtain the compound of formula (XII).

[0231] In a similar manner, compounds of formula (XVIII) (where Hal is Cl and PG is Boc) can be appropriately substituted 2-halo-heteroaryl (R) compounds, such as (2R,6S)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine. 5’ -Hal) is reacted in the presence of a suitable phosphonium salt, such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3]); in the presence of a suitable base, such as K2CO3; in the presence of a suitable catalyst, such as Pd(OAc)2; in a suitable solvent, such as 1,4-dioxane; at a suitable temperature, such as 150°C, to produce formula (XVI) (wherein R 5 This can yield a compound of 6-((2R,6S)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl.

[0232] Scheme 7

[0233] [ka]

[0234] According to Scheme 7, formula (XVIII) (wherein PG is Boc) can be used to provide the compound of formula (XIX) using acidic conditions known to those skilled in the art, or by deprotection as described above. The compound of formula (XIX) can be reacted with a commercially available or synthetically available carboxylic acid that is appropriately substituted using conventional amide bond formation techniques such as coupling reactions well known to those skilled in the art. For example, the compound of formula (XIX) can be used with formula R 1 Compounds of formula (XX) can be obtained by reacting a carboxylic acid of CO2H (wherein ring B is a appropriately substituted heteroaryl ring) with a suitable coupling agent such as HATU, HBTU, or 1-propanephosphonic anhydride, in the presence of a suitable base such as TEA or DIPEA, in a suitable solvent such as DCM or DMF, at a suitable temperature such as room temperature. Compounds of formula (XX) can be obtained with a commercially available or synthetically available appropriately substituted 2-halogenol-R such as 8-(4-chloropyrimidine-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione. 5 The compound of formula (I) can be obtained by reacting the two in the presence of a suitable phosphonium salt, such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3]), a suitable base such as K2CO3, a suitable catalyst such as Pd(OAc)2, a suitable solvent such as 1,4-dioxane, and a suitable temperature such as 115°C.

[0235] Scheme 8

[0236] [ka]

[0237] According to Scheme 8, equation (XVI) (where PG is Boc, R 5’ Compounds of formula (XXI) (where is a appropriately substituted heteroaryl halide) can be obtained by methods known to those skilled in the art, or by deprotection as described above. Compounds of formula (XXI) can be reacted with appropriately substituted commercially available or synthetically available carboxylic acids using conventional amide bond formation techniques such as coupling reactions well known to those skilled in the art. For example, compound (XXI) can be reacted with a carboxylic acid of formula (III) (wherein ring B is an appropriately substituted phenyl ring) in the presence of a suitable coupling agent such as HATU, HBTU, or 1-propanephosphonic anhydride, in the presence of a suitable base such as TEA or DIPEA, in a suitable solvent such as DCM or DMF, at a suitable temperature such as room temperature, to obtain compound (XXII).

[0238] In an alternative method, the compound of formula (XXII) can be prepared in two steps from the compound of formula (XXIII). In the first step, the compound of formula (XXIII) can be reacted in an amide bond formation reaction with the carboxylic acid of formula (III) (wherein ring B is a suitably substituted phenyl ring) using a method known to those skilled in the art or described above to obtain the compound of formula (XXIV). Alternatively, the compound of formula (XXIV) can be obtained by reacting an acid chloride derived from the acid of formula (III) with the compound of formula (XXIII) in the presence of a base such as DIPEA in a suitable solvent such as DCM. In the second step, the compound of formula (XXIV) can be reacted in a coupling reaction with R 5’A suitable boronic acid such as -B(OH)2, for example, a boronate derivative such as 6-fluoropyridine-2-boronic acid or 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, can be reacted in the presence of a suitable base such as Na2CO3 or NaHCO3, in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium(II) chloride (CAS[13965-03-2]) or Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4]), in a suitable solvent such as 1,4-dioxane and water, at a suitable temperature such as 85°C, to obtain the compound of formula (XXII).

[0239] Scheme 9

[0240] [ka]

[0241] According to Scheme 9, equation (XXIV) (wherein Hal is Cl, R 1 A compound of formula (XXV) (wherein is a appropriately substituted phenyl as described in claim 1) can be reacted with a suitable sulfinate, such as sodium 1-methyl-3-sulfinopropanoate (CAS[90030-48-1]), in the presence of a suitable catalyst, such as CuI, in a suitable solvent, such as DMSO, at a temperature in the range of 90 to 110°C to obtain a compound of formula (XXV).

[0242] Compounds of formula (XXV) include, for example, those of formula R 5- Hal(wherein Hal is Br or Cl, R 5 A appropriately substituted heteroaryl halide (where is a heteroaryl as defined in claim 1) can be reacted with a suitable phosphonium salt, such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3]), such as a suitable base, such as K2CO3, such as Pd(OAc)2, to obtain a compound of formula (I).

[0243] Scheme 10

[0244] [ka]

[0245] According to Scheme 10, the compound of formula (XXIV) is reacted with a commercially available or synthetically available appropriately substituted boronic acid or boronate derivative, such as (cis)-4-(3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-2,6-dimethylmorpholine, for example, using standard Suzuki coupling conditions, in the presence of a suitable base such as sodium carbonate, in the presence of a suitable catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS[72287-26-4]), in a suitable solvent such as a mixture of water and 1,4-dioxane, at a suitable temperature such as 100°C, to obtain formula (I) (wherein R 5 This allows you to obtain compounds of C-linked heteroaryl, aryl, or heterocycloalkyl groups.

[0246] Alternatively, the compound of formula (XXIV) can be used with a suitable heteroalkyl organozinc derivative R 5 -Zn-Hal (wherein Hal is a suitable halide such as a chloride) can be reacted with a suitable catalyst such as palladium tetrakis(triphenylphosphine) in a suitable solvent such as THF or a mixture of THF and DMF at a suitable temperature such as room temperature to obtain the compound of formula (I).

[0247] Scheme 11

[0248] [ka]

[0249] According to Scheme 11, the compound of formula (XII) can be reacted with a suitable commercially available or synthetically obtainable carboxylic acid using conventional amide bond formation techniques such as coupling reactions, which are well known to those skilled in the art. For example, formula (XII) (wherein R 5 The compound of formula (I) can be obtained by reacting a suitable carboxylic acid with a suitable coupling agent such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU, or 1-propanephosphonic anhydride, in the presence of a suitable base such as N-ethyldiisopropylamine (DIPEA) or triethylamine (TEA), in a suitable solvent such as DCM, THF, or DMF, at a suitable temperature such as 0°C to room temperature.

[0250] Alternatively, the compound of formula (I) can be prepared by reacting the compound of formula (XII) with a suitable activated form of a carboxylic acid, such as acyl chloride, or its corresponding anhydride, in the presence of a suitable base, such as DIPEA or Et3N, in a suitable solvent, such as DCM or DMF, at a suitable temperature, such as 0°C to room temperature.

[0251] Formula (XXII) (wherein, R 5 The compound is a suitable heteroaryl group such as 2-pyridyl, and Hal is a suitable halogen leaving group such as F (fluorine). 9a R 9b The reaction can then be carried out in the presence of a suitable base, such as DIPEA, in a suitable solvent, such as DMSO, at a suitable temperature, such as 90°C or 150°C, to obtain the compound of formula (I).

[0252] If the compound of formula (I) has a protecting group, such as Boc, the protecting group can be removed using conditions known to those skilled in the art. For example, reaction with a reagent such as pTsOH (p-toluenesulfonic acid), TFA, or HCl in a suitable solvent such as DCM or 1,4-dioxane at a suitable temperature such as room temperature or 40°C.

[0253] The compound of formula (I) has a protecting group such as Boc or THP, for example, R 1 If the protecting group is present on the base, it can be removed, for example, by reaction with a suitable reagent such as HCl, pTsOH, or pyridinium p-toluenesulfonate, in a suitable solvent such as 1,4-dioxane or EtOH, at a suitable temperature such as room temperature. If the protecting group is an ester, the compound of formula (I) can be reacted with a suitable hydrolyzing agent such as LiOH or NaOH, in a suitable solvent such as THF, MeOH, water, or a mixture thereof, at a suitable temperature such as room temperature.

[0254] Those skilled in the art will understand that another series of chemical reactions shown in the scheme may also yield the desired compound of formula (I).

[0255] Those skilled in the art will understand that the intermediates and final compounds shown in the following scheme can be further functionalized according to methods well known to those skilled in the art.

[0256] Those skilled in the art will recognize that in some cases, it may be recommended or necessary to carry out the reactions described herein under an inert atmosphere, such as an N2- gas atmosphere.

[0257] It will be apparent to those skilled in the art that cooling of the reaction mixture may be necessary before the reaction is carried out (meaning a series of operations necessary to isolate and purify the products of the chemical reaction, such as quenching, column chromatography, or extraction).

[0258] Those skilled in the art will understand that heating a reaction mixture under stirring can enhance the reaction outcome. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0259] The compounds of the present invention, prepared by the processes described below, may be synthesized in the form of a mixture of enantiomers, particularly a racemic mixture of enantiomers, which can be separated from each other by decomposition procedures known in the art. A racemic compound of formula (I) containing a basic nitrogen atom can be converted to the corresponding diastereomer salt form by reaction with a suitable chiral acid. The diastereomer salt form is then separated, for example, by selective or fractional crystallization, and the enantiomer is liberated therefrom by alkali. Alternative methods for separating the enantiomer form of the compound of formula (I), and its pharmaceutically acceptable addition salt, include liquid chromatography using a chiral stationary phase, such as supercritical fluid chromatography. The pure stereochemical isomer form may also be derived from the corresponding pure stereochemical isomer form of a suitable starting material, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously use the pure starting material as the enantiomer.

[0260] In all of these preparations, the reaction product may be isolated from the reaction medium and, if necessary, further purified according to methodologies commonly known in the art (e.g., extraction, crystallization, tritulation, and chromatography). The purity of the reaction product can be determined according to methods commonly known in the art, such as LC-MS, TLC, and HPLC.

[0261] Treatment methods and medical uses, pharmaceutical compositions, and combinations The present invention also provides a method for treating or preventing proliferative disorders (e.g., cancer, benign neoplasms, angiogenesis) in a subject. Such a method comprises administering to a subject in need an effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotope-labeled derivative thereof, or a pharmaceutically acceptable composition thereof.

[0262] The subjects of treatment are mammals. The subjects may be humans. The subjects may be domestic animals such as dogs, cats, cattle, pigs, horses, sheep, or goats. The subjects may be companion animals such as dogs or cats. The subjects may be domesticated animals such as cattle, pigs, horses, sheep, or goats. The subjects may be zoo animals. The subjects may be research animals such as rodents, dogs, or non-human primates. The subjects may be non-human transgenic animals such as transgenic mice or transgenic pigs.

[0263] Proliferative disorders treated or prevented with compounds of formula (I) are typically associated with abnormal activity of SMARCA2. Abnormal activity of SMARCA2 may be elevated and / or inappropriate (e.g., abnormal) activity of SMARCA2. In certain embodiments, SMARCA2 is not overexpressed, and its activity is elevated and / or inappropriate. In certain other embodiments, SMARCA2 is overexpressed, and its activity is elevated and / or inappropriate. The compounds of this disclosure, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotope-labeled derivatives, and compositions, may be useful for inhibiting SMARCA2 activity and treating and / or preventing proliferative disorders.

[0264] Proliferative disorders may also be associated with the inhibition of apoptosis in cells in biological specimens or subjects. All types of biological specimens described herein or known in the art are intended to be within the scope of the present invention. Inhibition of SMARCA2 activity is expected to cause cytotoxicity through the induction of apoptosis. The compounds of this disclosure, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, may be useful in inducing apoptosis and, consequently, in treating and / or preventing proliferative disorders.

[0265] In certain embodiments, the proliferative disorder treated or prevented using the compounds of this disclosure is cancer.

[0266] The cells described herein may be abnormal cells. The cells may be in vitro or in vivo. The cells may be proliferative cells.

[0267] In another embodiment, the present invention provides a method for downregulating the expression of SMARCA2 in a biological sample or subject.

[0268] The present invention relates to a compound of formula (I) for use in a method for treating SMARCA4-deficient cancer, the method comprising administering the compound of formula (I) to a subject requiring it.

[0269] The present invention relates to a compound of formula (I) for use in a method for treating SMARCA4-deficient NSCLC, the method comprising administering the compound of formula (I) to a subject requiring it.

[0270] In yet another embodiment, the present invention provides compounds of the present disclosure, as well as pharmaceutically acceptable salts, tautomers, stereoisomers, isotope-labeled derivatives, and compositions thereof, for use in the treatment of proliferative disorders in subjects. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used in the inhibition of cell proliferation. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used in the induction of apoptosis in cells. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used in the inhibition of transcription.

[0271] Those skilled in the art will recognize that a therapeutically effective amount of the compound of the present invention is sufficient to have therapeutic activity, and that this amount varies, among other things, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the patient's condition. Generally, the amount of the compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein is determined on a case-by-case basis by the attending physician.

[0272] Those skilled in the art in treating such diseases may determine an effective therapeutic daily dose from the test results shown below. The effective therapeutic daily dose may be approximately 0.005 mg / kg to 50 mg / kg body weight. The amount of the compound according to the present invention, also referred to herein as the active ingredient, required to achieve a therapeutic effect may vary on a case-by-case basis, for example, depending on the specific compound, route of administration, age and condition of the recipient, and the specific disorder or disease being treated. The treatment method may also involve administering the active ingredient in a regimen of 1 to 4 doses per day. In these treatment methods, the compound according to the present invention is preferably formulated before administration. As described below herein, a suitable pharmaceutical formulation is prepared by known procedures using well-known and readily available ingredients.

[0273] While the active ingredient can be administered alone, it is preferable to provide it as part of a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising the compound according to the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense that it is compatible with the other components of the composition and is not harmful to its recipient.

[0274] The pharmaceutical compositions of the present invention are, for example, described in Gennaro et al. Remington's Pharmaceutical Sciences (18 thPharmaceutical compositions can be prepared by any method well known in the field of pharmacy, such as those described in (see, in particular, Part 8: Pharmaceutical preparations and their Manufacture) of Mack Publishing Company, 1990. A therapeutically effective amount of a specific compound in base form or salt form, as the active ingredient, is closely mixed and combined with a pharmaceutically acceptable carrier, and can take on a wide variety of forms depending on the form of formulation preferred for administration. These pharmaceutical compositions are preferably in unit dosage forms suitable for systemic administration, such as oral, transdermal, or parenteral administration; or preferably in topical administration, such as by inhalation or nasal spray. For example, when preparing an oral dosage form composition, any of the usual pharmaceutical media can be used, such as water, glycol, oil, or alcohol in the case of oral liquid formulations such as suspensions, syrups, elixirs, and solutions; or, in the case of powders, pills, capsules, and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, and disintegrants. Tablets and capsules are the most advantageous oral unit dosage forms because they are easy to administer, in which case it is clear that a solid pharmaceutical carrier is used. In the case of parenteral compositions, the carrier usually contains at least a large portion of sterile water, but may also contain other components (e.g., to aid solubility). For example, an injectable solution may be prepared in which the carrier contains physiological saline, glucose solution, or a mixture of physiological saline and glucose solution. An injectable suspension may also be prepared, in which case a suitable liquid carrier, suspending agent, etc., may be used. In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable wetting agent, optionally in combination with some suitable additive that does not cause significant adverse effects on the skin in small amounts. Such additives can facilitate administration to the skin and / or may be useful in preparing the desired composition. These compositions can be administered in various ways, for example, as transdermal patches, spot-on treatments, or ointments.

[0275] The above-mentioned pharmaceutical compositions are particularly advantageous when formulated as unit dosage forms to facilitate administration and ensure uniformity of the dosage. As used herein and in the claims, a unit dosage form means a physically separated unit suitable as a single dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with the necessary pharmacological carrier. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons, and multiple portions thereof.

[0276] The precise dosage and frequency of administration depend, as is well known to those skilled in the art, on the specific compound of the present invention used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, degree of disability and overall health of the specific patient, and any other medications the individual may be taking. Furthermore, it is evident that the effective daily dose may be increased or decreased depending on the response of the subject being treated and / or on the assessment of the physician prescribing the compound of the present invention.

[0277] The methods described herein may also include a further step of administering one or more additional pharmaceuticals in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition comprising such compound or a pharmaceutically acceptable salt thereof. Thus, combinations of the compound or composition of the present invention with additional pharmaceuticals may be useful for treating proliferative disorders that are resistant to treatment using additional pharmaceuticals without the compound or composition of the present invention.

[0278] Combination therapy includes administering a single drug formulation containing the compound according to the present invention and one or more additional therapeutic agents, as well as administering the compound according to the present invention and each additional therapeutic agent in its own separate drug formulation. For example, the compound and therapeutic agent according to the present invention may be administered together to the patient in a single oral formulation such as a tablet or capsule, or each agent may be administered in a separate oral formulation.

[0279] Accordingly, one embodiment of the present invention relates to a product comprising a compound according to the present invention as a first active ingredient and one or more anticancer agents as further active ingredients, as a combination preparation for simultaneous, separate, or sequential use in the treatment of a patient suffering from cancer.

[0280] One or more other drugs and compounds according to the present invention may be administered simultaneously (e.g., separately or in a single composition) or sequentially in any order. In the latter case, the two or more compounds are administered for a period of time and in a quantity and manner sufficient to ensure that a favorable or synergistic effect is achieved. It will be understood that the preferred method and order of administration, as well as the respective dosages and regimens, for each component of the combination will depend on the specific other drugs and compounds of the present invention being administered, their routes of administration, the specific tumor being treated, and the specific host being treated. The optimal method and order of administration, as well as the dosages and administration plans, can be readily determined by those skilled in the art using conventional methods and taking into account the information described herein.

[0281] The weight ratio of the compound according to the present invention to one or more other anticancer agents when administered in combination can be determined by those skilled in the art. The ratio, as well as the exact dosage and frequency of administration, depends, as is well known to those skilled in the art, on the specific compound according to the present invention and the other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, administration time and general physical condition of the specific patient, the mode of administration, and other medications the individual may take. Furthermore, it is evident that the effective daily dose may be increased or decreased depending on the response of the subject being treated and / or the assessment of the physician prescribing the compound according to the present invention. Specific weight ratios of the compound of formula (I) and other anticancer agents may range from 1 / 10 to 1 / 10, more specifically from 1 / 5 to 1 / 5, and even more specifically from 1 / 3 to 1 / 3. [Examples]

[0282] The following examples further illustrate the present invention. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. Several methods for preparing the compounds of the present invention are shown in the following examples. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification, or can be synthesized by those skilled in the art using well-known methods. Commercial sources include, but are not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0283] [Table 2]

[0284] As will be understood by those skilled in the art, compounds synthesized using the indicated protocol may contain residual solvent or small amounts of impurities.

[0285] Those skilled in the art will understand, even if not explicitly mentioned in the following experimental protocol, that typically, after column chromatography purification, the desired fraction is collected and the solvent is evaporated.

[0286] If the stereochemistry is not shown, this means that it is a mixture of stereoisomers, unless otherwise specified or evident from the context.

[0287] When the stereocenter is indicated by "RS," it means that a racemic mixture has been obtained.

[0288] For intermediates that may be used in the next reaction step as crude or partially purified intermediates, the theoretical molar amounts may be shown in the reaction protocol described below.

[0289] Example A: Preparation of intermediate and final compounds, and their characterization. Preparation of intermediates For intermediates used in subsequent reaction steps, either as crude or partially purified intermediates, the molar amount of such intermediate in the subsequent reaction step may not be mentioned, or an estimated or theoretical molar amount of such intermediate in the subsequent reaction step may be indicated in the reaction protocol described below.

[0290] Typical synthesis methods Method A: A carboxylic acid (1.1 equivalents) and DIPEA (3 equivalents) were added to a solution of amine (1 equivalent) in DCM (2 mL). After 1 minute, HATU (1.15 equivalents) was added, and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (12 g column, DCM / MeOH (9 / 1) in DCM, 0%~25%) to obtain the title compound.

[0291] Method B: HBTU (1.5 equivalents) was added at room temperature to a stirred solution of carboxylic acid (1 equivalent), amine (1 equivalent), and DIPEA (3 equivalents) in DMF (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with Na₂CO₃ (1 M in water) and extracted with ethyl acetate. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by reverse-phase chromatography (72% H₂O - 28% ACN-MeOH to 36% H₂O - 64% ACN-MeOH - [0.1% HCOOH]). The desired fraction was neutralized with solid Na₂CO₃ and extracted with DCM. The organic layer was dried over MgSO₄, filtered, and evaporated to obtain the title compound.

[0292] Method C: Amine (1.2 equivalents) was added at room temperature to a stirred solution of carboxylic acid (1 equivalent), HATU (1.5 equivalents), and DIPEA (3 equivalents) in DCM (3 mL). The reaction mixture was then stirred at room temperature for 72 hours. The mixture was diluted with water and extracted with RINKAN. The organic layer was separated, dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by flash column chromatography (12 g silica; MeOH 0 / 100~3 / 97 in DCM), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30 × 100 mm 5 μm column; 59% [25 mM NH4HCO3]~41% [ACN:MeOH (1:1)]~17% [25 mM NH4HCO3]~83% [ACN:MeOH (1:1)]) to obtain the title compound.

[0293] Method E: A carboxylic acid (1.2 equivalents), an amine (1 equivalent), and DIPEA (4 equivalents) were dissolved in DMF (3 mL). After 15 minutes, HBTU (1.2 equivalents) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with an aqueous solution of Na2CO3 (1 M) and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g silica; DCM:MeOH(9:1) / DCM0 / 100~25 / 75). The desired fraction was collected and concentrated under vacuum. The resulting product was ground over ACN and filtered to obtain the title compound.

[0294] Method F: 1-Propanephosphonic anhydride (50% in ethyl acetate, CAS [68957-94-8], 1.3 equivalents) was added to a suspension of amine (1 equivalent) and carboxylic acid (1.1 equivalents) in 5 mL of dry DCM under a nitrogen atmosphere at room temperature. Then, Et3N (5 equivalents) was added dropwise to the orange suspension. The reaction mixture (clear yellow) was stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was purified by column chromatography (Biotage Sfar 10 g; eluate: heptane:EtOH / ethyl acetate 1 / 3 100:0 → 20:80) to obtain the title compound.

[0295] Method I: Amine (10 equivalents) was added to a solution of intermediate 4 (1 equivalent) in DMSO (1 mL), and the mixture was stirred at 120°C for 18 hours. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g; SiO2, DCM: methanol in DCM (9:1), 0 / 100~40 / 60) to obtain the title compound.

[0296] Method J: Amine (6 equivalents) was added to a solution of intermediate 21 (1 equivalent) and DIPEA (20 equivalents) in DMSO (1 mL), and the mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g column, DCM:MeOH 9:1 in DCM, 0%~35%) to obtain a yellow solid. The solid was ground in ACN, filtered, washed with Et2O, and dried under vacuum to obtain the title compound.

[0297] Method K: A solution of intermediate 21 (1 equivalent), amine (3 equivalents), and DIPEA (12 equivalents) in dry DMSO (0.5 mL) was stirred overnight at 120°C. After cooling, the reaction mixture was diluted with MeOH (2.5 mL) and filtered. The filtrate was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, ACN) to obtain the title compound.

[0298] Method M: 1-Propanephosphonic anhydride (50% in Â, 1.7 equivalents) was added to a solution of amine (1 equivalent), carboxylic acid (1.5 equivalents), and Et3N (6 equivalents) in DCM (5 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with MeOH and water, filtered, and purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-5 μm, 50 × 250 mm, mobile phase: solution of 0.25% NH4HCO3 in water, ACN) to obtain the title compound.

[0299] Method N: Three equivalents of amine were added to a solution of one equivalent of intermediate 21 and 1.3 equivalents of DIPEA in 0.6 mL of DMSO. The reaction mixture was stirred at 120°C for 48 hours. After cooling, the excess amine was evaporated under reduced pressure, and the resulting solution was directly purified by reversed-phase column chromatography (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm; mobile phase: solution of 0.25% NH4HCO3 in water, ACN, or MeOH) to obtain the title compound.

[0300] Method P: A solution of intermediate 23 (3 equivalents) and Et3N (6 equivalents) in DCM (1 mL) was added to carboxylic acid (1.7 equivalents). 1-Propanephosphonic anhydride (50% solution in SiO, 1.7 equivalents) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue was purified by reversed-phase column chromatography (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm; mobile phase: solution of 0.25% NH4HCO3 in water, ACN, or MeOH) to obtain the title compound.

[0301] Preparation of intermediates For intermediates used in subsequent reaction steps, either as crude or partially purified intermediates, the molar amount of such intermediate in the subsequent reaction step may not be mentioned, or an estimated or theoretical molar amount of such intermediate in the subsequent reaction step may be indicated in the reaction protocol described below.

[0302] Intermediate 1:

[0303] [ka]

[0304] In a 3 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, DMA (2.24 L), Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 22.4 g, 0.1 equivalent), 7-chloro-1H-1,6-naphthyrizin-2-one (CAS[1345091-18-0], 224 g, 1240.37 mmol), zinc (16.22 g, 248.07 mmol, 0.2 equivalent), and zinc cyanide (145.65 g, 1240.37 mmol, 1 equivalent) were added. The resulting solution was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature. The solid was filtered off and washed with 2 × 100 mL of DMA. The reaction was then stopped by adding 5 L of water / ice. The solid was recovered by filtration, and intermediate 1 (147g, yield: 69%) was obtained as a brown solid.

[0305] Intermediate 2:

[0306] [ka]

[0307] A 2 L three-necked round-bottom flask, purged and maintained under an inert nitrogen atmosphere, was filled with phosphorus oxychloride (1.47 L) and intermediate 1 (147.00 g, 858.85 mmol). The resulting solution was stirred at 80°C for 3 hours. The reaction mixture was concentrated. The resulting solution was diluted with 2 L of DCM. The reaction was then stopped by adding 4 L of water / ice. The resulting solution was extracted with 3 × 3 L of DCM, the organic layer was dried over Na₂SO₄, and concentrated to obtain intermediate 2 (58 g, yield: 36%) as a yellow solid.

[0308] Intermediate 3:

[0309] [ka]

[0310] A 5 L four-necked round-bottom flask, purged and maintained under an inert nitrogen atmosphere, was filled with DCM (1.74 L) and intermediate 2 (58 g, 305.90 mmol). Subsequently, DIBAL-H (1 N, 765 mL, 2.5 equivalents) was added dropwise over 30 minutes while stirring at -78°C. The resulting solution was stirred at -78°C for 2 hours. Potassium sodium tartrate (257 g, 1224 mmol, 4 equivalents) was added at -78°C. The resulting solution was stirred at room temperature for 1 hour. Subsequently, di-tert-butyl dicarbonate (73.3 g, 336.50 mmol, 1.1 equivalents) was added. The resulting solution was stirred overnight at room temperature. The solid was filtered off and washed with 3 × 300 mL of DCM. The filtrate was concentrated. The residue was purified by silica gel column chromatography (siRNA / petroleum ether 1 / 3 to 1 / 2) to obtain intermediate 3 (60.9 g, yield: 68%) as a yellow solid.

[0311] Intermediate 4:

[0312] [ka]

[0313] A suspension of intermediate 3 (9900 mg, 33.702 mmol), 6-fluoropyridine-2-boronic acid (CAS [916176-61-9], 5699 mg, 40.442 mmol, 1.2 equivalents), and sodium carbonate (10716 mg, 101.105 mmol, 3 equivalents) in 1,4-dioxane (90 mL) and water (30 mL) was degassed by bubbling nitrogen for 5 minutes. Bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 1183 mg, 1.685 mmol, 0.05 equivalents) was added, and the mixture was further degassed with nitrogen for 5 minutes. The reaction mixture was stirred overnight at 90°C under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and evaporated. The solid residue was ground in Et2O and filtered. The white solid was washed with a small amount of Et2O to obtain intermediate 4 (7.47 g, yield: 58%) as a white solid.

[0314] Intermediate 5:

[0315] [ka]

[0316] The suspensions of intermediate 4 (5208 mg, 11.169 mmol), cis-2,6-dimethylmorpholine (CAS[6485-55-8], 5.7 mL, 44.676 mmol, 4 equivalents), and DIPEA (5.8 mL, 33.507 mmol, 3 equivalents) in dry DMSO (20 mL) were divided into two pressure (microwave) vials. The vials were sealed and the reaction mixture was stirred overnight at 130 °C. The reaction mixture was diluted with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was ground in DCM / Et2O1 / 1. The solid was filtered and washed with a small amount of Et2O. This solid was combined with the filtrate and purified by column chromatography (Biotage Sfar 200g; eluate: heptane:EtOH / SiO2 1 / 3 100:0 → 20:80) to obtain intermediate 5 (5.1g, quantitative).

[0317] Intermediate 6:

[0318] [ka]

[0319] HCl (37% in H2O, 40 mL, 484.24 mmol, 20 equivalents) was added dropwise to a yellow suspension of intermediate 5 (10.85 g, 24.135 mmol) in 1,4-dioxane (100 mL) at room temperature (1 drop / second, slightly exothermic). The reaction mixture changed to red, then back to yellow, and was stirred at room temperature for 16 hours. The yellow suspension was evaporated to dryness, and the residue was co-evaporated several times with toluene to obtain intermediate 6 (HCl salt, 12 g, quantitative) as an orange solid, which was dried under vacuum at 50°C.

[0320] Intermediate 7:

[0321] [ka]

[0322] Iron(II) sulfate heptahydrate (CAS[7727-21-1], 31 mg, 0.093 mmol, 0.14 equivalents) was added to a solution of methyl 5-methylpyridine-2-carboxylate (CAS[29681-38-7], 100 mg, 0.662 mmol) and TFA (64 μL, 0.860 mmol, 1.3 equivalents) in acetaldehyde (3.3 mL). The reaction mixture was cooled to 0°C, and the first portion of H2O2 (365 μL, 3.572 mmol, 5.4 equivalents) was added dropwise, and the mixture was stirred for 30 minutes. Then, the second portion of H2O2 (365 μL, 3.572 mmol, 5.4 equivalents) was added dropwise, and stirring was continued for 90 minutes. The reaction mixture was slowly quenched at room temperature with a 5% aqueous Na2S2O3 solution, followed by the addition of a saturated aqueous NaHCO3 solution. The mixture was extracted twice with siRNA. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica; siRNA gradient in heptane 0 / 100 to 10 / 90) to obtain intermediate 7 (75 mg, yield: 59%) as a white solid.

[0323] Intermediate 8:

[0324] [ka]

[0325] NaBH4 (157 mg, 4.141 mmol, 2 equivalents) was added to a solution of intermediate 7 (400 mg, 2.07 mmol) in MeOH (10 mL) under a nitrogen atmosphere at 0°C, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and the mixture was diluted with ethyl acetate. The layers were separated, and the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (80 g silica; ethyl acetate gradient in heptane 0 / 100 to 50 / 50) to obtain intermediate 8 (240 mg, yield: 59%) as a colorless foam.

[0326] Intermediate 9:

[0327] [ka]

[0328] NaOH (2M in water, 1.229 mL, 2.459 mmol, 2 equivalents) was added to a solution of intermediate 8 (240 mg, 1.229 mmol, 1 equivalent) in MeOH (6 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to approximately pH 1 with HCl (1M in water), diluted with additional water, and extracted with SiO2 (3×). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 9 (223 mg, yield: 100%), which was used without further purification.

[0329] Intermediate 10:

[0330] [ka]

[0331] HCl (37% in H2O, 47 mL, 588.7 mmol, 20 equivalents) was added dropwise at room temperature to a pale brown solution of intermediate 4 (10 g, 27.94 mmol) in 1,4-dioxane (300 mL) (1 drop / second, slightly exothermic). The reaction mixture was stirred at room temperature for 30 minutes. The precipitate formed during the reaction was filtered, and the solid was washed with dioxane to obtain intermediate 10 (HCl salt, 8.3 g, quantitative) as a gray solid. This solid was dried under vacuum at 50°C and used without further purification.

[0332] Intermediate 11:

[0333] [ka]

[0334] Intermediate 3 (1.03 g, 3.506 mmol) was added to a solution of sodium 1-methyl-3-sulfinopropanoate (CAS[90030-48-1], 1.22 g, 7.013 mmol, 2 equivalents) and copper iodide (1.34 g, 7.013 mmol, 2 equivalents) in DMSO (10 mL). The reaction mixture was stirred at 110 °C for 1 hour under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with HCl and washed with water (1 mL) containing aqueous NH3 solution. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (25 g column, HCl / heptane gradient of 0 / 100 to 100 / 0) to obtain intermediate 11 (801 mg, yield: 53%) as an orange solid.

[0335] Intermediate 12:

[0336] [ka]

[0337] 2,6-Dibromo-4-nitropyridine (CAS[175422-04-5], 5 g, 17.737 mmol) and cis-2,6-dimethylmorpholine (CAS[6485-55-8], 2.42 mL, 19.511 mmol, 1.1 equivalents) were dissolved in toluene (140 mL), and the solution was degassed by bubbling with nitrogen for 15 minutes. Then, Cs2CO3 (8.67 g, 26.606 mmol, 1.5 equivalents), rac-BINAP (CAS[98327-87-8], 1.10 g, 1.774 mmol, 0.1 equivalents), and Pd(OAc)2 (CAS[3375-31-3], 398 mg, 1.774 mmol, 0.1 equivalents) were added, and the resulting mixture was refluxed under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 × 250 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (120 g column, siRNA / heptane gradient of 0 / 100 to 40 / 60) to obtain intermediate 12 (3.2 g, yield: 56%) as an orange solid.

[0338] Intermediate 13:

[0339] [ka]

[0340] Tetramethylammonium fluoride (CAS[373-68-2], 663 mg, 7.117 mmol, 1.5 equivalents) was added to a solution of intermediate 12 (1500 mg, 4.745 mmol) in DMF (40 mL) in a sealed tube. The mixture was stirred at 65°C for 3 hours. The reaction product was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (80 g column, 0 / 100 to 30 / 70 ethyl acetate / heptane gradient) to obtain intermediate 13 (1139 mg, yield: 81%) as an orange solid.

[0341] Intermediate 14:

[0342] [ka]

[0343] Intermediate 11 (950 mg, 2.32 mmol), intermediate 13 (1006 mg, 3.48 mmol, 1.5 equivalents), and K2CO3 (481 mg, 3.48 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (24 mL) in a sealed tube under a nitrogen stream. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 58 mg, 0.232 mmol, 0.1 equivalent) and Pd(OAc)2 (CAS[3375-31-3], 26 mg, 0.116 mmol, 0.05 equivalents) were added, and the reaction mixture was stirred at 150°C for 4 hours. The mixture was cooled to room temperature, diluted with SiO2, and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (25g column, siRNA / heptane gradient of 0 / 100 to 100 / 0) to obtain intermediate 14 (428mg, yield: 39%) as a yellow solid.

[0344] Intermediate 15:

[0345] [ka]

[0346] Intermediate 14 (428 mg, 0.906 mmol) was dissolved in a solution of HCl (4 M in 1,4-dioxane, 2.27 mL, 9.063 mmol, 10 equivalents) and 1,4-dioxane (40 mL), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum, and the residue was ground in Et2O to obtain intermediate 15 (HCl salt, 406 mg, quantitative) as an orange solid.

[0347] Intermediate 16:

[0348] [ka]

[0349] Sodium methyl thiolate (CAS[5188-07-8], 15 mg, 0.207 mmol, 1.2 equivalents) was added to a solution of 2-pyridinecarboxylic acid, 4-chloro-5-methyl-methyl ester (CAS[1104455-41-5], 32 mg, 0.172 mmol) in DMF (0.5 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with siRNA (10 mL) and washed with saturated aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (12 g column, gradient of siRNA in heptane from 0 to 100%) to obtain intermediate 16 (25 mg, yield: 73%) as a white solid.

[0350] Intermediate 17:

[0351] [ka]

[0352] m-CPBA (2.465 g, 10 mmol, 2.5 equivalents) was gradually added at 0°C to a solution of intermediate 16 (789 mg, 4 mmol) in DCM (35 mL). The reaction mixture was stirred for 20 hours, and the temperature was raised to room temperature. The reaction was quenched with saturated Na2S2O3 aqueous solution (1 mL) while stirring. Saturated NaHCO3 aqueous solution (5 mL) and DCM (10 mL) were added. The mixture was stirred for a further 10 minutes, and then the organic layer was separated. The aqueous layer was extracted twice with DCM (2 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (12 g column, gradient of 0-5% MeOH in DCM) to obtain intermediate 17 (771 mg, yield: 83%) as a white solid.

[0353] Intermediate 18:

[0354] [ka]

[0355] NaOH (1M in water, 5.0 mL, 5.038 mmol, 1.5 equivalents) was added at room temperature to a solution of intermediate 17 (770 mg, 3.359 mmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water, and KHSO4 (1M in water) was added to adjust the pH to approximately 2-3. The mixture was extracted with MeOH / CH2Cl2 (1:9). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 18 (630 mg, yield: 86%) as a white solid, which was used without further purification.

[0356] Intermediate 19:

[0357] [ka]

[0358] Intermediate 19 was prepared according to Method J, starting from intermediate 4 and (3α,4α,5α)-3,5-dimethyl-4-piperidinol (CAS[1236030-00-4]).

[0359] Intermediate 20:

[0360] [ka]

[0361] HCl (4M in 1,4-dioxane, 2.13 mL, 8.51 mmol, 10 equivalents) was added to intermediate 19 (411 mg, 0.85 mmol) in 1,4-dioxane (20 mL) and water (5 mL), and the reaction mixture was stirred overnight at 50°C. The reaction mixture was concentrated to obtain intermediate 20 (HCl salt, 452 mg, purity 92%, quantitative).

[0362] Intermediate 21:

[0363] [ka]

[0364] 1-Propanephosphonic anhydride (50% in siRNA, CAS [68957-94-8], 24.37 mL, 40.932 mmol, 1.7 equivalents) was added to a suspension of intermediate 10 (7000 mg, 24.078 mmol) and 5-(methylsulfonyl)nicotinic acid (CAS [893723-59-6], 5813 mg, 28.893 mmol, 1.2 equivalents) in dry DCM (200 mL) at room temperature under a nitrogen atmosphere. Then, Et3N (24.1 mL, 173.358 mmol, 7.2 equivalents) was added dropwise to the orange suspension over 5 minutes. The reaction mixture was stirred overnight at room temperature. The resulting solid was filtered and washed with Et2O. The solid was stirred in water and MeOH for 2 hours, filtered, and washed with toluene to obtain intermediate 21 (7.1 g, purity 95%, yield: 64%).

[0365] Intermediate 22:

[0366] [ka]

[0367] Intermediate 22 was prepared according to Method J, starting from intermediate 4 and (3α,4β,5α)-3,5-dimethyl-4-piperidinol (CAS[374067-78-4]).

[0368] Intermediate 23:

[0369] [ka]

[0370] Intermediate 23 was prepared by starting with intermediate 22 instead of intermediate 19, using the same method as for intermediate 20.

[0371] Intermediate 24 and Intermediate 25:

[0372] [ka] Intermediate 24: *R is a pure stereoisomer, but its stereochemistry is indeterminate.

[0373] [ka] Intermediate 25: * S is a pure stereoisomer, but its stereochemistry is indeterminate.

[0374] NaOH (2M in water, 19 mL, 38.034 mmol, 2 equivalents) was added to a solution of methyl 5-(1-hydroxyethyl)-3-pyridine carboxylate (CAS[38940-64-6], 3.45 g, 19.017 mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature for 18 hours. The pH of the mixture was adjusted to 4 with HCl aqueous solution (1 M). The solvent was evaporated, and DCM:MeOH (9:1) was added. The salt was filtered off, and the filtrate was concentrated. The residue was purified by preparative SFC (i-amylose-1 column; isocratic mode method: 10%[MeOH+0.1%DEA]-90%[CO2]) to obtain intermediate 24 (930 mg, yield: 29%) and intermediate 25 (631 mg, yield: 20%), both as brown oils.

[0375] Intermediate 26:

[0376] [ka]

[0377] Dess-Martin periodinane (CAS[87413-09-0], 124 mg, 0.293 mmol, 1.5 equivalents) was added to a solution of compound 4 (100 mg, 0.195 mmol) in DCM (2 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated to obtain intermediate 26 (99 mg, yield: 95%) as a yellow solid, which was used without further purification.

[0378] Intermediate 27:

[0379] [ka]

[0380] N-iodosuccinimide (199 mg, 0.884 mmol, 1 equivalent) was added at 0°C to a solution of intermediate 22 (410 mg, 0.884 mmol) in hexafluoroisopropanol (10 mL). The reaction mixture was stirred at 0°C for 30 minutes, then at room temperature for 1 hour. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic phase was dried with MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (silica; ethyl acetate / heptane 0 / 100~50 / 50) to obtain intermediate 27 (450 mg, purity 66%, yield: 57%) as a yellow oil.

[0381] Intermediate 28:

[0382] [ka]

[0383] A solution of intermediate 27 (450 mg, 66% purity, 0.504 mmol), trimethylboroxine (CAS[823-96-1], 423 μL, 3.023 mmol, 6 equivalents), and K2CO3 (418 mg, 3.023 mmol, 6 equivalents) in 1,4-dioxane (0.5 mL) and water (0.3 mL) was degassed with nitrogen for 5 minutes. Xanthophos PdG3 (CAS[1445085-97-1], 48 mg, 0.050 mmol, 0.1 equivalent) was added to the solution at room temperature, and the mixture was stirred at 80°C for 12 hours. After cooling, the mixture was diluted with water and extracted with siRNA. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g silica; HCl / heptane 0 / 100~100 / 0), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30×100 mm 5 μm column; 81% [0.1% HCOOH]-19% ACN to 45% [0.1% HCOOH]-55% ACN) to obtain intermediate 28 (77 mg, yield: 32%) as a yellow solid.

[0384] Intermediate 29:

[0385] [ka]

[0386] HCl (4M in 1,4-dioxane, 419 μL, 1.675 mmol, 20 equivalents) was added to a solution of intermediate 28 (40 mg, 0.084 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to obtain intermediate 29 (HCl salt, 42 mg, 90% purity, quantitative) as an orange solid.

[0387] Intermediate 30:

[0388] [ka]

[0389] A suspension of intermediate 21 (50 mg, 0.109 mmol), tert-butyl 1,7-diazaspiro[3.5]nonane-1-carboxylate (CAS[121693-62-7], 98 mg, 0.434 mmol, 4 equivalents), and DIPEA (56 μL, 0.326 mmol, 3 equivalents) in dry DMSO (0.5 mL) was stirred overnight at 90 °C. The reaction mixture was diluted with water and ethyl acetate. The resulting precipitate was filtered, washed with ethyl acetate, and then dried under vacuum to obtain intermediate 30 (48 mg, yield: 68%) as a pale yellow solid.

[0390] Intermediate 31:

[0391] [ka]

[0392] Intermediate 31 was prepared according to method K, starting from intermediate 21 and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (CAS[1180509-95-8]).

[0393] Intermediate 32:

[0394] [ka]

[0395] Intermediate 32 was prepared according to method K, starting from intermediate 21 and 3-(N-tert-butoxycarbonyl-N-methylamino)pyrrolidine (CAS[172478-00-1]).

[0396] Intermediate 33:

[0397] [ka]

[0398] Intermediate 33 was prepared according to method K, starting from intermediate 21 and DL-3-(Boc-amino)pyrrolidine (CAS[99724-19-3]).

[0399] Intermediate 34:

[0400] [ka]

[0401] Intermediate 34 was prepared according to Method J, starting from intermediate 21 and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (CAS[236406-55-6]).

[0402] Intermediate 35:

[0403] [ka]

[0404] Tert-butyl(pyrrolidine-2-ylmethyl)carbamate (CAS[149649-58-1], 176 mg, 0.879 mmol, 4 equivalents) and DIPEA (115 μL, 0.665 mmol, 3 equivalents) were added to a suspension of intermediate 21 (100 mg, 0.222 mmol) in dry DMSO (1 mL), and the reaction mixture was stirred overnight at 130°C. The reaction mixture was diluted with water and SiO2. The layers were separated, and the aqueous layer was extracted again with SiO2. The combined organic layers were dried over MgSO4, filtered, and evaporated to obtain intermediate 35, which was used directly in the next step without further purification.

[0405] Intermediate 36:

[0406] [ka]

[0407] A suspension of intermediate 21 (50 mg, 0.109 mmol), 3-(Boc-amino)-3-methylpyrrolidine (CAS[147459-52-7], 87 mg, 0.434 mmol, 4 equivalents), and DIPEA (56 μL, 0.326 mmol; 3 equivalents) in dry DMSO (0.5 mL) was stirred overnight at 90°C. The reaction mixture was diluted with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried by filtration on Extrelut NT3 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep 4 g, DCM / DCM:MeOH9:1, 100 / 0~0 / 100) to obtain intermediate 36 (51 mg, yield: 76%) as a dark yellow solid.

[0408] Intermediate 37:

[0409] [ka]

[0410] In a 2 L four-necked round-bottom flask purged and maintained under a nitrogen atmosphere, intermediate 83 (99 g, 464.24 mmol, 1 equivalent), EtOH (990 mL), and H2O2 (157.91 g, 4642.44 mmol, 10 equivalents) were added. Subsequently, ammonium molybdate tetrahydrate (57.37 g, 46.42 mmol, 0.1 equivalent) was added at 0°C. The resulting solution was stirred at 0°C for 1 hour. The resulting solution was extracted with DCM (3 × 1 L), and the combined organic layers were washed with saturated Na2S2O3 aqueous solution (3 × 1 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by grinding with MTBE (1 L) to obtain intermediate 37 (62 g, yield: 54%) as a white solid.

[0411] Intermediate 38:

[0412] [ka]

[0413] Intermediate 37 (62 g, 252.80 mmol), THF (240 mL), H2O (360 mL), and LiOH (30.27 g, 1264.01 mmol, 5 equivalents) were added to a 2 L four-necked round-bottom flask at room temperature. The resulting solution was stirred at 40 °C for 20 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water (500 mL). The mixture was acidified to pH 3 with aqueous HCl (6 N). The precipitated solid was recovered by filtration. The solid was purified by grinding with THF (600 mL), and the solid was recovered by filtration to obtain intermediate 38 (50.46 g, yield: 87%) as a white solid.

[0414] Intermediate 39:

[0415] [ka]

[0416] Intermediate 39 was prepared according to Method J, starting from intermediate 4 and (3α,4α,5α)-3,5-dimethyl-4-piperidinol (CAS[1236030-00-4]).

[0417] Intermediate 40:

[0418] [ka]

[0419] Intermediate 40 was prepared using intermediate 39 instead of intermediate 28, in the same manner as intermediate 29.

[0420] Intermediate 41:

[0421] [ka]

[0422] Iron(II) sulfate heptahydrate (CAS[7782-63-0], 545 mg, 1.632 mmol, 0.14 equivalents) was added to a solution of methyl 5-chloro-2-pyridine carboxylate (CAS[132308-19-1], 2 g, 11.656 mmol) in TFA (1.13 mL, 15.153 mmol, 1.3 equivalents) and acetaldehyde (58 mL, 1037.411 mmol, 89 equivalents). The mixture was cooled to 0°C, and the first portion of H2O2 (6.43 mL, 62.944 mmol, 5.4 equivalents) was added dropwise, and the reaction mixture was stirred at 0°C for 30 minutes. The second portion of H2O2 (6.43 mL, 62.944 mmol, 5.4 equivalents) was added dropwise to the reaction mixture, and it was stirred at 0°C for a further 90 minutes. Next, the mixture was warmed to room temperature. The reaction was quenched by slowly adding saturated Na2S2O3 aqueous solution, followed by saturated NaHCO3 aqueous solution, and the mixture was extracted twice with dimethyl ammonium. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica; gradient dimethyl / heptane 0 / 100~10 / 90) to obtain intermediate 41 (1.85 g, yield: 74%) as a colorless oil.

[0423] Intermediate 42:

[0424] [ka]

[0425] NaOH (2M in water, 8.7 mL, 17.321 mmol, 2 equivalents) was added to a solution of intermediate 41 (1.85 g, 8.66 mmol) in MeOH (45 mL). The reaction mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 1-2 with 1M aqueous HCl. The mixture was diluted with water and extracted with SiO2 (3 times). The combined organic layers were separated, dried (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain intermediate 42 (1.49 g, yield: 86%), which was used without further purification.

[0426] Intermediate 43:

[0427] [ka]

[0428] Benzoyl chloride (CAS[98-88-4], 1.8 mL, 15.507 mmol, 1.55 equivalents), Et3N (7 mL, 50.222 mmol, 5 equivalents), and DMAP (219 mg, 1.793 mmol, 0.18 equivalents) were added to a solution of (3α,4β,5α)-3,5-dimethyl-1-(phenylmethyl)-4-piperidinol (CAS[374067-77-3], 2.2 g, 10.031 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (80 g, toluene / heptane 0 / 100~20 / 80) to obtain intermediate 43 (2.88 g, yield: 88%) as a white solid.

[0429] Intermediate 44:

[0430] [ka]

[0431] Palladium hydroxide (CAS[12135-22-7], 238 mg, 0.34 mmol, 0.04 equivalents) was added to a solution of intermediate 43 (2.88 g, 8.905 mmol) in MeOH (50 mL) under a nitrogen atmosphere. The mixture was purged using vacuum and nitrogen. The mixture was then purged with hydrogen and stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a short pad of Celite, and the solvent was removed under vacuum to obtain intermediate 44 (1.98 g, yield: 94%) as a colorless oil.

[0432] Intermediate 45:

[0433] [ka]

[0434] A solution of 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 1.236 g, 4.384 mmol) in 1,4-dioxane (37 mL) was purged with nitrogen. Then, while bubbling nitrogen, Cs2CO3 (3.14 g, 9.644 mmol, 2.2 equivalents), intermediate 44 (1.36 g, 5.041 mmol, 1.15 equivalents), DavePhos (CAS[213697-53-1], 173 mg, 0.44 mmol, 0.1 equivalent), and Pd2dba3 (CAS[51364-51-3], 200 mg, 0.218 mmol, 0.05 equivalents) were added at room temperature. The vial was sealed and the mixture was stirred at 90°C for 3 hours. A saturated aqueous solution of NaHCO3 and toluene were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with toluene (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (25 g, toluene / heptane 0 / 100~25 / 75) to obtain intermediate 45 (1.686 g, yield: 84%) as a yellow solid.

[0435] Intermediate 46:

[0436] [ka]

[0437] Tetramethylammonium fluoride (CAS[373-68-2], 543 mg, 5.83 mmol, 1.5 equivalents) was added to a solution of intermediate 45 (1.686 g, 3.882 mmol) in DMF (15 mL). The reaction mixture was stirred at 65 °C for 3 hours. After cooling, the mixture was diluted with toluene (15 mL) and water (15 mL). The layers were separated, and the organic layer was washed with water (20 mL) and brine (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (80 g, toluene / heptane 0 / 100~30 / 100) to obtain intermediate 46 (1.265 g, yield: 79%) as a yellow solid.

[0438] Intermediate 47:

[0439] [ka]

[0440] Intermediate 47 was prepared using the same method as intermediate 14, starting from intermediate 46 instead of intermediate 13.

[0441] Intermediate 48:

[0442] [ka]

[0443] TFA (1.505 mL, 19.67 mmol, 30 equivalents) was added at 0°C to a solution of intermediate 47 (384 mg, 0.656 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum to obtain intermediate 48 (295 mg, yield: 91%), which was used without further purification.

[0444] Intermediate 49:

[0445] [ka]

[0446] Intermediate 49 was prepared starting from intermediate 48 and 2-methyl-6-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS [1780757-32-5]) according to method A (in DMF).

[0447] Intermediate 50:

[0448] [ka]

[0449] A solution of intermediate 47 (540 mg, 0.922 mmol) in an aqueous NaOH solution (2.5 M, 5.5 mL, 13.75 mmol, 15 equivalents) was stirred at 72°C for 16 hours. After cooling, the mixture was partitioned between toluene (25 mL) and a saturated aqueous NaHCO3 solution. The layers were separated, the organic layer was dried with (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g silica; DCM: MeOH (9:1) in DCM 0%~25%) to obtain intermediate 50 (401 mg, yield: 90%) as a yellow solid.

[0450] Intermediate 51:

[0451] [ka]

[0452] Trifluoroacetic acid (1.5 mL, 19.601 mmol, 24 equivalents) was added at 0°C to a solution of intermediate 50 (401 mg, 0.833 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain intermediate 51 (TFA salt, 508 mg, yield: 99%) as a yellow solid, which was used without further purification.

[0453] Intermediate 52:

[0454] [ka]

[0455] (Methoxymethyl)triphenylphosphonium chloride (CAS[4009-98-7], 1518 mg, 4.341 mmol, 1.1 equivalents) was dissolved in THF (16 mL) and cooled to 0°C under a nitrogen atmosphere. Potassium tert-butoxide (1.0 M in THF, 4.14 mL, 4.144 mmol, 1.05 equivalents) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, rel-1,1-dimethylethyl (3R,5S)-3,5-dimethyl-4-oxo-1-piperidine carboxylate (CAS[1221821-84-6], 897 mg, 3.946 mmol, 1 equivalent) in THF (8 mL) was added, and the reaction mixture was stirred at room temperature overnight. Concentrated aqueous HCl was added until the pH became acidic, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with Et2O (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (24 g SiO2, heptane / siRNA 100 / 0~80 / 20) to obtain intermediate 52 (576 mg, yield: 60%).

[0456] Intermediate 53:

[0457] [ka]

[0458] Intermediate 52 (576 mg, 2.387 mmol) was dissolved in MeOH (20 mL), and sodium borohydride (135 mg, 3.58 mmol, 1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was diluted with Et2O and washed with water. The aqueous layer was extracted twice with Et2O, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (12 g SiO2, heptane / siRNA 90 / 10~50 / 50) to obtain intermediate 53 (389 mg, yield: 64%) as a clear oil.

[0459] Intermediate 54:

[0460] [ka]

[0461] Intermediate 53 (389 mg, 1.519 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain intermediate 54 (HCl salt, 385 mg, quantitative).

[0462] Intermediate 55:

[0463] [ka]

[0464] Intermediate 4 (200 mg, 0.564 mmol) and intermediate 54 (200 mg, 0.792 mmol, 1.4 equivalents) were dissolved in DMSO (5.6 mL), and DIPEA (0.292 mL, 1.693 mmol, 3 equivalents) was added. The reaction mixture was stirred at 130 °C for 2 days. The reaction mixture was diluted with water, and the mixture was extracted with ELISA (3×). The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiO2, DCM / MeOH 100 / 0~90 / 10) to obtain intermediate 55 (112 mg, yield: 37%) as an orange foam.

[0465] Intermediate 56:

[0466] [ka]

[0467] Intermediate 55 (112 mg, 0.211 mmol) was dissolved in HCl (4 M, 4 mL, 4 M, 16 mmol in 1,4-dioxane) and DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the precipitate was isolated by filtration. It was dried under reduced pressure to obtain intermediate 56 (HCl salt, 117 mg, quantitative) as a grayish-white solid, which was used without further purification.

[0468] Intermediate 57:

[0469] [ka]

[0470] A suspension of intermediate 4 (263 mg, 0.742 mmol), 2-methyl-6-(trifluoromethyl)morpholine (CAS [1342385-23-2], 502 mg, 2.968 mmol, 4 equivalents), and DIPEA (384 μL, 2.226 mmol, 3 equivalents) in dry DMSO (1 mL) was introduced into a thick-walled vial. The vial was sealed and the reaction mixture was stirred at 130°C for 4.5 days. The reaction mixture was diluted with water and DCM. The layers were separated, and the aqueous layer was extracted again with DCM. The combined organic layers were dried by filtration on Extrelut NT3 and evaporated. The residue was subjected to column chromatography (SiO₂). 2、 25 g was purified with heptane EtOH / siRNA 1 / 3 (100:0~20:80) to obtain intermediate 57 (311 mg, yield: 77%) as a grayish-white solid.

[0471] Intermediate 58:

[0472] [ka]

[0473] HCl (37% in water, 959 μL, 11.488 mmol, 20 equivalents) was added dropwise to a solution of intermediate 57 (311 mg, 0.574 mmol) in 1,4-dioxane (20 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. The solid was co-evaporated with toluene to obtain intermediate 58 (HCl salt, 273 mg, quantitative) as an orange solid, which was used without further purification.

[0474] Intermediate 59:

[0475] [ka]

[0476] A suspension of 4-methyl-4,6-diazaspiro[2.4]heptan-5-one (CAS[1338493-29-0], 368 mg, 2.917 mmol), 2,6-dibromopyridine (CAS[626-05-1], 1.38 g, 5.834 mmol, 2 equivalents), xanthophos (CAS[161265-03-8], 675 mg, 1.167 mmol, 0.4 equivalents), and Cs2CO3 (3.80 g, 11.668 mmol, 4 equivalents) in dried 1,4-dioxane (15 mL) was degassed with nitrogen for 5 minutes. Pd(OAc)2 (CAS[3375-31-3], 65 mg, 0.292 mmol, 0.1 equivalent) was added, and the reaction mixture was further degassed for 5 minutes. The vial was closed and the reaction mixture was stirred in a microwave oven at 100°C for 30 minutes. The reaction mixture was diluted with DCM and the solid was filtered off. The filtrate was evaporated, and the residue was purified by column chromatography (SiO2, 25 g; heptane EtOH / Â1 / 3 100:0~20:80) to obtain intermediate 59 (291 mg, yield: 35%) as a yellow solid.

[0477] Intermediate 60:

[0478] [ka]

[0479] To a suspension of intermediate 59 (291 mg, 1.031 mmol, 1.5 equivalents), bis(pinacorato)diboron (CAS[72287-34-3], 314 mg, 1.238 mmol, 1.8 equivalents), and KOAc (pre-dried under vacuum at 50°C, 304 mg, 3.094 mmol, 4.5 equivalents) in dried 1,4-dioxane (6 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS[73183-26-4], 76 mg, 0.103 mmol, 0.15 equivalents) was added, and the mixture was degassed by bubbling nitrogen for 5 minutes. The vial was sealed, and the reaction mixture was stirred at 90°C for 2 hours. The vial was opened, and while maintaining a nitrogen atmosphere, intermediate 3 (202 mg, 0.688 mmol), K2CO3 (190 mg, 1.375 mmol, 2 equivalents), and copper(I) chloride (69 mg, 0.688 mmol, 1 equivalent) were added. The vial was sealed, and the reaction mixture was stirred at 75°C for 18 hours. After cooling, the reaction mixture was diluted with RINKAN and filtered. The solid was washed with RINKAN. Brine was added to the filtrate, and the layers were separated. The aqueous layer was extracted again with RINKAN. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (SiO2, 25 g; heptane EtOH / RINKAN 1 / 3 100:0~100:0) to obtain intermediate 60 (124 mg, 41% purity, yield: 16%) as a grayish-white solid, which was still impure but was used directly in the next step.

[0480] Intermediate 61:

[0481] [ka]

[0482] HCl (37% in water, 0.28 mL, 3.312 mmol, 30 equivalents) was added to a solution of intermediate 60 (41% purity, 124 mg, 0.11 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated to obtain intermediate 61 (HCl salt, 62 mg) as a brown solid, which was used without further purification.

[0483] Intermediate 62:

[0484] [ka]

[0485] A solution of oxone (CAS[7069-62-8], 5.8 g, 9.2 mmol) in water (35 mL) was added all at once at room temperature to a solution of methyl 4-[(2-hydroxyethyl)thio]-2-pyridinecarboxylate (CAS[1500860-13-8], 0.98 g, 4.6 mmol) in MeOH (40 mL). The mixture was stirred at room temperature for 20 hours. The mixture was diluted with toluene (150 mL) and water (250 mL). The organic layer was separated, and the aqueous layer was extracted with toluene (150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (40 g; MeOH / DCM0 / 100~20 / 80) to obtain intermediate 62 (535 mg, yield: 47%) as a white solid.

[0486] Intermediate 63:

[0487] [ka]

[0488] Sodium hydroxide (1 M in water, 6.5 mL, 6.5 mmol) was added at room temperature to a stirred solution of intermediate 62 (529 mg, 2.16 mmol) in MeOH (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH=4 with HCl (1 M in water) and extracted several times with SiO2. The combined organic layer was evaporated to obtain intermediate 63 (662 mg, quantitative) as a white solid, which was used without further purification.

[0489] Intermediate 64:

[0490] [ka]

[0491] Intermediate 4 (2.67 g, 7.54 mmol) and 4-Boc-4,7-diazaspiro[2.5]octane (CAS[674792-08-6], 4 g, 18.84 mmol) were suspended in DMSO (80 mL), and then DIPEA (3.9 mL, 22.61 mmol) was added. The mixture was stirred overnight at 130 °C. The reaction mixture was then diluted with siRNA and washed with water. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel chromatography (DCM / MeOH 100 / 0~98 / 2) to obtain intermediate 64 (1.72 g, yield: 42%).

[0492] Intermediate 65:

[0493] [ka]

[0494] Intermediate 64 (1.54 g, 2.82 mmol) was suspended in MeOH (15 mL), and HCl (6 M in iPrOH, 15 mL, 90 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under vacuum, and then evaporated once with toluene. The yellow powder was dried under reduced pressure at 50°C to obtain intermediate 65 (1.49 g, 100% yield).

[0495] Intermediate 66:

[0496] [ka]

[0497] 2,6-Dibromopyridine (CAS[626-05-1], 200 mg, 0.84 mmol), 4-Oxa-7-Azaspiro[2.5]Octane-6-one (CAS[1253790-21~4], 54 mg, 0.42 mmol), Xanthophos (CAS[161265-03-8], 98 mg, 0.17 mmol), Cs2CO3 (550 mg, 1.69 mmol), and Pd(OAc)2 (CAS[3375-31-3], 9 mg, 0.042 mmol) were suspended in 1,4-Dioxane (4.6 mL), and the suspension was degassed with nitrogen for 15 minutes. The reaction mixture was then stirred at 100°C under a nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with DCM and filtered through a Dicalite pad. The solvent was evaporated under vacuum, and the crude product was purified by silica gel chromatography (24 g, heptane / siRNA 100 / 0~50 / 50) to obtain intermediate 66 (83 mg, yield: 68%) as a white solid.

[0498] Intermediate 67:

[0499] [ka]

[0500] To a suspension of intermediate 66 (83 mg, 0.29 mmol), bis(pinacolato)diborone (CAS[73183-34-3], 88 mg, 0.34 mmol), and KOAc (dried overnight at 45°C under vacuum, 85 mg, 0.86 mmol) in dried 1,4-dioxane (2 mL), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (CAS[72287-26-4], 21 mg, 0.029 mmol) was added, and the mixture was degassed by bubbling nitrogen for 5 minutes. The reaction mixture was stirred at 90°C for 3.5 hours. After cooling to 75°C, the vial was opened, and while maintaining a nitrogen atmosphere, intermediate 3 (56 mg, 0.19 mmol), K2CO3 (53 mg, 0.38 mmol), and CuCl (CAS[7758-89-6], 19 mg, 0.19 mmol) were added. The reaction mixture was stirred overnight at 75°C. After cooling, the reaction mixture was diluted with brine and RINKAN. The layers were separated, and the aqueous layer was extracted again with RINKAN. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel chromatography (12 g, DCM / MeOH 100 / 0~99 / 1) to obtain intermediate 67 (50 mg, yield: 57%) as a yellow solid.

[0501] Intermediate 68:

[0502] [ka]

[0503] Intermediate 67 (50 mg, 0.11 mmol) was suspended in HCl (6 M in iPrOH, 2 mL, 12 mmol) and MeOH (1 mL), and the orange reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the crude product was evaporated once together with toluene to obtain intermediate 68 (46 mg, yield: 98%) as a yellow to orange solid.

[0504] Intermediate 69:

[0505] [ka]

[0506] Intermediate 69 was synthesized following a similar procedure to that used for intermediate 68, starting with 2,6-dimethylmorpholine-3-one (CAS[93240-61-0]) instead of 4-oxa-7-azaspiro[2.5]octan-6-one.

[0507] Intermediate 70:

[0508] [ka]

[0509] Intermediate 70 was synthesized following a similar procedure to that used for intermediate 68, starting with 6-(trifluoromethyl)morpholin-3-one (CAS[1354953-95-9]) instead of 4-oxa-7-azaspiro[2.5]octan-6-one.

[0510] Intermediate 71:

[0511] [ka]

[0512] Intermediate 71 was synthesized starting with 2,2-dimethylmorpholine-3-one (CAS[13882-78-5]) instead of 4-oxa-7-azaspiro[2.5]octan-6-one, following a similar procedure to that used for the synthesis of intermediate 68.

[0513] Intermediate 72:

[0514] [ka]

[0515] Sodium hydride (70 mg, 1.74 mmol) was added at room temperature to a stirred solution of (L)-proline (CAS[147-85-3], 200 mg, 1.74 mmol) in DMSO (12 mL). The mixture was stirred at room temperature for 30 minutes. Then, 5-bromo-6-methyl-3-pyridinecarboxylic acid, methyl ester ([CAS:1174028-22-8], 500 mg, 2.17 mmol), sodium methanesulfinate (CAS[20277-69-4], 1.8 g, 17.4 mmol), and copper iodide (CAS[7681-65-4], 331 mg, 1.74 mmol) were added, and the mixture was stirred at 120°C for 2 hours. After cooling, the reaction mixture was poured into a mixture of saturated NaHCO3 aqueous solution and siRNA. The formed precipitate was filtered, and the filtrate layer was separated. The aqueous layer was extracted with Âr, and the combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g silica; MeOH / DCM0 / 100~5 / 95) to obtain intermediate 73 (278 mg, yield: 55%) as a white solid.

[0516] Intermediate 73:

[0517] [ka]

[0518] A solution of sodium hydroxide (1 M in water, 9.2 mL, 9.2 mmol) was added at room temperature to a stirred solution of intermediate 72 (700 mg, 3.05 mmol) in MeOH (9 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified to approximately pH 1 with HCl (1 M in water) and then extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 73 (545 mg, yield: 79%) as a white solid.

[0519] Intermediate 74:

[0520] [ka]

[0521] 7-Bromo-1,6-naphthyrizine-2(1H)-one (CAS[1574395-48-4], 3.0 g, 13.33 mmol, 1.0 equivalent), potassium trifluoro(vinyl)borate (CAS[13682-77-4], 2.15 g, 16.0 mmol, 1.2 equivalents), bis(triphenylphosphine)palladium(II) chloride (CAS[13965-03-2], 280 mg, 0.4 mmol, 0.3 equivalents), and Cs2CO3 (13.0 g, 40.0 mmol, 3.0 equivalents) were dissolved in DMF (40 mL) and water (10 mL) under a nitrogen atmosphere. The mixture was stirred at 80°C for 16 hours. After cooling, the reaction mixture was diluted with RINKAN and water. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by flash column chromatography (80 g of SiO2, DCM: 0% to 30% MeOH (9:1) in DCM) to obtain intermediate 74 (1.267 g, yield: 49%) as a white solid.

[0522] Intermediate 75:

[0523] [ka]

[0524] Phosphoryl chloride (CAS[10025-87-3], 1.65 mL, 17.67 mmol, 3.0 equivalents) was added to a suspension of intermediate 74 (1.014 g, 5.889 mmol, 1.0 equivalent) in 1,2-dichloroethane (30 mL). The mixture was stirred at 80°C for 48 hours. The mixture was diluted with saturated aqueous Na2CO3 and SiO2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated to obtain intermediate 75 (981 mg, yield: 74%) as a beige solid.

[0525] Intermediate 76:

[0526] [ka]

[0527] Osmium tetroxide (CAS[20816-12-0], 33 mg, 0.13 mmol) was added at 0°C to a stirred mixture of water (14 mL) and 1,4-dioxane (55 mL) containing intermediate 75 (981 mg, 5.146 mmol, 1.0 equivalent), sodium periodate (CAS[7790-28-5], 4.4 g, 20.6 mmol, 4.0 equivalent), and 2,6-dimethylpyridine (CAS[108-48-5], 1.2 mL, 10.3 mmol, 2.0 equivalent). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated aqueous NaHCO3 and SiO2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated to obtain intermediate 76 (822 mg, yield: 75%) as a brown solid.

[0528] Intermediate 77:

[0529] [ka]

[0530] Intermediate 76 (200 mg, 1.038 mmol, 1.0 equivalent), 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (CAS[1009033-83-3], 467 mg, 0.494 mmol, 1.44 equivalents), and sodium carbonate (330 mg, 3.115 mmol, 3.0 equivalents) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) in a pressure flask at room temperature. The mixture was bubbling with nitrogen for 10 minutes. Next, bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (CAS[95464-05-4], 42 mg, 0.052 mmol, 0.05 equivalents) with DCM was added, and the mixture was stirred at 85°C for 16 hours. The mixture was diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was separated, dried, filtered, and the solvent evaporated. The crude product was purified by flash column chromatography (silica 12 g; ethyl acetate / heptane 0 / 100~80 / 20) to obtain intermediate 77 (90 mg, yield: 28%) as a white solid.

[0531] Intermediate 78:

[0532] [ka]

[0533] Sodium bicarbonate (24 mg, 0.289 mmol, 1.0 equivalent) and hydroxylamine hydrochloride (CAS[5470-11-1], 40 mg, 0.578 mmol, 2.0 equivalents) were added to a solution of intermediate 77 (90 mg, 0.289 mmol, 1.0 equivalent) in MeOH (30 mL). This suspension was stirred at room temperature for 24 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated to obtain intermediate 78 (45 mg, yield: 47%) as a beige solid, which was used without further purification.

[0534] Intermediate 79:

[0535] [ka]

[0536] Raney Ni (CAS[7440-02-0], 215 mg, 3.667 mmol, 4.0 equivalents) was added to a stirred solution of intermediate 78 (300 mg, 0.919 mmol, 1.0 equivalent) in MeOH (6 mL) and THF (3 mL) under a nitrogen atmosphere at room temperature. The nitrogen atmosphere was then replaced with hydrogen, and the reaction mixture was stirred at room temperature for 4 hours. The mixture was filtered through a Celite pad, and the filtrate was evaporated to obtain intermediate 79 (170 mg, yield: 58%) as a brown solid, which was used without further purification.

[0537] Intermediate 80:

[0538] [ka]

[0539] N-iodosuccinimide (CAS[516-12-1], 335 mg, 1.49 mmol, 1.0 equivalent) was added at 0°C to a solution of intermediate 50 (717 mg, 1.49 mmol, 1.0 equivalent) in 1,1,1,3,3,3-hexafluoro-2-propanol ([920-66-1], 4 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous Na2S2O3 solution. The organic layer was dried over (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (25 g SiO2, DCM: MeOH(9:1) in DCM 0%~18%) to obtain intermediate 80 (555 mg, yield: 60%) as a yellow solid.

[0540] Intermediate 81:

[0541] [ka]

[0542] Under a nitrogen atmosphere, trimethylboroxine (CAS[823-96-1], 264 μL, 0.19 mmol, 2.0 equivalents), Cs2CO3 (CAS[534-17-8], 595 mg, 1.83 mmol, 2.0 equivalents), and Pd(dppf)Cl2CH2Cl2 (CAS[95464-05-4], 75 mg, 91 μmol, 0.1 equivalents) were added to a solution of intermediate 80 (555 mg, 0.91 mmol) in 10 mL of 1,4-dioxane. The mixture was stirred at 95°C for 16 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (25 g SiO2 column, DCM: MeOH (9:1) 0 / 100~20 / 80 in DCM) to obtain intermediate 81 (413 mg, yield: 90%) as a colorless oil.

[0543] Intermediate 82

[0544] [ka]

[0545] Trifluoroacetic acid (CAS[76-05-1], 1.5 mL, 19.6 mmol, 23.5 equivalents) was added at 0°C to a stirred solution of intermediate 81 (413 mg, 0.83 mmol, 1.0 equivalent) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours, and then saturated aqueous NaHCO3 and DCM were added to the reaction mixture. The organic layer was separated, dried over MgSO4, filtered, and concentrated to obtain intermediate 82 (321 mg, yield: 96%) as a beige solid, which was used without further purification.

[0546] Intermediate 83:

[0547] [ka]

[0548] A mixture of methyl 5-bromonicotinate (CAS[29681-44-5], 5.05 g, 26.367 mmol), xanthophos (CAS[161265-03-8], 2.667 g, 4.606 mmol, 0.2 equivalents), and Pd2(dba)3 (CAS[51364-51-3], 2.136 g, 0.1 equivalents) was placed in a reaction vessel, sealed, evacuated, and purged with nitrogen. Dry 1,4-dioxane (100 mL) was added, followed by 2-mercaptoethanol (CAS[60-24-2], 1.8 mL, 25.663 mmol, 1.1 equivalents) and DIPEA (6 mL, 34.817 mmol, 1.5 equivalents). The reaction mixture was stirred at 95°C for 16 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (330 g of SiO2; Â1 / DCM0 / 100~100 / 0) to obtain intermediate 83 (5.18 g, quantitative).

[0549] Intermediate 84:

[0550] [ka]

[0551] Under a nitrogen atmosphere, 5-bromonicotinic acid (CAS[20826-04-4], 600 mg, 2.970 mmol, 1.0 equivalent) was dissolved in THF (15 mL), and the reaction mixture was cooled to -78°C and stirred for 10 minutes. n-butyllithium (2.5 M in hexane, 2.37 mL, 5.94 mmol, 2 equivalents) was added dropwise, and the reaction mixture was stirred at -78°C for 20 minutes. A solution of acetone (0.44 mL, 5.940 mmol, 2 equivalents) in THF (1 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution, and KHSO4 (1 M in water) was added dropwise over 10 minutes with vigorous stirring. The pH reached a value of 2-3. DCM and water were added. The organic layer was separated and concentrated, and the residue was purified by flash column chromatography (25 g silica, DCM: MeOH (9:1) in DCM 0 / 100~20 / 80) to obtain intermediate 84 (194 mg, yield: 32%) as a beige solid.

[0552] Intermediate 85:

[0553] [ka]

[0554] A solution of 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 2 g, 7.1 mmol, 1.0 equivalent) and tert-butyl 5,8-diazaspiro[2.5]octane-8-carboxylate (CAS[674792-08-6], 1.5 g, 7.1 mmol, 1.0 equivalent) in 1,4-dioxane (30 mL) was purged with nitrogen. Next, Cs2CO3 (5g, 15.35 mmol, 2.0 equivalents), DavePhos (CAS[213697-53-1], 303 mg, 0.77 mmol, 0.05 equivalents), and Pd2dba3 (CAS[51364-51-3], 330 mg, 0.36 mmol, 0.1 equivalents) were added to a stirred solution in a sealed tube under nitrogen at room temperature. The mixture was stirred at 90°C for 3.5 hours, and then saturated aqueous NaHCO3 and siRNA were added to the reaction mixture. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (80g; siRNA / heptane 0 / 100~10 / 90) to obtain intermediate 85 (2.6g, yield: 80%) as a yellow solid.

[0555] Intermediate 86:

[0556] [ka]

[0557] Anhydrous tetramethylammonium fluoride (CAS[373-68-2], 887 mg, 9.5 mmol, 1.5 equivalents) was added at room temperature to a solution of intermediate 85 (2.6 g, 6.3 mmol, 1.0 equivalent) in DMF (50 mL) in a sealed tube. The mixture was stirred at 65°C for 3 hours. After cooling, the reaction mixture was diluted with toluene and water. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (80 g; toluene / heptane 0 / 100~10 / 90) to obtain intermediate 86 (2.0 g, yield: 74%) as an orange oil.

[0558] Intermediate 87:

[0559] [ka]

[0560] Intermediate 11 (0.65 g, 1.59 mmol, 1.0 equivalent), intermediate 86 (0.65 g, 1.68 mmol, 1.06 equivalent), and K2CO3 (330 mg, 2.39 mmol, 1.5 equivalent) were dissolved in 1,4-dioxane (9 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 40 mg, 161.26 μmol, 0.1 equivalent) and Pd(OAc)2 (CAS[3375-31-3], 18 mg, 80.18 μmol, 0.05 equivalent) were added, and the reaction mixture was stirred at 120°C for 14 hours. After cooling, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO3 (×3). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25 g of SiO2, 0 / 100 to 100 / 0 siRNA / heptane) to obtain intermediate 87 (470 mg, yield: 52%) as a yellow oily substance.

[0561] Intermediate 88:

[0562] [ka]

[0563] HCl (4M in 1,4-dioxane, 4.1 mL, 16.4 mmol, 20 equivalents) was added to a solution of intermediate 87 (0.47 g, 0.83 mmol) in DCM (7 mL). The reaction mixture was stirred at room temperature for 2 hours, after which the solvent was evaporated. The crude product was pulverized with 1,4-dioxane and recovered by filtration to obtain intermediate 88 (390 mg, yield: 96%) as an orange solid.

[0564] Intermediate 89:

[0565] [ka]

[0566] 1,10-Phenanthroline (CAS[66-71-7], 132 mg, 0.72 mmol, 0.15 equivalents), Triphenylphosphine (CAS[603-35-0], 192 mg, 0.69 mmol, 0.15 equivalents), Potassium metabisulfite (CAS[16731-55-8], 2.17 g, 9.75 mmol, 2.2 equivalents), Sodium formate (CAS[141- 53-7) (739 mg, 10.87 mmol, 2.5 equivalents) and TBAB (CAS[1643-19-2], 1.75 g, 5.44 mmol, 1.25 equivalents) were added to a solution of 5-bromo-6-methyl-3-pyridinecarboxylate methyl ester (CAS[1174028-22-8], 1.0 g, 4.35 mmol, 1.0 equivalent) in DMSO (30 mL). The mixture was bubbling with nitrogen for 20 minutes. Palladium(II) acetate (CAS[3375-31-3], 55 mg, 0.24 mmol, 0.05 equivalents) was added, and the reaction mixture was stirred at 100°C for 3 hours. The temperature of the reaction mixture was cooled to room temperature. Next, 2-(3-bromopropoxy)tetrahydro-2H-pyran (CAS[33821-94-2], 0.9 mL, 5.35 mmol, 1.2 equivalents) was added, and the mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into water and extracted with DCM:MeOH(9:1) (x3). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (80 g SiO2; DCM:MeOH(9:1) in DCM 0 / 100~30 / 70) to obtain intermediate 89 (1045 mg, yield: 60%) as a brown oil.

[0567] Intermediate 90:

[0568] [ka]

[0569] Pyridinium p-toluenesulfonate (CAS[24057-28-1], 100 mg, 0.40 mmol, 0.4 equivalents) was added to a solution of intermediate 89 (350 mg, 0.98 mmol, 1.0 equivalent) in EtOH (5 mL) at room temperature, and the mixture was heated at 60 °C for 5 hours. The reaction mixture was cooled and concentrated. The crude product was purified by flash column chromatography (12 g of SiO2, DCM: MeOH (9:1) in DCM 0 / 100~30 / 70) to obtain intermediate 90 (171 mg, yield: 44%) as a yellow oily substance.

[0570] Intermediate 91:

[0571] [ka]

[0572] Dess-Martin periodinane (CAS[87413-09-0], 410 mg, 0.94 mmol, 1.5 equivalents) was gradually added to a stirred solution of intermediate 90 (171 mg, 0.63 mmol, 1.0 equivalent) in dry DCM (6 mL) under a nitrogen atmosphere at 0°C. The mixture was stirred at room temperature for 3 hours. DCM and saturated NaHCO3 aqueous solution were added, and the mixture was extracted with DCM (×3). The combined organic layer was dried over MgSO4, filtered, and concentrated to obtain intermediate 91 (165 mg, yield: 97%) as a colorless, viscous solid.

[0573] Intermediate 92:

[0574] [ka]

[0575] DAST (CAS[38078-09-0], 0.330 mL, 2.50 mmol, 4.0 equivalents) was added to a solution of intermediate 91 (165 mg, 0.61 mmol, 1.0 equivalent) in DCM (4 mL). The reaction mixture was stirred at 60°C for 3 hours. After cooling, water was added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with DCM (×3). The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (12 g SiO2, siRNA / heptane 0 / 100~40 / 60) to obtain intermediate 92 (85 mg, yield: 38%) as a white solid.

[0576] Intermediate 93:

[0577] [ka]

[0578] LiOH (37 mg, 0.88 mmol, 3.0 equivalents) was added at room temperature to a solution of intermediate 92 (85 mg, 0.29 mmol, 1.0 equivalent) in THF (2 mL) and H2O (1 mL). The reaction mixture was stirred at room temperature for 2 hours. SiO and HCl (1 M in water) were added to bring the pH to 2-3, and the mixture was extracted with SiO (×5). The combined organic layer was dried over MgSO4, filtered, and concentrated to obtain intermediate 93 (50 mg, yield: 51%) as a white solid.

[0579] Intermediate 94:

[0580] [ka]

[0581] Under a nitrogen atmosphere, 5-bromonicotinic acid (CAS[20826-04-4], 1 g, 4.95 mmol, 1.0 equivalent) was dissolved in dry THF (25 mL), the solution was cooled to -78°C and stirred for 10 minutes. n-butyllithium (1.6 M hexane, CAS[109-72-8], 6.19 mL, 9.90 mmol, 2.0 equivalents) was added dropwise, and the reaction mixture was stirred at -78°C for 20 minutes. Next, a solution of acetaldehyde (CAS[75-07-0], 0.56 mL, 9.90 mmol, 2.0 equivalents) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution. The layers were separated, and the organic layer was concentrated. The residue was ground with DCM:MeOH (9:1), filtered, and the filtrate was concentrated. The crude product was purified by reverse-phase column chromatography (Phenomenex Gemini C18 30×100mm 5μm; 95% [25mM NH4HCO3]-5% [ACN:MeOH 1:1]~28% [ACN:MeOH 1:1]~63% [25mM NH4HCO3]-37% [ACN:MeOH 1:1]) to obtain intermediate 94 (502 mg, yield: 57%) as a yellow oily substance.

[0582] Intermediate 95:

[0583] [ka]

[0584] Triethylamine (5.2 mL, 4.2 mmol, 2.0 equivalents) was added at room temperature to a stirred solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 600 mg, 2.1 mmol, 1.0 equivalent) and 4-(Boc-amino)-3,3-difluoropiperidine (CAS [1263180-22-8], 578 mg, 2.4 mmol, 1.15 equivalents) in toluene (14 mL). The mixture was stirred at 120 °C for 9 hours. The mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was washed with brine (×2), filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (25 g silica; ethyl acetate / heptane 0 / 100~40 / 60) to obtain intermediate 95 (311 mg, yield: 33%) as an orange solid.

[0585] Intermediate 96:

[0586] [ka]

[0587] Anhydrous tetramethylammonium fluoride (CAS[373-68-2], 100 mg, 1 mmol, 1.5 equivalents) was added in a sealed tube to a solution of intermediate 95 (311 mg, 0.71 mmol, 1.0 equivalent) in DMF (4 mL) at 65°C. The mixture was stirred for 3 hours. After cooling, the reaction mixture was diluted with siRNA (100 mL) and water (150 mL). The organic layer was separated, washed once with water (100 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (12 g SiO2, siRNA / heptane 0 / 100~30 / 70) to obtain intermediate 96 (202 mg, 68%) as a yellow oil.

[0588] Intermediate 97:

[0589] [ka]

[0590] Trifluoroacetic acid (1.33 mL, 17.4 mmol, 23.0 equivalents) was added at 0°C to a stirred solution of intermediate 11 (300 mg, 0.73 mmol, 1.0 equivalent) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and saturated Na2CO3 aqueous solution was added to pH 8. DCM was added, and the aqueous layer was extracted with DCM (×5). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain intermediate 97 (187 mg, yield 81%) as a yellow solid.

[0591] Intermediate 98:

[0592] [ka]

[0593] HATU (CAS[148893-10-1], 209 mg, 0.55 mmol, 1.25 equivalents) was added at room temperature to a solution of intermediate 97 (187 mg, 0.44 mmol, 1.0 equivalent), intermediate 171 (104 mg, 0.48 mmol, 1.15 equivalents), and DIPEA (0.3 mL, 1.71 mmol, 4.0 equivalents) in DMF (3 mL). The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of NaHCO3 and SiO2 were added to the reaction mixture. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (12 g of SiO2, DCM: 0% to 30% MeOH (9:1) in DCM), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30 × 100 mm 5 μm; 90% H2O (0.1% HCOOH) - 10% ACN-MeOH ~ 54% H2O (0.1% HCOOH) - 46% ACN-MeOH) to obtain intermediate 98 (162 mg, yield: 71%) as a yellow solid powder.

[0594] Intermediate 99:

[0595] [ka]

[0596] Intermediate 98 (148 mg, 0.3 mmol, 1.0 equivalent), intermediate 96 (120 mg, 0.3 mmol, 1.0 equivalent), and K2CO3 (60 mg, 0.44 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 11 mg, 0.04 mmol, 0.15 equivalents) and Pd(OAc)2 (CAS[3375-31-3], 6.5 mg, 0.03 mmol, 0.1 equivalents) were added, and the reaction mixture was stirred at 120°C for 14 hours. After cooling, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO3 (×3). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25 g of SiO2; Â / heptane 0 / 100~35 / 65) to obtain intermediate 99 (65 mg, yield: 32%) as a yellow solid.

[0597] Intermediate 100:

[0598] [ka]

[0599] Nitrogen was bubbled into a solution of 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 0.5 g, 1.77 mmol, 1.0 equivalent) and 5-azaspiro[2.4]heptan-7-ol hydrochloride (CAS[1152110-85-4], 0.26 g, 1.77 mmol, 1.0 equivalent) in 1,4-dioxane (8 mL) in a sealed tube. Next, Cs2CO3 (1.25 g, 3.84 mmol, 2.1 equivalents), DavePhos (CAS[213697-53-1], 0.076 mg, 0.19 mmol, 0.1 equivalent), and Pd2dba3 (CAS[51364-51-3], 0.083 mg, 0.090 mmol, 0.05 equivalents) were added. The mixture was stirred at 90°C for 3.5 hours. A saturated aqueous solution of NaHCO3 and siRNA were added to the reaction mixture. The organic layer was separated, dried over MgSO4, filtered, and concentrated. This crude product was purified by silica gel column (25 g; siRNA / heptane 0 / 100~10 / 90) to obtain intermediate 100 (337 mg, yield: 59%) as an orange solid.

[0600] Intermediate 101:

[0601] [ka]

[0602] To a solution of intermediate 100 (228 g, 0.72 mmol, 1.0 equivalent) in DCM (2 mL), benzoyl chloride (CAS[98-88-4], 123 μL, 1.0 mmol, 1.46 equivalents), Et3N (0.5 mL, 3.6 mmol, 5.0 equivalents), and 4-(dimethylamino)pyridine (CAS[1122-58-3], 15.7 mg, 0.13 mmol, 0.18 equivalents) were added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (12 g SiO2, siRNA / heptane 0 / 100~10 / 90) to obtain intermediate 101 (293 mg, yield: 91%) as a white solid.

[0603] Intermediate 102:

[0604] [ka]

[0605] Tetramethylammonium fluoride (CAS[373-68-2], 97 mg, 1.0 mmol, 1.42 equivalents) was added in a sealed tube to a solution of intermediate 101 (293 mg, 0.7 mmol, 1.0 equivalent) in DMF (4 mL) at 65°C. The mixture was stirred for 3 hours. After cooling, the reaction mixture was diluted with siRNA and water. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (12 g SiO2; siRNA / heptane 0 / 100~30 / 60) to obtain intermediate 102 (222 mg, yield: 80%) as a yellow oil.

[0606] Intermediate 103:

[0607] [ka]

[0608] Intermediate 11 (338 mg, 0.82 mmol, 1.0 equivalent), intermediate 102 (323 mg, 0.82 mmol, 1.0 equivalent), and K2CO3 (171 mg, 1.23 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (9 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 30 mg, 0.1 mmol) and Pd(OAc)2 (CAS[3375-31-3], 18 mg, 0.083 mmol, 0.1 equivalent) were added, and the reaction mixture was stirred at 120°C for 14 hours. After cooling, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25 g of SiO2, heptane / Â0 / 100~35 / 65) to obtain intermediate 103 (235 mg, yield: 49%) as a yellow solid.

[0609] Intermediate 104:

[0610] [ka]

[0611] Trifluoroacetic acid (0.75 mL, 9.8 mmol, 24.0 equivalents) was added at 0°C to a stirred solution of intermediate 103 (235 mg, 0.41 mmol, 1.0 equivalent) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and saturated Na2CO3 aqueous solution was added to pH 8. DCM was added, and the aqueous layer was extracted with DCM (×5). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain intermediate 104 (195 mg, yield 98%) as a yellow solid.

[0612] Intermediate 105:

[0613] [ka]

[0614] Intermediate 104 (195 mg, 0.33 mmol, 1.0 equivalent), intermediate 171 (79 mg, 0.36 mmol, 1.1 equivalent), and DIPEA (0.23 mL, 1.33 mmol, 3.7 equivalents) were dissolved in DMF (3 mL). HATU (CAS[148893-10-1], 158 mg, 0.41 mmol, 1.24 equivalents) was added at room temperature, and the reaction mixture was stirred for 2 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO2. The organic layer was separated, dried, filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (12 g column, DCM: MeOH(9:1) 0%~30% in DCM) to obtain intermediate 105 (117 mg, yield: 52%) as a yellow solid.

[0615] Intermediate 106:

[0616] [ka]

[0617] Iodomethane (CAS[74-88-4], 866 mg, 6.1 mmol, 1.0 equivalent) was added at 0°C to a stirred solution of 2,6-dichloro-3H-pyrimidine-4-one (CAS[120977-94-8], 1.0 g; 6.1 mmol, 1.0 equivalent) and K2CO3 (1.68 g; 12.1 mmol, 2.0) in DMF (20 mL). The mixture was stirred at 0°C for 2 hours. The mixture was diluted with water and extracted with siRNA. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (25 g silica; siRNA / heptane 0 / 100~50 / 50) to obtain intermediate 106 (732 mg, yield: 67%) as a white solid.

[0618] Intermediate 107:

[0619] [ka]

[0620] 2,2,6,6-Tetramethylmorpholine (CAS[19151-69-0], 234 mg, 1.64 mmol, 0.8 equivalents) was added to a stirred solution of intermediate 106 (366 mg, 2.045 mmol, 1.0 equivalent) and DIPEA (1.014 mL, 6.14 mmol, 3.0 equivalents) in DMSO (2 mL). The mixture was stirred at 130 °C for 16 hours. The mixture was diluted with water and extracted with SiO(×3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (24 g silica; SiO / heptane 0 / 100~70 / 30) to obtain intermediate 107 (350 mg, yield: 59%) as a yellow solid.

[0621] Intermediate 108:

[0622] [ka]

[0623] Intermediate 11 (200 mg, 0.5 mmol, 1.0 equivalent), intermediate 107 (139 mg, 0.48 mmol, 0.96 equivalents), and K2CO3 (101 mg, 0.73 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 18 mg, 0.07 mmol, 0.14 equivalents) and Pd(OAc)2 (CAS[3375-31-3], 11 mg, 0.07 mmol, 0.07 equivalents) were added, and the reaction mixture was stirred at 120°C for 14 hours. After cooling, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO3 (×3). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25 g of SiO2, siRNA / heptane 0 / 100~35 / 65) to obtain intermediate 108 (106 mg, yield: 42%) as a yellow solid.

[0624] Intermediate 109:

[0625] [ka]

[0626] Trifluoroacetic anhydride (0.31 mL, 4.1 mmol, 20.0 equivalents) was added at 0°C to a stirred solution of intermediate 108 (106 mg, 0.2 mmol, 1.0 equivalent) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and saturated Na2CO3 aqueous solution was added to pH 8. DCM was added, and the aqueous layer was extracted with DCM (×5). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain intermediate 109 (78 mg, yield: 90%) as a yellow solid.

[0627] Intermediate 110:

[0628] [ka]

[0629] Cis-2,6-dimethylmorpholine (CAS[6485-55-8], 0.201 mL, 1.64 mmol, 0.8 equivalents) was added to a stirred solution of intermediate 106 (366 mg, 2.045 mmol, 1.0 equivalent) and DIPEA (1.014 mL, 6.14 mmol) in DMSO (2 mL). The mixture was stirred at 130 °C for 16 hours. The mixture was diluted with water and extracted with SiO(×3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (24 g silica; SiO / heptane 0 / 100~70 / 30) to obtain intermediate 110 (384 mg, yield: 72%) as a yellow solid.

[0630] Intermediate 111:

[0631] [ka]

[0632] Intermediate 11 (200 mg, 0.49 mmol, 1.0 equivalent), intermediate 110 (126 mg, 0.49 mmol, 1.0 equivalent), and K2CO3 (101 mg, 0.73 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 18 mg, 0.07 mmol, 0.14 equivalents) and Pd(OAc)2 (CAS[3375-31-3], 11 mg, 0.05 mmol, 0.1 equivalents) were added, and the reaction mixture was stirred at 120°C for 14 hours. After cooling, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO3 (×3). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (12 g of SiO2, siRNA / heptane 0 / 100~20 / 80) to obtain intermediate 111 (83 mg, yield: 35%) as a yellow solid.

[0633] Intermediate 112:

[0634] [ka]

[0635] Trifluoroacetic acid (0.27 mL, 3.59 mmol, 20.0 equivalents) was added to a stirred solution of intermediate 111 (80 mg, 0.17 mmol, 1.0 equivalent) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and saturated NaHCO3 aqueous solution was added to bring the pH to 8. DCM was added, and the aqueous layer was extracted with DCM (3 times). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain intermediate 112 (68 mg, yield: 96%) as a beige solid.

[0636] Intermediate 113:

[0637] [ka]

[0638] (2R,6S)-Rel-2-methyl-6-(trifluoromethyl)-morpholine hydrochloride (1:1) (CAS [2417329-59-8], 260 mg, 1.54 mmol, 1.0 equivalent) was added to a stirred solution of intermediate 106 (344 mg, 1.9 mmol, 1.23 equivalents) and DIPEA (0.95 mL, 5.7 mmol, 3.7 equivalents) in DMSO (2 mL). The mixture was stirred at 130 °C for 16 hours. The mixture was diluted with water and extracted with SiO(×3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 24 g; SiO / heptane 0 / 100~70 / 30) to obtain intermediate 113 (264 mg, 35%) as a yellow solid.

[0639] Intermediate 114:

[0640] [ka]

[0641] Intermediate 11 (145 mg, 0.35 mmol, 1.0 equivalent), intermediate 113 (110 mg, 0.35 mmol, 1.0 equivalent), and K2CO3 (73 mg, 0.53 mmol, 1.5 equivalents) were dissolved in 1,4-dioxane (5 mL) in a sealed tube under a nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 14 mg, 0.05 mmol, 0.14 equivalents) and Pd(OAc)2 (CAS[3375-31-3], 8 mg, 0.03 mmol, 0.085 equivalents) were added, and the reaction mixture was stirred at 120°C for 14 hours. The mixture was cooled to room temperature, diluted with saturated NaHCO3 aqueous solution, and extracted with SiO3 (×3). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (heptane gradient 0% to 35% in 25 g of SiO2, siRNA) to obtain intermediate 114 (90 mg, yield: 47%) as a yellow solid.

[0642] Intermediate 115:

[0643] [ka]

[0644] Trifluoroacetic acid (0.26 mL, 3.3 mmol, 20.0 equivalents) was added at 0°C to a stirred solution of intermediate 114 (90 mg, 0.17 mmol, 1.0 equivalent) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and saturated Na2CO3 aqueous solution was added to pH 8. DCM was added, and the aqueous layer was extracted with DCM (×5). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain intermediate 115 (60 mg, yield: 81%).

[0645] Intermediate 116:

[0646] [ka]

[0647] Tert-butyl N-(3,3-difluoropiperidine-4-yl)carbamate (CAS[1263180-22-8], 0.217 g, 0.92 mmol, 2.0 equivalents) was added to a solution of intermediate 190 (0.215 g, 0.46 mmol, 1.0 equivalent) and DIPEA (0.227 mL, 1.38 mmol, 1.5 equivalents) in DMSO (1 mL). The mixture was stirred at 120 °C for 3 hours. After cooling, the reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO4 and concentrated. The crude product was ground with ACN, and the solid was recovered by filtration to obtain intermediate 116 (203 mg, yield: 65%) as a beige solid.

[0648] Intermediate 117:

[0649] [ka]

[0650] Sodium hydride (60% in mineral oil, 139 mg, 3.47 mmol, 0.8 equivalents) was added to a stirred solution of (L)-proline (CAS[147-85-3], 398 mg, 3.46 mmol, 0.8 equivalents) in DMSO (30 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Then, methyl 5-bromo-6-hydroxynicotinate (CAS[381247-99-0], 1.0 g, 4.3 mmol, 1.0 equivalent), sodium methanesulfinate (CAS[20277-69-4], 3.51 g, 34.4 mmol, 8.0 equivalents), and copper iodide (658 mg, 3.45 mmol, 0.8 equivalents) were added, and the mixture was stirred at 120°C for 4 hours. After cooling, the mixture was diluted with water and extracted with RINKAN. The organic layer was washed with brine (x2), and the solvent was evaporated. The crude product was purified by flash column chromatography (12 g of SiO2; DCM: 0%-20% MeOH (9:1) in DCM) to obtain intermediate 117 (478 mg, yield: 47%) as a white solid.

[0651] Intermediate 118:

[0652] [ka]

[0653] Iodomethane (CAS[74-88-4], 441 mg, 3.1 mmol, 3.6 equivalents) and silver carbonate (CAS[534-16-7], 310 mg, 1.1 mmol, 1.25 equivalents) were added at room temperature to a stirred solution of intermediate 117 (200 mg, 0.86 mmol, 1.0 equivalent) in CHCl3. The mixture was stirred at 50°C for 2 days. The mixture was cooled, filtered, and concentrated. The crude product was purified by flash column chromatography (25 g silica; siRNA / heptane 0 / 100~30 / 70) to obtain intermediate 118 (50 mg, 23%) as a white solid, and its N-alkylated isomer (130 mg, 60%) as a white solid.

[0654] Intermediate 119:

[0655] [ka]

[0656] NaOH (1M in water, 0.4 mL, 0.4 mmol, 2.0 equivalents) was added to a solution of intermediate 118 (50 mg, 0.2 mmol, 1.0 equivalent) in MeOH (1.2 mL), and the reaction mixture was stirred at room temperature for 16 hours. KHSO4 (1M in water, 1.4 mL) was added dropwise over 10 minutes with vigorous stirring. The pH reached a value of 2-3. This solution was concentrated to obtain intermediate 119 (45 mg, yield: 95%, crude) as a white solid, which was used in the next step without further purification.

[0657] Intermediate 120:

[0658] [ka]

[0659] Pyrrole-3-carboxylic acid (CAS[931-03-3], 3g, 27 mmol, 1 equivalent) and 1,1-bis-(1,1-dimethylethoxy)-N,N,N,triethylamine (CAS[36805-97-7], 26 mL, 108 mmol, 1 equivalent) were dissolved in toluene (57 mL) at room temperature. The mixture was stirred at 85°C for 16 hours. The solvent was removed under vacuum. The residue was diluted in toluene and washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with toluene (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (80 g SiO2; toluene / heptane 0 / 100~30 / 70) to obtain intermediate 120 (1.78 g, yield: 39%) as a white solid.

[0660] Intermediate 121:

[0661] [ka]

[0662] N-chlorosuccinimide (CAS[128-09-6], 2.8 g, 20.9 mmol, 2 equivalents) was added to a stirred solution of intermediate 120 (1.75 g, 10.5 mmol, 1 equivalent) in ACN (20 mL). The mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with water (10 mL) and extracted with siRNA. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g SiO2; siRNA / heptane 0 / 100~10 / 90) to obtain intermediate 121 (370 mg, yield: 14%) as a white solid.

[0663] Intermediate 122:

[0664] [ka]

[0665] Isopropylsulfonyl chloride (CAS[1310-66-3], 0.64 mL, 2.3 mmol, 1.5 equivalents) was added at room temperature to a stirred solution of intermediate 121 (370 mg, 1.6 mmol, 1 equivalent) and KHDMS (CAS[40949-94-8], 4.7 mL, 4.7 mmol, 3 equivalents) in dry THF (5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate. The organic layer was washed with brine (5 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (12 g SiO2; ethyl acetate / heptane 0 / 100~80 / 20). The desired fraction was collected and concentrated under vacuum to obtain intermediate 122 (362 mg, yield: 64%) as a colorless oil.

[0666] Intermediate 123:

[0667] [ka]

[0668] HCl (4M in 1,4-dioxane, CAS [7647-01-0], 7.9 mL, 31.6 mmol, 30 equivalents) was added dropwise to a stirred solution of intermediate 122 (360 mg, 1 mmol) in 1,4-dioxane (5 mL) at room temperature, and the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under vacuum to obtain intermediate 123 (300 mg, yield: 99%) as a white solid.

[0669] Intermediate 124:

[0670] [ka]

[0671] N-chlorosuccinimide (CAS[128-09-6], 77 mg, 0.58 mmol, 1.5 equivalents) was added at 0°C to a solution of intermediate 47 (227 mg, 0.387 mmol, 1 equivalent) in 1,1,1,3,3,3-hexafluoro-2-propanol (CAS[920-66-1], 11 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with SiO2. The organic layer was washed with water and saturated aqueous NaS2O3 solution, dried over MgSO4, filtered, and the solvent was concentrated under vacuum. The crude product was purified by flash column chromatography (25 g SiO2, 0-3% MeOH in DCM) to obtain intermediate 124 (172 mg, yield: 72%) as an orange powder.

[0672] Intermediate 125:

[0673] [ka]

[0674] NaOH (2.5 M in water, 2.8 mL, 2.0 mmol, 18 equivalents) was added at room temperature to a solution of intermediate 124 (172 mg, 0.28 mmol, 1 equivalent) in THF (3 mL). The mixture was stirred at 75 °C for 16 hours. The mixture was diluted with water (10 mL) and extracted with SiO (20 mL). Na2CO3 (1 M in water) was added to adjust the pH to 10. The aqueous layer was extracted with SiO (2 x 20 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under vacuum to obtain intermediate 125 (112 mg, yield 78%) as a yellow powder.

[0675] Intermediate 126:

[0676] [ka]

[0677] HCl (4M in 1,4-dioxane, 0.92 mL, 3.7 mmol, 20 equivalents) was added at room temperature to a solution of intermediate 125 (112 mg, 0.184 mmol, 1 equivalent) in 1,4-dioxane (2 mL). The mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum to obtain intermediate 126 (97 mg, yield: 99%) as an orange solid.

[0678] Intermediate 127:

[0679] [ka]

[0680] 1,10-Phenanthroline (CAS[66-71-7], 132 mg, 0.73 mmol, 0.17 equivalents), Triphenylphosphine (CAS[603-35-0], 192 mg, 0.69 mmol, 0.16 equivalents), Potassium metabisulfite (CAS[16731-55-8], 2.17 g, 9.7 mmol, 2.2 equivalents), Sodium formate (CAS[1 739 mg, 10.9 mmol, 2.5 equivalents of [41-53-7] and 1.75 g, 5.4 mmol, 1.2 equivalents of TBAB (CAS[1643-19-2]) were added to a solution of 5-bromo-6-methyl-3-pyridinecarboxylate methyl ester (CAS[1174028-22-8], 1 g, 4.35 mmol, 1 equivalent) in DMSO (30 mL). The mixture was bubbling with nitrogen for 20 minutes. Then, palladium(II) acetate (CAS[3375-31-3], 55 mg, 0.24 mmol, 0.06 equivalents) was added, and the reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature. Finally, 2-(2-bromoethoxy)tetrahydro-2H-pyran (CAS[17739-45-6], 0.8 mL, 5.35 mmol, 1.2 equivalents) was added, and the mixture was stirred at 60°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (x2) and brine (x2), then dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (24 g SiO2; ethyl acetate / heptane 0 / 100~50 / 50) to obtain intermediate 127 (456 mg, yield: 30%) as a yellow solid.

[0681] Intermediate 128:

[0682] [ka]

[0683] HCl (4M in 1,4-dioxane, 3.32 mL, 13.3 mmol, 10 equivalents) was added at room temperature to a solution of intermediate 127 (456 mg, 1.3 mmol, 1 equivalent) in 1,4-dioxane (8 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 128 (400 mg, yield: 96%) as a yellow solid.

[0684] Intermediate 129:

[0685] [ka]

[0686] An aqueous solution of NaOH (1 M, 3.8 mL, 3.84 mmol, 3 equivalents) was added to a stirred solution of intermediate 128 (400 mg, 1.28 mmol, 1 equivalent) in THF (10 mL). The mixture was stirred at room temperature for 72 hours. The mixture was diluted with water and extracted with SiO2. The aqueous layer was acidified to pH=1 with HCl (1 M in water) and extracted with SiO2 (twice). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 129 (220 mg, yield: 67%) as a white solid.

[0687] Intermediate 130:

[0688] [ka]

[0689] HATU (CAS[148893-10-1], 4.97 g, 13.0 mmol, 1.5 equivalents) was added at room temperature to a stirred solution of methyl 2-(benzylamino)propanoate hydrochloride (CAS[16975-44-3], 2.0 g, 8.7 mmol, 1 equivalent), 1-(Z-amino)cyclopropanecarboxylic acid (CAS[84677-06-5], 2.7 g, 8.7 mmol, 1 equivalent), and DIPEA (4.6 mL, 26.1 mmol, 3 equivalents) in DCM (45 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with SiO2. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (80 g of SiO2; Â / heptane 0 / 100-50%) to obtain intermediate 130 (3.8 g, yield: 66%) as a white solid.

[0690] Intermediate 131:

[0691] [ka]

[0692] Carbon-supported palladium (CAS[7440-05-3], 128 mg, 0.6 mmol, 0.1 equivalent) was added to a stirred solution of intermediate 130 (3.8 g, 6.0 mmol, 1 equivalent) in EtOH (10 mL) under a nitrogen atmosphere. The mixture was purged using vacuum and hydrogen. The mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered through a short pad of Celite. The filtrate was evaporated, and the crude product was purified by flash column chromatography (80 g SiO2; siRNA / heptane 0 / 100~100 / 0) to obtain intermediate 131 (1.7 g, yield: 80%) as a white solid.

[0693] Intermediate 132:

[0694] [ka]

[0695] A borane-methyl sulfide complex (CAS[13292-87-0], 13.1 mL, 26.2 mmol, 3 equivalents) was added at room temperature to a solution of intermediate 131 (2.7 g, 8.7 mmol, 1 equivalent) in THF (15 mL). The reaction mixture was stirred under reflux for 16 hours. The reaction mixture was cooled to 0°C and quenched with MeOH. The reaction mixture was then stirred at 70°C for 6 hours. The mixture was concentrated under vacuum, and the residue was purified by flash column chromatography (25 g SiO2, 0-5% MeOH in DCM) to obtain intermediate 132 (980 mg, yield: 50%) as a white solid.

[0696] Intermediate 133:

[0697] [ka]

[0698] Ditert-butyl dicarbonate (CAS[24424-99-5], 2.5 mL, 12.8 mmol) was added to a stirred solution of intermediate 132 (980 mg, 4.5 mmol) and Et3N (2.5 mL, 18.9 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (12 g SiO2, siRNA / heptane 0 / 100~60 / 40) to obtain intermediate 133 (1.25 g, yield: 86%) as a white solid.

[0699] Intermediate 134:

[0700] [ka]

[0701] 42 mg, 0.15 mmol, 0.1 equivalent of carbon-supported palladium (CAS[1314-15-4]) was added to a stirred solution of intermediate 133 (1.25 g, 3.9 mmol, 1 equivalent) in MeOH (15 mL) under a nitrogen atmosphere. The mixture was purged using vacuum and hydrogen. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered through a Celite pad, and the filtrate was evaporated under vacuum to obtain intermediate 134 (835 mg, yield: 93%) as a yellow oil.

[0702] Intermediate 135:

[0703] [ka]

[0704] DavePhos (CAS[213697-53-1], 81 mg, 0.21 mmol, 0.1 equivalent) and Pd2dba3 (CAS[51364-51-3], 94 mg, 0.10 mmol, 0.05 equivalent) were added to a stirred solution of 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 580 mg, 2 mmol, 1 equivalent), intermediate 134 (489 mg, 2.16 mmol, 1.05 equivalent), and Cs2CO3 (CAS[534-17-8], 1.4 g; 4.5 mmol, 2.2 equivalents) in 1,4-dioxane (8 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at 100 °C for 16 hours. The mixture was diluted with H2O and extracted with siRNA. The organic layer was washed with brine (×2), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (12 g; siRNA / heptane 0 / 100~20 / 80) to obtain intermediate 135 (322 mg, yield: 36%) as an orange oil.

[0705] Intermediate 136:

[0706] [ka]

[0707] Tetramethylammonium fluoride (CAS[373-68-2], 84 mg, 0.9 mmol, 1.2 equivalents) was added at room temperature to a solution of intermediate 135 (320 mg, 0.75 mmol, 1 equivalent) in dry DMF (3 mL). The mixture was stirred at 65 °C for 3 hours. The mixture was diluted with siRNA and washed with brine. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g SiO₂, siRNA / heptane 0 / 100~20 / 80) to obtain intermediate 136 (259 mg, yield: 84%) as an orange oil.

[0708] Intermediate 137:

[0709] [ka]

[0710] Pd(OAc)2 (CAS[3375-31-3], 14 mg, 0.06 mmol, 0.06 equivalents) and di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 31 mg, 0.128 mmol, 0.12 equivalents) were added under a nitrogen atmosphere to a solution of intermediate 11 (497 mg, 1.09 mmol, 1 equivalent), intermediate 136 (525 mg, 1.3 mmol, 1.2 equivalents), and K2CO3 (265 mg, 1.9 mmol, 1.8 equivalents) in 1,4-dioxane (4 mL). The mixture was stirred at 120 °C for 16 hours. The mixture was diluted with H2O and extracted with AcOEt. The organic layer was washed with brine (×2), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (24 g of SiO2; siRNA / heptane 0 / 100~70 / 30) to obtain intermediate 137 (336 mg, yield: 52%) as an orange oily substance.

[0711] Intermediate 138:

[0712] [ka]

[0713] HCl (4M in 1,4-dioxane, 1.45 mL, 5.8 mmol, 10 equivalents) was added at room temperature to a solution of intermediate 137 (336 mg, 0.580 mmol) in 1,4-dioxane (1.5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum to obtain intermediate 138 (260 mg, yield: 98%) as an orange solid.

[0714] Intermediate 139:

[0715] [ka]

[0716] Intermediate 6 (100 mg, 0.237 mmol) was added at room temperature to a stirred solution of 4-acetyl picolinic acid (CAS[20857-22-1], 47 mg, 0.284 mmol, 1.2 equivalents), HATU (CAS[94790-37-1], 135 mg, 0.655 mmol, 1.5 equivalents), and DIPEA (CAS[7087-68-5], 0.207 mL, 1.184 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO2. The organic phase was separated, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography column (12 g silica, siRNA / heptane, 0%~95%) and reversed phase (stationary phase: Phenomenex Gemini C18 (100 × 30 mm, 5 μm); mobile phase: gradient of 59% [25 mM NH4HCO3]-41% [ACN:MeOH (1:1)] to 17% [25 mM NH4HCO3]-83% [ACN:MeOH (1:1)]) to obtain intermediate 139 (4 mg, yield: 3%) as a yellow solid.

[0717] Intermediate 140:

[0718] [ka]

[0719] To a stirred solution of methyl-6-hydroxynicotinate (CAS[66171-50-4], 200 mg, 1.3 mmol) in CHCl3, iodomethane (CAS[74-88-4], 0.29 mL, 4.7 mmol, 3.6 equivalents) and silver carbonate (CAS[534-16-7], 468 mg, 1.7 mmol, 1.3 equivalents) were added at room temperature. The mixture was stirred at room temperature for 72 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g SiO2; ethyl acetate / heptane 0 / 100~30 / 70) to obtain intermediate 140 (135 mg, yield: 61%) as a white solid.

[0720] Intermediate 141:

[0721] [ka]

[0722] Sodium hydroxide (2.3 mL, 2.35 mmol) was added at room temperature to a stirred solution of intermediate 140 (130 mg, 0.78 mmol) in MeOH (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with SiO2. The aqueous layer was acidified to pH=1 with HCl (1 M in water) and then extracted with SiO2 (×2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 141 (102 mg, yield: 84%) as a white solid.

[0723] Intermediate 142:

[0724] [ka]

[0725] Sodium hydride (60% in mineral oil, 141 mg, 3.5 mmol) was added to a stirred solution of methyl-6-hydroxynicotinate (CAS[66171-50-4], 200 mg, 1.3 mmol) in ACN (4 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 20 minutes. Then, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (CAS[1717-59-5], 0.23 mL, 2.22 mmol) was added dropwise. The heterogeneous mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (12 g SiO2, ethyl acetate / heptane 0 / 100~20 / 80) to obtain intermediate 142 (150 mg, yield: 56%) as a white solid.

[0726] Intermediate 143:

[0727] [ka]

[0728] An aqueous solution of NaOH (1 M, 2.2 mL, 2.2 mmol, 3 equivalents) was added at room temperature to a stirred solution of intermediate 142 (150 mg, 0.74 mmol, 1 equivalent) in MeOH (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with SiO2. The aqueous layer was acidified to pH=1 with HCl (1 M in water) and then extracted with SiO2 (×2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 143 (115 mg, yield: 66%) as a white solid.

[0729] Intermediate 144:

[0730] [ka]

[0731] DIAD (CAS[2446-83-5], 0.39 mL, 1.96 mmol, 1.5 equivalents) dissolved in dry THF (1 mL) is mixed with methyl 6-hydroxynicotinate (CAS[66171-50-4], 200 mg, 1.3 mmol, 1 equivalent), 2-((tert-butyldimethylsilyl)oxy)ethanol (CAS[102229-10-7], 0.38 mL, 1.96 mmol, 1.5 equivalents), and triphenylphosphine (CAS[603 [-35-0] (514 mg, 1.96 mmol, 1.5 equivalents) was added dropwise to a stirred solution under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g SiO2; AcOEt / heptane 0 / 100~30 / 70) to obtain intermediate 144 (165 mg, yield: 40%) as a white solid.

[0732] Intermediate 145:

[0733] [ka]

[0734] Intermediate 145 was prepared using intermediate 144 instead of intermediate 142, following the same procedure as for intermediate 143.

[0735] Intermediate 146:

[0736] [ka]

[0737] HATU (CAS[148893-10-1], 195 mg, 0.48 mmol, 1.5 equivalents) was added at room temperature to a stirred solution of intermediate 145 (95 mg, 0.32 mmol, 1 equivalent), intermediate 6 (140 mg, 0.32 mmol, 1 equivalent), and DIPEA (0.24 mL, 1.28 mmol, 4 equivalents) in DCM (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, extracted with DCM, and washed with brine (×2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g SiO2; siRNA / heptane 0 / 100~100 / 0) to obtain intermediate 146 (165 mg, 82%) as a yellow solid.

[0738] Intermediate 147:

[0739] [ka]

[0740] A mixture of 2-chloro-6-methyl-4-pyridinecarboxylate methyl ester (CAS[3998-90-1], 8.4 g, 45.26 mmol), 2-mercaptoethanol ([CAS60-24-2], 3.8 mL, 54.18 mmol), potassium carbonate (8.8 g, 63.67 mmol), and dry acetone (266 mL) was refluxed for 36 hours, cooled to room temperature, and filtered. The filtrate was concentrated under vacuum, the residue was dissolved in Et2O, and washed with brine. The organic layer was concentrated, and the crude product was purified by flash column chromatography (120 g of SiO2; siRNA / heptane 0 / 100~45 / 55) to obtain intermediate 147 (0.86 g, yield: 7%) as a yellow solid.

[0741] Intermediate 148:

[0742] [ka]

[0743] TBDMSCl (CAS[18162-48-6], 684 mg, 4.54 mmol) was added in one go at 5°C to a solution of intermediate 147 (860 mg, 2.27 mmol) and imidazole (CAS[288-32-4], 355 mg, 5.2 mmol) in THF (12 mL). The mixture was stirred at room temperature for 20 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and Et2O. The layers were separated and the organic layer was evaporated. The crude product was purified by silica gel flash column chromatography (25 g; siRNA / DCM0 / 100~5 / 95) to obtain intermediate 148 (640 mg, yield: 78%) as an oil.

[0744] Intermediate 149:

[0745] [ka]

[0746] A solution of mCPBA (CAS[937-14-4], 0.846 g, 3.77 mmol) in DCM (18 mL) was added dropwise to a solution of intermediate 148 (640 mg, 1.87 mmol) in DCM (8 mL) over 10 minutes at 5°C. After the addition, the mixture was stirred at room temperature for 22 hours. A further mCPBA (218 mg, 0.97 mmol) in DCM (3 mL) was added dropwise over 10 minutes at 5°C, and the mixture was stirred at room temperature for 22 hours. The reaction was quenched by the addition of saturated NaHCO3 aqueous solution. The mixture was extracted with DCM. The organic layer was concentrated, and the crude product was purified by flash column chromatography (12 g of SiO2; siRNA / heptane 0 / 100~10 / 100) to obtain intermediate 149 (92 mg, yield: 13%) as an oil.

[0747] Intermediate 150:

[0748] [ka]

[0749] A solution of intermediate 149 (92 mg, 0.25 mmol) in a mixture of THF (1.3 mL), water (1.3 mL), and acetic acid (2.5 mL, 43.71 mmol) was stirred at room temperature for 3 days. The solvent was evaporated to obtain intermediate 150 (65 mg, yield: 79%) as an oily substance, which was used without further purification.

[0750] Intermediate 151:

[0751] [ka]

[0752] NaOH (1 M in water, 0.4 mL, 0.4 mmol) was added to a solution of intermediate 150 (64 mg, 0.25 mmol) in MeOH (1 mL), and the mixture was stirred at room temperature for 2 hours. KHSO4 (1 M in water, 0.5 mL) was added, and the mixture was stirred for 2 minutes. Then, it was concentrated under vacuum to obtain intermediate 151 (62 mg, yield: 71%) as a yellow solid, which was used without further purification.

[0753] Intermediate 152 and Intermediate 153:

[0754] [ka]

[0755] 5-(1-hydroxyethyl)-3-pyridinecarboxylic acid (CAS[1507931-60-3]) was separated into its stereoisomers by SFC (i-amylose-1; isocratic 10%[MeOH+0.1% DEA]-90%[CO2]), yielding intermediates 152 and 153, both as brown oily substances.

[0756] Intermediate 154:

[0757] [ka]

[0758] A solution of 1-propanephosphonic acid anhydride (CAS [68957-94-8], 50% in ethyl acetate, 5.57 mL, 9.35 mmol) was added dropwise at room temperature to a suspension of intermediate 10 (2 g, 5.5 mmol), intermediate 171 (1.42 g, 6.6 mmol), and Et3N (5.5 mL, 39.6 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 3 hours. The resulting solid was filtered, washed with DCM, and dried under vacuum to obtain intermediate 154 (1.03 g, yield: 40%) as a brown solid, which was used without further purification.

[0759] Intermediate 155:

[0760] [ka]

[0761] A suspension of intermediate 154 (100 mg, 0.213 mmol), 1,2-diamino-2-methylpropane (CAS[811-93-8], 67 μL, 0.638 mmol, 3 equivalents), and DIPEA (110 μL, 0.638 mmol, 3 equivalents) in dry DMSO (1 mL) was introduced into a thick-walled vial. The vial was sealed, and the reaction mixture was stirred at 130 °C for 24 hours. The reaction mixture was diluted with water and DCM. The layers were separated, and the aqueous layer was extracted again with DCM. The combined organic layers were dried by filtration through Extrelut NT3 and evaporated to obtain intermediate 155 (110 mg, yield: 90%), which was used without further purification.

[0762] Intermediate 156:

[0763] [ka]

[0764] Intermediate 3 (5 g, 17.021 mmol) and Na2CO3 (7.2 g, 68.1 mmol) were added to a stirred solution of phenylboronic acid (CAS[98-80-6], 6.2 g, 51.1 mmol) in 1,4-dioxane (240 mL) at room temperature under a nitrogen atmosphere. Then, Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 697 mg, 0.8 mmol) was added, and the mixture was stirred at 85°C for 16 hours under a nitrogen atmosphere. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2 350 g; heptane / siRNA 100 / 0~0 / 100) to obtain intermediate 156 (3.507 g, yield: 49%) as a sticky paste.

[0765] Intermediate 157:

[0766] [ka]

[0767] Intermediate 156 (3.507 g, 10.456 mmol) was dissolved in HCl (6 M in iPrOH, 34.8 mL, 209.12 mmol), and the resulting mixture was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure to obtain intermediate 157 (HCl salt, 2.965 g, yield: 92%) as a beige solid, which was used without further purification.

[0768] Intermediate 158:

[0769] [ka]

[0770] 5-Bromo-6-methylnicotinic acid (CAS[1190862-72-6], 282 mg, 1.308 mmol), HATU (CAS[148893-10-1], 497 mg, 1.308 mmol), and DIPEA (1.145 mL, 6.539 mmol) were combined in anhydrous DMF (3 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 minute. Then, intermediate 6 (500 mg, 1.09 mmol) was added all at once, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water. The resulting solid was filtered and washed with water to obtain intermediate 158 (556 mg, yield: 93%) as a yellowish-brown solid, which was used without further purification.

[0771] Intermediate 159:

[0772] [ka]

[0773] Diisopropyl azodicarboxylate (CAS[2446-83-5], 4.5 mL, 22.9 mmol, 2.14 equivalents) was added to a mixture of 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-ol (CAS[20931-50-4], 2.2 g, 13.8 mmol, 1.28 equivalents), 6-chloro-3-hydroxypyridazine (CAS[19064-67-6], 1.4 g, 10.7 mmol), Et3N (1.9 mL, 13.8 mmol, 1.28 equivalents), and triphenylphosphine (CAS[603-35-0], 6.4 g, 22.9 mmol, 2.14 equivalents) in dry THF (65 mL). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under vacuum, and the crude product was suspended in heptane / Â(5:1v / v). The precipitate was filtered off, and the filtrate was concentrated to dryness. The crude product was purified by flash column chromatography (120 g silica; Â / heptane 0 / 100~20 / 80) to obtain intermediate 159 (379 mg, yield: 13%) as a white solid.

[0774] Intermediate 160:

[0775] [ka]

[0776] A solution of intermediate 159 (376 mg, 1.4 mmol) and thiourea (CAS[62-56-6], 159 mg, 2.1 mmol, 1.5 equivalents) in methyl ethyl ketone (CAS[78-93-3], 5 mL) was stirred at 90°C for 16 hours. The mixture was cooled to room temperature, diluted with water, and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (40 g silica; 0% to 15% siRNA / heptane), followed by reversed-phase column chromatography (Phenomenex Gemini C18 100×30 mm 5 μm; gradient of 72% [25 mM NH4HCO3]-28% ACN to 36% [25 mM NH4HCO3]-64% ACN) to obtain intermediate 160 (159 mg, yield: 41%) as a yellow solid.

[0777] Intermediate 161:

[0778] [ka]

[0779] H2O2 (30% aqueous solution, 0.030 mL, 0.3 mmol, 0.5 equivalents) was added dropwise to a solution of intermediate 160 (159 mg, 0.6 mmol) in a mixture of water (2.6 mL) containing NaOH (31 mg, 0.8 mmol, 1.3 equivalents) and EtOH (2.6 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. H2O2 (30% aqueous solution, 0.015 mL, 0.1 mmol, 0.25 equivalents) was added dropwise to the mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under vacuum, and the residue was diluted with ELISA (200 mL). The layers were separated. The aqueous layer was co-evaporated with ACN to obtain intermediate 161 (180 mg, yield: 91%) as a white solid.

[0780] Intermediate 162:

[0781] [ka]

[0782] A mixture of intermediate 161 (180 mg, 0.6 mmol, 1.5 equivalents), intermediate 3 (109 mg, 0.4 mmol), and K2CO3 (78 mg, 0.6 mmol) in 1,4-dioxane (3 mL) was mixed with di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 22 mg, 0.09 mmol, 0.23 equivalents) and palladium(II) acetate (CAS[3375-31-3], 12 mg, 0.06 mmol, 0.1 equivalents) under a nitrogen atmosphere. The mixture was stirred at 120 °C for 18 hours. After cooling, the mixture was diluted with water and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (25 g silica; acetone / heptane 0 / 100~100 / 0) to obtain intermediate 162 (145 mg, yield: 76%) as a white solid.

[0783] Intermediate 163:

[0784] [ka]

[0785] HCl (4M in 1,4-dioxane, 1.4 mL, 5.6 mmol, 19 equivalents) was added to a stirred solution of intermediate 162 (145 mg, 0.3 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum to obtain intermediate 163 (0.2HCl, 134 mg, 96% yield) as a white solid.

[0786] Intermediate 164:

[0787] [ka]

[0788] A solution of 5-mercapto-3-pyridinecarboxylic acid, methyl ester (CAS[74470-37-4], 1.01 g, 5.96 mmol) in anhydrous DMF (12 mL) was treated with sodium 2-chloro-2,2-difluoroacetate (CAS[1895-39-2], 1.63 g, 10.6 mmol, 1.8 equivalents) and sodium carbonate (4.89 g, 46.13 mmol, 7.7 equivalents). The reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and treated with saturated aqueous NaHCO3 solution (50 mL). The mixture was extracted with DCM (twice with 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2, 80 g, DCM: MeOH in DCM 9:1 gradient 0% to 100%) to obtain intermediate 164 (325 mg, yield: 24%) as a white solid.

[0789] Intermediate 165:

[0790] [ka]

[0791] Lithium hydroxide monohydrate (CAS[1310-66-3], 70 mg, 1.63 mmol, 1.5 equivalents) was added at 0°C to a solution of intermediate 164 (226 mg, 1.03 mmol) in THF (2 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated to dryness. The crude product was acidified with HCl (1 N in water, 1.1 mL) and extracted with HCl (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness to obtain intermediate 165 (157 mg, yield: 74%) as a white solid.

[0792] Intermediate 166:

[0793] [ka]

[0794] Ruthenium(III) chloride hydrate (CAS[14898-67-0], 20 mg, 0.015 mmol, 0.06 equivalents) was added to a stirred solution of intermediate 165 (247 mg, 1.2 mmol) and sodium periodate (CAS[7790-28-5], 1 g, 4.67 mmol, 3.8 equivalents) in DCM (22 mL), ACN (22 mL), and water (44 mL). The mixture was stirred at room temperature for 16 hours. Volatile substances were removed under reduced pressure. The aqueous residue (pH<7) was extracted with DCM (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness to obtain intermediate 166 (249 mg, yield: 86%) as a white solid.

[0795] Intermediate 167:

[0796] [ka]

[0797] A solution of methyl 4-mercapto-2-pyridinecarboxylate (CAS[74470-47-6], 293 mg, 1.73 mmol) in anhydrous DMF (5 mL) was treated with sodium 2-chloro-2,2-difluoroacetate (CAS[1895-39-2], 800 mg, 5.24 mmol, 3 equivalents) and cesium carbonate (CAS[534-17-8], 1.7 g, 5.21 mmol, 3 equivalents). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, treated with saturated aqueous NaHCO3 solution (50 mL), and extracted with DCM (2 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2, 25 g; DCM: MeOH in DCM 9:1 gradient 0% to 100%) to obtain intermediate 167 (135 mg, yield: 35%) as a yellow oil.

[0798] Intermediate 168:

[0799] [ka]

[0800] Intermediate 168 was prepared using intermediate 167 instead of intermediate 164, following the same procedure as for intermediate 165.

[0801] Intermediate 169:

[0802] [ka]

[0803] Intermediate 169 was prepared using intermediate 168 instead of intermediate 165, following the same procedure as for intermediate 166.

[0804] Intermediate 170:

[0805] [ka]

[0806] CuI (CAS[7681-65-4], 1.98 g, 2.21 mmol, 1.1 equivalents) was added in a sealed tube at room temperature to a stirred solution of 5-bromo-6-methylnicotinate methyl ester (CAS[1174028-22-8], 2.176 g, 9.46 mmol) and sodium methanesulfinate (CAS[20277-69-4], 3.88 g, 38.0 mmol, 4 equivalents) in DMSO (28.5 mL). The reaction mixture was stirred at 120 °C for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 aqueous solution and DCM. The layers were separated, and the organic layer was washed with brine (5 × 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica; Â / heptane 0 / 100~50 / 50) to obtain intermediate 170 (899 mg, yield: 35%) as a white solid.

[0807] Intermediate 171:

[0808] [ka]

[0809] NaOH (1 M in water, 9.2 mL, 9.2 mmol, 3 equivalents) was added at room temperature to a stirred solution of intermediate 170 (700 mg, 3.05 mmol) in MeOH (9 mL). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and washed with SiO2. The aqueous layer was acidified to pH=1 with HCl (1 M in water) and then extracted with SiO2 (2 × 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to obtain intermediate 171 (545 mg, yield: 79%) as a white solid.

[0810] Intermediate 172:

[0811] [ka]

[0812] Acetaldehyde (CAS[75-07-0], 4.825 g, 109.524 mmol, 1.5 equivalents) and p-toluenesulfonic acid monohydrate (CAS[6192-52-5], 25 g, 131.429 mmol, 1.8 equivalents) were added at 0°C to a solution of 4-penten-2-ol (CAS[625-31-0], 7.5 mL, 73.016 mmol) in toluene (260 mL). The reaction mixture was slowly warmed to room temperature and then stirred at 70°C for 3 hours. The reaction mixture was diluted with Na2CO3 (1 M in water) and extracted with siRNA (2 × 150 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated. The crude product was purified by silica gel column chromatography (12 g silica, siRNA / heptane 20 / 80) to obtain intermediate 172 (11.76 g, yield: 57%) as an orange oily substance.

[0813] Intermediate 173:

[0814] [ka]

[0815] Cs2CO3 (CAS[534-17-8], 4.4 g, 13.51 mmol, 1.2 equivalents) was added to a mixture of hydroxy-6-chloropyridazine (CAS[19064-67-6], 1.46 g, 11.19 mmol) and intermediate 172 (3.82 g, 13.43 mmol, 1.2 equivalents) in DMF (36 mL). The mixture was stirred at 100°C for 72 hours. The mixture was diluted with water and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (silica 120 g; SiO2 / heptane 0 / 100~50 / 50) to obtain intermediate 173 (1.0 g, yield: 33%) as a white solid.

[0816] Intermediate 174:

[0817] [ka]

[0818] Intermediate 173 (500 mg, 2.06 mmol) and thiourea (CAS[62-56-6], 236 mg, 3.10 mmol, 1.5 equivalents) were diluted in methyl ethyl ketone (CAS[78-93-3], 6 mL), and the mixture was stirred at 90°C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (silica 12 g; ethyl acetate / heptane 0 / 100~15 / 85) to obtain intermediate 174 (325 mg, yield: 60%) as a yellow solid.

[0819] Intermediate 175:

[0820] [ka]

[0821] H2O2 (30% in water, CAS[7722-84-1], 60 μL, 0.59 mmol, 1.6 equivalents) was added dropwise to a solution of intermediate 174 (130 mg, 0.54 mmol) dissolved in a mixture of water (4.4 mL) containing NaOH (28 mg, 0.7 mmol) and EtOH (2.4 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was then cooled to 0°C, and H2O2 (30% aqueous solution, 30 μL, 0.6 mmol, 0.8 equivalents) was added. After stirring at room temperature for 60 minutes, the solvent was removed by distillation under reduced pressure, and the residue was washed with ethyl acetate. The aqueous phase was co-evaporated with ACN to obtain intermediate 175 (130 mg, yield: 86%) as a white solid.

[0822] Intermediate 176:

[0823] [ka]

[0824] A mixture of intermediate 175 (300 mg, 1.02 mmol, 1.49 equivalents), intermediate 3 (200 mg, 0.68 mmol), and K2CO3 (145 mg, 1.05 mmol, 1.5 equivalents) in 1,4-dioxane (5 mL) was mixed with di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS[870777-30-3], 17 mg, 0.069 mmol, 0.1 equivalent) and palladium(II) acetate (CAS[3375-31-3], 8 mg, 0.036 mmol, 0.05 equivalent) under a nitrogen atmosphere. The mixture was stirred at 120 °C for 18 hours. After cooling, the reaction mixture was diluted with water and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (silica 12 g; acetone / heptane 0 / 100~50 / 50) to obtain intermediate 176 (130 mg, yield: 39%) as a white solid.

[0825] Intermediate 177:

[0826] [ka]

[0827] HCl (4M in 1,4-dioxane, 1.4 mL, 5.6 mmol, 20 equivalents) was added to a stirred solution of intermediate 176 (130 mg, 0.28 mmol) in DCM (2.8 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum to obtain intermediate 177 (0.2HCl, 122 mg, yield: 97%) as a yellow solid impured with some (2α,4α,6α) isomers.

[0828] Intermediate 178:

[0829] [ka]

[0830] Intermediate 158 (175 mg, 0.32 mmol), sodium methanethiolate (CAS[5188-07-8], 71 mg, 0.96 mmol), and DMF (1.75 mL) were combined under a nitrogen atmosphere, and the mixture was stirred at 100°C for 1.5 hours. After cooling, the reaction mixture was diluted with water until a light brown solid precipitated. The suspension was stirred at room temperature for 5 minutes, then filtered and washed with further water. The solid was collected and dried under vacuum at 45°C to obtain intermediate 178 (120 mg, yield 73%) as a light brown solid.

[0831] Intermediate 179:

[0832] [ka]

[0833] Intermediate 158 (175 mg, 0.32 mmol) and XPhosPdG4 (CAS[1621274-19-8], 15 mg, 0.016 mmol, 0.05 equivalents) were dissolved in THF (1.6 mL) under a nitrogen atmosphere. 2-Mercaptoethanol (CAS[60-24-2], 25 μL, 0.352 mmol, 1.1 equivalents) and Et3N (49 μL, 0.352 mmol, 1.1 equivalents) were added sequentially. The mixture was stirred at 60°C for 1.5 hours. After cooling, the mixture was diluted with water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (12 g of SiO2, 0-15% MeOH / DCM) to obtain intermediate 179 (165 mg, yield: 95%) as a yellow solid.

[0834] Intermediate 180:

[0835] [ka]

[0836] 5-bromonicotinic acid (CAS[20826-04-4], 264 mg, 1.308 mmol, 1.2 equivalents), HATU (CAS[148893-10-1], 497 mg, 1.308 mmol, 1.2 equivalents), and DIPEA (1.15 mL, 6.539 mmol, 6.0 equivalents) were combined in dry DMF (8 mL) under a nitrogen atmosphere, and the mixture was stirred for 1 minute. Intermediate 6 (500 mg, 1.09 mmol) was added all at once, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water until precipitation was complete, then the suspension was stirred for 10 minutes, filtered, and the solid was washed to obtain a yellowish-brown solid. The solid was dried under vacuum to obtain intermediate 180 (543 mg, yield: 93%) as a yellowish-brown solid.

[0837] Intermediate 181:

[0838] [ka]

[0839] Intermediate 180 (220 mg, 0.412 mmol) and sodium methanethiolate (CAS[5188-07-8], 91 mg, 1.237 mmol) were combined in DMF (3.3 mL), and the mixture was stirred under a nitrogen atmosphere at 100°C for 1.5 hours. After cooling, the mixture was diluted with water until a light precipitate formed. The suspension was stirred for 10 minutes, then filtered to obtain a light brown solid, which was dried under vacuum to obtain intermediate 181 (106 mg, yield: 51%).

[0840] Intermediate 182:

[0841] [ka]

[0842] Intermediate 180 (125 mg, 0.23 mmol) and XantphosPdG4 (CAS[1621274-19-8], 11 mg, 0.012 mmol, 0.05 equivalents) were dissolved in dry THF (1.2 mL) under a nitrogen atmosphere. Then, 2-mercaptoethanol (CAS[60-24-2], 18 μL, 0.26 mmol, 1.1 equivalents) and Et3N (36 μL, 0.26 mmol, 1.1 equivalents) were added, and the mixture was stirred at 60°C for 1.5 hours. After cooling, the reaction mixture was diluted with water and SiO2. The layers were separated, and the aqueous layer was extracted twice with SiO2. The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (12 g silica gel, 0-12% MeOH in DCM) to obtain intermediate 182 (135 mg, yield 108%) as a green oily substance.

[0843] Intermediate 183:

[0844] [ka]

[0845] Sodium hydride (270 mg, 6.7 mmol) was added at room temperature to a stirred solution of (L)-proline (CAS[147-85-3], 773 mg, 6.7 mmol) in DMSO (25 mL). The mixture was stirred at room temperature for 30 minutes. Then, 5-bromo-6-methyl-3-pyridinecarboxylate methyl ester (CAS[1174028-22-8], 1.93 g, 8.3 mmol), sodium methanesulfinate (CAS[20277-69-4], 7 g, 68.5 mmol), and copper iodide (CAS[7681-65-4], 1.3 g, 6.8 mmol) were added, and the mixture was stirred at 120 °C for 2 hours. After cooling, the mixture was poured into saturated NaHCO3 aqueous solution and SiO2. The mixture was filtered, and the filtrate layer was separated. The aqueous layer was extracted with SiO2 (×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g silica; siRNA / heptane 0 / 100~100 / 0) to obtain intermediate 183 (850 mg, yield: 42%) as a yellow solid.

[0846] Intermediate 184:

[0847] [ka]

[0848] A homogeneous solution of intermediate 183 (0.492 g, 2.146 mmol) and 2,2,2-trifluoroethyl trifluoroacetate (CAS[407-38-5], 0.5 mL, 3.734 mmol) in dry THF (20 mL) was cooled to -78 °C under a nitrogen atmosphere, and LiHMDS (CAS[4039-32-1], 3.6 mL, 3.6 mmol, 1 M in THF) was added dropwise. After stirring at -78 °C for 5 minutes, the reaction mixture was slowly warmed to room temperature over 1 hour. The mixture was then cooled to 0 °C, and the reaction was quenched by adding saturated aqueous NaHCO3 solution. The mixture was diluted with SiO2 and washed twice with brine. The organic layer was dried over (MgSO4), filtered, and concentrated to obtain intermediate 184, which was used directly without further purification.

[0849] Intermediate 185:

[0850] [ka]

[0851] The solution of intermediate 184 in ACN (30 mL) was cooled to 0°C and treated in one step with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (CAS[140681-55-6], 2.947 g, 8.319 mmol). The reaction mixture was heated to room temperature, stirred at 60°C for 40 minutes, then cooled and concentrated to dryness. The crude product was suspended in SiO2 (500 mL), sonicated to break up all particles, filtered through Celite, and the filtrate was concentrated to obtain intermediate 185, which was used directly without further purification.

[0852] Intermediate 186:

[0853] [ka]

[0854] A solution of intermediate 185 in THF (20 mL) and water (5 mL) was treated with DIPEA (1.0 mL, 5.803 mmol) and stirred at room temperature for 15 minutes. The reaction mixture was diluted with SiO2 and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated. The crude material was purified by flash column chromatography (40 g SiO2, SiO2 / heptane 0 / 100~100 / 0) to obtain intermediate 186 (0.27 g, 47% in 3 steps) as a colorless oil, which was allowed to stand and crystallized into a white needle-shaped substance.

[0855] Intermediate 187:

[0856] [ka]

[0857] A suspension of intermediate 186 (0.522 g, 1.968 mmol) in MeOH (5 mL) was treated with an aqueous NaOH solution (0.7 mL, 2.1 mmol, 3 M water) and stirred at 50°C for 40 minutes. After cooling, the reaction mixture was concentrated to obtain intermediate 187 (0.518 g, 96%, sodium salt) as an orange solid, which was used without further purification.

[0858] Intermediate 188:

[0859] [ka]

[0860] A solution of 2-chloropyrimidine (CAS[1722-12-9], 4.58 g, 40.0 mmol) in THF (120 mL) was cooled to -60°C under a nitrogen atmosphere. Then, a 0.79 M THF-toluene solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (CAS[898838-07-8], 61 mL, 48.2 mmol) was added dropwise, and the resulting mixture was stirred at -60°C for 1.5 hours. Zinc chloride (CAS[7646-85-7], 1 M in diethyl ether, 60 mL, 60 mmol) was added, the reaction mixture was allowed to reach room temperature, and stirred for a further 1.5 hours to prepare the intermediate organozinc. In a separate flask, intermediate 3 (2 g, 6.81 mmol) and Pd(PPh3)4 (CAS[14221-01-3], 393 mg, 0.340 mmol, 0.05 equivalents) were placed under a nitrogen atmosphere and treated with an organozinc preparation solution (approximately 0.16 M, 128 mL, 20.4 mmol, 3 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with SiO2 and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was ground with ACN to obtain intermediate 188 (1.46 g, yield: 56%) as a white solid.

[0861] Intermediate 189:

[0862] [ka]

[0863] Intermediate 188 (0.650 g, 1.75 mmol) was dissolved in a solution of HCl (4N in 1,4-dioxane, 8.7 mL, 34.8 mmol, 20 equivalents) and 1,4-dioxane (23 mL), and the mixture was stirred at room temperature for 16 hours. The crude mixture was concentrated under vacuum, the residue was ground in diethyl ether, and filtered to obtain intermediate 189 (HCl salt, 0.475 g, yield: 99%) as a brownish solid.

[0864] Intermediate 190:

[0865] [ka]

[0866] HBTU (CAS[94790-37-1], 0.575 g, 1.516 mmol, 1.1 equivalents) was added at room temperature to a stirred solution of intermediates 189 (0.475 g, 1.378 mmol), 171 (0.326 g, 1.516 mmol, 1.1 equivalents), and DIPEA (0.96 mL, 5.513 mmol, 4 equivalents) in DMF (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with SiO2 and washed with 1 M Na2CO3 aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated. The product was ground in ACN and filtered to obtain intermediate 190 (0.477 g, yield: 71%) as a grayish-white solid.

[0867] Intermediate 191:

[0868] [ka]

[0869] 1,3,8-Triazaspiro[4.5]decane-2,4-dione (CAS[13625-39-3], 0.767 g, 4.53 mmol, 2 equivalents) was added to a solution of 4-benzyloxy-2-chloropyrimidine (CAS[108381-28-8], 0.5 g, 2.26 mmol) and DIPEA (0.75 mL, 4.53 mmol, 2 equivalents) in DMSO (2 mL). The mixture was stirred at 120 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with siRNA, and washed with H₂O. The organic layer was dried over MgSO₄, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (25 g SiO₂, siRNA / heptane 100 / 0~0 / 100) to obtain intermediate 191 (622 mg, yield: 74%).

[0870] Intermediate 192:

[0871] [ka]

[0872] Intermediate 191 (622 mg, 1.76 mmol) and Et3N (0.060 mL, 0.421 mmol, 0.24 equivalents) were dissolved in MeOH (15 mL). Pd / C (10%, CAS[7440-05-3], 59 mg, 0.055 mmol) was added, and the suspension was stirred at room temperature under a hydrogen atmosphere (1 atm) for 16 hours. The catalyst was filtered through a Celite pad and further rinsed with MeOH (5 × 40 mL). The filtrate was concentrated to obtain intermediate 192 (414 mg, yield: 68%) as a solid.

[0873] Intermediate 193:

[0874] [ka]

[0875] Phosphorus(V) oxychloride (CAS[10025-87-3], 0.176 mg, 1.89 mmol, 1.2 equivalents) was added to a solution of intermediate 192 (0.414 g, 1.57 mmol) and Et3N (0.22 mL, 1.57 mmol, 1 equivalent) in DMF (14 mL). The resulting mixture was stirred at 50°C for 2 hours under a nitrogen atmosphere. The mixture was poured onto ice, basicized with 1 M Na2CO3 aqueous solution, and extracted several times with SiO2. The combined organic layer was dried over MgSO4, filtered, and the solvent was evaporated under vacuum to obtain intermediate 193 (446 mg, yield: 91%) as a solid, which was used without further purification.

[0876] Intermediate 194:

[0877] [ka]

[0878] Intermediate 3 (0.2 g, 0.68 mmol) was dissolved in a solution of HCl (4 M in 1,4-dioxane, 6 mL, 24 mmol) and 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum to obtain intermediate 194 (HCl salt, 197 mg, yield: 78%) as a light brown solid, which was used without further purification.

[0879] Intermediate 195:

[0880] [ka]

[0881] HBTU (CAS[94790-37-1], 1.5 g, 4 mmol) was added at room temperature to a solution of intermediate 194 (0.9 g, 3.4 mmol), intermediate 171 (0.87 g, 4 mmol), and DIPEA (2.8 mL, 16.9 mmol) in DCM (15 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with Na2CO3 (1 M in water). The organic phase was dried with (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was ground in ACN, and the solid was filtered to obtain the first collectible of intermediate 195. The mother liquor was purified by flash column chromatography (25 g of SiO2; DCM / MeOH9 / 1, 0 / 100~20 / 80 in DCM). The pure fraction was collected, the solvent was evaporated, the product was pulverized in ACN, filtered, dried, and combined with the first collection to obtain intermediate 195 (0.915 g, yield: 67%) as a solid.

[0882] Intermediate 196:

[0883] [ka]

[0884] Intermediate 195 (0.665 g, 1.70 mmol) and sodium 1-methyl-3-sulfinopropanoate (CAS [90030-48-1], 0.60 g, 3.44 mmol, 2 equivalents) were dissolved in DMF (6 mL), and the mixture was degassed by bubbling nitrogen. Cuprous iodide ([CAS:7681-65-4], 650 mg, 3.41 mmol, 2 equivalents) was added. The vial was sealed, and the reaction mixture was stirred at 100°C for 1 hour. After cooling, the reaction mixture was partitioned into toluene (25 mL), water (25 mL), and 25% ammonia (5 mL). The organic layer was separated, washed with brine (3 × 5 mL), dried over MgSO4, and filtered. The solvent was evaporated, and the residue was purified by flash column chromatography (25 g of SiO2, MeOH / DCM0 / 100~5 / 95) to obtain intermediate 196 (0.26 g, yield: 30%) as a white solid.

[0885] Intermediate 197:

[0886] [ka]

[0887] 4-Boc-4,7-diazaspiro[2.5]octane (CAS[674792-08-6], 1.92 g, 9.07 mmol, 2 equivalents) was added to a solution of 4-benzyloxy-2-chloropyrimidine (CAS[108381-28-8], 1.33 g, 4.53 mmol) and DIPEA (1.5 mL, 9.07 mmol, 2 equivalents) in DMSO (4 mL). The reaction mixture was stirred at 120 °C for 2 hours. After cooling, the reaction mixture was diluted with siRNA and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2 25 g, heptane / siRNA 100 / 0~50 / 50) to obtain intermediate 197 (1.38 g, yield: 75%) as an oily substance.

[0888] Intermediate 198:

[0889] [ka]

[0890] Intermediate 197 (1.38 g, 3.48 mmol) and Et3N (0.116 mL, 0.833 mmol, 0.24 equivalents) were dissolved in MeOH (25 mL). Pd / C (10%, CAS[7440-05-3], 116 mg, 0.109 mmol) was added, and the suspension was stirred at room temperature under a hydrogen atmosphere (1 atm) for 16 hours. The catalyst was filtered off through a Celite pad and further rinsed with MeOH (5 × 40 mL). The filtrate was concentrated to obtain intermediate 198 (1.06 g, yield: 98%) as a solid, which was used without further purification.

[0891] Intermediate 199:

[0892] [ka]

[0893] Intermediate 199 was prepared using intermediate 198 instead of intermediate 192, following the same procedure as intermediate 193.

[0894] Intermediate 200:

[0895] [ka]

[0896] Intermediate 199 (335 mg, 1.031 mmol) was dissolved in 1,4-dioxane (5 mL) under a nitrogen atmosphere. AcOK (CAS[127-08-2], 253 mg, 2.58 mmol, 2.5 equivalents), bis(pinacorato)diborone (CAS[73183-34-3], 288 mg, 1.14 mmol, 1.1 equivalents), tricyclohexylphosphine (CAS[2622-14-2], 12 mg, 0.041 mmol, 0.04 equivalents), and Pd(OAc)2 (CAS[3375-31-3], 5 mg, 0.021 mmol, 0.02 equivalents) were added to the solution. The reaction mixture was stirred at 110°C for 1 hour under a nitrogen atmosphere. After cooling, the mixture was maintained under a nitrogen atmosphere, and K2CO3 (285 mg, 2.063 mmol, 2 equivalents), CuCl (CAS[7758-89-6], 102 mg, 1.031 mmol, 1 equivalent), and intermediate 3 (303 mg, 1.031 mmol, 1 equivalent) were added. The reaction mixture was stirred at 110°C for 16 hours. After cooling, the mixture was diluted with water and siRNA. The organic phase was separated, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g SiO2, heptane / siRNA0 / 100~80 / 20) to obtain intermediate 200 (100 mg, yield: 18%) as a foamy substance.

[0897] Intermediate 201:

[0898] [ka]

[0899] TFA (0.278 mL, 3.64 mmol, 22.6 equivalents) was added at room temperature to a stirred solution of intermediate 200 (0.100 g, 0.161 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with toluene (2 × 15 mL) to obtain intermediate 201 (TFA salt, 92 mg, yield: 98%) as a concentrated oil.

[0900] Intermediate 202:

[0901] [ka]

[0902] Sodium hydride (CAS[7646-69-7], 56 mg, 1.41 mmol, 0.8 equivalents) was added to a stirred solution of (L)-proline (CAS[147-85-3], 162 mg, 1.41 mmol, 0.8 equivalents) in DMSO (12 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Methyl 5-bromo-6-(trifluoromethyl)nicotinate (CAS[1198016-45-3], 562 mg, 1.76 mmol), sodium methanesulfinate (CAS[20277-69-4], 1.44 g, 14.08 mmol, 8 equivalents), and copper iodide (CAS[7681-65-4], 270 mg, 1.41 mmol, 0.8 equivalents) were added. The reaction vessel was closed, and the mixture was stirred at 120°C for 2 hours. After cooling, the reaction mixture was poured into water and DCM. The solid was filtered. The filtrate layer was separated, and the aqueous layer was extracted with siRNA. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (80 g SiO2, DCM / MeOH 100 / 0~90 / 10) to obtain intermediate 202 (149 mg, yield: 29%) as a white solid.

[0903] Intermediate 203:

[0904] [ka]

[0905] Lithium hydroxide monohydrate (CAS[1310-66-3], 88 mg, 2.10 mmol, 4 equivalents) was added at room temperature to a solution of intermediate 202 (149 mg, 0.526 mmol) in THF (6 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The pH was neutralized by adding 1 M aqueous KHSO4 solution. DCM was added, the organic layer was separated, dried over MgSO4, and filtered. The solvent was removed under vacuum to obtain intermediate 203 (131 mg, yield: 91%) as a white solid, which was used without further purification.

[0906] Intermediate 204:

[0907] [ka]

[0908] To a solution of methyl 5-bromo-6-methylnicotinate (CAS[1174028-22-8], 2 g, 8.70 mmol) in DCE (25 mL), N-bromosuccinimide (CAS[128-08-5], 4.6 g, 26 mmol, 3 equivalents), followed by 2,2'-azobis(2-methylpropionitrile) (CAS[78-67-1], 0.43 g, 2.6 mmol, 0.3 equivalents), was added under a nitrogen atmosphere. The reaction mixture was stirred at 90°C for 16 hours. After cooling, the solvent was evaporated, and the crude product was purified by flash column chromatography (80 g SiO2, heptane / (heptane:siRNA 5:1), 100 / 0~90 / 10) to obtain intermediate 204 (1.3 g, yield: 38%) as a colorless oil.

[0909] Intermediate 205:

[0910] [ka]

[0911] Intermediate 204 (1.14 g, 2.94 mmol) was dissolved in DCM (30 mL) under a nitrogen atmosphere, and silver tetrafluoroborate (CAS[14104-20-2], 1.7 g, 8.8 mmol, 3 equivalents) was added. The reaction mixture was stirred at 40°C for 16 hours. The solid was filtered off, and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography (12 g SiO2, heptane / (heptane:siRNA, 5:1) 100 / 0~90 / 10) to obtain intermediate 205 (840 mg, yield: 99%) as a white solid.

[0912] Intermediate 206:

[0913] [ka]

[0914] Under a nitrogen atmosphere, sodium hydride (CAS[7646-69-7], 48 mg, 1.20 mmol, 0.8 equivalents) was added to a stirred solution of (L)-proline (CAS[147-85-3], 138 mg, 1.20 mmol, 0.8 equivalents) in DMSO (7 mL), and the mixture was stirred at room temperature for 30 minutes. Intermediate 205 (400 mg, 1.50 mmol), sodium methanesulfinate (CAS[20277-69-4], 1.23 g, 12.0 mmol, 8 equivalents), and copper iodide (CAS[7681-65-4], 229 mg, 1.20 mmol, 0.8 equivalents) were added. The vial was sealed, and the reaction mixture was stirred at 120 °C for 16 hours. After cooling, the reaction mixture was poured into water and siRNA. The organic layer was separated, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (80 g SiO2, heptane / siRNA 100 / 0~85 / 15) to obtain intermediate 206 (110 mg, yield: 27%) as a white solid.

[0915] Intermediate 207:

[0916] [ka]

[0917] Lithium hydroxide monohydrate (CAS[1310-66-3], 70 mg, 1.70 mmol, 4 equivalents) was added at room temperature to a solution of intermediate 206 (110 mg, 0.41 mmol) in THF (3 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The pH was neutralized by adding 1 M aqueous KHSO4 solution. The mixture was extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain intermediate 207 (86 mg, yield: 82%) as a white solid.

[0918] Intermediate 208:

[0919] [ka]

[0920] Cis-2,6-dimethylmorpholine (CAS[6485-55-8], 1.14 mL, 9.20 mmol, 2 equivalents) was added to a solution of 4-benzyloxy-2-chloropyrimidine (CAS[108381-28-8], 1.56 g, 4.60 mmol) and DIPEA (1.52 mL, 9.20 mmol, 2 equivalents) in DMSO (5 mL). The mixture was stirred at 120 °C for 2 hours. After cooling, the reaction mixture was diluted with siRNA and washed with water. The organic layer was separated, dried over MgSO₄, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (80 g SiO₂, heptane / siRNA₀ / 100~80 / 20) to obtain intermediate 208 (1.14 g, yield: 82%) as a solid.

[0921] Intermediate 209:

[0922] [ka]

[0923] Intermediate 209 was prepared using intermediate 208 instead of intermediate 197, following the same procedure as for intermediate 198.

[0924] Intermediate 210:

[0925] [ka]

[0926] Intermediate 210 was prepared using intermediate 209 instead of intermediate 192, following the same procedure as for intermediate 193.

[0927] Intermediate 211:

[0928] [ka]

[0929] Intermediate 210 (223 mg, 1.031 mmol) was dissolved in 1,4-dioxane (4 mL) under a nitrogen atmosphere. AcOK (CAS[127-08-2], 251 mg, 2.55 mmol, 2.5 equivalents), bis(pinacorato)diborone (CAS[73183-34-3], 285 mg, 1.12 mmol, 1.1 equivalents), tricyclohexylphosphine (CAS[2622-14-2], 11 mg, 0.041 mmol, 0.04 equivalents), and Pd(OAc)2 (CAS[3375-31-3], 5 mg, 0.021 mmol, 0.02 equivalents) were added. The mixture was stirred at 110°C for 30 minutes under a nitrogen atmosphere. The mixture was cooled to room temperature and maintained under a nitrogen atmosphere. K2CO3 (282 mg, 2.04 mmol, 2 equivalents), CuCl (CAS[7758-89-6], 101 mg, 1.02 mmol, 1 equivalent), and intermediate 3 (300 mg, 1.02 mmol, 1 equivalent) were added. The reaction mixture was stirred at 110°C for 16 hours. After cooling, the mixture was diluted with water and SiO2. The organic phase was separated, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g SiO2, heptane / SiO2 / 100~60 / 40) to obtain intermediate 211 (136 mg, yield: 29%) as a foamy substance.

[0930] Intermediate 212:

[0931] [ka]

[0932] Intermediate 211 (0.136 g, 0.302 mmol) was dissolved in HCl (4N in 1,4-dioxane, 4.1 mL, 16.4 mmol, 54 equivalents) and 1,4-dioxane (3.5 mL), and the mixture was stirred at room temperature for 16 hours. The crude suspension was concentrated under vacuum to obtain intermediate 212 (HCl salt, 0.118 g, yield: 91%) as a solid.

[0933] Intermediate 213 and Intermediate 214:

[0934] [ka]

[0935] In a sealed tube, Cs2CO3 (2.16 g, 6.64 mmol, 2.1 equivalents) was added to a mixture of 5-bromo-2-hydroxypyridine (CAS[13466-38-1], 550 mg, 3.16 mmol) and 2,2,6,6-tetramethyloxane-4-ylmethanesulfonate (CAS[1160656-10-9], 1.5 g, 6.32 mmol, 2 equivalents) in DMF (5 mL). The reaction mixture was stirred at 120°C for 18 hours. The mixture was diluted with 1 M aqueous Na2CO3 and extracted with ethyl acetate. The organic layer was dried with (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (25 g of SiO2, heptane / siRNA 100 / 0~80 / 20) to obtain intermediate 214 (32 mg, yield: 3%) and intermediate 213 (220 mg, yield: 21%), both as white solids.

[0936] Intermediate 215:

[0937] [ka]

[0938] Intermediate 213 (220 mg, 0.700 mmol), bis(pinacolato)diborone (CAS[73183-34-3], 256 mg, 1.01 mmol, 1.44 equivalents), Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 29 mg, 0.035 mmol, 0.05 equivalents), and AcOK ([127-08-2], 213 mg, 2.18 mmol, 3.1 equivalents) were dissolved in 1,4-dioxane (2 mL) under a nitrogen atmosphere. The reaction vessel was sealed and the reaction mixture was stirred at 90°C for 3 hours. The mixture was diluted with 1 M Na2CO3 aqueous solution and extracted with siRNA (2×). The combined organic layer was dried over MgSO4, filtered, and evaporated under vacuum. The residue was analyzed by flash column chromatography (25 g SiO2). 2、 The intermediate 215 (253 mg, yield: 100%) was obtained as a white solid by purification with heptane / acetaldehyde (100 / 0~50 / 50).

[0939] Intermediate 216:

[0940] [ka]

[0941] 2-Isopropoxypyridine-5-boronic acid pinacol ester (CAS [871839-91-7], 175 mg, 0.664 mmol, 1.3 equivalents) and 1.5 mL, 1.5 mmol, 3 equivalents of 1 M Na2CO3 aqueous solution were added to a stirred solution of intermediate 3 (150 mg, 0.511 mmol) in 1,4-dioxane (3 mL) at room temperature. The reaction mixture was degassed by bubbling with nitrogen, and then Pd(PPh3)Cl2 (CAS [13965-03-2], 18 mg, 0.026 mmol, 0.05 equivalents) was added. The reaction mixture was stirred under a nitrogen atmosphere at 85°C for 4 hours. After cooling, the mixture was diluted with water. The mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (12 g of SiO2, DCM / MeOH0 / 100~95 / 5) to obtain intermediate 216 (200 mg, yield: 98%).

[0942] Intermediate 217:

[0943] [ka]

[0944] Intermediate 216 (0.20 g, 0.51 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 1.3 mL, 5.09 mmol, 10 equivalents) and 1,4-dioxane (1 mL). The suspension was stirred at room temperature for 20 hours. The solvent was removed under vacuum to obtain intermediate 217 (210 mg, yield: 100%) as a yellow solid, which was used without further purification.

[0945] Intermediate 218 and Intermediate 219:

[0946] [ka]

[0947] Cs2CO3 (2.86 g, 8.79 mmol, 1.2 equivalents) was added to a solution of 5-bromo-2-hydroxy-3-methylpyridine (CAS[89488-30-2], 1.38 g, 7.33 mmol) and (2R,6S)-rel-tetrahydro-2,6-dimethyl-2H-pyran-4-ol,4-(4-methylbenzenesulfonate) (CAS[1306785-92-1], 2.5 g, 8.79 mmol, 1.2 equivalents) in DMF (20 mL). The reaction mixture was stirred at 70°C for 48 hours. The mixture was diluted with water and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (40 g of SiO2; heptane / SiO2 100 / 0~50 / 50) to obtain intermediate 218 (1.72 g, yield: 77%) as a colorless oil and intermediate 219 (170 mg, yield: 8%) as a white solid.

[0948] Intermediate 220:

[0949] [ka]

[0950] Intermediate 218 (700 mg, 2.33 mmol), bis(pinacolato)diborone (CAS[73183-34-3], 855 mg, 3.37 mmol, 1.4 equivalents), Pd(dppf)Cl2.DCM (CAS[95464-05-4], 95 mg, 0.131 mmol, 0.05 equivalents), and AcOK (CAS[127-08-2], 712 mg, 8.16 mmol, 3.1 equivalents) were dissolved in 15 mL of 1,4-dioxane under a nitrogen atmosphere. The reaction vessel was sealed, and the reaction mixture was stirred at 90°C for 3 hours. After cooling, the mixture was diluted with 1 M aqueous Na2CO3 and extracted with siRNA. The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g of SiO2, heptane / siRNA 100 / 0~50 / 50) to obtain intermediate 220 (576 mg, yield: 64%) as a white solid impured with some (2α,4α,6α) isomers.

[0951] Intermediate 221 and Intermediate 222:

[0952] [ka]

[0953] Cs2CO3 (CAS[534-17-8], 2.86 g, 8.79 mmol, 1.2 equivalents) was added to a solution of 5-bromo-4-methyl-2(1H)pyridinone (CAS[164513-38-6], 1.38 g, 7.33 mmol) and (2R,6S)-rel-tetrahydro-2,6-dimethyl-2H-pyran-4-ol,4-(4-methylbenzenesulfonate) (CAS[1306785-92-1], 2.5 g, 8.79 mmol, 1.2 equivalents) in DMF (20 mL). The reaction mixture was stirred at 70°C for 48 hours. The mixture was diluted with water and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (40 g of SiO2; heptane / dimethyl 100 / 0~50 / 50) to obtain intermediate 221 (1.80 g, yield: 81%) as a colorless oil and intermediate 222 (113 mg, yield: 5%) as a white solid.

[0954] Intermediate 223:

[0955] [ka]

[0956] Intermediate 221 (700 mg, 2.33 mmol), bis(pinacolato)diborone (CAS[73183-34-3], 855 mg, 3.37 mmol, 1.4 equivalents), Pd(dppf)Cl2.DCM (CAS[95464-05-4], 95 mg, 0.131 mmol, 0.05 equivalents), and AcOK (CAS[127-08-2], 712 mg, 8.16 mmol, 3.1 equivalents) were dissolved in 15 mL of 1,4-dioxane under a nitrogen atmosphere. The reaction vessel was sealed and the mixture was stirred at 90°C for 3 hours. After cooling, the mixture was diluted with 1 M aqueous Na2CO3 and extracted with siRNA. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g of SiO2, heptane / siRNA 100 / 0~50 / 50) to obtain intermediate 223 (517 mg, yield: 61%) as a white solid impured with some (2α,4α,6α) isomers.

[0957] Intermediate 224:

[0958] [ka]

[0959] Cs2CO3 (CAS[534-17-8], 2.86 g, 8.79 mmol, 1.2 equivalents) was added to a solution of 5-bromo-6-methyl-2(1H)pyridinone (CAS[54923-31-8], 1.38 g, 7.33 mmol) and (2R,6S)-rel-tetrahydro-2,6-dimethyl-2H-pyran-4-ol,4-(4-methylbenzenesulfonate) (CAS[1306785-92-1], 2.5 g, 8.79 mmol, 1.2 equivalents) in DMF (20 mL). The reaction mixture was stirred at 70°C for 48 hours. The mixture was diluted with water and extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (40 g of SiO2; heptane / dimethyl 100 / 0~50 / 50) to obtain intermediate 224 (1.88 g, yield: 84%) as a colorless oil.

[0960] Intermediate 225:

[0961] [ka]

[0962] Intermediate 224 (904 mg, 3.01 mmol), bis(pinacolato)diborone (CAS[73183-34-3], 1.10 g, 4.34 mmol, 1.4 equivalents), Pd(dppf)Cl2.DCM (CAS[95464-05-4], 123 mg, 0.15 mmol, 0.5 equivalents), and AcOK (CAS[127-08-2], 920 mg, 9.37 mmol, 3.1 equivalents) were dissolved in 15 mL of 1,4-dioxane under a nitrogen atmosphere. The reaction vessel was sealed and the reaction mixture was stirred at 90°C for 3 hours. The mixture was diluted with 1 M aqueous Na2CO3 solution and extracted with SiO2. The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (25 g of SiO2; heptane / Â 100 / 0~50 / 50) to obtain intermediate 225 (990 mg, yield: 92%) as a white solid.

[0963] Intermediate 226 and Intermediate 227:

[0964] [ka]

[0965] Intermediates 226 and 227 were prepared using 5-bromo-2-hydroxypyridine (CAS[13466-38-1]) instead of 5-bromo-4-methyl-2(1H)pyridinone, following the same procedure as for intermediates 221 and 222, respectively.

[0966] Intermediate 228:

[0967] [ka]

[0968] Intermediate 228 was prepared using intermediate 227 instead of intermediate 224, following the same procedure as for intermediate 225.

[0969] Intermediate 229:

[0970] [ka]

[0971] (2α,4β,6α) intermediate 228 (250 mg, 0.75 mmol, 1.1 equivalents) and 1 M Na2CO3 aqueous solution (2.0 mL, 2.0 mmol, 3 equivalents) were added to a stirred solution of intermediate 3 (200 mg, 0.682 mmol) in 1,4-dioxane (7 mL) at room temperature under a nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (CAS[13965-03-2], 24 mg, 0.034 mmol, 0.05 equivalents) was added, and the mixture was stirred at 90°C for 4 hours under a nitrogen atmosphere. After cooling, the mixture was diluted with water and extracted with SiO2. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (12 g of SiO2, heptane / acetaldehyde 100 / 0~0 / 100) to obtain intermediate 229 (243 mg, yield: 69%) as a brown solid.

[0972] Intermediate 230:

[0973] [ka]

[0974] Intermediate 229 (0.243 g, 0.523 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 2.6 mL, 10.4 mmol, 20 equivalents) and 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under vacuum to obtain intermediate 230 (HCl salt, 239 mg, yield: 99%) as a brown solid, which was used without further purification.

[0975] Intermediate 231:

[0976] [ka]

[0977] Methyl 5-bromo-6-(trifluoromethyl)nicotinate (CAS[1198016-45-3], 500 mg, 1.76 mmol) was dissolved in 1,4-dioxane (10 mL) under a nitrogen atmosphere. DIPEA (0.92 mL, 5.28 mmol, 3 equivalents) and 2-mercaptoethanol (CAS[60-24-2], 0.12 mL, 1.76 mmol, 1 equivalent) were added. Then, xanthophos (CAS[161265-03-8], 102 mg, 0.18 mmol, 0.1 equivalent) and Pd2(dba)3 (CAS[32005-36-0], 30 mg, 0.05 mmol, 0.03 equivalents) were added, and the reaction mixture was stirred under a nitrogen atmosphere at 110°C for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography column (25 g SiO2, DCM / MeOH100 / 0~90 / 10) to obtain intermediate 231 (420 mg, yield: 74%) as a yellow oil.

[0978] Intermediate 232:

[0979] [ka]

[0980] m-CPBA (CAS[937-14-4], 77% purity, 335 mg, 1.49 mmol, 1 equivalent) was gradually added at 0°C to a solution of intermediate 231 (420 mg, 1.49 mmol) in DCM (10 mL). The mixture was then stirred at room temperature for 16 hours. Another 30 mL of DCM was added, and m-CPBA (77% purity, 1.5 g, 6.7 mmol, 4.5 equivalents) was gradually added over 24 hours until the reaction was complete. The mixture was diluted with DCM, and 1 M aqueous Na2CO3 was added while stirring. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (25 g SiO2DCM / MeOH 100 / 0~90 / 10) to obtain intermediate 232 (287 mg, 55% yield).

[0981] Intermediate 233:

[0982] [ka]

[0983] Lithium hydroxide monohydrate (CAS[1310-66-3], 85 mg, 1.99 mmol, 4 equivalents) was added at room temperature to a solution of intermediate 232 (156 mg, 0.49 mmol) in THF (2 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The pH was adjusted to 5 by adding 1 M aqueous KHSO4 solution, and the mixture was concentrated to dryness. The crude product was purified by reverse-phase column chromatography (Phenomenex Gemini C18 30 × 100 mm 5 μm; 95% [25 mM NH4HCO3] - 5% [ACN:MeOH (1:1)] ~ 63% [25 mM NH4HCO3] - 37% [ACN:MeOH (1:1)]) to obtain intermediate 233 (130 mg, yield: 86%).

[0984] Intermediate 234:

[0985] [ka]

[0986] In a sealed reaction vessel, tetrakistriphenylphosphinepalladium (0) (CAS[14221-01-3], 1.07 g, 0.927 mmol, 0.1 equivalent) was added to a solution of methyl 4-bromopicolinate (CAS[29681-42-3], 2 g, 9.258 mmol), triisopropylsiliantiol (CAS[156275-96-6], 2.4 mL, 11.179 mmol, 1.2 equivalents), and cesium carbonate (3.6 g, 11.09 mmol, 1.2 equivalents) in toluene (70 mL). The reaction mixture was purged with nitrogen and stirred at 110°C for 5 hours. The reaction mixture was filtered through a Celite pad and rinsed with siRNA. The filtrate was concentrated under vacuum to obtain intermediate 234 (4.0 g, yield: 54%) as an orange oil.

[0987] Intermediate 235:

[0988] [ka]

[0989] Sodium 2-chloro-2,2-difluoroacetate (CAS[1895-39-2], 4.3 g, 28.261 mmol, 5.9 equivalents) and cesium carbonate (9.1 g, 28.051 mmol, 5.9 equivalents) were added to a solution of intermediate 234 (4.0 g, 4.752 mmol) in anhydrous DMF (20 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution, and the mixture was extracted with siRNA. The combined organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel flash column chromatography (80 g column, siRNA / heptane 0 / 100~100 / 0) to obtain intermediate 235 (520 mg, yield: 48%) as an orange, viscous solid.

[0990] Intermediate 236:

[0991] [ka]

[0992] Ammonium carbamate (CAS[1111-78-0], 1.8 g, 23.056 mmol, 19 equivalents) was gradually added to a stirred solution of intermediate 235 (259 mg; 1.182 mmol) and (diacetoxyiodo)benzene (CAS[3240-34-4], 7.5 g; 23.056 mmol, 19 equivalents) in MeOH (10 mL) and DCM (10 mL). The reaction mixture was stirred at room temperature while bubbling O2 for 16 hours. The reaction mixture was stirred at 50°C for 2 hours. The solvent was evaporated, and the residue was dissolved in water and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (40 g, siRNA / heptane 0 / 100~100 / 0) to obtain intermediate 236 (95 mg, yield 31%) as a white solid.

[0993] Intermediate 237:

[0994] [ka] Lithium hydroxide monohydrate (25 mg, 0.573 mmol, 1.5 equivalents) was added at 0°C to a solution of intermediate 236 (95 mg, 0.38 mmol) in THF (3 mL) and water (1.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to the aqueous layer, which was acidified with HCl (1 M in water, 0.4 mL) and extracted with HCl. The organic layer was dried over MgSO4, filtered, and evaporated to obtain intermediate 237 (60 mg, yield 66%) as a white solid.

[0995] Intermediate 238:

[0996] [ka]

[0997] A mixture of 2-chloropyrimidine (CAS[1722-12-9], 229 mg, 2 mmol) in THF (30 mL) was cooled to -60°C under a nitrogen atmosphere. Then, 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (CAS[898838-07-8], 0.85 M in THF / toluene, 2.824 mL, 2.4 mmol) was added dropwise, and the reaction mixture was stirred at -60°C under a nitrogen atmosphere for 1.5 hours. Zinc chloride (CAS[7646-85-7], 1 M in Et2O, 3 mL, 3 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then used directly in the next step.

[0998] Intermediate 239:

[0999] [ka]

[1000] Intermediate 238 (0.18 M in THF / Et2O, 14.18 mL, 2.55 mmol, 3 equivalents) was added under a nitrogen atmosphere to a solution of intermediate 3 (0.250 g, 0.851 mmol) and tetrakis(triphenylphosphine)palladium (CAS[14221-01-3], 49 mg, 0.043 mmol, 0.05 equivalents). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. The mixture was diluted with SiO2 and washed with brine. The organic phase was separated, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was crystallized in ACN to obtain intermediate 239 (213 mg, yield: 65%) as a solid.

[1001] Intermediate 240:

[1002] [ka]

[1003] A solution of tert-butyl 2,5-dimethyl-4-oxopiperidine-1-carboxylate (CAS[1204654-37-4], 680 mg, 2.992 mmol) in EtOH (7 mL) and water (7 mL) was treated with sodium cyanide (CAS[143-33-9], 293 mg, 5.984 mmol, 2 equivalents) and ammonium carbonate (CAS[506-87-6], 1.43 g, 14.958 mmol, 5 equivalents). The reaction mixture was stirred at 60°C for 16 hours. The mixture was poured into water, and the aqueous layer was extracted twice with SiO2. The combined organic layers were washed with water and brine, dried, filtered, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (80g column, DCM / DCM with 0%-100% MeOH(9 / 1)) to obtain intermediate 240 (551mg, yield: 62%) as a solid.

[1004] Intermediate 241:

[1005] [ka]

[1006] Intermediate 240 (551 mg, 1.853 mmol) was dissolved in 1,4-dioxane (2.4 mL), and HCl (4 M in 1,4-dioxane, 2.3 mL, 9.26 mmol, 5 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to obtain intermediate 241 (HCl salt, 429 mg; yield: quantitative) as a white solid.

[1007] Intermediate 242: ((6R)-6-(aminomethyl)-4-(cyclopropylmethyl)morpholin-3-one).

[1008] [ka]

[1009] Intermediate 242 can be prepared by the reaction of 4-(cyclopropylmethyl)-6-[[[(1R)-1-phenylethyl]amino]methyl]-3-morpholinone hydrochloride (1:1) (CAS[1398377-83-7]) with hydrogen (1 atm) in MeOH in the presence of Pd / C (10%) at room temperature.

[1010] Intermediate 243: ((3S)-3-ethyl-4-(2-hydroxyethyl)-1,4-diazepan-5-one).

[1011] [ka]

[1012] Intermediate 243 can be prepared in four steps by first reacting N-(phenylmethyl)-β-alanine (CAS[5426-62-0]) with (2S)-2-aminobutanal (CAS[1243173-40-1]) at room temperature in the presence of sodium borohydride in MeOH; then, in the second step, cyclizing the formed intermediate at reflux temperature in the presence of sodium methoxide in MeOH; then, in the third step, reacting the formed intermediate with 2-bromoethanol (CAS[540-51-2]) at 0°C in the presence of sodium hydride in DMF; and finally, reacting it with hydrogen (1 atm) in MeOH at room temperature in the presence of Pd / C (10%).

[1013] Intermediate 244: (2-azabicyclo[3.1.1]heptane-5-carbonitride).

[1014] [ka]

[1015] Intermediate 244 can be prepared from 1,1-dimethylethyl 5-cyano-2-azabicyclo[3.1.1]heptane-2-carboxylate (CAS[1882055-84-6]) by reaction with TFA in DCM at room temperature.

[1016] Intermediate 245: ((5S)-3-methyl-1,7-dioxa-3,10-diazaspiro[4.6]undecane-2-one).

[1017] [ka]

[1018] Intermediate 245 can be obtained by chiral separation of 3-methyl-1,7-dioxa-3,10-diazaspiro[4.6]undecane-2-one (CAS[2173135-44-7]) by SFC.

[1019] Intermediate 246: ((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrole-6(1H)-one).

[1020] [ka]

[1021] Intermediate 246 can be prepared in two steps by reacting (3aR,6aR)-hexahydro-1-[(1R)-1-phenylethyl]pyrrolo[3,4-b]pyrrole-6(1H)-one (CAS[2007092-81-9]) with methyl iodide in the presence of sodium hydride in DMF at 0°C, and then reacting the resulting intermediate with hydrogen (1 atm) in the presence of Pd / C (10%) in EtOH at 50°C.

[1022] Intermediate 247: ((3aR,7aS)-5-(2,2-difluoroethyl)octahydro-1H-pyrrolo[3,4-c]pyridine)

[1023] [ka]

[1024] Intermediate 247 can be prepared in two steps by reacting 1,1-dimethylethyl (3aS,7aS)-octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (CAS[1416263-25-6]) with 2,2-difluoroethyl 1,1,1-trifluoromethanesulfonate (CAS[74427-22-8]) at room temperature in the presence of DIPEA in ACN, followed by reacting the resulting intermediate with TFA in DCM at room temperature.

[1025] Intermediate 248: ((3aS,6aR)-2-(2-methylpropyl)hexahydropyrrolo[3,4-c]pyrrole-1(2H)-one).

[1026] [ka]

[1027] Intermediate 248 can be prepared in two steps by first reacting (3aR,6aR)-hexahydro-5-[(1R)-1-phenylethyl]pyrrolo[3,4-c]pyrrole-1(2H)-one (CAS[1893359-89-1]) with 1-bromo-2-methylpropane (CAS[78-77-3]) at 0°C in the presence of sodium hydride in THF, and then reacting the resulting intermediate with hydrogen (1 atm) in MeOH at room temperature in the presence of Pd / C (10%).

[1028] Intermediate 249: (1-(isopropylimino)thiomorpholine 1-oxide).

[1029] [ka]

[1030] Intermediate 249 can be prepared in two steps by first reacting 1-imino-1λ4-thiomorpholine-4-carboxylic acid, 1,1-dimethylethyl ester, 1-oxide (CAS[1609964-38-6]) with acetone in MeOH in the presence of 2-picoline-borane (CAS[3999-38-0]) and acetic acid at room temperature, and then reacting the formed intermediate in DCM with TFA at room temperature.

[1031] Intermediate 250: (N-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-yl)acetamide).

[1032] [ka]

[1033] Intermediate 250 can be prepared in two steps: firstly, by reacting 1,1-dimethylethyl 1-amino-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (CAS[1517323-66-8]) with acetyl chloride in the presence of DIPEA in DCM at room temperature; and subsequently, by reacting the resulting intermediate with TFA in DCM at room temperature.

[1034] Intermediate 251: (2-(methoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine)

[1035] [ka]

[1036] Intermediate 251 can be prepared in four steps by first reacting ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (CAS[1301713-93-8]) with di-tert-butyl decarboxylate (CAS[24424-99-5]) at room temperature in the presence of Et3N in DCM; then reacting the formed intermediate with methyl iodide at 0°C in the presence of sodium hydride in THF; then reducing the ester with sodium borohydride in THF at room temperature; and finally reacting the resulting intermediate with TFA in DCM at room temperature.

[1037] compound The compounds in Table 3 were prepared from intermediate 6 and the corresponding acid using the same procedure as shown in the table:

[1038] [Table 3]

[1039] Compound 5: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( * R)-1-hydroxyethyl)-5-methylpicolinamide and compound 6:N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( * S)-1-hydroxyethyl)-5-methylpicolinamide.

[1040] [ka] Compound 5( * R, cis; a pure enantiomer, but its absolute stereochemistry is uncertain.

[1041] [ka] Compound 6(* S, cis; a pure enantiomer, but its absolute stereochemistry is uncertain.

[1042] Compound 4 was separated into its stereoisomers by preparative SFC (i-amylose-1 column; isocratic mode: 50% [EtOH + 0.1% DEA] - 50% [CO2]), yielding compounds 5 and 6, both as yellow solids.

[1043] Compound 7: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-methyl-4-(methylsulfonyl)picolinamide.

[1044] [ka]

[1045] The title compound was prepared using intermediates 18 and 15 in the same manner as in Method E.

[1046] Compound 8: N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1047] [ka]

[1048] Compound 8 was prepared according to Method M using intermediate 20 and 5-(methylsulfonyl)nicotinic acid (CAS [893723-59-6]).

[1049] Compound 9: N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1050] [ka]

[1051] A mixture of intermediate 21 (2.7 g, 5.863 mmol), (3α,4β,5α)-3,5-dimethyl-4-piperidinol (CAS[374067-78-4], 4.22 g, 25.467 mmol, 4.3 equivalents), and DIPEA (28.2 mL, 161.954 mmol, 27.6 equivalents) was stirred overnight at 130°C. The reaction mixture was diluted with DCM (500 mL) and brine (300 mL), and the layers were separated. The aqueous layer was extracted with DCM (3 × 100 mL). The combined organic layers were dried with (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica, 120 g; MeOH in DCM, 0%~10%). The obtained solid was suspended in a mixture of EtOH, MeOH, and water, stirred for 30 minutes, and filtered to obtain compound 9 (2.27 g, yield: 69%) as a yellow solid.

[1052] The compounds in Table 4 were prepared according to Method N using the amines listed in the table (compounds for which stereochemistry is not shown in this table are mixtures of stereoisomers).

[1053] [Table 4-1]

[1054] [Table 4-2]

[1055] [Table 4-3]

[1056] [Table 4-4]

[1057] [Table 4-5]

[1058] [Table 4-6]

[1059] [Table 4-7]

[1060] [Table 4-8]

[1061] [Table 4-9]

[1062] [Table 4-10]

[1063] [Table 4-11]

[1064] [Table 4-12]

[1065] [Table 4-13]

[1066] The compounds in Table 5 were prepared according to Method P using the acids listed in the table. In this table, all compounds have (3α,4β,5α) stereochemistry with respect to the dimethylpiperidinol group.

[1067] [Table 5]

[1068] Compound 137: N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-methyl-6-(methylsulfonyl)isonicotinamide.

[1069] [ka]

[1070] Compound 137 was prepared according to Method A (in DMF), starting from intermediate 40 and 2-methyl-6-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS [1780757-32-5]).

[1071] Compound 138: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(2-hydroxypropan-2-yl)-5-methylpicolinamide.

[1072] [ka]

[1073] Methylmagnesium bromide (3M in Et2O, CAS[75-16-1], 144 μL, 0.431 mmol, 2.2 equivalents) was added dropwise at 0°C to a solution of intermediate 26 (100 mg, 0.196 mmol) in dry THF (1 mL). Further methylmagnesium bromide (3M in Et2O, 65 μL, 0.196 mmol, 1 equivalent) was added at 0°C, and the reaction mixture was stirred overnight at room temperature. The mixture was cooled to 0°C, and the reaction was quenched by adding saturated aqueous NH4Cl solution. The mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica; ethyl acetate / heptane 0 / 100~40 / 60) to obtain compound 138 (51 mg, 47%) as a yellow solid.

[1074] Compound 139: N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide.

[1075] [ka]

[1076] Compound 139 was prepared according to Method A (in DMF), starting from intermediate 23 and 2-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS[1186663-27-3]).

[1077] Compound 140: N-((2-(6-((3α,5α)-4-hydroxy-3,4,5-trimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1078] [ka]

[1079] DIPEA (0.3 mL, 1.74 mmol) was added to a solution of intermediate 21 (80 mg, 0.17 mmol) and (3α,4α,5α)-3,4,5-trimethyl-4-piperidinol hydrochloride (1:1) (CAS [2306425-61-4], 76 mg, 0.43 mmol) in DMSO (1 mL), and the reaction mixture was stirred overnight at 130°C. The reaction mixture was diluted with DCM (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica, MeOH in DCM 0-10%) to obtain compound 140 (66 mg, yield: 67%).

[1080] Compound 141:( * R)-N-((2-(6-(2-(methoxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide and compound 142:( * S)-N-((2-(6-(2-(methoxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1081] [ka] Compound 141:( * R) is a pure stereoisomer, but its absolute stereochemistry is indeterminate.

[1082] [ka] Compound 142:( * S) is a pure stereoisomer, but its absolute stereochemistry is indeterminate.

[1083] Compounds 141 and 142 were prepared according to Method J using intermediate 21 and 2-(methoxymethyl)pyrrolidine (CAS [76946-27-5]), followed by preparative SFC (stationary phase: Chiralcel Diacel OJ 20 × 250 mm, mobile phase: CO2, EtOH + 0.4% iPrNH2).

[1084] Compound 143: N-((2-(6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1085] [ka]

[1086] Compound 143 was prepared according to Method J using intermediate 21 and 1-methyl-4-(piperidine-4-yl)piperazine (CAS[436099-90-0]).

[1087] Compound 144: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( * R)-1-hydroxyethyl)nicotinamide and compound 145:N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( * S)-1-hydroxyethyl)nicotinamide.

[1088] [ka] Compound 144:( * R (cis) is a pure stereoisomer, but its absolute stereochemistry is indeterminate.

[1089] [ka] Compound 145:(* S, cis) is a pure stereoisomer, but its absolute stereochemistry is indeterminate.

[1090] Compounds 144 and 145 were prepared by reacting intermediate 24 and intermediate 25, respectively, with intermediate 15 according to Method B.

[1091] Compound 146: 4-acetyl-5-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)picolinamide.

[1092] [ka]

[1093] Compound 146 was prepared using intermediates 6 and 42 according to method C (in DMF).

[1094] The compounds in Table 6 were prepared according to Method K using intermediate 21 and the indicated amine.

[1095] [Table 6]

[1096] Compound 150: N-((2-(6-(1,7-diazaspiro[3.5]nonane-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1097] [ka]

[1098] TFA (56 μL, 0.735 mmol, 10 equivalents) was added to a suspension of intermediate 30 (48 mg, 0.073 mmol) in DCM (0.5 mL) at room temperature. The reaction mixture was stirred at 40°C for 72 hours. The reaction mixture was evaporated, and the residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm, mobile phase: solution of 0.25% NH4HCO3 in water, ACN), followed by preparative SFC (stationary phase: TorusDiol 30 × 150 mm, mobile phase: CO2, MeOH) to obtain compound 150 (3 mg, yield: 7%).

[1099] Compound 155: N-((2-(6-(2,8-diazaspiro[4.5]decane-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1100] [ka]

[1101] HCl (4M in 1,4-dioxane, 1.5 mL, 6 mmol, 88 equivalents) was added to a solution of intermediate 31 (45 mg, 0.068 mmol) in DCM (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The precipitate that appeared was filtered and washed with 1,4-dioxane. The solid was dissolved in MeOH and evaporated to dryness to obtain compound 155 (HCl salt, 34 mg, yield: 79%) as an orange solid.

[1102] Compound 156: (Racemic)-N-((2-(6-(3-(methylamino)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1103] [ka]

[1104] Compound 156 was prepared in the same manner as compound 155, using intermediate 32 instead of intermediate 31.

[1105] Compound 157: (R)-N-((2-(6-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1106] [ka]

[1107] Compound 157 was prepared according to Method J using intermediate 21 and D-prolinol (CAS[68832-13-3]).

[1108] Compound 158: N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-methyl-6-(methylsulfonyl)isonicotinamide.

[1109] [ka]

[1110] A solution of intermediate 49 (73 mg, 0.107 mmol) in an aqueous NaOH solution (2.5 M, 0.43 mL, 1.069 mmol, 10 equivalents) was stirred at 65°C for 72 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted by DCM (×3). The organic layer was dried with (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography (12 g silica, DCM / MeOH(9 / 1) in DCM, 0%~30%) to obtain compound 158 (19 mg, yield: 30%) as a yellow solid.

[1111] Compound 159: (Rasemic)-N-((2-(6-(3-aminopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1112] [ka]

[1113] Compound 159 was prepared in the same manner as compound 155, using intermediate 33 instead of intermediate 31.

[1114] Compound 160: N-((2-(6-(3,3-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1115] [ka]

[1116] 2,2-dimethylpiperazine dihydrochloride (CAS[128427-07-6], 83 mg, 0.443 mmol, 4 equivalents) and DIPEA (210 μL, 1.22 mmol, 11 equivalents) were added to a suspension of intermediate 21 (50 mg, 0.111 mmol) in dry DMSO (1 mL). The reaction mixture was stirred at 90°C overnight, then at 130°C for 5 hours. Further 2,2-dimethylpiperazine dihydrochloride (83 mg, 0.443 mmol, 4 equivalents) was added, and the mixture was stirred at 140°C for 24 hours. The reaction mixture was diluted with SiO2 aqueous solution (1 M). The mixture was extracted twice with SiO2. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-5μm, 50×250mm, mobile phase: solution of 0.25% NH4HCO3 in water, ACN) to obtain compound 160 (5 mg, yield: 9%).

[1117] Compound 161: N-((2-(6-(2,5-dioxa-8-azaspiro[3.5]nonanane-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1118] [ka]

[1119] 2,5-Dioxa-8-Azaspiro[3.5]nonanehemiooxalate (CAS[1184185-17-8], 77 mg, 0.222 mmol, 2 equivalents) and DIPEA (210 μL, 1.22 mmol, 11 equivalents) were added to a suspension of intermediate 21 (50 mg, 0.111 mmol) in dry DMSO (1 mL), and the reaction mixture was stirred at 90°C overnight, then at 130°C for 5 hours. Further 2,5-Dioxa-8-Azaspiro[3.5]nonanehemiooxalate (77 mg, 0.222 mmol, 2 equivalents) was added, and the reaction mixture was stirred at 140°C overnight. The reaction mixture was diluted with SiO2 and NaOH aqueous solution (1 M). The mixture was extracted twice with SiO2 and twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10μm, 30×150mm, mobile phase: solution of 0.25% p NH4HCO3 in water, ACN), followed by another preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-5μm, 50×250mm, mobile phase: solution of 0.25% NH4HCO3 in water and MeOH) to obtain compound 161 (17mg, yield: 29%).

[1120] Compound 162: 5-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(2-hydroxypropan-2-yl)picolinamide.

[1121] [ka]

[1122] Methylmagnesium bromide (3M in Et2O, 116 μL, 0.348 mmol, 2.2 equivalents) was added dropwise at 0°C to a solution of compound 146 (84 mg, 0.158 mmol) in dry THF (1 mL). Further methylmagnesium bromide (3M in Et2O, 53 μL, 0.158 mmol, 1 equivalent) was added at 0°C, and the mixture was stirred overnight at room temperature. The mixture was cooled to 0°C, and the reaction was quenched by adding saturated aqueous NH4Cl solution. The mixture was diluted with water and extracted with RINKAN (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica, siRNA / heptane 0 / 100~40 / 60), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30×100 mm 5 μm column; 39% [25 mM NH4HCO3]-61% [ACN:MeOH (1:1)]~11% [25 mM NH4HCO3]-89% [ACN:MeOH (1:1)]), yielding compound 162 (15 mg, yield: 17%) as a yellow solid.

[1123] Compound 163: N-((2-(6-(2,7-diazaspiro[3.5]nonane-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1124] [ka]

[1125] TFA (1 mL, 13.067 mmol, 83 equivalents) was added to a solution of intermediate 34 (101 mg, 0.157 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by adding aqueous NaOH (1 M) solution, and the mixture was extracted with ELISA. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g DCM / MeOH with 7 N NH3:DCM 1:9) 100 / 0~0 / 100) to obtain compound 163 (31 mg, yield: 36%) as a yellow solid.

[1126] Compound 164: (Racemic)-N-((2-(6-(2-(aminomethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1127] [ka]

[1128] Intermediate 35 (136 mg, 0.22 mmol) was dissolved in TFA (1 mL, 13.067 mmol, 59 equivalents), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and basicized to pH 10 with 1 M NaOH aqueous solution. The mixture was extracted with DCM (5 ×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-5 μm, 50 × 250 mm, mobile phase: solution of 0.25% NH4HCO3 in water, ACN) to obtain compound 164 (19 mg, yield: 16%).

[1129] Compound 165: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide.

[1130] [ka]

[1131] Compound 165 was prepared according to Method M using intermediates 6 and 38.

[1132] Compound 166: N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide.

[1133] [ka]

[1134] Compound 166 was prepared according to Method A (in DMF) using intermediate 51 and 2-(methylsulfonyl)-4-pyridinecarboxylic acid (CAS[1186663-27-3]).

[1135] Compound 167: N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)isonicotinamide.

[1136] [ka]

[1137] Compound 167 was prepared according to Method M using intermediate 29 and 5-(methylsulfonyl)nicotinic acid (CAS [893723-59-6]).

[1138] Compound 168: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( *R)-1-hydroxyethyl)picolinamide and compound 169:N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( * S)-1-hydroxyethyl)picolinamide.

[1139] [ka] Compound 168( * R), cis: Pure stereoisomer, but absolute stereochemistry is indeterminate.

[1140] [ka] Compound 169( * S), cis: Pure stereoisomers, but their absolute stereochemistry is indeterminate.

[1141] Sodium borohydride (15 mg, 0.403 mmol, 2 equivalents) was added at 0°C under a nitrogen atmosphere to a solution of intermediate 139 (100 mg, 0.201 mmol) in MeOH (2 mL) and dry THF (2 mL), and the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate (3 ×). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g silica, ethyl acetate / heptane 0 / 100~50 / 50), followed by SFC (Amilose_2 column, SCP2: isocratic 10% iPrOH / heptane + 0.1% DEA) to obtain impurity compound 168 and impurity compound 169. Both compounds were re-purified by reverse-phase chromatography (Phenomenex Gemini C18 30×100 mm 5 μm column; 50% [25 mM NH4HCO3]-50% [ACN:MeOH (1:1)] to 25% [25 mM NH4HCO3]-75% [ACN:MeOH (1:1)]) to obtain compound 168 (6 mg, yield: 6%) and compound 169 (10 mg, yield: 9%), both as yellow solids.

[1142] Compound 170: (racemic)-N-((2-(6-(3-amino-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1143] [ka]

[1144] TFA (63 μL, 0.824 mmol, 10 equivalents) was added to a suspension of intermediate 36 (51 mg, 0.082 mmol) in DCM (0.5 mL) at room temperature. The reaction mixture was stirred at 40°C for 72 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm, mobile phase: solution of 0.25% NH4HCO3 in water, ACN) to obtain compound 170 (28 mg, yield: 65%).

[1145] Compound 171: N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide.

[1146] [ka]

[1147] 2-[(2-hydroxyethyl)sulfonyl]-4-pyridinecarboxylic acid (CAS[1855331-07-5], 405 mg, 0.35 mmol) and DIPEA (305 μL, 1.75 mmol) were added to a solution of intermediate 23 (106 mg, 0.29 mmol) in DMF (7 mL). The reaction mixture was stirred and treated with HATU (CAS[148893-10-1], 144 mg, 0.38 mmol). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (12 g of SiO2; siRNA / heptane, 0 / 100 to 30 / 70), followed by reverse-phase HPLC (Phenomenex Gemini ID (mm) 100 × 21.2, 5 μm (C18) 110A; 72% H2O (0.1% HCOOH) - 28% ACN:MeOH 1:1 to 36% H2O (0.1% HCOOH) - 64% ACN:MeOH 1:1) to obtain compound 171 (14 mg, yield: 8%) as a yellow solid.

[1148] Compound 172: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide.

[1149] [ka]

[1150] DIPEA (0.35 mL, 1.94 mmol) was added at room temperature to a stirred solution of intermediate 171 (100 mg, 0.46 mmol) and HATU (CAS[148893-10-1], 221 mg, 0.58 mmol) in DMF (3.5 mL). The reaction mixture was stirred at room temperature for 1 hour. Intermediate 6 (163 mg, 0.387 mmol) was then added, and the mixture was stirred at room temperature for 3 hours, then at 50°C for 5 hours. Further HATU (221 mg, 0.58 mmol) was added, and the reaction mixture was stirred at 50°C for 2 hours. After cooling, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO2 (×3). The combined organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (25 g silica; DCM / MeOH in DCM 0 / 100~25 / 75), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30×100 mm 5 μm; 59% [25 mM NH4HCO3] - 41% [ACN:MeOH (1:1)] ~ 17% [25 mM NH4HCO3] - 83% [ACN:MeOH (1:1)]), yielding compound 172 (15 mg, yield: 7%) as a yellow solid.

[1151] Compound 173: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide.

[1152] [ka]

[1153] Intermediate 38 (140 mg, 0.24 mmol) and DIPEA (230 μL, 1.32 mmol) were added to a solution of intermediate 15 (89 mg, 0.22 mmol) in DMF (3 mL). The reaction mixture was stirred and treated with HATU (CAS [148893-10-1], 105 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with siRNA. The organic phase was separated, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (12 g of SiO2; DCM: MeOH (9:1) in DCM 0%~40%) to obtain compound 173 (29 mg, yield: 22%) as a yellow solid.

[1154] Compound 174: N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-4-(methylsulfonyl)picolinamide.

[1155] [ka]

[1156] HATU (CAS[148893-10-1], 90 mg, 0.155 mmol) was added to a solution of intermediate 51 (75 mg, 0.123 mmol), 6-methyl-4-(methylsulfonyl)-2-pyridinecarboxylic acid (CAS[2735727-68-9], 59 mg, 0.137 mmol), and DIPEA (0.11 mL, 0.632 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with AcOEt (×3). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (12 g SiO2; AcOEt / DCM0 / 100~70 / 30) to obtain compound 174 (45 mg, yield: 62%) as a yellow solid.

[1157] Compound 175: N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide.

[1158] [ka]

[1159] Intermediate 151 (61 mg, 0.25 mmol) and DIPEA (218 μL, 1.25 mmol) were added to a solution of intermediate 23 (91 mg, 0.21 mmol) in DMF (3 mL). The reaction mixture was stirred and treated with HATU (CAS [148893-10-1], 103 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with SiO2 (×3). The organic phase was separated, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified twice by flash column chromatography (12 g SiO2; DCM:MeOH (9:1) 0 / %~40%) to obtain compound 175 (19 mg, yield: 15%) as a yellow solid.

[1160] Compound 176: (Rasemic)-N-((2-(6-(4-hydroxy-2,2-dimethylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1161] [ka]

[1162] In a sealed vial, a suspension of 5,5-dimethylpyrrolidine-3-ol (CAS[1784937-75-2], 183 mg, 1.589 mmol) and intermediate 21 (170 mg, 0.377 mmol) in DIPEA (1 mL, 5.803 mmol) was stirred overnight at 150°C. After cooling, DMSO (0.5 mL) was added, and the reaction mixture was stirred at 150°C for 10 days. The reaction mixture was diluted with water and extracted with pharmaceutically acceptable (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (RP XBridge Prep C18 OBD-10μm, 30×150mm; 0.5% NH4Ac solution in water + 10% ACN, ACN), followed by flash column chromatography (SiO2; DCM / DCM:MeOH9:1, 100 / 0~0 / 100) to obtain compound 176 (5 mg, yield: 2%).

[1163] Compound 177: N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide.

[1164] [ka]

[1165] Intermediate 38 (49 mg, 0.21 mmol) and DIPEA (201 μL, 1.16 mmol) were added to a solution of intermediate 51 (88 mg, 0.19 mmol) in DMF (2 mL). The reaction mixture was stirred and treated with HATU (CAS [148893-10-1], 92 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (×3). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (12 g SiO2; DCM: MeOH (9:1) 0 / 100~100 / 0 in DCM) to obtain compound 177 (21 mg, yield: 18%) as a yellow solid.

[1166] Compound 178: N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( * R)-1-hydroxyethyl)nicotinamide.

[1167] [ka]

[1168] In a round-bottom flask, intermediate 51 (50 mg; 0.11 mmol) was added at room temperature to a stirred solution in DMF (5 mL) containing intermediate 152 (19 mg; 0.11 mmol), HATU (CAS [148893-10-1], 64 mg; 0.17 mmol), and DIPEA (0.163 mL, 0.93 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with AcOEt. The organic layer was washed with brine (×2), dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (24 g silica; MeOH / DCM0 / 100~10 / 90), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30×100 mm 5 μm; 70% [25 mM NH4HCO3] - 30% [ACN:MeOH (1:1)] ~ 27% [25 mM NH4HCO3] - 73% [ACN:MeOH (1:1)]). The product was ground in Et2O, filtered, and dried to obtain compound 178 (9 mg; yield: 16%) as a white solid.

[1169] Compound 179: N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( * S)-1-hydroxyethyl)nicotinamide.

[1170] [ka]

[1171] Compound 179 was prepared using intermediate 153 instead of intermediate 152, following the same procedure as for compound 178.

[1172] Compound 180: 1-(methylsulfonyl)-N-((2-(3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)-1H-pyrrole-3-carboxamide.

[1173] [ka]

[1174] 1-Methanesulfonyl-1H-pyrrole-3-carboxylic acid (CAS[1521806-48-3], 70 mg, 0.310 mmol, 1.1 equivalents) and DIPEA (147 μL, 0.844 mmol, 3.0 equivalents) were added to a solution of intermediate 79 (120 mg, 0.281 mmol, 1.0 equivalent) in DCM (20 mL). The reaction mixture was stirred for 1 minute, and HATU (CAS[148893-10-1], 123 mg, 0.324 mmol, 1.15 equivalents) was added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with SiO2. The organic layer was dried over (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by flash chromatography (12 g of SiO2, DCM; MeOH (9:1) in DCM, 0%-30%) to obtain compound 180 (38 mg, yield: 27%) as a beige solid.

[1175] Compound 181: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide.

[1176] [ka]

[1177] 1-Methanesulfonyl-1H-pyrrole-3-carboxylic acid (CAS[1521806-48-3], 48 mg, 0.252 mmol, 1.1 equivalents) and DIPEA (120 μL, 0.687 mmol, 3.0 equivalents) were added to a solution of intermediate 6 (80 mg, 0.229 mmol, 1.0 equivalent) in DCM (2 mL) and DMF (1 mL). The reaction mixture was stirred for 1 minute, and HATU (CAS[148893-10-1], 100 mg, 0.263 mmol, 1.15 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with siRNA. The organic layer was dried over (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by flash chromatography (12 g of SiO2, DCM; 0% to 25% MeOH (9:1) in DCM) to obtain compound 181 (37 mg, yield: 30%) as a yellow solid.

[1178] Compound 182: 4,5-dichloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1-(isopropylsulfonyl)-1H-pyrrole-3-carboxamide.

[1179] [ka]

[1180] HATU (CAS[148893-10-1], 285 mg, 0.75 mmol, 1.5 equivalents) was added at room temperature to a stirred solution of intermediate 6 (211 mg, 0.5 mmol, 1 equivalent), intermediate 123 (143 mg, 0.5 mmol, 1 equivalent), and DIPEA (0.26 mL, 1.5 mmol, 3 equivalents) in DCM (5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with 1 M aqueous Na2CO3 solution and extracted with siRNA (2 × 15 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (25 g SiO2, 0-2% MeOH in DCM) to obtain compound 182 (170 mg, yield: 54%) as a yellow powder.

[1181] Compound 183: N-((2-(6-((3α,4β,5α))-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)thiophene-2-carboxamide.

[1182] [ka]

[1183] A solution of intermediate 23 (35 mg, 0.0718 mmol) and Et3N (60 μL, 0.43 mmol, 6 equivalents) in DCM (1 mL) was added to 5-(methylsulfonyl)-2-thiophenecarboxylic acid (CAS[60166-86-1], 25 mg, 0.12 mmol, 1.7 equivalents). 1-propanephosphonic anhydride (CAS[68957-94-8], 50% in ethyl acetate, 72 μL, 0.12 mmol, 1.7 equivalents) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature. DMSO (500 μL) was added, and the DCM was evaporated under reduced pressure. The residual DMSO solution was purified by reverse-phase column chromatography (RP XBridge Prep C18 OBD-10μm, 30×150mm; 0.25% NH4HCO3 solution in water, ACN) to obtain compound 183 (21 mg, yield: 54%).

[1184] Compound 184: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1-methyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxamide.

[1185] [ka]

[1186] Compound 184 was prepared using the same procedure as for compound 192, but with intermediate 6 instead of intermediate 23 and 1-methyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxylic acid (CAS[1227070-38-3]) instead of intermediate 171.

[1187] Compound 185: N-((2-(3-chloro-4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide.

[1188] [ka]

[1189] HATU (CAS [148893-10-1], 76 mg, 0.2 mmol, 1.5 equivalents) was added at room temperature to a stirred solution of intermediate 126 (97 mg, 0.05 mmol, 1 equivalent), 5-(methylsulfonyl)nicotinic acid (CAS [893723-59-6], 40 mg, 0.2 mmol, 1.1 equivalents), and DIPEA (0.13 mL, 0.7 mmol, 3 equivalents) in DCM (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and...

Claims

1. Equation (I) 【Chemistry 1】 Compounds thereof, or pharmaceutically acceptable salts or stereoisomers thereof, During the ceremony, R １ but, (a) 【Chemistry 2】 A five-membered heteroaryl selected from; or (b) 【Transformation 3】 Here, Each R ａ Hello, C １～４ C substituted with alkyl and OH groups １～４ Alkyl, C １～４ Haloalkyl and (C=O)CH ３ Selected independently of; R ｂ is C substituted with OH １～４ alkyl; OC １～４ alkyl; OCH ２ CH ２ OH; and OCHF ２ selected from; or (c) 【Chemistry 4】 A six-membered heteroaryl selected from; Here, Each R ｄ Independently, C １～４ Alkyl, C １～４ Haloalkyl and OC １～４ It is alkyl; R ｅ C １～４ Alkyl, OH, or OCH ３ C replaced by １～４ Alkyl and C １～４ Selected from haloalkyls; X is either N or O. It is a heteroaryl that is optionally substituted from; R ５ but, (i) 【Transformation 5】 Here, ring A is, 【Transformation 6】 【Transformation 7】 A nitrogen-linked monocyclic, polycyclic, crosslinked, spirocyclic, or condensed heterocycloalkyl selected from the following, each R ｃ These are independently, Halo or CH ３ is; or (ii) 【Transformation 8】 Here, ring B is, 【Chemistry 9】 It is a nitrogen-linked monocyclic, polycyclic, or spirocyclic heterocycloalkyl selected from; or (iii) Phenyl, 【Chemistry 10】 Here, R ｋ (CH)(CH ３ ) ２ , oxetane-3-yl, 【Chemistry 11】 Selected from; R ｆ is H or CH ３ And; R ｇ teeth, 【Chemistry 12】 Selected from; R ｈ C １～４ It is alkyl; R ｊ teeth, 【Chemistry 13】 Selected from; n is 0, 1, or 2. A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

2. R １ but, 【Chemistry 14】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. (i) R １ but, 【Chemistry 15】 is, or (ii) R １ but, 【Chemistry 16】 is, or (iii) R １ but, 【Chemistry 17】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. (i) X is O; or (ii) The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N.

5. (i) n is 0; or (ii) n is 1, or (iii) The compound according to claim 1, wherein n is 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. R ５ but, [Chemistry 18] The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. (i) R ５ but, 【Chemistry 19】 is; or (ii) R ５ but, 【Chemistry 20】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-methyl-4-(methylsulfonyl)picolinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(methylsulfonyl)picolinamide; (Racemic)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(1-hydroxyethyl)-5-methylpicolinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( ＊ R)-1-hydroxyethyl)-5-methylpicolinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( ＊ S)-1-hydroxyethyl)-5-methylpicolinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-methyl-4-(methylsulfonyl)picolinamide; N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(2-hydroxy-7-azaspiro[3.5]nonane-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((1α,5α)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(2-methoxyethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(methyl(2-morpholinoethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(2-(2-hydroxyethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(4-hydroxy-6-azaspiro[2.5]octan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(methyl(tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-methoxy-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-(N-((2-(6-(3-(methoxymethyl)-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-hydroxy-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-(3-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-(3-hydroxypyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-(hydroxymethyl)-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-3-hydroxy-4-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((trans)-3-hydroxy-4-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(2-(hydroxymethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-(((1,2,4,4-tetramethyl-5-oxopyrrolidine-2-yl)methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(3-(4-methyl-4-oxide-1,4-azaphosfinan-1-yl)azetidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-(((4-(cyclopropylmethyl)-5-oxomorpholin-2-yl)methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-(3-ethyl-4-(2-hydroxyethyl)-5-oxo-1,4-diazepan-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(5-cyano-2-azabicyclo[3.1.1]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-(3-methyl-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3aR,6aR)-5-methyl-6-oxohexahydropyrrolo[3,4-b]pyrrole-1(2H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3aR,4S,7R,7aS)-4-methyloctahydro-2H-4,7-epoxyisoindole-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3aS,7aS)-5-(2,2-difluoroethyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3aR,6aS)-5-isobutyl-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((4-(2H-tetrazole-2-yl)butyl)aminopyridine-2-yl)-1,6-naphthyrizine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2R,5S)-5-(hydroxymethyl)-2,4-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-(methyl(1-(methylcarbamoyl)pyrrolidine-3-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3R,4R)-3-(hydroxymethyl)-4-(pyridine-2-yl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((3S,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)(methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-(3-(2-(ethyl(methyl)amino)-2-oxoethoxy)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-((2-hydroxypropyl)(propyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(3-cyclopropyl-3-hydroxyazetidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-(6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; 5-(methylsulfonyl)-N-((2-(6-(3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(3-(tert-butyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((3-fluorooxetan-3-yl)methyl)aminopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(1-imino-1-oxide-1λ ６ -Thiomolfolino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2-((dimethyl(oxo)-λ ６ -Sulfanylidene)amino)ethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(1-(isopropylimino)-1-oxide-1λ ６ -Thiomolfolino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(1-acetamido-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(3-fluoroazetidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 5-(methylsulfonyl)-N-((2-(6-(4-(methylsulfonyl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(4-hydroxy-4-(trifluoromethyl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-(quinuclidin-3-ylamino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-((2-(1H-imidazole-1-yl)ethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-isopropyl-3-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 5-(methylsulfonyl)-N-((2-(6-(5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; (Racemic)-N-((2-(6-(3-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-((1-methyl-2-oxoazepan-3-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-((7-Oxaspiro[3.5]nonane-1-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-(2-(3-methylisoxazole-5-yl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-(2-(pyridine-3-yl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(4-(6-(hydroxymethyl)pyridine-3-yl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; (S)-N-((2-(6-(2-(methylcarbamoyl)pyrroridine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(2-hydroxyethyl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-(1-oxo-2,7-diazaspiro[4.5]decane-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-((cis)-1,1-dioxidehexahydro-5H-thieno[2,3-c]pyrrole-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((4-isopropyl-4H-1,2,4-triazole-3-yl)methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(([1,2,4]triazolo[4,3-a]pyridine-3-ylmethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-((dimethylamino)methyl)-4-hydroxypiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-((1-(1H-1,2,4-triazole-1-yl)propan-2-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-(hydroxymethyl)-3-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-(3-(methyl(pyrimidine-2-yl)amino)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(2-(methoxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(7-methyl-2,7-diazaspiro[4.5]decane-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-(4-(((tetrahydrofuran-2-yl)methyl)amino)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(((1-(hydroxymethyl)cyclopropyl)methyl)(methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(7-methyl-6-oxa-2-azaspiro[3.4]octan-2-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-5-(methylsulfonyl)-N-((2-(6-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; (Racemic)-N-((2-(6-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)-1,6-naphthyrizine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2-methyl-2-morpholinopropyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(2-methyl-1-oxidethiomorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(((2,3-dihydrofl[2,3-c]pyridine-3-yl)methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(4-hydroxy-2-methylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-5-(methylsulfonyl)-N-((2-(6-((1-(oxetan-3-yl)pyrrolidine-3-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; (Racemic)-N-((2-(6-(3-methyl-5-oxopiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3-(2-methyl-1H-imidazole-1-yl)propyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(cyclobutanecarbonyl)piperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-5-(methylsulfonyl)-N-((2-(6-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazine-7(1H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-hydroxy-4,4-dimethoxypiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(ethyl((tetrahydrofuran-2-yl)methyl)aminopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2-(4-acetylpiperazine-1-yl)ethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(2-(dimethylamino)-2-oxoethyl)-4-hydroxypiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2-(dimethylamino)-2-oxoethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((1-(3-cyanopropyl)piperidine-4-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 5-(methylsulfonyl)-N-((2-(6-((3-(2-oxopyrrolidine-1-yl)propyl)aminopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; (Racemic)-N-((2-(6-(4-hydroxy-3-(pyrroridine-1-ylmethyl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2-(2-oxabicyclo[2.1.1]hexane-1-yl)ethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(3-methoxyazetidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(4-methoxy-3,3-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((((cis)-3-(dimethylamino)cyclobutyl)methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(((1,4-oxathian-2-yl)methyl)aminopyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-(6-(hydroxymethyl)-2,2-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(3-(2H-tetrazole-5-yl)azetidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(6-(methoxymethyl)-2,2-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(([1,3]dioxolo[4,5-b]pyridine-6-ylmethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-((1-(dimethylamino)propane-2-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-cyanopiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (S)-N-((2-(6-(2-(dimethylcarbamoyl)pyrroridine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(methyl(1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(ethyl(2-morpholinoethyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 5-(methylsulfonyl)-N-((2-(6-((1R,5S)-8-oxo-1,5,6,8-tetrahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazosin-3(4H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; (Racemic)-N-((2-(6-(3,3-dimethyl-1-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 5-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)pyrimidine-2-carboxamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(trifluoromethyl)picolinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-iodopicolinamide; N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-methyl-6-(methylsulfonyl)isonicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(2-hydroxypropan-2-yl)-5-methylpicolinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide; N-((2-(6-((3α,5α)-4-hydroxy-3,4,5-trimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; ( ＊ R)-N-((2-(6-(2-(methoxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; ( ＊ S)-N-((2-(6-(2-(methoxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ R)-1-hydroxyethyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ S)-1-hydroxyethyl)nicotinamide; 4-acetyl-5-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)picolinamide; N-((2-(6-((2-(dimethylamino)ethyl)(methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-3,5-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-(dimethylamino)piperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(1,7-diazaspiro[3.5]nonane-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-(dimethylamino)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2-hydroxyethyl)(methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((2-hydroxy-2-methylpropyl)(methyl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(methyl(1-methylpyrrolidine-3-yl)amino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(2,8-diazaspiro[4.5]decane-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(3-(methylamino)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (R)-N-((2-(6-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-methyl-6-(methylsulfonyl)isonicotinamide; (Racemic)-N-((2-(6-(3-aminopyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(3,3-dimethylpiperazine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(2,5-dioxa-8-azaspiro[3.5]nonane-8-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 5-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(2-hydroxypropan-2-yl)picolinamide; N-((2-(6-(2,7-diazaspiro[3.5]nonane-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; (Racemic)-N-((2-(6-(2-(aminomethyl)pyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-(methylsulfonyl)isonicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)isonicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( ＊ R)-1-hydroxyethyl)picolinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-(( ＊ S)-1-hydroxyethyl)picolinamide; (Racemic)-N-((2-(6-(3-amino-3-methylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-4-(methylsulfonyl)picolinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisonicotinamide; (Racemic)-N-((2-(6-(4-hydroxy-2,2-dimethylpyrrolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ R)-1-hydroxyethyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ S)-1-hydroxyethyl)nicotinamide; 1-(methylsulfonyl)-N-((2-(3-(pyridine-4-yl)phenyl)-1,6-naphthyridine-7-yl)methyl)-1H-pyrrole-3-carboxamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide; 4,5-Dichloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1-(isopropylsulfonyl)-1H-pyrrole-3-carboxamide; N-((2-(6-((3α,4β,5α))-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)thiophene-2-carboxamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1-methyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxamide; N-((2-(3-chloro-4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(2-hydroxypropane-2-yl)nicotinamide; N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; 5-((3,3-difluoropropyl)sulfonyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methylnicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ R)-1-hydroxyethyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)-3-methylpyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ S)-1-hydroxyethyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(S-methylsulfonimidoyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(2-hydroxyethylsulfonimidoyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ R)-2-hydroxyethylsulfonimidoyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ S)-2-hydroxyethylsulfonimidoyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(S-methylsulfonimidoyl)nicotinamide; N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(( ＊ R)-S-methylsulfonimidoyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(( ＊ S)-S-methylsulfonimidoyl)nicotinamide; N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)-6-(trifluoromethyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(6-(6-oxo-4-oxa-7-azaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(2-hydroxyethylsulfonimidoyl)nicotinamide; N-((2-(6-((3α,4β,5α))-4-(hydroxymethyl)-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(6-(5-oxo-2-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; ( ＊ R)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ S)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-phenyl-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(2,6-dimethyl-3-oxomorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-(2,2-dimethyl-3-oxomorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4-amino-3,3-difluoropiperidine-1-yl)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(6-((trans)-2-methyl-6-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(6-((cis)-2-methyl-6-(trifluoromethyl)morpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(1-methyl-6-oxo-2-(2,2,6,6-tetramethylmorpholino)-1,6-dihydropyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(6-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(4,4-dimethyl-2-oxoimidazolidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ R)-2-hydroxyethylsulfonimidoyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-(( ＊ S)-2-hydroxyethylsulfonimidoyl)nicotinamide; N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)-6-(trifluoromethyl)nicotinamide; N-((2-(2-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-(difluoromethyl)-5-(methylsulfonyl)nicotinamide; N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-isopropoxypyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(2-(2-oxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; 6-methyl-N-((2-(2-(1-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-(1-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(2-(6,8-dioxo-2,5,7-triazaspiro[3,4]octan-2-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(2-(6-oxo-2,5,7-triazaspiro[3,4]octan-2-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(2-(2,4-dioxo-1,3,7-triazaspiro[4,4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-(6,8-dioxo-5,7,11-triazadespiro[2.0.44.43]dodecane-11-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methoxynicotinamide; 6-methyl-N-((2-(2-(6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(1-methyl-2-((trans)-2-methyl-6-(trifluoromethyl)morpholino)-6-oxo-1,6-dihydropyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(2-(6,6-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ R)-N-((2-(2-(2,4-dioxo-1,3,7-triazaspiro[4,4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ S)-N-((2-(2-(2,4-dioxo-1,3,7-triazaspiro[4,4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-(trifluoromethyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 6-methyl-N-((2-(2-((6 ＊ R)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(2-(4-amino-3,3-difluoropiperidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-(4-acetamido-3,3-difluoropiperidine-1-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ R)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; ( ＊ S)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-((6 ＊ S)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4β,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5-methylpyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ R)-N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ S)-N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-((5 ＊ R, 6 ＊ R)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-((5 ＊ S, 6 ＊ S)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; ( ＊ R)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ S)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-((5 ＊ R, 6 ＊ R)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 6-methyl-N-((2-(2-((5 ＊ S, 6 ＊ S)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-5-(methylsulfonyl)nicotinamide; 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methylnicotinamide; 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; ( ＊ R)-N-((2-(2-(6,8-dioxo-5,7,11-triazadespiro[2.0.44.43]dodecane-11-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ S)-N-((2-(2-(6,8-dioxo-5,7,11-triazadespiro[2.0.44.43]dodecane-11-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylpyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4β,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylpyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4β,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4β,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-2-methylpyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 4-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)picolinamide; N-((2-(2-((trans)-2,4-dioxo-6-(trifluoromethyl)-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-((cis)-2,4-dioxo-6-(trifluoromethyl)-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(6-(oxetan-3-yloxy)pyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; ( ＊ R)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; ( ＊ S)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5-methylpyridine-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; 6-methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-1,6-naphthyridine-7-yl)methyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methoxy-5-(methylsulfonyl)nicotinamide; 4-(S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)picolinamide; 4-(( ＊ S)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)picolinamide; 4-(( ＊ R)-S-(difluoromethyl)sulfonimidoyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)picolinamide; N-((2-(2-((5 ＊ R,6 ＊ R,9 ＊ S)-6,9-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-((5 ＊ S, 6 ＊ S, 9 ＊ R)-6,9-dimethyl-2,4-dioxo-1,3,8-triazapiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-((5 ＊ R, 6 ＊ S, 9 ＊ R)-6,9-dimethyl-2,4-dioxo-1,3,8-triazapiro[4.5]decane-8-yl)pyrimidine-4-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(2-((5 ＊ S,6 ＊ R,9 ＊ S)-6,9-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-4-((2-methoxyethyl)sulfonyl)picolinamide A compound according to claim 1, selected from the group consisting of; and their pharmaceutically acceptable salts or stereoisomers.

9. N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine-1-yl)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methyl-5-(( ＊ S)-S-methylsulfonimidoyl)nicotinamide; and Compounds according to claim 1, selected from the group consisting of 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-6-methylnicotinamide; and pharmaceutically acceptable salts and stereoisomers thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 9 and at least one pharmaceutically acceptable excipient.

11. A compound according to any one of claims 1 to 9 for use in therapeutic purposes.

12. A compound according to any one of claims 1 to 9, for use in the treatment of SMARCA4-deficient cancer.

13. The compound for use according to claim 12, wherein the SMARCA4-deficient cancer is SMARCA4-deficient non-small cell lung cancer (NSCLC).

14. A compound according to any one of claims 1 to 9, for use in the treatment of a pathological condition or state mediated by the SMARCA2 protein.

15. The compound for use according to claim 14, wherein the pathological condition or state mediated by the SMARCA2 protein is cancer or non-small cell lung cancer (NSCLC).

16. Use of a compound according to any one of claims 1 to 9 for manufacturing a pharmacopoeia for the treatment of cancer or NSCLC.

17. An in vitro method for modulating SMARCA2 activity, comprising contacting the SMARCA2 protein, or a portion thereof, with a compound described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

18. A method for treating SMARCA4-deficient cancer, comprising administering a compound according to any one of claims 1 to 9 to a subject in need thereof.

19. The method according to claim 18, wherein the SMARCA4-deficient cancer is SMARCA4-deficient NSCLC.

20. A method for treating a pathological condition or state mediated by the SMARCA2 protein, comprising administering the compound described in any one of claims 1 to 9 to a subject in need thereof.

21. The method according to claim 20, wherein the disease or condition is selected from cancer or NSCLC.

22. The method according to any one of claims 18 to 21, wherein the subject is a mammal.

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