O-Linked Thiadiazolyl Compounds as Inhibitors of DNA Polymerase Theta

Abstract

Provided herein is a compound that inhibits the activity of DNA polymerase theta (Pol θ), in particular inhibiting Pol θ activity by inhibiting the ATP-dependent helicase domain activity of Pol θ, represented by formula (I): [Formula 1] Disclosed are certain thiadiazolyl derivatives of TIFF2024522373000721.tif36170. Also disclosed are pharmaceutical compositions comprising such compounds and methods for treating and / or preventing diseases treatable by inhibition of Pol θ, such as cancers, including homologous recombination (HR) deficient cancers.

Description

[Background technology]

[0001] Background of the Invention Targeting DNA repair deficiencies has become a proven and effective strategy in cancer therapy. However, DNA repair-deficient cancers often become dependent on backup DNA repair pathways, which present an "Achilles' heel" that can be targeted to eliminate cancer cells and provide the basis for synthetic lethality. Synthetic lethality is exemplified by the successful treatment of BRCA-deficient breast and ovarian cancers with poly(ADP-ribose) polymerase (PARP) inhibitors (Audeh MW, et al., Lancet (2010); 376 (9737): 245-51).

[0002] DNA damage repair processes are important for genome maintenance and stability, and double-strand breaks (DSBs) in particular are primarily repaired by the non-homologous end joining (NHEJ) pathway during the G1 phase of the cell cycle and by homologous recombination (HR) during the S-G2 phase. Alternative end joining (alt-EJ), also known as microhomology-mediated end joining (MMEJ), has received less attention and is generally considered a "backup" DSB repair pathway when NHEJ or HR are impaired. Many genetic studies have highlighted the role of DNA polymerase theta (Polθ, encoded by POLQ) in stimulating MMEJ in higher organisms (Chan SH, et al., PLoS Genet. (2010); 6: e1001005; Roerink SF, et al., Genome research. (2014); 24: 954-962; Ceccaldi R., et. al., Nature (2015); 518: 258-62; and Mateos-Gomez PA, et al., Nature (2015); 518: 254-57).

[0003] Polθ is unique among human DNA polymerases in that it possesses not only a C-terminal DNA polymerase domain but also an N-terminal helicase domain, separated by a long, less conserved central domain whose function other than Rad51 binding is unknown (Seki et al., 2003, Shima et al., 2003; Yousefzadeh and Wood, 2013). The N-terminal ATPase / helicase domain belongs to the HELQ class of the SF2 helicase superfamily. In homologous recombination-deficient (HRD) cells, Polθ can perform error-prone DNA synthesis at DNA damage sites via the alt-EJ pathway. The helicase domain of Polθ has been shown to suppress the HR pathway by inhibiting the formation of the Rad51 nucleoprotein complex, which is involved in the initiation of HR-dependent DNA repair reactions after ionizing radiation. This anti-recombinase activity of Polθ promotes the alt-EJ pathway. Furthermore, the helicase domain of Polθ contributes to microhomology-mediated strand annealing (Chan SH et al., PLoS Genet. (2010); 6: e1001005; and Kawamura K et al., Int. J. Cancer (2004); 109: 9-16). Polθ utilizes this annealing activity to efficiently promote end-joining in the alt-EJ pathway when the ssDNA overhang contains more than 2 bp of microhomology (Kent T., et al., Elife (2016); 5: e13740; and Kent T., et al., Nat. Struct. Mol. Biol. (2015); 22: 230-237). This reannealing activity is achieved through the coupled interaction with Rad51 and subsequent ATPase-mediated exclusion of Rad51 from DSB damage sites. Once annealed, the primer strand of DNA can be extended by the polymerase domain of Pol θ.

[0004] Pol θ expression is rarely observed in normal cells, but is upregulated in breast, lung, and ovarian cancers (Ceccaldi R., et al., Nature (2015); 518, 258-62). Furthermore, increased Pol θ expression correlates with poor prognosis in breast cancer (Lemee F et al., Proc Natl Acad Sci USA. (2010); 107: 13390-5). Cancer cells defective in HR, NHEJ, or ATM have been shown to be highly dependent on Pol θ expression (Ceccaldi R., et al., Nature (2015); 518: 258-62, Mateos-Gomez PA et al., Nature (2015); 518: 254-57, and Wyatt DW, et al., Mol. Cell (2016); 63: 662-73). Pol θ is therefore an attractive target for novel synthetic lethal therapies in cancers involving DNA repair deficiencies. Summary of the Invention

[0005] Summary of the Invention Disclosed herein are certain thiadiazolyl derivatives that inhibit Pol θ activity, particularly by inhibiting the ATP-dependent helicase domain activity of Pol θ. Also disclosed are pharmaceutical compositions containing such compounds and methods for treating and / or preventing diseases treatable by inhibition of Pol θ, such as cancers, including homologous recombination (HR)-deficient cancers.

[0006] In one embodiment, the compound of formula (I): [ka] [In the formula, ring A, Ar 1 , R 1 , R 2 , R 3 and the subscripts n and m have the meanings given below. or a pharmaceutically acceptable salt thereof.

[0007] In a related aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0008] In another aspect, there is provided a method for treating and / or preventing a disease characterized by overexpression of Pol Theta in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof. In one embodiment, the patient is identified as being in need of such treatment. In another embodiment, the compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition. In yet another embodiment, the disease is cancer.

[0009] In yet another aspect, there is provided a method for treating and / or preventing homologous recombination (HR) deficient cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof. In one embodiment, the patient is identified as being in need of such treatment. In another embodiment, the compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.

[0010] In another aspect, there is provided a method for inhibiting DNA repair by Pol θ in a cancer cell, comprising contacting the cell with an effective amount of a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is an HR-deficient cancer.

[0011] In yet another aspect, there is provided a method for treating and / or preventing cancer in a patient, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, wherein the cancer is characterized by reduced or absent BRCA gene expression, an absence of a BRCA gene, or reduced function of a BRCA protein.

[0012] In yet another aspect, there is provided a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, for use in a method of treatment.

[0013] In yet another aspect, there is provided a compound of Formula (I) or a subembodiment thereof, or a pharmaceutically acceptable salt thereof, for inhibiting DNA repair by Pol θ in a cell. In one embodiment, the cell is an HR-deficient cell.

[0014] In another aspect, there is provided a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease in a patient, wherein the disease is characterized by overexpression of Pol θ.

[0015] In yet another aspect, there is provided a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent BRCA gene expression, an absence of a BRCA gene, or reduced function of a BRCA protein.

[0016] In yet another aspect, there is provided a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing HR deficient cancer in a patient.

[0017] In another aspect, there is provided a compound of Formula (I) or a subembodiment thereof, or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer in a patient resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. Examples of cancers resistant to PARP inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer.

[0018] In yet another aspect, there is provided the use of a compound of formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and / or prevention of cancer, wherein the cancer is characterized by reduced or absent BRCA gene expression, an absence of a BRCA gene, or reduced function of a BRCA protein.

[0019] In yet another aspect, there is provided the use of a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and / or prevention of HR deficient cancer.

[0020] In yet another aspect, there is provided the use of a compound of Formula (I) or a subembodiment thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and / or prevention of cancer resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a patient.

[0021] In related aspects of the above methods, uses and compositions, the cancer is lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, cancer of the peripheral nervous system, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblastic cancer, cancer of the central nervous system, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer or pancreatic cancer (data from large-scale dropout screening in cancer cell lines indicates that some cell lines derived from the above cancers are dependent on polymerase theta for proliferation https: / / depmap.org / portal / ).

[0022] In some embodiments, the HR-deficient cancer is breast cancer, including, but not limited to, lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or another breast cancer (triple-negative breast cancer, HER-positive breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, HER- and estrogen receptor-positive breast cancer, HER- and progesterone receptor-positive breast cancer, estrogen receptor- and progesterone receptor-positive breast cancer, and HER-, estrogen receptor- and progesterone receptor-positive breast cancer). In other embodiments, the HR-deficient cancer is ovarian cancer. Ovarian cancers include, but are not limited to, epithelial ovarian cancer (EOC), mature teratoma, dysgerminoma, endodermal sinus tumor, granulosa-thecal tumor, Sertoli-Leydig cell tumor, and primary peritoneal carcinoma. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description Before the present invention is further described, it is to be understood that the present invention is not limited to particular embodiments described herein and that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0024] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude optional elements. Accordingly, this specification is intended to serve as a precedent for using exclusive language, such as "solely," "only," and the like, or for using a "negative" limitation in connection with the recitation of claim elements.

[0025] Where a range of values ​​is given, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the invention, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0026] Where appropriate, any definition herein may be used in combination with any other definition to describe groups of composite structure. By convention, the last element of such a definition is the one that is attached to the parent moiety. For example, the composite group alkoxyalkyl means that the alkoxy group is attached to the parent molecule via the alkyl group.

[0027] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0028] definition Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this application and have the following meanings:

[0029] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1-8 means 1 to 8 carbons). Alkyl is C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0030] The term "alkylene" refers to a straight-chain or branched-chain saturated aliphatic radical, i.e., a divalent hydrocarbon group, having the indicated number of carbon atoms and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n It can be a divalent radical of -, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, hexylene, and the like.

[0031] The term "alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. In the case of alkyl groups, alkoxy groups are C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as methyl, propyl ...

[0032] As used herein, the term "cyano," by itself or as part of another substituent, refers to a moiety having the formula --CN, i.e., a carbon atom triple-bonded to a nitrogen atom.

[0033] The term "cycloalkyl" refers to a group having the indicated number of ring atoms (e.g., C 3-6 Cycloalkyl refers to a saturated or partially unsaturated hydrocarbon ring having a C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 and C 3-10 It can contain any number of carbons, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 12

[0034] The term "cycloalkyloxy" refers to a cycloalkyl group having an oxygen atom connecting the cycloalkyl group to the point of attachment: cycloalkyl-O-. Cycloalkyl groups are as defined herein.

[0035] The term "spirocyclyl" or "spirocycloalkyl" refers to a saturated or partially unsaturated bicyclic ring having 6 to 12 ring atoms, with the two rings connected by a single carbon atom (also called a spiro atom). Partially unsaturated spirocycloalkyl groups have one or more double or triple bonds within the ring, but the spirocycloalkyl group is not aromatic. Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[4.4]nonane, spiro[3.4]octane, and the like.

[0036] The term "bridged cycloalkyl" refers to a group in which two non-adjacent ring atoms are (CH) n"bridged cycloalkyl" refers to a monocyclic 6- to 11-membered hydrocarbon group linked by a group (where n is 1-3) (also referred to herein as a bridging group). Examples of bridged cycloalkyl include, but are not limited to, bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane. For brevity, the term is intended to include bridged polycyclic hydrocarbon groups such as adamantane.

[0037] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic ring having the indicated number of ring vertices (e.g., a 3- to 7-membered ring) and having 1 to 5 heteroatoms selected from N, O, and S as ring vertices. Partially unsaturated heterocycloalkyl groups have one or more double or triple bonds in the ring, but the heterocycloalkyl group is not aromatic. Heterocycloalkyl groups can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 7, 4 to 7, or 5 to 7 ring members. Heterocycloalkyl groups can contain 1, 2, 3, or 4, or any suitable number of heteroatoms, such as 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0038] The term "bicyclic heterocycloalkyl" or "bicyclic heterocyclyl" refers to a saturated or partially unsaturated fused bicyclic ring having the indicated number of ring vertices (e.g., a 6- to 12-membered ring) and having 1 to 5 heteroatoms selected from N, O, and S as ring vertices. Partially unsaturated bicyclic heterocycloalkyl groups have one or more double or triple bonds in the ring, but the bicyclic heterocycloalkyl group is not aromatic. Bicyclic heterocycloalkyl groups can contain any number of ring atoms, such as 6 to 8, 6 to 9, 6 to 10, 6 to 11, or 6 to 12 ring members. Heterocycloalkyl groups can contain 1, 2, 3, or 4, or any suitable number of heteroatoms, such as 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Non-limiting examples of bicyclic heterocycloalkyl groups include decahydro-1,5-naphthyridine, octahydropyrrolo[1,2-a]pyrazine, and the like.

[0039] The term "bridged heterocyclyl" or "bridged heterocycloalkyl" refers to a heterocyclic ring system in which two non-adjacent ring atoms are (CRR') n "R" refers to heterocycloalkyl rings (having 5 to 8 ring vertices) connected by a group (where n is 1 to 3 and each R is independently H or methyl) (sometimes referred to herein as a "bridging" group). Bridged heterocyclyl groups have 1 to 5 heteroatoms selected from N, O, and S as ring vertices. The heteroatom ring vertices may be located in both the heterocycloalkyl ring portion and the bridging group. When located in the bridging group, the heteroatom is replaced by a CRR' group. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like.

[0040] The term "spiroheterocyclyl" or "spiroheterocycloalkyl" refers to a saturated or partially unsaturated bicyclic ring having 6 to 12 ring atoms, with the two rings connected via a single carbon atom (also called a spiro atom). Spiroheterocyclyl groups have 1 to 5 heteroatoms selected from N, O, and S as ring vertices, with the nitrogen atom optionally being quaternized. Partially unsaturated spiroheterocycloalkyl groups have one or more double or triple bonds in the ring, but the spiroheterocycloalkyl groups are not aromatic. Representative examples include, but are not limited to, 4-oxaspiro[2.4]heptane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane, 2,7-diazaspiro[4.4]nonane, and the like.

[0041] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0042] The term "haloalkyl" refers to an alkyl as defined above in which some or all of the hydrogen atoms have been replaced with halogen atoms. As with alkyl groups, haloalkyl groups include C 1-6 For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0043] The term "haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms have been replaced with halogen atoms. As with alkyl groups, haloalkoxy groups include C 1-6The haloalkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62

[0044] The term "hydroxyalkyl" refers to an alkyl group in which one of the hydrogen atoms has been replaced with a hydroxy (-OH) group. As with alkyl groups, hydroxyalkyl groups can be C 1-6 The hydroxyalkyl group may have any suitable number of carbon atoms, such as 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-propyl- ...

[0045] The term "aryl," unless otherwise specified, means a polyunsaturated, generally aromatic, hydrocarbon group which may be fused or covalently linked, monocyclic or polycyclic (up to three rings). Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

[0046] The term "heteroaryl" refers to a 5-10 membered aromatic ring (or fused ring system) containing 1-5 heteroatoms selected from N, O, and S. A heteroaryl group can contain any number of ring atoms, such as 5-6, 5-8, 6-8, 6-9, 9-10, 9, or 10 ring members. A heteroaryl group can contain 1, 2, 3, 4, or 5 heteroatoms, or any suitable number of heteroatoms, such as 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like.

[0047] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).

[0048] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as salts of arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginate and salts of organic acids such as glucuronic acid or galacturonic acid. (See, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19.) Certain compounds of the present invention contain both basic and acidic functional groups, allowing the compounds to be converted into either base or acid addition salts.

[0049] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise these salts are equivalent to the parent form of the compound for purposes of this invention.

[0050] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. For purposes of the present invention, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. It is intended that all possible physical forms are within the scope of the present invention.

[0051] Certain compounds of the present invention have asymmetric carbon atoms (optical centers). Racemates, diastereomers, and separate isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical depiction is shown, it is meant to refer to a compound in which one of the isomers is present and substantially free of the other isomer. "Substantially free" of another isomer indicates that the ratio of the two isomers is at least an 80 / 20 ratio, more preferably a 90 / 10 ratio or a 95 / 5 ratio, or greater. In some embodiments, one of the isomers is present in an amount of at least 99%.

[0052] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. An unnatural proportion of an isotope can be defined as a range from the amount found in nature to the amount consisting of 100% of that atom. For example, the compounds may contain unnatural amounts of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon 13 ( 13 Non-radioactive isotopes such as C) can be incorporated into compounds of the present invention. Such isotopic variations can provide additional utilities to those described elsewhere in this application. For example, isotopic variations of the compounds of the present invention can find additional utilities, including, but not limited to, utility as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variations of the compounds of the present invention can have altered pharmacokinetic and pharmacodynamic properties that can contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0053] The terms "administration," "administering," and the like, when applied to, e.g., a subject, cell, tissue, organ, or biological fluid, refer to contacting, e.g., a Pol theta modulator, a pharmaceutical composition comprising same, or a diagnostic agent with the subject, cell, tissue, organ, or biological fluid. With respect to cells, administration includes contacting of a reagent with the cell (e.g., in vitro or ex vivo), as well as contacting of a reagent with the fluid when the fluid is in contact with the cell.

[0054] The terms "treat," "treating," "treatment," and the like refer to a course of action (e.g., administration of a Pol θ modulator or a pharmaceutical composition comprising same) initiated after a disease, disorder, or condition, or a symptom thereof, has been diagnosed or observed, to temporarily or permanently eliminate, reduce, inhibit, alleviate, or ameliorate at least one underlying cause of the disease, disorder, or condition from which the subject is afflicted, or at least one symptom associated with the disease, disorder, or condition from which the subject is afflicted. Thus, treatment includes inhibiting active disease (e.g., preventing the onset or further progression of the disease, disorder, or condition, or clinical symptoms associated therewith).

[0055] The term "in need of treatment," as used herein, refers to a determination made by a physician or other caregiver that a subject needs or would benefit from treatment. This determination is made based on a variety of factors within the physician's or caregiver's area of ​​expertise. For example, a patient has been diagnosed with a disease associated with overexpression of Pol θ or a homologous recombination (HR)-deficient cancer.

[0056] The terms "prevent," "preventing," "prevention," and the like refer to a course of action (e.g., administration of a Pol θ modulator or a pharmaceutical composition comprising same) initiated in such a manner as to temporarily or permanently prevent, suppress, inhibit, or reduce a subject's risk of developing a disease, disorder, condition, etc. (e.g., as determined by the absence of clinical symptoms), or generally, in the case of a subject predisposed to having a particular disease, disorder, or condition, delay its onset (e.g., prior to the onset of the disease, disorder, condition, or symptoms thereof).

[0057] The term "in need of prevention," as used herein, refers to a judgment made by a physician or other caregiver that a subject needs or would benefit from preventative care. This judgment is made based on a variety of factors within the physician's or caregiver's area of ​​expertise.

[0058] The phrase "therapeutically effective amount" refers to the administration of an amount of an agent to a subject that, when administered to a subject, alone or as part of a pharmaceutical composition, and in a single dose or as part of a series of doses, can have any detectable positive effect on any symptom, aspect, or characteristic of a disease, disorder, or condition. A therapeutically effective amount can be ascertained by measuring the relevant physiological effect and can be adjusted in conjunction with dosing regimens, diagnostic assays for the subject's condition, and the like. As an example, measuring serum levels of a Pol θ modulator (or its metabolite, etc.) at a particular time point after administration can indicate whether a therapeutically effective amount has been used.

[0059] The terms "modulate," "modulation," and the like refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease the function or activity of Pol θ. Modulators may act alone or may use cofactors, e.g., proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules.

[0060] The "activity" of a molecule may describe or refer to the binding of the molecule to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation, or maturation; antigenic activity; modulation of the activity of other molecules, etc. The term "proliferative activity" includes, for example, activity that promotes, is required for, or is specifically associated with normal cell division, as well as cancer, tumors, metaplasia, cell transformation, metastasis, and angiogenesis.

[0061] Certain compounds of the present disclosure may exist as tautomers and / or geometric isomers. All possible tautomers, cis and trans isomers, as individual forms and mixtures thereof, are within the scope of the present disclosure. For example, certain hydroxy-substituted compounds may be represented by the following: [ka] It can exist as a tautomer as shown in

[0062] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0063] As used herein, a wavy line crossing a single, double, or triple bond in any chemical structure depicted herein: [ka] represents a single, double, or triple point bond to the remainder of the molecule. Additionally, a bond extending into the center of a ring (e.g., a phenyl ring) is meant to indicate attachment at any of the available ring vertices. One of ordinary skill in the art will understand that multiple substituents shown attached to a ring will occupy any ring vertex that provides a stable compound and otherwise sterically fits.

[0064] The term "about," as used herein, is intended to qualify the numerical value it modifies and indicates a value that varies within a range of error. When a specific error range, such as the standard deviation for a given mean value in a graph or table of data, is not given, the term "about" should be understood to mean that the numerical value encompasses a range of ±10%, preferably ±5%, of the given numerical value.

[0065] "Disease," as used herein, is generally synonymous with, and intended to be used interchangeably with, the terms "disorder," "syndrome," and "pathology" (in medical conditions), i.e., all terms reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function, is typically manifested by characteristic signs and symptoms, and reduces the lifespan or quality of life of the human or animal.

[0066] "Patient" is generally synonymous with the term "subject" and, as used herein, includes all mammals, including humans. Examples of patients include humans, livestock (such as cows, goats, sheep, pigs, and rabbits), and companion animals (such as dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0067] "Inhibit," "reduce," or variations of these terms with respect to Pol Theta include any measurable reduction or complete inhibition to achieve a desired result. For example, there can be about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more reduction in Pol Theta activity compared to normal activity, or any range derivable therein.

[0068] The term "homologous recombination" refers to the intracellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA sequences.

[0069] The term "homologous recombination (HR)-deficient cancer" refers to cancer characterized by a reduction or absence of a functional HR repair pathway. HR deficiency can result from the absence of one or more HR-associated genes or the presence of one or more mutations in one or more HR-associated genes. Examples of HR-associated genes include BRCA1, BRCA2, RAD54, RAD51B, Ct1P (Choline Transporter-Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, one or more HR-associated Genes encoding Fanconi anemia (FA) proteins or FA-like genes include FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.

[0070] The term "Pol θ overexpression" refers to increased expression or activity of Pol θ in a diseased cell, e.g., a cancer cell, compared to the expression or activity of Pol θ in a normal cell (e.g., an unaffected cell of the same type). The amount of Pol θ can be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, or more, compared to Pol θ expression in a normal cell. Examples of Pol θ cancers include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, lung cancer, colon cancer, stomach cancer, bladder cancer, and prostate cancer.

[0071] Compound: In some embodiments herein, a compound of formula (I): [ka] [In the formula, Ring A is selected from the group consisting of phenyl and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from N, O and S; the subscripts m and n are each independently 0 or 1; R 1 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 1 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, -X 1 -Cyano, -NO2, -C(O)OR a , -NR a C(O)R b , -X 1 -C(O)NR a R b , -X 1 -OH, C 3-6 Cycloalkyl, -X 1 -OC 3-6 Cycloalkyl, C 1-6 Hydroxyalkynyl, -X 1 -NR a R b , -X 1 -S(O)2R a , -X 1 -S(O)2NR a R b , X 1 -X 1a -OR a and 4-6 membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; R 2 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -X 1 -cyano; each X 1 is a bond and C 1-4 alkylene; X 1ais a 3- to 6-membered heterocycloalkylene having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, R a and R b is hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; Ar 1 is selected from the group consisting of phenyl, naphthyl, pyridin-2-one, and a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S, wherein Ar 1 is 0 to 4 R 1a is substituted with a substituent, Each R 1a is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, -C(O)R c , -C(O)2R c , -NR c C(O)R d , -OC 1-4 Alkylene-OC 1-4 Alkyl, -X 2 -C(O)NR c R d , -X 2 -S(O)2NR c R d , -X 2 -NR c R d , -C(O)NR c R d , -X 2 -cyano, -OX 2 -Cyano, -X 2 -S(O)R c , -X 2 -S(O)2R c , -X 2 -N(R d )S(O)2R c , -P(O)R c R d, -Y and -X 2 -OH, or two R's located at adjacent vertices of the ring 1a The groups taken together form a 4-6 membered cycloalkyl or heterocycloalkyl having 0-2 heteroatoms independently selected from N, O, and S as ring vertices, and two R 1a The cycloalkyl or heterocycloalkyl formed by the group is selected from oxo, halo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted with 0 to 4 groups independently selected from haloalkyl; Each Y is independently selected from phenyl, benzyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein each of the heterocycloalkyl and heteroaryl represented by Y has 1 or 2 ring members independently selected from O, N, and S, and each Y is independently selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted with 0, 1, or 2 groups independently selected from haloalkyl; each X 2 is a bond and C 1-4 alkylene; Each R c and R d is hydrogen, C 1-6 Alkyl, C 3-5 Cycloalkyl and C 1-6 haloalkyl; R 3 teeth, (I C 3-6 Cycloalkyl, C 6-11 Bridged cycloalkyl and C 6-12 spirocycloalkyl; (ii) a 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iii) a 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iv) a 6- to 10-membered bridged heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (v) a 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (vi) hydrogen; (vii)C 1-6 Alkyl or C 2-6 Alkynyl is a member selected from the group consisting of Each R of (i) to (v) 3 Members have 0 to 4 R 3a is substituted with a substituent, R 3a Each of the substituents is C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;Halo;C 1-6 Haloalkyl;C 1-6 Haloalkoxy;-X 3 -OC 1-6 Alkyl;-X 3 -OH;-NR e R f -ONO2; 4-6 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O and S as ring vertices; -NR e C(O)R f ;-X 3 -NR e R f ;-X 3 - independently selected from cyano and oxo; R 3 Member (vii) is Haro, C 1-3 Haloalkyl, C 1-6 Haloalkoxy, -OC 1-6 Alkyl, cyano, -OH, -NR e R f , -CONR e R f and 0 to 3 R selected from the group consisting of oxo 3b is substituted with a substituent, each X 3 is a bond and C 1-4 alkylene; Each R e and R f is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and -C 1-3 Alkylene-C 3-6 cycloalkyl. or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments herein, a compound of formula (I): [ka] [In the formula, Ring A is selected from the group consisting of phenyl and 5-10 membered heteroaryl rings having 1-4 heteroatoms independently selected from N, O, and S; the subscripts m and n are each independently 0 or 1; R 1 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 1 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, -X 1 -Cyano, -NO2, -C(O)OR a , -NR a C(O)R b , -X 1 -C(O)NR a R b , -X 1 -OH, C 3-6 Cycloalkyl, -X 1 -OC 3-6 Cycloalkyl, C 1-6 Hydroxyalkynyl, -X 1 -NR a R b , -X 1 -S(O)2R a , -X 1 -S(O)2NR a R b , X 1 -X 1a -OR aand 4-6 membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; R 2 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -X 1 -cyano; each X 1 is a bond and C 1-4 alkylene; X 1a is a 3- to 6-membered heterocycloalkylene having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, R a and R b is hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; Ar 1 is selected from the group consisting of phenyl, naphthyl, pyridin-2-one, and a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S, wherein Ar 1 is 0 to 4 R 1a is substituted with a substituent, Each R 1a is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, -C(O)R c , -C(O)2R c , -NR c C(O)R d , -OC 1-4 Alkylene-OC 1-4 Alkyl, -X 2 -C(O)NR c R d , -X 2 -S(O)2NR c Rd , -X 2 -NR c R d , -C(O)NR c R d , -X 2 -cyano, -OX 2 -Cyano, -X 2 -S(O)R c , -X 2 -S(O)2R c , -X 2 -N(R d )S(O)2R c , -P(O)R c R d , -Y and -X 2 -OH, or two R's located at adjacent vertices of the ring 1a The groups taken together form a 4-6 membered cycloalkyl or heterocycloalkyl having 0-2 heteroatoms independently selected from N, O, and S as ring vertices, and two R 1a The cycloalkyl or heterocycloalkyl formed by the group is selected from oxo, halo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted with 0 to 4 groups independently selected from haloalkyl; Each Y is independently selected from phenyl, benzyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein each of the heterocycloalkyl and heteroaryl represented by Y has 1 or 2 ring members independently selected from O, N, and S, and each Y is independently selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted with 0, 1, or 2 groups independently selected from haloalkyl; each X 2 is a bond and C 1-4 alkylene; Each R c and R d is hydrogen, C 1-6 Alkyl, C 3-5 Cycloalkyl and C 1-6haloalkyl; R 3 teeth, (I C 3-6 Cycloalkyl, C 6-11 Bridged cycloalkyl and C 6-12 spirocycloalkyl; (ii) a 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iii) a 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iv) a 6- to 10-membered bridged heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (v) a 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (vi) hydrogen; (vii)C 1-6 Alkyl or C 2-6 Alkynyl is a member selected from the group consisting of Each R of (i) to (v) 3 Members have 0 to 4 R 3a is substituted with a substituent, R 3a Each of the substituents is C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;Halo;C 1-6 Haloalkyl;C 1-6 Haloalkoxy;-X 3 -OC 1-6 Alkyl;-X 3 -OH;-NR e R f -ONO2; 4-6 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O and S as ring vertices; -NR e C(O)R f ;-X 3 -NR e R f ;-X 3- independently selected from cyano and oxo; R 3 Member (vii) is Haro, C 1-3 Haloalkyl, C 1-6 Haloalkoxy, -OC 1-6 Alkyl, cyano, -OH, -NR e R f , -CONR e R f and 0 to 3 R selected from the group consisting of oxo 3b is substituted with a substituent, each X 3 is a bond and C 1-4 alkylene; Each R e and R f is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and -C 1-3 Alkylene-C 3-6 cycloalkyl. or a pharmaceutically acceptable salt thereof provided that the compound of formula I is the following compound: [ka] isn't it.

[0073] In some embodiments herein, a compound of formula (I): [ka] [In the formula, Ring A is selected from the group consisting of phenyl and a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S; the subscripts m and n are each independently 0 or 1; R 1 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 1 -OC 1-6 Alkyl, C 1-6Haloalkoxy, -X 1 -Cyano, -NO2, -C(O)OR a , -NR a C(O)R b , -X 1 -C(O)NR a R b , -X 1 -OH, C 3-6 Cycloalkyl, -X 1 -OC 3-6 Cycloalkyl, C 1-6 Hydroxyalkynyl, -X 1 -NR a R b , -X 1 -S(O)2R a , -X 1 -S(O)2NR a R b , X 1 -X 1a -OR a and 4-6 membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; R 2 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -X 1 -cyano; each X 1 is a bond and C 1-4 alkylene; X 1a is a 3- to 6-membered heterocycloalkylene having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, R a and R b is hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; Ar 1 is selected from the group consisting of phenyl, naphthyl, pyridin-2-one, and a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S, wherein Ar 1is 0 to 4 R 1a is substituted with a substituent, Each R 1a is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, -C(O)R c , -C(O)2R c , -NR c C(O)R d , -OC 1-4 Alkylene-OC 1-4 Alkyl, -X 2 -C(O)NR c R d , -X 2 -S(O)2NR c R d , -X 2 -NR c R d , -C(O)NR c R d , -X 2 -cyano, -OX 2 -Cyano, -X 2 -S(O)R c , -X 2 -S(O)2R c , -X 2 -N(R d )S(O)2R c , -P(O)R c R d , -Y and -X 2 -OH, or two R's located at adjacent vertices of the ring 1a groups together form a 4- to 6-membered cycloalkyl or heterocycloalkyl having 0-2 heteroatoms independently selected from N, O, and S as ring vertices, and two R 1a The cycloalkyl or heterocycloalkyl formed by the group is selected from oxo, halo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4substituted with 0 to 4 groups independently selected from haloalkyl; Each Y is independently selected from phenyl, benzyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein each of the heterocycloalkyl and heteroaryl represented by Y has 1 or 2 ring members independently selected from O, N, and S, and each Y is independently selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted with 0, 1, or 2 groups independently selected from haloalkyl; each X 2 is a bond and C 1-4 alkylene; Each R c and R d is hydrogen, C 1-6 Alkyl, C 3-5 Cycloalkyl and C 1-6 haloalkyl; R 3 teeth, (I C 3-6 Cycloalkyl, C 6-11 Bridged cycloalkyl and C 6-12 spirocycloalkyl; (ii) a 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iii) a 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iv) a 6- to 10-membered bridged heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (v) a 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (vi) hydrogen; (vii)C 1-6 Alkyl or C 2-6 Alkynyl is a member selected from the group consisting of Each R of (i) to (v) 3Members have 0 to 4 R 3a is substituted with a substituent, R 3a Each of the substituents is C 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl;Halo;C 1-6 Haloalkyl;C 1-6 Haloalkoxy;-X 3 -OC 1-6 Alkyl;-X 3 -OH;-NR e R f -ONO2; 4-6 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O and S as ring vertices; -NR e C(O)R f ;-X 3 -NR e R f ;-X 3 - independently selected from cyano and oxo; R 3 Member (vii) is Haro, C 1-3 Haloalkyl, C 1-6 Haloalkoxy, -OC 1-6 Alkyl, cyano, -OH, -NR e R f , -CONR e R f and 0 to 3 R selected from the group consisting of oxo 3b is substituted with a substituent, each X 3 is a bond and C 1-4 alkylene; Each R e and R f is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and -C 1-3 Alkylene-C 3-6 cycloalkyl. or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the compound of formula I is the following compound: [ka] N-(4,5-dihydro-5-oxo-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydro-6,6-dimethyl-1H-indazol-3-yl)-1H-indole-5-carboxamide (CAS No. 1309787-94-7); or [ka] N-(5-Methoxy-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydro-6,6-dimethyl-1H-indazol-3-yl)-1H-indole-5-carboxamide (CAS No. 1309795-15-0) isn't it.

[0075] In some embodiments, compounds of formula I have ring A as follows: [ka] It is not a compound that is

[0076] In some embodiments, the compound of formula I is not a compound where ring A is indole.

[0077] In some embodiments herein, a compound of formula (I): [ka] [In the formula, Ring A is selected from the group consisting of phenyl and 5-10 membered heteroaryl rings having 1-4 heteroatoms independently selected from N, O, and S; the subscripts m and n are each independently 0 or 1; R 1 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 1 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, -X1 -cyano, -C(O)OR a , -NR a C(O)R b , -X 1 -C(O)NR a R b , -X 1 -OH, C 3-6 Cycloalkyl, -X 1 -OC 3-6 Cycloalkyl, C 1-6 Hydroxyalkynyl, -X 1 -NR a R b , -X 1 -S(O)2R a , -X 1 -S(O)2NR a R b and X 1 -X 1a -OR a is selected from the group consisting of R 2 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -X 1 -cyano; each X 1 is a bond and C 1-4 alkylene; X 1a is a 3- to 6-membered heterocycloalkylene having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, R a and R b is hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; Ar 1 is selected from the group consisting of phenyl and a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O and S, wherein Ar 1 is 0 to 4 R 1a is substituted with a substituent, Each R 1a is C 1-6 Alkyl, Halo, C1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, -C(O)R c , -NR c C(O)R d , -NR c R d , -X 2 -NR c R d , -C(O)NR c R d , -X 2 -Cyano, -X 2 -S(O)R c and -X 2 -OH, or two R's located at adjacent vertices of the ring 1a the groups taken together form a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S as ring vertices; each X 2 is a bond and C 1-4 alkylene; Each R c and R d is hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; R 3 teeth, (I C 3-6 Cycloalkyl and C 6-12 spirocycloalkyl; (ii) a 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iii) a 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iv) a 6- to 10-membered bridged heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (v) a 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (vi) hydrogen; (vii)C 1-6 Alkyl or C 2-6 Alkynyl is a member selected from the group consisting of Each R of (i) to (v) 3 Members have 0 to 4 R 3a is substituted with a substituent, R 3a Each of the substituents is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -X 3 -OC 1-6 Alkyl, -X 3 -OH, -NR e R f , -NR e C(O)R f , -X 3 -NR e R f , -X 3 -independently selected from cyano and oxo; R 3 Member (vii) is Haro, C 1-6 Haloalkoxy, -OC 1-6 Alkyl, cyano, -OH, -NR e R f and 0 to 3 R selected from the group consisting of oxo 3b is substituted with a substituent, each X 3 is a bond and C 1-4 alkylene; Each R e and R f is H and C 1-6 alkyl. or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments herein, a compound of formula (I): [ka] [In the formula, Ring A is selected from the group consisting of phenyl and 5-10 membered heteroaryl rings having 1-4 heteroatoms independently selected from N, O, and S; the subscripts m and n are each independently 0 or 1; R 1 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 1 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, -X 1 -cyano, -C(O)OR a , -NR a C(O)R b , -X 1 -C(O)NR a R b , -X 1 -OH, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkynyl, -X 1 -NR a R b , -X 1 -S(O)2R a and -X 1 -S(O)2NR a R b is selected from the group consisting of R 2 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -X 1 -cyano; each X 1 is a bond and C 1-4 alkylene; R a and R b is hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; Ar 1is selected from the group consisting of phenyl and a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O and S, wherein Ar 1 is 0 to 4 R 1a is substituted with a substituent, Each R 1a is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, -C(O)R c , -NR c C(O)R d , -NR c R d , -X 2 -NR c R d , -C(O)NR c R d , -X 2 -cyano and -X 2 -OH, each X 2 is a bond and C 1-4 alkylene; Each R c and R d is hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; R 3 teeth, (I C 3-6 Cycloalkyl and C 6-12 spirocycloalkyl; (ii) a 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iii) a 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iv) a 6- to 10-membered bridged heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (v) a 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (vi) hydrogen; (vii)C 1-6 Alkyl or C 2-6 Alkynyl is a member selected from the group consisting of Each R of (i) to (v) 3 Members have 0 to 4 R 3a is substituted with a substituent, R 3a Each of the substituents is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -X 3 -OC 1-6 Alkyl, -X 3 -OH, -NR e R f , -NR e C(O)R f , -X 3 -NR e R f , -X 3 -independently selected from cyano and oxo; R 3 Member (vii) is Haro, C 1-6 Haloalkoxy, -OC 1-6 Alkyl, cyano, -OH, -NR e R f and 0 to 3 R selected from the group consisting of oxo 3b is substituted with a substituent, each X 3 is a bond and C 1-4 alkylene; Each R e and R f is H and C 1-6 alkyl. or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, Ring A of Formula (I) is phenyl, pyridinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, imidazo[1,2-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 1,6-naphthyridinyl, or 1,7-naphthyridinyl.

[0080] In some embodiments, ring A of Formula (I) is a 9- or 10-membered heteroaryl ring. In some embodiments, ring A of Formula (I) is a 9-membered heteroaryl ring. In some embodiments, ring A of Formula (I) is a 10-membered heteroaryl ring.

[0081] In some embodiments, ring A of formula (I) is imidazo[1,2-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 1,6-naphthyridinyl, or 1,7-naphthyridinyl.

[0082] In some embodiments, ring A of Formula (I) is a 5- or 6-membered heteroaryl ring. In some embodiments, ring A of Formula (I) is a 5-membered heteroaryl ring. In some embodiments, ring A of Formula (I) is a 6-membered heteroaryl ring.

[0083] In some embodiments, ring A of formula (I) is pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, or triazolyl.

[0084] In some embodiments, Ar of formula (I) 1 , R 1 and R 2 The ring A having [ka] is selected from the group consisting of:

[0085] In some embodiments, Ar of formula (I) 1 , R 1 and R 2 The ring A having [ka] is selected from the group consisting of:

[0086] In some embodiments, Ar of formula (I) 1 , R 1 and R 2 The ring A having [ka] is selected from the group consisting of:

[0087] In some embodiments, Ar of formula (I) 1 , R 1 and R 2 The ring A having [ka] is selected from the group consisting of:

[0088] In some embodiments, Ar of formula (I) 1 and R 1 and ring A has [ka] is.

[0089] In some embodiments, Ar of formula (I) 1 The ring A having [ka] is.

[0090] In some embodiments, Ar of formula (I) 1 The ring A having [ka] is.

[0091] In some embodiments, Ar of formula (I) 1 The ring A having [ka] is.

[0092] In some embodiments, Ar of formula (I) 1 The ring A having [ka] is.

[0093] In some embodiments, ring A of formula (I) is not pyrimidine.

[0094] In some embodiments, ring A of formula (I) is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, and imidazo[1,2-a]pyridinyl, 1,2,3-triazole, pyrazolyl, isoxazolyl, and imidazo[1,5-a]pyridinyl.

[0095] In some embodiments, ring A of formula (I) is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, and imidazo[1,2-a]pyridinyl.

[0096] In some embodiments, ring A of Formula (I) is phenyl.

[0097] In some embodiments, ring A of formula (I) is pyridinyl.

[0098] In some embodiments, Ar 1 is attached to ring A ortho to the amide substituent.

[0099] In some embodiments, when Ring A is pyridyl, the N atom of the pyridyl is oxidized to form an N-oxide.

[0100] In some embodiments, n in Formula (I) and subembodiments thereof is 1. In some embodiments, n in Formula (I) and subembodiments thereof is 0.

[0101] In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is a 4-6 membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices. In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is a 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices. In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is a 5-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices. In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is a 4-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices. In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is selected from the group consisting of azetinidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, and piperazinyl. In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is azetinidinyl.

[0102] In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 1 -OC1-6 Alkyl, C 1-6 Haloalkoxy, -X 1 -Cyano, -X 1 -OH, C 3-6 Cycloalkyl and -X 1 -NR a R b In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 is C 1-6 Alkyl, halo, -X 1 -cyano and C 1-6 In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 -X 1 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, -X 1 -OH and -X 1 -NR a R b In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 -X 1 -OC 3-6 Cycloalkyl and X 1 -X 1a -OR a In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 is C 1-6 Alkyl, halo, -X 1 -Cyanno, C 1-6 Haloalkyl, -X 1 -OC 3-6 Cycloalkyl and X 1 -X 1a -OR a In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 is C 1-6 Alkyl, halo, -X 1 -Cyanno, C 1-6 Haloalkyl and -X 1 -OC 3-6cycloalkyl.

[0103] In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is C 1-6 Alkyl and -X 1 —OH.

[0104] In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is selected from the group consisting of methyl and hydroxymethyl. In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is selected from the group consisting of ethyl and hydroxyethyl.

[0105] In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 is ethyl or propyl. In some embodiments, n in Formula (I) and subembodiments thereof is 1 and R 1 is O-cyclopropyl. In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 is O-cyclopropyl. In some embodiments, n in formula (I) and subembodiments thereof is 1 and R 1 is -CH2-O-cyclopropyl.

[0106] In some embodiments, m in Formula (I) is 1 and R 2 is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl and C 1-6 In some embodiments, m in Formula (I) is 1 and R 2 is C 1-6 Alkyl, halo and C 1-6 It is haloalkyl.

[0107] In some embodiments, m in Formula (I) and subembodiments thereof is 0. In some embodiments, m in Formula (I) and subembodiments thereof is 1.

[0108] In some embodiments, each X in formula (I) and subembodiments thereof 1 is a bond. In some embodiments, each X in formula (I) and subembodiments thereof 1 is C 1-4 In some embodiments, each X in formula (I) and subembodiments thereof is alkylene. 1 is C 1-2 In some embodiments, each X in formula (I) and subembodiments thereof is alkylene. 1 is methylene.

[0109] In some embodiments, each R in formula (I) and subembodiments thereof a and R b is hydrogen. In some embodiments, each R in formula (I) and subembodiments thereof a is hydrogen, and each R in formula (I) and subembodiments thereof b is C 1-4 Alkyl or C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is haloalkyl. a and R b is C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is alkyl. a and R b is C 1-2 In some embodiments, each R in formula (I) and subembodiments thereof is alkyl. a and R b is methyl. In some embodiments, each R in formula (I) and subembodiments thereof a and R b is C 1-4In some embodiments, each R in formula (I) and subembodiments thereof is haloalkyl. a and R b is C 1-2 It is haloalkyl.

[0110] In some embodiments, the compound has the formula (Iaa): [ka] or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 2 are ring vertices of ring A connected by a single or double bond, and Z 1 and Z 2 Each of is a carbon atom.

[0111] In some embodiments, the compound has Formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound has the formula (Ib): [ka] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound has the formula (Ic): [ka] or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 are 0 to 4 R 1ais selected from the group consisting of phenyl, pyridinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[1,2-a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, benzo[d]thiazole, indazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyridazinyl and tetrazolo[1,5-a]pyridinyl, substituted with

[0115] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 are 0 to 4 R 1a and substituted with phenyl, pyridinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, and pyridazyl.

[0116] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 are 0 to 4 R 1a and [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, tetrazolo[1,5-a]pyridinyl, and [1,2,4]triazolo[1,5-a]pyridinyl, substituted with 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, benzo[d]thiazole, benzo[c]isothiazolyl, indazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, tetrazolo[1,5-a]pyridinyl, and [1,2,4]triazolo[1,5-a]pyridinyl.

[0117] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 4 R 1a is phenyl substituted with

[0118] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 teeth, [ka] is.

[0119] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 4 R 1a and pyridinyl substituted with

[0120] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 4 R 1a and naphthyl substituted with

[0121] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 4 R 1a is a pyridin-2-one substituted with

[0122] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 4 R 1a and naphthyl substituted with

[0123] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 4 R 1a is a pyridin-2-one substituted with

[0124] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 3 R 1a is replaced by .

[0125] In some embodiments, Ar in formula (I), (Ia), (Ib), and (Ic) 1 is 0 to 2 R 1a is replaced by .

[0126] In some embodiments, the compound has the formula (Ia1): [ka] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound has the formula (Ib1): [ka] or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compound has the formula (Ic1): [ka] or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the compound has the formula (Ia2): [ka] or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the compound has the formula (Ib2): [ka] or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the compound has the formula (Ic2): [ka] or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, each R in formula (I) and subembodiments thereof 1a is C 1-6Alkyl, Halo, C 1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, -NR a R b , -X 2 -cyano and -X 2 In some embodiments, each R in formula (I) and subembodiments thereof is independently selected from: 1a is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, -NR a R b , -X 2 -Cyano, -X 2 -OH and -X 2 -S(O)R c are independently selected from

[0133] In some embodiments, each R in formula (I) and subembodiments thereof 1a is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, -NR a R b and -X 2 In some embodiments, each R in formula (I) and subembodiments thereof is independently selected from: 1a is C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, -X 2 -OC 1-6 Alkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, -NR a R b , -X 2 -Cyano, -X 2 -OH and -S(O)Rc are independently selected from

[0134] In some embodiments, each R in formula (I) and subembodiments thereof 1a is independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, cyclopropyl, —NH, hydroxymethyl, and 1-hydroxyethyl. 1a is independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, cyclopropyl, -NH, hydroxymethyl, 1-hydroxyethyl, and -S(=O)CH. In some embodiments, each R in Formula (I) and subembodiments thereof is 1a is independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, and difluoromethoxy. 1a is independently selected from ethyl, fluoro, chloro, difluoromethyl, and ethoxy. In some embodiments, each R in formula (I) and subembodiments thereof is 1a is independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, and difluoromethoxy. In some embodiments, each R in formula (I) and subembodiments thereof is 1a is independently selected from methyl, ethyl, fluoro, cyclopropyl, —NH 2 , hydroxymethyl, and 1-hydroxyethyl.

[0135] In some embodiments, each R in formula (I) and subembodiments thereof 1a is C 1-6 Alkyl, halo, -OC 1-6 Alkyl, -C(O)R c , -C 1-4 Alkoxy-C 1-4 Alkoxy, -X2 -C(O)NR c R d , -X 2 -S(O)2NR c R d , -OX 2 -Cyano, -X 2 -S(O)2R c and -X 2 -N(R d )S(O)2R c In some embodiments, each R in formula (I) and subembodiments thereof is independently selected from 1a is -C(O)2R c , -C 1-4 Alkoxy-C 1-4 Alkoxy, -X 2 -C(O)NR c R d , -X 2 -S(O)2NR c R d , -OX 2 -Cyano, -X 2 -S(O)2R c and -X 2 -N(R d )S(O)2R c are independently selected from

[0136] In some embodiments, each R in formula (I) and subembodiments thereof 1a , where at least one R 1a is Y, wherein Y is selected from phenyl, benzyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of the heterocycloalkyl and heteroaryl represented by Y having 1 or 2 ring members independently selected from O, N, and S, and each Y is selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 and substituted with 0, 1, or 2 groups independently selected from haloalkyl.

[0137] In some embodiments, each R in formula (I) and subembodiments thereof 1a , where at least one R 1ais Y, Y is phenyl or benzyl, and each Y is selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 and substituted with 0, 1, or 2 groups independently selected from haloalkyl.

[0138] In some embodiments, each R in formula (I) and subembodiments thereof 1a , where at least one R 1a is Y, wherein Y is a 4- to 6-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, and each of the heterocycloalkyl and heteroaryl represented by Y has 1 or 2 ring members independently selected from O, N, and S, and each Y is selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 and substituted with 0, 1, or 2 groups independently selected from haloalkyl.

[0139] In some embodiments, each R in formula (I) and subembodiments thereof 1a , where at least one R 1a is Y, wherein Y is a 4- to 6-membered heterocycloalkyl, each heterocycloalkyl represented by Y having 1 or 2 ring members independently selected from O, N, and S, and each Y is selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted with 0, 1, or 2 groups independently selected from haloalkyl, In some embodiments, the 4-6 membered heterocycloalkyl is selected from the group consisting of piperidinyl, morpholinyl, and tetrahydropyranyl.

[0140] In some embodiments, each R in formula (I) and subembodiments thereof 1a , where at least one R 1a is Y, wherein Y is a 5-6 membered heteroaryl, the heteroaryl represented by Y having 1 or 2 ring members independently selected from O, N and S, and each Y is selected from halo, oxo, C1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is substituted with 0, 1, or 2 groups independently selected from haloalkyl. 1a , where at least one R 1a is Y, wherein Y is a 5-membered heteroaryl, the heteroaryl represented by Y having 1 or 2 ring members independently selected from O, N, and S, and each Y is selected from halo, oxo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted with 0, 1, or 2 groups independently selected from haloalkyl, hi some embodiments, the 5-6 membered heteroaryl is pyrazolyl.

[0141] In some embodiments, two R s located at adjacent vertices of the ring in Formula (I) and its subembodiments 1a The groups taken together form a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, and S as ring vertices. In some embodiments, two R groups at adjacent vertices of the ring in Formula (I) and its subembodiments are 1a The groups taken together form a 5-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S as ring vertices. In some embodiments, the heterocycloalkyl ring has 1 or 2 double bonds between ring members. In some embodiments, the heterocycloalkyl ring is selected from oxo, halo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 and substituted with 0 to 4 groups independently selected from haloalkyl.

[0142] In some embodiments, two R s located at adjacent vertices of the ring in Formula (I) and its subembodiments 1aThe groups taken together form a 4- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl ring has 1 or 2 double bonds between ring members. In some embodiments, the cycloalkyl ring is selected from the group consisting of oxo, halo, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is substituted with 0 to 4 groups independently selected from haloalkyl. 1a is independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.

[0143] In some embodiments, each X in formula (I) and subembodiments thereof 2 is a bond. In some embodiments, each X in formula (I) and subembodiments thereof 2 is C 1-4 In some embodiments, each X in formula (I) and subembodiments thereof is alkylene. 2 is C 1-2 In some embodiments, each X in formula (I) and subembodiments thereof is alkylene. 2 is methylene.

[0144] In some embodiments, each R in formula (I) and subembodiments thereof c and R d is hydrogen, C 1-6 Alkyl, C 3-5 Cycloalkyl and C 1-6 In some embodiments, each R in formula (I) and subembodiments thereof is haloalkyl. c and R d is hydrogen, C 1-6 Alkyl and C 1-6 In some embodiments, each R in formula (I) and subembodiments thereof is haloalkyl. c and R d is hydrogen. In some embodiments, each R cis hydrogen, and each R in formula (I) and subembodiments thereof d is C 1-4 Alkyl or C 1-4 In some embodiments, R in each of Formula (I) and subembodiments thereof is haloalkyl. c and R d is C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is alkyl. c and R d is C 1-2 In some embodiments, each R in formula (I) and subembodiments thereof is alkyl. c and R d is methyl. In some embodiments, each R in formula (I) and subembodiments thereof c and R d is C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is haloalkyl. c and R d is C 1-2 It is haloalkyl.

[0145] In some embodiments, R in formula (I) and its subembodiments 3 are 0 to 4 R 3a is replaced by C 6-12 Spirocyclyl or C 3-6 In some embodiments, R in formula (I) and subembodiments thereof is cycloalkyl. 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is selected from the group consisting of spiro[3.3]heptane, spiro[4.4]nonane, and spiro[3.4]octane.

[0146] In some embodiments, R in formula (I) and its subembodiments 3 are 0 to 4 R3a C is replaced by 6-11 In some embodiments, C is a bridged cycloalkyl. 6-11 A bridged cycloalkyl has the structure: [ka] Each has 0 to 4 R 3a is replaced by .

[0147] In some embodiments, R 3 is a 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, and 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is a 5-membered heterocycloalkyl substituted with 3 is 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is a 6-membered heterocycloalkyl substituted with 3 are 0 to 4 R 3a In some embodiments, R in Formula (I) and subembodiments thereof is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, 2-oxopiperazinyl, 2-tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 2-oxo-1,2-dihydropyridinyl, thiomorpholinyl, and 1,1-dioxothiomorpholinyl, substituted with 3 are 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is selected from the group consisting of tetrahydropyran, oxetanyl, tetrahydrofuranyl, and tetrahydrothiopyranyl, substituted with 3 is tetrahydrothiopyranyl substituted with two oxo groups.

[0148] In some embodiments, R in formula (I) and its subembodiments 3 is a 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, and 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is selected from the group consisting of 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl and 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl, and 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is selected from the group consisting of 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, benzo[d][1,3]dioxol-4-yl, (3,4-dihydro-2H-1,4-benzoxazin-8-yl), [5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl] and 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl; and 0 to 4 R 3a is replaced by .

[0149] In some embodiments, R in formula (I) and its subembodiments 3 is a 6- to 10-membered bridged heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, and 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is selected from the group consisting of 2-azabicyclo[2.2.2]octane, quinuclidine, and 7-oxabicyclo[2.2.1]heptane; and 0 to 4 R 3a is replaced by .

[0150] In some embodiments, R in formula (I) and its subembodiments 3is a 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, and 0 to 4 R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is selected from the group consisting of 4-oxaspiro[2.4]heptane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane, and 2,7-diazaspiro[4.4]nonane; and 0 to 4 R 3a is replaced by .

[0151] In some embodiments, R in formula (I) and its subembodiments 3 is 0 to 2 R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is one R 3a In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is two R 3a In some embodiments, each R in formula (I) and subembodiments thereof is substituted with 3a is C 1-6 Alkyl;Halo;-X 3 -OC 1-6 Alkyl; C 1-6 Haloalkyl;C 1-6 Haloalkoxy;-X 3 -OH; -ONO; 4- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; and oxo. In some embodiments, each R in formula (I) and its subembodiments is selected from the group consisting of: -OH; -ONO; 4- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; and oxo. 3a is C 1-6 Alkyl, halo, -X 3 -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -X 3In some embodiments, each R in formula (I) and subembodiments thereof is selected from the group consisting of —OH and oxo. 3a is C 1-6 Alkyl, halo, -X 3 In some embodiments, each R in formula (I) and subembodiments thereof is selected from the group consisting of —OH and oxo. 3a is selected from the group consisting of methyl, —OH, and oxo. In some embodiments, at least one R in formula (I) and subembodiments thereof is 3a is selected from the group consisting of 4-6 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, and S as ring vertices, and oxo. In some embodiments, at least one R in Formula (I) and its subembodiments is 3a is selected from the group consisting of tetrahydropyranyl and oxetanyl.

[0152] In some embodiments, R in formula (I) and its subembodiments 3 is hydrogen.

[0153] In some embodiments, R in formula (I) and its subembodiments 3 is C 1-6 Alkyl or C 2-6 alkynyl, and 0 to 4 R 3b In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is selected from the group consisting of 2-propynyl, ethyl, methyl, 2,2-dimethylpropyl, isobutyl, isopropyl, and n-propyl, and 0 to 4 R 3b is replaced by .

[0154] In some embodiments, R in formula (I) and its subembodiments 3 is methyl, and 0 to 3 R 3b In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is methyl.

[0155] In some embodiments, R in formula (I) and its subembodiments 3 is C 1-6 Alkyl or C 2-6 alkynyl, and 0 to 3 R 3b In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is C 1-6 Alkyl or C 2-6 alkynyl, and 0 to 2 R 3b In some embodiments, R in formula (I) and subembodiments thereof is substituted with 3 is C 1-6 Alkyl or C 2-6 alkynyl, and one R 3b is replaced by .

[0156] In some embodiments, each R in formula (I) and subembodiments thereof 3b Ha, Halo, C 1-3 Haloalkyl, -OC 1-6 Alkyl, cyano, -OH and -CONR e R f In some embodiments, each R in formula (I) and subembodiments thereof is selected from the group consisting of: 3b Ha, halo, -OC 1-6 In some embodiments, each R in formula (I) and subembodiments thereof is selected from the group consisting of alkyl, cyano, and —OH. 3b is selected from the group consisting of fluoro, methoxy, cyano, and —OH. In some embodiments, each R in formula (I) and subembodiments thereof 3b -OC 1-6 In some embodiments, each R in formula (I) and subembodiments thereof is selected from the group consisting of alkyl, cyano, and —OH. 3b is selected from the group consisting of methoxy, cyano and —OH.

[0157] In some embodiments, each X in formula (I) and subembodiments thereof 3is a bond. In some embodiments, each X in formula (I) and subembodiments thereof 3 is C 1-4 In some embodiments, each X in formula (I) and subembodiments thereof is alkylene. 3 is C 1-2 In some embodiments, each X in formula (I) and subembodiments thereof is alkylene. 3 is methylene.

[0158] In some embodiments, each R in formula (I) and subembodiments thereof e and R f is hydrogen. In some embodiments, each R e is hydrogen, and each R in formula (I) and subembodiments thereof f is C 1-4 Alkyl or C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is haloalkyl. e and R f is C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is alkyl. e and R f is C 1-2 In some embodiments, each R in formula (I) and subembodiments thereof is alkyl. e and R f is methyl. In some embodiments, each R in formula (I) and subembodiments thereof e and R f is C 1-4 In some embodiments, each R in formula (I) and subembodiments thereof is haloalkyl. e and R f is C 1-2 It is haloalkyl.

[0159] Representative compounds of formula (I) are listed in Table 1 below.

[0160] [Table 1] TIFF2024522373000036.tif229170TIFF2024522373000037.tif225170TIFF20245223730 00038.tif232170TIFF2024522373000039.tif241170TIFF2024522373000040.tif138170

[0161] Further representative compounds of formula (I) are listed in Table 2 below.

[0162] [Table 2] TIFF2024522373000042.tif242166TIFF2024522373000043.tif240166TIFF2024522373000044.t if225167TIFF2024522373000045.tif245166TIFF2024522373000046.tif232166TIFF20245223730 00047.tif249166TIFF2024522373000048.tif245166TIFF2024522373000049.tif239165TIFF202 4522373000050.tif240165TIFF2024522373000051.tif237165TIFF2024522373000052.tif118166

[0163] Further representative compounds of formula (I) are listed in Table 3 below.

[0164] [Table 3] TIFF2024522373000054.tif246166TIFF2024522373000055.tif238166TIFF20245223730 00056.tif228166TIFF2024522373000057.tif246166TIFF2024522373000058.tif233166 TIFF2024522373000059.tif251166TIFF2024522373000060.tif250166TIFF20245223730 00061.tif240166TIFF2024522373000062.tif226165TIFF2024522373000063.tif240165 TIFF2024522373000064.tif249165TIFF2024522373000065.tif249168TIFF20245223730 00066.tif223165TIFF2024522373000067.tif225166TIFF2024522373000068.tif254167 TIFF2024522373000069.tif222166TIFF2024522373000070.tif239167TIFF20245223730 00071.tif242167TIFF2024522373000072.tif249166TIFF2024522373000073.tif162166

[0165] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Table 1, Table 2, or an Example.

[0166] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Table 1, Table 2, Table 3, or an Example.

[0167] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Table 1, Table 2, or Table 3.

[0168] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Table 1 or Table 2.

[0169] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Table 1.

[0170] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Table 2.

[0171] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Table 3.

[0172] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound selected from Examples 86, 87, 89, 90, 96, 97, 106, 108, 111, and 113.

[0173] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound selected from Examples 79-85, 88, 91-93, 100-105, 109, 112, 114-119, 122, 124-143, and 145-233.

[0174] The compounds disclosed herein can be prepared as described in the Examples section below. For compounds without detailed synthetic descriptions, it is understood that these compounds can be prepared according to the general procedures described herein.

[0175] Assay The ability of the compounds of the present disclosure to inhibit Pol theta can be measured as described in the biological assay below.

[0176] Pharmaceutical Composition The compounds of Formula (I) or subembodiments, or pharmaceutically acceptable salts thereof, provided herein may be in the form of compositions suitable for administration to a subject. Generally, such compositions are pharmaceutical compositions comprising a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is present in a therapeutically effective amount. The pharmaceutical compositions can be used in all of the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject to practice the therapeutic methods and uses described herein.

[0177] Pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration, exemplary routes of administration being described herein. Additionally, pharmaceutical compositions can be used in combination with other therapeutically effective agents or compounds described herein to treat the diseases, disorders, and conditions contemplated by the present disclosure.

[0178] Pharmaceutical compositions containing the active ingredient (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) may be in a form suitable for oral use, such as a tablet, capsule, troche, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup, solution, microbeads or elixir.

[0179] Tablets, capsules, etc. contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets, capsules, etc. These excipients may include diluents, granulating agents, disintegrating agents, binding agents, and lubricating agents.

[0180] Tablets, capsules, and the like suitable for oral administration may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action.

[0181] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium.

[0182] Aqueous suspensions contain the active materials in admixture with excipients suitable for their manufacture. Such excipients may include suspending agents, dispersing agents, and wetting agents. Aqueous suspensions may also contain one or more preservatives.

[0183] Oily suspensions may be formulated by suspending the active ingredient in oil. Suitable oils are known in the art. Oily suspensions may contain additives such as thickening agents or sweeteners.

[0184] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0185] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. Suitable emulsifying agents are known in the art.

[0186] Pharmaceutical compositions generally comprise a therapeutically effective amount of a compound of Formula (I) or a subembodiment thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants, preservatives, emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, detergents, buffers, vehicles, diluents, and / or adjuvants. Those skilled in the art will readily recognize the variety of excipients that can be used in the pharmaceutical compositions and dosage forms contemplated herein.

[0187] Depot injections, generally administered subcutaneously or intramuscularly, can also be used to release the compounds of Formula (I) or subembodiments disclosed herein or their pharmaceutically acceptable salts over a defined period of time. Depot injections are usually either solid-based or oil-based and generally contain at least one of the formulation components set forth herein. Those skilled in the art are familiar with the possible formulations and uses of depot injections.

[0188] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. The suspension may be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents as described herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, which are known in the art.

[0189] The compounds of Formula (I) or subembodiments or pharmaceutically acceptable salts thereof may also be administered in the form of suppositories for rectal administration or in the form of a spray for nasal or inhalation use. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are known in the art.

[0190] All of the compounds and pharmaceutical compositions provided herein can be used in all of the methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all of the methods for treating and / or preventing any of the diseases or disorders provided herein. Thus, the compounds and pharmaceutical compositions provided herein are intended for use as pharmaceuticals.

[0191] Route of administration The compounds of Formula (I) or subembodiments, or pharmaceutically acceptable salts thereof, and compositions containing them, can be administered in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intracerebral) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Depot injections, generally administered subcutaneously or intramuscularly, can also be used to administer the compounds of Formula (I) or subembodiments, or pharmaceutically acceptable salts thereof, over a predetermined period of time. Certain embodiments of the invention contemplate oral administration.

[0192] Combination therapy The present invention contemplates the use of a compound of Formula (I) or a subembodiment thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents often have different, complementary mechanisms of action. Such combination therapy can be particularly advantageous by allowing for a reduction in the dosage of one or more of the agents, thereby reducing or eliminating adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect against the underlying disease, disorder, or condition.

[0193] As used herein, "combination" is meant to include therapies that can be administered separately, e.g., that can be formulated separately for separate administration (e.g., that can be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a "co-formulation").

[0194] In certain embodiments, the compounds of Formula (I) or subembodiments or pharmaceutically acceptable salts thereof are administered or applied sequentially, e.g., when one agent is administered before one or more other agents. In other embodiments, the compounds of Formula (I) or subembodiments or pharmaceutically acceptable salts thereof are administered simultaneously, e.g., when two or more agents are administered simultaneously or near simultaneously. These two or more agents may be present in two or more separate formulations or may be combined in a single formulation (i.e., a combination formulation). Whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of this disclosure.

[0195] A compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, can be used in combination with at least one other (active) agent in any manner appropriate under the circumstances. In one embodiment, treatment with at least one active agent and at least one compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is maintained for a period of time. In another embodiment, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable), while treatment with the compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is maintained at a constant dosage regimen. In a further embodiment, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable), and treatment with the compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is reduced (e.g., to a lower dose, less frequent administration, or a shorter treatment regimen). In yet another embodiment, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable) and treatment with the compound of Formula (I) or any subembodiment or a pharmaceutically acceptable salt thereof is increased (e.g., to a higher dose, more frequent administration, or a longer treatment regimen). In yet another embodiment, treatment with at least one active agent is maintained and treatment with the compound of Formula (I) or any subembodiment or a pharmaceutically acceptable salt thereof is reduced or discontinued (e.g., to a lower dose, less frequent administration, or a shorter treatment regimen). In yet another embodiment, treatment with at least one active agent and treatment with the compound of Formula (I) or any subembodiment or a pharmaceutically acceptable salt thereof are reduced or discontinued (e.g., to a lower dose, less frequent administration, or a shorter treatment regimen).

[0196] The present disclosure provides methods for treating cancer using a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic or diagnostic agent.

[0197] In some embodiments, a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is administered in combination with at least one additional therapeutic agent, hi some embodiments, the additional therapeutic agent is a signal transduction inhibitor (STI) or a chemotherapeutic agent.

[0198] In certain embodiments, the present disclosure provides a method for treating cancer comprising administering a compound of Formula (I) or a subembodiment thereof as described herein in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic inhibition of tumor growth. As used herein, the term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. Agents involved in immune modulation can also be used in combination with one or more compounds of Formula (I) or subembodiments described herein, or pharmaceutically acceptable salts thereof, to inhibit tumor growth in cancer patients.

[0199] In certain embodiments, the present disclosure provides a method for treating cancer comprising administering a compound of Formula (I) or a subembodiment thereof as described herein, or a pharmaceutically acceptable salt thereof, in combination with a chemotherapeutic agent.

[0200] Chemotherapeutic agents also include antihormonal agents, such as antiestrogens, which act to regulate or inhibit hormone action on tumors. In certain embodiments, combination therapy includes the administration of hormones or related hormone agents.

[0201] The present disclosure also contemplates the use of a compound of Formula (I) or a subembodiment thereof as described herein in combination with an immune checkpoint inhibitor. The vast array of genetic and epigenetic alterations characteristic of all cancers provides a diverse set of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the ultimate magnitude (e.g., cytokine production level or proliferation level) and quality (e.g., the type of immune response generated, e.g., the pattern of cytokine production) of the response initiated by antigen recognition by the T cell receptor (TCR) are regulated by the balance of costimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for suppressing autoimmunity (i.e., maintaining self-tolerance) and for protecting tissues from damage when the immune system is responding to pathogenic infections. Expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism. Examples of immune checkpoint inhibitors include, but are not limited to, CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ, CD73, CD39, A2AR, A2BR, IDO1, TDO2, arginase, B7-H3, and B7-H4. Cell-based modulators of anti-cancer immunity are also contemplated. Examples of such modulators include, but are not limited to, chimeric antigen receptor T cells, tumor-infiltrating T cells, and dendritic cells.

[0202] The present disclosure includes pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0203] Administration A compound of Formula (I) or a subembodiment thereof provided herein, or a pharmaceutically acceptable salt thereof, can be administered to a subject in an amount that depends, for example, on the purpose of administration (e.g., the desired degree of relief); the age, weight, sex, health, and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, disorder, condition, or symptoms thereof. The dosing regimen can also take into account the existence, nature, and extent of any side effects associated with the administered agent. Effective dosages and dosing regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0204] In general, dosing parameters dictate that the dose is less than the amount that would be irreversibly toxic to the subject (maximum tolerated dose (MTD)) and greater than or equal to the amount required to produce a measurable effect in the subject, which will be determined by, for example, pharmacokinetic and pharmacodynamic parameters relevant to ADME, taking into account the route of administration and other factors.

[0205] The effective dose (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect in a percentage of subjects taking the drug. 50 ED is the dose or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which it is administered. 50 The effective dose is generally used as a measure of the reasonable expectation of a drug's effect, but is not necessarily the dose that a clinician would consider appropriate considering all relevant factors. Therefore, in some situations, the effective dose may be calculated as the ED 50 In other situations, the effective dose is calculated as ED 50 In other situations, the effective dose is less than the calculated ED 50 is the same as

[0206] Furthermore, an effective amount of a compound of Formula (I) or a subembodiment thereof as provided herein, or a pharmaceutically acceptable salt thereof, can be an amount that, when administered in one or more doses to a subject, produces a desired result compared to a healthy subject. For example, in a subject suffering from a particular disorder, an effective amount can be one that improves a diagnostic parameter, measurement, marker, etc. of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measurement, marker, etc. exhibited by a normal subject.

[0207] In certain embodiments, a compound of Formula (I) or a subembodiment disclosed herein, or a pharmaceutically acceptable salt thereof, may be administered (e.g., orally) at a dosage level of from about 0.01 mg / kg to about 50 mg / kg, or from about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day to achieve the desired therapeutic effect.

[0208] For oral pharmaceutical administration, the compositions may be provided in the form of tablets, capsules, and the like containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient.

[0209] In certain embodiments, the dose of a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, is contained in a "unit dosage form." The phrase "unit dosage form" refers to a physically discrete unit, each unit containing a predetermined amount of a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents, sufficient to produce a desired effect. It will be recognized that the parameters of the unit dosage form will depend on the particular agent and the effect to be achieved.

[0210] kit The present invention also contemplates kits comprising a compound of Formula (I) or a subembodiment, or a pharmaceutically acceptable salt thereof. The kits are generally in the form of a physical structure housing various components, as described below, that can be utilized, for example, in practicing the methods described above.

[0211] The kits can include one or more of the compounds of Formula (I) or subembodiments disclosed herein, or pharmaceutically acceptable salts thereof, which may be in the form of pharmaceutical compositions suitable for administration to a subject (e.g., provided in a sterile container). The compounds of Formula (I) or subembodiments, or pharmaceutically acceptable salts thereof, can be provided in a ready-to-use form (e.g., tablet or capsule) or in a form that requires, for example, reconstitution or dilution before administration (e.g., powder). When the compounds of Formula (I) or subembodiments, or pharmaceutically acceptable salts thereof, are in a form that requires reconstitution or dilution by the user, the kits can also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., packaged together or separately from the compounds of Formula (I) or subembodiments, or pharmaceutically acceptable salts thereof. When combination therapy is contemplated, the kits can include several agents separately, or they can be already combined in the kit. Each component of the kit can be enclosed in an individual container, or the various containers can all be in a single package. The kits of the present invention can be designed for the conditions (eg, refrigeration or freezing) required to properly maintain the components contained therein.

[0212] The kit may include a label or package insert containing identification and instructions for use of the components therein (e.g., administration parameters, mechanism of action, clinical pharmacology of the active ingredients including pharmacokinetics and pharmacodynamics, side effects, contraindications, etc.). The label or insert may also include manufacturer information such as lot number and expiration date. The label or insert may, for example, be integral to the physical structure that contains the component, may be contained separately within the physical structure, or may be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0213] The label or package insert may further comprise or be incorporated into a computer-readable medium such as a disk (e.g., hard disk, card, memory disk), optical disk (CD- or DVD-ROM / RAM, DVD, MP3, etc.), magnetic tape or electronic recording media (RAM and ROM, etc.), or a hybrid thereof (magnetic / optical storage media, FLASH media, or memory-type cards, etc.). In some embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, for example, via the internet. [Example]

[0214] The following examples and reference examples (intermediates) are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments have been performed or that they are all that may be performed. Exemplary descriptions written in the present tense should be understood as not necessarily performed, but rather, that the descriptions may be performed to generate data of the nature described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0215] Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (°C), and pressure is at or near atmospheric. Standard abbreviations are used, including: THF = tetrahydrofuran; DIEA = diisopropylethylamine; EtOAc = ethyl acetate; NMP = N-methylpyridine; TFA = trifluoroacetic acid; DCM = dichloromethane; Cs2CO3 = cesium carbonate; XPhos Pd G3 = 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2-(2'-amino-1,1'-biphenyl))palladium-(II) methanesulfonate; LiCl = lithium chloride; POCl3 = phosphoryl chloride; PE = petroleum ether; DMSO = dimethyl sulfoxide; HCl = hydrochloric acid; Na2SO4 = sodium sulfate; DMF = dimethylformamide; NaOH = sodium hydroxide; K2CO3 = potassium carbonate; MeCN = acetonitrile; BOC = tert-butoxycarbonyl; MTBE = methyl tert-butyl ether; MeOH = methanol; NaHCO3 = sodium bicarbonate; NaBH3CN = sodium cyanoborohydride; EtOH = ethanol; PCl5 = phosphorus pentachloride; NH4 OAc = ammonium acetate; Et2O = ether; HOAc = acetic acid; Ac2O = acetic anhydride; i-PrOH = isopropanol; NCS = N-chlorosuccinimide; K3PO4 = potassium phosphate; Pd(dtbpf)Cl2 = 1,1'-bis(di-tert-butylphosphino)ferrocene)dichloro-palladium(II); Zn(CN)2 = zinc cyanide; Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0); Et3N = triethylamine; CuCN = copper cyanide; t-BuONO = tert-butyl nitrite; HATU = 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide hexafluorophosphate; DBU = 1,8-diazabicyclo(5.4).0) Undec-7-ene; LiAlH4 = lithium aluminum hydride; NH3 = ammonia; H2SO4 = sulfuric acid; H2O2 = hydrogen peroxide; EDCI = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HOBT = 1-hydroxybenzotriazole hydrate; DHP = dihydropyran; TsOH = p-toluenesulfonic acid; FA = formic acid; TCFH = N,N,N,N'-tetramethylchloroformamidium hexafluorophosphate; NMI = N-methylimidazole; Pd(dppf)Cl2 = (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II); Pd(dppf)Cl2-DCM = (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II), dichloromethane complex.

[0216] If the absolute or relative stereochemistry of one or more examples has not been determined, this will be indicated in the text of the example. The reported characteristics and compound listings in these examples have been assigned any absolute stereochemistry. It is understood that routine methods well within the skill of one in the art will enable one to ascertain the absolute stereochemistry of each relevant example disclosed herein.

[0217] Synthesis Example Intermediate A 3-(2-Methoxyphenyl)pyridine-4-carboxylic acid

[0218] [ka]

[0219] To a solution of 3-bromopyridine-4-carboxylic acid (2.0 g, 9.9 mmol) in dioxane (10 mL) and water (10 mL) at room temperature under nitrogen, 2-methoxyphenylboronic acid (2.3 g, 14.9 mmol), NaCO (1.1 g, 9.9 mmol), and Pd(PPh) (1.1 g, 0.99 mmol) were added. The mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2 times). The aqueous layer was acidified to pH 6 with HCl (1 M). A solid formed, and the mixture was filtered to give 3-(2-methoxyphenyl)pyridine-4-carboxylic acid as a white solid, which was used in the next step without further purification.

[0220] Intermediate B 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine

[0221] [ka]

[0222] Step 1 Preparation of (5-chloropyridin-2-yl)methanol [ka]

[0223] To a solution of methyl 5-chloropicolinate (95 g, 554 mmol) in MeOH (950 mL) was added NaBH (42.0 g, 1.11 mol) in small portions at 0 °C. The mixture was then stirred at room temperature for 2 h. The mixture was poured into H O. The mixture was cooled to 0 °C, and 6 N HCl was added until the pH of the solution reached 1-2. The temperature of the solution reached 0-10 °C. The mixture was then concentrated under reduced pressure to remove MeOH. 6 N NaOH was added until the pH of the solution reached 8-10. The mixture was extracted with EtOAc (3 times). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound (158 g) as a yellow oil, which was used in the next step without further purification.

[0224] Step 2 Preparation of 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine

[0225] [ka]

[0226] To a solution of NaH (65.7 g, 1.64 mol, 60.0% purity) in THF (1.20 L) was added dropwise a solution of (5-chloropyridin-2-yl)methanol (158 g, 1.10 mol) in THF (400 mL) at 5° C. The mixture was stirred at 5° C. for 1 h. Then, 2-amino-5-bromo-1,3,4-thiadiazole (237 g, 1.31 mol) was added in portions at 5° C. The mixture was stirred at 5° C. for 4 h. The mixture was poured into H2O and extracted with EtOAc (4 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was diluted with MeOH, and the slurry was stirred at 25° C. for 0.5 h. The solid was collected and diluted with MeOH. The slurry was stirred at 80° C. for 2 h. The solid was collected to give 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (57.6 g, 21% yield) as a grey solid.

[0227] Intermediate C 4-(2-Methoxyphenyl)-6-methylnicotinic acid

[0228] [ka]

[0229] Step 1: Methyl 4-chloro-6-methylnicotinate [ka]

[0230] To a stirred solution of 4-chloro-6-methylnicotinic acid (5.0 g, 29.1 mmol) in dichloromethane (100 mL) was added methanol (10 mL) and (diazomethyl)trimethylsilane (29 mL, 58.3 mmol) dropwise at 0 °C. The resulting solution was stirred at room temperature for 16 h. The organic solvent was removed under vacuum. The resulting residue was dissolved in dichloromethane (5 mL) and purified by Combi Flash (Biotage Isolera Prime) on an 80.0 g silica gel column eluted with 0–50% ethyl acetate in petroleum ether within 30 min to give methyl 4-chloro-6-methylnicotinate (4.5 g, 81% yield) as a yellow oil. MS (ESI) calculation for (C8H8ClNO2) (M+1) + , 186.0; found 186.0.

[0231] Step 2: Methyl 4-(2-methoxyphenyl)-6-methylnicotinate

[0232] [ka]

[0233] To a stirred solution of methyl 4-chloro-6-methylnicotinate (500.0 mg, 2.69 mmol) and 2-methoxyphenylboronic acid (819.0 mg, 5.39 mmol) in 1,4-dioxane (1 mL) at 23 °C, water (0.2 mL), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (591.0 mg, 0.81 mmol), and potassium carbonate (1.1 g, 8.08 mmol) were added sequentially. The resulting solution was stirred at 80 °C for 2 hours under nitrogen. The combined organic layers were diluted with ethyl acetate, and the suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (5 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0 to 35% ethyl acetate in petroleum ether within 30 min to give methyl 4-(2-methoxyphenyl)-6-methylnicotinate (700.0 mg, 98%) as a yellow oil. MS (ESI) calculations for (C 15 H 15 NO3) (M+1) + , 258.1; found 258.0.

[0234] Step 3: 4-(2-methoxyphenyl)-6-methylnicotinic acid

[0235] [ka]

[0236] To a stirred solution of methyl 4-(2-methoxyphenyl)-6-methylnicotinate (400.0 mg, 1.56 mmol) in methanol (3 mL) at 23° C., water (3 mL) and sodium hydroxide (249.0 mg, 6.22 mmol) were added. The resulting solution was stirred at 23° C. for 2 hours. The organic solvent was removed under vacuum. The aqueous layer was acidified with citric acid solution to pH 6 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-methoxyphenyl)-6-methylnicotinic acid (342.0 mg, crude) as a yellow oil. MS (ESI) calculation for (C 14 H 13 NO3) (M+1) + , 244.1; found 244.0.

[0237] Intermediate D 4-(2-(difluoromethoxy)-6-fluorophenyl)-6-methylnicotinic acid

[0238] [ka]

[0239] Step 1 2-Bromo-1-(difluoromethoxy)-3-fluorobenzene

[0240] [ka]

[0241] To a stirred solution of 2-bromo-3-fluorophenol (25.00 g, 130.89 mmol) in DMF (100.00 mL) and HO (10 mL) was added sodium 2-chloro-2,2-difluoroacetate (16.95 g, 130.89 mmol) in portions at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0-10% ethyl acetate in petroleum ether to give 2-bromo-1-(difluoromethoxy)-3-fluorobenzene (12.2 g, 34.8%) as a white oil. MS (ESI) calculation for (C7H4BrF3O) (M+1) + , 240.9; found 241.0.

[0242] Step 2: 2-(2-(difluoromethoxy)-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0243] [ka]

[0244] To a degassed solution of 2-bromo-1-(difluoromethoxy)-3-fluorobenzene (3.00 g, 12.44 mmol) in dioxane (15.00 mL) was added Pd(dppf)Cl (0.91 g, 1.245 mmol), B2Pin (6.30 g, 24.89 mmol), and KOAc (2.44 g, 24.89 mmol). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The solvent was removed in vacuo, and the residue was purified by flash column chromatography using 0–10% ethyl acetate in petroleum ether to give 2-(2-(difluoromethoxy)-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 g, 46.01%) as a green solid.

[0245] Step 3: Methyl 4-(2-(difluoromethoxy)-6-fluorophenyl)-6-methylpyridine-3-carboxylate

[0246] [ka]

[0247] To a degassed solution of 2-(2-(difluoromethoxy)-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.00 g, 10.41 mmol) in dioxane (15.00 mL) and water (3 mL) was added methyl 4-chloro-6-methylpyridine-3-carboxylate (1.93 g, 10.39 mmol), K2CO3 (4.32 g, 31.25 mmol), and Pd(dppf)Cl2 (762.00 mg, 1.041 mmol). The resulting mixture was stirred at 80 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0-50% ethyl acetate in petroleum ether to give methyl 4-(2-(difluoromethoxy)-6-fluorophenyl)-6-methylpyridine-3-carboxylate (700 mg, 19%) as a yellow solid. MS (ESI) calculations for (C 15 H 12 F3NO3) (M+1) + , 312.1; found 312.0.

[0248] Step 4 4-(2-(difluoromethoxy)-6-fluorophenyl)-6-methylpyridine-3-carboxylic acid

[0249] [ka]

[0250] To a stirred solution of methyl 4-(2-(difluoromethoxy)-6-fluorophenyl)-6-methylpyridine-3-carboxylate (470.00 mg, 1.51 mmol) in THF (3.00 mL) and water (3 mL) was added LiOH.HO (253.68 mg, 6.040 mmol). The resulting mixture was stirred at room temperature for 16 hours. The organic solvent was removed in vacuo and then diluted with water. The solution was acidified to pH 6 with HCl (1N). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-(difluoromethoxy)-6-fluorophenyl)-6-methylpyridine-3-carboxylic acid (370 mg, 82.4%) as a white solid. MS (ESI) calculation for (C 14 H 10 F3NO3) (M+1) + , 298.1; found 298.0.

[0251] Intermediate E 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0252] [ka]

[0253] The title compound was prepared according to the procedure of Intermediate C, steps 2 and 3, using methyl 3-bromoisonicotinate and 2-fluoro-6-methoxyphenylboronic acid to afford 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid as a white solid, which was used without further purification.

[0254] Intermediate F 5'-Methoxy-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid

[0255] [ka]

[0256] Step 1: Benzyl 4-chloro-6-methylnicotinate

[0257] [ka]

[0258] To a mixture of 4-chloro-6-methylpyridine-3-carboxylic acid (10.00 g, 58.3 mmol) and CsCO (37.98 g, 116.6 mmol) in DMF (100 mL) was added benzyl bromide (14.95 g, 87.45 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 0-30% ethyl acetate in petroleum ether to give benzyl 4-chloro-6-methylnicotinate (12.94 g, 84.8%) as a yellow oil. MS (ESI) calculations for (C 14 H 12 ClNO2) (M+1) + , 262.0, found 262.1.

[0259] Step 2: Benzyl 2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate

[0260] [ka]

[0261] To a degassed mixture of methylbenzyl 4-chloro-6-methylpyridine-3-carboxylate (6.00 g, 22.926 mmol) and 2-chloro-5-methoxypyridin-4-ylboronic acid (4.30 g, 22.926 mmol) in 1,4-dioxane (50 mL) and HO (5 mL) was added KCO (9.51 g, 0.069 mmol) and Pd(DtBPF)Cl (1.49 g, 2.29 mmol). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 0-50% ethyl acetate in petroleum ether to give benzyl 2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (4 g, 47.3%) as a yellow oil. MS (ESI) calculations for (C 20 H 17 ClN2O3) (M+1) + , 369.1, found 369.0.

[0262] Step 3: Benzyl 5'-methoxy-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate

[0263] [ka]

[0264] To a degassed mixture of benzyl 2-chloro-5-methoxy-6-methyl-(4,4-bipyridine)-3-carboxylate (4.00 g, 10.845 mmol) and K2CO3 (4.50 g, 33.0 mmol) in DME (30 mL) was added Pd(dppf)Cl2 (0.79 g, 1.0 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborinane (1.50 g, 12.0 mmol). The resulting mixture was stirred at 120 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using 5-70% acetonitrile in water to give benzyl 5'-methoxy-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate (2.8 g, 74.1%) as a yellow oil. MS (ESI) calculations for (C 21 H 20 N2O3) (M+1) + , 349.1, found 349.0.

[0265] Step 4: 5'-Methoxy-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid

[0266] [ka]

[0267] To a mixture of benzyl 5'-methoxy-2',6-dimethyl-(4,4-bipyridine)-3-carboxylate (2.80 g, 8.037 mmol) in THF (20.00 mL) was added Pd / C (2.80 g, 10%). The resulting mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give 5'-methoxy-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid (2.5 g, crude) as a yellow solid, which was used directly in the next step without further purification. MS (ESI) calculation for (C 14 H 14 N2O3) (M+1) +, 259.1, found 259.0.

[0268] intermediate G 2-chloro-5-methoxy-6-methyl-(4,4-bipyridine)-3-carboxylic acid

[0269] [ka]

[0270] Step 1 2-chloro-5-methoxypyridin-4-ylboronic acid [ka]

[0271] To a stirred solution of 2-chloro-5-methoxypyridine (10.0 g, 69.65 mmol) in THF (500 mL) was added dropwise LDA (14.9 g, 139.30 mmol) at -78 °C under a N atmosphere. The resulting mixture was stirred at -78 °C for 2 hours. Next, triisopropyl borate (26.2 g, 139.30 mmol) was added to the above mixture at -78 °C. The resulting mixture was stirred at -78 °C for 2 hours. The resulting mixture was then stirred at room temperature for 16 hours. The resulting mixture was quenched with HCl (2N) and stirred at room temperature for 30 minutes. The resulting mixture was extracted with ethyl acetate. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 2-Chloro-5-methoxypyridin-4-ylboronic acid (9 g, 68.9%) was obtained as a brown solid. MS (ESI) calc'd for (C6H7BClNO3) (M+1) + , 188.0; found 188.0.

[0272] Step 2: 2-chloro-5-methoxy-6-methyl-(4,4-bipyridine)-3-carboxylate methyl

[0273] [ka]

[0274] To a degassed solution of methyl 4-chloro-6-methylpyridine-3-carboxylate (700 mg, 3.77 mmol) and 2-chloro-5-methoxypyridin-4-ylboronic acid (918 mg, 4.90 mmol) in dioxane (6 mL) and HO (2 mL) under a nitrogen atmosphere, Pd(dppf)Cl (275 mg, 0.37 mmol) and KCO (1563 mg, 11.31 mmol) were added. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using 0-60% ethyl acetate in petroleum ether to give methyl 2-chloro-5-methoxy-6-methyl-(4,4-bipyridine)-3-carboxylate (220 mg, 19.9%) as a white solid. MS (ESI) calculations for (C 14 H 13 ClN2O3) (M+1) + , 293.1; found 293.1.

[0275] Step 3: 2-chloro-5-methoxy-6-methyl-(4,4-bipyridine)-3-carboxylic acid

[0276] [ka]

[0277] To a stirred solution of methyl 2-chloro-5-methoxy-6-methyl-(4,4-bipyridine)-3-carboxylate (220 mg, 0.75 mmol) in THF (2 mL) and water (2 mL) was added LiOH.HO (126 mg, 3.01 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 3 with citric acid. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-chloro-5-methoxy-6-methyl-(4,4-bipyridine)-3-carboxylic acid (160 mg, 76.3%) as a white solid. MS (ESI) calculation for (C13 H 11 ClN2O3) (M+1) + , 279.0; found, 279.0.

[0278] Example 1 3-(2-Methoxyphenyl)-N-(5-(prop-2-yn-1-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide

[0279] [ka]

[0280] Step 1: O-(prop-2-yn-1-yl)carbonodithioic acid S-methyl ester [ka]

[0281] To a stirred solution of propargyl alcohol (15.00 g, 267.551 mmol, 1.00 equiv) in THF (200 mL) was added NaH (12.84 g, 321.062 mmol, 1.20 equiv, 60%) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under a nitrogen atmosphere. To the above mixture was added CS (24.45 g, 0.321 mmol, 1.2 equiv) dropwise at 0 °C. The resulting mixture was stirred for an additional 10 min at 0 °C, after which MeI (45.57 g, 0.321 mmol, 1.2 equiv) was added. The resulting mixture was stirred for 10 min at 0 °C. The reaction was quenched by adding 100 mL of NH Cl (aq) at room temperature. The aqueous layer was extracted with EtOAc (2 × 2 100 mL). The residue was purified by silica gel column chromatography eluting with PE / EA (20:1) to give (methylsulfanyl)(prop-2-yn-1-yloxy)methanethione as a brown oil.

[0282] Step 2 Hydrazinecarbothioic acid O-(prop-2-yn-1-yl)

[0283] [ka]

[0284] To a stirred solution / mixture of (methylsulfanyl)(prop-2-yn-1-yloxy)methanethione (25.00 g, 170.975 mmol, 1.00 equiv) in MeOH at 0° C. under a nitrogen atmosphere, (methylsulfanyl)(prop-2-yn-1-yloxy)methanethione (25.00 g, 170.975 mmol, 1.00 equiv) was added dropwise. The resulting mixture was stirred for 30 minutes at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. This afforded (((prop-2-yn-1-yloxy)methanethioyl)amino)amine (23 g, 95.08%) as a brown oil.

[0285] Step 3: 5-(prop-2-yn-1-yloxy)-1,3,4-thiadiazol-2-amine

[0286] [ka]

[0287] To a stirred solution of (((prop-2-yn-1-yloxy)methanethioyl)amino)amine (23.00 g, 176.692 mmol, 1.00 equiv) and TEA (35.76 g, 353.384 mmol, 2 equiv) in MeOH at 0 °C under a nitrogen atmosphere, BrCN (22.46 g, 212.030 mmol, 1.2 equiv) was added in small portions. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was precipitated by the addition of EtOAc. This gave 5-(prop-2-yn-1-yloxy)-1,3,4-thiadiazol-2-amine (7.8 g, 26.46%) as an off-white solid.

[0288] Step 4 3-(2-methoxyphenyl)-N-(5-(prop-2-yn-1-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide

[0289] [ka]

[0290] To a stirred solution of Intermediate A (5.00 g, 0.22 mmol, 1.00 equiv) and DIEA (8.45 g, 0.65 mmol, 3.00 equiv) in DMF (150 mL) at room temperature under a nitrogen atmosphere was added HATU (9.94 mg, 0.26 mmol, 1.20 equiv). The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added 5-(prop-2-yn-1-yloxy)-1,3,4-thiadiazol-2-amine (3.38 g, 0.22 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for an additional 2 h at room temperature. The resulting mixture was diluted with water (450 mL). The aqueous layer was extracted with EtOAc (3 × 200 mL). The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (40:1). The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 20 min; detector, UV 254 nm to give 3-(2-methoxyphenyl)-N-(5-(prop-2-yn-1-yloxy)-1,3,4-thiadiazol-2-yl)isonicotinamide (5.01 g, 61.84%) as an orange solid. LC-MS: m / z 367 (M+H) + ; H-NMR: 1 H NMR (300 MHz, methanol-d4) δ 8.68–8.67 (d, 1H), 8.60 (s, 1H), 7.65–7.64 (d, 1H), 7.42–7.36 (m, 2H), 7.11–7.08 (m, 1H), 6.99–6.96 (d, 1H), 5.09 (s, 2H), 3.60 (s, 3H), 3.11 (s, 1H) ppm.

[0291] Example 2 4-(2-fluoro-6-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide

[0292] [ka]

[0293] To a mixture of 5-methoxy-1,3,4-thiadiazol-2-amine (33.1 mg, 0.25 mmol) in acetonitrile (2 mL) was added Intermediate E (55.0 mg, 0.21 mmol) and NMI (36.3 mg, 0.44 mmol). To this was added a solution of TCFH (64.9 mg, 0.23 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The mixture was stirred at 20 °C for 2 hours under nitrogen. The mixture was concentrated in vacuo. The residue was dissolved in DMF (1 mL) and purified by Combi Flash (Biotage Isolera Prime) on a 20 g C18 column eluted with 5-60% acetonitrile in water to give 5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide (47.1 mg, 58%) as a white solid. MS (ESI) calculations for (C 17 H 15 FN4O3S) (M+1) + , 375.1, found 375.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.80 (s, 1H), 7.40 - 7.36 (m, 1H), 7.34 - 7.28 (m, 1H), 6.95 - 6.86 (m, 2H), 4.06 (s, 3H), 3.58 (s, 3H), 2.56 (s, 3H).

[0294] Example 3 4-(2-fluoro-6-methoxyphenyl)-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0295] [ka]

[0296] Step 1 N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0297] [ka]

[0298] To a mixture of Intermediate B (111.4 mg, 0.46 mmol) in acetonitrile (2 mL) was added Intermediate E (100.0 mg, 0.38 mmol) and NMI (66.0 mg, 0.80 mmol). To this was added a solution of TCFH (118.1 mg, 0.42 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The mixture was stirred at 20° C. for 2 hours under nitrogen. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (3 mL) and purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g C18 column and eluted with 15–60% acetonitrile in water within 30 min to give N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (170.0 mg, 91%) as a white solid. MS (ESI) calculations for (C 22 H 17 ClFN5O3S) (M+1) + , 486.1, found 486.0.

[0299] Step 2: 4-(2-fluoro-6-methoxyphenyl)-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0300] [ka]

[0301] A mixture of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylpyridine-3-carboxamide (170.0 mg, 0.35 mmol) in concentrated HCl (3 mL) was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was basified with NH3·H2O to pH 9-10. The aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC using the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10B to 40B in 8 min; 220 nm; RT: 7.23 min) to give 4-(2-fluoro-6-methoxyphenyl)-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (56.4 mg, 44%) as a white solid. MS (ESI) calculations for (C 16 H 13 FN4O3S) (M+1) + , 361.1, found 361.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 2H), 8.75 (s, 1H), 7.46 - 7.32 (m, 1H), 7.30 (s, 1H), 6.95 - 6.82 (t, J = 8.0 Hz, 2H), 3.64 (s, 3H), 2.55 (s, 3H).

[0302] Example 4 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1,3,4-thiadiazol-2-yl)pyridine-3-carboxamide

[0303] [ka]

[0304] Step 1 (Methylsulfanyl)(3,3,3-trifluoro-2,2-dimethylpropoxy)methanethione [ka]

[0305] To a degassed solution of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (100.0 mg, 0.71 mmol) in dry tetrahydrofuran (3 mL) was added NaH (34.0 mg, 1.41 mmol, 60%) in portions at 0° C. and stirred at 0° C. for 1 hour under a nitrogen atmosphere. CS2 (81.0 mg, 1.00 mmol) was then added to the above mixture at 0° C. for 20 minutes. MeI (150.0 mg, 1.05 mmol) was then added to the above mixture at 0° C. for 30 minutes. The resulting mixture was then stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (2 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g C18 column and eluting with 5–45% acetonitrile in water within 30 min to give (methylsulfanyl)(3,3,3-trifluoro-2,2-dimethylpropoxy)methanethione (160.0 mg, 97%) as a white solid. MS (ESI) calculations for (CH 11 F3N2OS) (M+1) + , 234.0; found 234.0.

[0306] Step 2 (((3,3,3-trifluoro-2,2-dimethylpropoxy)methanethioyl)amino)amine

[0307] [ka]

[0308] To a stirred solution of (methylsulfanyl)(3,3,3-trifluoro-2,2-dimethylpropoxy)methanethione (160.0 mg, 0.70 mmol) in MeOH (3 mL) at 0 °C under a nitrogen atmosphere was added NHNH.H0 (34.0 mg, 0.70 mmol) dropwise. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to give (((3,3,3-trifluoro-2,2-dimethylpropoxy)methanethioyl)amino)amine (150.0 mg, crude) as a yellow oil. MS (ESI) calculation for (CH 11 F3N2OS) (M+1) + , 217.1; found 217.1.

[0309] Step 3: 5-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1,3,4-thiadiazol-2-amine

[0310] [ka]

[0311] To a stirred solution of (((3,3,3-trifluoro-2,2-dimethylpropoxy)methanethioyl)amino)amine (150.0 mg, 0.70 mmol) in MeOH (3 mL) at 0° C. under a nitrogen atmosphere was added TEA (140.0 mg, 1.39 mmol) and BrCN (81.0 mg, 0.76 mmol). The resulting mixture was stirred at 0° C. for 1 h under a nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1,3,4-thiadiazol-2-amine (140.0 mg, crude) as a pink solid. MS (ESI) calculation for (CH 10 F3N3OS) (M+1) + , 242.1; found 242.1.

[0312] Step 4 4-(2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1,3,4-thiadiazol-2-yl)pyridine-3-carboxamide

[0313] [ka]

[0314] To a stirred solution of 5-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1,3,4-thiadiazol-2-amine (50.0 mg, 0.21 mmol) and Intermediate E (54.0 mg, 0.21 mmol) in DMF (1 mL) was added NMI (68.0 mg, 0.83 mmol) and TCFH (87.0 mg, 0.31 mmol) under a nitrogen atmosphere at 25° C. The mixture was stirred at 25° C. for 1 hour under a nitrogen atmosphere. The resulting mixture was purified by prep-HPLC using the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 42% B to 57% B in 8 min, UV: 254 nm) to give 4-(2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1,3,4-thiadiazol-2-yl)pyridine-3-carboxamide (23.2 mg, 23%) as a white solid. MS (ESI) calculations for (C 21 H 20 F4N4O3S) (M+1) + , 485.1; found, 485.3. 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.83 (s, 1H), 7.42 - 7.37 (m, 1H), 7.31 (d, J = 1.6 Hz, 1H), 6.93 - 6.87 (m, 2H), 4.45 (s, 2H), 3.58 (s, 3H), 2.57 (s, 3H), 1.22 (s, 6H).

[0315] Example 5 2'-chloro-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0316] [ka]

[0317] To a mixture of Intermediate G (50.0 mg, 0.17 mmol) in MeCN (1 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (28.2 mg, 0.21 mmol) and NMI (30.9 mg, 0.37 mmol). To this was added a solution of TCFH (55.3 mg, 0.19 mmol) in MeCN (1 mL) dropwise under nitrogen. The mixture was stirred at 20° C. for 2 hours under nitrogen. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (3 mL) and purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g C18 column and eluted with 10–60% acetonitrile in water within 30 min to give 2′-chloro-5′-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4′-bipyridine)-3-carboxamide (34.7 mg, 33%) as a white solid. MS (ESI) calculations for (C 16 H 14 ClN5O3S) (M+1) + , 392.0, found 392.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 4.08 (s, 3H), 3.63 (s, 3H), 2.59 (s, 3H).

[0318] Example 6 2'-chloro-N-(5-isopropoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0319] [ka]

[0320] Step 1 ((Isopropoxymethanethioyl)amino)amine

[0321] [ka]

[0322] A mixture of isopropoxy(potassiosulfanyl)methanethione (1.0 g, 5.73 mmol) and hydrazine (200.0 mg, 5.61 mmol) in MeOH (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give ((isopropoxymethanethioyl)amino)amine (800.0 mg, crude) as a yellow solid, which was used in the next step without further purification.

[0323] Step 2: 5-isopropoxy-1,3,4-thiadiazol-2-amine

[0324] [ka]

[0325] To a mixture of ((isopropoxymethanethioyl)amino)amine (400.0 mg, 2.98 mmol), TEA (603.2 mg, 5.96 mmol) in MeOH (20 mL) was added BrCN (173.6 mg, 1.63 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DMF (3 mL) and purified by Combi Flash (Biotage Isolera Prime) on a 40 g C18 column eluted with 15–90% acetonitrile in water within 30 min to give 5-isopropoxy-1,3,4-thiadiazol-2-amine (79.0 mg, 16%) as a white solid. MS (ESI) calculation for (C5H9N3OS) (M+1) + , 160.0, found 160.0 .

[0326] Step 3 2'-chloro-N-(5-isopropoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0327] [ka]

[0328] To a mixture of Intermediate G (80.0 mg, 0.28 mmol) in MeCN (3 mL) was added 5-isopropoxy-1,3,4-thiadiazol-2-amine (59.4 mg, 0.37 mmol) and NMI (49.4 mg, 0.60 mmol). To this was added a solution of TCFH (88.6 mg, 0.31 mmol) in MeCN (1 mL) dropwise under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (3 mL) and purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g C18 column and eluted with 15–65% acetonitrile in water within 30 min to give 2′-chloro-N-(5-isopropoxy-1,3,4-thiadiazol-2-yl)-5′-methoxy-6-methyl-(4,4′-bipyridine)-3-carboxamide (29.4 mg, 23%) as a white solid. MS (ESI) calculations for (C 18 H 18 ClN5O3S) (M+1) + , 420.0, found 420.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 5.17 - 5.05 (m, 1H), 3.63 (s, 3H), 2.58 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H).

[0329] Example 7 2'-chloro-N-(5-cyclopropoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0330] [ka]

[0331] Step 1 Cyclopropoxy(methylsulfanyl)methanethione

[0332] [ka]

[0333] To a mixture of cyclopropanol (1.0 g, 17.21 mmol) in THF (20 mL) was added NaH (1.4 g, 34.40 mmol, 60%) in small portions at 0° C. and stirred at 0° C. for 30 minutes. CS2 (1.9 g, 25.82 mmol) was added to the above mixture at 0° C. and stirred at 0° C. for 30 minutes. Next, MeI (3.7 g, 25.82 mmol) was added to the above mixture at 0° C. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo to give cyclopropoxy(methylsulfanyl)methanethione (2.0 g, crude) as a yellow oil.

[0334] Step 2: N-amino-1-cyclopropoxymethanethioamide

[0335] [ka]

[0336] To a mixture of cyclopropoxy(methylsulfanyl)methanethione (1.5 g, 10.11 mmol) in MeOH (10 mL) was added hydrazine (389.1 mg, 12.14 mmol). The mixture was stirred at 25° C. for 2 hours. The mixture was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo to give N-amino-1-cyclopropoxymethanethioamide (2.4 g, crude) as a yellow oil. MS (ESI) calculation for (C4H8N2OS) (M-1) + , 133.0, found 133.0.

[0337] Step 3: 5-cyclopropoxy-1,3,4-thiadiazol-2-amine

[0338] [ka]

[0339] To a mixture of N-amino-1-cyclopropoxymethanethioamide (1.5 g, 11.34 mmol), TEA (2.3 g, 22.69 mmol) in MeOH (10 mL) was added BrCN (1.3 g, 12.48 mmol), and the resulting solution was stirred at 25 °C for 30 min. The mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude material. The residue was dissolved in DMF (3 mL) and purified by Combi Flash (Biotage Isolera Prime) on a 40 g C18 column eluted with 15–90% acetonitrile in water within 30 min to give 5-cyclopropoxy-1,3,4-thiadiazol-2-amine (400.0 mg, 22% over three steps) as a yellow solid. MS (ESI) calculation for (C5H7N3OS) (M+1) + , 158.0, found 158.0.

[0340] Step 4 2'-chloro-N-(5-cyclopropoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0341] [ka]

[0342] To a mixture of Intermediate G (100.0 mg, 0.35 mmol) in DMF (5 mL) was added 5-cyclopropoxy-1,3,4-thiadiazol-2-amine (84.6 mg, 0.53 mmol), HATU (204.6 mg, 0.53 mmol), and DIEA (139.1 mg, 1.07 mmol), and the resulting solution was stirred at 25° C. for 2 h. The resulting mixture was purified by prep-HPLC using the following conditions: (Column: YMC-Actus Triart C18 ExRS, 30 mm × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 40% B in 8 min, 40% B to 95% B in 9 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 10 min; Wavelength: 254 nm; RT (min): 7.80) to give 2'-chloro-N-(5-cyclopropoxy-1,3,4-thiadiazol-2-yl)-5-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (54.6 mg, 36%) as a white solid. MS (ESI) calculations for (C 18 H 16 ClN5O3S) (M+1) + , 418.0, found 418.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.83 (s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 4.39 - 4.29 (m, 1H), 3.64 (s, 3H), 2.59 (s, 3H), 0.91 - 0.77 (m, 4H).

[0343] Example 8 5'-Methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxamide

[0344] [ka]

[0345] To a mixture of 5-methoxy-1,3,4-thiadiazol-2-amine (60.9 mg, 0.46 mmol) in DMF (1 mL) and acetonitrile (1 mL) was added Intermediate F (100.0 mg, 0.38 mmol) and NMI (95.0 mg, 1.16 mmol). To this was added a solution of TCFH (163.0 mg, 0.58 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The mixture was stirred at 20° C. for 2 hours under nitrogen. The resulting solution was purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g C18 column and eluting with 5–30% acetonitrile in water within 30 min to give 5′-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2′,6-dimethyl-(4,4′-bipyridine)-3-carboxamide (124.0 mg, 85%) as a white solid. MS (ESI) calculated for (C 17 H 17 N5O3S) (M+1) + , 372.1; found, 372.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1H), 7.36 (s, 1H), 7.26 (s, 1H), 4.08 (s, 3H), 3.58 (s, 3H), 2.59 (s, 3H), 2.48 (s, 3H).

[0346] Example 9 4-(5-chloro-2-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0347] [ka]

[0348] Step 1 4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxylate

[0349] [ka]

[0350] To a stirred solution of methyl 4-chloro-6-methylpyridine-3-carboxylate (600.0 mg, 3.23 mmol) and 5-chloro-2-methoxyphenylboronic acid (905.0 mg, 4.85 mmol) in dioxane (6 mL) was added water (2 mL) and Pd(PPh3)4 (375.0 mg, 0.32 mmol) and K2CO3 (1.3 g, 9.72 mmol). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere and then concentrated in vacuo. The crude residue was applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–50% acetonitrile in water within 45 min to give methyl 4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxylate (730.0 mg, 76%) as a yellow oil. MS (ESI) calculated for (C 15 H 14 ClNO3) (M+1) + , 292.1; found, 292.0.

[0351] Step 2: 4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid

[0352] [ka]

[0353] To a stirred solution of methyl 4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxylate (100.0 mg, 0.34 mmol) in tetrahydrofuran (1 mL) was added LiOH.HO (58.0 mg, 1.38 mmol) and water (0.3 mL). The resulting mixture was stirred at 25° C. for 1 hour. The residue was acidified to pH 7 with citric acid. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid (93.0 mg, crude) as a white solid. MS (ESI) calculated for (C 14 H 12 ClNO3) (M+1) + , 278.1; found, 278.1.

[0354] Step 3 4-(5-chloro-2-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0355] [ka]

[0356] To a mixture of 5-methoxy-1,3,4-thiadiazol-2-amine (57.0 mg, 0.43 mmol) in acetonitrile (3 mL) was added 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid (93.0 mg, 0.36 mmol) and NMI (89.0 mg, 1.08 mmol). To this was added a solution of TCFH (111.0 mg, 0.39 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The mixture was stirred at 20° C. for 2 hours under nitrogen. The reaction mixture was applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–40% acetonitrile in water within 45 min to give 4-(5-chloro-2-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (91.3 mg, 64%) as a white solid. MS (ESI) calculations for (C 17 H 15 ClN4O3S) (M+1) + , 391.0, found 391.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.70 (s, 1H), 7.48 - 7.40 (m, 2H), 7.35 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.07 (s, 3H), 3.50 (s, 3H), 2.57 (s, 3H).

[0357] Example 10 2'-chloro-N-(5-(2-cyano-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0358] [ka] Step 1 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)-2,2-dimethylpropanenitrile

[0359] [ka]

[0360] To a solution of NaH (303.0 mg, 7.57 mmol, 60%) in tetrahydrofuran (5 mL) at 0° C., a solution of 3-hydroxy-2,2-dimethylpropanenitrile (500.0 mg, 5.04 mmol) in tetrahydrofuran (2 mL) was added dropwise and stirred at 0° C. for 30 minutes. To the above solution was added 5-bromo-1,3,4-thiadiazol-2-amine (908.0 mg, 5.04 mmol) at 0° C. under nitrogen. The resulting solution was then stirred at 0° C. for 1.5 hours. The reaction mixture was quenched by the addition of water. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (5 mL), applied to an 80 g C18 column, and purified by Combi Flash eluting with 5 to 70% acetonitrile in water within 30 min to give 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)-2,2-dimethylpropanenitrile (50.0 mg, 5%) as a yellow solid. MS (ESI) calculations for (C7H 10 N4OS) (M+1)+, 199.1; found 199.2.

[0361] Step 2 2'-chloro-N-(5-(2-cyano-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0362] [ka]

[0363] To a solution of Intermediate G (70.0 mg, 0.25 mmol) and 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)-2,2-dimethylpropanenitrile (50.0 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL) was added DIEA (98 mg, 0.76 mmol) and HATU (142.5 mg, 0.37 mmol) at 20° C. The resulting solution was stirred at 80° C. under nitrogen for 2 hours. The resulting mixture was applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5-60% acetonitrile in water within 30 min to give 2'-chloro-N-(5-(2-cyano-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (51.6 mg, 43%) as a white solid. MS (ESI) calculations for (C 20 H 19 ClN6O3S) (M+1) + , 459.1; found, 459.0. 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 4.49 (s, 2H), 3.64 (s, 3H), 2.60 (s, 3H), 1.42 (s, 6H).

[0364] Example 11 2'-chloro-N-(5-cyclobutoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0365] [ka]

[0366] Step 1: 5-cyclobutoxy-1,3,4-thiadiazol-2-amine

[0367] [ka]

[0368] To a solution of NaH (416.0 mg, 10.40 mmol, 60%) in tetrahydrofuran (THF) (5 mL) was added dropwise cyclobutanol (500.0 mg, 6.93 mmol) at 0° C. The resulting solution was then stirred at 0° C. for 30 minutes under nitrogen. To the above solution was added 5-bromo-1,3,4-thiadiazol-2-amine (1.3 g, 6.93 mmol) at 0° C. under nitrogen. The resulting solution was then stirred at 0° C. for 1 hour. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL), applied to a 20 g silica gel column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 0 to 50% ethyl acetate in petroleum ether within 30 min to give 5-cyclobutoxy-1,3,4-thiadiazol-2-amine (140.0 mg, 12%) as a yellow solid. MS (ESI) calculation for (C6H9N3OS) (M+1) + ,172.1, found 172.1.

[0369] Step 2 2'-chloro-N-(5-cyclobutoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0370] [ka]

[0371] To a solution of Intermediate G (146.0 mg, 0.53 mmol) in acetonitrile (1 mL) was added 5-cyclobutoxy-1,3,4-thiadiazol-2-amine (90.0 mg, 0.53 mmol) and NMI (216.0 mg, 2.63 mmol). To the above was added TCFH (162.0 mg, 0.58 mmol) at 23° C. The resulting solution was stirred at 23° C. for 1 hour. This mixture was dissolved in DMF (1 mL), applied to a 20 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–50% acetonitrile in water within 30 min to give 2′-chloro-N-(5-cyclobutoxy-1,3,4-thiadiazol-2-yl)-5′-methoxy-6-methyl-(4,4′-bipyridine)-3-carboxamide (24.7 mg, 11%) as a white solid. MS (ESI) calculations for (C 19 H 18 ClN5O4S ) (M+1) + 432.1; found 432.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.53 - 7.34 (m, 2H), 5.22 - 5.16 (m, 1H), 3.63 (s, 3H), 2.59 (s, 3H), 2.59 - 2.18 (m, 4H), 1.77 - 1.85 (m, 1H), 1.71 - 1.53 (m, 1H).

[0372] Example 12 2'-chloro-N-(5-(cyclohexyloxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0373] [ka]

[0374] Step 1 Carbonodithioic acid O-cyclohexyl S-methyl

[0375] [ka]

[0376] To a degassed mixture of NaH (200.0 mg, 4.99 mmol, 60%) in tetrahydrofuran (6 mL) was added dropwise cyclohexanol (500.0 mg, 4.99 mmol) at 0° C. and stirred at 0° C. for 30 minutes. To the above solution was added dropwise CS2 (570.0 mg, 7.49 mmol) at 0° C. and stirred at 0° C. for 20 minutes. To the above solution was added dropwise MeI (1.1 g, 7.49 mmol) at 0° C. and stirred at 0° C. for 30 minutes. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (3 mL), applied to a 20 g silica gel column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 0–10% ethyl acetate in petroleum ether within 20 min to give O-cyclohexyl S-methyl carbonodithioate (400.0 mg, 42%) as a colorless oil. MS (ESI) calculations for (CH 14 OS) (M+1) + , 191.0; found, 191.1.

[0377] Step 2: O-Cyclohexyl hydrazinecarbothioate

[0378] [ka]

[0379] To a degassed solution of O-cyclohexyl S-methyl carbodithioate (400.0 mg, 2.10 mmol) in methanol (4 mL) at 0° C. under a nitrogen atmosphere was added hydrazine (126.1 mg, 3.15 mmol). The resulting solution was then stirred at 23° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give O-cyclohexyl hydrazinecarbothioate (320.1 mg, crude) as a white solid. MS (ESI) calculations for (CH 14 N2OS) (M+1) + , 175.1; found, 175.1.

[0380] Step 3: 5-(cyclohexyloxy)-1,3,4-thiadiazol-2-amine

[0381] [ka]

[0382] To a degassed solution of O-cyclohexyl hydrazinecarbothioate (320.0 mg, 1.84 mmol) in methanol (4 mL) at 23 °C under a nitrogen atmosphere, TEA (372.0 mg, 3.67 mmol) and BrCN (270.0 mg, 2.57 mmol) were added. The resulting solution was stirred at 23 °C under nitrogen for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was applied to a 20 g silica gel column and purified by Combi Flash (Biotage Isolera Prime) eluting with 0 to 30% ethyl acetate in petroleum ether within 25 min to give 5-(cyclohexyloxy)-1,3,4-thiadiazol-2-amine (220.0 mg, 57%) as a white solid. MS (ESI) calculations for (CH 13 N3OS) (M+1) + ,200.1, found 200.1.

[0383] Step 4 2'-chloro-N-(5-(cyclohexyloxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0384] [ka]

[0385] To a solution of Intermediate G (280.1 mg, 1.01 mmol) in N,N-dimethylformamide (2 mL) was added 5-(cyclohexyloxy)-1,3,4-thiadiazol-2-amine (200.0 mg, 1.01 mmol) and 1-methylimidazole (247.2 mg, 3.01 mmol). To the above was added a solution of TCFH (310.0 mg, 1.10 mmol) in acetonitrile (1 mL) at 23° C. The resulting solution was stirred under nitrogen at 23° C. for 2 hours. The mixture was diluted with DMF (2 mL) and applied to a 20 g C18 column. Purification was performed on a Combi Flash (Biotage Isolera Prime) column, eluting with 5–50% acetonitrile in water within 30 min, to give 2′-chloro-N-(5-(cyclohexyloxy)-1,3,4-thiadiazol-2-yl)-5′-methoxy-6-methyl-(4,4′-bipyridine)-3-carboxamide (240.1 mg, 52%) as a white solid. MS (ESI) calculations for (C 21 H 22 ClN5O3S) (M+1) + , 460.1, found 460.1. 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 4.94 - 4.83 (m, 1H), 3.63 (s, 3H), 2.59 (s, 3H), 2.10 - 1.99 (m, 2H), 1.75 - 1.67 (m, 2H), 1.56 - 1.49 (m, 3H), 1.45 - 1.23 (m, 3H).

[0386] Example 13 2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0387] [ka]

[0388] Step 1: 5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-amine

[0389] [ka]

[0390] To a degassed solution of NaH (405.2 mg, 10.12 mmol, 60%) in tetrahydrofuran (8 mL) at 0° C., oxetan-3-ol (500.1 mg, 6.75 mmol) was added and stirred at 0° C. for 30 minutes. To the above mixture, under nitrogen, was added 5-bromo-1,3,4-thiadiazol-2-amine (1.2 g, 6.75 mmol). The resulting solution was then stirred at 0° C. for 1 hour. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (1.5 mL), applied to a 40 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–20% acetonitrile in water within 20 min to give 5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-amine (112.2 mg, 9%) as a yellow solid. MS (ESI) calculation for (C5H7N3O2S) (M+1) + , 174.0; found 174.0.

[0391] Step 2 2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0392] [ka]

[0393] To a solution of 5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-amine (100.0 mg, 0.58 mmol) in N,N-dimethylformamide (1 mL) and acetonitrile (1 mL) was added Intermediate G (161.2 mg, 0.58 mmol) and 1-methylimidazole (142.2 mg, 1.73 mmol). To the above mixture was added a solution of TCFH (178.3 mg, 0.64 mmol) in acetonitrile (1 mL) at 23° C. The mixture was stirred under nitrogen at 23° C. for 2 hours. The resulting mixture was dissolved in DMF (2 mL) and applied to a 20 g C18 column. It was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5–40% acetonitrile in water within 30 min to give 2′-chloro-5′-methoxy-6-methyl-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-yl)-(4,4′-bipyridine)-3-carboxamide (65.3 mg, 25%) as a white solid. MS (ESI) calculations for (C 18 H 16 ClN5O4S) (M+1) + , 434.1; found, 434.0. 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 5.72 - 5.62 (m, 1H), 4.94 - 4.86 (m, 2H), 4.69 - 4.61 (m, 2H), 3.63 (s, 3H), 2.59 (s, 3H).

[0394] Example 14 2'-chloro-N-(5-(2-hydroxy-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0395] [ka]

[0396] Step 1: 2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)acetate methyl

[0397] [ka]

[0398] To a degassed solution of methyl 2-hydroxyacetate (3.0 g, 33.3 mmol) in tetrahydrofuran (30 mL) was added NaH (2.0 g, 50.0 mmol, 60%) in small portions at 0° C. The resulting solution was stirred at 0° C. for 1 hour under nitrogen. To the above solution was added 5-bromo-1,3,4-thiadiazol-2-amine (6.0 g, 33.3 mmol) at 0° C. The resulting solution was then stirred at 0° C. for 2 hours under nitrogen. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was applied to a 40 g silica gel column and purified by Combi Flash (Biotage Isolera Prime) normal phase flash chromatography eluting with 0 to 66% ethyl acetate in petroleum ether within 30 min to give methyl 2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)acetate (418.0 mg, 6%) as a white solid. MS (ESI) calculated for (C5H7N3O3S) (M+1). + , 190.0; found, 190.0.

[0399] Step 2: 2-((5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamido)-1,3,4-thiadiazol-2-yl)oxy)acetate methyl

[0400] [ka]

[0401] To a stirred solution of methyl 2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)acetate (200.0 mg, 1.06 mmol) in N,N-dimethylformamide (2 mL) was added Intermediate G (295.0 mg, 1.06 mmol) and 1-methyl-1H-imidazole (347.0 mg, 4.23 mmol) sequentially. To this was added a solution of TCFH (445.0 mg, 1.59 mmol) in acetonitrile (2 mL) at 23° C. The mixture was stirred at 23° C. for 1 hour. The resulting mixture was diluted with DMF (2 mL), applied to a 40 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–34% acetonitrile in water within 30 min to give methyl 2-((5-(2′-chloro-5′-methoxy-6-methyl-(4,4′-bipyridine)-3-carboxamido)-1,3,4-thiadiazol-2-yl)oxy)acetate (350.0 mg, 72%) as a white solid. MS (ESI) calculated for (C 18 H 16 ClN5O5S) (M+1) + , 450.1; found, 450.1.

[0402] Step 3 2'-chloro-N-(5-(2-hydroxy-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0403] [ka]

[0404] To a degassed solution of methyl 2-((5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamido)-1,3,4-thiadiazol-2-yl)oxy)acetate (100.0 mg, 0.22 mmol) in dry tetrahydrofuran (1 mL) at 0°C, methylmagnesium bromide (0.3 mL, 0.90 mmol, 3N in THF) was added dropwise. The mixture was stirred at 0°C for 30 minutes under a nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (4 mL) and purified under the following conditions: (Column: Xbridge Prep OBD C18 column, 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol / L) Purification by prep-HPLC using 2'-chloro-N-(5-(2-hydroxy-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (41.7 mg, 41%) as a white solid. MS (ESI) calculated for (C 19 H 20 ClN5O4S) (M+1) + , 450.1; found, 450.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 4.77 (s, 1H), 4.18 (s, 2H), 3.64 (s, 3H), 2.59 (s, 3H), 1.18 (s, 6H).

[0405] Examples 15 and 16 2'-chloro-N-(5-((1s,3s)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-((1r,3r)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0406] [ka]

[0407] Step 1: Carbonodithioic acid O-(3-(benzyloxy)cyclobutyl)S-methyl

[0408] [ka]

[0409] To a solution of NaH (242 mg, 6.06 mmol, 60%) in THF (5 mL) was added dropwise a solution of 3-(benzyloxy)cyclobutan-1-ol (900 mg, 5.06 mmol) in THF (5 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes. To the above mixture was added dropwise CS2 (576 mg, 7.59 mmol) at 0° C. and stirred at 0° C. for 20 minutes. Next, to the above mixture was added dropwise MeI (1.07 mg, 7.59 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was dissolved in acyl acetate (5 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0 to 82% ethyl acetate in petroleum ether within 35 min to give O-(3-(benzyloxy)cyclobutyl)S-methyl carbonodithioate (940 mg, 69%) as a yellow oil. MS (ESI) calculated for (C 13 H16 O2S2) (M+1) + , 269.06; found, 269.06.

[0410] Step 2: O-(3-(benzyloxy)cyclobutyl)hydrazinecarbothioate

[0411] [ka]

[0412] To a mixture of O-(3-(benzyloxy)cyclobutyl)S-methyl carbonodithioate (940 mg, 3.50 mmol) in MeOH (5 mL) was added hydrazine (241 mg, 3.80 mmol 80%). The mixture was stirred at 0° C. for 1 hour. The resulting mixture was concentrated in vacuo and then diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give O-(3-(benzyloxy)cyclobutyl)hydrazinecarbothioate (830 mg, crude) as a yellow oil. MS (ESI) calculated for (C 12 H 16 N2O2S) (M+1) + , 253.09; found, 253.09.

[0413] Step 3: 5-(3-(benzyloxy)cyclobutoxy)-1,3,4-thiadiazol-2-amine

[0414] [ka]

[0415] To a mixture of O-(3-(benzyloxy)cyclobutyl)hydrazinecarbothioate (860 mg, 3.40 mmol) and EtN (689 mg, 6.81 mmol) in MeOH (5 mL) was added BrCN (394 mg, 3.74 mmol). The mixture was stirred at 23 °C for 1 h. The resulting mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) on a 40 g silica gel column eluted with 0-55% ethyl acetate in petroleum ether within 35 min to give 5-(3-(benzyloxy)cyclobutoxy)-1,3,4-thiadiazol-2-amine (410 mg, 43%) as a white solid. MS (ESI) calculated for (C 13 H 15 N3O2S) (M+1) + , 278.09; found, 278.09.

[0416] Step 4: 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)cyclobutan-1-ol

[0417] [ka]

[0418] To a stirred solution of 5-(3-(benzyloxy)cyclobutoxy)-1,3,4-thiadiazol-2-amine (320 mg, 1.154 mmol) in dichloromethane (5 mL) at −78 °C was added BBr (0.545 mL, 5.77 mmol). The resulting solution was stirred at −78 °C for 1 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was dissolved in DMF (3 mL), applied to a 20 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–35% acetonitrile in water within 25 min to give 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)cyclobutan-1-ol (105 mg, 48%) as a white solid. MS (ESI) calculated for (C6H9N3O2S) (M+1) + , 188.04; found, 188.04.

[0419] Step 5 2'-chloro-N-(5-(3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0420] [ka]

[0421] To a stirred solution of 3-((5-amino-1,3,4-thiadiazol-2-yl)oxy)cyclobutan-1-ol (100 mg, 0.534 mmol) in N,N-dimethylformamide (0.5 mL) and acetonitrile (0.5 mL) was added 1-methylimidazole (0.213 mL, 2.67 mmol), Intermediate G (149 mg, 0.534 mmol), and TCFH (165 mg, 0.588 mmol) at 23° C. The resulting solution was stirred at 23° C. for 1 hour. The resulting residue was dissolved in DMF (0.5 mL) and applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–42% acetonitrile in water within 25 min to give 2′-chloro-N-(5-(3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5′-methoxy-6-methyl-(4,4′-bipyridine)-3-carboxamide (50 mg, 19%) as a yellow solid. MS (ESI) calculated for (C 19 H 18 ClN5O4S) (M+1) + , 448.1; found, 448.1.

[0422] Step 6 2'-chloro-N-(5-((1s,3s)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-((1r,3r)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0423] [ka]

[0424] The compound mixture (50 mg) was dissolved in DMF (7 mL) and purified by prep-HPLC using the following conditions: (Column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeOH -----preparative; Flow rate: 25 mL / min; Gradient: 40% B to 50% B in 12 min, 50% B to 95% B in 12.2 min, 95% B to 95% B in 14 min, 95% B to 5% B in 14.2 min, 5% B to 5% B in 16 min; Wavelength: 254 nm; Injection volume: 0.6 mL; Number of runs: 11) to give 2'-chloro-N-(5-((1r,3r)-3-hydroxycyclobutoxy)-1,3, 4-Thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (18.8 mg, 37.1% yield) was obtained as a white solid, and 2'-chloro-N-(5-((1s,3s)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (5.8 mg, 11.43% yield) was obtained as a white solid.

[0425] 2'-chloro-N-(5-((1s,3s)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide: MS (ESI) calculated for (C 19 H 18 ClN5O4S) (M+1) + , 448.1; found, 448.1. 1 H NMR (400 MHz, DMSO-d6) δ12.88 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 5.24 (d, J = 6.0 Hz, 1H), 4.72 (d, J = 6.0 Hz, 1H), 3.83 (d, J = 6.0 Hz, 1H), 3.63 (s, 3H), 2.82 - 2.76 (m, 2H), 2.59 (s, 3H), 2.10 - 1.96 (m, 2H).

[0426] 2'-chloro-N-(5-((1r,3r)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide: MS (ESI) calculated for (C 19 H 18 ClN5O4S) (M+1) + , 448.1; found, 448.1. 1 H NMR (400 MHz, DMSO-d6) δ12.89 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 5.29 - 5.25 (m, 2H), 4.39 (d, J = 6.0 Hz, 1H), 3.63 (s, 3H), 2.58 (s, 3H), 2.43 - 2.38 (m, 2H), 2.36 - 2.31 (m, 2H).

[0427] 2'-Chloro-N-(5-((1s,3s)-3-hydroxycyclobutoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide was resynthesized according to the procedure described above using (1s,3s)-3-(benzyloxy)cyclobutan-1-ol as starting material to confirm the absolute stereochemistry.

[0428] Example 17 2'-chloro-N-(5-(cyclopentyloxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0429] [ka]

[0430] Step 1 Carbonodithioic acid O-cyclopentyl S-methyl [ka]

[0431] To a degassed solution of cyclopentanol (500 mg, 5.80 mmol) in dry tetrahydrofuran (THF) (2 mL) was added NaH (464 mg, 11.61 mmol) in small portions at 0 °C and stirred at 25 °C for 30 min. CS₂ (0.525 mL, 8.71 mmol) and MeI (0.544 mL, 8.71 mmol) were added sequentially to the above solution at 25 °C. The resulting mixture was then stirred at 25 °C for 30 min. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (3 mL) and applied to a 20 g silica gel column. Elution with 0–30% ethyl acetate in petroleum ether within 25 min afforded O-cyclopentyl S-methyl carbonodithioate (972 mg, 93% yield) as a colorless oil. MS (ESI) calculated for (C7H 12 OS2) (M+1) + ,177.0, found 177.0.

[0432] Step 2: O-Cyclopentyl hydrazinecarbothioate

[0433] [ka]

[0434] To a stirred solution of O-cyclopentyl S-methyl carbodithioate (970 mg, 5.50 mmol) in methanol (5 mL) at 25 °C was added N2H4·H2O (344 mg, 5.50 mmol). The resulting solution was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give O-cyclopentyl hydrazinecarbothioate (826 mg, crude) as a yellow oil. The crude product (from the crude procedure) was used in the next step without further purification. MS (ESI) calculations for (C6H 12 N2OS) (M+1) + ,161.11, found 161.1.

[0435] Step 3: 5-(cyclopentyloxy)-1,3,4-thiadiazol-2-amine

[0436] [ka]

[0437] To a stirred solution of O-cyclopentyl hydrazinecarbothioate (826 mg, 5.15 mmol) in ethanol (5 mL) at 25 °C, TEA (0.719 mL, 5.15 mmol) and BrCN (546 mg, 5.15 mmol) were added. The resulting solution was stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (5 mL), applied to a 40 g silica gel column, and eluted with 0 to 50% ethyl acetate in petroleum ether within 30 min to give 5-(cyclopentyloxy)-1,3,4-thiadiazol-2-amine (627 mg, 44% yield) as a yellow solid. MS (ESI) calculations for (CH 11 N3OS) (M+1) + ,185.1, found 185.1.

[0438] Step 4 2'-chloro-N-(5-(cyclopentyloxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0439] [ka]

[0440] To a stirred solution of Intermediate G (301 mg, 1.080 mmol) and 5-(cyclopentyloxy)-1,3,4-thiadiazol-2-amine (200 mg, 1.080 mmol) in ACN (2 mL) and N,N-dimethylformamide (1 mL) at 25 °C, 1-methylimidazole (0.430 mL, 5.40 mmol) and TCFH (333 mg, 1.188 mmol) were added. The resulting solution was stirred at 25 °C for 1 h. This reaction mixture (3 mL) was purified under the following conditions: (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L) Purification by prep-HPLC using 2'-chloro-N-(5-(cyclopentyloxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (51.7 mg, 10% yield) as a white solid. MS (ESI) calculations for (C 20 H 20 ClN5O3S) (M+1) + 446.1; found 446.1. 1H NMR (400 MHz, DMSO-d6) δ12.86 (s, 1H), 8.82 (s, 1H), 8.16 (s, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 5.29 - 5.28 (m, 1H), 3.63 (s, 3H), 2.58 - 2.51 (m, 3H), 1.99 - 1.91 (m, 2H), 1.85 - 1.82 (m, 2H), 1.72 - 1.59 (m, 4H).

[0441] Example 18 2'-chloro-N-(5-(2,2-difluoroethoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0442] [ka]

[0443] Step 1 5-(2,2-difluoroethoxy)-1,3,4-thiadiazol-2-amine

[0444] [ka]

[0445] To a degassed solution of 2,2-difluoroethan-1-ol (1 g, 12.19 mmol) in dry tetrahydrofuran (THF) (10 mL) was added sodium hydride (0.975 g, 24.38 mmol, 60%) in small portions at 0 °C and stirred for 30 minutes under nitrogen. Next, 5-bromo-1,3,4-thiadiazol-2-amine (2.63 g, 14.63 mmol) was added to the above mixture at 0 °C. The resulting solution was stirred at 0-5 °C for 30 minutes. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (4 mL), applied to an 80 g C18 column, and eluted with 5–36% acetonitrile in water within 20 min to give 5-(2,2-difluoroethoxy)-1,3,4-thiadiazol-2-amine (330 mg, 12% yield) as a white solid. MS (ESI) calculated for (C4H5F2N3OS) (M+1). + , 182.0, found 182.1.

[0446] Step 2 2'-chloro-N-(5-(2,2-difluoroethoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0447] [ka]

[0448] To a solution of intermediate G (250 mg, 0.897 mmol) in acetonitrile (3 mL) was added NMI (221 mg, 2.69 mmol), 5-(2,2-difluoroethoxy)-1,3,4-thiadiazol-2-amine (244 mg, 1.346 mmol), and TCFH (302 mg, 1.076 mmol) sequentially at 23° C. and stirred for 2 hours at 30° C. The organic solvent was removed under vacuum. The resulting residue was dissolved in DMF (2 mL) and purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g C18 column and eluted with 5-53% acetonitrile in water within 22 min to give 2'-chloro-N-(5-(2,2-difluoroethoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (34.9 mg, 9% yield) as a white solid. MS (ESI) calculated for (C 17 H 14 ClF2N5O3S) (M+1) + , 442.0, found 442.0. 1 H NMR (400 MHz, DMSO-d6) δ13.04 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 6.65 - 6.25 (m, 1H), 4.85 - 4.62 (m, 2H), 3.63 (s, 3H), 2.59 (s, 3H).

[0449] Example 19 2'-chloro-N-(5-(2-fluoro-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0450] [ka]

[0451] Step 1: 5-(2-fluoro-2-methylpropoxy)-1,3,4-thiadiazol-2-amine

[0452] [ka]

[0453] To a stirred solution of 2-fluoro-2-methylpropan-1-ol (600.0 mg, 6.52 mmol) in THF (10 mL) at 0° C., NaH (313.0 mg, 7.82 mmol, 60%) was added portionwise and stirred at 0° C. for 30 minutes under a nitrogen atmosphere. Next, 5-bromo-1,3,4-thiadiazol-2-amine (1.4 g, 7.82 mmol) was added to the above mixture at 0° C. The resulting solution was stirred at 0° C. for 2 hours. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (1 mL) and applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–50% acetonitrile in water within 20 min to give 5-(2-fluoro-2-methylpropoxy)-1,3,4-thiadiazol-2-amine (150.0 mg, 25%) as a white solid. MS (ESI) calculated for (CH 10 FN3OS) (M+1) + , 192.2; found, 192.1.

[0454] Step 2: 2'-chloro-N-(5-(2-fluoro-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0455] [ka]

[0456] To a stirred solution of 5-(2-fluoro-2-methylpropoxy)-1,3,4-thiadiazol-2-amine (130.0 mg, 0.68 mmol) in acetonitrile (1 mL) was added Intermediate G (189.0 mg, 0.68 mmol) and 1-methylimidazole (278.8 mg, 3.40 mmol). To the above solution was added a solution of TCFH (191.0 mg, 0.68 mmol) in acetonitrile (1 mL) at 23° C. The resulting solution was stirred at 23° C. for 1 hour. The reaction mixture (4 mL) was purified by prep-HPLC using the following conditions: (Column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeOH - preparative; Flow rate: 60 mL / min; Gradient: 50% B to 70% B, 70% B in 8 min; Wavelength: 254 nm; RT1 (min): 7.2) to give 2'-chloro-N-(5-(2-fluoro-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (142.0 mg, 46%) as a white solid. MS (ESI) calculated for (C 19 H 19 ClFN5O3S) (M+1) + , 452.1; found, 452.1. 1 H NMR (400 MHz, DMSO-d6) δ12.96 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 4.48 (d, J = 20.8 Hz, 2H), 3.63 (s, 3H), 2.67 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H).

[0457] Example 20 6'-chloro-N-(5-(2,2-difluoropropoxy)-1,3,4-thiadiazol-2-yl)-3'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0458] [ka]

[0459] Step 1: 5-(2,2-difluoropropoxy)-1,3,4-thiadiazol-2-amine

[0460] [ka]

[0461] To a degassed solution of 2,2-difluoropropan-1-ol (1.0 g, 10.41 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride (0.8 g, 20.82 mmol) in small portions at 0° C. and stirred for 30 minutes. Next, 5-bromo-1,3,4-thiadiazol-2-amine (1.8 g, 10.41 mmol) was added to the above mixture at 0° C. The resulting solution was stirred at 0° C. for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (4 mL), applied to an 80 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–36% acetonitrile in water within 20 min to give 5-(2,2-difluoropropoxy)-1,3,4-thiadiazol-2-amine (300.0 mg, 9%) as a brown solid. MS (ESI) calculation for (C5H7F2N3OS) (M+1) + , 196.0, found 196.0.

[0462] Step 2 6'-chloro-N-(5-(2,2-difluoropropoxy)-1,3,4-thiadiazol-2-yl)-3'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0463] [ka]

[0464] To a solution of intermediate G (200.0 mg, 0.71 mmol) in acetonitrile (4 mL) at 20 °C, 1-methyl-1H-imidazole (206.0 mg, 2.51 mmol), 5-(2,2-difluoropropoxy)-1,3,4-thiadiazol-2-amine (140.0 mg, 0.71 mmol), and TCFH (201.0 mg, 0.71 mmol) were added sequentially. The mixture was stirred at 30 °C for 16 h. The organic solvent was removed under vacuum. The residue was dissolved in DMF (2 mL) and purified under the following conditions: (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: MeOH—HPLC; flow rate: 60 mL / min; gradient: 44% B to 58% B in 8 min, 58% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 2% B in 11 min, 2% B; wavelength: 254 nm; RT1 (min): 7; injection volume: 0.7 mL; number of runs: 3) to give 2'-chloro-N-(5-(2,2-difluoropropoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (24.7 mg, 7%) as a white solid. MS (ESI) calculations for (C 18 H 16 ClF2N5O3S) (M+1) + , 456.0, found 456.0. 1 H NMR (400 MHz, DMSO-d6) δ13.01 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 4.74 (t, J = 12.8 Hz, 2H), 3.63 (s, 3H), 2.59 (s, 3H), 1.74 (t, J = 19.2 Hz, 3H).

[0465] Example 21 2'-chloro-N-(5-isobutoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0466] [ka]

[0467] Step 1 5-Isobutoxy-1,3,4-thiadiazol-2-amine

[0468] [ka]

[0469] To a degassed solution of 2-methylpropan-1-ol (1.0 g, 13.49 mmol) in dry tetrahydrofuran (10 mL) was added NaH (540.0 mg, 13.49 mmol, 60%) in small portions at 0° C. The resulting solution was stirred at 0° C. for 40 minutes. To the above solution was added 5-bromo-1,3,4-thiadiazol-2-amine (2.4 g, 13.49 mmol) at 0° C. The resulting mixture was then stirred at 0° C. for 1 hour. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying it to a 40 g silica gel column and eluting with 0 to 40% ethyl acetate in petroleum ether within 30 min to give 5-isobutoxy-1,3,4-thiadiazol-2-amine (25.0 mg, 1%) as a white solid. MS (ESI) calculations for (CH 11 N3OS) (M+1) + , 174.1; found, 174.0.

[0470] Step 2 2'-chloro-N-(5-isobutoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0471] [ka]

[0472] To a mixture of Intermediate G (40.0 mg, 0.14 mmol) in acetonitrile (3 mL) was added 5-isobutoxy-1,3,4-thiadiazol-2-amine (24.0 mg, 0.14 mmol) and 1-methyl-1H-imidazole (58.0 mg, 0.71 mmol). To this was added a solution of TCFH (60.0 mg, 0.21 mmol) in acetonitrile (1 mL) dropwise. The mixture was stirred at 30° C. for 16 hours. The solvent was removed in vacuo. The resulting residue was dissolved in DMF (2 mL) and applied to a 40 g C18 column, which was purified by Combi Flash (Biotage Isolera Prime) eluting with 5–45% acetonitrile in water within 40 min to give 2′-chloro-N-(5-isobutoxy-1,3,4-thiadiazol-2-yl)-5′-methoxy-6-methyl-(4,4′-bipyridine)-3-carboxamide (21.1 mg, 45%) as a white solid. MS (ESI) calculations for (C 19 H 20 ClN5O3S) (M+1) + , 434.1, found 434.0. 1 H NMR (400 MHz, DMSO-d6) δ12.87 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 4.21 (d, J = 6.4 Hz, 2H), 3.64 (s, 3H), 2.59 (s, 3H), 2.15 - 2.03 (m, J = 6.8 Hz, 1H), 0.97 (d, J = 6.4 Hz, 6H).

[0473] Examples 22 and 23 (S)-2'-Chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide and (R)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0474] [ka]

[0475] Step 1 5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-amine

[0476] [ka]

[0477] A degassed solution of tetrahydrofuran-3-ol (1.0 g, 11.35 mmol) in dry tetrahydrofuran (20 mL) was stirred in small portions at 0 °C for 30 min. To the above mixture was added 5-bromo-1,3,4-thiadiazol-2-amine (2.0 g, 11.35 mmol) at 0 °C. The resulting solution was stirred at 23 °C for 1 h under nitrogen. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (2.5 mL), applied to a 40 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–30% acetonitrile in water within 30 min to give 5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-amine (80.0 mg, 3%) as a yellow solid. MS (ESI) calc'd for (C6H9N3O2S) (M+1) + , 188.1, found 188.2.

[0478] Step 2 2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0479] [ka]

[0480] To a stirred solution of 5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-amine (80.0 mg, 0.43 mmol) in N,N-dimethylformamide (1 mL) and acetonitrile (1 mL) was added Intermediate G (119.0 mg, 0.43 mmol) and 1-methylimidazole (175.0 mg, 2.13 mmol). To the above mixture was added a solution of TCFH (132.0 mg, 0.47 mmol) in acetonitrile (1 mL) at 23 °C. The resulting solution was stirred at 23 °C for 1 hour. The resulting mixture was dissolved in DMF (3 mL) and purified under the following conditions: (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile Phase A: water (10 mmol / L) Purification by prep-HPLC using 2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (100.0 mg, 49%) as a white solid. MS (ESI) calculations for (C 19 H 18 ClN5O4S) (M+1) + , 448.0, found 448.0.

[0481] Step 3: (S)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide and (R)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0482] [ka]

[0483] The racemic compound (99.0 mg) was separated by prep-chiral HPLC using the following conditions: (Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Mobile Phase A: Hex-HPLC, Mobile Phase B: MeOH:EtOH = 1:1-HPLC; Flow Rate: 20 mL / min; Gradient: 50% B to 50% B in 15.5 min; Wavelength: 220 / 254 nm; RT1 (min): 9.82; RT2 (min): 13.73; Sample Solvent: MeOH:DCM = 1:1; Injection Volume: 1 mL; Run Number: 8) and (S)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrachloromethane)-2-yl)-2 ... (R)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (24.3 mg, 24%) was obtained as a white solid with a retention time of 9.82 minutes, and (R)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (20.9 mg, 21%) was obtained as a white solid with a retention time of 13.73 minutes.

[0484] (S)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide: MS (ESI) calculation for (C 19 H 18 ClN5O4S) (M+1) + , 448.0, found 448.0. 1H NMR (400 MHz, DMSO-d6) δ12.92 (s, 1H), 8.89 (s, 1H), 8.14 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 5.44 (s, 1H), 3.91 - 3.81 (m, 3H), 3.81 - 3.70 (m, 1H), 3.63 (s, 3H), 2.56 (s, 3H), 2.28 - 2.20 (m, 1H), 2.13 - 2.05 (m, 1H).

[0485] (R)-2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide: MS (ESI) calculation for (C 19 H 18 ClN5O4S) (M+1) + , 448.0, found 448.0. 1H NMR (400 MHz, DMSO-d6) δ12.92 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 5.49 (s, 1H), 3.91 - 3.81 (m, 3H), 3.81 - 3.72 (m, 1H), 3.64 (s, 3H), 2.58 (s, 3H), 2.34 - 2.20 (m, 1H), 2.20 - 2.11 (m, 1H).

[0486] (R)-2'-Chloro-5'-methoxy-6-methyl-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide was resynthesized using the procedure described above with (R)-tetrahydrofuran-3-ol as the starting material to confirm the absolute stereochemistry.

[0487] Example 24 2'-chloro-5'-methoxy-6-methyl-N-(5-((3-methyloxetan-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0488] [ka]

[0489] Step 1: 5-((3-methyloxetan-3-yl)oxy)-1,3,4-thiadiazol-2-amine

[0490] [ka]

[0491] To a degassed solution of 3-methyloxetan-3-ol (500.0 mg, 5.67 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride (340.0 mg, 8.51 mmol, 60%) in small portions at 0° C. and stirred at 0° C. for 1 hour under a nitrogen atmosphere. Next, 5-bromo-1,3,4-thiadiazol-2-amine (1.0 g, 5.67 mmol) was added to the above mixture at 0° C. This mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0-90% ethyl acetate in petroleum ether within 40 min to give 5-((3-methyloxetan-3-yl)oxy)-1,3,4-thiadiazol-2-amine (35.0 mg, 1%) as a yellow oil. MS (ESI) calculation for (C6H9N3O2S) (M+1) + , 188.0; found 188.0.

[0492] Step 2 2'-chloro-5'-methoxy-6-methyl-N-(5-((3-methyloxetan-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0493] [ka]

[0494] To a stirred solution of 5-((3-methyloxetan-3-yl)oxy)-1,3,4-thiadiazol-2-amine (60.0 mg, 0.32 mmol) and Intermediate G (93.0 mg, 0.35 mmol) in acetonitrile (1.5 mL) at 23 °C, 1-methylimidazole (131.2 mg, 1.60 mmol) and TCFH (90.0 mg, 0.32 mmol) were added sequentially. The resulting solution was stirred at 23 °C for 2 h under nitrogen. The resulting residue was dissolved in acetonitrile (1 mL), which was applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) within 25 min, eluting with 544% acetonitrile in water, and further purified under the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile Phase A: water (10 mmol / L) Purification by prep-HPLC using 2'-chloro-5'-methoxy-6-methyl-N-(5-((3-methyloxetan-3-yl)oxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (30.0 mg, 20%) as a white solid. MS (ESI) calculations for (C 19 H 18 ClN5O4S) (M+1) + , 448.1; found 448.1. 1H NMR (400 MHz, DMSO-d6) δ12.96 (s, 1H), 8.83 (s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 4.80 (d, J = 7.2 Hz, 2H), 4.55 (d, J = 7.2 Hz, 2H), 3.64 (s, 3H), 2.59 (s, 3H), 1.80 (s, 3H).

[0495] Example 25 2'-chloro-N-(5-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0496] [ka]

[0497] Step 1: Carbonodithioic acid O-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)S-methyl

[0498] [ka]

[0499] To a degassed solution of 4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (300.0 mg, 2.00 mmol) in dry tetrahydrofuran (THF) (6 mL) was added NaH (160.0 mg, 4.00 mmol, 60%) in portions at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 minutes. To the above solution was added CS2 (228.0 mg, 3.0 mmol) at 0° C. under nitrogen. The resulting solution was then stirred at 0° C. for 20 minutes. To the above solution was added MeI (426.0 mg, 3.0 mmol) at 0° C. under nitrogen. The resulting mixture was then stirred at 23° C. for 2 hours. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 20 g silica gel column and eluting with 0-40% ethyl acetate in petroleum ether within 30 min to give O-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)S-methyl carbonodithioate (370.0 mg, 76%) as a white solid. MS (ESI) calculated for (C7H 12 O3S3) (M+1) + , 241.0; found, 241.0.

[0500] Step 2: Hydrazinecarbothioic acid O-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)

[0501] [ka]

[0502] To a stirred solution of O-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)S-methyl carbodithioate (350.0 mg, 1.46 mmol) in methanol (5 mL) at 23 °C was added hydrazinium hydroxide solution (58.0 mg, 1.46 mmol). The resulting solution was stirred at 23 °C for 1 h. The resulting mixture was concentrated in vacuo to give O-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)hydrazinecarbothioate (322.0 mg, crude) as a yellow solid. MS (ESI) calculated for (CH 12 N2O3S2) (M+1) + , 225.0; found, 225.0.

[0503] Step 3: 4-((5-amino-1,3,4-thiadiazol-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide

[0504] [ka]

[0505] To a stirred solution of hydrazinecarbothioic acid O-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl) (322.0 mg, 1.44 mmol) in methanol (3 mL) at 0° C., TEA (436.3 mg, 4.32 mmol) and cyanogen bromide (167.0 mg, 1.58 mmol) were added sequentially. The resulting solution was stirred at 23° C. for 2 hours. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-((5-amino-1,3,4-thiadiazol-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide (230.0 mg, 46%) as a yellow solid. MS (ESI) calculated for (C7H 11 N3O3S2) (M+1) + , 250.0; found, 250.0.

[0506] Step 4 2'-chloro-N-(5-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0507] [ka]

[0508] To a stirred solution of 4-((5-amino-1,3,4-thiadiazol-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide (190.0 mg, 0.76 mmol) and Intermediate G (234.0 mg, 0.84 mmol) in acetonitrile (0.5 mL) at 23 °C under nitrogen, 1-methylimidazole (0.3 mL) and TCFH (214.0 mg, 0.76 mmol) in acetonitrile (0.2 mL) were added sequentially. The resulting solution was stirred at 23 °C for 2 h. The mixture was dissolved in acetonitrile (2 mL) and applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–40% acetonitrile in water within 30 min to give an off-white solid (88% pure). The product was dissolved in DMF (3 mL) and further purified under the following conditions: (Column: Xselect CSH F-phenyl OBD column, 19 × 250 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: MeOH - HPLC; Flow rate: 25 mL / min; Gradient: 53% B to 68% B in 10 min, 68% B to 95% B in 10.2 min, 95% B to 95% B in 12 min, 95% B to 5% B in 12.2 min, 5% B to 5% B in 14 min; Wavelength: 254 nm; RT1 (min): 8; Injection Purification by prep-HPLC using a 0.7 mL (4 runs) afforded 2'-chloro-N-(5-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (100.0 mg, 25%) as a white solid. MS (ESI) calculated for (C 20 H20 ClN5O5S2) (M+1) + , 510.1; found, 510.2. 1 H NMR (400 MHz, DMSO-d6) δ8.84 (s, 1H), 8.15 (s, 1H), 7.65 - 7.48(m, 2H), 5.25 - 5.15 (m, 1H), 3.62 (s, 3H), 3.29 - 3.10 (m, 4H), 2.63 (s, 3H), 2.44 - 2.26 (m, 4H).

[0509] Examples 26 and 27 2'-chloro-N-(5-(((1s,4s)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide and 2'-chloro-N-(5-(((1r,4r)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0510] [ka]

[0511] Step 1: Carbonodithioic acid O-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)S-methyl

[0512] [ka]

[0513] To a degassed solution of 4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol (550.0 mg, 2.39 mmol) in dry tetrahydrofuran (4 mL) was added NaH (191.0 mg, 4.77 mmol, 60%) at 0° C. and stirred at 0° C. for 30 minutes under a nitrogen atmosphere. CS2 (0.2 mL, 3.58 mmol) was then added to the above mixture at 0° C. and stirred at 0° C. for 20 minutes. MeI (0.2 mL, 3.58 mmol) was then added to the above solution at 0° C. under nitrogen. The resulting mixture was then stirred at 0° C. for 1 hour. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL) and purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g silica gel column and eluted with 0–20% ethyl acetate in petroleum ether within 20 min to give O-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)S-methyl carbonodithioate (711.0 mg, 74% yield) as a yellow oil.

[0514] Step 2: O-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl) hydrazinecarbothioate

[0515] [ka]

[0516] To a stirred solution of O-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)S-methyl carbonodithioate (710.0 mg, 2.22 mmol) in methanol (4 mL) at 20° C. was added hydrazine (0.1 mL, 2.22 mmol). The resulting solution was stirred at 20° C. for 30 min. The volatiles were removed in vacuo to give O-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl) hydrazinecarbothioate (670.0 mg, crude) as a pale yellow oil. MS (ESI) calculated for (C 13 H 28N2O2SSi) (M+1) + , 305.0; found, 305.3.

[0517] Step 3: 5-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-1,3,4-thiadiazol-2-amine

[0518] [ka]

[0519] To a stirred solution of O-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)hydrazinecarbothioate (730.0 mg, 2.40 mmol) in methanol (3 mL) at 20 °C, TEA (0.7 mL, 4.79 mmol) and BrCN (279.0 mg, 2.64 mmol) were added sequentially. The resulting solution was stirred at 20 °C for 1 h. The resulting residue was dissolved in DMF (3 mL), applied to a 40.0 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–50% acetonitrile in water within 40 min to give 5-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-1,3,4-thiadiazol-2-amine (290.0 mg, 33%) as a white solid. MS (ESI) calculated for (C 14 H 27 N3O2SSi) (M+1) + , 330.0; found, 659.5.

[0520] Step 4 N-(5-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0521] [ka]

[0522] To a stirred solution of 5-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-1,3,4-thiadiazol-2-amine (290.0 mg, 0.88 mmol) in acetonitrile (5 mL) was added Intermediate G (270.0 mg, 0.97 mmol) and 1-methylimidazole (361.0 mg, 4.40 mmol) sequentially. Then, to the above mixture was added a solution of TCFH (247.0 mg, 0.88 mmol) in acetonitrile (1 mL) at 20° C. The resulting solution was stirred at 20° C. for 16 h. The volatiles were removed in vacuo. The resulting residue was dissolved in DMF (4 mL) and applied to a 40.0 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–60% acetonitrile in water within 40 min to give N-(5-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-2′-chloro-5′-methoxy-6-methyl-(4,4′-bipyridine)-3-carboxamide (400.0 mg, 75%) as a white solid. MS (ESI) calculated for (C 27 H 36 ClN5O4SSi) (M+1) + , 590.0; found, 590.4.

[0523] Step 5: 2'-chloro-N-(5-(((1s,4s)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide and 2'-chloro-N-(5-(((1r,4r)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0524] [ka]

[0525] To a mixture of N-(5-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (400.0 mg, 0.68 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred at 20 °C for 30 minutes. The organic solvent was removed in vacuo. The residue was diluted with water. The aqueous layer was basified with NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (2 mL) and applied to a 40.0 g C18 column. It was purified by Combi Flash (Biotage Isolera Prime) and eluted with 25 to 90% acetonitrile in water within 45 minutes to give 2'-chloro-N-(5-((4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (204.0 mg, 63%) as a white solid. The mixture of compounds (204.0 mg) was purified under the following conditions: (Column: CHIRALPAK The mixture was separated by prep-chiral HPLC using IE, 2 × 25 cm, 5 μm; mobile phase A: Hex-HPLC, mobile phase B: MeOH:EtOH = 1:1-HPLC; flow rate: 14 mL / min; gradient: 80% B to 80% B in 29 min; wavelength: 220 / 254 nm; RT1 (min): 16.46; RT2 (min): 20.27; sample solvent: MeOH:DCM = 1:1; injection volume: 0.5 mL; number of runs: 8). The first peak, 2'-chloro-N-(5-(((1s,4s)-4-hydroxycyclohexyl)-4-hydroxycyclohexyl)-4-hydroxycyclohexyl ... The resulting product was 2'-chloro-N-(5-(((1r,4r)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (45.6 mg, 22%) as a white solid, and the second peak in chiral HPLC was 2'-chloro-N-(5-(((1r,4r)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (98.5 mg, 48%) as a white solid.The absolute stereochemistry was not determined but was arbitrarily assigned.

[0526] 2'-chloro-N-(5-(((1s,4s)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: MS (ESI) calculated for (C 21 H 22 ClN5O4S) (M+1) + , 476.0; found, 476.2, 1 H NMR (400 MHz, DMSO-d6) δ12.89 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 4.93 - 4.90 (m, 1H), 4.55 - 4.54 (m, 1H), 3.63 - 3.59 (m, 4H), 2.58 (s, 3H), 1.99 - 1.91 (m, 4H), 1.75 - 1.72 (m, 4H).

[0527] 2'-chloro-N-(5-(((1r,4r)-4-hydroxycyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: MS (ESI) calculated for (C 21 H 22 ClN5O4S) (M+1) + , 476.0; found, 476.2, 1H NMR (400 MHz, DMSO-d6) δ12.87 (s, 1H), 8.81 (s, 1H), 8.16 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 4.89 - 4.82 (m, 1H), 4.61 - 4.60 (m, 1H), 3.63 (s, 3H), 3.62 - 3.45 (m, 1H), 2.59 (s, 3H), 2.14 - 2.08 (m, 2H), 1.86 - 1.82 (m, 2H), 1.60 - 1.50 (m, 2H), 1.38 - 1.24 (m, 2H).

[0528] Example 28 2'-chloro-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0529] [ka]

[0530] Step 1: O-ethyl hydrazinecarbothioate

[0531] [ka]

[0532] A mixture of potassium O-ethyl carbodithioate (2.0 g, 12.48 mmol) and hydrazine hydrate (0.8 g, 12.48 mmol) in methanol (20 mL) was stirred at 20° C. for 2 hours. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give O-ethyl hydrazinecarbothioate (1.4 g, crude) as a yellow oil. MS (ESI) calculation for (C3H8N2OS) (M+1) + , 121.0, found 121.0.

[0533] Step 2: 5-ethoxy-1,3,4-thiadiazol-2-amine

[0534] [ka]

[0535] To a mixture of O-ethyl hydrazinecarbothioate (1.4 g, 9.32 mmol) in methanol (10 mL) at 20 °C, NaOH (0.8 g, 18.64 mmol) and cyanogen bromide (1.1 g, 10.25 mmol) were added. The resulting solution was stirred at 20 °C for 30 min. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DMF (3 mL) and purified by Combi Flash (Biotage Isolera Prime) on a 40 g C18 column eluted with 5–40% acetonitrile in water within 45 min to give 5-ethoxy-1,3,4-thiadiazol-2-amine (280 mg, 10%) as a red solid. MS (ESI) calculation for (C4H7N3OS) (M+1) + , 146.0, found 146.0.

[0536] Step 3 2'-chloro-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0537] [ka]

[0538] To a mixture of 5-ethoxy-1,3,4-thiadiazol-2-amine (268.0 mg, 0.92 mmol) in acetonitrile (2 mL) was added Intermediate G (260.0 mg, 0.84 mmol) and NMI (344.0 mg, 4.20 mmol). To this was added a solution of TCFH (259.0 mg, 0.92 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The mixture was stirred at 20° C. for 2 hours under nitrogen. The resulting mixture was dissolved in DMF (6 mL) and purified under the following conditions: Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; Mobile Phase A: water (10 mmol / L) Purification by prep-HPLC using (NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 40% B in 8 min, 40% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; wavelength: 254 nm; RT1 (min): 7.5; injection volume: 1 mL; number of runs: 6) gave 2'-chloro-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (144.3 mg, 42%) as a white solid. MS (ESI) calculations for (C 17 H 16 ClN5O3S) (M+1) + , 406.0, found 406.0. 1 H NMR (400 MHz, DMSO-d6) δ12.81 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 4.48 - 4.42 (m, 2H), 3.63 (s, 3H), 2.58 (s, 3H), 1.37 (t, J = 8.0 Hz, 3H).

[0539] Example 29 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0540] [ka]

[0541] Step 1: 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine

[0542] [ka]

[0543] To a solution of 2,2,2-trifluoroethan-1-ol (1.0 g, 10.00 mmol) in tetrahydrofuran (30 mL) at 0° C., NaH (0.80 g, 19.99 mmol, 60%) was added portionwise and stirred at 0° C. for 1 hour. To the above solution was added 5-bromo-1,3,4-thiadiazol-2-amine (1.8 g, 10.00 mmol) at 0° C. The resulting solution was stirred at 0° C. for 2 hours. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude material (1.3 g, crude) as a gray solid. The resulting residue was dissolved in DMF (8 mL) and applied to an 80 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–23% acetonitrile in water within 39 min to give 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine (583.0 mg, 25%) as a grey solid. MS (ESI) calculation for (C4H4F3N3OS) (M+1) + , 200.0, found 200.0.

[0544] Step 2 2'-chloro-5'-methoxy-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0545] [ka]

[0546] To a mixture of Intermediate G (100.0 mg, 0.35 mmol) in acetonitrile (2 mL) was added 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine (100.0 mg, 0.423 mmol) and 1-methyl-1H-imidazole (87.0 mg, 1.05 mmol). To this was added a solution of TCFH (148.0 mg, 0.52 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The resulting solution was stirred at 20° C. for 2 hours under nitrogen. The resulting mixture was purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g C18 column and eluted with 5-54% acetonitrile in water within 45 min to give 2'-chloro-5'-methoxy-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (60.7 mg, 36%) as a white solid. MS (ESI) calculations for (C 17 H 13 ClF3N5O3S) (M+1) + , 460.0, found 460.0. 1 H NMR (400 MHz, DMSO-d6) δ13.08 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 5.16 - 5.22 (m, 2H), 3.63 (s, 3H), 2.60 (s, 3H).

[0547] Example 30 N-(5-methoxy-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-methylphenyl)-6-methylnicotinamide

[0548] [ka]

[0549] Step 1: Methyl 4-(2-methoxy-5-methylphenyl)-6-methylpyridine-3-carboxylate

[0550] [ka]

[0551] A degassed mixture of methyl 4-chloro-6-methylpyridine-3-carboxylate (500.0 mg, 2.69 mmol), 2-methoxy-5-methylphenylboronic acid (894.2 mg, 5.388 mmol), Pd(dppf)Cl2 (394.21 mg, 0.53 mmol), and potassium carbonate (744.6 mg, 5.38 mmol) in dioxane (10.0 mL) and water (1.0 mL) was stirred at 110 °C for 2 h under nitrogen. The solvent was removed in vacuo. The residue was purified by flash column chromatography using 0 to 44% ethyl acetate in petroleum ether to give methyl 4-(2-methoxy-5-methylphenyl)-6-methylpyridine-3-carboxylate (800.0 mg, 57%) as a yellow oil. MS (ESI) calc'd for (C16H17NO3) (M+1)+, 272.1, found 272.1.

[0552] Step 2: 4-(2-methoxy-5-methylphenyl)-6-methylpyridine-3-carboxylic acid

[0553] [ka]

[0554] A mixture of methyl 4-(2-methoxy-5-methylphenyl)-6-methylpyridine-3-carboxylate (700.0 mg, 2.58 mmol), NaOH (309.5 mg, 7.74 mmol) in THF (10.0 mL) and water (3.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified with HCl (1N) to pH 4. The aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-methoxy-5-methylphenyl)-6-methylpyridine-3-carboxylic acid (550.0 mg, crude) as a yellow oil. MS (ESI) calculation for (C15H15NO3) (M+1)+, 258.1, found 258.4.

[0555] Step 3: N-(5-methoxy-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-methylphenyl)-6-methylnicotinamide

[0556] [ka]

[0557] To a stirred solution of 4-(2-methoxy-5-methylphenyl)-6-methylnicotinic acid (100.0 mg, 0.39 mmol) in acetonitrile (1 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (51.1 mg, 0.39 mmol) and 1-methylimidazole (160.0 mg, 1.94 mmol) at 23° C. To the above solution was added a solution of TCFH (109.6 mg, 0.39 mmol) in acetonitrile (1 mL) at 23° C. under nitrogen. The resulting mixture was then stirred at 23° C. for 2 hours under nitrogen. The mixture was diluted with DMF (2 mL) and purified by prep-HPLC using the following conditions: (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 43% B in 8 min, 43% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; Wavelength: 254 nm; RT1 (min): 7.4; Injection volume: 0.5 mL; Number of runs: 5) to give N-(5-methoxy-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-methylphenyl)-6-methylnicotinamide (72.6 mg, 50%) as a white solid. MS (ESI) calc'd for (C18H18N4O3S) (M+1)+, 371.1; found, 371.1. 1H NMR (400 MHz, DMSO-d6) δ12.69 (s, 1H), 8.65 (s, 1H), 7.29 (s, 1H), 7.26 - 7.15 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.46 (s, 3H), 2.56 (s, 3H), 2.31 (s, 3H).

[0558] Example 31 2'-chloro-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0559] [ka]

[0560] Step 1 2'-chloro-N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0561] [ka]

[0562] To a solution of Intermediate G (300.0 mg, 1.08 mmol) in acetonitrile (2 mL) was added Intermediate B (261.1 mg, 1.08 mmol) and 1-methylimidazole (441.2 mg, 5.38 mmol) at 20° C. under nitrogen. To the above solution was added a solution of TCFH (301.5 mg, 1.08 mmol) in acetonitrile (2 mL) at 20° C. under nitrogen. The resulting mixture was then stirred at 20° C. for 1 hour. This mixture was dissolved in DMF (1 mL) and applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5-55% acetonitrile in water within 30 min to give 2'-chloro-N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (372.0 mg, 63%) as a white solid. MS (ESI) calculations for (C 21 H 16 Cl2N6O3S) (M+1) + , 503.1; found, 503.1.

[0563] Step 2 2'-chloro-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0564] [ka]

[0565] A solution of 2'-chloro-N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (320.0 mg, 0.64 mmol) in concentrated hydrochloric acid (1 mL) was stirred at 20 °C for 1 hour. The mixture was diluted with water. The aqueous layer was neutralized with NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (1 mL) and applied to a 20 g C18 column. Purification by Combi Flash (Biotage Isolera Prime) was performed using 5-60% acetonitrile in water within 25 min to give 2'-chloro-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (61.4 mg, 25% yield) as a white solid. MS (ESI) calculations for (C 15 H 12 ClN5O3S) (M+1) + , 378.1 found 378.1. 1 H NMR (400 MHz, DMSO-d6) δ12.35 - 12.30 (m, 2H), 8.75 (s, 1H), 8.20 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 3.72 (s, 3H), 2.58 (s, 3H).

[0566] Example 32 4-(2-(difluoromethoxy)-6-fluorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0567] [ka]

[0568] To a mixture of Intermediate D (65.0 mg, 0.19 mmol) in acetonitrile (1 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (28.4 mg, 0.21 mmol) and NMI (81.0 mg, 0.98 mmol). To this was added a solution of TCFH (60.6 mg, 0.21 mmol) in acetonitrile (0.5 mL) dropwise under nitrogen. The mixture was stirred at 20° C. for 2 hours under nitrogen. The resulting mixture was dissolved in DMF (2 mL) and purified by prep-HPLC using the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 38% B in 8 min, 38% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; Wavelength: 254 nm; RT1 (min): 7.67; Injection volume: 0.7 mL; Number of runs: 3) to give 4-(2-(difluoromethoxy)-6-fluorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (54.4 mg, 67%) as a white solid. MS (ESI) calculated for (C 17 H 13 F3N4O3S) (M+1) + , 411.0, found 411.1. 1 H NMR (400 MHz, methanol-d4) δ 8.98 (s, 1H), 7.49–7.43 (m, 1H), 7.32 (s, 1H), 7.14–7.05 (m, 2H), 6.92–6.55 (m, 1H), 4.08 (s, 3H), 2.65 (s, 3H).

[0569] Example 33 4-(5-chloro-2-(difluoromethoxy)phenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0570] [ka]

[0571] Step 1: 2-(5-chloro-2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0572] [ka]

[0573] To a stirred solution of 2-bromo-4-chloro-1-(difluoromethoxy)benzene (1.0 g, 3.88 mmol) in 1,4-dioxane (10 mL) at 25 °C, potassium acetate (1.1 g, 11.65 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.2 g, 4.66 mmol), and PdCl(dppf) (280.0 mg, 0.39 mmol) were added sequentially. The resulting solution was stirred at 80 °C for 16 hours under nitrogen. The solvent was removed in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0–25% ethyl acetate in petroleum ether within 30 min to give 2-(5-chloro-2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (800.0 mg, 67%) as a brown solid. MS (ESI) calculated for (C13H16BClF2O3) (M+1)+, 305.0, found 305.1.

[0574] Step 2: Methyl 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylnicotinate

[0575] [ka]

[0576] To a stirred solution of 2-(5-chloro-2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (800.0 mg, 2.63 mmol) in 1,4-dioxane (10 mL) and water (0.5 mL) at 25 °C, K2CO3 (1.1 g, 7.88 mmol), PdCl2(dppf) (192.0 mg, 0.26 mmol), and methyl 4-chloro-6-methylnicotinate (683.0 mg, 3.68 mmol) were added sequentially. The resulting solution was stirred at 80 °C for 2 hours under nitrogen. The mixture was diluted with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0 to 80% ethyl acetate in petroleum ether within 30 min to give methyl 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylnicotinate (1.2 g, 98%) as a white solid. MS (ESI) calculated for (C15H12ClF2NO3) (M+1)+, 328.0, found 328.1.

[0577] Step 3: 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylnicotinic acid

[0578] [ka]

[0579] To a stirred solution of methyl 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylnicotinate (1.2 g, 3.66 mmol) in tetrahydrofuran (10 mL) and water (5 mL) at 25 °C was added lithium hydroxide (87.8 mg, 3.66 mmol). The resulting solution was stirred at 25 °C for 1 hour. The organic solvent was removed in vacuo. The aqueous layer was acidified with 2 N HCl to pH 4 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylnicotinic acid (900 mg, crude) as a pale yellow oil. MS (ESI) calc'd for (C14H10ClF2NO3) (M+1)+, 314.0, found 314.0.

[0580] Step 4 4-(5-chloro-2-(difluoromethoxy)phenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0581] [ka]

[0582] To a stirred solution of 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylnicotinic acid (200.0 mg, 0.57 mmol) in acetonitrile (2 mL) at 25° C., 1-methyl-1H-imidazole (236 mg, 2.87 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (77.1 mg, 0.57 mmol) were added sequentially. To the above solution at 25° C. under nitrogen was added a solution of TCFH (161.0 mg, 0.57 mmol). The resulting mixture was then stirred at 25° C. for 2 hours. The resulting residue was dissolved in DMF (3 mL) and applied to a 40 g C18 column. Purification by Combi Flash (Biotage Isolera Prime) was performed using 5 to 100% acetonitrile in water within 40 min to give 4-(5-chloro-2-(difluoromethoxy)phenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (52.0 mg, 21%) as a white solid. MS (ESI) calculations for (C 17 H 13 ClF2N4O3S) (M+1) + , 427.0, found 427.0. 1 H NMR (400 MHz, DMSO-d6) δ12.93 (s, 1H), 8.85 (s, 1H), 7.60 - 7.51 (m, 2H), 7.38 (s, 1H), 7.31 - 7.21 (m, 1H), 7.04 - 6.82 (m, 1H), 4.07 (s, 3H), 2.59 (s, 3H).

[0583] Example 34 4-(2,6-dichlorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0584] [ka]

[0585] Step 1: Methyl 4-(2,6-dichlorophenyl)-6-methylnicotinate

[0586] [ka]

[0587] To a stirred solution of methyl 4-chloro-6-methylnicotinate (500.0 mg, 2.69 mmol) and (2,6-dichlorophenyl)boronic acid (1.0 g, 5.39 mmol) in toluene (5 mL) at 23 °C, tris(dibenzylideneacetone)dipalladium(0) (247.0 mg, 0.27 mmol) and KCO (1.1 g, 8.08 mmol) were added sequentially. The resulting solution was stirred at 100 °C for 16 h under a nitrogen atmosphere. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was dissolved in DCM (2 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0-20% ethyl acetate in petroleum ether within 30 min to give methyl 4-(2,6-dichlorophenyl)-6-methylnicotinate (498.0 mg, 61%) as a yellow solid. MS (ESI) calculated for (C 14 H 11 Cl2NO2) (M+1) + , 296.0; found, 296.0.

[0588] Step 2: 4-(2,6-dichlorophenyl)-6-methylnicotinic acid

[0589] [ka]

[0590] To a stirred solution of methyl 4-(2,6-dichlorophenyl)-6-methylnicotinate (490.0 mg, 1.66 mmol) in methanol (3 mL) at 20 °C was added sodium hydroxide (265.0 mg, 6.62 mmol) in water (3 mL). The resulting solution was stirred at 80 °C for 30 minutes, and the organic solvent was removed in vacuo. The aqueous layer was acidified to pH 5-6 with citric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(2,6-dichlorophenyl)-6-methylnicotinic acid (430.0 mg, crude) as a yellow solid. MS (ESI) calculated for (C 13 H9Cl2NO2) (M+1) + , 282.0; found, 282.0.

[0591] Step 3 4-(2,6-dichlorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0592] [ka]

[0593] To a stirred solution of 4-(2,6-dichlorophenyl)-6-methylnicotinic acid (300.0 mg, 1.06 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (139.0 mg, 1.06 mmol) in acetonitrile (3 mL) was added 1-methylimidazole (437.0 mg, 5.32 mmol). To the above solution was added a solution of TCFH (298.0 mg, 1.06 mmol) in acetonitrile at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 2 hours. The resulting mixture was dissolved in DMF (3 mL) and purified by prep-HPLC using the following conditions: (Column: Atlantis HILIC OBD column, 19 × 150 mm × 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 48% B, 48% B in 8 min; Wavelength: 254 nm; RT1 (min): 7.8) to give 4-(2,6-dichlorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (29.1 mg, 7% yield) as a white solid. MS (ESI) calculated for (C 16 H 12 Cl2N4O2S) (M+1) + , 395.0; found, 395.1. 1 H NMR (400 MHz, DMSO-d6) δ13.07 (s, 1H), 9.04 (s, 1H), 7.65 - 7.55 (m, 2H), 7.48 - 7.40 (m, 1H), 7.33 - 7.20 (m, 1H), 4.06 (s, 3H), 2.61 (s, 3H).

[0594] Example 35 4-(2-chloro-6-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0595] [ka]

[0596] Step 1: Methyl 4-(2-chloro-6-methoxyphenyl)-6-methylnicotinate

[0597] [ka]

[0598] To a stirred solution of methyl 4-chloro-6-methylnicotinate (500.0 mg, 2.69 mmol) in 1,4-dioxane (5 mL) at 17 °C, water (1.0 mL), K2CO3 (1.1 g, 8.08 mmol), and Pd(dppf)Cl2 (220.0 mg, 0.27 mmol) were added sequentially. The resulting solution was stirred at 80 °C for 1 h under nitrogen. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was dissolved in DMF (3 mL) and applied to a 40 g C18 column. Purification by Combi Flash (Biotage Isolera Prime) was performed using a 5-60% acetonitrile in water mixture within 35 min, affording methyl 4-(2-chloro-6-methoxyphenyl)-6-methylnicotinate (635.0 mg, 80%) as a yellow oil. MS (ESI) calculated for (C 15 H 14 ClNO3) (M+1) + , 292.0; found, 292.2.

[0599] Step 2: 4-(2-chloro-6-methoxyphenyl)-6-methylnicotinic acid

[0600] [ka]

[0601] To a stirred solution of methyl 4-(2-chloro-6-methoxyphenyl)-6-methylnicotinate (635.0 mg, 2.18 mmol) in methanol (4 mL) at 17° C., water (4 mL) and NaOH (348.0 mg, 8.71 mmol) were added sequentially. The resulting solution was stirred at 80° C. for 30 minutes and then diluted with water. The aqueous layer was acidified with citric acid to pH 6 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-chloro-6-methoxyphenyl)-6-methylnicotinic acid (600.0 mg, crude) as a brown solid. MS (ESI) calculated for (C 14 H 12 ClNO3) (M+1) + , 278.0; found, 278.0.

[0602] Step 3 4-(2-chloro-6-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0603] [ka]

[0604] To a stirred solution of 4-(2-chloro-6-methoxyphenyl)-6-methylnicotinic acid (300.0 mg, 1.08 mmol) in acetonitrile (2 mL) at 17° C., 5-methoxy-1,3,4-thiadiazol-2-amine (156.0 mg, 1.19 mmol) and 1-methylimidazole (443.0 mg, 5.40 mmol) were added sequentially. To the above solution at 17° C. under nitrogen, a solution of TCFH (303.0 mg, 1.08 mmol) in acetonitrile (1 mL) was added. The resulting mixture was then stirred at 17° C. for 1 hour. The solvent was removed under vacuum. The resulting residue was dissolved in DCM (3 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0-10% methanol in dichloromethane within 20 min to give 4-(2-chloro-6-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (86.1 mg, 20%) as a white solid. MS (ESI) calculated for (C 17 H 15 ClN4O3S) (M+1) + , 391.0; found, 391.15. 1 H NMR (400 MHz, DMSO-d6) δ12.88 (s, 1H), 8.86 (s, 1H), 7.39 - 7.35 (m, 1H), 7.25 (s, 1H), 7.14 - 7.11 (m, 1H), 7.04 - 7.02 (m, 1H), 4.06 (s, 3H), 3.60 (s, 3H), 2.57 (s, 3H).

[0605] Example 36 4-(2-(difluoromethoxy)phenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0606] [ka] Step 1: Methyl 4-(2-(difluoromethoxy)phenyl)-6-methylnicotinate

[0607] [ka]

[0608] To a stirred solution of methyl 4-chloro-6-methylnicotinate (1.0 g, 5.39 mmol) in 1,4-dioxane (5 mL) was added bis(pinacolato)diboron (2.7 g, 10.78 mmol), potassium acetate (1.6 g, 16.16 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.2 g, 1.62 mmol) sequentially at 23° C. The resulting solution was stirred at 100° C. for 4 hours under nitrogen. To the above mixture at 23 °C was added a mixture of 1-bromo-2-(difluoromethoxy)benzene (1.0 g, 4.50 mmol), water (2 mL), potassium carbonate (1.9 g, 13.50 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (800.0 mg, 1.09 mmol) in dioxane (10 mL). The resulting solution was stirred at 80 °C for 2 h under nitrogen. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) on an 80.0 g silica gel column eluted with 0 to 14% methanol in dichloromethane within 40 min to give methyl 4-(2-(difluoromethoxy)phenyl)-6-methylnicotinate (1.1 g, 97% yield) as a brown oil. MS (ESI) calculations for (C 15 H 13 F2NO3) (M+1) + , 294.1; found, 294.1.

[0609] Step 2: 4-(2-(difluoromethoxy)phenyl)-6-methylnicotinic acid

[0610] [ka]

[0611] To a stirred solution of methyl 4-(2-(difluoromethoxy)phenyl)-6-methylnicotinate (1.0 g, 3.41 mmol) in methanol (4 mL) at 20° C. was added water (4 mL) and sodium hydroxide (546.0 mg, 13.64 mmol). The resulting solution was stirred at 20° C. for 2 hours under nitrogen. The organic solvent was removed under vacuum. The aqueous layer was acidified to pH 6 with saturated citric acid solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-(difluoromethoxy)phenyl)-6-methylnicotinic acid (823.0 mg, 70% yield) as a brown solid. MS (ESI) calculation for (C 14 H 11 F2NO3) (M+1) + , 280.1, found 280.1.

[0612] Step 3 4-(2-(difluoromethoxy)phenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0613] [ka]

[0614] To a stirred solution of 4-(2-(difluoromethoxy)phenyl)-6-methylnicotinic acid (200.0 mg, 0.72 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (103.0 mg, 0.79 mmol) in acetonitrile (2 mL) was added 1-methylimidazole (293.5 mg, 3.58 mmol). Then, to the above mixture was added TCFH (201.0 mg, 0.72 mmol) in acetonitrile (1 mL) at 20° C. The resulting solution was stirred under nitrogen at 20° C. for 2 hours. The resulting residue was dissolved in acetonitrile (1 mL) and applied to a 20 g C18 column. It was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5–40% acetonitrile in water within 30 min to give 4-(2-(difluoromethoxy)phenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (143.0 mg, 50% yield) as a white solid. MS (ESI) calculations for (C 17 H 14 F2N4O3S) (M+1) + , 393.1; found 393.1. 1 H NMR (400 MHz, DMSO-d6) δ12.90 (s, 1H), 8.81 (s, 1H), 7.53 - 7.39 (m, 2H), 7.37 - 7.30 (m, 2H), 7.23 - 6.84 (m, 2H), 4.06 (s, 3H), 2.59 (s, 3H).

[0615] Example 37 2'-Chloro-5'-methoxy-6-methyl-N-(5-propoxy-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0616] [ka]

[0617] Step 1 O-propyl hydrazinecarbothioate

[0618] [ka]

[0619] To a solution of potassium O-propyl carbodithioate (2.0 g, 11.47 mmol) in methanol (15 mL) at 16° C. was added hydrazine (0.5 mL, 13.77 mmol). The resulting solution was stirred at 16° C. for 2 hours. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give O-propyl hydrazinecarbothioate (2.3 g, crude) as a yellow oil.

[0620] Step 2: 5-propoxy-1,3,4-thiadiazol-2-amine

[0621] [ka]

[0622] To a solution of O-propyl hydrazinecarbothioate (2.0 g, 8.94 mmol) in methanol (10 mL) at 20 °C, TEA (1.2 mL, 8.94 mmol) and cyanogen bromide (1.0 g, 9.84 mmol) were added. The resulting solution was stirred at 20 °C for 30 min. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DMF (4 mL), applied to a 40 g C18 column, and purified by Combi Flash (Biotage Isolera Prime) using 5–24% acetonitrile in water within 43 min to give 5-propoxy-1,3,4-thiadiazol-2-amine (97.0 mg, 6%) as a yellow solid. MS (ESI) calculation for (C5H9N3OS) (M+1) + , 160.0; found 160.0.

[0623] Step 3 2'-chloro-5'-methoxy-6-methyl-N-(5-propoxy-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide

[0624] [ka]

[0625] To a mixture of 5-propoxy-1,3,4-thiadiazol-2-amine (89.0 mg, 0.49 mmol) in acetonitrile (4 mL) was added Intermediate G (120.0 mg, 0.40 mmol) and 1-methyl-1H-imidazole (101.0 mg, 1.22 mmol). To this was added a solution of TCFH (172.0 mg, 0.61 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The resulting solution was stirred at 20°C for 2 hours. The organic solvent was removed under vacuum. The residue was dissolved in DMF (5 mL) and purified using the following conditions: (Column: XBridge Prep OBD C 18 Purification by prep-HPLC using a 30 x 150 mm, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 40% B, 40% B in 8 min; wavelength: 254 nm; RT1 (min): 7.82 gave 2'-chloro-5'-methoxy-6-methyl-N-(5-propoxy-1,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (102.9 mg, 59%) as a white solid. MS (ESI) calculations for (C 18 H 18 ClN5O3S) (M+1) + , 420.0; found 420.1. 1H NMR (400 MHz, DMSO-d6) δ12.89 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 4.33 - 4.37 (t, J = 6.4 Hz, 2H), 3.63 (s, 3H), 2.58 (s, 3H), 1.73 - 1.81 (m, 2H), 0.94 - 0.98 (t, J = 7.6 Hz, 3H).

[0626] Example 38 4-(2-chloro-6-fluorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0627] [ka]

[0628] Step 1: Methyl 4-(2-chloro-6-fluorophenyl)-6-methylnicotinate

[0629] [ka]

[0630] To a stirred solution of (2-chloro-6-fluorophenyl)boronic acid (2.0 g, 11.47 mmol) in 1,4-dioxane (10 mL) was added methyl 4-chloro-6-methylnicotinate (532.2 mg, 2.87 mmol), potassium carbonate (1.1 g, 8.60 mmol), and water (2 mL) at 23 °C. To the above solution was added Pd(dtbpf)Cl (187.2 mg, 0.28 mmol) under nitrogen at 23 °C. The resulting mixture was then stirred at 80 °C under nitrogen for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (5 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to an 80 g silica gel column and eluting with 0 to 60% ethyl acetate in petroleum ether within 30 min to give methyl 4-(2-chloro-6-fluorophenyl)-6-methylnicotinate (200.0 mg 24%) as a yellow oil. MS (ESI) calculations for (C 14 H 11 ClFNO2) (M+1) + , 280.0; found, 280.0.

[0631] Step 2: 4-(2-chloro-6-fluorophenyl)-6-methylnicotinic acid

[0632] [ka]

[0633] To a stirred solution of methyl 4-(2-chloro-6-fluorophenyl)-6-methylnicotinate (200.0 mg, 0.72 mmol) in tetrahydrofuran (1 mL) and water (1 mL) at 23 °C, LiOH (34.2 mg, 1.44 mmol) was added. The resulting solution was stirred at 23 °C for 1 h and then diluted with water. The aqueous layer was acidified with citric acid to pH 3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (2 mL), which was applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–60% acetonitrile in water within 25 min to give 4-(2-chloro-6-fluorophenyl)-6-methylnicotinic acid (100.0 mg, 50%) as a white solid. MS (ESI) calculations for (C 13 H9ClFNO2) (M+1) + , 266.0; found, 266.1.

[0634] Step 3 4-(2-chloro-6-fluorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0635] [ka]

[0636] To a stirred solution of 4-(2-chloro-6-fluorophenyl)-6-methylnicotinic acid (80.0 mg, 0.30 mmol) in acetonitrile (2 mL) at 23 °C, 5-methoxy-1,3,4-thiadiazol-2-amine (39.5 mg, 0.30 mmol) and 1-methylimidazole (124.2 mg, 1.50 mmol) were added. To the above solution at 23 °C under nitrogen, a solution of TCFH (85.0 mg, 0.30 mmol) in acetonitrile (0.5 mL) was added. The resulting mixture was then stirred at 23 °C for 2 hours under nitrogen. This mixture was dissolved in DMF (4 mL) and purified under the following conditions: Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile Phase A: water (10 mmol / L NH4HCO 3) Purification by prep-HPLC using mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B in 8 min, 45% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; wavelength: 254 nm; RT (min): 7; injection volume: 1.5 mL; number of runs: 4) gave 4-(2-chloro-6-fluorophenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (51.3 mg, 45%) as a white solid. MS (ESI) calculations for (C 16 H 12 ClFN4O2S) (M+1) + , 379.0; found, 379.0. 1 H NMR (400 MHz, DMSO-d6) δ13.09 (s, 1H), 9.01 (s, 1H), 7.53 - 7.28 (m, 4H), 4.05 (s, 3H), 2.60 (s, 3H).

[0637] Example 39 2'-chloro-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-5',6-dimethyl-(4,4'-bipyridine)-3-carboxamide

[0638] [ka]

[0639] Step 1: 2'-chloro-5',6-dimethyl-(4,4'-bipyridine)-3-carboxylate methyl

[0640] [ka]

[0641] To a solution of methyl 4-chloro-6-methylnicotinate (1.5 g, 7.89 mmol) in 1,4-dioxane (5 mL) and water (1 mL) at 20 °C under nitrogen, methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (4.4 g, 15.88 mmol), K2CO3 (1.6 g, 11.8 mmol), and PdCl2(dppf) (0.8 g, 1.19 mmol) were added. The resulting solution was stirred at 80 °C for 2 hours under nitrogen. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0 to 50% ethyl acetate in petroleum ether within 35 min to give methyl 2'-chloro-5',6-dimethyl-(4,4'-bipyridine)-3-carboxylate (1.1 g, 96%) as a yellow solid. MS (ESI) calculations for (C 14 H 13 ClN2O2) (M+1) + , 277.1; found, 277.1.

[0642] Step 2: 2'-chloro-5',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid

[0643] [ka]

[0644] To a stirred solution of methyl 2'-chloro-5',6-dimethyl-(4,4'-bipyridine)-3-carboxylate (500.0 mg, 1.81 mmol) in tetrahydrofuran (2 mL) at 20°C was added a solution of lithium hydroxide (43.3 mg, 1.81 mmol) in water (2 mL). The resulting solution was stirred at 20°C for 1 hour. The organic solvent was removed in vacuo. The aqueous layer was acidified with citric acid to pH 5 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2'-chloro-5',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid (384.0 mg, crude) as a yellow solid. MS (ESI) calculation for (C 13 H 11 ClN2O2) (M+1) + , 263.1; found, 263.1.

[0645] Step 3 2'-chloro-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-5',6-dimethyl-(4,4'-bipyridine)-3-carboxamide

[0646] [ka]

[0647] To a solution of 2'-chloro-5',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid (150.0 mg, 0.57 mmol) in acetonitrile (2 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (74.9 mg, 0.57 mmol) and 1-methylimidazole (234.5 mg, 2.86 mmol) at 20°C under nitrogen. To the above solution was added a solution of TCFH (160.0 mg, 0.57 mmol) in acetonitrile (2 mL) at 20°C under nitrogen. This mixture was then stirred at 20°C for 1 hour. The resulting mixture was dissolved in DMF (1 mL) and applied to a 20 g C18 column. It was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5–55% acetonitrile in water within 30 min to give 2′-chloro-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-5′,6-dimethyl-(4,4′-bipyridine)-3-carboxamide (48.5 mg, 22%) as a white solid. MS (ESI) calculations for (C 16 H 14 ClN5O2S) (M+1) + , 376.1; found 376.1. 1 H NMR (400 MHz, DMSO-d6) δ13.05 (s, 1H), 8.98 (s, 1H), 8.30 (s, 1H), 7.29 - 7.36 (m, 2H), 4.04 (s, 3H), 2.58 (s, 3H), 1.98 (s, 3H).

[0648] Example 40 4-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0649] [ka]

[0650] Step 1: Methyl 4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methylnicotinate

[0651] [ka]

[0652] To a stirred solution of methyl 4-chloronicotinate (500.0 mg, 2.91 mmol) in 1,4-dioxane (5 mL) at 17 °C, 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (971.0 mg, 4.37 mmol), water (1.0 mL), K2CO3 (1.2 g, 8.74 mmol), and Pd(dppf)Cl2 (238.0 mg, 0.29 mmol) were added sequentially. The resulting solution was stirred at 80 °C for 16 hours under nitrogen. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to an 80.0 g silica gel column and eluting with 0-10% methanol in dichloromethane within 25 min to give methyl 4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methylnicotinate (202.0 mg, 26%) as a red solid. MS (ESI) calculated for (C 13 H 15 N3O2) (M+1) + , 246.0; found, 246.2.

[0653] Step 2: 4-(3,5-dimethyl-4H-pyrazol-4-yl)-6-methylnicotinic acid

[0654] [ka]

[0655] To a stirred solution of methyl 4-(3,5-dimethyl-4H-pyrazol-4-yl)-6-methylnicotinate (160.0 mg, 0.65 mmol) in methanol (2 mL) at 17° C. was added a solution of NaOH (104.0 mg, 2.61 mmol) in water (2 mL). The resulting solution was stirred at 17° C. for 30 minutes and then diluted with water. The organic solvent was removed in vacuo. The aqueous layer was acidified to pH 6 with citric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (2 mL) and applied to a 40 g C18 column. Purification by Combi Flash (Biotage Isolera Prime) was performed using 5–7% acetonitrile in water within 20 min to give 4-(3,5-dimethyl-4H-pyrazol-4-yl)-6-methylnicotinic acid (42.0 mg, 27%) as a white solid. MS (ESI) calculated for (C 12 H 13 N3O2) (M+1) + , 231.0; found, 231.

[0656] Step 3 4-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0657] [ka]

[0658] To a stirred solution of 4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methylnicotinic acid (140.0 mg, 0.61 mmol) in acetonitrile (2 mL) at 17° C., 5-methoxy-1,3,4-thiadiazol-2-amine (87.0 mg, 0.67 mmol) and 1-methylimidazole (249.0 mg, 3.03 mmol) were added sequentially. To the above solution at 17° C. under nitrogen, a solution of TCFH (170.0 mg, 0.61 mmol) in acetonitrile (1 mL) was added. The resulting mixture was then stirred at 17° C. for 1 hour. The organic solvent was removed under vacuum. The residue was dissolved in DMF (3 mL) and purified by prep-HPLC using the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 7% B to 27% B, 27% B in 8 min; Wavelength: 254 nm; RT1 (min): 7) to give 4-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (60.4 mg, 29%) as a white solid. MS (ESI) calculated for (C 15 H 16 N6O2S) (M+1) + , 345.0; found, 345.1. 1 H NMR (400 MHz, DMSO-d6) δ12.38 (s, 1H), 8.68 (s, 1H), 7.18 (s, 1H), 4.06 (s, 3H), 2.59 (s, 3H), 2.08 - 1.87 (m, 6H).

[0659] Example 41 5'-chloro-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxamide

[0660] [ka]

[0661] Step 1: 2',5'-dichloro-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0662] [ka]

[0663] To a stirred solution of (2,5-dichloropyridin-4-yl)boronic acid (0.5 g, 2.69 mmol) in 1,4-dioxane (10 mL) at 25 °C, methyl 4-chloro-6-methylnicotinate (1.0 g, 5.39 mmol), PdCl(DTBPF) (0.3 g, 0.53 mmol), and KCO (2.2 g, 16.16 mmol) were added sequentially. The resulting solution was stirred at 80 °C for 2 hours under nitrogen. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 50-80% ethyl acetate in petroleum ether within 30 min to give methyl 2',5'-dichloro-6-methyl-(4,4'-bipyridine)-3-carboxylate (400.0 mg, 20%) as a pale yellow solid. MS (ESI) calculations for (C 13 H 10 Cl2N2O2) (M+1) + , 297.0, found 297.0.

[0664] Step 2 5'-chloro-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate

[0665] [ka]

[0666] To a stirred solution of methyl 2',5'-dichloro-6-methyl-(4,4'-bipyridine)-3-carboxylate (400.0 mg, 1.34 mmol) in tetrahydrofuran (3 mL) at 25 °C, trimethylaluminum (4 mL, 4.04 mmol) was added. The resulting solution was stirred at 85 °C for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow oil. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) on a 20 g silica gel column eluted with 30–60% ethyl acetate in petroleum ether within 30 min to give methyl 5'-chloro-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate (270.0 mg, 58%) as a colorless oil. MS (ESI) calculations for (C 14 H 13 ClN2O2) (M+1) + , 277.0, found 277.1.

[0667] Step 3: 5'-chloro-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid

[0668] [ka]

[0669] To a stirred solution of methyl 5'-chloro-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate (270.0 mg, 0.78 mmol) in tetrahydrofuran (3 mL) and water (1 mL) at 25°C was added lithium hydroxide (18.6 mg, 0.78 mmol). The resulting solution was stirred at 25°C for 1 hour and then diluted with water. The organic solvent was removed in vacuo. The aqueous layer was acidified with 2N HCl to pH 4 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5'-chloro-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid (150.0 mg, crude) as a white solid. MS (ESI) calculations for (C 13 H 11 ClN2O2) (M+1), 263.0, found 263.0.

[0670] Step 4 5'-chloro-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxamide

[0671] [ka]

[0672] To a stirred solution of 5'-chloro-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid (150.0 mg, 0.51 mmol) in acetonitrile (2 mL) was added 1-methyl-1H-imidazole (211.0 mg, 2.57 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (81.0 mg, 0.61 mmol) sequentially at 25 °C. To the above solution was added TCFH (159.0 mg, 0.56 mmol) at 25 °C under nitrogen. The resulting mixture was then stirred at 25 °C for 2 hours. The suspension was filtered. The filter cake was washed with water (20 mL × 3) and tert-butyl methyl ether (20 mL). The solid was collected and dried under vacuum to give 5'-chloro-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxamide (79.0 mg, 40%) as a pale yellow solid. MS (ESI) calculations for (C 16 H 14 ClN5O2S) (M+1) + , 376.0, found 376.1. 1 H NMR (400 MHz, methanol-d4) δ 13.10 (s, 1H), δ 8.97 (s, 1H), 8.51 (s, 1H), 7.36–7.30 (m, 2H), 4.06 (s, 3H), 2.69 (s, 3H), 2.59 (s, 3H).

[0673] Example 42 2'-Chloro-5'-ethoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0674] [ka]

[0675] Step 1 2-chloro-5-ethoxypyridine

[0676] [ka]

[0677] To a stirred solution of 6-chloropyridin-3-ol (1.0 g, 7.72 mmol) in N,N-dimethylformamide (15 mL) at 20 °C, K2CO3 (2.1 g, 15.44 mmol) and iodoethane (1.4 g, 8.97 mmol) were added sequentially. The resulting solution was stirred at 40 °C for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (4 mL) and purified by Combi Flash (Biotage Isolera Prime) on a 40 g silica gel column eluted with 0–20% ethyl acetate in petroleum ether within 30 min to give 2-chloro-5-ethoxypyridine (827.0 mg, 67%) as a white solid. MS (ESI) calculated for (C7H8ClNO) (M+1) + , 158.0; found, 158.0.

[0678] Step 2 (2-chloro-5-ethoxypyridin-4-yl)boronic acid

[0679] [ka]

[0680] To a stirred solution of 2-chloro-5-ethoxypyridine (800.0 mg, 5.08 mmol) in tetrahydrofuran (30 mL) was added dropwise lithium diisopropylamide (5 ml, 10.00 mmol, 2N in THF) at −78° C. The resulting solution was stirred at −78° C. for 3 hours under nitrogen. To the above solution was added dropwise triisopropyl borate (1.9 g, 10.15 mmol) at −78° C. under nitrogen. This mixture was then stirred at −78° C. for 2 hours before being acidified to pH 4-5 with HCl (2N) at 0° C. The resulting mixture was stirred from 0° C. to room temperature for 30 minutes and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (2-chloro-5-ethoxypyridin-4-yl)boronic acid (650.0 mg, crude) as a yellow solid. MS (ESI) calculated for (C7H9BClNO3) (M+1) + , 202.0; found, 202.0.

[0681] Step 3: 2'-chloro-5'-ethoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0682] [ka]

[0683] To a stirred solution of methyl 4-chloro-6-methylnicotinate (500.0 mg, 2.69 mmol) in 1,4-dioxane (7 mL) at 23 °C, water (1.5 mL), (2-chloro-5-ethoxypyridin-4-yl)boronic acid (543.0 mg, 2.69 mmol), dichloro(1,1'-bis(di-t-butylphosphino)ferrocene)palladium(II) (176.0 mg, 0.27 mmol), and K2CO3 (1.1 g, 8.08 mmol) were added sequentially. The resulting solution was stirred at 80 °C for 3 hours under nitrogen. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (3 mL) and purified by Combi Flash (Biotage Isolera Prime) on a 40 g silica gel column, eluting with 0-3% methanol in dichloromethane within 20 min to give methyl 2'-chloro-5'-ethoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (360.0 mg, 43%) as a colorless oil. MS (ESI) calculated for (C 15 H 15 ClN2O3) (M+1) + , 307.1; found, 307.1.

[0684] Step 4 2'-chloro-5'-ethoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0685] [ka]

[0686] To a stirred solution of methyl 2'-chloro-5'-ethoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (350.0 mg, 1.14 mmol) in methanol (3 mL) at 20 °C was added a solution of sodium hydroxide (183.0 mg, 4.56 mmol) in water (3 mL). The resulting solution was stirred at 80 °C for 1 hour. The mixture was diluted with water. The volatiles were removed in vacuo. The aqueous layer was acidified to pH 5-6 with citric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2'-chloro-5'-ethoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (330.0 mg, crude) as a pink solid. MS (ESI) calculated for (C 14 H 13 ClN2O3) (M+1) + , 293.1; found, 293.1.

[0687] Step 5 2'-chloro-5'-ethoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0688] [ka]

[0689] To a stirred solution of 2'-chloro-5'-ethoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (310.0 mg, 1.06 mmol) in acetonitrile (4 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (153.0 mg, 1.17 mmol) and 1-methylimidazole (435.0 mg, 5.30 mmol). To the above solution was added a solution of TCFH (297.0 mg, 1.06 mmol) in acetonitrile (1 mL) at 20 °C under nitrogen. The resulting solution was stirred at 20 °C for 2 h. The resulting mixture was dissolved in DMF (2 mL) and applied to a 40 g C18 column. The column was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5–70% acetonitrile in water within 30 min to give a yellow solid (88% pure). The product was dissolved in DMF (3 mL) and further purified under the following conditions: (Column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L) Purification by prep-HPLC using 2'-chloro-5'-ethoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide (70.5 mg, 16%) as a white solid was obtained. MS (ESI) calculated for (C 17 H 16 ClN5O3S) (M+1) + , 406.1; found, 406.1. 1 H NMR (400 MHz, DMSO-d6) δ12.95 (s, 1H), 8.83 (s, 1H), 8.13 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 4.08 (s, 3H), 3.97 - 3.87 (m, 2H), 2.59 (s, 3H), 1.12 - 1.04 (m, 3H).

[0690] Example 43 N-(5-methoxy-1,3,4-thiadiazol-2-yl)-4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinamide

[0691] [ka]

[0692] Step 1: Methyl 4-(6-chloro-3-methoxypyridazin-4-yl)-6-methylnicotinate

[0693] [ka]

[0694] To a stirred solution of methyl 4-chloro-6-methylnicotinate (1.0 g, 5.39 mmol) in 1,4-dioxane (5 mL) was added bis(pinacolato)diboron (2.7 g, 10.78 mmol), potassium acetate (1.6 g, 16.16 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.2 g, 1.62 mmol) sequentially at 23 °C. The resulting solution was stirred at 100 °C for 4 hours under nitrogen. To the above mixture was added water (0.4 mL), potassium carbonate (299.0 mg, 2.17 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (158.0 mg, 0.22 mmol) in 1,4-dioxane (2 mL) at 23 °C. The resulting solution was stirred at 80°C for 16 hours under nitrogen. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was dissolved in acetonitrile (2 mL) and applied to a 40.0 g C18 column. Purification was performed by Combi Flash (Biotage Isolera Prime) and eluted with 5 to 38% acetonitrile in water within 30 minutes to give methyl 4-(6-chloro-3-methoxypyridazin-4-yl)-6-methylnicotinate (114.0 mg, 50%) as a yellow oil. MS (ESI) calculations for (C 13 H12 ClN3O3) (M+1) + , 294.1; found, 294.1.

[0695] Step 2: Methyl 4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinate

[0696] [ka]

[0697] To a stirred solution of methyl 4-(6-chloro-3-methoxypyridazin-4-yl)-6-methylnicotinate (100.0 mg, 0.34 mmol) in 1,4-dioxane (1 mL) at 23° C., trimethylboroxine (51.0 mg, 0.41 mmol), cesium carbonate (333.0 mg, 1.02 mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (25.0 mg, 0.03 mmol) were added sequentially. The resulting solution was stirred at 100° C. for 16 hours under nitrogen. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was dissolved in acetonitrile (2 mL) and applied to a 40.0 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5 to 28% acetonitrile in water within 30 min to give methyl 4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinate (75.0 mg, 79%) as a yellow oil. MS (ESI) calculations for (C 14 H 15 N3O3) (M+1) + , 274.1, found 274.1.

[0698] Step 3: 4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinic acid

[0699] [ka]

[0700] To a stirred solution of methyl 4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinate (55.0 mg, 0.20 mmol) in methanol (0.9 mL) at 23 °C, water (0.3 mL) and lithium hydroxide (19.0 mg, 0.81 mmol) were added. The resulting solution was stirred at 23 °C for 0.5 h under nitrogen. The resulting residue was acidified with citric acid, which was applied to a 20.0 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–28% acetonitrile in water within 30 min to give 4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinic acid (47.0 mg, 89%) as a yellow solid. MS (ESI) calculations for (C 13 H 13 N3O3) (M+1) + , 260.1, found 260.1.

[0701] Step 4 N-(5-methoxy-1,3,4-thiadiazol-2-yl)-4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinamide

[0702] [ka]

[0703] To a stirred solution of 4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinic acid (47.0 mg, 0.18 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (26.0 mg, 0.20 mmol) in acetonitrile (1 mL) was added 1-methylimidazole (74.6 mg, 0.91 mmol). Next, to the above mixture was added TCFH (51.0 mg, 0.18 mmol) in acetonitrile (1 mL) at 23° C. The resulting solution was stirred under nitrogen at 23° C. for 2 hours. The resulting residue was dissolved in acetonitrile (1 mL) and applied to a 20.0 g C18 column. Purification by Combi Flash (Biotage Isolera Prime) was performed using 5–34% acetonitrile in water within 30 min to give N-(5-methoxy-1,3,4-thiadiazol-2-yl)-4-(3-methoxy-6-methylpyridazin-4-yl)-6-methylnicotinamide (31.0 mg, 45%) as a white solid. MS (ESI) calculations for (C 16 H 16 N6O3S) (M+1) + , 373.1; found 373.2. 1 H NMR (400 MHz, DMSO-d6) δ13.01 (s, 1H), 8.86 (s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 4.08 (s, 3H), 3.74 (s, 3H), 2.60 (s, 6H).

[0704] Example 44 2'-Ethyl-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0705] [ka]

[0706] Step 1: 5'-methoxy-6-methyl-2'-vinyl-(4,4'-bipyridine)-3-carboxylate methyl

[0707] [ka]

[0708] To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (400.0 mg, 1.33 mmol) in 1,4-dioxane (8 mL) at 20 °C, Pd(dppf)Cl (87.0 mg, 0.13 mmol), KCO (370.0 mg, 2.68 mmol), trifluoro(vinyl)-14-borane potassium salt (179.0 mg, 1.33 mmol), and water (2 mL) were added. The resulting solution was stirred at 80 °C for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0 to 26% ethyl acetate in petroleum ether within 35 min to give methyl 5'-methoxy-6-methyl-2'-vinyl-(4,4'-bipyridine)-3-carboxylate (350.0 mg, 65%) as a red oil. MS (ESI) calculations for (C 16 H 16 N2O3) (M+1) + , 285.1, found 285.1.

[0709] Step 2: 2'-ethyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0710] [ka]

[0711] To a mixture of methyl 5'-methoxy-6-methyl-2'-vinyl-(4,4'-bipyridine)-3-carboxylate (342.0 mg, 0.85 mmol) in methanol (2 mL) under a hydrogen atmosphere, Pd / C (dry, 50.0 mg) was added. The resulting solution was stirred at 20 °C for 2 h under a hydrogen atmosphere. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The residue was dissolved in DCM (3 mL) and purified by Combi Flash (Biotage Isolera Prime) onto a 40 g silica gel column eluted with 0 to 7% methanol in dichloromethane within 35 min to give methyl 2'-ethyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (300.0 mg, 96%) as a yellow oil. MS (ESI) calculations for (C 16 H 18 N2O3) (M+1) + , 287.1, found 287.1.

[0712] Step 3: 2'-ethyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0713] [ka]

[0714] To a solution of methyl 2'-ethyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (300.0 mg, 0.81 mmol) in tetrahydrofuran (THF) (3 mL) at 17°C, LiOH (78.0 mg, 3.27 mmol) and water (1.0 mL) were added. The resulting solution was stirred at 50°C for 2 hours. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2'-ethyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (246.0 mg, 88%) as a red oil. MS (ESI) calculation for (C 15 H 16 N2O3) (M+1) +, 273.1, found 273.1.

[0715] Step 4 2'-ethyl-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0716] [ka]

[0717] To a mixture of 5-methoxy-1,3,4-thiadiazol-2-amine (69.4 mg, 0.52 mmol) in acetonitrile (2 mL) was added 2'-ethyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (150.0 mg, 0.44 mmol) and 1-methyl-1H-imidazole (109.0 mg, 1.32 mmol). To this was added a solution of TCFH (185.0 mg, 0.66 mmol) in acetonitrile (1 mL) dropwise under nitrogen. The organic solvent was removed under vacuum. The resulting residue was dissolved in DMF (5 mL) and applied to a 40 g C18 column. The column was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5–23% acetonitrile in water within 34 min to give a white solid (70%). The product (70%) was dissolved in DMF (5 mL) and further purified under the following conditions: (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L) Purification by prep-HPLC using 2'-ethyl-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide (51.1 mg, 29%) as a white solid was obtained. MS (ESI) calculations for (C 18 H19 N5O3S) (M+1) + , 386.1, found 386.1. 1 H NMR (400 MHz, DMSO-d6) δ12.87 (s, 1H), 8.76 (s, 1H), 8.22 (s, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 4.06 (s, 3H), 3.60 (s, 3H), 2.74 - 2.76 (m, 2H), 2.58 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H).

[0718] Examples 45 and 46 2'-chloro-N-(5-(((1s,3s)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-(((1s,3r)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0719] [ka]

[0720] Step 1: 3-((tert-butyldimethylsilyl)oxy)cyclopentan-1-ol

[0721] [ka]

[0722] To a stirred solution of cyclopentane-1,3-diol (1.0 g, 9.79 mmol) in dichloromethane (5 mL) at 0 °C, TBS-Cl (1.5 g, 9.79 mmol) and imidazole (0.7 g, 9.79 mmol) were added sequentially. The resulting solution was stirred at 0 °C for 2 h. The organic solvent was removed under vacuum. The resulting residue was dissolved in DCM (2 mL) and purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g silica gel column and eluted with 0–10% methanol in dichloromethane within 30 min to give 3-((tert-butyldimethylsilyl)oxy)cyclopentan-1-ol (620.0 mg, 25%) as a colorless oil.

[0723] Step 2: Carbonodithioic acid O-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)S-methyl

[0724] [ka]

[0725] To a degassed solution of 3-((tert-butyldimethylsilyl)oxy)cyclopentan-1-ol (600.0 mg, 2.77 mmol) in dry tetrahydrofuran (4 mL) was added NaH (222.0 mg, 5.55 mmol, 60%) in small portions at 0° C. and stirred at 0° C. for 30 minutes under a nitrogen atmosphere. CS2 (0.3 mL, 4.16 mmol) was then added to the above mixture at 0° C. and stirred at 0° C. for 20 minutes. MeI (0.3 mL, 4.16 mmol) was then added to the above solution at 0° C. under nitrogen. The resulting mixture was then stirred at 0° C. for 1 hour. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (2 mL) and purified by Combi Flash (Biotage Isolera Prime) applied to a 40 g silica gel column and eluted with 0–30% ethyl acetate in petroleum ether within 20 min to give O-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)S-methyl carbonodithioate (744.0 mg, 74%) as a yellow oil.

[0726] Step 3: O-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)hydrazinecarbothioate

[0727] [ka]

[0728] To a stirred solution of O-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)S-methyl carbodithioate (710.0 mg, 2.32 mmol) in methanol (5 mL) at 20° C. was added hydrazine (0.1 mL, 2.32 mmol). The resulting solution was stirred at 20° C. for 1 h. The solvent was removed in vacuo to give O-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)hydrazinecarbothioate (673.0 mg, crude) as a colorless oil. MS (ESI) calculated for (C 12 H 26 N2O2SSi) (M+1)+ , 291.0; found, 291.3.

[0729] Step 4: 5-((3-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)-1,3,4-thiadiazol-2-amine

[0730] [ka]

[0731] To a stirred solution of O-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)hydrazinecarbothioate (670.0 mg, 2.31 mmol) in methanol (4 mL) at 20° C., TEA (0.7 mL, 4.61 mmol) and BrCN (366.0 mg, 3.46 mmol) were added sequentially. The resulting solution was stirred at 20° C. for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (4 mL) and applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 15 to 80% acetonitrile in water within 30 min to give 5-((3-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)-1,3,4-thiadiazol-2-amine (301.0 mg, 34%) as a yellow solid. MS (ESI) calculated for (C 13 H 25 N3O2SSi) (M+1) + , 316.0; found, 316.3.

[0732] Step 5 2-(5-((3-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridin)-3-yl)ethan-1-one

[0733] [ka]

[0734] To a stirred solution of 5-((3-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)-1,3,4-thiadiazol-2-amine (300.0 mg, 0.95 mmol) in acetonitrile (3 mL) at 23° C. was added Intermediate G (240.6 mg, 0.86 mmol) and 1-methylimidazole (354.0 mg, 4.32 mmol). To the above solution at 23° C. under nitrogen was added a solution of TCFH (242.0 mg, 0.86 mmol) in acetonitrile (1 mL). The resulting mixture was then stirred at 23° C. for 1 h. The solvent was removed under vacuum. The resulting residue was dissolved in DMF (4 mL) and applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–70% acetonitrile in water within 35 min to give 2-(5-((3-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2′-chloro-5′-methoxy-6-methyl-(4,4′-bipyridin)-3-yl)ethan-1-one (330.0 mg, 66%) as a white solid. MS (ESI) calculated for (C 26 H 34 ClN5O4SSi) (M+1) + , 576.0; found, 576.4.

[0735] Step 6 2'-chloro-N-(5-(((1s,3s)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-(((1s,3r)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0736] [ka]

[0737] To a stirred solution of N-(5-((3-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (330.0 mg, 0.57 mmol) in dichloromethane (4 mL) at 0 °C was added trifluoroacetic acid (0.8 mL). The resulting solution was stirred at 23 °C for 2 h. The organic solvent was removed in vacuo. The mixture was diluted with water. The aqueous layer was basified to pH 7-8 with NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (6 mL) and applied to an 80 g C18 column. This was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5 to 80% acetonitrile in water within 30 min to give a mixture of 2'-chloro-N-(5-((3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamides (160.0 mg, 59%) as a white solid. The mixture of compounds (160.0 mg) was purified under the following conditions: (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 40% B, 40% B in 8 min; wavelength: 254 nm; RT1 (min): 6.25), and the first peak in the chiral HPLC was 2'-chloro-N-(5-(((1s,3s)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl 4,4'-bipyridine)-3-carboxamide (9.0 mg, 6% yield) was obtained as a white solid, and the second peak by chiral HPLC was 2'-chloro-N-(5-(((1s,3r)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (70.2 mg, 43% yield) as a white solid. The absolute stereochemistry was not determined and was arbitrarily assigned.

[0738] 2'-chloro-N-(5-(((1s,3s)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide: MS (ESI) calculated for (C 20 H 20 ClN5O4S) (M+1) + , 462.0; found, 462.1. 1 H NMR (400 MHz, DMSO-d6) δ12.92 (s, 1H), 8.83 (s, 1H), 8.15 (s, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 5.25 - 5.11 (m, 1H), 4.68 - 4.53 (m, 1H), 4.27 - 4.09 (m, 1H), 3.63 (s, 3H), 2.67 (s, 3H), 2.35 - 2.28 (m, 1H), 2.02 - 1.76 (m, 2H), 1.74 - 1.73 (m, 3H).

[0739] 2'-chloro-N-(5-(((1s,3r)-3-hydroxycyclopentyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide: MS (ESI) calculated for (C 20 H 20 ClN5O4S) (M+1) + , 462.0; found, 462.1. 1H NMR (400 MHz, DMSO-d6) δ12.85 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 5.39 - 5.26 (m, 1H), 4.64 - 4.50 (m, 1H), 4.27 - 4.13 (m, 1H), 3.63 (s, 3H), 2.59 (s, 3H), 2.20 - 2.18 (m, 1H), 2.00 - 1.70 (m, 2H), 1.74 - 1.73 (m, 2H), 1.54 - 1.50 (m, 1H).

[0740] Example 47 2'-chloro-3'-fluoro-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0741] [ka]

[0742] Step 1 2-chloro-3-fluoro-5-methoxypyridine [ka]

[0743] To a solution of 6-chloro-5-fluoropyridin-3-ol (20.0 g, 135.60 mmol) in acetone (150 mL) at 25 °C under a nitrogen atmosphere was added MeI (17 mL, 271.00 mmol) and K2CO3 (37.5 g, 271.00 mmol). The resulting solution was stirred at 25 °C under nitrogen for 16 h and then concentrated in vacuo. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) on a 330 g silica gel column eluted with 0–22% ethyl acetate in petroleum ether within 45 min to give 2-chloro-3-fluoro-5-methoxypyridine (16.0 g, 80%) as a colorless oil. MS (ESI) calculation for (C6H5ClFNO) (M+1) + , 162.0; found 162.0.

[0744] Step 2: 2-chloro-3-fluoro-4-iodo-5-methoxypyridine [ka]

[0745] To a degassed solution of 2-chloro-3-fluoro-5-methoxypyridine (16.0 g, 99.00 mmol) in dry tetrahydrofuran (160 mL) at -60 °C, n-butyllithium (44 mL, 110.00 mmol, 2.5 N in hexane) was added dropwise and stirred at -60 °C for 1 hour under a nitrogen atmosphere. Next, iodine (27.6 g, 109.00 mmol) was added to the above mixture at -60 °C. The resulting solution was stirred at -60 to 20 °C for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to a 330 g silica gel column and eluting with 0-50% ethyl acetate in petroleum ether within 40 min to give 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (22.0 g, 73%) as a white solid. MS (ESI) calculation for (C6H4ClFINO) (M+1) + , 287.9; found, 287.9.

[0746] Step 3: 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0747] [ka]

[0748] To a degassed solution of methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (7.2 g, 26.10 mmol) and 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (5.0 g, 17.39 mmol) in dry 1,4-dioxane (50 mL) was added water (10 mL), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane complex (4.2 g, 5.15 mmol), and K2CO3 (7.2 g, 52.20 mmol) at 25 °C under a nitrogen atmosphere. The resulting solution was stirred at 25 °C for 2 hours under a nitrogen atmosphere. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) on a 120 g silica gel column eluted with 0 to 46% ethyl acetate in petroleum ether within 45 min to give methyl 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (2.8 g, 53%) as a white solid. MS (ESI) calculations for (C 14 H 12 ClFN2O3) (M+1) + , 311.1; found, 311.1.

[0749] Step 4 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0750] [ka]

[0751] To a stirred solution of methyl 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (2.8 g, 9.17 mmol) in methanol (10 mL) at 25°C was added NaOH (1.4 g, 36.70 mmol) and water (10 mL). The resulting solution was stirred at 25°C for 2 hours and then diluted with water. The organic solvent was removed in vacuo. The aqueous layer was acidified with citric acid to pH 5 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (1.3 g, crude) as a yellow oil. MS (ESI) calculation for (C 13 H 10 ClFN2O3) (M+1) + , 297.0, found 297.0.

[0752] Step 5 2'-chloro-3'-fluoro-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0753] [ka]

[0754] To a solution of 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (130.0 mg, 0.43 mmol) in dry acetonitrile (1 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (57.0 mg, 0.43 mmol) and 1-methyl-1H-imidazole (180.0 mg, 2.15 mmol) at 25° C. Next, to the above mixture was added a solution of TCFH (123 mg, 0.44 mmol) in acetonitrile at 25° C. The resulting solution was stirred at 25° C. for 2 hours. This mixture was applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–45% acetonitrile in water within 40 min to give 2′-chloro-3′-fluoro-5′-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4′-bipyridine)-3-carboxamide (21.4 mg, 11%) as a white solid. MS (ESI) calculations for (C 16 H 13 ClF2N2O3S) (M+1) + , 410.0, found 410.0. 1 H NMR (400 MHz, DMSO-d6) δ13.04 (s, 1H), 8.98 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 4.07 (s, 3H), 3.74 (s, 3H), 2.60 (s, 3H).

[0755] Example 48 2'-chloro-5'-(difluoromethoxy)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0756] [ka] Step 1 2-chloro-5-(difluoromethoxy)-4-iodopyridine

[0757] [ka]

[0758] To a stirred solution of 6-chloro-4-iodopyridin-3-ol (10.0 g, 39.14 mmol) in N,N-dimethylformamide (DMF) (50 mL) at 25 °C was added sodium 2-chloro-2,2-difluoroacetate (11.9 g, 78.20 mmol) and CsCO (16.6 g, 50.80 mmol). The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) on a 330 g silica gel column eluted with 0–25% ethyl acetate in petroleum ether within 40 min to give 2-chloro-5-(difluoromethoxy)-4-iodopyridine (10.5 g, 79%) as a white solid. MS (ESI) calc'd for (C6H3ClF2INO) (M+1) + , 305.4; found 305.4.

[0759] Step 2: 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0760] [ka]

[0761] To a degassed solution of methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (5.0 g, 18.04 mmol) in 1,4-dioxane (40 mL) was added 2-chloro-5-(difluoromethoxy)-4-iodopyridine (5.5 g, 18.04 mmol), water (8 mL), KCO (7.5 g, 54.1 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane complex (4.4 g, 5.41 mmol) at 23 °C under a nitrogen atmosphere. The resulting solution was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The suspension was filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) by applying to a 120 g silica gel column and eluting with 0 to 56% ethyl acetate in petroleum ether within 40 min to give methyl 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylate (5.7 g, 63%) as a white solid. MS (ESI) calculations for (C 14 H 11 ClF2N2O3) (M+1) + , 329.0; found, 329.0.

[0762] Step 3: 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0763] [ka]

[0764] To a stirred solution of methyl 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylate (3.0 g, 9.13 mmol) in methanol (20 mL) at 25°C was added NaOH (1.4 g, 36.50 mmol) and water (20 mL). The resulting solution was stirred at 25°C for 1 hour and then diluted with water. The organic solvent was removed in vacuo. The aqueous layer was acidified with citric acid to pH 6 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (2.5 g, crude) as a yellow oil. MS (ESI) calculation for (C 13 H9ClF2N2O3) (M+1) + , 315.0, found 315.0.

[0765] Step 4 2'-chloro-5'-(difluoromethoxy)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0766] [ka]

[0767] To a stirred solution of 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (50.0 mg, 0.15 mmol) in acetonitrile (1 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (22.0 mg, 0.17 mmol) and 1-methyl-1H-imidazole (65.0 mg, 0.79 mmol) at 25°C. Next, to the above mixture was added a solution of TCFH (44.0 mg, 0.15 mmol) in acetonitrile (0.5 mL) at 25°C. The resulting solution was stirred at 25°C for 1 hour. The resulting mixture was applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–45% acetonitrile in water within 40 min to give 2′-chloro-5′-(difluoromethoxy)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4′-bipyridine)-3-carboxamide (27.5 mg, 38% yield) as a white solid. MS (ESI) calculations for (C 16 H 12 ClF2N5O3S) (M+1) + ,428.0, found 428.1. 1 H NMR (400 MHz, DMSO-d6) δ13.08 (s, 1H), 8.97 (s, 1H), 8.33 (s, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 7.31 - 6.80 (m, 1H), 4.07 (s, 3H), 2.61 (s, 3H).

[0768] Example 49 2'-chloro-5'-ethyl-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0769] [ka]

[0770] Step 1: 5'-bromo-2'-chloro-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0771] [ka]

[0772] To a degassed solution of methyl 4-chloro-6-methylnicotinate (1.0 g, 5.39 mmol) in 1,4-dioxane (10 mL) under a nitrogen atmosphere at 25° C., bis(pinacolato)diboron (2.7 g, 10.78 mmol), potassium acetate (1.6 g, 16.16 mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.2 g, 1.62 mmol) were added sequentially. The resulting solution was stirred under nitrogen at 25° C. for 3 hours. To the above mixture was added a solution of 5-bromo-2-chloro-4-iodopyridine (1.0 g, 3.61 mmol), water (2 mL), potassium carbonate (1.5 g, 10.83 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.792 mg, 1.08 mmol) in 1,4-dioxane (10 mL) at 25 °C under a nitrogen atmosphere. The resulting solution was stirred at 80 °C for 2 h under nitrogen. The suspension was filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) on an 80 g silica gel column eluted with 0–10% methanol in dichloromethane within 40 min to give methyl 5'-bromo-2'-chloro-6-methyl-(4,4'-bipyridine)-3-carboxylate (2.1 g, 99%) as a brown oil. MS (ESI) calculated for (C 13 H 10 BrClN2O2) (M+1) + , 341.0; found, 341.0.

[0773] Step 2: 2'-chloro-6-methyl-5'-vinyl-(4,4'-bipyridine)-3-carboxylate methyl

[0774] [ka]

[0775] To a stirred solution of methyl 5'-bromo-2'-chloro-6-methyl-(4,4'-bipyridine)-3-carboxylate (400.0 mg, 1.17 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (180.0 mg, 1.17 mmol) in toluene (2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocenepalladium dichloride (76.0 mg, 0.12 mmol) at 20 °C under a nitrogen atmosphere. To the above solution was added potassium phosphate (994.0 mg, 4.68 mmol) in water (0.2 mL) at 50 °C. The resulting solution was stirred at 100 °C for 16 hours under nitrogen. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (4 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0-40% ethyl acetate in petroleum ether within 30 min to give methyl 2'-chloro-6-methyl-5'-vinyl-(4,4'-bipyridine)-3-carboxylate (260.0 mg, 67%) as a brown oil. MS (ESI) calculated for (C 15 H 13 ClN2O2) (M+1) + , 289.1; found, 289.1.

[0776] Step 3: 2'-chloro-5'-ethyl-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0777] [ka]

[0778] To a stirred solution of methyl 2'-chloro-6-methyl-5'-vinyl-(4,4'-bipyridine)-3-carboxylate (250.0 mg, 0.87 mmol) in ethyl acetate (10 mL) at 20°C was added platinum(IV) oxide (25.0 mg, 0.11 mmol). The resulting solution was stirred at 20°C for 1 hour under a hydrogen atmosphere. The suspension was filtered. The filtrate was collected and concentrated in vacuo to give methyl 2'-chloro-5'-ethyl-6-methyl-(4,4'-bipyridine)-3-carboxylate (240.0 mg, crude) as a brown oil. MS (ESI) calculated for (C 15 H 15 ClN2O2) (M+1) + , 291.1; found, 291.1.

[0779] Step 4 2'-chloro-5'-ethyl-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0780] [ka]

[0781] To a stirred solution of methyl 2'-chloro-5'-ethyl-6-methyl-(4,4'-bipyridine)-3-carboxylate (240.0 mg, 0.83 mmol) in methanol (3 mL) at 20 °C was added a solution of sodium hydroxide (132.0 mg, 3.30 mmol) in water (3 mL). The resulting solution was stirred at 80 °C for 1 hour. The organic solvent was removed in vacuo. The aqueous layer was acidified to pH 5-6 with citric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2'-chloro-5'-ethyl-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (190.0 mg, crude) as a white solid. MS (ESI) calculated for (C 14 H 13 ClN2O2) (M+1) + , 277.1; found, 277.1.

[0782] Step 5 2'-chloro-5'-ethyl-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0783] [ka]

[0784] To a stirred solution of 2'-chloro-5'-ethyl-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (210.0 mg, 0.76 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (100.0 mg, 0.76 mmol) in acetonitrile (1 mL) was added 1-methyl-1H-imidazole (312.0 mg, 3.79 mmol). To the above solution was added a solution of TCFH (213.0 mg, 0.76 mmol) in acetonitrile (1 mL) at 20 °C under nitrogen. The resulting solution was stirred at 20 °C for 2 h. The resulting residue was dissolved in DMF (3 mL) and applied to a 40 g C18 column. The column was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5–60% acetonitrile in water within 30 min to give a yellow solid (90% pure). The yellow solid (90% purity) was dissolved in DMF (2 mL) and purified under the following conditions: (Column: Atlantis HILIC Purification by prep-HPLC using an OBD column, 19 x 150 mm x 5 μm; mobile phase A: water (0.1% FA), mobile phase B: MeOH; flow rate: 25 mL / min; gradient: 65% B to 65% B in 8 min, 65% B to 95% B in 8.2 min, 95% B to 95% B in 10 min, 95% B to 65% B in 11 min, 65% B; wavelength: 220-254 nm; RT (min): 7; injection volume: 0.4 mL; number of runs: 5) gave 2'-chloro-5'-ethyl-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide (64.5 mg, 21%) as a white solid. MS (ESI) calculated for (C 17 H 16 ClN5O2S) (M+1) +, 390.1; found, 390.0. 1 H NMR (400 MHz, DMSO-d6) δ13.04 (s, 1H), 8.97 (s, 1H), 8.36 (s, 1H), 7.33 (s, 1H), 7.29 (s, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 2.41 - 2.29 (m, 2H), 1.00 - 0.92 (m, 3H).

[0785] Example 50 7-(2-Fluoro-6-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)imidazo(1,2-a)pyridine-6-carboxamide

[0786] [ka]

[0787] Step 1: 7-chloroimidazo(1,2-a)pyridine-6-carboxylate methyl ester

[0788] [ka]

[0789] To a solution of 6-amino-4-chloronicotinemethyl acid (900.0 mg, 4.82 mmol) in ethanol (6 mL) at 20 °C was added sodium bicarbonate (689.0 mg, 8.20 mmol) and 2-chloroacetaldehyde (4.3 g, 40% in water, 21.70 mmol). The resulting solution was stirred at 80 °C under nitrogen for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting mixture was dissolved in DCM (6 mL) and purified by Combi Flash (Biotage Isolera Prime) on an 80 g silica gel column eluted with 0–10% methanol in dichloromethane within 35 min to give methyl 7-chloroimidazo(1,2-a)pyridine-6-carboxylate (900.0 mg, 70%). MS (ESI) calc'd for (C9H7ClN2O2) (M+1) + , 211.0, found 211.0.

[0790] Step 2: 7-(2-fluoro-6-methoxyphenyl)imidazo(1,2-a)pyridine-6-carboxylate methyl ester

[0791] [ka]

[0792] A mixture of methyl 7-chloroimidazo(1,2-a)pyridine-6-carboxylate (600.0 mg, 2.56 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (654.0 mg, 3.85 mmol), XPhos (146.0 mg, 0.31 mmol), and XPhos Pd G3 (217.0 mg, 0.26 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was stirred at 80 °C for 2 hours under nitrogen. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting mixture was dissolved in DMF (5 mL) and applied to a 40 g C18 column. It was purified by Combi Flash (Biotage Isolera Prime) and eluted with 5–35% acetonitrile in water within 40 min to give methyl 7-(2-fluoro-6-methoxyphenyl)imidazo(1,2-a)pyridine-6-carboxylate (200.0 mg, 23%) as a white solid. MS (ESI) calculations for (C 16 H 13 FN2O3) (M+1) + , 301.0, found 301.0.

[0793] Step 3 7-(2-fluoro-6-methoxyphenyl)imidazo(1,2-a)pyridine-6-carboxylic acid

[0794] [ka]

[0795] A mixture of methyl 7-(2-fluoro-6-methoxyphenyl)imidazo(1,2-a)pyridine-6-carboxylate (120.0 mg, 0.36 mmol) and LiOH (34.5 mg, 1.43 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was stirred at 50° C. for 12 hours. The volatiles were removed in vacuo. The aqueous layer was acidified with citric acid to pH 5. The solvent was removed in vacuo to give 7-(2-fluoro-6-methoxyphenyl)imidazo(1,2-a)pyridine-6-carboxylic acid (950.0 mg, crude) as a yellow solid, which was used directly without further purification. MS (ESI) calculation for (C 15 H 11 FN2O3) (M+1) + , 287.0, found 286.9.

[0796] Step 4 7-(2-fluoro-6-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)imidazo(1,2-a)pyridine-6-carboxamide

[0797] [ka]

[0798] To a mixture of 7-(2-fluoro-6-methoxyphenyl)imidazo(1,2-a)pyridine-6-carboxylic acid (700.0 mg, 0.24 mmol) in acetonitrile (3 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (38.5 mg, 0.29 mmol) and NMI (120.0 mg, 1.46 mmol). To the above solution was added a solution of TCFH (103.0 mg, 0.36 mmol) in acetonitrile (1 mL) at 20° C. under nitrogen. The mixture was stirred at 20° C. for 2 hours under nitrogen. The volatiles were removed under vacuum. The residue was dissolved in DMF (3 mL) and applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–30% acetonitrile in water within 40 min to give 7-(2-fluoro-6-methoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)imidazo(1,2-a)pyridine-6-carboxamide (30.9 mg, 30%) as a yellow solid. MS (ESI) calculations for (C 18 H 14 FN5O3S) (M+1) + , 400.0, found 400.0. 1 H NMR (400 MHz, DMSO-d6) δ12.82 (s, 1H), 9.13 (s, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.54 (s, 1H), 7.45 - 7.32 (m, 1H), 6.97 - 6.75 (m, 2H), 4.07 (s, 3H), 3.59 (s, 3H).

[0799] Example 51 2'-Cyclopropyl-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0800] [ka]

[0801] Step 1: 2'-cyclopropyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate methyl

[0802] [ka]

[0803] To a stirred solution of methyl 2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (800.0 mg, 2.73 mmol) in 1,4-dioxane (10 mL) at 20 °C, cyclopropylboronic acid (235.0 mg, 2.73 mmol) and K3PO4 (1.2 g, 5.47 mmol) were added. To the above solution at 20 °C under nitrogen, PdAMphos (230.1 mg, 0.27 mmol) was added. The resulting mixture was then stirred at 80 °C for 2 hours under nitrogen. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (5 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to a 40 g silica gel column and eluting with 0 to 70% ethyl acetate in petroleum ether within 25 min to give methyl 2'-cyclopropyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (300.0 mg, 33%) as a yellow oil. MS (ESI) calculations for (C 17 H 18 N2O3) (M+1) + , 299.2; found, 299.2.

[0804] Step 2: 2'-cyclopropyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0805] [ka]

[0806] To a stirred solution of methyl 2'-cyclopropyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (300.0 mg, 1.01 mmol) in tetrahydrofuran (2 mL) at 20°C was added a solution of lithium hydroxide (24.1 mg, 1.01 mmol) in water (2 mL). The resulting solution was stirred at 20°C for 1 hour. The organic solvent was removed in vacuo. The aqueous layer was acidified with citric acid to pH 5 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2'-cyclopropyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (111.0 mg, crude) as a yellow solid. MS (ESI) calculations for (C 16 H 16 N2O3) (M+1)+, 245.1; found, 245.1.

[0807] Step 3 2'-cyclopropyl-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide

[0808] [ka]

[0809] To a solution of 2'-cyclopropyl-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (100 mg, 0.35 mmol) in acetonitrile (2 mL) was added 5-methoxy-1,3,4-thiadiazol-2-amine (46.1 mg, 0.35 mmol) and 1-methylimidazole (144.3 mg, 1.76 mmol) at 20°C under nitrogen. To the above solution was added a solution of TCFH (98.3 mg, 0.35 mmol) in acetonitrile (2 mL) at 20°C under nitrogen. The resulting mixture was then stirred at 20°C for 1 hour. The resulting residue was dissolved in DMF (1 mL) and applied to a 20 g C18 column. Purification by Combi Flash (Biotage Isolera Prime) was performed using 5-55% acetonitrile in water within 30 min to give 2'-cyclopropyl-5'-methoxy-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3-carboxamide (82.4 mg, 58%) as a white solid. MS (ESI) calculations for (C 19 H 19 N5O3S) (M+1)+, 398.1; found 398.1. 1 H NMR (400 MHz, DMSO-d6) δ12.84 (s, 1H), 8.75 (s, 1H), 8.15 (s, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 4.07 (s, 3H), 3.56 (s, 3H), 2.59 (s, 3H), 2.13 - 2.16 (m, 1H), 0.98 - 0.85 (m, 4H).

[0810] Example 52 5'-(Difluoromethoxy)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxamide

[0811] [ka]

[0812] Step 1: 5'-(difluoromethoxy)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate methyl

[0813] [ka]

[0814] To a degassed solution of methyl 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylate (150.0 mg, 0.45 mmol) in 1,2-dimethoxyethane (2 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II), K2CO3 (186.3 mg, 1.35 mmol) at 25 °C under a nitrogen atmosphere. Next, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (63 mg, 0.50 mmol) was added to the above mixture at 120 °C. The resulting mixture was stirred at 120 °C for 3 hours. The suspension was filtered. The filtrate was concentrated in vacuo. The resulting residue was dissolved in acetonitrile (4 mL) and applied to a 40 g C18 column. Purification by Combi Flash (Biotage Isolera Prime) was performed using 5-55% acetonitrile in water within 40 min to give methyl 5'-(difluoromethoxy)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate (70 mg, 42%) as a yellow oil. MS (ESI) calculations for (C 15 H 14 F2N2O3) (M+1) + , 309.1; found 309.1.

[0815] Step 2: 5'-(Difluoromethoxy)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid

[0816] [ka]

[0817] To a stirred solution of methyl 5'-(difluoromethoxy)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylate (70.0 mg, 0.227 mmol) in methanol (1 mL) was added NaOH (36.0 mg, 0.91 mmol) and water (1 mL) at 25°C. The resulting solution was stirred at 25°C for 2 hours. The organic solvent was removed in vacuo. The aqueous layer was acidified with citric acid to pH 7 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetonitrile (2 mL) and applied to a 20 g C18 column. Purification was performed by Combi Flash (Biotage Isolera Prime) eluting with 5–30% acetonitrile in water within 30 min to give 5′-(difluoromethoxy)-2′,6-dimethyl-(4,4′-bipyridine)-3-carboxylic acid (60.0 mg, 89%) as a yellow oil. MS (ESI) calculations for (C 14 H 12 F2N2O3) (M+1) + , 295.1; found, 295.1.

[0818] Step 3 5'-(Difluoromethoxy)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxamide

[0819] [ka]

[0820] To a stirred solution of 5'-(difluoromethoxy)-2',6-dimethyl-(4,4'-bipyridine)-3-carboxylic acid (60.0 mg, 0.20 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (26.0 mg, 0.20 mmol) in acetonitrile (1 mL) was added 1-methyl-1H-imidazole (84.0 mg, 1.02 mmol) at 25° C. Then, to the above mixture was added a solution of TCFH (56.0 mg, 0.20 mmol) in acetonitrile (0.5 mL) at 25° C. The mixture was stirred at 25° C. for 1 hour. The resulting mixture was applied to a 20 g C18 column and purified by Combi Flash (Biotage Isolera Prime) eluting with 5–38% acetonitrile in water within 30 min to give 5′-(difluoromethoxy)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-2′,6-dimethyl-(4,4′-bipyridine)-3-carboxamide (25.0 mg, 29%) as a white solid. MS (ESI) calculations for (C 17 H 15 F2N5O3S) (M+1) + ,408.1, found 408.1. 1 H NMR (400 MHz, DMSO-d6) δ13.01 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 7.42 - 7.32 (m, 2H), 7.22 - 6.85 (m, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 2.53 (s, 3H).

[0821] Example 53 4-(5-chloro-2-ethoxyphenyl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0822] [ka]

[0823] Step 1: Methyl 4-(5-chloro-2-ethoxyphenyl)-6-methylnicotinate

[0824] [ka]

[0825] To a solution of methyl 4-chloro-6-methylnicotinate (500.0 mg, 2.56 mmol) in 1,4-dioxane (8 mL) was added (5-chloro-2-ethoxyphenyl)boronic acid (513.0 mg, 2.56 mmol), Pd(dppf)Cl (209.0 mg, 0.25 mmol), KCO (707.0 mg, 5.12 mmol), and water (2 mL) at 18 °C. The resulting solution was stirred at 80 °C for 2 hours. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM (6 mL) and purified by Combi Flash (Biotage Isolera Prime) by applying to an 80 g silica gel column and eluting with 0 to 45% ethyl acetate in petroleum ether within 40 min to give methyl 4-(5-chloro-2-ethoxyphenyl)-6-methylnicotinate (680.0 mg, 70%) as a white solid. MS (ESI) calculations for (C 16 H 16 ClNO3) (M+1) + , 306.0; found 306.0.

[0826] Step 2: 4-(5-chloro-2-ethoxyphenyl)-6-methylnicotinic acid

[0827] [ka]

[0828] To a solution of methyl 4-(5-chloro-2-ethoxyphenyl)-6-methylnicotinate (200.0 mg, 0.52 mmol) in tetrahydrofuran (1.5 mL) at 20° C. was added LiOH (37.6 mg, 1.57 mmol) and water (0.5 mL). The resulting solution was stirred at 50° C. for 16 hours. The reaction mixture was diluted with water. The aqueous layer was acidified with citric acid to pH 5 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-chloro-2-ethoxyphenyl)-6-methylnicotinic acid (160.0 mg, crude) as a yellow solid. MS (ESI) calculations for (C 15 H 14 ClNO3) (M+1) + , 292.0; found 292.0.

[0829] Step 3 4-(5-chloro-2-ethoxyphenyl)-N-(5-methoxy-1...

Claims

1. A compound of formula (I): 【Chemical 1】 [wherein, ring A is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from N, O, and S, the subscripts m and n are each independently 0 or 1, R １ is C １－６ alkyl, halo, C １－６ haloalkyl, -X １ -O-C １－６ alkyl, C １－６ haloalkoxy, -X １ -cyano, -NO ２ , -C(O)OR ａ , -NR ａ C(O)R ｂ , -X １ -C(O)NR ａ R ｂ , -X １ , -OH, C ３－６ cycloalkyl, -X １ -O-C ３－６ cycloalkyl, C １－６ hydroxyalkynyl, -X １ , -NR ａ R ｂ , -X １ , -S(O) ２ R ａ , -X １ , -S(O) ２ NR ａ R ｂ , X １ , -X １ａ , -OR ａ and is selected from the group consisting of 4- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, R ２ is selected from the group consisting of C １－６ alkyl, halo, C １－６ haloalkyl, C １－６ haloalkoxy and -X １ -cyano, Each X １ is independently selected from bonding and C １－４ alkylene, X １ａ is a 3- to 6-membered heterocycloalkylene having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, R ａ and R ｂ are each independently selected from the group consisting of hydrogen, C １－６ alkyl, and C １－６ haloalkyl. Ar １ is selected from the group consisting of phenyl, naphthyl, pyridin-2-one, and 5- to 10-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from N, O, and S, where Ar １ is substituted with 0 to 4 R １ａ substituents, Each R １ａ is C １－６ alkyl, halo, C １－６ haloalkyl, -X ２ -O-C １－６ alkyl, C １－６ haloalkoxy, C ３－６ cycloalkyl, C ３－６ cycloalkyloxy, -C(O)R ｃ , -C(O) ２ R ｃ , -NR ｃ C(O)R ｄ , -O-C １－４ alkylene-O-C １－４ alkyl, -X ２ , -C(O)NR ｃ R ｄ , -X ２ , -S(O) ２ NR ｃ R ｄ , -X ２ , -NR ｃ R ｄ , -C(O)NR ｃ R ｄ , -X ２ , -cyano, -O-X ２ , -cyano, -X ２ , -S(O)R ｃ , -X ２ , -S(O) ２ R ｃ , -X ２ , -N(R ｄ ), -S(O) ２ R ｃ , -P(O)R ｃ R ｄ , -Y and -X ２ is independently selected from, or two R １ａ groups present at adjacent vertices of the ring together form a 4- to 6-membered cycloalkyl or heterocycloalkyl having 0 to 2 heteroatoms independently selected from N, O, and S as ring vertices, and the cycloalkyl or heterocycloalkyl formed by the two R １ａ groups is oxo, halo, C １－４ alkyl, C １－４ alkoxy, and C １－４ which is substituted with 0 to 4 groups independently selected from haloalkyl, Each Y is independently selected from phenyl, benzyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein each of the heterocycloalkyl and the heteroaryl represented by Y has 1 or 2 ring members independently selected from O, N, and S, and each Y is substituted with 0, 1, or 2 groups independently selected from halo, oxo, C １－４ alkyl, C １－４ alkoxy, and C １－４ haloalkyl. Each X ２ is independently selected from a bond and C １－４ alkylene, Each R ｃ and R ｄ are independently selected from the group consisting of hydrogen, C １－６ alkyl, C ３－５ cycloalkyl and C １－６ haloalkyl R ３ is (i) C ３－６ cycloalkyl, C ６－１１ bridged cycloalkyl and C ６－１２ spirocycloalkyl; (ii) 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iii) 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (iv) 6- to 10-membered bridged heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (v) 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; (vi) hydrogen; (vii) C １－６ alkyl or C ２－６ alkynyl is a member selected from the group consisting of, Each R in (i) to (v) ３ member is substituted with 0 to 4 R ３ａ substituents, R ３ａ Each of the substituents is C １－６ alkyl; C ２－６ alkenyl; C ２－６ alkynyl; halo; C １－６ haloalkyl; C １－６ haloalkoxy; -X ３ -O-C １－６ alkyl; -X ３ -OH; -NR ｅ R ｆ ; -ONO ２ ; 4- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices; -NR ｅ C(O)R ｆ ; -X ３ -NR ｅ R ｆ ; -X ３ independently selected from -cyano and oxo, R ３ member (vii) is halo, C １－３ haloalkyl, C １－６ haloalkoxy, -O-C １－６ alkyl, cyano, -OH, -NR ｅ R ｆ , -CONR ｅ R ｆ and is substituted with 0 to 3 R substituents selected from the group consisting of oxo, ３ｂ and is substituted with substituents, Each X ３ is independently selected from a bond and C １－４ alkylene, Each R ｅ and R ｆ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl and -C １－３ alkylene-C ３－６ cycloalkyl.] or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, imidazo[1,2-a]pyridinyl, 1,2,3-triazole, pyrazolyl, isoxazolyl, and imidazo[1,5-a]pyridinyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridinyl.

4. n is 1, and R １ is C １－６ alkyl, halo, C １－６ haloalkyl, -X １ -O-C １－６ alkyl, C １－６ haloalkoxy, -X １ -cyano, -X １ -OH, C ３－６ cycloalkyl and -X １ -NR ａ R ｂ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

5. n is 1 and R １ is methyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0.

7. Ar １ is each substituted with 0 to 4 R １ａ and is selected from the group consisting of phenyl, pyridinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazinyl, imidazo[1,2-a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, benzo[d]thiazole, indazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyridazinyl and tetrazolo[1,5-a]pyridinyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. Ar １ is pyridinyl substituted with 0 to 4 R １ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

9. A compound having formula (Ia2), (Ib2), or (Ic2): 【Chemical Formula 2】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. Each R １ａ is C １－６ alkyl, halo, C １－６ haloalkyl, -X ２ -O-C １－６ alkyl, C １－６ haloalkoxy, C ３－６ cycloalkyl, -NR ａ R ｂ , -X ２ -cyano and -X ２ -OH, independently selected from, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. Each R １ａ is independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, cyclopropyl, -NH ２ , hydroxymethyl and 1-hydroxyethyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ３ is C １－６ alkyl or C ２－６ alkynyl, and is substituted with 0 to 4 R ３ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R ３ wherein each of R is substituted with 0 to 4 R ３ａ and is a C ６－１２ spirocyclic or C ３－６ cycloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. R ３ is a 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, and is substituted with 0 to 4 R ３ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. R ３ is a 6- to 10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, and 0 to 4 R ３ａ substituted thereon, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. A compound selected from the compounds listed in Table 1 or a pharmaceutically acceptable salt thereof, a compound selected from the compounds listed in Table 2 or a pharmaceutically acceptable salt thereof, a compound selected from the compounds listed in Table 3 or a pharmaceutically acceptable salt thereof, or a compound selected from the compounds described in the Examples or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. A medicament for treating a disease characterized by overexpression of Polθ in a patient, comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. The medicament according to claim 18, wherein the disease is lymphoma, loboid tumor, multiple myeloma, uterine cancer, gastric cancer, cancer of the peripheral nervous system, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, cancer of fibroblasts, cancer of the central nervous system, urinary tract cancer, upper aerodigestive tract cancer, leukemia, kidney cancer, skin cancer, esophageal cancer or pancreatic cancer. A medicament for treating homologous recombination (HR)-deficient cancer in a patient, comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. The medicament according to claim 20, wherein the cancer is lymphoma, loboid tumor, multiple myeloma, uterine cancer, gastric cancer, cancer of the peripheral nervous system, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, cancer of fibroblasts, cancer of the central nervous system, urinary tract cancer, upper aerodigestive tract cancer, leukemia, kidney cancer, skin cancer, esophageal cancer or pancreatic cancer. A medicament for treating cancer in a patient, wherein the cancer is characterized by a decrease or absence of BRCA gene expression, an absence of the BRCA gene, or a decrease in the function of the BRCA protein, and the medicament comprises the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. The medicament according to claim 22, wherein the cancer is lymphoma, loboid tumor, multiple myeloma, uterine cancer, gastric cancer, cancer of the peripheral nervous system, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, cancer of fibroblasts, cancer of the central nervous system, urinary tract cancer, upper aerodigestive tract cancer, leukemia, kidney cancer, skin cancer, esophageal cancer or pancreatic cancer.

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