1, 6-naphthyridine compounds as SMARCA2 inhibitors useful for treatment of SMARCA4 deletion cancers

Abstract

The present invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, methods for preparing said compounds and uses of said compounds as SMARCA2 protein inhibitors and their use in the treatment of SMARCA4 deletion cancers, such as SMARCA4 deletion non-small cell lung cancer (NSCLC).

Description

Technical Field

[0001] This invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, methods for preparing said compounds, the use of said compounds as SMARCA2 protein inhibitors, and their use in the treatment of SMARCA4-deficient cancers such as SMARCA4-deficient non-small cell lung cancer (NSCLC). Background Technology

[0002] The sucrose nonfermentation complex (SWI / SNF), 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, chromatin actin-dependent regulators, subfamily A, member 2 (SMARCA2, BRAHMA, or BRM) and SWI / SNF-associated, matrix-associated, chromatin actin-dependent regulators, subfamily A, member 4 (SMARCA4 or BRG1). The core and regulatory subunits combine ATP hydrolysis with perturbations of histone-DNA contacts, thereby providing entry points for transcription factors and homologous DNA elements that facilitate gene activation and repression.

[0003] Mutations in genes encoding twenty typical SWI / SNF subunits have been observed in nearly 20% of all cancers, with the highest frequency observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer, and clear cell renal cell carcinoma. Despite their high homology and presumed overlapping functions, SMARCA2 and SMARCA4 have been reported to play distinct roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is uncommon in tumor development. In fact, many types of cancer have been shown to be SMARCA4-related (e.g., cancers with SMARCA4 mutations or SMARCA4 deletions, such as lack of expression), including, for example, lung cancers (such as non-small cell lung cancer or NSCLC).

[0004] SMARCA2 has been shown to be one of the most important essential genes in SMARCA4-related or mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells are entirely dependent on SMARCA2 activity—that is, SMARCA2 is incorporated more into the complex to compensate for SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The co-occurrence of the loss of expression of two (or more) genes leading to cell death is called synthetic lethality. Therefore, synthetic lethality can be used to treat certain SMARCA2 / SMARCA4-related cancers.

[0005] There remains a persistent need for effective treatments for diseases that can be managed by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecificity and the inability to selectively target and modulate SMARCA2 remain obstacles to the development of effective treatments. Therefore, small molecule therapeutics targeting SMARCA2 would be extremely valuable.

[0006] One object of the present invention is to provide compounds that are more selective for SMARCA2 than for SMARCA4.

[0007] One object of the present invention is to provide an effective SMARCA2 inhibitor for the treatment of SMARCA4-deficient cancers.

[0008] One object of the present invention is to provide a compound, SMARCA2 inhibitor, for the effective treatment of SMARCA4-deficient NSCLC. Summary of the Invention

[0009] Embodiments of the present invention relate to certain uses and methods of use of 1,6-naphthidine chemical entities having SMARCA2 regulatory properties as claimed in the claims, and pharmaceutical compositions comprising these chemical entities, the use of said chemical entities as SMARCA2 protein inhibitors, and methods of treating SMARCA4-deficient cancers or their use in treating SMARCA4-deficient cancers.

[0010] Additional embodiments, features, and advantages of the present invention will become apparent from the following detailed description and by practicing the invention.

[0011] Embodiments of the present invention are uses and treatments utilizing compounds of formula (I). (I) Or its pharmaceutically acceptable salts or stereoisomers. in R 1 It is selected from the following optionally substituted heteroaryl groups: (a) Selected from the following 5-membered heteroaryl groups: , , and ;or (b) , and ; in Each R a Independently selected from: halogenated group, C 1-4 Alkyl groups, C groups substituted with OH1-4 Alkyl, C 1-4 Halogenated alkyl groups and (C=O)CH3; R b Selected from: C replaced by OH 1-4 Alkyl; OC 1-4 Alkyl; OCH2CH2OH; and OCHF2; or (c) Selected from the following 6-membered heteroaryl groups: , and ; in Each R d C is independent 1-4 Alkyl, C 1-4 Halogenated alkyl groups and OC 1-4 alkyl; R e Selected from: C 1-4 Alkyl groups, C atoms substituted with OH or OCH3 1-4 Alkyl and C 1-4 Halogenated alkyl groups; X is NH or O; R 5 yes (i) Wherein ring A is selected from the following nitrogen-linked monocyclic, polycyclic, bridged, spirocyclic, or fused heterocyclic alkyl groups: And each R c It is independently a halogenated group or CH3; or (ii) , , and Wherein ring B is selected from the following nitrogen-linked monocyclic, polycyclic, spirocyclic heterocyclic alkyl groups: ,or (iii) Phenyl, , , , and ; Where R k Selected from: (CH)(CH3)2, oxetane-3-yl, and ; R f It is H or CH3; R g Selected from: R h It is C 1-4 alkyl; R j Selected from: or ;as well as n is 0, 1, or 2; And its pharmaceutically acceptable salts and stereoisomers.

[0012] Incorporated by reference All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, patent application, or published nucleotide and amino acid sequence is specifically and individually indicated to be incorporated herein by reference. Detailed Implementation

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in relation to the subject matter to which protection is sought. In the reference to URLs or other such identifiers or addresses, it should be understood that such identifiers can change, and specific information on the Internet can change over time, but equivalent information can be found by searching the Internet. The reference to such references demonstrates the availability and public dissemination of such information.

[0014] It should be understood that the foregoing general description and the following detailed description are merely exemplary and illustrative, and do not constitute a limitation on any subject matter claimed.

[0015] In this application, unless otherwise specified, the use of the singular includes the plural. It must be noted that, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms “a,” “an,” “the,” and “described” include the plural referents. In this application, unless otherwise specified, the use of “or” means “and / or.”

[0016] When the word "about" is used to indicate an approximate value, it should be understood that the specific value constitutes another implementation. As used herein, "about X" (where X is a numerical value) preferably refers to the referenced value ±10%, inclusive. For example, the phrase "about 8" refers to a value of 7.2 to 8.8, inclusive; similarly, the phrase "about 8%" refers to a value of 7.2% to 8.8%, inclusive. Where applicable, all ranges are inclusive and composable. For example, when a range of "1 to 5" is referenced, the referenced range should be understood to include ranges such as "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. Furthermore, when a list of alternatives is provided affirmatively, such a list may also include implementations of any alternatives that may exclude the alternatives. For example, when describing a range of “1 to 5”, such a description may cover cases in which any of 1, 2, 3, 4 or 5 is excluded; therefore, a reference to “1 to 5” may cover “1 and 3 to 5, but not 2”, or simply “not including 2”.

[0017] Some of the quantitative expressions given in this article are not modified by the term “approximately”. It should be understood that, whether or not the term “approximately” is explicitly used, each quantity given in this article is intended to refer to an actual given value, and also to an approximation of such given values ​​that can be reasonably inferred by one of ordinary skill in the art, including approximations of such given values ​​caused by experimental and / or measurement conditions and acceptable error tolerances.

[0018] As used in this article, the expression “one or more” means at least one, such as one, two, three, four, five or more, as long as possible and depending on the context.

[0019] Furthermore, the use of the term "including" and other forms such as "including," "contains," and "comprises" is not restrictive.

[0020] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0021] Definitions of standard chemical terms can be found in the references, including but not limited to Carey and Sundberg, "Advanced Organic Chemistry 4". th Ed. A (2000) and B (2001), Plenum Press, New York.

[0022] Unless specifically defined, the nomenclature, laboratory procedures, and techniques used in analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are those generally accepted in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). Reaction and purification techniques can be performed, for example, using kits provided with the manufacturer's instructions or as commonly performed in the art or as described herein. The foregoing techniques and procedures can generally be performed according to conventional methods and are described in the various general and more specific references cited and discussed throughout this specification.

[0023] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs, and reagents described herein, and therefore can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0024] In the preceding and following text, the term "compound having formula (I)" means including its addition salts as well as stereoisomers.

[0025] As used in this article, "C" x-y "(where x and y are integers) refers to the number of carbon atoms constituting the specified part (excluding optional substituents). Therefore, C 1-6 Alkyl groups contain 1 to 6 carbon atoms, C 3-6 Cycloalkyl groups contain 3 to 6 carbon atoms, etc.

[0026] The term “halogenated group” or alternatively “halogen” refers to fluorine, chlorine, bromine and iodine.

[0027] An alkyl group can have 1 to 6 carbon atoms (when used herein, numerical ranges such as "1 to 6" refer to each integer within a given range; for example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., and may contain up to 6 carbon atoms, but the definition of this invention also covers the term "alkyl" when no numerical range is specified). The alkyl group of the compounds described herein can be specified as "C". 1-6Alkyl or similar names.

[0028] By way of example, as used herein, the term "C" as a group or part of a group 1-4 "alkyl" or "C" 1-6 "Alkyl" refers to a straight-chain 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, hexyl, etc.

[0029] 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. The term "haloalkyl" includes "halogenated C..." 1-4 Alkyl group, halogenated C 1-6 Alkyl group, monohalogenated C 1-4 Alkyl, monohalogenated C 1-6 Alkyl, polyhalogenated C 1-4 Alkyl and polyhalogenated C 1-6 Alkyl groups. They can contain one, two, three, or more hydrogen atoms replaced by halogens, thus halogenated C... 1-4 Alkyl or halogenated C 1-6 Alkyl groups may have one, two, 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 groups that, in accordance with those skilled in the art and the teachings provided herein, would be considered equivalent to any of the foregoing examples.

[0030] "Amino" refers to the -NH2 group.

[0031] The term "aromatic" refers to a planar ring having a delocalized π-electron system comprising 4n+2 π electrons, where n is an integer. Aromatic rings can be formed of five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term "aromatic" includes aryl groups (e.g., phenyl, naphthyl) and heteroaryl groups (e.g., pyridyl, quinolinyl).

[0032] Unless the context otherwise indicates, the term "non-aromatic group" includes unsaturated ring systems without aromatic characteristics, partially saturated and fully saturated heterocyclic ring systems.

[0033] The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure contains atoms sharing more than one valence bond, that is, the ring contains at least one multiple bond, such as C=C, C≡C or N=C bond.

[0034] The term "fully saturated" refers to a ring in which there are no multiple bonds between the ring atoms. Saturated heterocyclic groups include piperidine, morpholine, thiomorpholine, and piperazine. Partially saturated heterocyclic groups include pyrazolines, such as 2-pyrazoline and 3-pyrazoline.

[0035] The term "aryl" refers to a monocyclic aromatic carbon ring (a ring structure in which all ring atoms are carbon) with 6 atoms per ring (the carbon atoms in the aryl group are sp2 hybridized).

[0036] The term "phenyl" refers to the following part: .

[0037] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each cyclic atom (i.e., the skeletal atom) is a carbon atom. Cycloalkyl groups can be saturated or partially unsaturated. An example of "cycloalkyl" is "C 3-6 "Cycloalkyl". Cycloalkyl groups can be fused with aromatic rings (in which case, the cycloalkyl group is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Exemplary examples of cycloalkyl groups include, but are not limited to, the following: The terms “heterocyclic” or “heterocyclic alkyl” as defined herein contain at least one heteroatom typically selected from nitrogen, oxygen, or sulfur, and particularly contain up to five, four, three, two, or a single heteroatom. Where reference is made herein to a heterocyclic or heterocyclic cyclic system, unless the context otherwise indicates, the heterocyclic or heterocyclic ring may optionally be substituted (i.e., unsubstituted or substituted) by one or more substituents as described herein. It should be understood that a heterocyclic or heterocyclic group may be bonded by a heteroatom in the ring (where chemically possible) or by one carbon atom comprising the heterocyclic alkyl ring. This group may be fused with an aryl or heteroaryl group. Illustrative examples of heterocyclic alkyl groups (also known as non-aromatic heterocycles) include: wait.

[0038] Heterocyclic ring systems or heterocyclic alkyl ring systems can be heteroaryl ring systems having 5 to 12 ring members, more typically 5 to 10 ring members.

[0039] Heterocyclic rings also include bridging ring systems, such as bridging cycloalkanes, such as norbornane (1,4-methylene-cyclohexane), adamantane, and oxadamantane; bridging morpholine rings, such as 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, and 3-oxa-8-azabicyclo[3.2.1]octane; bridging piperazine rings, such as 3,6-diazabicyclo[3.1.1]heptane; and bridging piperidine rings, such as 1,4-ethylidene piperidine. For an explanation of the distinction between fused and bridging ring systems, see Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pp. 131-133, 1992.

[0040] The term "heteroaryl" is used herein to refer to a heterocyclic ring system having aromatic properties. The term "heteroaryl" includes 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 can be attached to the remainder of the compound via an aromatic ring or via a non-aromatic ring.

[0041] Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. A heteroaryl group can be, for example, a five- or six-membered monocyclic ring or a bicyclic structure formed by fused five- and six-membered rings, or two fused six-membered rings, or two fused five-membered rings. A heteroaryl ring system can contain up to about five heteroatoms, typically selected from nitrogen, oxygen, and sulfur. Typically, a heteroaryl ring will contain up to four heteroatoms, more typically up to three heteroatoms, and more typically up to two, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. It should be understood that a heteroaryl group can be bonded by a heteroatom in the ring (where chemically possible) or by one carbon atom comprising the carbon of the heteroaryl ring. Generally, the number of basic nitrogen atoms (including any amino substituents in the ring) present in a heteroaryl group will be less than five. Illustrative examples of heteroaryl groups include: A nitrogen-containing heteroaryl ring must contain at least one cyclic nitrogen atom. In addition, each ring may contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, such as one, two, or three, and more usually up to two nitrogen atoms, such as a single nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents in the ring) will be less than five.

[0042] Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more typically 5 to 10 ring members. For example, such groups can be monocyclic or bicyclic and typically have 1 to 5 heteroatom ring members (more typically 1, 2, 3, or 4 heteroatom ring members) usually selected from nitrogen, oxygen, and sulfur. Heterocyclic groups can contain, for example, cyclic ether moieties (e.g., as in tetrahydrofuran and dioxane), cyclic sulfide moieties (e.g., as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., as in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0043] Heterocyclic and cycloalkyl rings also include bridging ring systems, such as bridging cycloalkanes, such as norbornane (1,4-methylene-cyclohexane), adamantane, and oxadamantane; bridging morpholine rings, such as 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, and 3-oxa-8-azabicyclo[3.2.1]octane; bridging piperazine rings, such as 3,6-diazabicyclo[3.1.1]heptane; and bridging piperidine rings, such as 1,4-ethylidene piperidine. For an explanation of the distinction between fused and bridging ring systems, see Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pp. 131-133, 1992.

[0044] The lines drawn in the ring system indicate which ring atom the bond can attach to, and whichever ring atom is suitable and available. The term "variable attachment point" means that the group is allowed to attach at more than one alternative location in the structure. The attachment always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations of the bonds are represented by a single schematic diagram, as illustrated in the following example.

[0045] The terms “optional” or “optionally” mean that the event described below may or may not occur. This term includes situations in which the event may or may not occur.

[0046] In the compounds disclosed herein, the carbon atom represented by "*" in the drawn formula is a chiral center. When a carbon atom is represented by "(*R)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R enantiomer or an S enantiomer. Similarly, when a carbon atom is represented by "(*S)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R enantiomer or an S enantiomer.

[0047] The term “bond” or “single bond” refers to a chemical bond between two atoms, or a chemical bond between two parts when the atoms bonded by the bond are considered part of a larger substructure.

[0048] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally considered to be a chemical entity that is embedded in or attached to a molecule.

[0049] As used herein, the term “therapeutic effective amount” refers to the amount of an active compound or agent that, when administered to a mammal in need, effectively at least partially improves or at least partially prevents the disease, condition, or symptom described herein.

[0050] As used herein, the term "composition" is intended to cover a product containing a specified amount of a specified ingredient, and any product obtained directly or indirectly by combining a specified amount of the specified ingredient.

[0051] As used in this article, the term “expression” includes the process of transcribing polynucleotides into mRNA and translating them into peptides, polypeptides, or proteins.

[0052] As used herein, the term "antagonist" refers to a small molecule agent that binds to the receptor and subsequently reduces agonist-induced receptor transcriptional activity.

[0053] As used in this article, the term "agonist" refers to a small molecule agent that binds to a receptor in the absence of a known agonist and subsequently increases the receptor's transcriptional activity.

[0054] As used in this article, the term "reverse agonist" refers to a small molecule agent that binds to the receptor and subsequently reduces the baseline level of receptor transcriptional activity in the absence of a known agonist.

[0055] As used herein, the term “modulation” means interacting directly or indirectly with a target to alter the target’s activity, including (by way of example only) enhancing, inhibiting, limiting, or extending the target’s activity.

[0056] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, the mammal is human. Those skilled in the art recognize that a therapy that reduces the severity of a symptom in one mammal can predict the effect of that therapy on another mammal.

[0057] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, relieving a disease or condition, causing the remission of a disease or condition, relieving a condition caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0058] "Proliferative disorders" are diseases caused by abnormal growth or expansion of cells due to proliferation. Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant growths"), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0059] The terms “vesicle” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and is not in harmony with the growth of normal tissue. A vegetation or tumor may be “benign” or “malignant” depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A “benign vegetation” is typically well-differentiated, grows more slowly than a malignant vegetation, and remains confined to its primary site. Furthermore, a benign vegetation does not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign vegetations include, but are not limited to, lipomas, chondromas, adenomas, acral hemangiomas, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, certain “benign” tumors may subsequently develop into malignant vegetations, possibly due to additional genetic changes in a subset of the tumor’s vesicular cells, and these tumors are referred to as “premalignant vegetations.” An exemplary premalignant vegetation is a teratoma. In contrast, "malignant growths" are typically poorly differentiated (underdeveloped) and are characterized by rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant growths often have the ability to metastasize to distant sites.

[0060] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a subject's healthy body to heal wounds and restore blood flow to tissues after injury. The healthy body controls angiogenesis in several ways, such as through growth factors that stimulate angiogenesis and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis that is larger than normal in the body, particularly in adults unrelated to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels to nourish diseased tissues and / or destroy normal tissues, and in the case of cancer, new blood vessels can allow tumor cells to escape into the circulation and remain in other organs (tumor metastasis).

[0061] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissues); cell samples (e.g., cell smears (such as Pap smears or blood smears) or cell samples obtained through microdissection); samples of intact organisms (such as samples of yeast or bacteria); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspiration, breast milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules derived from the first biological sample. Biological samples also include those that are genetically modified, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0062] Isomers, salts, N-oxides, isotope-labeled derivatives In the foregoing and hereinafter, the terms “compound of formula (I),” “compound of this disclosure or invention,” “compound provided herein,” or similar terms are intended to include its addition salts and stereoisomers.

[0063] In some embodiments, the compounds provided herein have one or more stereocenters, each center existing independently in either an R or S configuration. The compounds provided herein include all diastereomers, enantiomers, transisomers, and epimeric forms, and suitable mixtures thereof. Stereoisomers are obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography. In some embodiments, the compounds of this disclosure are used as single enantiomers. In some embodiments, the compounds of this disclosure are used as racemic mixtures. In some embodiments, the compounds of this disclosure have hindered rotation around a single bond, producing transisomers.

[0064] In some cases, compounds can exist as tautomers. All tautomers are included within the scope of the compounds provided herein.

[0065] To avoid ambiguity, when a compound can exist in one of several geometric isomers or tautomers and only one is specifically described or shown, all other forms are still included. Examples of tautomer forms include, for example, ketone forms, enol forms, and enolized forms, such as in the following tautomer pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / enediamine, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0066] Such forms, provided they can exist, are intended to be included within the scope of the compounds presented herein. Thus, a single compound can exist as both stereoisomers and tautomers.

[0067] Where a compound described herein contains one or more chiral centers and may exist in two or more optical isomers, unless the context otherwise requires, reference to a compound herein includes all its optical isomers (e.g., enantiomers, epimers, and diastereomers), as individual optical isomers, or mixtures of two or more optical isomers (e.g., racemic mixtures). When a compound has more than one chiral center and one chiral center is represented as having an absolute stereoconfiguration, unless the context otherwise requires, the other chiral centers include all their optical isomers, as individual optical isomers, or mixtures of two or more optical isomers (e.g., racemic mixtures). Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers, depending on the direction of their rotational plane-polarized light, or d and l isomers), or they can be characterized by their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold, and Prelog, see Jerry March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, New York, 1992, pp. 109–114, and also see Cahn, Ingold & Prelog (1966), Angew. Chem. Int. Ed. Engl., 5, 385–415. For example, a split enantiomer with an unknown absolute configuration can be specified by (+) or (–) according to the direction of its rotational plane-polarized light.

[0068] Optical isomers can be separated using a variety of techniques, including chiral chromatography (chromatography on a chiral support), and these techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, by preferential crystallization of the diastereomeric isomers, followed by dissociation of the salts to yield the individual enantiomers of the free base.

[0069] When a compound exists in two or more isomers, one isomer (e.g., one enantiomer of a pair of enantiomers) may exhibit superiority over another isomer (e.g., over another enantiomer), for example, in terms of biological activity. Therefore, in some cases, it may be necessary to use only one enantiomer of a pair, or only one diastereomer of a plurality of diastereomers, as a therapeutic agent.

[0070] When identifying a specific stereoisomer, this means that the stereoisomer is substantially free of other isomers, i.e., 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%. Therefore, when a compound described herein is designated, for example, as (S), it means that the compound is substantially free of the (R) isomer; when a compound described herein is designated, for example, as E, it means that the compound is substantially free of the Z isomer; and when a compound described herein is designated, for example, as cis, it means that the compound is substantially free of the trans isomer.

[0071] As used herein, any chemical formula having bonds shown only as solid lines and not as real wedges or virtual wedges, or not otherwise represented as having a special configuration (e.g., R, S) around one or more atoms, considers every possible stereoisomer, or a mixture of two or more stereoisomers.

[0072] The terms “stereoisomer,” “stereoisomeric form,” or “stereochemical isomeric form” are used interchangeably in the preceding or following text.

[0073] Enantiomers are stereoisomers that are each a non-overlapping mirror image. Diastereomers (or diastereomers) are stereoisomers that are not enantiomers, i.e., they are not mirror images. If the compound contains a double bond, the substituent can be E or Z configuration. Substituents on a divalent cyclic (partially) saturated group can have cis or trans configurations; for example, if the compound contains a disubstituted cycloalkyl group, the substituent can be cis or trans configuration. Therefore, this disclosure includes enantiomers, trans-blocked isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0074] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers can be designated by prefixes such as cis and trans. Cis and trans isomers are also called “geometric isomers.” When a compound described herein is designated “cis,” this means that the two groups point in the same direction relative to the ring plane. In the “trans” isomer, they point in opposite directions. Examples below are the “cis” and “trans” isomers of 2,6-dimethylmorpholine. Based on the relative positions of the two substituents and whether they are on the same side or opposite faces of the ring structure, there are two possible relative configurations.

[0075] For example, .

[0076] In this invention, the trisubstituted piperidine moiety having a stereocenter is defined as (3α, 4α, 5α) or (3α, 4β, 5α). For example: The meanings of all those terms, namely enantiomer, de-rotated isomer, diastereomer, racemic, E isomer, Z isomer, cis isomer, trans isomer, and mixtures thereof, are known to those skilled in the art.

[0077] The methods and formulations described herein include N-oxides (if appropriate) of compounds having the structure shown herein and having the same type of activity, pharmaceutically acceptable salts, and combinations thereof.

[0078] The salt forms of the compounds presented herein are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977), “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, non-pharmaceutically acceptable salts may also be prepared as intermediates, which can then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which can be used, for example, to purify or isolate the compounds of the present invention, also constitute part of this invention.

[0079] Pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts, and are intended to include non-toxic acid and base addition salt forms in which the compounds described herein can form therapeutically active salts.

[0080] The salts disclosed herein can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use", P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, hardcover, page 388, August 2002. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a suitable base or acid in water, in an organic solvent, or in a mixture of both; generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compounds of the present invention can exist as monosalts or disalts, depending on the pKa of the acid forming the salt.

[0081] Pharmaceutically acceptable acid addition salts can be readily obtained by treating the base form with a suitable inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) in anionic form or an organic acid (such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.).

[0082] Suitable anions include, for example, acetates, 2,2-dichloroacetate, adipic acid salts, alginates, ascorbic acid salts (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetaminophen, butyrate, bicarbonate, tartrate, bromide, (+) camphorate, camphor sulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, camphor sulfonate, decanoate, hexanoate, octanoate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecyl sulfate, edetate, estolatate. e) Ethyl sulfonate, ethane-1,2-disulfonate, ethane sulfonate, formate, fumarate, galacturonate, gentianate, gluconate, gluconate, gluconate, D-gluconate, glucuronate (e.g., D-glucuronate), glutamate (e.g., L-glutamate), α-oxoglutarate, glycolate, glycolyllarsanilate, hexylresorcinol salt, hippurate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethane sulfonate, hydroxynaphthyl carboxylate, iodide, hydroxyethyl sulfonate (i Sethionate, lactates (e.g., (+)-L-lactate, (±)-DL-lactate), lacturonates, malates, (-)-L-malates, maleates, malonates, mandelates, (±)-DL mandelates, mesylates, methansulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates (e.g., naphthalene-2-sulfonate), naphthalene-1,5-disulfonate, 1-hydroxy-2-naphthocarboxylate, naphthalene sulfonate, nicotinate, nitrates, oleates, orotates Oxalate, palmitate, embonate, pantothenate, phosphate / bisphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylic acid, sebate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, theochloroate, thiocyanate, toluenesulphonate (e.g., p-toluenesulphonate), tosylate, triethyliodide, undecenoate, valeric acid, and acylated amino acids and cation exchange resins. Conversely, the salt forms can be converted to free base forms by treatment with a suitable alkali.

[0083] Compounds containing acidic protons can also be converted to their non-toxic metal or amine addition salt forms by treatment with suitable cationic organic and inorganic bases. Suitable basic salts include those that form with organic cations such as arginine, benzylamine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, diprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, tromethamine, etc.; and those that form with ammonium ions (i.e., NH4+). + ), Quaternary ammonium ion N(CH3)4 + and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + These salts can be formed with amine functional groups, and with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. When the compounds described herein contain amine functional groups, these can form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds presented herein.

[0084] Conversely, the salt form can be converted into a free form by treatment with a suitable acid.

[0085] In some embodiments, the sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporating suitable substituents at metabolic reaction sites will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, suitable substituents that reduce or eliminate the sensitivity of aromatic rings to metabolic reactions are (by way of example only) halogen, deuterium, or alkyl groups.

[0086] The compounds disclosed herein include isotopically labeled compounds (i.e., compounds having one or more isotopic substitutions). These compounds are identical to those listed in the various chemical formulas and structures presented herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. References to a particular element include, within their scope, all isotopes of that element, whether naturally occurring or synthetically produced, whether in natural abundance or in isotopically enriched forms. For example, references to hydrogen include, within their scope, all isotopes of that element. 1 H, 2 H(D) and 3 H(T). Similarly, references to carbon and oxygen within their scope include, respectively, 12 C 13 C and 14 C and 16 O and 18O. The isotope may be radioactive or non-radioactive. In one embodiment of the invention, the compound does not contain a radioactive isotope. In another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes can also be used for environmental diagnostics. The radiolabeled compounds described herein may include radioactive isotopes selected from the group consisting of: 2 H, 3 H, 11 C 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br、 76 Br、 77 Br and 82 Br. Preferably, the radioactive isotope is selected from the group consisting of: 2 H, 3 H, 11 C and 18 F. More preferably, the radioactive isotope is 2 H. Specifically, deuterated compounds are intended to be included within the scope of this invention. In some embodiments, the metabolic sites on the compounds described herein are deuterated.

[0087] Throughout the specification, their groups and substituents can be selected to provide stable moieties and compounds.

[0088] The embodiments of the 1,6-naphthidine compounds used as described herein are compounds of formula (I): (I) Or its pharmaceutically acceptable salts or stereoisomers. in R 1 It is selected from the following optionally substituted heteroaryl groups: (a) Selected from the following 5-membered heteroaryl groups: , , and ;or (b) , and ; in Each R a Independently selected from: halogenated group, C 1-4 Alkyl groups, C groups substituted with OH 1-4 Alkyl, C 1-4 Halogenated alkyl groups and (C=O)CH3; R b Selected from: C replaced by OH 1-4 Alkyl; OC 1-4 Alkyl; OCH2CH2OH; and OCHF2; or (c) Selected from the following 6-membered heteroaryl groups: , and ; in Each R d C is independent 1-4 Alkyl, C 1-4 Halogenated alkyl groups and OC 1-4 alkyl; R e Selected from: C 1-4 Alkyl groups, C atoms substituted with OH or OCH3 1-4 Alkyl and C 1-4 Halogenated alkyl groups; X is N or O; R 5 yes (i) Wherein ring A is selected from the following nitrogen-linked monocyclic, polycyclic, bridged, spirocyclic, or fused heterocyclic alkyl groups: And each R c It is independently a halogenated group or CH3; or (ii) , , and Wherein ring B is selected from the following nitrogen-linked monocyclic, polycyclic, spirocyclic heterocyclic alkyl groups: ,or (iii) Phenyl, , , , and ; Where R k Selected from: (CH)(CH3)2, oxetane-3-yl, and ; R f It is H or CH3; R g Selected from: R h It is C 1-4 alkyl; R j Selected from: or ;as well as n is 0, 1, or 2; And its pharmaceutically acceptable salts and stereoisomers.

[0089] In some implementation schemes, R 1 yes In some implementation schemes, R 1 yes In some implementation schemes, R 1 yes In some implementation schemes, R 1 yes In some implementations, X is N. In some implementations, X is O.

[0090] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2.

[0091] In some implementation schemes, R 5 yes In some implementation schemes, R 5 yes In some implementation schemes, R 5 yes In some embodiments, the compounds of formula (I) are the compounds shown in Table 1 below. Compound numbering Compound structure and compound name 1 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-methyl-4-(methylsulfonyl)pyridinecarboxamide; 2 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide; 3 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-(methylsulfonyl)pyridinecarboxamide; 4 (racemic)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-(1-hydroxyethyl)-5-methylpyridinecarboxamide 5 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-((*R)-1-hydroxyethyl)-5-methylpyridinecarboxamide 6 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-((*S)-1-hydroxyethyl)-5-methylpyridinecarboxamide 7 N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-methyl-4-(methylsulfonyl)pyridinecarboxamide 8 N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 9 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 10 N-((2-(6-(2-hydroxy-7-azaspiro[3.5]nonane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 11 N-((2-(6-((1α,5α)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 12 N-((2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 13 N-((2-(6-(methyl(2-morpholinoethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 14 (racemic)-N-((2-(6-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 15 (racemic)-N-((2-(6-(2-(2-hydroxyethyl)morpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 16 (racemic)-N-((2-(6-(4-hydroxy-6-azaspiro[2.5]octane-6-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 17 N-((2-(6-(6-methoxy-2-azaspiro[3.3]heptane-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 18 N-((2-(6-(4-methyl-4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 19 N-((2-(6-(methyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 20 (racemic)-N-((2-(6-(3-methoxy-3-methylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 21 (racemic)-(N-((2-(6-(3-(methoxymethyl)-3-methylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 22 N-((2-(6-(6-hydroxy-2-azaspiro[3.3]heptane-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 23 (S)-N-((2-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 24 (racemic)-N-((2-(6-(3-hydroxy-3-methylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 25 (R)-N-((2-(6-(3-methylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 26 (S)-N-((2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 27 (racemic)-N-((2-(6-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 28 N-((2-(6-((cis)-3-hydroxy-4-methylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 29 N-((2-(6-((trans)-3-hydroxy-4-methylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 30 N-((2-(6-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 31 N-((2-(6-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 32 (racemic)-N-((2-(6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 33 (racemic)-5-(methanesulfonyl)-N-((2-(6-(((1,2,4,4-tetramethyl-5-oxopyrrolid-2-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 34 N-((2-(6-(3-(4-methyl-4-oxy-1,4-azaphosphacyclohexane-1-yl)azacyclobutane-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 35 (R)-N-((2-(6-(((4-(cyclopropylmethyl)-5-oxomorpholin-2-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 36 (S)-N-((2-(6-(3-ethyl-4-(2-hydroxyethyl)-5-oxo-1,4-diazacycloheptane-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 37 N-((2-(6-(5-cyano-2-azabicyclo[3.1.1]heptane-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 38 (S)-N-((2-(6-(3-methyl-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 39 N-((2-(6-((3aR,6aR)-5-methyl-6-oxohexahydropyrrolo[3,4-b]pyrrolo-1(2H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 40 N-((2-(6-((3aR,4S,7R,7aS)-4-methyloctahydro-2H-4,7-epoxyisoindol-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 41 N-((2-(6-((3aS,7aS)-5-(2,2-difluoroethyl)octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 42 N-((2-(6-((3aR,6aS)-5-isobutyl-4-oxohexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 43 N-((2-(6-((4-(2H-tetrazol-2-yl)butyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 44 N-((2-(6-((2R,5S)-5-(hydroxymethyl)-2,4-dimethylpiperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 45 (S)-N-((2-(6-(methyl(1-(methylcarbamoyl)pyrrolidone-3-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 46 N-((2-(6-((3R,4R)-3-(hydroxymethyl)-4-(pyridin-2-yl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 47 N-((2-(6-(((3S,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)(methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 48 (R)-N-((2-(6-(3-(2-(ethyl(methyl)amino)-2-oxoethoxy)pyrrolid-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 49 (S)-N-((2-(6-((2-hydroxypropyl)(propyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 50 N-((2-(6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 51 N-((2-(6-(3-cyclopropyl-3-hydroxyazacyclobutane-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 52 (racemic)-5-(methanesulfonyl)-N-((2-(6-(6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptatrien[d]pyrimidin-10-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 53 5-(methylsulfonyl)-N-((2-(6-(3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 54 N-((2-(6-(3-(tert-butyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 55 (racemic)-N-((2-(6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 56 N-((2-(6-(((3-fluorooxocyclobutane-3-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 57 (racemic)-N-((2-(6-(5-acetyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 58 <![CDATA[ N-((2-(6-1-imino-1-oxidation-1l) 6 -Thiomorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 59 <![CDATA[ N-((2-(6-((2-((dimethyl(oxo)-l) 6 -Thionyl)amino)ethyl)amino)pyridin-2-yl)-1,6-naphthid-7-yl)methyl)-5-(methanesulfonyl)nicotinamide]]> 60 <![CDATA[ N-((2-(6-(1-(isopropylimino)-1-oxidation-1l) 6 -Thiomorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 61 N-((2-(6-(1-acetamido-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 62 N-((2-(6-(3-fluorozacricyclobutan-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 63 (racemic)-N-((2-(6-(7,7-difluoro-3-azabicyclo[4.1.0]heptane-3-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 64 5-(methanesulfonyl)-N-((2-(6-(4-(methanesulfonyl)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 65 N-((2-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 66 (racemic)-5-(methanesulfonyl)-N-((2-(6-(quininyl-3-ylamino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 67 N-((2-(6-((2-(1H-imidazol-1-yl)ethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 68 N-((2-(6-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 69 N-((2-(6-(4-isopropyl-3-oxopiperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 70 5-(methylsulfonyl)-N-((2-(6-(5-oxo-3,4,5,6-tetrahydro-2,6-naphthidin-2(1H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 71 (racemic)-N-((2-(6-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 72 (R)-N-((2-(6-((1-methyl-2-oxozylidene-3-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 73 (racemic)-N-((2-(6-((7-oxaspiro[3.5]nonane-1-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 74 (R)-N-((2-(6-(2-(3-methylisoxazo-5-yl)pyrrolidone-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 75 (racemic)-5-(methanesulfonyl)-N-((2-(6-(2-(pyridin-3-yl)morpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 76 N-((2-(6-(4-(6-(hydroxymethyl)pyridin-3-yl)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 77 (racemic)-5-(methanesulfonyl)-N-((2-(6-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 78 (S)-N-((2-(6-(2-(methylcarbamoyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 79 N-((2-(6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 80 (racemic)-5-(methanesulfonyl)-N-((2-(6-(1-oxo-2,7-diazaspiro[4.5]decane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 81 N-((2-(6-((cis)-1,1-hexahydro-5H-thieno[2,3-c]pyrrolo-5-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 82 N-((2-(6-(((4-isopropyl-4H-1,2,4-triazol-3-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 83 N-((2-(6-(([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 84 N-((2-(6-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 85 (racemic)-N-((2-(6-((1-(1H-1,2,4-triazol-1-yl)propane-2-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 86 (racemic)-N-((2-(6-(3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 87 (R)-N-((2-(6-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 88 N-((2-(6-(2-(methoxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazacycloheptatrien-5(6H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 89 N-((2-(6-(7-methyl-2,7-diazaspiro[4.5]decane-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 90 N-((2-(6-((1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 91 (racemic)-5-(methanesulfonyl)-N-((2-(6-(4-(((tetrahydrofuran-2-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 92 N-((2-(6-(((1-(hydroxymethyl)cyclopropyl)methyl)(methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 93 (racemic)-N-((2-(6-(7-methyl-6-oxa-2-azaspiro[3.4]octane-2-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 94 (racemic)-5-(methanesulfonyl)-N-((2-(6-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 95 (racemic)-N-((2-(6-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 96 N-((2-(6-(((2-methyl-2-morpholinopropyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 97 (racemic)-N-((2-(6-(2-methyl-1-oxomorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 98 (racemic)-N-((2-(6-(((2,3-dihydrofurano[2,3-c]pyridin-3-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 99 (racemic)-N-((2-(6-(4-hydroxy-2-methylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 100 N-((2-(6-(6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 101 (R)-5-(methanesulfonyl)-N-((2-(6-((1-(oxecyclobutan-3-yl)pyrrolidine-3-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 102 (racemic)-N-((2-(6-(3-methyl-5-oxoperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 103 N-((2-(6-((3-(2-methyl-1H-imidazol-1-yl)propyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 104 N-((2-(6-(4-(cyclobutanecarbonyl)piperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 105 N-((2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 106 N-((2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 107 (S)-5-(methanesulfonyl)-N-((2-(6-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 108 N-((2-(6-(((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 109 (racemic)-N-((2-(6-(3-hydroxy-4,4-dimethoxypiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 110 (racemic)-N-((2-(6-(ethyl((tetrahydrofuran-2-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 111 N-((2-(6-((2-(4-acetylpiperazin-1-yl)ethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 112 N-((2-(6-(4-(2-(dimethylamino)-2-oxoethyl)-4-hydroxypiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 113 N-((2-(6-((2-(dimethylamino)-2-oxoethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 114 N-((2-(6-((1-(3-cyanopropyl)piperidin-4-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 115 5-(methanesulfonyl)-N-((2-(6-((3-(2-oxopyrrolidone-1-yl)propyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 116 (racemic)-N-((2-(6-(4-hydroxy-3-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 117 N-((2-(6-((2-(2-oxabicyclo[2.1.1]hexane-1-yl)ethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 118 N-((2-(6-(3-methoxyazacyclobutane-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 119 (racemic)-N-((2-(6-(4-methoxy-3,3-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 120 N-((2-(6-((((cis)-3-(dimethylamino)cyclobutyl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 121 (racemic)-N-((2-(6-(((1,4-oxathiacyclohexane-2-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 122 N-((2-(6-(((1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 123 (R)-N-((2-(6-(6-(hydroxymethyl)-2,2-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 124 N-((2-(6-(3-(2H-tetrazol-5-yl)azacyclobutane-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 125 (racemic)-N-((2-(6-(6-(methoxymethyl)-2,2-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 126 N-((2-(6-(([1,3]dioxacyclopenteno[4,5-b]pyridin-6-ylmethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 127 (R)-N-((2-(6-((1-(dimethylamino)propane-2-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 128 N-((2-(6-(4-cyanopiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 129 (S)-N-((2-(6-(2-(dimethylcarbamoyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 130 N-((2-(6-(methyl(1-methylpiperidin-4-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 131 N-((2-(6-(ethyl(2-morpholinoethyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 132 5-(methanesulfonyl)-N-((2-(6-((1R,5S)-8-oxo-1,5,6,8-tetrahydro-2H-1,5-bridged methylenepyrido[1,2-a][1,5]diazacyclooctane-3(4H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 133 (racemic)-N-((2-(6-(3,3-dimethyl-1-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 134 5-Chloro-N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)pyrimidin-2-carboxamide 135 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(trifluoromethyl)pyridinecarboxamide 136 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-iodopyridinecarboxamide 137 N-((2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-methyl-6-(methylsulfonyl)isonicotinamide 138 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-(2-hydroxypropane-2-yl)-5-methylpyridinecarboxamide 139 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-(methanesulfonyl)isonicotinamide 140 N-((2-(6-((3a,5a)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 141 (*R)-N-((2-(6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 142 (*S)-N-((2-(6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 143 N-((2-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 144 N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*R)-1-hydroxyethyl)nicotinamide 145 N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*S)-1-hydroxyethyl)nicotinamide 146 4-Acetyl-5-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)pyridinecarboxamide 147 N-((2-(6-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 148 N-((2-(6-((cis)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 149 N-((2-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 150 N-((2-(6-(1,7-diazaspiro[3.5]nonane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 151 (racemic)-N-((2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 152 N-((2-(6-(((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 153 N-((2-(6-(((2-hydroxy-2-methylpropyl)(methyl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 154 (racemic)-N-((2-(6-(methyl(1-methylpyrrolidin-3-yl)amino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 155 N-((2-(6-(2,8-diazaspiro[4.5]decane-8-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 156 (racemic)-N-((2-(6-(3-(methylamino)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 157 (R)-N-((2-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 158 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-methyl-6-(methanesulfonyl)isonicotinamide 159 (racemic)-N-((2-(6-(3-aminopyrrolidone-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 160 N-((2-(6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 161 N-((2-(6-(2,5-dioxa-8-azaspiro[3.5]nonane-8-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 162 5-Chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-(2-hydroxypropane-2-yl)pyridinecarboxamide 163 N-((2-(6-(2,7-diazaspiro[3.5]nonane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 164 (racemic)-N-((2-(6-(2-(aminomethyl)pyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 165 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide 166 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-(methanesulfonyl)isonicotinamide 167 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)isonicotinamide 168 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-((*R)-1-hydroxyethyl)pyridinecarboxamide 169 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-((*S)-1-hydroxyethyl)pyridinecarboxamide 170 (racemic)-N-((2-(6-(3-amino-3-methylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 171 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisocyanamide 172 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 173 N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide 174 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-4-(methylsulfonyl)pyridinecarboxamide 175 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-((2-hydroxyethyl)sulfonyl)-6-methylisocyanamide 176 (racemic)-N-((2-(6-(4-hydroxy-2,2-dimethylpyrrolidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 177 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide 178 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*R)-1-hydroxyethyl)nicotinamide 179 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*S)-1-hydroxyethyl)nicotinamide 180 1-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)phenyl)-1,6-naphthidin-7-yl)methyl)-1H-pyrrole-3-carboxamide 181 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-1-(methanesulfonyl)-1H-pyrrolo-3-carboxamide 182 4,5-Dichloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-1-(isopropylsulfonyl)-1H-pyrrole-3-carboxamide 183 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)thiophene-2-carboxamide 184 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-1-methyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxamide 185 N-((2-(3-chloro-4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 186 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)-3-methylpyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 187 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide 188 N-((2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide 189 N-((2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 190 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)-3-methylpyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(2-hydroxypropane-2-yl)nicotinamide 191 N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 192 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 193 N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide 194 N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide 195 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide 196 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide 197 5-((3,3-difluoropropyl)sulfonyl)-N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methylnicotinamide 198 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)-3-methylpyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*R)-1-hydroxyethyl)nicotinamide 199 N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)-3-methylpyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*S)-1-hydroxyethyl)nicotinamide 200 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(S-methylsulfonylimide)nicotinamide 201 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(2-hydroxyethylsulfonylimide)-6-methylnicotinamide 202 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*R)-2-hydroxyethylsulfonylimide)-6-methylnicotinamide 203 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*S)-2-hydroxyethylsulfonylimide)-6-methylnicotinamide 204 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(S-methylsulfonylimide)nicotinamide 205 N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 206 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-((*R)-S-methylsulfonylimide)nicotinamide 207 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-((*S)-S-methylsulfonylimide)nicotinamide 208 N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)-6-(trifluoromethyl)nicotinamide 209 6-Methyl-5-(methanesulfonyl)-N-((2-(6-(6-oxo-4-oxa-7-azaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 210 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(2-hydroxyethylsulfonylimide)nicotinamide 211 N-((2-(6-((3α,4β,5α))-4-(hydroxymethyl)-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 212 6-Methyl-5-(methylsulfonyl)-N-((2-(6-(5-oxo-2-(trifluoromethyl)morpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 213 (*R)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 214 (*S)-N-((2-(4-fluoro-6-(6-methyl-4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 215 6-Methyl-5-(methylsulfonyl)-N-((2-phenyl-1,6-naphthid-7-yl)methyl)nicotinamide 216 N-((2-(6-(2,6-dimethyl-3-oxomorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 217 6-Methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 218 N-((2-(6-(2,2-dimethyl-3-oxomorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 219 N-((2-(6-(4-amino-3,3-difluoropiperidin-1-yl)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 220 6-Methyl-N-((2-(6-((trans)-2-methyl-6-(trifluoromethyl)morpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 221 6-Methyl-N-((2-(6-((cis)-2-methyl-6-(trifluoromethyl)morpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 222 N-((2-(4-fluoro-6-(7-hydroxy-5-azaspiro[2,4]heptane-5-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 223 6-Methyl-N-((2-(1-methyl-6-oxo-2-(2,2,6,6-tetramethylmorpholino)-1,6-dihydropyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 224 N-((2-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 225 6-Methyl-N-((2-(6-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptane-6-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 226 N-((2-(6-(4,4-dimethyl-2-oxoimidazolidine-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 227 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*R)-2-hydroxyethylsulfonylimide)nicotinamide 228 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((*S)-2-hydroxyethylsulfonylimide)nicotinamide 229 N-((2-(2-(4,7-diazaspiro[2.5]octane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)-6-(trifluoromethyl)nicotinamide 230 N-((2-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 231 N-((2-(2-(4,7-diazaspiro[2.5]octane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-(difluoromethyl)-5-(methanesulfonyl)nicotinamide 232 N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 233 N-((2-(6-isopropoxypyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 234 6-Methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 235 6-Methyl-5-(methanesulfonyl)-N-((2-(2-(2-oxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 236 6-Methyl-N-((2-(2-(1-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 237 6-Methyl-N-((2-(2-(1-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 238 N-((2-(2-(6,8-dioxo-2,5,7-triazaspiro[3,4]octane-2-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 239 6-Methyl-5-(methanesulfonyl)-N-((2-(2-(6-oxo-2,5,7-triazaspiro[3,4]octane-2-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 240 N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 241 6-Methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 242 N-((2-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 243 N-((2-(2-(6,8-dioxo-5,7,11-triazabispiro[2.0.44.43]dodecane-11-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 244 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methoxynicotinamide 245 6-Methyl-N-((2-(2-(6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 246 6-Methyl-N-((2-(1-methyl-2-((trans)-2-methyl-6-(trifluoromethyl)morpholino)-6-oxo-1,6-dihydropyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methylsulfonyl)nicotinamide 247 N-((2-(2-(6,6-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 248 (*R)-N-((2-(2-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 249 (*S)-N-((2-(2-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 250 N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-(trifluoromethyl)nicotinamide 251 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide) 252 6-Methyl-N-((2-(2-((6*R)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 253 6-(difluoromethoxy)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 254 N-((2-(2-(4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 255 N-((2-(2-(4-acetamido-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 256 (*R)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 257 (*S)-6-methyl-N-((2-(2-(3-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 258 6-Methyl-N-((2-(2-((6*S)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 259 N-((2-(6-(((2a,4b,6a)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5-methylpyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 260 (*R)-N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 261 (*S)-N-((2-(2-(1,3-dimethyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 262 6-Methyl-N-((2-(2-((5*R,6*R)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 263 6-Methyl-N-((2-(2-((5*S,6*S)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 264 (*R)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 265 (*S)-N-((2-(2-(6,6-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 266 6-Methyl-N-((2-(2-((5*R,6*R)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 267 6-Methyl-N-((2-(2-((5*S,6*S)-6-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-5-(methanesulfonyl)nicotinamide 268 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methylnicotinamide 269 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 270 (*R)-N-((2-(2-(6,8-dioxo-5,7,11-triazabispiro[2.0.44.43]dodecane-11-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 271 (*S)-N-((2-(2-(6,8-dioxo-5,7,11-triazabispiro[2.0.44.43]dodecane-11-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 272 N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylpyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 273 N-((2-(6-(((2α,4β,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylpyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 274 N-((2-(6-(((2α,4β,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 275 N-((2-(6-(((2α,4β,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-2-methylpyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 276 4-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)pyridinecarboxamide 277 N-((2-(2-((trans)-2,4-dioxo-6-(trifluoromethyl)-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 278 N-((2-(2-((cis)-2,4-dioxo-6-(trifluoromethyl)-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 279 N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 280 6-Methyl-5-(methylsulfonyl)-N-((2-(6-(oxecyclobutane-3-yloxy)pyridin-3-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 281 (*R)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 282 (*S)-N-((2-(2-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 283 N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 284 N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-5-methylpyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 285 N-((2-(6-(((2α,4α,6α)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide 286 6-Methyl-5-(methylsulfonyl)-N-((2-(6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)-1,6-naphthidin-7-yl)methyl)nicotinamide 287 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methoxy-5-(methylsulfonyl)nicotinamide 288 4-(S-(difluoromethyl)sulfonylimide)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)pyridinecarboxamide 289 4-((*S)-S-(difluoromethyl)sulfonylimide)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)pyridinecarboxamide 290 4-((*R)-S-(difluoromethyl)sulfonylimide)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)pyridinecarboxamide 291 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-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 292 N-((2-(2-((5*S,6*S,9*R)-6,9-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 293 N-((2-(2-((5*R,6*S,9*R)-6,9-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 294 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-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide 295 N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-4-((2-methoxyethyl)sulfonyl)pyridinecarboxamide

[0092] And its pharmaceutically acceptable salts and stereoisomers.

[0093] In some embodiments, the 1,6-naphthidine compound is selected from the group consisting of: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methanesulfonyl)nicotinamide; N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(4-fluoro-6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methyl-5-((*S)-S-methylsulfonylimide)nicotinamide; and 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-6-methylnicotinamide; and its pharmaceutically acceptable salts and stereoisomers.

[0094] Compound Synthesis In this section, as in all other sections of this application, unless the context otherwise indicates, the reference to formula (I) also includes all other subgroups and examples thereof as defined herein.

[0095] The compounds described herein were synthesized using methods described in the chemical literature, or by combination thereof. Furthermore, the solvents, temperatures, and other reaction conditions presented herein may be varied. The techniques and materials generally accepted in this field are described in, 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 Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001); and Green and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (Wiley 1999) (all of which are incorporated herein by reference). General methods for preparing compounds as disclosed herein can be derived from reactions, and these reactions can be modified by using appropriate reagents and conditions to introduce the parts found in the formulas provided herein.

[0096] The starting materials and reagents used to synthesize the compounds described herein may be synthesized or available from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0097] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, which are required by the final product to prevent them from unnecessarily participating in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in the chemical reaction until the protecting groups are removed. Preferably, each protecting group can be removed in a different manner. Protecting groups broken under completely different reaction conditions satisfy the requirement of differential removal.

[0098] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidizing conditions. Groups such as triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl are acid-labile and can be used to protect the carboxyl and hydroxyl reactive moieties in the presence of an amino group protected with a Cbz group that can be removed by hydrogenolysis and a base-labile Fmoc group. The carboxylic acid and hydroxyl reactive moieties can be capped with base-labile unstable groups (such as, but not limited to, methyl, ethyl, and acetyl) in the presence of an amine capped with an acid-labile unstable group such as tert-butyl carbamate or an amine capped with an acid- and base-stable but hydrolyzable carbamate.

[0099] The reactive moiety of the carboxylic acid and hydroxyl group can also be capped with a hydrolyzable protecting group such as a benzyl group; however, the amino group capable of forming hydrogen bonds with acids can be capped with a base-instable group such as acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The reactive moiety of the carboxylic acid can be protected by conversion to simple ester compounds as illustrated herein, including conversion to alkyl esters, or they can be capped with an oxidically removable protecting group such as 2,4-dimethoxybenzyl, while the coexisting amino group can be capped with a fluorine-instable silyl carbamate.

[0100] Allyl-terminated groups are useful in the presence of both acid-protecting and base-protecting groups, as the former is stable and can subsequently be removed by metal or π-acid catalysts. For example, allyl-terminated carboxylic acids can be degraded using Pd in ​​the presence of acid-instable tert-butyl carbamate or base-instable amine acetate protecting groups. 0 Catalytic deprotection reactions. Another form of protecting group is a resin that can attach to a compound or intermediate. Once the residue is attached to the resin, the functional group is capped and cannot react. Once released from the resin, the functional group can be used for the reaction.

[0101] Typically, the end-capping / protecting groups can be selected from: Other protecting groups, along with a detailed description of techniques applicable to the generation and removal of protecting groups, are described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th Edition, Wiley, Hoboken, New Jersey, 2007, the contents of which are incorporated herein by reference.

[0102] General synthesis path Option 1 Suitable substituted ester compounds of formula (II) are commercially available or synthetically derived. Heteroaryl halides of formula (II) (such as methyl 5-bromo-6-methyl-3-pyridinecarboxylate) can be reacted in palladium-catalyzed sulfinization using triphenylphosphine; 1,10-phenanthroline; in the presence of K₂S₂O₅ and sodium formate; tert-butylammonium bromide; and a palladium catalyst (such as palladium acetate); followed by in-situ alkylation with, for example, 2-(2-bromoethoxy)tetrahydro-2H-pyran; in a suitable solvent (such as DMSO, ACN, etc.); at a temperature ranging from room temperature to 100 °C; to give methyl 6-methyl-5-((3-(((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)nicotinic acid. The deprotection of pyran can be achieved under acidic conditions (such as HCl / MeOH) known to those skilled in the art to provide methyl 5-((3-hydroxypropyl)sulfonyl)-6-methylnicotinate.

[0103] Ester compounds of formula (II), wherein R 1 Having halides such as Br, for example 5-bromonicotinic acid; can be further functionalized by reacting with n-butyllithium; and acetone; in a suitable solvent (such as THF); at a temperature ranging from -78°C to room temperature; to give compounds of formula (II), wherein Br is now replaced by C(OH)(CH3)2.

[0104] A commercially available or synthetically obtainable ester compound of formula (II) (where ring B is a suitably substituted heteroaryl group) can be reacted under basic conditions (such as NaOH, LiOH, KOH, etc.); in a suitable solvent (such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O or mixtures thereof); at a temperature of 60°C to 80°C; for a period of 1 hour to 6 hours; to give an acid compound of formula (III).

[0105] Acidic compounds of formula (III) (where R) 1 It has halides, such as Br (bromine), such as 5-bromonicotinic acid); and can be further functionalized by reacting with BuLi in a suitable solvent (such as THF); and acetaldehyde; at a temperature of about -78°C for a period of 1 hour; to provide a compound of formula (III), wherein Br is now replaced by CH(OH)CH3.

[0106] The commercially available or synthetically obtainable ester compound of formula (II) (where ring B is a suitably substituted halo-heteroaryl) can be reacted in two steps, first with a suitable alkyl thiolate (such as, for example, sodium methanethiol) in a suitable solvent (such as, for example, DMF) at a suitable temperature (such as, for example, room temperature); then in the second step, the intermediate alkyl sulfide can be oxidized using a suitable oxidant (such as, for example, mCPBA) in a suitable solvent (such as, for example, DCM) at a suitable temperature (such as, for example, 0°C or room temperature).

[0107] A commercially available or synthetically derived ester compound of formula (II) (in which ring B is thiol group) can be difluoromethylsulfonylated in three steps: first, reacting with sodium 2-chloro-2,2-difluoroacetate in a suitable solvent (such as, for example, DMF) at a suitable temperature (such as, for example, 100 °C); then, in a second step, hydrolyzing the intermediate ester under conditions known in the art (such as, for example, LiOH, in a suitable solvent (such as, for example, a mixture of THF and water) at a suitable temperature (such as, for example, room temperature)); and in a third step, reacting the intermediate with a suitable oxidant (such as, for example, NaIO4) in the presence of a suitable catalyst (such as, for example, RuCl3) in a suitable solvent (such as, for example, DCM, ACN, water, or a mixture thereof) at a suitable temperature (such as, for example, room temperature). Alternatively, a commercially available or synthetically obtainable ester compound of formula (II) (where ring B is a methylsulfonyl-heteroaryl) can be difluoromethylsulfonylated in three steps: first, reacting with 2,2,2-trifluoroethyl trifluoroacetate in the presence of a suitable base (such as, for example, LiHMDS) in a suitable solvent (such as, for example, THF) at a suitable temperature (such as, for example, -78°C); then, in a second step, reacting the intermediate 3,3,3-trifluoro-2-oxopropyl sulfone with a suitable fluorinating agent (such as, for example, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) (CAS) [140681-55-6])) is reacted in a suitable solvent (such as, for example, ACN) at a suitable temperature (such as, for example, room temperature to 60°C); and in the third step, the intermediate 1,1,3,3,3-pentafluoro-2-oxopropyl sulfone is reacted with a suitable base (such as, for example, DIPEA) in a suitable solvent (such as, for example, THF, water or a mixture thereof) at a suitable temperature (such as, for example, room temperature).

[0108] Commercially available or synthetically available ester compounds of formula (II) (where ring B is a heteroaryl group substituted with an alkyl thiolate) can be reacted with a suitable oxidant (such as, for example, oxone) in a suitable solvent (such as, for example, MeOH) at a suitable temperature (such as, for example, room temperature) to give the corresponding alkylsulfonylated heteroaryl compound.

[0109] Option 2 According to scheme 2, the compound of formula (IV) (where Hal is Br or Cl and R) 5 The appropriately substituted heteroaryl group can be borated using conditions known to those skilled in the art (such as the Miyaura boration conditions). For example, a compound of formula (IV) (where Hal is Br or Cl) can be prepared using a transition metal catalyst (such as 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2), etc.); in a suitable solvent (such as dimethyl sulfoxide (DMSO) or 1,4-dioxane, etc.); and a base (such as potassium acetate, etc.); and a boron source (such as, for example, bis(pinacolyl)diboron, pinacolborane, etc.); treated at a temperature ranging from 80°C to 100°C for a period of time from 2 hours to 8 hours to provide a compound of formula (V).

[0110] Option 3 According to scheme 3, the compound of formula (VI) can be prepared in the presence of a commercially available or synthetically available compound of formula (VII) (where Hal is a suitable halogen, such as Br (bromine)); in a metal-mediated coupling reaction with boric acid or borate ester (such as potassium trifluoro(vinyl)borate); in the presence of a catalyst (such as bis(triphenylphosphine)palladium(II) chloride); in a base (such as (Cs2CO3)); in a suitable solvent (such as THF, 1,4-dioxane, toluene, water, or mixtures thereof); at a temperature in the range of 70°C to 100°C; for a duration of 12 to 18 hours.

[0111] Compounds of formula (VI) can be obtained by halogenating a compound of formula (VI) in a suitable solvent (such as 1,2-dichloroethane, chloroform, etc.) with a chlorinating agent (such as POCl3) at a temperature ranging from 70°C to 90°C. Compounds of formula (VIII) can be oxidized by treatment with osmium tetroxide and NaIO4 in a suitable solvent (such as 1,4-dioxane, THF, water, or mixtures thereof) to provide compounds of formula (IX). Compounds of formula (IX) (where Hal is Cl) can be reacted with commercially available or synthetically available compounds of formula R in a metal-mediated cross-coupling reaction using methods known in the art. 5 The reaction of -B(OH)2 with boric acid or its borate ester derivatives, wherein R 5It is the optionally substituted heteroaryl group as described in claim 1. For example, the compound of formula (IX) can be reacted with 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]pyridine; a suitable base (such as Cs2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3, NaHCO3, etc.); a palladium catalyst (such as bis(diphenylphosphine)ferrocene]palladium(II) dichloride, etc.); in a suitable solvent (such as 1,4-dioxabane, DMF, acetonitrile (ACN), ethanol, water, or mixtures thereof); at a temperature ranging from 50°C to 100°C; for a period of about 16 hours to 24 hours; to provide a compound of formula (X), wherein R 5 It is 3-(pyridin-4-yl)phenyl. The compound of formula (X) can be reacted with hydroxylamine in the presence of a base (such as, for example, NaHCO3) in a suitable solvent (such as, for example, MeOH) at a suitable temperature (such as, for example, room temperature) to give the compound of formula (XI). The compound of formula (XI) can be reduced using, for example, hydrogen in the presence of a catalyst (such as, for example, Raney Ni) in a suitable solvent (such as, for example, MeOH, THF, or mixtures thereof) at a suitable temperature (such as, for example, room temperature) to give the compound of formula (XII).

[0112] Option 4 According to Scheme 4, using conditions known to those skilled in the art, the compound of formula (VII) (where Hal is Cl) can undergo a palladium-catalyzed cyanation reaction. For example, the compound of formula (VII) can be reacted with a palladium catalyst (such as Pd(dppf)Cl2.CH2Cl2, etc.); and zinc cyanide as a nucleophile; in a suitable solvent (such as DMA, N,N-dimethylformamide (DMF), etc.); at a temperature of about 100°C; and for a period of 2 to 6 hours; to provide the cyano compound of formula (XIII).

[0113] The previously described methods, such as using POCl3, can be used to halogenate the compound of formula (XIII) to obtain the compound of formula (XIV). The compound of formula (XIV) can be reduced using a suitable reducing agent (such as DIBAL-H); in a suitable solvent (such as DCM, toluene, etc.); at a temperature from -78°C to room temperature; and subsequently reacted with a suitable protecting precursor (such as, for example, DCM) in a suitable solvent at a suitable temperature (such as, for example, room temperature) to obtain the compound of formula (XV).

[0114] Option 5 According to scheme 5, the compound of formula (XV) (where PG is Boc and Hal is Cl) can be coupled with a commercially available or synthetically available compound of formula R in a metal-mediated cross-coupling reaction using methods known in the art. 5' The reaction of -B(OH)2 with boric acid or borate ester derivatives of formula (Va), wherein R 5' It is the optionally substituted heteroaryl group as described in claim 1. For example, the compound of formula (XV) can be reacted with 6-fluoropyridine-2-boronic acid or 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine; a suitable base (such as Cs2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3, NaHCO3, etc.); a palladium catalyst (such as bis(triphenylphosphine)palladium(II) chloride, etc.); in a suitable solvent (such as 1,4-dioxabane, DMF, acetonitrile (ACN), ethanol, water, or mixtures thereof); at a temperature ranging from 50°C to 100°C; for a period of about 16 hours to 24 hours; to provide a compound of formula (XVI), wherein R 5' It is 6-fluoropyridyl.

[0115] Compounds of formula (XVI) (where R) 5' A suitable heteroaryl group, such as, for example, a 2-pyridyl group substituted with a suitable halogen leaving group such as, for example, F (fluorine), can react with optionally substituted heterocyclic alkyl groups (including, but not limited to, 4- to 8-membered heterocyclic alkyl groups, fused, spiro- and bridged 8- to 10-membered heterocyclic alkyl groups, each optionally having one or two heteroatoms independently selected from N, S, and O) (such as cis-2,6-dimethylmorpholine); a base (such as DIPEA, etc.) is reacted in a suitable solvent (such as DMSO, ACN, etc.) at a temperature ranging from 50°C to 130°C for a period of 12 to 24 hours to provide a compound of formula (XVII) (wherein R... 5 It is a suitable heteroaryl group substituted with a nitrogen-linked heterocyclic alkyl group.

[0116] The compound of formula (XVII) can be obtained in two steps at R 5Alkylation of the group: First, the compound of formula (XVII) is halogenated in a suitable solvent (such as hexafluoroisopropanol) with a suitable halogenating agent (such as N-iodosuccinimide) at a suitable temperature (such as 0°C to room temperature); and in a second step, the intermediate halide is reacted with a suitable methylboron derivative (such as trimethylcycloborone) in the presence of a suitable base (such as K2CO3) and a suitable catalyst (such as Xantphos Pd G3 (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).

[0117] The deprotection of compounds of formula (XVII), where PG is Boc, can be achieved according to procedures known to those skilled in the art and using recognized methods (such as those described in TWgreene and PGM Wuts, *Protectivegroups in Organic Synthesis*, 3rd ed., John Wiley & Sons, 1999, pp. 518-525). For example, deprotection can be achieved by a period of 2 hours at room temperature under acidic conditions (such as trifluoroacetic acid (TFA) / CH2Cl2, HCl / dioxane, etc.) to provide compounds of formula (XII).

[0118] Option 6 According to Scheme 6, a compound of formula (XV) (where Hal is Cl and PG is Boc) can be reacted with a suitable sulfinate (such as, for example, sodium 1-methyl-3-sulfinpropionate (CAS [90030-48-1])); in the presence of a suitable catalyst (such as, for example, CuI); in a suitable solvent (such as, for example, DMSO, etc.); at a suitable temperature (such as, for example, 110 °C) to provide a compound of formula (XVIII). The compound of formula (XVIII) can be reacted with a commercially available or synthetically derived appropriately substituted 2-halo-R 5(e.g., (cis)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine); in the presence of a suitable phosphonium salt (e.g., di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3])); in the presence of a suitable base (e.g., K₂CO₃); in the presence of a suitable catalyst (e.g., Pd(OAc)₂); in a suitable solvent (e.g., 1,4-dioxane); at a suitable temperature (e.g., 150 °C); to provide a compound of formula (XVII). Deprotection of the BOC protecting group on the compound of formula (XVII) is achieved using acidic conditions known to those skilled in the art or as previously described, to provide a compound of formula (XII).

[0119] In a similar manner, compounds of formula (XVIII) (where Hal is Cl and PG is Boc) can be combined with suitable substituted 2-halo-heteroaryl groups (R... 5' -Hal)(such as (2R,6S)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine) reacts 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); and at a suitable temperature (such as 150 °C) to provide a compound of formula (XVI) (wherein R 5 It is 6-((2R,6S)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl).

[0120] Option 7 According to Scheme 7, the compound of formula (XVIII) (where PG is Boc) can be deprotected under acidic conditions known to those skilled in the art or as previously described to provide the compound of formula (XIX). The compound of formula (XIX) can be reacted with a commercially available or synthetically derived carboxylic acid with appropriate substitution; the reaction is carried out using conventional amide bond forming techniques, such as coupling reactions well known to those skilled in the art. For example, the compound of formula (XIX) can be reacted with formula R... 1A carboxylic acid of CO2H (where ring B is a suitably substituted heteroaryl ring); reacted in the presence of a suitable coupling agent (e.g., HATU, HBTU, 1-propanephosphonic anhydride, etc.); in the presence of a suitable base (e.g., TEA, DIPEA, etc.); in a suitable solvent (e.g., DCM, DMF, etc.); and at a suitable temperature (e.g., room temperature); to provide a compound of formula (XX). The compound of formula (XX) can be reacted with a commercially available or synthetically derived suitably substituted 2-halo-R 5 (such as, for example, 8-(4-chloropyrimidin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione); 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, for example, K2CO3, etc.); in the presence of a suitable catalyst (such as, for example, Pd(OAc)2, etc.); in a suitable solvent (such as, for example, 1,4-dioxane); at a suitable temperature (such as, for example, 115°C); to provide a compound of formula (I).

[0121] Option 8 According to scheme 8, the compound of formula (XVI) (where PG is Boc and is R) 5' The appropriately substituted heteroaryl halide can be deprotected using methods known to or previously described by those skilled in the art to provide a compound of formula (XXI). The compound of formula (XXI) can be reacted with an appropriately substituted commercially available or synthetically available carboxylic acid using conventional amide bond forming techniques, such as coupling reactions well known to those skilled in the art. For example, the compound of formula (XXI) can be reacted with a carboxylic acid of formula (III) (where ring B is an appropriately substituted benzene ring); in the presence of a suitable coupling agent (such as, for example, HATU, HBTU, 1-propanephosphonic anhydride, etc.); in the presence of a suitable base (such as TEA, DIPEA, etc.); in a suitable solvent (such as, for example, DCM, DMF, etc.); at a suitable temperature (such as, for example, room temperature); to provide a compound of formula (XXII).

[0122] In an alternative method, the compound of formula (XXII) can be prepared from the compound of formula (XXIII) in two steps. In the first step, the compound of formula (XXIII) can be reacted with a carboxylic acid of formula (III) (where ring B is a suitably substituted benzene ring) in an amide bond forming reaction; the reaction is carried out using methods known to those skilled in the art or previously described to provide the compound of formula (XXIV). Alternatively, the acyl chloride of an acid derived from formula (III) can be reacted with the compound of formula (XXIII) in a suitable solvent (such as DCM, etc.) in the presence of a base (such as DIPEA); to provide the compound of formula (XXIV). In the second step, the compound of formula (XXIV) can be reacted with a suitable boric acid (such as R...) in a coupling reaction. 5' -B(OH)2, for example, 6-fluoro-pyridine-2-boronic acid, or borate derivatives such as 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine; reacted in the presence of a suitable base (such as, for example, 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 a mixture of 1,4-dioxane and water) at a suitable temperature (such as 85°C); to provide a compound of formula (XXII).

[0123] Option 9 According to scheme 9, the compound of formula (XXIV) (where Hal is Cl and R) 1 The phenyl group (as described in claim 1) can be reacted with a suitable sulfinate (such as sodium 1-methyl-3-sulfinpropionate (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°C to 110°C; to provide a compound of formula (XXV).

[0124] Compounds of formula (XXV) can react with formula R 5- Appropriately substituted heteroaryl halides of Hal (where Hal is Br or Cl, and R is Br or Cl) 5 The heteroaryl group as defined in claim 1 is reacted in the presence of a suitable phosphonium salt (such as, for example, di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3])); in the presence of a suitable base (such as K2CO3, etc.); in the presence of a suitable catalyst (such as Pd(OAc)2, etc.) to provide a compound of formula (I).

[0125] Option 10 According to Scheme 10, the compound of formula (XXIV) can be reacted with a commercially available or synthetically derived, appropriately substituted boric acid or borate ester derivative (such as (cis)-4-(3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)-2,6-dimethylmorpholine) for example using standard Suzuki coupling conditions in the presence of a suitable base (such as, for example, sodium carbonate) in the presence of a suitable catalyst (such as, for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (CAS [72287-26-4])) in a suitable solvent (such as, for example, a mixture of water and 1,4-dioxacyclohexane) at a suitable temperature (such as, for example, 100 °C) to provide a compound of formula (I) (wherein R 5 Defined as a C-linked heteroaryl, aryl, or heterocyclic alkyl group.

[0126] Alternatively, compounds of formula (XXIV) can be reacted with suitable heteroalkyl organozinc derivatives R 5 -Zn-Hal (where Hal is a suitable halogen, such as, for example, chlorine) is reacted in the presence of a suitable catalyst (such as, for example, tetra(triphenylphosphine)palladium) in a suitable solvent (such as, for example, THF or a mixture of THF and DMF) at a suitable temperature (such as, for example, room temperature) to provide a compound of formula (I).

[0127] Option 11 According to scheme 11, conventional amide bond formation techniques (such as coupling reactions well known to those skilled in the art) can be used to react the compound of formula (XII) with a suitable commercially available or synthetically available carboxylic acid. For example, the compound of formula (XII) (wherein R...) 5 The compound of formula (I) can be reacted with a suitable carboxylic acid in the presence of a suitable coupling agent (such as, for example, 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, for example, N-ethyldiisopropylamine (DIPEA), triethylamine (TEA), etc.); in a suitable solvent (such as, for example, DCM, THF, DMF, etc.); and at a suitable temperature (such as, for example, in the range of 0°C to room temperature) to provide the compound of formula (I).

[0128] 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, for example, an acyl chloride or its corresponding anhydride) in the presence of a suitable base (such as, for example, DIPEA or Et3N) in a suitable solvent (such as, for example, DCM or DMF) at a suitable temperature (such as, for example, 0°C or room temperature).

[0129] Compounds of formula (XXII) (where R) 5 It is a suitable heteroaryl group, such as, for example, 2-pyridyl, and Hal is a suitable halogen leaving group, such as, for example, F (fluorine) that can react with a suitable amine HNR. 9a R 9b The compound of formula (I) is reacted in the presence of a suitable base (such as, for example, DIPEA) in a suitable solvent (such as, for example, DMSO) at a suitable temperature (such as, for example, 90°C or at most 150°C) to provide the compound.

[0130] When the compound of formula (I) has a protecting group (such as, for example, Boc), the protecting group can be removed using conditions known to those skilled in the art. For example, it can be reacted with a reagent (such as, for example, pTsOH (p-toluenesulfonic acid), TFA, or HCl) in a suitable solvent (such as, for example, DCM or 1,4-dioxane) at a suitable temperature (such as, for example, room temperature or 40°C).

[0131] The compound of formula (I) is in R 1 The group has a protecting group (such as, for example, Boc or THP), which can be removed by reacting with a suitable reagent (such as, for example, HCl, pTsOH or pyridinium p-toluenesulfonate) in a suitable solvent (such as, for example, 1,4-dioxane or EtOH) at a suitable temperature (such as, for example, room temperature). Where the protecting group is an ester, the compound of formula (I) can be reacted with a suitable hydrolyzing agent (such as, for example, LiOH or NaOH) in a suitable solvent (such as, for example, THF, MeOH, water or mixtures thereof) at a suitable temperature (such as, for example, room temperature).

[0132] Technicians will recognize that an alternative sequence of chemical reactions shown in the scheme can also produce the desired compound of formula (I).

[0133] Those skilled in the art will recognize that the intermediates and final compounds shown in the following scheme can be further functionalized using methods well known to those skilled in the art.

[0134] Those skilled in the art will recognize that, in some cases, it may be desirable or necessary to carry out the reactions described herein in an inert atmosphere, such as an N2 gas atmosphere.

[0135] It is obvious to those skilled in the art that the reaction mixture may need to be cooled before post-reaction processing, which means a series of operations required to separate and purify the products of the chemical reaction, such as quenching, column chromatography, or extraction.

[0136] Technicians will recognize that heating the reaction mixture with stirring can enhance the reaction results. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0137] The compounds of the invention prepared in the methods described herein can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from each other according to resolution methods known in the art. Racemic compounds of formula (I) containing a basic nitrogen atom can be converted to their corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are released therefrom by a base. Alternative methods for separating the enantiomers of compounds of formula (I) and their pharmaceutically acceptable addition salts involve liquid chromatography using a chiral stationary phase, for example by supercritical fluid chromatography. The pure stereochemical isomers can also be derived from their corresponding pure stereochemical isomers from suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods will advantageously employ optically pure starting materials.

[0138] In all these preparations, the reaction products can be separated from the reaction medium and, if necessary, further purified according to methods commonly known in the art, such as extraction, crystallization, grinding, and chromatography. The purity of the reaction products can be determined according to methods commonly known in the art, such as LC-MS, TLC, and HPLC.

[0139] Treatment methods and medical uses, pharmaceutical compositions and combinations The present invention also provides methods for treating or preventing proliferative diseases (e.g., cancer, benign tumors, angiogenesis) in a subject. Such methods include the step of administering to a subject in need an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.

[0140] The subjects being treated are mammals. Subjects can be humans. Subjects can be domesticated animals, such as dogs, cats, cattle, pigs, horses, sheep, or goats. Subjects can be companion animals, such as dogs or cats. Subjects can be livestock, such as cattle, pigs, horses, sheep, or goats. Subjects can be zoo animals. Subjects can be research animals, such as rodents, dogs, or non-human primates. Subjects can be non-human transgenic animals, such as transgenic mice or transgenic pigs.

[0141] The use of compounds of formula (I) to treat or prevent proliferative diseases is generally associated with aberrant activity of SMARCA2. Aberrant activity of SMARCA2 can be elevated and / or inappropriate (e.g., abnormal) SMARCA2 activity. In some embodiments, SMARCA2 is not expressed, and SMARCA2 activity is elevated and / or inappropriate. In some other embodiments, SMARCA2 is overexpressed, and SMARCA2 activity is elevated and / or inappropriate. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can inhibit SMARCA2 activity and can be used to treat and / or prevent proliferative diseases.

[0142] Proliferative diseases may also be associated with inhibition of apoptosis in biological samples or subjects. All types of biological samples described herein or known in the art are considered to be within the scope of this invention. Inhibition of SMARCA2 activity is expected to cause cytotoxicity via induction of apoptosis. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can induce apoptosis and are therefore useful for the treatment and / or prevention of proliferative diseases.

[0143] In some embodiments, the proliferative disease to be treated or prevented by using the compounds disclosed herein is cancer.

[0144] The cells described in this article may be abnormal cells. Cells may be in vitro or in vivo. Cells may be proliferating cells.

[0145] In another aspect, the present invention provides a method for downregulating SMARCA2 expression in biological samples or subjects.

[0146] This invention relates to a compound of formula (I) and a method for treating SMARCA4-deficient cancers, the method comprising administering the compound of formula (I) to a subject in need.

[0147] This invention relates to a compound of formula (I) and a method for treating SMARCA4-deficient NSCLC, the method comprising administering the compound of formula (I) to a subject in need.

[0148] In another aspect, the present invention provides the compounds disclosed herein, and their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment of proliferative disorders in subjects. The compounds described herein, and their pharmaceutically acceptable salts and compositions thereof, can be used to inhibit cell growth. The compounds described herein, and their pharmaceutically acceptable salts and compositions thereof, can be used to induce apoptosis. The compounds described herein, and their pharmaceutically acceptable salts and compositions thereof, can be used to inhibit transcription.

[0149] Those skilled in the art will recognize that the therapeutically effective amount of the compounds of the present invention is an amount sufficient to have therapeutic activity, and this amount varies particularly depending on the type of disease, the concentration of the compound in the therapeutic agent, and the patient's condition. Generally, the amount of the compounds of the present invention administered as a therapeutic agent for the treatment of the conditions referred to herein will be determined by the attending physician based on the specific circumstances.

[0150] Technicians treating such diseases can determine the effective daily therapeutic dose from the test results given below. An effective daily therapeutic dose can range from about 0.005 mg / kg body weight to 50 mg / kg body weight. The amount of the compound according to the invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect can vary depending on the specific circumstances, such as the specific compound, the route of administration, the recipient's age and symptoms, and the specific condition or disease being treated. Treatment methods may also include administration of the active ingredient in a regimen of one to four times daily. In these treatment methods, it is preferable to formulate the compound according to the invention prior to administration. As described below, suitable pharmaceutical formulations are prepared using well-known and readily available ingredients by known methods.

[0151] While the active ingredient can be administered alone, it is preferred to be present in the form of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of compatibility with the other components of the composition and harmless to its recipient.

[0152] The pharmaceutical compositions of the present invention can be prepared by any method well known in the pharmacy field, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A specific compound, in a therapeutically effective amount as the active ingredient, in the form of a base or addition salt, is combined with a pharmaceutically acceptable carrier in a close mixture, the carrier being available in various forms depending on the desired formulation for administration. These pharmaceutical compositions are advantageously preferably suitable for systemic administration, such as oral, transdermal, or parenteral administration; or for topical administration, such as via inhalation or nasal spray in unit dosage forms. For example, in preparing compositions for oral dosage forms, in the case of oral liquid formulations such as suspensions, syrups, elixirs, and solutions, any commonly used pharmaceutical medium, such as water, glycols, oils, alcohols, etc., can be used; or in the case of powders, pills, capsules, and tablets, solid carriers, such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., can be used. Tablets and capsules represent the most advantageous oral unit dosage forms due to their ease of administration, in which case a solid pharmaceutical carrier is obviously employed. For parenteral compositions, the carrier will typically consist at least substantially of sterile water, but may also include other components, such as those that aid in dissolution. For example, injectable solutions can be prepared in which the carrier comprises an aqueous saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions can also be prepared, in which case a suitable liquid carrier, suspending agent, etc., can be used. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and / or a suitable wetting agent, optionally combined with a small proportion of a suitable additive of any nature that does not cause any significant adverse effects on the skin. The additive may facilitate application to the skin and / or may contribute to the preparation of the desired composition. These compositions can be administered in various ways, such as as transdermal patches, spot-on drops, or ointments.

[0153] Particularly advantageous is the formulation of the above-described pharmaceutical compositions into unit dosage forms that are easy to administer and provide uniform dosage. As used in this specification and the claims herein, a unit dosage form refers to a physically discrete unit suitable for a single dose, each unit containing a predetermined amount of the active ingredient, calculated to combine with a desired drug carrier to produce the desired therapeutic effect. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, dry films, injectable solutions or suspensions, teaspoon-sized amounts, tablespoon-sized amounts, and their separate multiple dosage forms.

[0154] As is well known to those skilled in the art, the exact dosage and frequency of administration depend on the specific compound used, the specific condition being treated, the severity of the condition being treated, the patient's age, weight, sex, severity of the condition, general health, and any other medications the individual may be taking. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the response of the treated subject and / or on the evaluation of the physician prescribing the compound of the present invention.

[0155] The method described herein may further include the additional step of administering one or more other agents in combination with the compounds of the present invention, pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof. Therefore, combinations of the compounds or compositions of the present invention with other agents can be used to treat proliferative diseases resistant to treatment with other agents that do not contain the compounds or compositions of the present invention.

[0156] Combination therapy includes administration of a single-dose formulation containing a compound according to the invention and one or more additional therapeutic agents, as well as administration of the compound according to the invention and each additional therapeutic agent in their respective separate drug dose formulations. For example, the compound and therapeutic agent according to the invention may be administered together to a patient in a single oral dose composition such as a tablet or capsule, or each agent may be administered in a separate oral dose formulation.

[0157] Therefore, one embodiment of the present invention relates to a product comprising a compound according to the invention as a first active ingredient and one or more anticancer agents as additional active ingredients, for use as a combination formulation in the treatment of patients with cancer, either simultaneously, alone or sequentially.

[0158] One or more other pharmaceutical agents and the compounds according to the invention may be administered simultaneously (e.g., in a single or individual composition) or sequentially. In the latter case, two or more compounds will be administered for a period of time sufficient to ensure a beneficial or synergistic effect and in an amount and manner sufficient to ensure a beneficial or synergistic effect. It should be understood that the preferred method and order of administration of each component of the combination, as well as the corresponding dosage and regimen, will depend on the specific other pharmaceutical agents and the compounds of the invention administered, their route of administration, the specific tumor treated, and the specific host treated. The optimal method and order of administration, as well as the dosage and regimen, can be readily determined by those skilled in the art using conventional methods and based on the information listed herein.

[0159] When administered in combination, the weight ratio of the compound according to the invention to one or more other anticancer agents can be determined by those skilled in the art. As is well known to those skilled in the art, the ratio, as well as the exact dosage and frequency of administration, depend on the specific compound according to the invention and the other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, general condition, method of administration, and other medications the individual may be taking. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the response of the treated subject and / or based on the evaluation of the physician prescribing the compound of the invention. The specific weight ratio of the compound of formula (I) of the invention to another anticancer agent may range from 1 / 10 to 10 / 1, more particularly from 1 / 5 to 5 / 1, and even more particularly from 1 / 3 to 3 / 1.

[0160] Example The following examples further illustrate the invention. These examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. Several methods for preparing the compounds of the invention are illustrated in the following examples. Unless otherwise stated, all starting materials are commercially available and can be used without further purification, or alternatively synthesized by a skilled person using well-known methods. Commercial sources include, but are not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0161] Table 2. Abbreviations . abbreviation meaning <![CDATA[ACN or CH3CN]]> Acetonitrile AcOH Acetic acid Boc tert-butoxycarbonyl <![CDATA[Celite ® ]]> diatomite Co compound Co. No. or Cpd. No. or Cmpd number Compound numbering DavePhos 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (CAS [213697-53-1]) DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene <![CDATA[DCM or CH2Cl2]]> dichloromethane DIBALH Diisobutylaluminum hydride DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone alcohol DEA Diethylamine DIAD Diisopropyl azodicarbonate DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide eq. equivalent <![CDATA[Et3N or TEA]]> Triethylamine EtOAc Ethyl acetate EtOH ethanol h or h. Hour HATU Hexafluorophosphate azirbenzotriazole tetramethylurea HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate HPLC High performance liquid chromatography <![CDATA[iPrNH2]]> Isopropylamine iPrOH Isopropanol <![CDATA[KHSO4]]> Potassium bisulfate led LED mCPBA m-chloroperoxybenzoic acid Me methyl MeOH methanol <![CDATA[MgSO4]]> Magnesium sulfate MsCl Methanesulfonyl chloride <![CDATA[NaBH(OAc)3]]> Sodium triacetoxyborohydride <![CDATA[Na2CO3]]> Sodium carbonate <![CDATA[NH4Cl]]> ammonium chloride <![CDATA[NH4HCO3]]> ammonium bicarbonate <![CDATA[NH4OAc]]> ammonium acetate <![CDATA[NH4OH]]> ammonium hydroxide <![CDATA[Pd2dba3]]> Tris(dibenzylacetone)bispalladium (CAS [51364-51-3]) <![CDATA[POCl3]]> Phosphorus oxychloride <![CDATA[PPh3]]> Triphenylphosphine quant. Quantitative rac racemic RP Inverted rt or rt room temperature SFC Supercritical fluid chromatography <![CDATA[SOCl2]]> thionyl chloride TBAF Tetrabutylammonium fluoride TBDMSCl tert-butyldimethylsilyl chloride TBDPSCl tert-butyldiphenylsilyl chloride TFA Trifluoroacetic acid THF Tetrahydrofuran

[0162] As will be understood by those skilled in the art, compounds synthesized using the methods indicated may contain residual solvents or small amounts of impurities.

[0163] Technicians will recognize that, even if not explicitly mentioned in the following experimental protocol, the desired fraction is typically collected and the solvent evaporated after column chromatography purification.

[0164] In the absence of a specified stereochemistry, this means that it is a mixture of stereoisomers unless otherwise indicated or is clear from the context.

[0165] When the center of the solid is represented by "RS", it means that a racemic mixture has been obtained.

[0166] For intermediates that can be used as crude products or as partially purified intermediates in the next reaction step, the theoretical molar amounts can be indicated in the reaction scheme below.

[0167] Example A: Preparation and characterization of intermediates and final compounds Preparation of intermediates For intermediates used as crude products or as partially purified intermediates in the next reaction step, in some cases, the molar amount of such intermediates is not mentioned in the next reaction step, or alternatively, the estimated or theoretical molar amount of such intermediates in the next reaction step is indicated in the reaction scheme below.

[0168] Representative 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 a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by rapid chromatography (12 g column, DCM / MeOH (9 / 1) / DCM, 0% to 25%) to give the title compound.

[0169] Method B : At room temperature, HBTU (1.5 equivalents) was added 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 reaction mixture was diluted with Na₂CO₃ (1 M in water) and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by reversed-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 give the title compound.

[0170] Method C : At room temperature, an amine (1.2 equivalents) was added 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 stirred at room temperature for 72 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by rapid column chromatography (12 g silica; MeOH / DCM, 0 / 100 to 3 / 97) followed by reversed-phase column chromatography (Phenomenex Gemini C18 30 mm × 100 mm 5 µm column; from 59% [25 mM NH4HCO3] – 41% [ACN:MeOH (1:1)] to 17% [25 mM NH4HCO3] – 83% [ACN:MeOH (1:1)]) to give the title compound.

[0171] Method E : Carboxylic acid (1.2 equivalents), 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 aqueous Na₂CO₃ solution (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 rapid column chromatography (25 g silica; DCM:MeOH (9:1) / DCM 0 / 100 to 25 / 75). The desired fraction was collected and concentrated under vacuum. The resulting product was ground with ACN and filtered to give the title compound.

[0172] Method F : 1-Propanephosphonic anhydride (50% in EtOAc, CAS [68957-94-8], 1.3 equivalents) was added to a suspension of amine (1 equivalent) and carboxylic acid (1.1 equivalent) in dry DCM (5 mL) under a nitrogen atmosphere at room temperature. Et3N (5 equivalents) was then added dropwise to the orange suspension. The reaction mixture (transparent 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; eluent: heptane:EtOH / EtOAc 1 / 3 100:0 -> 20:80) to give the title compound.

[0173] Method I : The 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 a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (12 g; SiO2; DCM:methanol (9:1) / DCM, 0 / 100 to 40 / 60) to give the title compound.

[0174] Method J : An 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 a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (25 g column, DCM:MeOH 9:1 / DCM gradient from 0% to 35%) to give a yellow solid. The solid was ground in ACN, filtered, washed with Et2O, and dried under vacuum to give the title compound.

[0175] 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 mm × 150 mm; mobile phase: 0.25% NH4HCO3 aqueous solution, ACN) to give the title compound.

[0176] Method M : 1-Propanephosphonic anhydride (50% in EtOAc, 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 mm × 250 mm; mobile phase: 0.25% NH4HCO3 aqueous solution, ACN) to give the title compound.

[0177] Method N : An amine (3 equivalents) was added to a solution of intermediate 21 (1 equivalent) and DIPEA (1.3 equivalents) in DMSO (0.6 mL). The reaction mixture was stirred at 120 °C for 48 hours. After cooling, excess amine was evaporated under reduced pressure, and the resulting solution was purified directly by reversed-phase column chromatography (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 mm × 150 mm; mobile phase: 0.25% NH4HCO3 aqueous solution, ACN, or MeOH) to give the title compound.

[0178] Method P : A solution of intermediate 23 (3 equivalents) and Et3N (6 equivalents) in DCM (1 mL) was added to a carboxylic acid (1.7 equivalents). 1-Propanephosphonic anhydride (50% solution in EtOAc, 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 C18OBD – 10 µm, 30 mm × 150 mm; mobile phase: 0.25% NH4HCO3 aqueous solution, ACN, or MeOH) to give the title compound.

[0179] Preparation of intermediates For intermediates used as crude products or as partially purified intermediates in the next reaction step, in some cases, the molar amount of such intermediates is not mentioned in the next reaction step, or alternatively, the estimated or theoretical molar amount of such intermediates in the next reaction step is indicated in the reaction scheme below.

[0180] Intermediate 1 : To a 3L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, add DMA (2.24L), Pd(dppf)Cl2.CH2Cl2 (CAS [95464-05-4], 22.4g, 0.1 equivalent), 7-chloro-1H-1,6-naphthid-2-one (CAS [1345091-18-0], 224g, 1240.37mmol), zinc (16.22g, 248.07mmol, 0.2 equivalent), and zinc cyanide (145.65g, 1240.37mmol, 1 equivalent). Stir the resulting solution at 100°C for 4 hours. Allow the reaction mixture to cool to room temperature. Filter the solids and wash with 2 × 100mL DMA. Then quench the reaction by adding 5L of water / ice. The solid was collected by filtration to obtain intermediate 1 (147 g, yield: 69%), which was a brown solid.

[0181] Intermediate 2 : Phosphorus oxychloride (1.47 L) and intermediate 1 (147.00 g, 858.85 mmol) were added to a 2 L three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 80 °C for 3 h. The reaction mixture was concentrated. The resulting solution was diluted with 2 L of DCM. The reaction was then quenched by adding 4 L of water / ice. The resulting solution was extracted with 3 × 3 L of DCM, and the organic layer was dried over Na₂SO₄ and concentrated to give intermediate 2 (58 g, yield: 36%) as a yellow solid.

[0182] Intermediate 3 : Add 1.74 L of DCM and intermediate 2 (58 g, 305.90 mmol) to a 5 L, 4-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, while stirring at -78 °C, add DIBAL-H (1 N, 765 mL, 2.5 equivalents) dropwise over 30 minutes. Stir the resulting solution at -78 °C for 2 hours. Add sodium potassium tartrate (257 g, 1224 mmol, 4 equivalents) to the solution at -78 °C. Stir the resulting solution at room temperature for 1 hour. Then, add di-tert-butyl dicarbonate (73.3 g, 336.50 mmol, 1.1 equivalents). Stir the resulting solution at room temperature overnight. Filter the solid and wash with 3 × 300 mL of DCM. Concentrate the filtrate. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether 1 / 3 to 1 / 2) to give intermediate 3 (60.9 g, yield: 68%) as a yellow solid.

[0183] Intermediate 4 : 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 under nitrogen for 5 min. 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 under nitrogen for 5 min. The reaction mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted once more with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The solid residue was ground with Et2O and filtered. The white solid was washed with a small amount of Et2O to give intermediate 4 (7.47 g, yield: 58%), which was a white solid.

[0184] Intermediate 5 : 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 a suspension in dry DMSO (20 mL) were partitioned 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 EtOAc. The layers were separated, and the aqueous layer was extracted once more with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was milled in DCM / Et2O 1 / 1. The solid was filtered and washed with a small amount of Et2O. The solid was combined with the filtrate and purified by column chromatography (Biotage Sfar 200g; eluent: heptane:EtOH / EtOAc1 / 3100:0->20:80) to give intermediate 5 (5.1g, quantitative).

[0185] Intermediate 6 : At room temperature, HCl (37% in H₂O, 40 mL, 484.24 mmol, 20 equivalents) was added dropwise (1 drop / second, slightly exothermic) to a yellow suspension of intermediate 5 (10.85 g, 24.135 mmol) in 1,4-dioxane (100 mL). The reaction mixture turned red, then yellow again, 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 give intermediate 6 (HCl salt, 12 g, quantitative) as an orange solid, which was dried under vacuum at 50 °C.

[0186] Intermediate 7 : Ferrous 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 min. Then, the second portion of H2O2 (365 μL, 3.572 mmol, 5.4 equivalents) was added dropwise, and stirring was continued for 90 min. The reaction was slowly quenched at room temperature with a 5% Na2S2O aqueous solution, followed by the addition of a saturated NaHCO3 aqueous solution. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (12 g silica; EtOAc / heptane gradient 0 / 100 to 10 / 90) to give intermediate 7 (75 mg, yield: 59%) as a white solid.

[0187] Intermediate 8 : NaBH4 (157 mg, 4.141 mmol, 2 equivalents) was added to intermediate 7 (400 mg, 2.07 mmol) in a solution of MeOH (10 mL) at 0 °C under a nitrogen atmosphere, and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with a saturated aqueous NH4Cl solution, and the mixture was diluted with EtOAc. The layers were separated, and the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (80 g silica; EtOAc / heptane gradient 0 / 100 to 50 / 50) to give intermediate 8 (240 mg, yield: 59%) as a colorless foam.

[0188] Intermediate 9 : 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 pH ~1 with HCl (1M in water), diluted with additional water, and extracted with EtOAc (3x). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 9 (223 mg, yield: 100%), which was ready for use without further purification.

[0189] Intermediate 10 : At room temperature, HCl (37% in H₂O, 47 mL, 588.7 mmol, 20 equivalences) was added dropwise (1 drop / second, slightly exothermic) to a light brown solution of intermediate 4 (10 g, 27.94 mmol) in 1,4-dioxane (300 mL). The reaction mixture was stirred at room temperature for 30 minutes. The precipitate that appeared during the reaction was filtered off, and the solid was washed with dioxane to give intermediate 10 (HCl salt, 8.3 g, quantified) as a gray solid, which was dried under vacuum at 50 °C and was ready for use without further purification.

[0190] Intermediate 11 : Intermediate 3 (1.03 g, 3.506 mmol) was added to a solution of sodium 1-methyl-3-sulfinylpropionate (CAS [90030-48-1], 1.22 g, 7.013 mmol, 2 equivalents) and cuprous iodide (1.34 g, 7.013 mmol, 2 equivalents) in DMSO (10 mL). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with EtOAc and washed with water containing an aqueous solution of NH3 (1 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (25 g column, EtOAc / heptane gradient 0 / 100 to 100 / 0) to give intermediate 11 (801 mg, yield: 53%) as an orange solid.

[0191] Intermediate 12 : Cis 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 and stirred 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 layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (120 g column, EtOAc / heptane gradient 0 / 100 to 40 / 60) to give intermediate 12 (3.2 g, yield: 56%) as an orange solid.

[0192] Intermediate 13 : Cis Tetramethylammonium fluoride (CAS [373-68-2], 663 mg, 7.117 mmol, 1.5 equivalences) 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 was quenched by adding water, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (80 g column, EtOAc / heptane gradient 0 / 100 to 30 / 70) to give intermediate 13 (1139 mg, yield: 81%) as an orange solid.

[0193] Intermediate 14 : Cis Under a nitrogen stream, intermediates 11 (950 mg, 2.32 mmol), 13 (1006 mg, 3.48 mmol, 1.5 equivalents), and K₂CO₃ (481 mg, 3.48 mmol, 1.5 equivalents) were dissolved in 24 mL of 1,4-dioxane in a sealed tube. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 58 mg, 0.232 mmol, 0.1 equivalents) 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 EtOAc, and washed with water. The organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (25 g column, EtOAc / heptane gradient 0 / 100 to 100 / 0) to give intermediate 14 (428 mg, yield: 39%) as a yellow solid.

[0194] Intermediate 15 : Cis 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 milled in Et2O to give intermediate 15 (HCl salt, 406 mg, quantified) as an orange solid.

[0195] Intermediate 16 : Sodium methanethiol (CAS [5188-07-8], 15 mg, 0.207 mmol, 1.2 equivalents) was added to a solution of methyl 4-chloro-5-methyl-2-pyridinecarboxylate (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 EtOAc (10 mL) and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (12 g column, EtOAc / heptane gradient 0 to 100%) to give intermediate 16 (25 mg, yield: 73%) as a white solid.

[0196] Intermediate 17 : At 0 °C, m-CPBA (2.465 g, 10 mmol, 2.5 equivalents) was added partically to a solution of intermediate 16 (789 mg, 4 mmol) in DCM (35 mL). The reaction mixture was stirred for 20 hours, allowing the temperature to rise to room temperature. The reaction was quenched with a saturated aqueous solution of Na₂S₂O₃ (1 mL) with stirring. A saturated aqueous solution of NaHCO₃ (5 mL) and DCM (10 mL) were added. The mixture was stirred for another 10 minutes, and then the organic layers were 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, MeOH / DCM gradient 0 to 5%) to give intermediate 17 (771 mg, yield: 83%) as a white solid.

[0197] Intermediate 18 : At room temperature, NaOH (1 M in water, 5.0 mL, 5.038 mmol, 1.5 equivalents) was added 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 (1 M in water) was added to achieve a pH of ~2-3. The mixture was extracted with MeOH / CH2Cl2 (1:9). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 18 (630 mg, yield: 86%) as a white solid, which was ready for use without further purification.

[0198] Intermediate 19 : (3α,4α,5α) According to method J, intermediate 19 was prepared starting from intermediate 4 and (3α,4α,5α)-3,5-dimethyl-4-piperidinol (CAS [1236030-00-4]).

[0199] Intermediate 20 : (3α,4α,5α) (HCl salt) HCl (4 M 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 give intermediate 20 (HCl salt, 452 mg, 92% pure, quantitative).

[0200] Intermediate 21 : At room temperature under a nitrogen atmosphere, 1-propanephosphonic anhydride (50% in EtOAc, CAS [68957-94-8], 24.37 mL, 40.932 mmol, 1.7 equivalents) was added to intermediate 10 (7000 mg, 24.078 mmol) and 5-(methanesulfonyl)nicotinic acid (CAS [893723-59-6], 5813 mg, 28.893 mmol, 1.2 equivalents) in a suspension in dry DCM (200 mL). Et3N (24.1 mL, 173.358 mmol, 7.2 equivalents) was then added dropwise to the orange suspension over 5 minutes. The reaction mixture was stirred overnight at room temperature. The resulting solids were filtered and washed with Et2O. The solids were stirred in water and MeOH for 2 hours, filtered, and washed with toluene to give intermediate 21 (7.1 g, 95% pure, yield: 64%). Intermediate 22 : (3α,4β,5α) According to method J, intermediate 22 was prepared starting from intermediate 4 and (3α,4β,5α)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4]).

[0201] Intermediate 23 : (3α,4β,5α) Intermediate 23 is prepared by replacing intermediate 19 with intermediate 22 in a similar manner to intermediate 20.

[0202] Intermediate 24 and Intermediate 25 : Intermediate 24: *R, a pure stereoisomer, but its stereochemistry was not determined. Intermediate 25: *S, a pure stereoisomer, but its stereochemistry was not determined. NaOH (2M in water, 19 mL, 38.034 mmol, 2 equivalents) was added to a solution of methyl 5-(1-hydroxyethyl)-3-pyridinecarboxylate (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 aqueous HCl (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 give intermediate 24 (930 mg, yield: 29%) and intermediate 25 (631 mg, yield: 20%), both of which were brown oils.

[0203] Intermediate 26 : Cis Under a nitrogen atmosphere, Dess-Martin periodane (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), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3, followed by washing with brine. The organic layer was dried over MgSO4, filtered, and concentrated to give intermediate 26 (99 mg, yield: 95%) as a yellow solid, which was ready for use without further purification.

[0204] Intermediate 27 : (3α,4β,5α) At 0 °C, N-iodosuccinimide (199 mg, 0.884 mmol, 1 equivalent) was added 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 min, then at room temperature for 1 h. The mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (silica; EtOAc / heptane, 0 / 100 to 50 / 50) to give intermediate 27 (450 mg, 66% pure, yield: 57%) as a yellow oil.

[0205] Intermediate 28 : (3α,4β,5α) A solution of intermediate 27 (450 mg, 66% pure, 0.504 mmol), trimethylcyclotriboroxane (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 min. XantPhos Pd G₃ (CAS [1445085-97-1], 48 mg, 0.050 mmol, 0.1 equivalents) was added to the solution at room temperature, and the mixture was stirred at 80 °C for 12 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (25 g silica; EtOAc / heptane, 0 / 100 to 100 / 0) followed by reversed-phase column chromatography (Phenomenex Gemini C18 30 mm × 100 mm 5 µm column; 81% [0.1% HCOOH] – 19% ACN to 45% [0.1% HCOOH] – 55% ACN) to give intermediate 28 (77 mg, yield: 32%) as a yellow solid.

[0206] Intermediate 29 : (3α,4β,5α) 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 give intermediate 29 (HCl salt, 42 mg, 90% pure, quantified) as an orange solid.

[0207] Intermediate 30 : 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 EtOAc. The resulting precipitate was filtered and washed with EtOAc, then dried under vacuum to give intermediate 30 (48 mg, yield: 68%) as a pale yellow solid.

[0208] Intermediate 31 : According to method K, intermediate 31 was prepared starting from intermediate 21 and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (CAS[1180509-95-8]).

[0209] Intermediate 32 : According to method K, intermediate 32 was prepared starting from intermediate 21 and 3-(N-tert-butoxycarbonyl-N-methylamino)pyrrolidine (CAS [172478-00-1]).

[0210] Intermediate 33 : According to method K, intermediate 33 was prepared starting from intermediate 21 and DL-3-(Boc-amino)pyrrolidine (CAS [99724-19-3]).

[0211] Intermediate 34 : According to method J, intermediate 34 was prepared starting from intermediate 21 and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (CAS [236406-55-6]).

[0212] Intermediate 35 : tert-butyl (pyrrolidone-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 intermediate 21 (100 mg, 0.222 mmol) in a suspension in dry DMSO (1 mL), and the reaction mixture was stirred overnight at 130 °C. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted once more with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated to give intermediate 35, which was used directly in the next step without further purification.

[0213] Intermediate 36 : 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 EtOAc. The layers were separated, and the aqueous layer was extracted once more with EtOAc. The combined organic layers were dried by filtration on an Extralut NT3 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep 4 g, DCM / DCM:MeOH 9:1, 100 / 0 to 0 / 100) to give intermediate 36 (51 mg, yield: 76%) as a deep yellow solid.

[0214] Intermediate 37 : Intermediate 83 (99 g, 464.24 mmol, 1 equivalent), EtOH (990 mL), and H2O2 (157.91 g, 4642.44 mmol, 10 equivalents) were added to a 2 L four-necked round-bottom flask purged and maintained under a nitrogen atmosphere. Following this, ammonium molybdate tetrahydrate (57.37 g, 46.42 mmol, 0.1 equivalents) 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 a saturated aqueous solution of Na2S2O3 (3 × 1 L), dried over Na2SO4, and concentrated. The residue was purified by grinding with MTBE (1 L) to give intermediate 37 (62 g, yield: 54%) as a white solid.

[0215] Intermediate 38 : At room temperature, 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. 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 an aqueous HCl solution (6 N). The precipitated solid was collected by filtration. The solid was purified by grinding with THF (600 mL) and collected by filtration to give intermediate 38 (50.46 g, yield: 87%) as a white solid.

[0216] Intermediate 39 : (3α,4α,5α) According to method J, intermediate 39 was prepared starting from intermediate 4 and (3α,4α,5α)-3,5-dimethyl-4-piperidinol (CAS [1236030-00-4]).

[0217] Intermediate 40 : (3α,4α,5α) Intermediate 40 is prepared by using intermediate 39 instead of intermediate 28, in a similar manner to intermediate 29.

[0218] Intermediate 41 : Ferrous sulfate heptahydrate (CAS [7782-63-0], 545 mg, 1.632 mmol, 0.14 equivalents) was added to a solution of methyl 5-chloro-2-pyridinecarboxylate (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, while 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 an additional 90 minutes. The mixture was then warmed to room temperature. The reaction was quenched by slow addition of a saturated aqueous solution of Na₂S₂O₃, followed by the addition of a saturated aqueous solution of NaHCO₃, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (12 g silica; EtOAc / heptane gradient 0 / 100 to 10 / 90) to give intermediate 41 (1.85 g, yield: 74%) as a colorless oil.

[0219] Intermediate 42 : 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 EtOAc (x3). The combined organic layers were separated, dried (MgSO4), filtered, and the solvent was evaporated under vacuum to give intermediate 42 (1.49 g, yield: 86%), which was ready for use without further purification.

[0220] Intermediate 43 : (3α,4β,5α) 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 mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (80 g, EtOAc / heptane, 0 / 100 to 20 / 80) to give intermediate 43 (2.88 g, yield: 88%) as a white solid.

[0221] Intermediate 44 : (3α,4β,5α) Under a nitrogen atmosphere, 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). The mixture was purged with 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 diatomaceous earth pad and the solvent was removed under vacuum to give intermediate 44 (1.98 g, yield: 94%) as a colorless oil.

[0222] Intermediate 45 : (3α,4β,5α) Nitrogen gas was used to purge a solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 1.236 g, 4.384 mmol) in 1,4-dioxane (37 mL). Then, 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 equivalents), and Pd₂dba₃ (CAS [51364-51-3], 200 mg, 0.218 mmol, 0.05 equivalents) were added at room temperature while nitrogen gas was purged. The vial was sealed, and the mixture was stirred at 90 °C for 3 hours. A saturated aqueous solution of NaHCO₃ and EtOAc were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted again with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (25 g, EtOAc / heptane, 0 / 100 to 25 / 75) to give intermediate 45 (1.686 g, yield: 84%) as a yellow solid.

[0223] Intermediate 46 : (3α,4β,5α) Tetramethylammonium fluoride (CAS [373-68-2], 543 mg, 5.83 mmol, 1.5 equivalences) 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 EtOAc (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 rapid column chromatography (80 g, EtOAc / heptane, 0 / 100 to 30 / 100) to give intermediate 46 (1.265 g, yield: 79%) as a yellow solid.

[0224] Intermediate 47 : (3α,4β,5α) Intermediate 47 is prepared by replacing intermediate 13 with intermediate 46 in a similar manner to intermediate 14.

[0225] Intermediate 48 : (3α,4β,5α) At 0 °C, TFA (1.505 mL, 19.67 mmol, 30 equivalents) was added 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 give intermediate 48 (295 mg, yield: 91%), which was ready for use without further purification.

[0226] Intermediate 49 : (3α,4β,5α) According to method A (in DMF), intermediate 49 is prepared starting from intermediate 48 and 2-methyl-6-(methanesulfonyl)-4-pyridinecarboxylic acid (CAS [1780757-32-5]).

[0227] Intermediate 50 : (3α,4β,5α) Intermediate 47 (540 mg, 0.922 mmol) was stirred in an aqueous NaOH solution (2.5 M, 5.5 mL, 13.75 mmol, 15 equivalents) at 72 °C for 16 hours. After cooling, the mixture was partitioned between EtOAc (25 mL) and a saturated aqueous NaHCO3 solution. The layers were separated, and the organic layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (25 g silica, DCM:MeOH (9:1) / DCM, 0% to 25%) to give intermediate 50 (401 mg, yield: 90%) as a yellow solid.

[0228] Intermediate 51 : (3α,4β,5α) At 0 °C, trifluoroacetic acid (1.5 mL, 19.601 mmol, 24 equivalents) was added 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 give intermediate 51 (TFA salt, 508 mg, yield: 99%) as a yellow solid, which was ready for use without further purification.

[0229] Intermediate 52 : (3α, 4β, 5α) (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, a solution of 1,1-dimethyl ethyl rel-(3R,5S)-3,5-dimethyl-4-oxo-1-piperidinic acid (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 an acidic pH was reached and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with Et2O (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by rapid column chromatography (24 g SiO2, heptane / EtOAc, 100 / 0 to 80 / 20) to give intermediate 52 (576 mg, yield: 60%).

[0230] Intermediate 53 : (3α, 4β, 5α) Intermediate 52 (576 mg, 2.387 mmol) was dissolved in MeOH (20 mL), and sodium borohydride (135 mg, 3.58 mmol, 1.5 equivalences) was added. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The residue was diluted in 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 rapid column chromatography (12 g SiO2, heptane / EtOAc, 90 / 10 to 50 / 50) to give intermediate 53 (389 mg, yield: 64%) as a clear oil.

[0231] Intermediate 54 : (3α, 4β, 5α) 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 give intermediate 54 (HCl salt, 385 mg, quantified).

[0232] Intermediate 55 : (3α, 4β, 5α) 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 extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by rapid column chromatography (12 g SiO2, DCM / MeOH, 100 / 0 to 90 / 10) to give intermediate 55 (112 mg, yield: 37%) as an orange foam.

[0233] Intermediate 56 : (3α, 4β, 5α) Intermediate 55 (112 mg, 0.211 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 4 mL, 4 M, 16 mmol) and DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the precipitate was separated by filtration and dried under reduced pressure to give intermediate 56 (HCl salt, 117 mg, quantified) as a grayish-white solid, which was used without further purification.

[0234] Intermediate 57 : 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 once more with DCM. The combined organic layers were dried by filtration on an Extralut NT3 filter and evaporated. The residue was purified by column chromatography (SiO2, 25 g; heptane:EtOH / EtOAc 1 / 3, 100:0 to 20:80) to give intermediate 57 (311 mg, yield: 77%) as a grayish-white solid.

[0235] Intermediate 58 : At room temperature, 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 20 mL of 1,4-dioxane. After addition, the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. The solid was co-evaporated with toluene to give intermediate 58 (HCl salt, 273 mg, quantified) as an orange solid, which was ready for use without further purification.

[0236] Intermediate 59 : A suspension of 4-methyl-4,6-diazaspiro[2,4]heptane-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), Xantphos (CAS [161265-03-8], 675 mg, 1.167 mmol, 0.4 equivalents), and Cs₂CO₃ (3.80 g, 11.668 mmol, 4 equivalents) in dry 1,4-dioxane (15 mL) was degassed with nitrogen for 5 min. Pd(OAc)₂ (CAS [3375-31-3], 65 mg, 0.292 mmol, 0.1 equivalents) was added, and the reaction mixture was further degassed for 5 min. The vial was sealed, 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 / EtOAc 1 / 3, 100:0 to 20:80) to give intermediate 59 (291 mg, yield: 35%) as a yellow solid.

[0237] Intermediate 60 : [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (CAS [72287-26-4], 76 mg, 0.103 mmol, 0.15 equivalents) was added to intermediate 59 (291 mg, 1.031 mmol, 1.5 equivalents), bis(pinacolyl)diboron (CAS [73183-34-3], 314 mg, 1.238 mmol, 1.8 equivalents), and KOAc (previously vacuum-dried at 50 °C, 304 mg, 3.094 mmol, 4.5 equivalents) in a suspension in dried 1,4-dioxane (6 mL), and the mixture was degassed by bubbling through it with nitrogen for 5 minutes. The vial was sealed and the reaction mixture was stirred at 90 °C for 2 hours. Open the vial and maintain it under a nitrogen atmosphere while adding intermediate 3 (202 mg, 0.688 mmol), K₂CO₃ (190 mg, 1.375 mmol, 2 equivalents), and cuprous(I) chloride (69 mg, 0.688 mmol, 1 equivalent). Reseal the vial and stir the reaction mixture at 75 °C for 18 hours. After cooling, dilute the reaction mixture with EtOAc and filter. Wash the solid with EtOAc. Add brine to the filtrate and separate the layers. Extract the aqueous layer again with EtOAc. Dry the combined organic layers over MgSO₄, filter, and evaporate. Purify the residue by column chromatography (SiO₂, 25 g; heptane:EtOH / EtOAc 1 / 3, 100:0 to 100:0) to give intermediate 60 (124 mg, 41% pure, yield: 16%) as a grayish-white solid, which is still impure but can be used directly in the next step.

[0238] Intermediate 61 : At room temperature, HCl (37% in water, 0.28 mL, 3.312 mmol, 30 equivalents) was added dropwise to a solution of intermediate 60 (41% pure, 124 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated to give intermediate 61 (HCl salt, 62 mg) as a brown solid, which could be used without further purification.

[0239] Intermediate 62 : A solution of oxone (CAS [7069-62-8], 5.8 g, 9.2 mmol) in water (35 mL) was added in a single step 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) at room temperature. The mixture was stirred at room temperature for 20 hours. The mixture was diluted with EtOAc (150 mL) and water (250 mL). The organic layers were separated, and the aqueous layer was extracted with EtOAc (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 / DCM, 0 / 100 to 20 / 80) to give intermediate 62 (535 mg, yield: 47%) as a white solid.

[0240] Intermediate 63 : Sodium hydroxide (1 M in water, 6.5 mL, 6.5 mmol) was added to a stirred solution of intermediate 62 (529 mg, 2.16 mmol) in methanol (3 mL) at room temperature. 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 EtOAc. The combined organic layers were evaporated to give intermediate 63 (662 mg, quantified) as a white solid, which was ready for use without further purification.

[0241] Intermediate 64 : 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 in EtOAc 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 to 98 / 2) to give intermediate 64 (1.72 g, yield: 42%).

[0242] Intermediate 65 : 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 co-evaporated once with toluene. The yellow powder was dried under reduced pressure at 50 °C to give intermediate 65 (1.49 g, yield: 100%).

[0243] Intermediate 66 : 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), Xantphos (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 min. The reaction mixture was then stirred at 100 °C under a nitrogen atmosphere for 30 min. The reaction mixture was diluted with DCM and filtered through a diatomaceous earth mat. The solvent was evaporated under vacuum, and the crude product was purified by silica gel chromatography (24 g, heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 66 (83 mg, yield: 68%) as a white solid.

[0244] Intermediate 67 : Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (CAS [72287-26-4], 21 mg, 0.029 mmol) was added to intermediate 66 (83 mg, 0.29 mmol), bis(pinacolyl)diboron (CAS [73183-34-3], 88 mg, 0.34 mmol), and KOAc (vacuum dried overnight at 45 °C, 85 mg, 0.86 mmol) in a suspension of dried 1,4-dioxane (2 mL), and the mixture was degassed by bubbling through it with 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 kept under a nitrogen atmosphere, while 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 EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layers were washed with brine and water, dried over MgSO₄, filtered, and evaporated. The residue was purified by silica gel chromatography (12 g, DCM / MeOH, 100 / 0 to 99 / 1) to give intermediate 67 (50 mg, yield: 57%) as a yellow solid.

[0245] Intermediate 68 : 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 co-evaporated once with toluene to give intermediate 68 (46 mg, yield: 98%) as a yellow-orange solid.

[0246] Intermediate 69 : Following a similar sequence of procedures as that for intermediate 68, intermediate 69 was synthesized starting with the substitution of 4-oxa-7-azaspiro[2.5]octane-6-one with 2,6-dimethylmorpholino-3-one (CAS[93240-61-0]).

[0247] Intermediate 70 : Following a similar sequence of procedures as that for intermediate 68, intermediate 70 was synthesized starting with the substitution of 4-oxa-7-azaspiro[2.5]octane-6-one with 6-(trifluoromethyl)morpholin-3-one (CAS[1354953-95-9]).

[0248] Intermediate 71 : Following a similar sequence of procedures as that for intermediate 68, intermediate 71 was synthesized starting with the substitution of 4-oxa-7-azaspiro[2.5]octane-6-one with 2,2-dimethylmorpholino-3-one (CAS[13882-78-5]).

[0249] Intermediate 72 : Sodium hydride (70 mg, 1.74 mmol) was added to a stirred solution of (L)-proline (CAS [147-85-3], 200 mg, 1.74 mmol) in DMSO (12 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. Then, methyl 5-bromo-6-methyl-3-pyridinecarboxylate ([CAS: 1174028-22-8], 500 mg, 2.17 mmol), sodium methanesulfinate (CAS [20277-69-4], 1.8 g, 17.4 mmol), and cuprous 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 EtOAc. The precipitate formed was filtered, and the filtrate layer was separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (25 g silica; MeOH / DCM, 0 / 100 to 5 / 95) to give intermediate 73 (278 mg, yield: 55%) as a white solid.

[0250] Intermediate 73 : A sodium hydroxide solution (1 M in water, 9.2 mL, 9.2 mmol) was added to a stirred solution of intermediate 72 (700 mg, 3.05 mmol) in MeOH (9 mL) at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH ~1 with an aqueous HCl solution (1 M in water) and then extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 73 (545 mg, yield: 79%) as a white solid.

[0251] Intermediate 74 : Under a nitrogen atmosphere, 7-bromo-1,6-naphthidium-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 equivalent), bis(triphenylphosphine)palladium(II) dichloride (CAS [13965-03-2], 280 mg, 0.4 mmol, 0.3 equivalent), and Cs₂CO₃ (13.0 g, 40.0 mmol, 3.0 equivalent) were placed in DMF (40 mL) and water (10 mL). The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by rapid column chromatography (80 g SiO2, DCM:MeOH (9:1) / DCM, 0% to 30%) to give intermediate 74 (1.267 g, yield: 49%) as a white solid.

[0252] Intermediate 75 : Phosphoryl chloride (CAS [10025-87-3], 1.65 mL, 17.67 mmol, 3.0 equivalent) 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 a saturated aqueous solution of Na₂CO₃ and EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated to give intermediate 75 (981 mg, yield: 74%) as a beige solid.

[0253] Intermediate 76 : At 0 °C, osmium tetroxide (CAS [20816-12-0], 33 mg, 0.13 mmol) was added to 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) in a stirred mixture of water (14 mL) and 1,4-dioxane (55 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with a saturated aqueous solution of NaHCO3 and EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated to give intermediate 76 (822 mg, yield: 75%) as a brown solid.

[0254] Intermediate 77 : At room temperature, intermediate 76 (200 mg, 1.038 mmol, 1.0 equivalent), 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]pyridine acid (CAS [1009033-83-3], 467 mg, 0.494 mmol, 1.44 equivalent) and sodium carbonate (330 mg, 3.115 mmol, 3.0 equivalent) were dissolved in 1,4-dioxabane (4 mL) and water (1 mL) in a pressure flask. The mixture was bubbled with nitrogen for 10 minutes. Then, the complex of bis(diphenylphosphino)ferrocene]palladium(II) dichloride with DCM (CAS [95464-05-4], 42 mg, 0.052 mmol, 0.05 equivalent) was added, and the mixture was stirred at 85 °C for 16 hours. The mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by rapid column chromatography (12 g silica; EtOAc / heptane, 0 / 100 to 80 / 20) to give intermediate 77 (90 mg, yield: 28%) as a white solid.

[0255] Intermediate 78 : Sodium bicarbonate (24 mg, 0.289 mmol, 1.0 equivalent) and hydroxylamine hydrochloride (CAS [5470-11-1], 40 mg, 0.578 mmol, 2.0 equivalent) were added to a solution of intermediate 77 (90 mg, 0.289 mmol, 1.0 equivalent) in MeOH (30 mL). The suspension was stirred at room temperature for 24 hours. The mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated to give intermediate 78 (45 mg, yield: 47%) as a beige solid, which was ready for use without further purification.

[0256] Intermediate 79 : 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 equivalents) in MeOH (6 mL) and THF (3 mL) at room temperature and under a nitrogen atmosphere. 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 diatomaceous earth pad, and the filtrate was evaporated to give intermediate 79 (170 mg, yield: 58%) as a brown solid, which was ready for use without further purification.

[0257] Intermediate 80 : (3α, 4β, 5α) At 0 °C, N-iodosuccinimide (CAS [516-12-1], 335 mg, 1.49 mmol, 1.0 equivalent) was added to intermediate 50 (717 mg, 1.49 mmol, 1.0 equivalent) in a solution of 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 EtOAc. The organic layer was washed with water and a saturated aqueous solution of Na2S2O3. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by rapid column chromatography (25 g SiO2, DCM:MeOH (9:1) / DCM, 0% to 18%) to give intermediate 80 (555 mg, yield: 60%) as a yellow solid.

[0258] Intermediate 81 : (3α, 4β, 5α) Under a nitrogen atmosphere, trimethylcycloboroxane (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 1,4-dioxane (10 mL). The mixture was stirred at 95 °C for 16 hours. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated. The crude product was purified by rapid column chromatography (25 g SiO2 column, DCM:MeOH (9:1) / DCM, 0 / 100 to 20 / 80) to give intermediate 81 (413 mg, yield: 90%) as a colorless oil.

[0259] Intermediate 82 (3α, 4β, 5α) At 0 °C, trifluoroacetic acid (CAS [76-05-1], 1.5 mL, 19.6 mmol, 23.5 equivalents) was added to intermediate 81 (413 mg, 0.83 mmol, 1.0 equivalents) in a stirred solution of DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours, and then a saturated aqueous solution of NaHCO3 and DCM were added to the reaction mixture. The organic layer was separated, dried over MgSO4, filtered, and concentrated to give intermediate 82 (321 mg, yield: 96%) as a beige solid, which was ready for use without further purification.

[0260] Intermediate 83 : A mixture of methyl 5-bromonicotinic acid (CAS [29681-44-5], 5.05 g, 26.367 mmol), Xantphos (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 sealed, evacuated, and nitrogen-purged reaction vessel. 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 crude residue was purified by rapid column chromatography (330 g SiO2; EtOAc / DCM 0 / 100 to 100 / 0) to obtain intermediate 83 (5.18 g, quantified).

[0261] Intermediate 84 : 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 min. Butyllithium (2.5 M in hexane, 2.37 mL, 5.94 mmol, 2 equivalent) was added dropwise, and the reaction mixture was stirred at -78 °C for 20 min. Acetone (0.44 mL, 5.940 mmol, 2 equivalent) in THF (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched with a saturated aqueous NH4Cl solution, and KHSO4 (1 M in water) was added dropwise over 10 min with vigorous stirring. The pH was adjusted to 2-3. Then, DCM and water were added. The organic layer was separated and concentrated, and the residue was purified by rapid column chromatography (25 g silica, DCM:MeOH (9:1) / DCM, 0 / 100 to 20 / 80) to give intermediate 84 (194 mg, yield: 32%) as a beige solid.

[0262] Intermediate 85 : Nitrogen gas was used to purge 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). Then, under nitrogen gas at room temperature, Cs2CO3 (5 g, 15.35 mmol, 2.0 equivalent), DavePhos (CAS [213697-53-1], 303 mg, 0.77 mmol, 0.05 equivalent) and Pd2dba3 (CAS [51364-51-3], 330 mg, 0.36 mmol, 0.1 equivalent) were added to the stirred solution in a sealed tube. The mixture was stirred at 90°C for 3.5 hours, and then a saturated aqueous solution of NaHCO3 and EtOAc 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 (80 g; EtOAc / heptane, 0 / 100 to 10 / 90) to give intermediate 85 (2.6 g, yield: 80%) as a yellow solid.

[0263] Intermediate 86 : Anhydrous tetramethylammonium fluoride (CAS [373-68-2], 887 mg, 9.5 mmol, 1.5 equivalents) was added to a solution of intermediate 85 (2.6 g, 6.3 mmol, 1.0 equivalents) in DMF (50 mL) at room temperature in a sealed tube. The mixture was stirred at 65 °C for 3 hours. After cooling, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (80 g; EtOAc / heptane, 0 / 100 to 10 / 90) to give intermediate 86 (2.0 g, yield: 74%) as an orange oil.

[0264] Intermediate 87 : 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 a saturated aqueous solution of NaHCO₃ and extracted with EtOAc (x3). The organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (25 g SiO2, EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 87 (470 mg, yield: 52%), which was a yellow oil.

[0265] Intermediate 88 : HCl (4 M 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. The solvent was evaporated. The crude product was ground together with 1,4-dioxane and collected by filtration to give intermediate 88 (390 mg, yield: 96%) as an orange solid.

[0266] Intermediate 89 : 110-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 methyl 5-bromo-6-methyl-3-pyridinecarboxylate (CAS [1174028-22-8], 1.0 g, 4.35 mmol, 1.0 equivalents) in DMSO (30 mL). The mixture was bubbled 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 reaction mixture was cooled to room temperature. Then, 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 rapid column chromatography (80 g SiO2; DCM:MeOH (9:1) / DCM, 0 / 100 to 30 / 70) to give intermediate 89 (1045 mg, yield: 60%) as a brown oil.

[0267] Intermediate 90 : At room temperature, pyridinium p-toluenesulfonate (CAS [24057-28-1], 100 mg, 0.40 mmol, 0.4 equivalents) was added to intermediate 89 (350 mg, 0.98 mmol, 1.0 equivalents) in a solution of EtOH (5 mL) and heated at 60 °C for 5 hours. The reaction mixture was cooled and concentrated. The crude product was purified by rapid column chromatography (12 g SiO2, DCM:MeOH (9:1) / DCM, 0 / 100 to 30 / 70) to give intermediate 90 (171 mg, yield: 44%) as a yellow oil.

[0268] Intermediate 91 : Under a nitrogen atmosphere at 0 °C, Dess-Martin periodide (CAS [87413--09-0], 410 mg, 0.94 mmol, 1.5 equivalents) was added in portions to intermediate 90 (171 mg, 0.63 mmol, 1.0 equivalents) in a stirred solution of dry DCM (6 mL). The mixture was stirred at room temperature for 3 hours. DCM and a saturated aqueous solution of NaHCO3 were added, and the mixture was extracted with DCM (x3). The combined organic layers were dried over MgSO4, filtered, and concentrated to give intermediate 91 (165 mg, yield: 97%) as a colorless, viscous solid.

[0269] Intermediate 92 : 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 equivalents) in DCM (4 mL), and 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 times). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by rapid column chromatography (12 g SiO2, EtOAc / heptane, 0 / 100 to 40 / 60) to give intermediate 92 (85 mg, yield: 38%) as a white solid.

[0270] Intermediate 93 : At room temperature, LiOH (37 mg, 0.88 mmol, 3.0 equivalent) was added 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. EtOAc and HCl (1 M in water) were added until pH 2–3, and the mixture was extracted with EtOAc (x5). The combined organic layers were dried over MgSO4, filtered, and concentrated to give intermediate 93 (50 mg, yield: 51%) as a white solid.

[0271] Intermediate 94 : 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), and the solution was cooled to -78 °C and stirred for 10 min. Butyllithium (1.6 M, hexane, CAS [109-72-8], 6.19 mL, 9.90 mmol, 2.0 equivalent) was added dropwise, and the reaction mixture was stirred at -78 °C for 20 min. Then, acetaldehyde (CAS [75-07-0], 0.56 mL, 9.90 mmol, 2.0 equivalent) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The reaction was quenched with a saturated aqueous NH4Cl 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 reversed-phase column chromatography (Phenomenex Gemini C18 30mm×100mm 5µm; 95% [25mMNH4HCO3] - 5% [ACN: MeOH 1:1] - 28% [ACN: MeOH 1:1] to 63% [25mM NH4HCO3] - 37% [ACN: MeOH 1:1]) to give intermediate 94 (502 mg, yield: 57%), which was a yellow oil.

[0272] Intermediate 95 : Triethylamine (5.2 mL, 4.2 mmol, 2.0 equivalence) was added to a stirred solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 600 mg, 2.1 mmol, 1.0 equivalence) and 4-(Boc-amino)-3,3-difluoropiperidine (CAS [1263180-22-8], 578 mg, 2.4 mmol, 1.15 equivalence) in toluene (14 mL). The mixture was stirred at 120 °C for 9 hours. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine (x2), filtered, and the solvent was evaporated. The crude product was purified by rapid column chromatography (25 g silica; EtOAc / heptane, 0 / 100 to 40 / 60) to give intermediate 95 (311 mg, yield: 33%) as an orange solid.

[0273] Intermediate 96 : Anhydrous tetramethylammonium fluoride (CAS [373-68-2], 100 mg, 1 mmol, 1.5 equivalents) was added to a solution of intermediate 95 (311 mg, 0.71 mmol, 1.0 equivalents) in DMF (4 mL) in a sealed tube at 65 °C. The mixture was stirred for 3 hours. After cooling, the reaction mixture was diluted with EtOAc (100 mL) and water (150 mL) was added. 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 rapid column chromatography (12 g SiO2, EtOAc / heptane, 0 / 100 to 30 / 70) to give intermediate 96 (202 mg, yield: 68%) as a yellow oil.

[0274] Intermediate 97 : At 0 °C, trifluoroacetic acid (1.33 mL, 17.4 mmol, 23.0 equivalent) was added to intermediate 11 (300 mg, 0.73 mmol, 1.0 equivalent) in a stirred solution of 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 until pH 8. DCM was added, and the aqueous layer was extracted with DCM (x5). The combined organic layers were dried over MgSO₄, filtered, and concentrated to give intermediate 97 (187 mg, yield: 81%) as a yellow solid.

[0275] Intermediate 98 : At room temperature, HATU (CAS [148893-10-1], 209 mg, 0.55 mmol, 1.25 equivalents) was added to a solution of intermediate 97 (187 mg, 0.44 mmol, 1.0 equivalents), 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 EtOAc 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 rapid column chromatography (12 g SiO2, DCM:MeOH (9:1) / DCM, 0% to 30%), followed by reversed-phase column chromatography (Phenomenex Gemini C18 30 mm × 100 mm 5 µm; 90% H2O (0.1% HCOOH) - 10% ACN-MeOH to 54% H2O (0.1% HCOOH) - 46% ACN-MeOH) to give intermediate 98 (162 mg, yield: 71%) as a yellow solid.

[0276] Intermediate 99 : 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 equivalent) 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 equivalent) and Pd(OAc)₂ (CAS [3375-31-3], 6.5 mg, 0.03 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 a saturated aqueous solution of NaHCO₃ and extracted with EtOAc (x3). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (25 g SiO2; EtOAc / heptane, 0 / 100 to 35 / 65) to give intermediate 99 (65 mg, yield: 32%) as a yellow solid.

[0277] Intermediate 100 : In a closed tube, nitrogen gas was bubbled through 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]heptane-7-ol hydrochloride (CAS [1152110-85-4], 0.26 g, 1.77 mmol, 1.0 equivalent) in 1,4-dioxane (8 mL). Then, Cs2CO3 (1.25 g, 3.84 mmol, 2.1 equivalent), 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 equivalent) were added. The mixture was stirred at 90°C for 3.5 hours. A saturated aqueous solution of NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (25 g; EtOAc / heptane, 0 / 100 to 10 / 90) to give intermediate 100 (337 mg, yield: 59%) as an orange solid.

[0278] Intermediate 101 : (RS) Benzoyl chloride (CAS [98-88-4], 123 μL, 1.0 mmol, 1.46 equivalent), Et3N (0.5 mL, 3.6 mmol, 5.0 equivalent), and 4-(dimethylamino)pyridine (CAS [1122-58-3], 15.7 mg, 0.13 mmol, 0.18 equivalent) were added to a solution of intermediate 100 (228 g, 0.72 mmol, 1.0 equivalent) in DCM (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (12 g SiO2; EtOAc / heptane, 0 / 100 to 10 / 90) to give intermediate 101 (293 mg, yield: 91%) as a white solid.

[0279] Intermediate 102 : Tetramethylammonium fluoride (CAS [373-68-2], 97 mg, 1.0 mmol, 1.42 equivalents) was added to intermediate 101 (293 mg, 0.7 mmol, 1.0 equivalents) in a solution of DMF (4 mL) in a sealed tube at 65 °C. The mixture was stirred for 3 hours. After cooling, the reaction mixture was diluted with EtOAc 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 rapid column chromatography (12 g SiO2; EtOAc / heptane, 0 / 100 to 30 / 60) to give intermediate 102 (222 mg, yield: 80%) as a yellow oil.

[0280] Intermediate 103 : 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 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], 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 a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (25 g SiO2, heptane / EtOAc, 0 / 100 to 35 / 65) to give intermediate 103 (235 mg, yield: 49%) as a yellow solid.

[0281] Intermediate 104 : At 0 °C, trifluoroacetic acid (0.75 mL, 9.8 mmol, 24.0 equivalents) was added to a stirred solution of intermediate 103 (235 mg, 0.41 mmol, 1.0 equivalents) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C, and a saturated aqueous solution of Na₂CO₃ was added until pH 8. DCM was added, and the aqueous layer was extracted with DCM (x5). The combined organic layers were dried over MgSO₄, filtered, and concentrated to give intermediate 104 (195 mg, yield: 98%) as a yellow solid.

[0282] Intermediate 105 : 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 equivalent) were placed in DMF (3 mL). HATU (CAS [148893-10-1], 158 mg, 0.41 mmol, 1.24 equivalent) 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 EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The crude product was purified by rapid column chromatography (12 g column, DCM:MeOH (9:1) / DCM, 0% to 30%) to give intermediate 105 (117 mg, yield: 52%) as a yellow solid.

[0283] Intermediate 106 : At 0 °C, iodomethane (CAS [74-88-4], 866 mg, 6.1 mmol, 1.0 equivalent) was added to a stirred solution of 2,6-dichloro-3H-pyrimidin-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 EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by rapid column chromatography (25 g silica; EtOAc / heptane, 0 / 100 to 50 / 50) to give intermediate 106 (732 mg, yield: 67%) as a white solid.

[0284] Intermediate 107 : 2,2,6,6-Tetramethylmorpholine (CAS [19151-69-0], 234 mg, 1.64 mmol, 0.8 equivalence) was added to intermediate 106 (366 mg, 2.045 mmol, 1.0 equivalence) and DIPEA (1.014 mL, 6.14 mmol, 3.0 equivalence) in a stirred solution of DMSO (2 mL). The mixture was stirred at 130 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (x3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by rapid column chromatography (24 g silica; EtOAc / heptane, 0 / 100 to 70 / 30) to give intermediate 107 (350 mg, yield: 59%) as a yellow solid.

[0285] Intermediate 108 : Intermediate 11 (200 mg, 0.5 mmol, 1.0 equivalent), intermediate 107 (139 mg, 0.48 mmol, 0.96 equivalent), and K₂CO₃ (101 mg, 0.73 mmol, 1.5 equivalent) 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 equivalent) and Pd(OAc)₂ (CAS [3375-31-3], 11 mg, 0.07 mmol, 0.07 equivalent) were added, and the reaction mixture was stirred at 120 °C for 14 hours. After cooling, the mixture was diluted with a saturated aqueous solution of NaHCO₃ and extracted with EtOAc (x3). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (25 g SiO2, EtOAc / heptane, 0 / 100 to 35 / 65) to give intermediate 108 (106 mg, yield: 42%) as a yellow solid.

[0286] Intermediate 109 : At 0 °C, trifluoroacetic acid (0.31 mL, 4.1 mmol, 20.0 equivalent) was added to an intermediate 108 (106 mg, 0.2 mmol, 1.0 equivalent) in a stirred solution of DCM (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C, and a saturated aqueous solution of Na₂CO₃ was added until pH 8. DCM was added, and the aqueous layer was extracted with DCM (x5). The combined organic layers were dried over MgSO₄, filtered, and concentrated to give intermediate 109 (78 mg, yield: 90%) as a yellow solid.

[0287] Intermediate 110 : (Civic) Cis-2,6-Dimethylmorpholine (CAS [6485-55-8], 0.201 mL, 1.64 mmol, 0.8 equivalence) was added to intermediate 106 (366 mg, 2.045 mmol, 1.0 equivalence) and DIPEA (1.014 mL, 6.14 mmol) in a stirred solution of DMSO (2 mL). The mixture was stirred at 130 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (x3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by rapid column chromatography (24 g silica; EtOAc / heptane, 0 / 100 to 70 / 30) to give intermediate 110 (384 mg, yield: 72%) as a yellow solid.

[0288] Intermediate 111 : (Civic) 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 equivalent) 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 equivalent) and Pd(OAc)₂ (CAS [3375-31-3], 11 mg, 0.05 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 a saturated aqueous solution of NaHCO₃ and extracted with EtOAc (x3). The organic layer was separated, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (12 g SiO2, EtOAc / heptane, 0 / 100 to 20 / 80) to give intermediate 111 (83 mg, yield: 35%) as a yellow solid.

[0289] Intermediate 112 : (Civic) Trifluoroacetic acid (0.27 mL, 3.59 mmol, 20.0 equivalent) 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 until pH 8. DCM was added and the aqueous layer was extracted with DCM (x3). The combined organic layers were dried over MgSO4, filtered, and concentrated to give intermediate 112 (68 mg, yield: 96%) as a beige solid.

[0290] Intermediate 113 : (Trans) (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 intermediate 106 (344 mg, 1.9 mmol, 1.23 equivalent) and DIPEA (0.95 mL, 5.7 mmol, 3.7 equivalent) in a stirred solution of DMSO (2 mL). The mixture was stirred at 130 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (x3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by rapid column chromatography (24 g silica; EtOAc / heptane, 0 / 100 to 70 / 30) to give intermediate 113 (264 mg, 35%) as a yellow oil.

[0291] Intermediate 114 : (Trans) 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 equivalent) 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 equivalent) and Pd(OAc)₂ (CAS [3375-31-3], 8 mg, 0.03 mmol, 0.085 equivalent) were added, and the reaction mixture was stirred at 120 °C for 14 hours. The mixture was then cooled to room temperature, diluted with a saturated aqueous solution of NaHCO₃, and extracted with EtOAc (x3). The organic layer was separated, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (25 g, SiO2, heptane / EtOAc gradient of 0% to 35%) to give intermediate 114 (90 mg, yield: 47%) as a yellow solid.

[0292] Intermediate 115 : (Trans) At 0 °C, trifluoroacetic acid (0.26 mL, 3.3 mmol, 20.0 equivalent) was added 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 until pH 8. DCM was added, and the aqueous layer was extracted with DCM (x5). The combined organic layers were dried over MgSO₄, filtered, and concentrated to give intermediate 115 (60 mg, yield: 81%).

[0293] Intermediate 116 : tert-butyl N-(3,3-difluoropiperidin-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 equivalents) 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 collected by filtration to give intermediate 116 (203 mg, yield: 65%) as a beige solid.

[0294] Intermediate 117 : Sodium hydride (60% in mineral oil, 139 mg, 3.47 mmol, 0.8 equivalence) was added to (L)-proline (CAS [147-85-3], 398 mg, 3.46 mmol, 0.8 equivalence) in a stirred solution of 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 equivalence), sodium methanesulfinate (CAS [20277-69-4], 3.51 g, 34.4 mmol, 8.0 equivalence), and cuprous iodide (658 mg, 3.45 mmol, 0.8 equivalence) were added, and the mixture was stirred at 120 °C for 4 hours. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (x2), and the solvent was evaporated. The crude product was purified by rapid column chromatography (12 g SiO2; DCM:MeOH (9:1) / DCM, 0 to 20%) to give intermediate 117 (478 mg, yield: 47%) as a white solid.

[0295] Intermediate 118 : At room temperature, methyl iodoform (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 to a stirred solution of intermediate 117 (200 mg, 0.86 mmol, 1.0 equivalents) 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 rapid column chromatography (25 g silica; EtOAc / heptane, 0 / 100 to 30 / 70) to give intermediate 118 (50 mg, 23%) as a white solid and its N-alkylated isomer (130 mg, 60%) as a white solid.

[0296] Intermediate 119 : NaOH (1M in water, 0.4 mL, 0.4 mmol, 2.0 equivalent) 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 was adjusted to 2–3. The solution was concentrated to give intermediate 119 (45 mg, yield: 95%, crude) as a white solid, which could be used in the next step without further purification.

[0297] Intermediate 120 : At room temperature, pyrrole-3-carboxylic acid (CAS [931-03-3], 3 g, 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). The mixture was stirred at 85 °C for 16 hours. The solvent was removed under vacuum. The residue was diluted in EtOAc and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3 times). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (80 g SiO2; EtOAc / heptane, 0 / 100 to 30 / 70) to give intermediate 120 (1.78 g, yield: 39%) as a white solid.

[0298] Intermediate 121 : N-chlorosuccinimide (CAS [128-09-6], 2.8 g, 20.9 mmol, 2 equivalents) was added to intermediate 120 (1.75 g, 10.5 mmol, 1 equivalent) in a stirred solution of 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 EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (25 g SiO2; EtOAc / heptane, 0 / 100 to 10 / 90) to give intermediate 121 (370 mg, yield: 14%) as a white solid.

[0299] Intermediate 122 : At room temperature, isopropyl sulfonyl chloride (CAS [1310-66-3], 0.64 mL, 2.3 mmol, 1.5 equivalents) was added to intermediate 121 (370 mg, 1.6 mmol, 1 equivalent) and KHDMS (CAS [40949-94-8], 4.7 mL, 4.7 mmol, 3 equivalents) in a stirred solution of 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 EtOAc. The organic layer was washed with brine (5 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (12 g SiO2; EtOAc / heptane, 0 / 100 to 80 / 20). The desired fraction was collected and concentrated under vacuum to give intermediate 122 (362 mg, yield: 64%) as a colorless oil.

[0300] Intermediate 123 : At room temperature, HCl (4 M 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), and the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under vacuum to give intermediate 123 (300 mg, yield: 99%) as a white solid.

[0301] Intermediate 124 : (3α, 4β, 5α) At 0 °C, N-chlorosuccinimide (CAS [128-09-6], 77 mg, 0.58 mmol, 1.5 equivalents) was added to intermediate 47 (227 mg, 0.387 mmol, 1 equivalent) in a solution of 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 EtOAc. The organic layer was washed with water and saturated NaS2O3 aqueous solution, dried over MgSO4, filtered, and the solvent was concentrated under vacuum. The crude product was purified by rapid column chromatography (25 g SiO2, MeOH / DCM, 0 to 3%) to give intermediate 124 (172 mg, yield: 72%) as an orange powder.

[0302] Intermediate 125 : (3α, 4β, 5α) At room temperature, an aqueous solution of NaOH (2.5 M in water, 2.8 mL, 2.0 mmol, 18 equivalents) was added 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 EtOAc (20 mL). The pH was adjusted to 10 by adding Na₂CO₃ (1 M in water). The aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layer was dried over MgSO₄, filtered, and the solvent was evaporated under vacuum to give intermediate 125 (112 mg, yield: 78%) as a yellow powder.

[0303] Intermediate 126 : (3α, 4β, 5α) At room temperature, HCl (4 M in 1,4-dioxane, 0.92 mL, 3.7 mmol, 20 equivalents) was added 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 give intermediate 126 (97 mg, yield: 99%) as an orange solid.

[0304] Intermediate 127 : 110-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 [141-53-7], 739 mg, 10.9 mmol, 2.5 equivalents), and TBAB (CAS [1643-19-2], 1.75 g, 5.4 mmol, 1.2 equivalents) were added to a solution of methyl 5-bromo-6-methyl-3-pyridinecarboxylate (CAS [1174028-22-8], 1 g, 4.35 mmol, 1 equivalent) in DMSO (30 mL). The mixture was bubbled 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 EtOAc. The organic layer was washed with water (x2) and brine (x2), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (24 g SiO2; EtOAc / heptane, 0 / 100 to 50 / 50) to give intermediate 127 (456 mg, yield: 30%) as a yellow solid.

[0305] Intermediate 128 : At room temperature, HCl (4 M in 1,4-dioxane, 3.32 mL, 13.3 mmol, 10 equivalents) was added 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 a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 128 (400 mg, yield: 96%) as a yellow solid.

[0306] Intermediate 129 : 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 EtOAc. The aqueous layer was acidified to pH 1 with HCl (1 M in water) and extracted with EtOAc (x2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 129 (220 mg, yield: 67%) as a white solid.

[0307] Intermediate 130 : HATU (CAS [148893-10-1], 4.97 g, 13.0 mmol, 1.5 equivalents) was added to a stirred solution of 2-(benzylamino)propionate 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 a DCM (45 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (80 g SiO2; EtOAc / heptane, 0 / 100 to 50%) to give intermediate 130 (3.8 g, yield: 66%) as a white solid.

[0308] Intermediate 131 : Under a nitrogen atmosphere, carbon-supported palladium (CAS [7440-05-3], 128 mg, 0.6 mmol, 0.1 equivalent) was added to intermediate 130 (3.8 g, 6.0 mmol, 1 equivalent) in a stirred solution of EtOH (10 mL). The mixture was purged with vacuum and hydrogen. The mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through a short diatomaceous earth pad. The filtrate was evaporated and the crude product was purified by rapid column chromatography (80 g SiO2; EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 131 (1.7 g, yield: 80%) as a white solid.

[0309] Intermediate 132 : At room temperature, a borane-methyl sulfide complex (CAS [13292-87-0], 13.1 mL, 26.2 mmol, 3 equivalents) was added 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 rapid column chromatography (25 g SiO2, MeOH / DCM, 0 to 5%) to give intermediate 132 (980 mg, yield: 50%) as a white solid.

[0310] Intermediate 133 : Di-tert-butyl dicarbonate (CAS [24424-99-5], 2.5 mL, 12.8 mmol) was added to intermediate 132 (980 mg, 4.5 mmol) and Et3N (2.5 mL, 18.9 mmol) in a stirred solution of DCM (15 mL). The mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (12 g SiO2, EtOAc / heptane, 0 / 100 to 60 / 40) to give intermediate 133 (1.25 g, yield: 86%) as a white solid.

[0311] Intermediate 134 : Under a nitrogen atmosphere, carbon-supported palladium (CAS [1314-15-4], 42 mg, 0.15 mmol, 0.1 equivalent) was added to an intermediate 133 (1.25 g, 3.9 mmol, 1 equivalent) in a stirred solution of MeOH (15 mL). 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 diatomaceous earth pad and the filtrate was evaporated under vacuum to give intermediate 134 (835 mg, yield: 93%) as a yellow oil.

[0312] Intermediate 135 : Under a nitrogen atmosphere at room temperature, 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 equivalent) in 1,4-dioxane (8 mL). The mixture was stirred at 100 °C for 16 hours. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine (x2), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (12 g; EtOAc / heptane, 0 / 100 to 20 / 80) to give intermediate 135 (322 mg, yield: 36%) as an orange oil.

[0313] Intermediate 136 : Tetramethylammonium fluoride (CAS [373-68-2], 84 mg, 0.9 mmol, 1.2 equivalents) was added to intermediate 135 (320 mg, 0.75 mmol, 1 equivalent) in a solution of dried DMF (3 mL) at room temperature. The mixture was stirred at 65 °C for 3 hours. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (25 g SiO2; EtOAc / heptane, 0 / 100 to 20 / 80) to give intermediate 136 (259 mg, yield: 84%) as an orange oil.

[0314] Intermediate 137 : Under a nitrogen atmosphere, 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 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 (x2), dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (24 g SiO2; EtOAc / heptane, 0 / 100 to 70 / 30) to give intermediate 137 (336 mg, yield: 52%), which was an orange oil.

[0315] Intermediate 138 : At room temperature, HCl (4 M in 1,4-dioxane, 1.45 mL, 5.8 mmol, 10 equivalents) was added 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 give intermediate 138 (260 mg, yield: 98%) as an orange solid.

[0316] Intermediate 139 : Cis Intermediate 6 (100 mg, 0.237 mmol) was added to a stirred solution of 4-acetylpyridinecarboxylic 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) at room temperature. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (12 g silica, EtOAc / heptane, 0% to 95%) and by reversed-phase chromatography (stationary phase: Phenomenex Gemini C18 (100 mm × 30 mm, 5 μm); mobile phase: gradient 59% [25 mM NH4HCO3] - 41% [ACN:MeOH (1:1)] to 17% [25 mM NH4HCO3] - 83% [ACN:MeOH (1:1)]) to give intermediate 139 (4 mg, yield: 3%) as a yellow solid.

[0317] Intermediate 140 : Iodomethane (CAS [74-88-4], 0.29 mL, 4.7 mmol, 3.6 equivalences) and silver carbonate (CAS [534-16-7], 468 mg, 1.7 mmol, 1.3 equivalences) were added to a stirred solution of methyl 6-hydroxynicotinic acid (CAS [66171-50-4], 200 mg, 1.3 mmol) in CHCl3 at room temperature. The mixture was stirred at room temperature for 72 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel rapid column chromatography (25 g SiO2; EtOAc / heptane, 0 / 100 to 30 / 70) to give intermediate 140 (135 mg, yield: 61%) as a white solid.

[0318] Intermediate 141 : Sodium hydroxide (2.3 mL, 2.35 mmol) was added to a stirred solution of intermediate 140 (130 mg, 0.78 mmol) in MeOH (3 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH 1 with HCl (1 M in water) and then extracted with EtOAc (x2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 141 (102 mg, yield: 84%) as a white solid.

[0319] Intermediate 142 : Sodium hydride (60% in mineral oil, 141 mg, 3.5 mmol) was added to a stirred solution of methyl 6-hydroxynicotinic acid (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 EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (12 g SiO2, EtOAc / heptane, 0 / 100 to 20 / 80) to give intermediate 142 (150 mg, yield: 56%) as a white solid.

[0320] Intermediate 143 : At room temperature, an aqueous solution of NaOH (1 M, 2.2 mL, 2.2 mmol, 3 equivalents) was added 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 EtOAc. The aqueous layer was acidified to pH 1 with HCl (1 M in water) and then extracted with EtOAc (x2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 143 (115 mg, yield: 66%) as a white solid.

[0321] Intermediate 144 : Under a nitrogen atmosphere, DIAD (CAS [2446-83-5], 0.39 mL, 1.96 mmol, 1.5 equivalents) dissolved in dry THF (1 mL) was added dropwise to a stirred solution of methyl 6-hydroxynicotinic acid (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) in dry THF (6 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc (x3). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (25 g SiO2; AcOEt / heptane, 0 / 100 to 30 / 70) to give intermediate 144 (165 mg, yield: 40%) as a white solid.

[0322] Intermediate 145 : Intermediate 145 is prepared using intermediate 144 instead of intermediate 142, following the same procedure as intermediate 143.

[0323] Intermediate 146 : (Civic) HATU (CAS [148893-10-1], 195 mg, 0.48 mmol, 1.5 equivalents) was added to 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 a stirred solution of DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, extracted with DCM, and washed with brine (x2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (25 g SiO2; EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 146 (165 mg, 82%) as a yellow solid.

[0324] Intermediate 147 : A mixture of methyl 2-chloro-6-methyl-4-pyridinecarboxylate (CAS [3998-90-1], 8.4 g, 45.26 mmol), 2-mercaptoethanol ([CAS 60-24-2], 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, and the residue was dissolved in Et2O and washed with brine. The organic layer was concentrated, and the crude product was purified by rapid column chromatography (120 g SiO2; EtOAc / heptane, 0 / 100 to 45 / 55) to give intermediate 147 (0.86 g, yield: 7%) as a yellow solid.

[0325] Intermediate 148 : At 5 °C, TBDMSCl (CAS [18162-48-6], 684 mg, 4.54 mmol) was added in a single step to 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 aqueous NaHCO3 solution and Et2O. The layers were separated and the organic layer was evaporated. The crude product was purified by silica gel rapid column chromatography (25 g; EtOAc / DCM, 0 / 100 to 5 / 95) to give intermediate 148 (640 mg, yield: 78%) as an oil.

[0326] Intermediate 149 : A solution of mCPBA (CAS [937-14-4], 0.846 g, 3.77 mmol) in DCM (18 mL) was added dropwise over a 10-minute period at 5 °C to a solution of intermediate 148 (640 mg, 1.87 mmol) in DCM (8 mL). After addition, the mixture was stirred at room temperature for 22 hours. More mCPBA (218 mg, 0.97 mmol) in DCM (3 mL) was added dropwise over a 10-minute period at 5 °C, and the mixture was stirred at room temperature for 22 hours. The reaction was quenched by adding a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM. The organic layer was concentrated, and the crude product was purified by rapid column chromatography (12 g SiO2; EtOAc / heptane, 0 / 100 to 10 / 100) to give intermediate 149 (92 mg, yield: 13%) as an oil.

[0327] Intermediate 150 : The 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 give intermediate 150 (65 mg, yield: 79%) as an oil, which could be used without further purification.

[0328] Intermediate 151 : NaOH (1M 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 (1M in water, 0.5 mL) was added, and the mixture was stirred for 2 minutes, then concentrated under vacuum to give intermediate 151 (62 mg, yield: 71%) as a yellow solid, which could be used without further purification.

[0329] Intermediate 152 and Intermediate 153 : (*R) Intermediate 152 (*S) Intermediate 153 5-(1-hydroxyethyl)-3-pyridinecarboxylic acid (CAS [1507931-60-3]) was isolated into its stereoisomers by SFC (i-Amylose-1; isocratic 10% [MeOH + 0.1% DEA] – 90% [CO2]) to obtain intermediates 152 and 153, both of which were brown oily substances.

[0330] Intermediate 154 : At room temperature, a solution of 1-propanephosphonic anhydride (CAS [68957-94-8], 50% in EtOAc, 5.57 mL, 9.35 mmol) was added dropwise 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 give intermediate 154 (1.03 g, yield: 40%) as a brown solid, which was ready for use without further purification.

[0331] Intermediate 155 : 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 h. The reaction mixture was diluted with water and DCM. The layers were separated, and the aqueous layer was extracted once more with DCM. The combined organic layers were dried by filtration on an Extralut NT3 filter and evaporated to give intermediate 155 (110 mg, yield: 90%), which was ready for use without further purification.

[0332] Intermediate 156 : 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) under a nitrogen atmosphere at room temperature. Then, Pd(dppf)Cl2.CH2Cl2 (CAS [95464-05-4], 697 mg, 0.8 mmol) was added, and the mixture was stirred at 85 °C under a nitrogen atmosphere for 16 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2 350 g; heptane / EtOAc, 100 / 0 to 0 / 100) to give intermediate 156 (3.507 g, yield: 49%) as a viscous paste.

[0333] Intermediate 157 : 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 give intermediate 157 (HCl salt, 2.965 g, yield: 92%) as a beige solid, which was ready for use without further purification.

[0334] Intermediate 158 : (Civic) Under a nitrogen atmosphere, 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), and the mixture was stirred at room temperature for 1 minute. Then, intermediate 6 (500 mg, 1.09 mmol) was added in a single batch, 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 give intermediate 158 (556 mg, yield: 93%) as a brown solid, which was ready for use without further purification.

[0335] Intermediate 159 : Diisopropyl azodicarbonate (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 / EtOAc (5:1 v / v). The precipitate was filtered off, and the filtrate was concentrated to dryness. The crude product was purified by rapid column chromatography (silica 120 g; EtOAc / heptane, 0 / 100 to 20 / 80) to give intermediate 159 (379 mg, yield: 13%) as a white solid.

[0336] Intermediate 160 : 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 EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (40 g silica; EtOAc / heptane, 0% to 15%), followed by reversed-phase column chromatography (Phenomenex Gemini C18 100 mm × 30 mm, 5 µm; gradient 72% [25 mM NH4HCO3] - 28% ACN to 36% [25 mM NH4HCO3] - 64% ACN) to give intermediate 160 (159 mg, yield: 41%) as a yellow solid.

[0337] Intermediate 161 : At room temperature, H₂O₂ (30% in water, 0.030 mL, 0.3 mmol, 0.5 equivalent) was added dropwise to intermediate 160 (159 mg, 0.6 mmol) in a solution of water (2.6 mL) containing NaOH (31 mg, 0.8 mmol, 1.3 equivalent) and EtOH (2.6 mL). The mixture was stirred at room temperature for 16 hours. H₂O₂ (30% aqueous solution, 0.015 mL, 0.1 mmol, 0.25 equivalent) was then 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 EtOAc (200 mL). The layers were separated. The aqueous layer was co-evaporated with ACN to give intermediate 161 (180 mg, yield: 91%) as a white solid.

[0338] Intermediate 162 : Under a nitrogen atmosphere, 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) were added to 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). The mixture was stirred at 120 °C for 18 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 25 g; EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 162 (145 mg, yield: 76%) as a white solid.

[0339] Intermediate 163 : An HCl solution (4 M in 1,4-dioxane, 1.4 mL, 5.6 mmol, 19 equivalents) was added to an intermediate 162 (145 mg, 0.3 mmol) in a stirred solution of DCM (1.5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum to give intermediate 163 (0.2 HCl, 134 mg, yield: 96%) as a white solid.

[0340] Intermediate 164 : A solution of methyl 5-mercapto-3-pyridinecarboxylate (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 a saturated aqueous solution of NaHCO3 (50 mL). The mixture was 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 rapid column chromatography (SiO2, 80 g; DCM:MeOH 9:1 / DCM gradient from 0% to 100%) to give intermediate 164 (325 mg, yield: 24%) as a white solid.

[0341] Intermediate 165 : At 0 °C, lithium hydroxide monohydrate (CAS [1310-66-3], 70 mg, 1.63 mmol, 1.5 equivalence) was added to intermediate 164 (226 mg, 1.03 mmol) in a solution of 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 EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness to give intermediate 165 (157 mg, yield: 74%) as a white solid.

[0342] Intermediate 166 : Ruthenium(III) chloride hydrate (CAS [14898-67-0], 20 mg, 0.015 mmol, 0.06 equivalents) was added to intermediate 165 (247 mg, 1.2 mmol) and sodium periodate (CAS [7790-28-5], 1 g, 4.67 mmol, 3.8 equivalents) in a stirred solution of 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 give intermediate 166 (249 mg, yield: 86%) as a white solid.

[0343] Intermediate 167 : 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 a saturated aqueous solution of NaHCO3 (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 rapid column chromatography (SiO2, 25 g; DCM:MeOH 9:1 / DCM gradient from 0% to 100%) to obtain intermediate 167 (135 mg, yield: 35%), which was a yellow oil.

[0344] Intermediate 168 : Intermediate 168 was prepared using intermediate 167 instead of intermediate 164, following the same procedure as intermediate 165.

[0345] Intermediate 169 : Intermediate 169 was prepared using intermediate 168 instead of intermediate 165, following the same procedure as intermediate 166.

[0346] Intermediate 170 : At room temperature, CuI (CAS [7681-65-4], 1.98 g, 2.21 mmol, 1.1 equivalents) was added to a stirred solution of methyl 5-bromo-6-methylnicotinate (CAS [1174028-22-8], 2.176 g, 9.46 mmol) and sodium methanesulfonate (CAS [20277-69-4], 3.88 g, 38.0 mmol, 4 equivalents) in DMSO (28.5 mL) in a sealed tube. 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 aqueous NaHCO3 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 rapid column chromatography (80 g silica; EtOAc / heptane, 0 / 100 to 50 / 50) to give intermediate 170 (899 mg, yield: 35%) as a white solid.

[0347] Intermediate 171 : At room temperature, NaOH (1 M in water, 9.2 mL, 9.2 mmol, 3 equivalents) was added 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 EtOAc. The aqueous layer was acidified to pH 1 with HCl (1 M in water) and then extracted with EtOAc (2 × 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 171 (545 mg, yield: 79%) as a white solid.

[0348] Intermediate 172 : At 0 °C, 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 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 EtOAc (2 × 150 mL). The combined organic layers were dried over MgSO₄, filtered, and evaporated. The crude product was purified by silica gel column chromatography (12 g silica, EtOAc / heptane 20 / 80) to give intermediate 172 (11.76 g, yield: 57%), which was an orange oil.

[0349] Intermediate 173 : (2α,4β,6α) Cs₂CO₃ (CAS [534-17-8], 4.4 g, 13.51 mmol, 1.2 equivalences) 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 equivalences) in DMF (36 mL). The mixture was stirred at 100 °C for 72 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (120 g silica; EtOAc / heptane, 0 / 100 to 50 / 50) to give intermediate 173 (1.0 g, yield: 33%) as a white solid.

[0350] Intermediate 174 : (2α,4β,6α) Intermediate 173 (500 mg, 2.06 mmol) and thiourea (CAS [62-56-6], 236 mg, 3.10 mmol, 1.5 equivalences) 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 EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 12 g; EtOAc / heptane, 0 / 100 to 15 / 85) to give intermediate 174 (325 mg, yield: 60%) as a yellow solid.

[0351] Intermediate 175 : (2α,4β,6α) At room temperature, 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 NaOH (28 mg, 0.7 mmol) and water (2.4 mL), 4.4 mL. 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. The mixture was stirred at room temperature for 60 minutes. The solvent was evaporated under vacuum, and the residue was washed with EtOAc. The aqueous phase was co-evaporated with ACN to give intermediate 175 (130 mg, yield: 86%) as a white solid.

[0352] Intermediate 176 : (2α,4β,6α) Under a nitrogen atmosphere, 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) were added to a mixture of intermediate 175 (300 mg, 1.02 mmol, 1.49 equivalent), intermediate 3 (200 mg, 0.68 mmol), and K₂CO₃ (145 mg, 1.05 mmol, 1.5 equivalent) in 1,4-dioxane (5 mL). The mixture was stirred at 120 °C for 18 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 12 g; EtOAc / heptane, 0 / 100 to 50 / 50) to give intermediate 176 (130 mg, yield: 39%) as a white solid.

[0353] Intermediate 177 : (2α,4β,6α) HCl (4 M 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 give intermediate 177 (.2 HCl, 122 mg, yield: 97%) as a yellow solid, which was contaminated with some (2α,4α,6α) isomers.

[0354] Intermediate 178 : Under a nitrogen atmosphere, intermediate 158 (175 mg, 0.32 mmol), sodium methanethiol (CAS [5188-07-8], 71 mg, 0.96 mmol), and DMF (1.75 mL) were combined and stirred at 100 °C for 1.5 h. After cooling, the reaction mixture was diluted with water until a light brown solid precipitated. The suspension was stirred at room temperature for 5 min, then filtered and washed with additional water. The solid was collected and dried under vacuum at 45 °C to give intermediate 178 (120 mg, yield: 73%) as a light brown solid.

[0355] Intermediate 179 : (Civic) Under a nitrogen atmosphere, intermediate 158 (175 mg, 0.32 mmol) and Xantphos Pd G4 (CAS [1621274-19-8], 15 mg, 0.016 mmol, 0.05 equivalent) were dissolved in THF (1.6 mL). 2-Mercaptoethanol (CAS [60-24-2], 25 μL, 0.352 mmol, 1.1 equivalent) and Et3N (49 μL, 0.352 mmol, 1.1 equivalent) were added sequentially. The mixture was stirred at 60 °C for 1.5 h. After cooling, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by rapid column chromatography (12 g SiO2, 0-15% MeOH / DCM) to give intermediate 179 (165 mg, yield: 95%) as a yellow solid.

[0356] Intermediate 180 : (Civic) Under a nitrogen atmosphere, 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) and the mixture was stirred for 1 minute. Intermediate 6 (500 mg, 1.09 mmol) was added in a single batch, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water until precipitation was complete, and the suspension was stirred for 10 minutes, filtered, and the solid was washed to give a brown solid, which was dried under vacuum to give intermediate 180 (543 mg, yield: 93%) as a brown solid.

[0357] Intermediate 181 : (Civic) Intermediate 180 (220 mg, 0.412 mmol) and sodium methanethiol (CAS [5188-07-8], 91 mg, 1.237 mmol) were combined in DMF (3.3 mL), and the mixture was stirred at 100 °C under a nitrogen atmosphere for 1.5 h. After cooling, the mixture was diluted with water until a light-colored precipitate formed. The suspension was stirred for 10 min and then filtered to give a light brown solid, which was dried under vacuum to give intermediate 181 (106 mg, yield: 51%).

[0358] Intermediate 182 : (Civic) Under an argon atmosphere, intermediate 180 (125 mg, 0.23 mmol) and Xantphos Pd G4 (CAS [1621274-19-8], 11 mg, 0.012 mmol, 0.05 equivalents) were dissolved in dry THF (1.2 mL). 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 h. After cooling, the reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by rapid column chromatography (12g silica gel, 0-12% MeOH / DCM) to give intermediate 182 (135mg, yield: 108%), which was a green oil.

[0359] Intermediate 183 : Sodium hydride (270 mg, 6.7 mmol) was added to a stirred solution of (L)-proline (CAS [147-85-3], 773 mg, 6.7 mmol) in DMSO (25 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. Then, methyl 5-bromo-6-methyl-3-pyridinecarboxylate (CAS [1174028-22-8], 1.93 g, 8.3 mmol), sodium methanesulfinate (CAS [20277-69-4], 7 g, 68.5 mmol), and cuprous 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 a saturated aqueous solution of NaHCO3 and EtOAc. The mixture was filtered, and the filtrate layer was separated. The aqueous layer was extracted with EtOAc (x2). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (25 g silica; EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 183 (850 mg, yield: 42%) as a yellow solid.

[0360] Intermediate 184 : Under a nitrogen atmosphere, intermediate 183 (0.492 g, 2.146 mmol) and 2,2,2-trifluoroethyl trifluoroacetate (CAS [407-38-5], 0.5 mL, 3.734 mmol) were cooled to -78 °C in a homogeneous solution of dried THF (20 mL) and treated dropwise with LiHMDS (CAS [4039-32-1], 3.6 mL, 3.6 mmol, 1 M in THF). 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 a saturated aqueous solution of NaHCO3. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated to give intermediate 184, which was ready for use without further purification.

[0361] Intermediate 185 : The solution (30 mL) of intermediate 184 in ACN was cooled to 0 °C and treated once with 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octanebis(tetrafluoroborate) (CAS [140681-55-6], 2.947 g, 8.319 mmol). The reaction mixture was warmed to room temperature and then stirred at 60 °C for 40 min. After cooling, the reaction mixture was concentrated to dryness. The crude material was suspended in EtOAc (500 mL), sonicated to destroy all particles, filtered through diatomaceous earth, and the filtrate was concentrated to give intermediate 185, which could be used directly without further purification.

[0362] Intermediate 186 : The 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 EtOAc and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated. The crude material was purified by rapid column chromatography (40 g SiO2, EtOAc / heptane 0 / 100 to 100 / 0) to give intermediate 186 (0.27 g, 47%, in 3 steps) as a colorless oil, which crystallized into white needles upon standing.

[0363] Intermediate 187 : The suspension of intermediate 186 (0.522 g, 1.968 mmol) in MeOH (5 mL) was treated with an aqueous solution of NaOH (0.7 mL, 2.1 mmol, 3 M in water) and stirred at 50 °C for 40 min. After cooling, the reaction mixture was concentrated to give intermediate 187 (0.518 g, 96%, sodium salt) as an orange solid, which could be used without further purification.

[0364] Intermediate 188 : Under a nitrogen atmosphere, a solution of 2-chloropyrimidine (CAS [1722-12-9], 4.58 g, 40.0 mmol) in 120 mL of THF was cooled to -60 °C. Then, a 0.79 M HF-toluene solution of the 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 h. Zinc chloride (CAS [7646-85-7], 1 M in diethyl ether, 60 mL, 60 mmol) was added, and the reaction mixture was allowed to reach room temperature and stirred for another 1.5 h 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 a prepared organozinc solution (approximately 0.16 M, 128 mL, 20.4 mmol, 3 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was ground with ACN to give intermediate 188 (1.46 g, yield: 56%) as a white solid.

[0365] Intermediate 189 : Intermediate 188 (0.650 g, 1.75 mmol) was dissolved in HCl (4 N 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, and the residue was ground with diethyl ether and filtered to give intermediate 189 (HCl salt, 0.475 g, yield: 99%) as a brownish solid.

[0366] Intermediate 190 : At room temperature, HBTU (CAS [94790-37-1], 0.575 g, 1.516 mmol, 1.1 equivalents) was added to intermediate 189 (0.475 g, 1.378 mmol), intermediate 171 (0.326 g, 1.516 mmol, 1.1 equivalents), and DIPEA (0.96 mL, 5.513 mmol, 4 equivalents) in a stirred solution of DMF (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc 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 give intermediate 190 (0.477 g, 71% yield) as a grayish-white solid.

[0367] Intermediate 191 : 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 EtOAc, and washed with H2O. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by rapid column chromatography (25 g SiO2, heptane / EtOAc, 100 / 0 to 0 / 100) to give intermediate 191 (622 mg, yield: 74%).

[0368] Intermediate 192 : Intermediate 191 (622 mg, 1.76 mmol) and Et3N (0.060 mL, 0.421 mmol, 0.24 equivalence) 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 diatomaceous earth mat, which was further washed with MeOH (5 × 40 mL). The filtrate was concentrated to give intermediate 192 (414 mg, yield: 68%) as a solid.

[0369] Intermediate 193 : Phosphorus oxychloride (V) (CAS [10025-87-3], 0.176 mL, 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 under a nitrogen atmosphere for 2 hours. The mixture was poured onto ice, alkalized with 1 M Na2CO3 aqueous solution, and extracted several times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under vacuum to give intermediate 193 (446 mg, yield: 91%) as a solid, which was ready for use without further purification.

[0370] Intermediate 194 : 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 give intermediate 194 (HCl salt, 197 mg, yield: 78%) as a pale brown solid, which was ready for use without further purification.

[0371] Intermediate 195 : At room temperature, HBTU (CAS [94790-37-1], 1.5 g, 4 mmol) was added 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 layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was ground in ACN and the solid was filtered to give the first batch of intermediate 195. The mother liquor was purified by rapid column chromatography (25 g SiO2; DCM / MeOH 9 / 1 / DCM, 0 / 100 to 20 / 80). The pure fraction was collected, the solvent was evaporated, and the product was ground in ACN, filtered, dried, and combined with the first batch to give intermediate 195 as a solid (0.915 g, yield: 67%).

[0372] Intermediate 196 : Intermediate 195 (0.665 g, 1.70 mmol) and sodium 1-methyl-3-sulfinylpropionate (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 with 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 between EtOAc (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 rapid column chromatography (25 g SiO2, MeOH / DCM, 0 / 100 to 5 / 95) to give intermediate 196 (0.26 g, yield: 30%) as a white solid.

[0373] Intermediate 197 : 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 EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by rapid column chromatography (SiO2 25 g, heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 197 (1.38 g, yield: 75%) as an oil.

[0374] Intermediate 198 : Intermediate 197 (1.38 g, 3.48 mmol) and Et3N (0.116 mL, 0.833 mmol, 0.24 equivalence) 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 through a diatomaceous earth pad, which was further washed with MeOH (5 × 40 mL). The filtrate was concentrated to give intermediate 198 (1.06 g, yield: 98%) as a solid, which was ready for use without further purification.

[0375] Intermediate 199 : Intermediate 199 was prepared using the same procedure as intermediate 193, but in place of intermediate 192, using intermediate 198. Intermediate 200 : Under a nitrogen atmosphere, intermediate 199 (335 mg, 1.031 mmol) was dissolved in 1,4-dioxane (5 mL). AcOK (CAS [127-08-2], 253 mg, 2.58 mmol, 2.5 equivalents), bis(pinacol)diboron (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. Under a nitrogen atmosphere, the reaction mixture was stirred at 110 °C for 1 hour. After cooling, the mixture was kept 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 EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (25 g SiO₂, heptane / EtOAc, 0 / 100 to 80 / 20) to give foamy intermediate 200 (100 mg, yield: 18%).

[0376] Intermediate 201 : At room temperature, TFA (0.278 mL, 3.64 mmol, 22.6 equivalents) was added 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 give intermediate 201 (TFA salt, 92 mg, yield: 98%) as a viscous oil.

[0377] Intermediate 202 : Under a nitrogen atmosphere, sodium hydride (CAS [7646-69-7], 56 mg, 1.41 mmol, 0.8 equivalence) was added to a stirred solution of (L)-proline (CAS [147-85-3], 162 mg, 1.41 mmol, 0.8 equivalence) in 12 mL of DMSO, 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 equivalence) and copper iodide (CAS [7681-65-4], 270 mg, 1.41 mmol, 0.8 equivalence) were added. The reaction vessel was sealed, 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 off. The layers of the filtrate were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (80 g SiO2, DCM / MeOH, 100 / 0 to 90 / 10) to give intermediate 202 (149 mg, yield: 29%) as a white solid.

[0378] Intermediate 203 : At room temperature, lithium hydroxide monohydrate (CAS [1310-66-3], 88 mg, 2.10 mmol, 4 equivalents) was added 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 KHSO4 aqueous solution. DCM was added, and the organic layer was separated, dried over MgSO4, and filtered. The solvent was removed under vacuum to give intermediate 203 (131 mg, yield: 91%) as a white solid, which was ready for use without further purification.

[0379] Intermediate 204 : Under a nitrogen atmosphere, N-bromosuccinimide (CAS [128-08-5], 4.6 g, 26 mmol, 3 equivalents) was added to a solution of methyl 5-bromo-6-methylnicotinate (CAS [1174028-22-8], 2 g, 8.70 mmol) in DCE (25 mL), followed by the addition of 2,2'-azobis(2-methylpropionitrile) (CAS [78-67-1], 0.43 g, 2.6 mmol, 0.3 equivalents). The reaction mixture was stirred at 90 °C for 16 hours. After cooling, the solvent was evaporated, and the crude product was purified by rapid column chromatography (80 g SiO2, heptane / (heptane:EtOAc, 5:1), 100 / 0 to 90 / 10) to give intermediate 204 (1.3 g, yield: 38%) as a colorless oil.

[0380] Intermediate 205 : Under a nitrogen atmosphere, intermediate 204 (1.14 g, 2.94 mmol) was dissolved in DCM (30 mL), 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 rapid column chromatography (12 g SiO2, heptane / (heptane:EtOAc, 5:1), 100 / 0 to 90 / 10) to give intermediate 205 (840 mg, yield: 99%) as a white solid.

[0381] Intermediate 206 : Under a nitrogen atmosphere, sodium hydride (CAS [7646-69-7], 48 mg, 1.20 mmol, 0.8 equivalence) was added to a stirred solution of (L)-proline (CAS [147-85-3], 138 mg, 1.20 mmol, 0.8 equivalence) 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 equivalence), and copper iodide (CAS [7681-65-4], 229 mg, 1.20 mmol, 0.8 equivalence) were added. The reaction vial was sealed, and the mixture was stirred at 120 °C for 16 hours. After cooling, the reaction mixture was poured into water and EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (80 g SiO2, heptane / EtOAc, 100 / 0 to 85 / 15) to give intermediate 206 (110 mg, yield: 27%) as a white solid.

[0382] Intermediate 207 : At room temperature, lithium hydroxide monohydrate (CAS [1310-66-3], 70 mg, 1.70 mmol, 4 equivalents) was added 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 KHSO4 aqueous solution. The mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under vacuum to give intermediate 207 (86 mg, yield: 82%) as a white solid.

[0383] Intermediate 208 : (Civic) 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 EtOAc and washed with water. The organic layer was collected, dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by rapid column chromatography (80 g SiO2, heptane / EtOAc, 100 / 0 to 80 / 20) to give intermediate 208 (1.14 g, yield: 82%) as a solid.

[0384] Intermediate 209 : (Civic) Intermediate 209 was prepared using intermediate 208 instead of intermediate 197, following the same procedure as intermediate 198.

[0385] Intermediate 210 : (Civic) Intermediate 210 is prepared using intermediate 209 instead of intermediate 192, following the same procedure as intermediate 193.

[0386] Intermediate 211 : (Civic) Under a nitrogen atmosphere, intermediate 210 (223 mg, 1.031 mmol) was dissolved in 1,4-dioxane (4 mL). AcOK (CAS [127-08-2], 251 mg, 2.55 mmol, 2.5 equivalents), bis(pinacol)diboron (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 reaction 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 EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (25 g SiO₂, heptane / EtOAc, 0 / 100 to 60 / 40) to give foamy intermediate 211 (136 mg, yield: 29%).

[0387] Intermediate 212 : (Civic) Intermediate 211 (0.136 g, 0.302 mmol) was dissolved in HCl (4 N 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 give intermediate 212 (HCl salt, 0.118 g, yield: 91%) as a solid.

[0388] Intermediate 213 and Intermediate 214 : Intermediate 213 Intermediate 214 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-tetramethyloxacyclopropane-4-ester methanesulfonic acid (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 Na₂CO₃ aqueous solution and extracted with EtOAc. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (25 g SiO2, heptane / EtOAc, 100 / 0 to 80 / 20) to give intermediate 214 (32 mg, yield: 3%) and intermediate 213 (220 mg, yield: 21%), both of which were white solids.

[0389] Intermediate 215 : Under a nitrogen atmosphere, intermediate 213 (220 mg, 0.700 mmol), bis(pinacol)diboron (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). 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 EtOAc (2x). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (25 g SiO2, heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 215 (253 mg, yield: 100%) as a white solid.

[0390] Intermediate 216 : At room temperature, 2-isopropoxypyridine-5-boronic acid pinacol ester (CAS [871839-91-7], 175 mg, 0.664 mmol, 1.3 equivalents) and 1 M Na2CO3 aqueous solution (1.5 mL, 1.5 mmol, 3 equivalents) were added to a stirred solution of intermediate 3 (150 mg, 0.511 mmol) in 1,4-dioxane (3 mL). 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 at 85 °C under a nitrogen atmosphere for 4 hours. After cooling, the mixture was diluted with water. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by rapid column chromatography (12 g SiO2, DCM / MeOH, 100 / 0 to 95 / 5) to give intermediate 216 (200 mg, yield: 98%), which was an orange gel.

[0391] Intermediate 217 : 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 give intermediate 217 (210 mg, yield: 100%) as a yellow solid, which was ready for use without further purification.

[0392] Intermediate 218 and Intermediate 219 : (2α,4β,6α) (2α,4β,6α) Intermediate 218 Intermediate 219 Cs₂CO₃ (2.86 g, 8.79 mmol, 1.2 equivalences) 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 equivalences) in DMF (20 mL). The reaction mixture was stirred at 70 °C for 48 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (40 g SiO2; heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 218 (1.72 g, yield: 77%) as a colorless oil and intermediate 219 (170 mg, yield: 8%) as a white solid.

[0393] Intermediate 220 : (2α, 4β, 6α) Under a nitrogen atmosphere, intermediate 218 (700 mg, 2.33 mmol), bis(pinacol)diboron (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 placed in 1,4-dioxane (15 mL). 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 Na2CO3 aqueous solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (25 g SiO2, heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 220 (576 mg, yield: 64%) as a white solid, which was contaminated with some (2α,4α,6α) isomers.

[0394] Intermediate 221 and Intermediate 222 : (2α,4β,6α) (2α,4β,6α) Intermediate 221 Intermediate 222 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)pyridone (CAS [164513-38-6], 1.38 g, 7.33 mmol) and (2R,6S)-rel-t 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 EtOAc. The organic layer was separated, dried over MgSO₄, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (40 g SiO2; heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 221 (1.80 g, yield: 81%) as a colorless oil and intermediate 222 (113 mg, yield: 5%) as a white solid.

[0395] Intermediate 223 : (2α, 4β, 6α) Under a nitrogen atmosphere, intermediate 221 (700 mg, 2.33 mmol), bis(pinacol)diboron (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 placed in 1,4-dioxane (15 mL). 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 Na2CO3 aqueous solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (25 g SiO2, heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 223 (517 mg, yield: 61%) as a white solid, which was contaminated with some (2α,4α,6α) isomers.

[0396] Intermediate 224 : (2α, 4β, 6α) Cs₂CO₃ (CAS [534-17-8], 2.86 g, 8.79 mmol, 1.2 equivalences) was added to a solution of 5-bromo-6-methyl-2(1H)pyridone (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 equivalences) in DMF (20 mL). The reaction mixture was stirred at 70 °C for 48 hours. The mixture was diluted with water and extracted with EtOAc. The organic layers were separated, dried over MgSO₄, filtered, and the solvent was evaporated under vacuum. The crude product was subjected to rapid column chromatography (40 g) SiO2; heptane / EtOAc, 100 / 0 to 50 / 50) was purified to give intermediate 224 (1.88 g, yield: 84%) as a colorless oil.

[0397] Intermediate 225 : (2α, 4β, 6α) Under a nitrogen atmosphere, intermediate 224 (904 mg, 3.01 mmol), bis(pinacol)diboron (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 placed in 1,4-dioxane (15 mL). 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 EtOAc. The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (25 g SiO2; heptane / EtOAc, 100 / 0 to 50 / 50) to give intermediate 225 (990 mg, yield: 92%) as a white solid.

[0398] Intermediate 226 and Intermediate 227 : (2α,4β,6α) (2α,4β,6α) Intermediates 226 and 227 were prepared using 5-bromo-2-hydroxypyridine (CAS[13466-38-1]) instead of 5-bromo-4-methyl-2(1H)pyridone, following the same procedure as intermediates 221 and 222, respectively.

[0399] Intermediate 228 : (2α, 4β, 6α) Intermediate 228 is prepared using intermediate 227 instead of intermediate 224, following the same procedure as intermediate 225.

[0400] Intermediate 229 : (2α,4β,6α) Intermediate 228 (250 mg, 0.75 mmol, 1.1 equivalence) and 1 M Na₂CO₃ aqueous solution (2.0 mL, 2.0 mmol, 3 equivalence) 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 equivalence) was added, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 4 hours. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated to dryness. The crude product was purified by rapid column chromatography (12 g SiO2, heptane / EtOAc, 100 / 0 to 0 / 100) to give intermediate 229 (243 mg, yield: 69%) as a brown solid.

[0401] Intermediate 230 : (2α, 4β, 6α) 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 give intermediate 230 (HCl salt, 239 mg, yield: 99%) as a brown solid, which could be used without further purification.

[0402] Intermediate 231 : Methyl 5-bromo-6-(trifluoromethyl)nicotinic acid (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, Xantphos (CAS [161265-03-8], 102 mg, 0.18 mmol, 0.1 equivalents) and Pd2(dba)3 (CAS [32005-36-0], 30 mg 0.05 mmol, 0.03 equivalents) were added, and the reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (25 g SiO2, DCM / MeOH, 100 / 0 to 90 / 10) to give intermediate 231 (420 mg, yield: 74%) as a yellow oil.

[0403] Intermediate 232 : At 0 °C, m-CPBA (CAS [937-14-4], 77% pure, 335 mg, 1.49 mmol, 1 equivalent) was added participle 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. More DCM (30 mL) was added, and m-CPBA (77% pure, 1.5 g, 6.7 mmol, 4.5 equivalent) was added participle over 24 hours until the reaction was complete. The mixture was diluted with DCM and 1 M Na2CO3 aqueous solution was added with stirring. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by rapid column chromatography (25 g SiO2, DCM / MeOH, 100 / 0 to 90 / 10) to give intermediate 232 (287 mg, yield: 55%).

[0404] Intermediate 233 : At room temperature, lithium hydroxide monohydrate (CAS [1310-66-3], 85 mg, 1.99 mmol, 4 equivalents) was added to intermediate 232 (156 mg, 0.49 mmol) in a solution of 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 KHSO4 aqueous solution, and the mixture was concentrated to dryness. The crude product was purified by reversed-phase column chromatography (Phenomenex Gemini C18 30 mm × 100 mm 5 µm; 95% [25 mM NH4HCO3] - 5% [ACN:MeOH (1:1)] to 63% [25 mM NH4HCO3] - 37% [ACN:MeOH (1:1)]) to give intermediate 233 (130 mg, yield: 86%).

[0405] Intermediate 234 : In a sealed reactor, tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 1.07 g, 0.927 mmol, 0.1 equivalent) was added to a solution of methyl 4-bromopyridinecarboxylate (CAS [29681-42-3], 2 g, 9.258 mmol), triisopropylsilanethiol (CAS [156275-96-6], 2.4 mL, 11.179 mmol, 1.2 equivalent), and cesium carbonate (3.6 g, 11.09 mmol, 1.2 equivalent) 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 diatomaceous earth pad and washed with EtOAc. The filtrate was concentrated under vacuum to give intermediate 234 (4.0 g, yield: 54%) as an orange oil.

[0406] Intermediate 235 : 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 a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel rapid column chromatography (80 g column, EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 235 (520 mg, yield: 48%) as an orange viscous solid.

[0407] Intermediate 236 : Ammonium carbamate (CAS [1111-78-0], 1.8 g, 23.056 mmol, 19 equivalents) was added in portions to intermediate 235 (259 mg; 1.182 mmol) and (diacetoxyiodine)benzene (CAS [3240-34-4], 7.5 g; 23.056 mmol, 19 equivalents) in a stirred solution of 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 placed in water and EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel rapid column chromatography (40 g, EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 236 (95 mg, yield: 31%) as a white solid.

[0408] Intermediate 237 : RAC At 0 °C, lithium hydroxide monohydrate (25 mg, 0.573 mmol, 1.5 equivalents) was added to intermediate 236 (95 mg, 0.38 mmol) in a solution of THF (3 mL) and water (1.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to an aqueous layer, acidified with HCl (1 M in water, 0.4 mL), and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated to give intermediate 237 (60 mg, yield: 66%) as a white solid.

[0409] Intermediate 238: Under a nitrogen atmosphere, a mixture of 2-chloropyrimidine (CAS [1722-12-9], 229 mg, 2 mmol) in THF (30 mL) was cooled to -60 °C. 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 h. 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 h. The reaction mixture was used as is for the next step.

[0410] Intermediate 239 : Under a ...

Claims

1. A compound of Formula (I), (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is an optionally substituted heteroaryl selected from the group consisting of (a) the 5-membered heteroaryl is selected from the group consisting of: , , and ; or (b) , and ; wherein each R is independently selected from the group consisting of: halo, C a alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl and (C=0)CH3; R b selected from: C 1-4 alkyl; OC 1-4 alkyl; OCH2CH2OH; and OCHF2; or (c) the 6-membered heteroaryl is selected from the group consisting of: , and ; wherein Each R d Independently is C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and OC 1-4 alkyl; R e selected from: C 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl; X is N or O; R 5 is (i) wherein ring A is a nitrogen-linked monocyclic, polycyclic, bridged, spirocyclic, or fused heterocycloalkyl selected from the group consisting of: And each R c It is independently a halogenated group or CH3; or (ii) 、 、 and wherein ring B is a nitrogen-linked monocyclic, polycyclic, spirocyclic heterocycloalkyl selected from the group consisting of: or (iii) phenyl, , , , and ; wherein R k is selected from: (CH)(CH3)2, oxetan-3-yl, and ; R f is H or CH3; R g selected from the group consisting of: R h is C 1-4 alkyl; R j selected from the group consisting of: or ; and n is 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is 3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) R 1 is ， or (ii) R 1 is , or (iii) R 1 is 4. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) X is O; or (ii) X is N.

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

6. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is:

7. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) R 5 is or (ii) R 5 is 8. The compound according to claim 1, selected from the group consisting of: and pharmaceutically acceptable salts or stereoisomers thereof.

9. The compound according to claim 1, selected from the group consisting of: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5- ((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-6- methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(4-fluoro-6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-5-((2-hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-5-((2- hydroxyethyl)sulfonyl)nicotinamide; N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-6-methyl- 5-(methylsulfonyl)nicotinamide; N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3a,4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-6-methyl-5-(methylsulfonyl)nicotinamide; N-((2-(6-((3a,4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((3a,4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((3a,4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((3a,4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((3a,4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; N-((2-(6-((3a,4b,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-5-((2-hydroxyethyl)sulfonyl)-6-methylnicotinamide; 5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- 1,6-naphthyridin-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 the preceding claims and at least one pharmaceutically acceptable excipient.

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

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

13. The compound for use according to claim 12, wherein the SMARCA4-deleted cancer is a SMARCA4-deleted 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 disease state or condition mediated by a SMARCA2 protein.

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

16. Use of a compound as defined in any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a cancer or NSCLC.

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

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

19. The method of claim 18, wherein the SMARCA4 -deleted cancer is a SMARCA4- deleted NSCLC.

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

21. The method of claim 20, wherein the disease or disorder is selected from a cancer or NSCLC.

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

Images