Thiadiazolyl derivatives as inhibitors of DNA polymerase theta.

Abstract

Disclosed herein are compounds of formula (I): which inhibit DNA polymerase theta (Pol θ) activity, particularly by inhibiting the ATP-dependent helicase domain activity of Pol θ: TIFF2022535227000795.tif52140. Also disclosed are pharmaceutical compositions containing the compounds, and methods for treating and / or preventing diseases treatable by inhibition of Pol θ, such as cancer, e.g., homologous recombination deficient (HRD) cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent Application No. 62 / 855,495, filed May 31, 2019, and U.S. Provisional Patent Application No. 62 / 990,239, filed March 16, 2020, the contents of each of which are incorporated herein by reference in their entirety for all purposes.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable.

[0003] Reference to a "Sequence Listing," a table, or a computer program listing appendix submitted on a compact disc Not applicable.

[0004] Field Disclosed herein are certain thiadiazolyl derivatives that inhibit DNA polymerase theta (Pol θ) activity, particularly by inhibiting the activity of the ATP-dependent helicase domain of Pol θ. Also disclosed are pharmaceutical compositions containing the compounds, and methods for treating and / or preventing diseases treatable by inhibition of Pol θ, such as cancer, e.g., homologous recombination-deficient (HRD) cancer. [Background technology]

[0005] Targeting DNA repair deficiency has become a proven and effective strategy in cancer therapy. However, DNA repair-deficient cancers often become dependent on backup DNA repair pathways, which represent an "Achilles' heel" that can be targeted to eliminate cancer cells and provide the basis for synthetic lethality. Synthetic lethality is exemplified by the success of poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of BRCA-deficient breast and ovarian cancers (Audeh MW, et al., Lancet (2010); 376 (9737): 245-51).

[0006] DNA damage repair processes are important for genome maintenance and stability. Among them, double-strand breaks (DSBs) 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. Numerous 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).

[0007] Polθ is unique among human DNA polymerases in that it exhibits 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 binding to Rad51 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 execute error-prone DNA synthesis at DNA damage sites via the alt-EJ pathway. The helicase domain of Polθ has been shown to cause inhibition of the HR pathway through disruption of the Rad51 nucleoprotein complex formation, 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 uses this annealing activity to promote end-joining in the alt-EJ pathway when the ssDNA overhang contains microhomology of more than 2 bp (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 combined action of Rad51 interaction and subsequent ATPase-mediated displacement of Rad51 from DSB damage sites. Once annealed, the primer strand of DNA can be extended by the polymerase domain of Pol θ.

[0008] Polθ 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 Polθ 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 Polθ 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 that contain DNA repair defects. Summary of the Invention

[0009] 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 the compounds, and methods for treating and / or preventing diseases treatable by inhibition of Pol θ, such as cancer, e.g., homologous recombination-deficient (HRD) cancer.

[0010] In a first aspect, the compound of formula (I): [ka] [In the formula, X is -N- or -C-; alk is alkylene; Ring A is phenyl or a 5-10 membered heteroaryl ring, including X, containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ar 1is phenyl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl or spiroheterocyclyl; Ar 1 Each of said rings represented by R a , R b and / or R c is replaced by R a and R b are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, acyl, acylamino, monoalkylamino, dialkylamino, alkylsulfonyl, cyano, and hydroxy; or R a and R b If they are on adjacent vertices of the ring, then together they form C 3-6 forming a cycloalkyl, or R a and R b are taken together to form an oxo when they are on the same vertex of the ring, R c is selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, heterocyclyloxy, aminocarbonyl; Ar 2 is phenyl, heteroaryl or cycloalkyl; Ar 2 The phenyl and heteroaryl represented by R d , R e and / or R f is replaced by R d and R e are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano; R f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl; R f wherein the heteroaryl and heterocyclyl represented by the formula: are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from alkyl, halo, haloalkyl and hydroxy; R 1 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, optionally substituted heteroaryl, hydroxyalkyl, cycloalkyl, hydroxyalkynyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, sulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl or optionally substituted heterocyclylalkyl; R 2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, or cyano. or a pharmaceutically acceptable salt thereof.

[0011] In a second aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable compound thereof and at least one pharmaceutically acceptable excipient.

[0012] In a third aspect, there is provided a method of treating and / or preventing a disease characterized by overexpression of Pol θ in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (or an embodiment thereof disclosed herein). In a first embodiment of the third aspect, the patient is identified as being in need of the treatment. In a second embodiment of the third aspect, and a first embodiment therein, the compound of Formula (I) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition. In the third embodiment of the third aspect, and the first and second embodiments therein, the disease is cancer.

[0013] No. 4In a fourth aspect, there is provided a method of treating and / or preventing homologous recombination (HR) deficient cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof. In a first embodiment of the fourth aspect, the patient is identified as being in need of the treatment. In a second embodiment of the fourth aspect, and a first embodiment therein, the compound of Formula (I) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.

[0014] In a fifth aspect, there is provided a method of 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 an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof. In a first embodiment, the cancer is an HR-deficient cancer.

[0015] In a sixth aspect, a method for treating cancer in a patient includes the steps of: and / and a method for treating or preventing cancer characterized by reduced or absent BRCA gene expression, an absence of a BRCA gene, or reduced function of a BRCA protein, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (I) (or an embodiment thereof disclosed herein) 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.

[0016] In a seventh aspect, there is provided a compound of Formula (I) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof for inhibiting DNA repair by Pol θ in a cell. In a first embodiment, the cell is an HR-deficient cell.

[0017] In an eighth aspect, there is provided a compound of formula (I) (or an embodiment thereof disclosed herein) 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.

[0018] In a ninth aspect, there is provided a compound of formula (I) (or an embodiment thereof as disclosed herein) or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer in a patient, wherein said cancer is characterised by reduced or absent BRCA gene expression, an absence of a BRCA gene, or reduced function of a BRCA protein.

[0019] In a tenth aspect, there is provided a compound of formula (I) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof for use in treating and / or preventing HR deficient cancer in a patient.

[0020] In an eleventh aspect, there is provided a compound of Formula (I) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a patient. 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.

[0021] In any of the third to eleventh aspects, the cancer is lymphoma, soft tissue cancer, 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, fibroblast cancer, cancer of the central nervous system, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer (data from large-scale dropout screens in cancer cell lines indicate that some cell lines derived from the above cancers are dependent on polymerase theta for proliferation. https: / / depmap.org / portal / ).

[0022] In a first embodiment, 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 adenocarcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or another breast cancer (including, but not limited to, 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- and estrogen receptor- and progesterone receptor-positive breast cancer). In a second embodiment, 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-theca tumor, Sertoli-Leydig cell tumor, and primary peritoneal carcinoma.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS Not applicable. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description Before the present invention is further described, it is to be understood that this 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.

[0025] 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 any optional element. Accordingly, this statement is intended to serve as a prelude to using exclusive terminology, e.g., "solely," "only," etc., in connection with the recitation of claim elements, or to use a "negative" limitation.

[0026] Where a range of values ​​is provided, each intervening value from the upper to lower limit of that range, and any other stated or intervening value in that stated range, to one-tenth of the unit of the lower limit, unless the context clearly dictates otherwise, is included in the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also included in the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both 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.

[0027] Where appropriate, any definition herein can be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is the element that attaches 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.

[0028] 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.

[0029] 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:

[0030] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. It will be recognized by those skilled in the art that the term "alkyl" can include "alkylene" groups.

[0031] "Alkylene," unless otherwise specified, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0032] "Alkylsulfonyl" means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, 2-propylsulfonyl, and the like.

[0033] "Alkoxy" means an --OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

[0034] "Alkoxycarbonyl" means a -COOR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, propoxy, 2-propoxycarbonyl, n-, iso-, or tert-butoxycarbonyl, and the like.

[0035] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of one to three carbon atoms, substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0036] "Acyl" means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.

[0037] "Acylamino" means a --NHC(O)R radical where R is alkyl as defined herein, e.g., methylcarbonylamino, ethylcarbonylamino, and the like.

[0038] "Amino" means -NH2.

[0039] "Aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of one to three carbon atoms substituted by -NR'R", e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like, where R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or methylaminomethyl, each as defined herein. Acyl is.

[0040] "Aminocarbonyl" means a -CONRR' radical where R and R' are independently hydrogen or alkyl as defined herein, e.g., -CONH2, methylaminocarbonyl, dimethylaminocarbonyl, and the like.

[0041] "Aminocarbonylalkyl" means an alkyl radical as defined above substituted with a -CONRR' radical where R and R' are independently hydrogen or alkyl as defined herein, e.g., -(CH)CONH, methylaminocarbonylmethyl, dimethylaminocarbonylethyl, and the like.

[0042] "Aminocarbonylmethyl" means a -CH2CONRR' radical where R and R' are independently hydrogen or alkyl as defined herein, e.g., -CH2CONH2, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, and the like.

[0043] "Aminosulfonylalkyl" means an alkyl radical as defined above substituted with a -SONR-R radical where R and R' are independently hydrogen or alkyl as defined herein, e.g., -(CH)SONH, methylaminosulfonylmethyl, dimethylaminosulfonylethyl, and the like.

[0044] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, e.g., phenyl or naphthyl.

[0045] "Bicyclic heterocyclyl" means a saturated monocyclic ring having from 4 to 7 ring carbon atoms, in which one or two ring carbon atoms are N, O, or S(O). n (n is an integer from 0 to 2) and is fused to a phenyl, 5- or 6-membered heteroaryl, or heterocyclyl (each as defined herein). Exemplary bicyclic heterocyclyl groups include: [ka] These include, but are not limited to:

[0046] A "bridged heterocyclyl" is a saturated monocyclic ring having 5 to 7 ring carbon atoms, in which two non-adjacent ring atoms are (CRR') n wherein n is 1 to 3 and each R is independently H or methyl; sometimes referred to herein as a "bridging" group; and wherein one or two ring carbon atoms (including the atoms of the bridging group) are N, O, or S(O). n (wherein n is an integer from 0 to 2). The bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, etc.

[0047] "Cycloalkyl" means a monocyclic monovalent hydrocarbon radical of 3 to 6 carbon atoms, which may be saturated or contain one double bond. Cycloalkyls can be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocycloprop-1-yl, 1-cyanomethylcycloprop-1-yl, 3-fluorocyclohexyl, and the like. When a cycloalkyl contains a double bond, it is sometimes referred to herein as a cycloalkenyl.

[0048] "Cycloalkyloxy" means an -OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, and the like.

[0049] "Cyanoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms substituted with one cyano as defined above, e.g., cyanomethyl, 2-cyanoethyl, and the like.

[0050] "Heavy alkyl" means an alkyl radical as defined above, wherein one to six hydrogen atoms in the alkyl radical have been replaced by deuterium, e.g., -CD3, -CH2CD3, etc.

[0051] "Dialkylamino" means an --NRR' radical where R and R' are independently alkyl as defined herein.

[0052] "Halo" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

[0053] "Haloalkyl" means an alkyl radical, as defined above, that is substituted with one to five halogen atoms, e.g., fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When alkyl is substituted with only fluoro, it may be referred to in this application as fluoroalkyl.

[0054] "Haloalkoxy" means an -OR radical where R is haloalkyl as defined above, e.g., -OCF, -OCHF, etc. When R is haloalkyl and the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.

[0055] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0056] "Hydroxyalkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond and substituted with a hydroxy group.

[0057] "Heteroaryl" means, unless otherwise specified, a monovalent monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, in which one or more (in one embodiment one, two, or three) ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon, unless otherwise specified. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl.

[0058] "Heterocyclyl" means a saturated or unsaturated monovalent monocyclic radical having four to eight ring atoms, in which one or two ring atoms are N, O, or S(O). n (n is an integer from 0 to 2), and the remaining ring atoms are C. Furthermore, one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced by a -CO- group. More specifically, the term heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, as long as the ring is not aromatic.

[0059] "Heterocyclyloxy" means an -OR radical where R is heterocyclyl as defined above.

[0060] "Heterocyclylalkyl" means a -(alkylene)-R radical, where R is heterocyclyl, and each group is defined herein.

[0061] "Monoalkylamino" means an --NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.

[0062] The term "oxo" as used herein, alone or in combination, refers to =(O).

[0063] "Optionally substituted heteroaralkyl" means -(alkylene)-heteroaryl, each as defined above, wherein heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano, unless otherwise specified.

[0064] "Optionally substituted heterocyclyl" means -(alkylene)-heterocyclyl, each as defined above, wherein the heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless otherwise specified.

[0065] "Sulfonylalkyl" means an alkyl radical as defined above substituted with a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonylmethyl, ethylsulfonylethyl, and the like.

[0066] "Spiroheterocyclyl" refers to a saturated bicyclic ring having 6 to 10 ring atoms in which 1, 2, or 3 ring atoms are N, O, or S(O). n (n is an integer from 0 to 2), the remaining ring atoms are C, and the rings are connected through only one atom. The connecting atom is also called a spiroatom and is most often a quaternary carbon ("spirocarbon"). Examples include, but are not limited to, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 4-oxa-7-azaspiro[2.5]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane, 2,7-diazaspiro[4.4]nonane, etc.

[0067] As used herein, "pharmaceutically acceptable salts" is meant 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 disclosed herein 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 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 phosphoric acid, as well as salts derived from relatively innocuous 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 arginine acid, and 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 that allow the compounds to be converted into either base or acid addition salts.

[0068] 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 may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention.

[0069] The present disclosure also includes protected derivatives of the compounds of the present disclosure. For example, if the compounds of the present disclosure contain groups such as hydroxy, carboxy, thiol, or any group containing a nitrogen atom, these groups can be protected with a suitable protecting group. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

[0070] The present disclosure also includes prodrugs of the compounds of Formula (I) (and any embodiment thereof disclosed herein, including specific compounds) or pharmaceutically acceptable salts thereof. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to form the compounds of the invention. A non-limiting example of a prodrug is a compound that is administered as an ester, but is then metabolically hydrolyzed to the carboxylic acid, the active entity (the "prodrug"). Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0071] Certain compounds of formula (I) (as well as any embodiments disclosed herein that include the specific compound) can exist in unsolvated forms as well as solvated forms, for example, hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be within the scope of the present invention. Certain compounds of formula (I) can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.

[0072] Certain compounds of Formula (I) (as well as any embodiments disclosed herein that include the specific compounds) possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, positional isomers, and separate isomers (e.g., separate enantiomers) are all intended to be included 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 80 / 20, more preferably 90 / 10, or 95 / 5 or greater. In some embodiments, one of the isomers is present in an amount of at least 99%.

[0073] Certain compounds of the present disclosure can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as separate forms and mixtures thereof, are within the scope of the present disclosure. For example, certain hydroxy-substituted compounds of formula (I) can exist as tautomers as shown below: [ka]

[0074] Compounds of Formula (I) (and any embodiment thereof disclosed herein, including specific compounds) may also contain unnatural amounts of isotopes at one or more atoms that constitute such compounds. An unnatural amount of an isotope may be defined as a range from the amount found in nature of the atom in question to 100% of the amount, differing only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention, e.g., compounds of Formula (I) (and any embodiment thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g., 100% of the amount of each of the isotopes. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 Isotopically labeled compounds (e.g., 3 H and 14 C) may be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14C) isotopes can be useful for their ease of preparation and detectability. Additionally, heavy isotopes, such as deuterium (i.e., 2 Substitution with 1 or more hydrogen atoms may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dosage). In some embodiments, in the compounds disclosed herein, including in Table 1 below, one or more hydrogen atoms may be substituted with 1 or more hydrogen atoms. 2 H or 3 H or one or more carbon atoms are replaced by 13 C or 14 C is replaced by enriched carbon. Positron-emitting isotopes, e.g. 15 O. 13 N, 11 C and 15 F is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the schemes or examples herein, by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0075] A "pharmaceutically acceptable carrier or excipient" generally means a carrier or excipient that is safe, non-toxic, and not biologically or otherwise unsuitable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0076] As used herein, "about" is intended to modify the numerical value that it modifies to indicate such value as variable within a tolerance. When a specific tolerance, such as a standard deviation relative to the mean value shown in a chart or table of data, is not stated, the term "about" should be understood to mean a range including ±10%, preferably ±5%, of the stated value and that range.

[0077] As used herein, "disease" is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (pathological condition), all of which reflect an abnormal state of the human or animal body or one of its parts that impairs normal function, is usually manifested by noticeable signs and symptoms, and reduces the length or quality of life of the human or animal.

[0078] The term "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.

[0079] As used herein, "in need of treatment" means that the patient has been treated by a physician or other caregiver after diagnosis of a disease, e.g., the patient has been diagnosed with a disease associated with Pol θ overexpression or a homologous recombination (HR)-deficient cancer.

[0080] "Administration," "administering," and the like, when applied to, e.g., a patient, cell, tissue, organ, or biological fluid, refer to the contacting of, e.g., a compound of Formula (I), a pharmaceutical composition comprising a compound of Formula (I), or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contacting of a reagent with the cell (e.g., in vitro or ex vivo), as well as contacting of a reagent with a fluid when the fluid is in contact with the cell.

[0081] As used herein, a "therapeutically effective amount" refers to an amount of a compound of Formula (I) (and any embodiment thereof disclosed herein, including specific compounds) or a pharmaceutically acceptable salt thereof, which, when administered to a patient for treating a disease, either alone or as part of a pharmaceutical composition, either in a single dose or as part of a series of doses, is sufficient to affect treatment for the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated. A therapeutically effective amount may be ascertained by measuring the relevant physiological effects and may be adjusted in conjunction with dosing regimens, diagnostic analysis of the subject's condition, etc. By way of example, measuring serum levels of a compound of Formula (I) (or, e.g., its metabolites) at specific time points after administration may indicate whether a therapeutically effective amount has been used.

[0082] "Treating" a disease or "treatment" of a disease includes: (1) inhibiting the disease, i.e., preventing or reducing the onset of the disease or its clinical symptoms; or (2) Relieving the disease, i.e., causing regression of the disease or its clinical symptoms Includes:

[0083] "Inhibit," "reduce," or any variation of these terms relating to Pol Theta include a measurable decrease or complete inhibition to achieve a desired result, such as about, up to 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, or any range derivable therein, in reduction of Pol Theta activity compared to normal activity.

[0084] The term "prevent" refers to preventing the development of clinical symptoms of a disease in a mammal that may be exposed to or susceptible to the disease, but that has not yet experienced or exhibited symptoms of the disease.

[0085] The term "homologous recombination" refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNAs.

[0086] The term "homologous recombination (HR) deficient cancer" refers to cancers 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, CtlP (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-related genes), Nbs1 (nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes (e.g., FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF).

[0087] 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 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, colorectal cancer, gastric cancer, bladder cancer, and prostate cancer.

[0088] Representative compounds of formula (I) are listed in Table 1 below.

[0089] [Table 1] TIFF0007655863000005.tif228168TIFF0007655863000006.tif220170TIFF0007655863000007.tif209168TIFF0007655863000008.tif213167TIFF0007655863000009.tif220168TIFF0007655863000010.tif221168TIFF0007655863000011.tif226169TIFF0007655863000012.tif209168TIFF0007655863000013.tif209170TIFF0007655863000014.tif213168TIFF0007655863000015.tif227170TIFF0007655863000016.tif224169TIFF0007655863000017.tif219169TIFF0007655863000018.tif224168TIFF0007655863000019.tif230168TIFF0007655863000020.tif223170TIFF0007655863000021.tif221167TIFF0007655863000022.tif218168TIFF0007655863000023.tif213168TIFF0007655863000024.tif197170TIFF0007655863000025.tif229169TIFF0007655863000026.tif207170TIFF0007655863000027.tif211169TIFF0007655863000028.tif224170TIFF0007655863000029.tif223169TIFF0007655863000030.tif207168TIFF0007655863000031.tif225169TIFF0007655863000032.tif208168TIFF0007655863000033.tif216170TIFF0007655863000034.tif209170TIFF0007655863000035.tif232170TIFF0007655863000036.tif200170TIFF0007655863000037.tif141170

[0090] Embodiment In further embodiments 1-16 below, the present disclosure includes the following embodiments.

[0091] Embodiment 1 In embodiment 1, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X, alk, ring A, Ar 1 and Ar 2 is as described in the Summary of the Invention above. In a first subembodiment of embodiment 1, alk is methylene or ethylene. In a second subembodiment of embodiment 1, alk is C 1-3 In a third subembodiment of embodiment 1, alk is methylmethylene.

[0092] Embodiment 2 In embodiment 2, provided is a compound having the formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 3 In embodiment 3, provided is a compound of embodiment 1 or 2 (or embodiments therein), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or a 5- or 6-membered heteroaryl ring. In a first subembodiment of embodiment 3, Ring A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, or imidazo[1,2-a]pyridinyl. In a second subembodiment of embodiment 3, Ring A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, 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. In a subembodiment of embodiment 3, Ring A is a 9- or 10-membered heteroaryl ring. In a subembodiment of embodiment 3, Ring A 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.

[0094] Embodiment 4 In embodiment 4, provided is a compound of embodiment 1 or 2 (or embodiments therein), or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heteroaryl ring. In a first subembodiment of embodiment 4, ring A is pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, or triazolyl. In a second subembodiment of embodiment 4, ring A is [ka] is.

[0095] In a third subembodiment of embodiment 4, ring A is [ka] is.

[0096] In a subembodiment of the third subembodiment, ring A is [ka] is.

[0097] In a fourth subembodiment of embodiment 4, ring A is [ka] is.

[0098] In a subembodiment of the fourth subembodiment, ring A is [ka] is.

[0099] In a subembodiment of the fourth subembodiment, ring A is [ka] is.

[0100] In a subembodiment of the fourth subembodiment, ring A is [ka] is.

[0101] In a subembodiment of the fourth subembodiment, ring A is [ka] is.

[0102] In a fifth subembodiment of embodiment 4, ring A is [ka] is.

[0103] Embodiment 5 In embodiment 5, provided is a compound of any one of embodiments 1-4 and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

[0104] Embodiment 6 In embodiment 6, there is provided a method for preparing a cyclohexyl methyl acrylate (C12-C16), comprising administering to a subject a subject a compound of formula (I) comprising: 1 But R a , R b and / or R c or a pharmaceutically acceptable salt thereof. In a first subembodiment of embodiment 6, Ar 1 is R a , R b and / or R c In a second subembodiment of embodiment 6, Ar is substituted with piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 2-oxo-1,2-dihydropyridinyl, thiomorpholinyl, or 1,1-dioxothiomorpholinyl. 1 is R a , R b and / or R c In one subembodiment of embodiment 6, Ar is substituted with piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 3-oxopiperazin-1-yl, 3-oxohomopiperazin-1-yl, 5-oxohomopiperazin-1-yl, tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 6-oxo-1,6-dihydropyridin-4-yl, thiomorpholin-4-yl, or 1,1-dioxothiomorpholin-4-yl. 1 is R a , Rb and / or R c In the third subembodiment of embodiment 6, and the first and second subembodiments therein, R a is hydrogen or alkyl, and R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy; R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl. a and R b When present on adjacent vertices of a ring, they are joined together to form a cyclopropyl or cyclobutyl ring, and R c is hydrogen. In one subembodiment of embodiment 6, R a and R b When present on adjacent vertices of the ring, they are joined together to form a cyclopropyl ring, and R c In the fourth subembodiment of embodiment 6 and the first and second subembodiments therein, Ar 1 But R b and / or R c is substituted with R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl or methylcarbonyl, and R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-1-ylethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl. 1are morpholin-4-yl, homomorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, 3R-methylmorpholin-4-yl, 3S-methylmorpholin-4-yl, 3-oxopiperazin-1-yl, 4-methyl-3-oxo-piperazin-1-yl, 2-methyl-3-oxopiperazin-1-yl, 6-methyl-3-oxopiperazin-1-yl, 5-methyl-3-oxopiperazin-1-yl, 3-oxohomopiperazin-1-yl, 5-oxohomopiperazin-1-yl, 4-dimethylaminocarbonylpiperazin-1-yl, tetrahydro 4-(2-morpholin-4-ylethyl)-3-oxopiperazin-1-yl, 4-methylcarbonylpiperazin-1-yl, 4-methylsulfonylpiperazin-1-yl, 1,1-dioxothiomorpholin-4-yl, or 4,4-difluoropiperidin-1-yl.

[0105] Embodiment 7 In embodiment 7, there is provided a compound comprising Ar 1 But R a , R b and / or R c or a pharmaceutically acceptable salt thereof. In a first subembodiment of embodiment 7, Ar 1 is 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl or 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl, and Ar 1 Each of the rings represented by R a , R b and / or R c In a subembodiment of embodiment 7, Ar 1is 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; Ar 1 Each of the rings represented by R a , R b and / or R c In the second subembodiment of embodiment 7 and the first subembodiment therein, R a is hydrogen and R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy; R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl. In the third subembodiment of embodiment 7, and the first and second subembodiments therein, Ar 1 is R b and / or R c is substituted with R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl or methylcarbonyl, R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-1-ylethyl, -CONH2, methylaminocarbonyl or dimethylaminocarbonyl.

[0106] Embodiment 8 In embodiment 8, there is provided a compound comprising Ar 1 But R a , Rb and / or R c or a pharmaceutically acceptable salt thereof. In a first subembodiment of embodiment 8, Ar 1 is R a , R b and / or R c In a second subembodiment of embodiment 8, and a first subembodiment therein, R a is hydrogen and R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy; R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl. In the third subembodiment of embodiment 8, and the first and second subembodiments therein, Ar 1 is R b and / or R c is substituted with R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl or methylcarbonyl, R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-1-ylethyl, -CONH2, methylaminocarbonyl or dimethylaminocarbonyl.

[0107] Embodiment 9 In embodiment 9, there is provided a compound comprising Ar 1 But R a , R b and / or R cIn a subembodiment of embodiment 9, Ar is phenyl substituted with , or a pharmaceutically acceptable salt thereof. 1 teeth, [ka] In a first subembodiment of embodiment 9, R a is hydrogen or alkyl, and R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy; R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl. 1 is R b and / or R c is substituted with R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl or methylcarbonyl, R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-1-ylethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl. 1 teeth, [ka] In a third subembodiment of embodiment 9, Ar 1 is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2-chlorophenyl, 2-cyanophenyl, or 2-cyclopropyl-oxyphenyl. In a third subembodiment of embodiment 9, Ar 1In a fourth subembodiment of embodiment 9, Ar 1 In a fifth subembodiment of embodiment 9, Ar 1 is 2,4-dimethoxyphenyl.

[0108] Embodiment 10 In embodiment 10, there is provided a compound comprising Ar 1 But R a , R b and / or R c or a pharmaceutically acceptable salt thereof. In one subembodiment of embodiment 10, Ar is a heteroaryl substituted with 1 is R a , R b and / or R c benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazolyl, 1H-indazolyl, substituted by R a is hydrogen or alkyl, and R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy; R c is selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl. 1 is R a , R b and / or R c pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl substituted by R a is hydrogen or alkyl, and R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy; R cis selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl. 1 is R b and / or R c is substituted with R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl or methylcarbonyl, R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-1-ylethyl, -CONH2, methylaminocarbonyl or dimethylaminocarbonyl.

[0109] Embodiment 11 In embodiment 11, there is provided a compound comprising Ar 2 But R d , R e and / or R f In a first subembodiment of embodiment 11, R is phenyl substituted with d is hydrogen and R e is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, or cyano; R f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl; R f Heteroaryl and heterocyclyl represented by the formula: are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, haloalkyl, and hydroxy. In one subembodiment of embodiment 11, R fIn a first subembodiment of embodiment 11, Ar 2 is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2-chloro-4-fluorophenyl, 4-cyanophenyl, 4-bromophenyl, 4-oxetan-3-ylphenyl, 4-chloro-3-methoxyphenyl, 4-cyclopropylphenyl, or 4-oxazol-2-ylphenyl. 2 teeth, [ka] In a third subembodiment of embodiment 11, Ar 2 In a fourth subembodiment of embodiment 11, Ar 2 is 4-chlorophenyl.

[0110] Embodiment 12 In embodiment 12, there is provided a compound comprising Ar 2 But R d , R e and / or R f In a first subembodiment of embodiment 12, R is a heteroaryl substituted with d is hydrogen and R e is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, or cyano; R f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl; R f Heteroaryl and heterocyclyl represented by the formula: are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, haloalkyl, and hydroxy. In one subembodiment of embodiment 12, R fIn a second subembodiment of embodiment 12 and a first subembodiment therein, Ar 2 In one subembodiment and subembodiments of embodiment 12, Ar is heteroaryl selected from pyridinyl and pyrimidinyl. 2 teeth, [ka] In a subembodiment of embodiment 12 and subembodiments therein, Ar 2 teeth, [ka] In a third subembodiment of embodiment 12, Ar 2 is 6-chloropyridin-3-yl, 6-bromopyridin-3-yl or 5-chloropiazin-2-yl.

[0111] Embodiment 13 In embodiment 13, there is provided a compound comprising Ar 2 In a first subembodiment of embodiment 13, Ar is a compound of any one of embodiments 1 to 12 and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein Ar is cycloalkyl. 2 is cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0112] Embodiment 14 In embodiment 14, there is provided a method for producing a medicament for the treatment of rhesus macular degeneration, comprising: R 1 but, Hydrogen, cyano, -CONH 2 , methylaminocarbonyl, dimethylaminocarbonyl, imidazol-2-yl, methoxy, hydroxy, bromo, carboxy or fluoro or a pharmaceutically acceptable salt thereof. In a subembodiment of embodiment 14, R 1 is hydrogen, Alkyl, halo, haloalkyl or cyano is.

[0113] Embodiment 15 In embodiment 15, there is provided a compound comprising R 1 or a pharmaceutically acceptable salt thereof.

[0114] Embodiment 16 In embodiment 16, provided is a compound comprising R 2 is a compound of any one of embodiments 1-14 and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, cyano, or fluoro, preferably hydrogen.

[0115] It is understood that the above embodiments include combinations of one or more of the embodiments and / or sub-embodiments described therein. For example, the Ar described in embodiment 10 and sub-embodiments therein. 1 Groups may be independently combined with one or more of embodiments 1 to 9 and 11 to 16 and / or subembodiments contained therein.

[0116] Assay The ability of compounds of the present disclosure to inhibit Pol theta can be measured as described in Biological Test Example 1 below.

[0117] Pharmaceutical Composition The compounds of formula (I) 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 pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable or physiologically acceptable excipients. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount. The pharmaceutical compositions may be used in the methods disclosed herein. Thus, for example, the pharmaceutical compositions may be administered to a subject ex vivo or in vivo to carry out the therapeutic methods and uses described herein.

[0118] Pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration. Exemplary routes of administration are described herein. Furthermore, 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.

[0119] 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, syrup, solution, microbeads, or elixir. Pharmaceutical compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide pharmaceutically elegant and palatable preparations. Tablets, capsules, etc. contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets, capsules, etc. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin or acacia; and lubricants, such as magnesium stearate, stearic acid or talc.

[0120] Tablets, capsules, and the like suitable for oral administration may be uncoated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action. For example, time-delay materials, such as glyceryl monostearate or glyceryl distearate, can be used. Tablets can also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or polymeric materials (e.g., polyesters, polyamic acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers) to control delivery of the administered composition. For example, oral formulations can be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization using hydroxymethylcellulose or gelatin-microcapsules or poly(methyl methacrylate) microcapsules, respectively, or colloidal drug delivery systems. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems (e.g., oil-in-water emulsions, micelles, mixed micelles, and liposomes). Methods for preparing the above formulations are known in the art.

[0121] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0122] Aqueous suspensions contain the active substance in admixture with excipients suitable for their manufacture. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptodecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0123] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (e.g., arachis oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.

[0124] 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, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0125] The pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (e.g., olive oil or peanut oil), or a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers can be naturally occurring gums, such as acacia gum or tragacanth gum; naturally occurring phosphatides, such as esters or partial esters derived from soybeans, lecithin, and fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0126] Pharmaceutical compositions typically contain a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl, p-hydroxybenzoic acid), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, detergents, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be saline or citrate-buffered saline, optionally supplemented with other substances commonly used in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize various buffers that may be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. By way of example, buffer components may be water-soluble substances such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0127] After the pharmaceutical composition has been formulated, it may be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or any other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an auto-injector (e.g., similar to an EpiPen®)), while in other embodiments, it is provided in a multi-use container (e.g., a multi-use vial).

[0128] The formulation may also include a carrier to protect the composition against rapid degradation or elimination from the body, such as a controlled-release formulation (including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems). For example, a time-delay material, such as glyceryl monostearate or glyceryl stearate, alone or in combination with a wax, can be used. Any drug delivery device can be used to deliver the compound of formula (I) or a pharmaceutically acceptable salt thereof, including implants (e.g., implantable pumps) and catheter systems, slow infusion pumps and devices, all of which are well known to those skilled in the art.

[0129] Depot injections, generally administered subcutaneously or intramuscularly, can also be used to release the compound of formula (I) disclosed herein or its pharmaceutically acceptable salt over a predetermined period of time. Depot injections are usually either solid-based or oil-based, and generally contain at least one of the formulation components described herein. Those skilled in the art are familiar with the possible formulations and uses of depot injections.

[0130] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Suspensions may be formulated 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, such as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, CremophorEL™ (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile bland fixed oil, such as synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, have been used in the preparation of injectables. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0131] The compound of formula (I) or its pharmaceutically acceptable salt can also be administered in the form of a suppository for rectal administration or a spray for nasal or inhalation administration.Suppositories can be prepared by mixing a drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0132] Administration route The compound of formula (I) or its pharmaceutically acceptable salt and compositions comprising the same 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 utilized to administer the compound of formula (I) or its pharmaceutically acceptable salt over a predetermined period of time. Certain embodiments of the present invention contemplate oral administration.

[0133] Combination therapy The present invention contemplates the use of a compound of Formula (I) 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 therapies, the various active ingredients often have different, complementary mechanisms of action. Such combination therapies can be particularly advantageous by allowing for reduced dosages of one or more agents, thereby reducing or eliminating side effects associated with one or more agents. Furthermore, such combination therapies may provide a synergistic therapeutic or prophylactic effect against the underlying disease, disorder, or condition.

[0134] As used herein, "combination" refers to 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), as well as therapies that can be administered together in a single formulation (i.e., a "co-formulation").

[0135] In certain embodiments, the compounds of formula (I) 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 pharmaceutically acceptable salts thereof are administered simultaneously, e.g., when two or more agents are administered simultaneously or near simultaneously. The 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). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of this disclosure.

[0136] The compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with at least one other (active) ingredient in any manner appropriate at the site. In one embodiment, treatment with at least one active ingredient and at least one compound of formula (I) or a pharmaceutically acceptable salt thereof is maintained for a period of time. In another embodiment, treatment with at least one active ingredient is reduced or stopped (e.g., when the subject is stable), while treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof is maintained at a constant dosage regimen. In a further embodiment, treatment with at least one active ingredient is reduced or stopped (e.g., when the subject is stable), and treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof is reduced (e.g., to a lower dose, less frequent dosing, or a shorter treatment regimen). In yet another embodiment, treatment with the at least one active ingredient is reduced or stopped (e.g., if the subject is stable) and treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof is increased (e.g., to a higher dose, more frequent dosing, or a longer treatment regimen). In yet another embodiment, treatment with the at least one active ingredient is maintained and treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof is reduced or stopped (e.g., to a lower dose, less frequent dosing, or a shorter treatment regimen). In yet another embodiment, treatment with the at least one active ingredient and treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof are reduced or stopped (e.g., to a lower dose, less frequent dosing, or a shorter treatment regimen).

[0137] The present disclosure provides methods for treating cancer using a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic or diagnostic agent.

[0138] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent selected from temozolomide, pemetrexed, pegylated liposomal doxorubicin (Doxil), eribulin (Halaven), ixabepilone (Ixenpra), protein-bound paclitaxel (Abraxane), oxaliplatin, irinotecan, venetoclax (a bcl2 inhibitor), 5-azacytadine, anti-CD20 therapeutic agents (e.g., rituxan and obinutuzumab), hormones (anastrozole, exemestane, letrozole, zoladex, lupon, eligard), CDK4 / 6 inhibitors, palbociclib, abemaciclib, CPIs (avelumab, cemiplimab-rwlc, and bevacizumab).

[0139] In certain embodiments, the present disclosure provides a method for treating cancer, comprising administering a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof 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. Examples of signal transduction inhibitors (STIs) useful in the methods described herein include, but are not limited to, the following inhibitors: (i) bcr / abl kinase inhibitors (e.g., Gleevec); (ii) epidermal growth factor (EGF) receptor inhibitors, e.g., kinase inhibitors and kinase antibodies; (iii) her-2 / neu receptor inhibitors (e.g., Herceptin); (iv) inhibitors of Akt family kinases or Akt pathways (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidylinositol kinase inhibitors. Agents involved in immune modulation may also be used in combination with one or more compounds of formula (I) or pharmaceutically acceptable salts thereof described herein for the inhibition of tumor growth in cancer patients.

[0140] In certain embodiments, the present disclosure provides a method for treating cancer, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, in combination with a chemotherapeutic agent. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride oxide. hydrochloride), melphalan, novembichin, fenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Antibiotics such as aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptomycin, nigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine androgens, e.g., calcitabine, drostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., folinic acid acid); aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine;Pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, such as paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16 ); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the compounds of the present disclosure are co-administered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere, and mitomycin C. In certain embodiments, the cytostatic compound is doxorubicin.

[0141] Chemotherapeutic agents include antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens (e.g., tamoxifen, raloxifene, the aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene); and antiandrogens (e.g., flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin); and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy includes the administration of a hormone or related hormone agent.

[0142] The present disclosure also contemplates the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof described herein in combination with an immune checkpoint inhibitor. The vast number 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 through 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 preventing autoimmunity (i.e., maintaining self-tolerance) and for protecting tissues from damage when the immune system is responding to pathogenic infections. The expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism. Examples of immune checkpoint inhibitors include 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.

[0143] The present disclosure contemplates the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, in combination with inhibitors of the immune checkpoint receptors and ligands described above, for example, ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab.

[0144] Additional therapeutic modalities that may be used in combination with the compounds of formula (I) or pharmaceutically acceptable salts thereof described herein include radiation therapy, monoclonal antibodies against tumor antigens, conjugates of monoclonal antibodies and toxins, T-cell adjuvants, bone marrow transplantation or antigen-presenting cells (e.g., dendritic cell therapy).

[0145] The present disclosure contemplates the use of compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, alone or in combination with radiation and / or temozolomide (TMZ), avastin, or lomustine, to treat glioblastoma.

[0146] The present disclosure includes pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0147] dosage The compounds of Formula (I) or pharmaceutically acceptable salts thereof provided herein can be administered to a subject in an amount that depends, for example, on the purpose of administration (e.g., the desired degree of recovery); the age, weight, sex, health status, and physical condition of the subject to whom the formulation is to be administered; the route of administration; and the nature of the disease, disorder, condition, or symptom. The dosing regimen may also take into account the existence, nature, and extent of side effects associated with the agent to be administered. Effective dosages and administration 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.

[0148] Generally, dosing parameters dictate that the amount administered be less than that which would be irreversibly toxic to the subject (the maximum tolerated dose (MTD)), and greater than or equal to that required to produce a measurable effect in the subject. Such an amount is determined, for example, by pharmacokinetic and pharmacodynamic parameters relevant to ADME, taking into account the route of administration and other factors.

[0149] The effective dose (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect in some percentage of subjects taking it. The "median effective dose" or ED of a 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 ED is commonly used as a measure of the reasonable expectation of a drug's effect, but it is not necessarily the dose that a clinician would consider appropriate, taking into account all relevant factors. Therefore, in some situations, the ED calculated as the effective dose may be used. 50 In other situations, the effective dose is calculated as ED 50 and in other situations, the effective dose is calculated as ED 50 is the same as

[0150] Furthermore, an effective dose of a compound of Formula (I) or a salt thereof provided herein 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 the case of a subject experiencing a particular disorder, an effective dose 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.

[0151] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof described herein is administered (e.g., orally) at a dosage level of about 0.01 mg / kg to about 50 mg / kg, or 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.

[0152] For oral administration, the compositions may be provided in the form of tablets, capsules, etc. 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.

[0153] In certain embodiments, the dosage of the compound of formula (I) 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 the compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with one or more active ingredients, sufficient to produce the desired effect. It will be understood that the parameters of the unit dosage form depend on the particular agent and the effect to be achieved.

[0154] kit The present invention also contemplates kits comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof. The kits are generally in the form of a physical structure housing various components, as described below, that can be used, for example, in carrying out the methods described above.

[0155] The kit can include one or more compounds of Formula (I) or pharmaceutically acceptable salts thereof (e.g., provided in a sterile container) described herein, which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compound of Formula (I) or a pharmaceutically acceptable salt thereof can be provided in a ready-to-use form (e.g., a tablet or capsule) or in a form that requires reconstitution or dilution before administration (e.g., a powder). When the compound of Formula (I) or a pharmaceutically acceptable salt thereof is in a form that requires reconstitution or dilution by the user, the kit can also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc., packaged together with or separately from the compound of Formula (I) or a pharmaceutically acceptable salt thereof. When combination therapy is intended, the kit can include several agents separately, or they can be pre-combined within the kit. Each component of the kit can be contained in a separate container, and all of the various containers can be contained in a single package. The kits of the present invention may be designed for conditions (eg, refrigeration or freezing) necessary to properly maintain the components contained therein.

[0156] The kit can include a label or package insert containing the identity of the components therein and instructions for their use (e.g., administration parameters, clinical pharmacology of the active ingredients (e.g., mechanism of action, pharmacokinetics, pharmacodynamics, side effects, contraindications, etc.)). The label or package insert can include manufacturing information, e.g., lot number and expiration date. The label or package insert can, for example, be integrated into the physical structure that houses the components, be contained separately within the physical structure, or be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0157] 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 (e.g., CD-ROM / RAM, DVD-ROM / RAM, DVD), MP3, magnetic tape, or electronic storage medium (e.g., RAM and ROM), or a hybrid thereof (e.g., magnetic / optical storage medium), FLASH media, or memory type card. In some embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source (e.g., via the internet). [Example]

[0158] The following examples and reference examples (intermediates) are presented 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 experiments below have been performed or are all experiments that could be performed. It should be understood that exemplary descriptions written in the present tense have not necessarily been performed, and descriptions may be made to generate data of the nature described herein. 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.

[0159] 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: μg = microgram; μl or μL = microliter; mM = millimole; μM = micromole; 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; NHO Ac = 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]-dichloropalladium(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'-tetramethylchloroformamidinium 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), complex with dichloromethane.

[0160] Synthesis Example General Procedure General Procedure A Amide formation using HATU [ka]

[0161] To a solution of carboxylic acid (1 equiv.) and amine (1 equiv.) in DMF (0.5 M) was added DIEA (2 equiv.) and HATU (1.5 equiv.) The mixture was stirred under nitrogen at room temperature overnight.

[0162] General Procedure B Amination of 2-chloropyridine [ka]

[0163] To a solution of 2-chloropyridine-3-carboxylic acid (1 eq.) in NMP (0.6 M) was added the heterocyclyl of formula 1 (1 eq.) and DIEA (3 eq.) at room temperature under nitrogen, and the mixture was stirred at 80° C. for 5 h.

[0164] General Procedure C Amination of 2-fluorobenzene and 2-fluoropyridine [ka]

[0165] To a solution of arylcarboxylic acid (1 eq) in MeCN (0.7 M) was added heterocyclyl of formula I (1.5 eq) and DIEA (2 eq) under nitrogen at room temperature. The mixture was stirred at 80° C. overnight.

[0166] General Procedure D Amide formation using propylphosphonic anhydride [ka]

[0167] To a solution of carboxylic acid (1 equiv.) and amine (1 equiv.) in THF (0.5 M) under nitrogen was added T3P (1.5 equiv.) and DIEA (2 equiv.), and the mixture was stirred at 50° C. overnight.

[0168] General Procedure E Aryl amination using Suzuki coupling [ka]

[0169] To a solution of aryl halogen (1 equiv.) in dioxane:water (5:1, 0.4 M) was added boronic acid or boronic ester (1.5 equiv.), Pd(dppf)Cl (0.2 equiv.), and KCO (2 equiv.), and the mixture was stirred at 100 °C overnight.

[0170] General Procedure F Ester hydrolysis [ka]

[0171] To a solution of the ester (1 eq) in methanol:water (1:1, 0.2 M) was added NaOH (5 eq). The mixture was stirred at room temperature for 1 hour.

[0172] Intermediate A Synthesis of 5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0173] Step 1: Preparation of O-(4-fluorobenzyl) S-methyl carbonodithioate [ka]

[0174] To a solution of (4-fluorophenyl)methanol (2.0 g, 15.9 mmol) in THF (20 mL) at 0° C. was added NaH (0.63 g, 15.9 mmol, 60% oil dispersion). CS2 (1.21 g, 15.9 mmol) was added dropwise over 5 min at 0° C., and the mixture was stirred at 0° C. for an additional 30 min. CHCl (2.25 g, 15.9 mmol) was added dropwise over 5 min at 0° C. The mixture was stirred at 0° C. for an additional 6 h and then quenched with water. The aqueous layer was extracted with EtOAc, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give the title compound as a yellow oil.

[0175] Step 2: Preparation of 5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0176] O-(4-fluorobenzyl) S-methylcarbonodithioate (1.20 g, 5.548A mixture of 2.9 g (5.8 mmol) and hydrazine hydrate (2.9 g, 5.8 mmol) in MeOH (12 mL) was stirred under nitrogen at room temperature for 3 h, then EtN (1.1 g, 11.1 mmol) was added. BrCN (0.88 g, 8.308 mmol) was added and the reaction mixture was stirred for 3 h. The mixture was diluted with water, and the solid was collected by filtration and washed with MeOH to give the title compound as a red solid.

[0177] Intermediate B Synthesis of 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0178] Step 1: Preparation of O-(4-chlorobenzyl) S-methyl carbonodithioate [ka]

[0179] To a solution of (4-chlorophenyl)methanol (20 g, 140 mmol) in THF (200 mL) under nitrogen was added NaOH (11.2 g, 280 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then CS2 (12.8 g, 168 mmol) was added. The mixture was stirred at 0° C. for an additional 30 minutes, and then MeI (23.9 g, 168 mmol) was added. After 30 minutes, water was added, and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to give the title compound as a yellow oil.

[0180] Step 2: Preparation of 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0181] To a solution of O-(4-chlorobenzyl) S-methylcarbonodithioate (15 g, 64 mmol) in methanol (450 mL) under nitrogen was added hydrazine hydrate (3.2 g, 64 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes and then concentrated under reduced pressure. The residue was diluted with MeOH, and then EtN (14 g, 139 mmol) and BrCN (8 g, 77 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration and washed with MeOH to give the title compound as a yellow solid.

[0182] Alternative synthesis of intermediate B Synthesis of 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0183] Step 1: Preparation of 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine A solution of (4-chlorophenyl)methanol (100 g, 701 mmol) in THF (250 mL) was added dropwise to a solution of NaH (42.0 g, 1.05 mol, 60.0% purity) in THF (750 mL) at 5 °C. The mixture was stirred at 5 °C for 4 h. Then, 2-amino-5-bromo-1,3,4-thiadiazole (152 g, 842 mmol) was added to the mixture at 5 °C. The mixture was stirred at 5 °C for 3 h. The mixture was poured into H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 9% to 66% EtOAc in PE to give a residue. 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 16 h. The solid was collected to give the title compound (61.0 g, 18% yield) as a grey solid.

[0184] Intermediate C Synthesis of 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine [ka]

[0185] Step 1: O-((5-chloropyridin-2-yl)methyl)S-methyl carbonodithioate [ka]

[0186] To a solution of (5-chloropyridin-2-yl)methanol (3.0 g, 21 mmol) in THF (30 mL) at 0°C under nitrogen, NaOH (1.3 g, 31.5 mmol) was added. The mixture was stirred at 0°C for 15 minutes. CS2 (1.8 g, 23 mmol) was then added, and the mixture was stirred at 0°C for 30 minutes. MeI (3.3 g, 23 mmol) was then added, and the mixture was stirred at 0°C for 30 minutes. Saturated NH4Cl (30 mL) was then added, and the mixture was allowed to warm to room temperature. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 1% EtOAc in PE, to give O-((5-chloropyridin-2-yl)methyl)S-methylcarbonodithioate as a yellow oil.

[0187] Step 2: Preparation of 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine [ka]

[0188] To a solution of O-((5-chloropyridin-2-yl)methyl)S-methylcarbonodithioate (1.8 g, 7.7 mmol) in MeOH (18 mL) under nitrogen was added hydrazine hydrate (387 mg, 7.7 mmol). The mixture was stirred at room temperature for 15 minutes. Then, BrCN (819 mg, 7.7 mmol) and EtN (1638 mg, 15 mmol) were added. The mixture was stirred at room temperature for 15 minutes. A solid formed and was collected by filtration. The solid was washed with MeOH (3 × 5 mL) to give 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine as a gray solid.

[0189] Alternative synthesis of intermediate C Intermediate C Synthesis of 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine [ka]

[0190] Step 1: Preparation of (5-chloropyridin-2-yl)methanol [ka]

[0191] To a solution of methyl 5-chloropicolinate (95 g, 554 mmol) in MeOH (950 mL) was added NaBH (42.0 g, 1.11 mol) portionwise at 0 °C. The mixture was then stirred at room temperature for 2 hours. 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 was 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 (3x). 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.

[0192] Step 2: Preparation of 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine [ka]

[0193] 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 portionwise at 5° C. The mixture was stirred at 5° C. for 4 h. The mixture was poured into H2O and extracted with EtOAc (4x). 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 the title compound (57.6 g, 21% yield) as a gray solid.

[0194] Intermediate D Synthesis of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-fluoropyridine-3-carboxamide [ka]

[0195] To a solution of 2-fluoropyridine-3-carboxylic acid (1 g, 7.1 mmol) in SOCl (1052 mg, 7.8 mmol) was added DMF (51.80 mg, 0.709 mmol) under nitrogen. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was diluted with DCM (10 mL), and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (1679 mg, 6.9 mmol, Intermediate B) and EtN (1434 mg, 14.2 mmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (10 mL) and water (10 mL). The organic layer was concentrated under reduced pressure. The residue was recrystallized from MeOH:water (10:1) to give N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-fluoropyridine-3-carboxamide as an off-white solid.

[0196] Intermediate E Synthesis of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-chloropyridine-3-carboxamide [ka]

[0197] The title compound was prepared using general procedure D employing 2-chloropyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B).

[0198] Intermediate F N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-chloronicotinamide [ka]

[0199] The title compound was prepared using general procedure D using 2-chloropyridine-3-carboxylic acid and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ice water. The mixture was filtered and the solid was washed with ice water to give the desired product as an off-white solid.

[0200] intermediate G N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-fluoronicotinamide [ka]

[0201] The title compound was prepared using a similar procedure to Intermediate F, replacing 2-chloropyridine-3-carboxylic acid with 2-fluoropyridine-3-carboxylic acid.

[0202] Intermediate H 3-(2-Methoxyphenyl)pyridine-4-carboxylic acid [ka]

[0203] [ka] To a solution of 3-bromopyridine-4-carboxylic acid (2.0 g, 9.9 mmol) in dioxane (10 mL) and water (10 mL) was added 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) at room temperature under nitrogen. 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 (2x). The aqueous layer was acidified to pH 6 with HCl (1 M). A solid formed and the mixture was filtered to give the title compound as a white solid.

[0204] Alternative synthesis of intermediate H Intermediate H 3-(2-Methoxyphenyl)pyridine-4-carboxylic acid [ka]

[0205] Step 1: Preparation of methyl 3-(2-methoxyphenyl)isonicotinate [ka]

[0206] To a solution of methyl 3-bromoisonicotinate (150 g, 694 mmol) in dioxane (1.5 L) and HO (150 mL) was added KCO (95.9 g, 694 mmol), Pd(dppf)Cl (25.4 g, 34.7 mmol), and 2-methoxyphenylboronic acid (126 g, 833 mmol). The mixture was stirred at 85 °C for 16 h. The mixture was poured into HO and extracted with EtOAc (3x). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with 9-100% EtOAc in PE to give a residue. The residue was diluted with MTBE, and the slurry was stirred at room temperature for 0.5 h to give the title compound (94.0 g, 83% yield) as a white solid.

[0207] Step 2: Preparation of 3-(2-methoxyphenyl)pyridine-4-carboxylic acid [ka]

[0208] To a solution of methyl 3-(2-methoxyphenyl)isonicotinate (108 g, 444 mmol) in MeOH (648 mL) and HO (648 mL) was added NaOH (53.2 g, 1.33 mol). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with 2 N HCl until the pH was 2-3. The mixture was filtered. The solid was washed with HO (3x). The solid was dried under vacuum to give the title compound (70.0 g, 79% yield) as a white solid, which was used in the next step without further purification.

[0209] Synthesis Example 1: Synthesis of N-(5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0210] The title compound was prepared using general procedure A employing 2-(morpholin-4-yl)pyridine-3-carboxylic acid and 5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate A). The mixture was diluted with water (6 mL) and extracted with EtOAc (2×3 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 100:1) to afford N-(5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a white solid. 1 H NMR (300MHz; DMSO-d6): δ3.21-3.24 (t, 4H), 3.65-3.68 (t, 4H), 5.49 (s, 2H), 6.98-7.02 (m, 1H), 7.22-7.30 (m, 2H), 7.57-7.61 (m, 2H), 7.90-7.93 (m, 1H), 8.35-8.37 (m, 1H), 12.87 (s, 1H). m / z 416 (M+H + ).

[0211] Synthesis Example 2: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0212] The title compound was prepared using general procedure A employing 2-(morpholin-4-yl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a white solid. 1 H NMR (300MHz; DMSO-d6): δ 3.17-3.25 (m, 4H), 3.65- 3.68 (t, 4H), 5.51 (s, 2H), 6.98-7.02 (m, 1H), 7.48-7.58 (m, 4H), 7.90-7.93 (m, 1H), 8.35-8.38 (m, 1H), 12.89 (s, 1H) ppm. m / z 432 (M+H + ).

[0213] Synthesis Example 3: Synthesis of N-[5-[(5-chloropyridin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(morpholin-4-yl)benzamide [ka]

[0214] The title compound was prepared using general procedure A employing 2-(morpholin-4-yl)pyridine-3-carboxylic acid and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was diluted with water (2 mL) and extracted with EtOAc (4 x 2 mL). The combined organic layers were concentrated under reduced pressure. The residue was triturated with 3 mL of MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a white solid. 1H NMR (300MHz; DMSO-d6): δ 3.21-3.24 (t, 4H), 3.64-3.68 (t, 4H), 5.61 (s, 2H), 6.98-7.02 (m, 1H), 7.62-7.64 (d, 1H), 7.90-7.94 (m, 1H), 8.00-8.04 (m, 1H), 8.32-8.38 (m, 1H), 8.66-8.69 (m, 1H), 12.91 (s, 1H) ppm. m / z 433 (M+H + ).

[0215] Synthesis Example 4: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-phenyl-1H-imidazole-5-carboxamide [ka]

[0216] The title compound was prepared according to general procedure D using 1-phenyl-1H-imidazole-5-carboxylic acid and intermediate B to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-phenyl-1H-imidazole-5-carboxamide (20 mg, 6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.53 - 7.45 (m, 7H), 7.41 (d, J = 6.6 Hz, 2H), 5.46 (s, 2H) ppm. m / z 412 (M+H + ).

[0217] Synthesis Example 5: Synthesis of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methylmorpholino)nicotinamide and (S)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methylmorpholino)nicotinamide [ka]

[0218] To a vial equipped with a stir bar was added 2-chloro-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide Intermediate E (100 mg, 1 eq.), followed by racemic 3-methylmorpholine (79 mg, 3 eq.) and THF (1.3 mL). DIPEA (0.274 mL, 6 eq.) was then added and the reaction was heated to 75° C. and stirred for 8 hours. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, hexane / ethyl acetate 0-100%) to afford a racemic mixture of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methylmorpholino)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methylmorpholino)nicotinamide as a white solid (12 mg, 10% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 4.0 Hz, 1H), 8.49 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.32 - 7.25 (m, 1H), 5.49 (s, 2H), 4.04 (t, J = 8.5 Hz, 3H), 3.27 (td, J = 11.4, 10.6, 4.5 Hz, 1H), 3.23 - 3.09 (m, 2H), 2.98 (t, J = 11.3 Hz, 1H), 1.23 (d, J = 6.2 Hz, 3H) ppm. m / z 446 (M+H + ).

[0219] Synthesis Example 6: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(1,4-oxazepan-4-yl)nicotinamide [ka]

[0220] Step 1: Preparation of 2-(1,4-oxazepan-4-yl)nicotinic acid [ka]

[0221] The title compound was prepared using general procedure B using 1,4-oxazepane. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column C 18 The residue was purified by reverse-phase preparative HPLC [(XBridge Prep OBD C)]. 18 Further purification using a column; gradient elution with 2-15% ACN in 0.16% NH4HCO3 in water] gave 2-(1,4-oxazepan-4-yl)nicotinic acid as a pale yellow solid.

[0222] Step 2: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(1,4-oxazepan-4-yl)nicotinamide [ka]

[0223] The title compound was prepared using General Procedure A, which employs 2-(1,4-oxazepan-4-yl)nicotinic acid and 5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate A). The mixture was stirred at room temperature for 2 days. The mixture was diluted with water (5 mL). The mixture was extracted with EtOAc (3×3 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:hexane, 1:1) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(1,4-oxazepan-4-yl)nicotinamide as a white solid. 1H NMR (300MHz; DMSO-d6): δ 1.80-1.90 (m, 2H), 3.46-3.52 (m, 2H), 3.53-3.60 (m, 4H), 3.73-3.74 (d, 2H), 5.49 (s, 2H), 6.73-6.77 (m, 1H), 7.48-7.56 (m, 4H), 7.75-7.78 (m, 1H), 8.22-8.24 (m, 1H), 12.82 (s, 1H) ppm. m / z 446 (M+H + ).

[0224] Synthesis Example 7: Synthesis of (R)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methylmorpholino)nicotinamide and (S)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methylmorpholino)nicotinamide [ka]

[0225] Step 1: Preparation of racemic 2-(2-methylmorpholin-4-yl)pyridine-3-carboxylic acid [ka]

[0226] The title compound was prepared using general procedure C using racemic 2-methylmorpholine. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1) to afford racemic 2-(2-methylmorpholin-4-yl)pyridine-3-carboxylic acid as a white solid.

[0227] Step 2: Synthesis of (R)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methylmorpholino)nicotinamide and (S)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methylmorpholino)nicotinamide [ka]

[0228] The title compound was prepared using general procedure A employing racemic 2-(2-methylmorpholin-4-yl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 35:1) to afford a racemic mixture of (R)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methylmorpholino)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methylmorpholino)nicotinamide as a white solid. 1 H NMR (300MHz; DMSO-d6): δ 1.27 (s, 3H), 2.96-3.33 (m, 4H), 4.03-4.15 (m, 3H), 5.52 (s, 2H), 7.30-7.34 (m, 1H), 7.38-7.48 (m, 4H), 8.52-8.60 (m, 2H), 13.51 (s, 1H) ppm. m / z 446 (M+H + ).

[0229] Synthesis Example 8: Synthesis of N-(5-((6-chloropyridin-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0230] Step 1: Preparation of [(6-chloropyridin-3-yl)methoxy](methylsulfanyl)methanethione [ka]

[0231] The title compound was prepared using a procedure similar to Step 1 of Intermediate B, replacing (4-chlorophenyl)methanol with (6-chloropyridin-3-yl)methanol. The residue was purified by silica gel column chromatography eluting with 1% EtOAc in PE to afford [(6-chloropyridin-3-yl)methoxy](methylsulfanyl)methanethione as a yellow oil.

[0232] Step 2: Preparation of 5-[(6-chloropyridin-3-yl)methoxy]-1,3,4-thiadiazol-2-amine [ka]

[0233] The title compound was prepared using a procedure similar to Step 2 of Intermediate B, replacing O-(4-chlorobenzyl)S-methylcarbonodithioate with [(6-chloropyridin-3-yl)methoxy]-(methylsulfanyl)methanethione. The mixture was concentrated under reduced pressure. The residue was triturated with MeOH to give 5-[(6-chloropyridin-3-yl)methoxy]-1,3,4-thiadiazol-2-amine as a white solid.

[0234] Step 3: Preparation of N-(5-((6-chloropyridin-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0235] The title compound was prepared using general procedure A using 5-[(6-chloropyridin-3-yl)methoxy]-1,3,4-thiadiazol-2-amine and 2-(morpholin-4-yl)pyridine-3-carboxylic acid. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 35:1). The residue was purified by preparative HPLC [column, XBridge Prep OBD C18 ; mobile phase 15-25% ACN in 0.05% NH4OH in water] to give N-(5-((6-chloropyridin-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.23 (t, 4H), 3.66 (t, 4H), 5.56 (s, 2H), 6.97-7.01 (m, 1H), 7.59-7.62 (m, 1H), 7.90-7.92 (m, 1H), 8.03-8.06 (m, 1H), 8.35-8.36 (m, 1H), 8.59 (d, 1H), 12.90 (s, 1H) ppm. m / z 433 (M+H + ).

[0236] Synthesis Example 9: Synthesis of (R)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methylmorpholino)nicotinamide [ka]

[0237] To a vial equipped with a stir bar was added 2-chloro-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide Intermediate E (200 mg, 1 equiv.), followed by (R)-3-methylmorpholine (159 mg, 3 equiv.) and THF (2.6 mL). DIPEA (0.548 mL, 6 equiv.) was then added, and the reaction was heated to 75 °C and stirred for 8 h. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, hexanes / ethyl acetate 0-100%) to afford the title compound (28 mg, 12% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 4.8 Hz, 1H), 8.50 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.32 - 7.24 (m, 1H), 5.49 (s, 2H), 4.08 - 4.00 (m, 3H), 3.28 (td, J = 11.6, 4.3 Hz, 1H), 3.16 (dd, J = 23.0, 12.2 Hz, 2H), 2.98 (t, J = 11.2 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H) ppm. m / z 446 (M+H + ).

[0238] Synthesis Example 10: Synthesis of (S)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methylmorpholino)nicotinamide [ka]

[0239] Proceeding similarly as described in Synthesis Example 9 above, but substituting (S)-3-methylmorpholine for (R)-3-methylmorpholine, the title compound was obtained as a white solid. [LC / MS [M+H]+ 445.92. 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 4.7 Hz, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.32 - 7.24 (m, 1H), 5.49 (s, 2H), 4.11 - 3.93 (m, 3H), 3.26 (td, J = 11.4, 10.8, 4.6 Hz, 1H), 3.22 - 3.07 (m, 2H), 2.97 (t, J = 11.3 Hz, 1H), 1.23 (d, J = 6.0 Hz, 3H) ppm. m / z 446 (M+H + ).

[0240] Synthesis Example 11: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(1H-tetrazol-1-yl)nicotinamide [ka]

[0241] Step 1: Preparation of methyl 2-(1H-tetrazol-1-yl)nicotinate [ka]

[0242] To a solution of tetrazole (0.68 g, 9.7 mmol) in NMP (15 mL) at 0° C. under nitrogen, NaH (0.58 g, 14.5 mmol, 60% oil dispersion) was added portionwise. The mixture was stirred at 0° C. for 30 minutes, and then methyl 2-fluoropyridine-3-carboxylate (1.50 g, 9.7 mmol) was added. The mixture was heated to 80° C. and stirred at 80° C. overnight. The mixture was cooled to room temperature and quenched with saturated NH4Cl. The mixture was extracted with EtOAc (3×), and the combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column, C 18 Purification on silica gel; mobile phase, 5-100% MeCN in water) gave methyl 2-(1H-tetrazol-1-yl)nicotinate as a white solid.

[0243] Step 2: Preparation of 2-(1H-tetrazol-1-yl)nicotinic acid [ka]

[0244] To a solution of methyl 2-(1H-tetrazol-1-yl)nicotinate (620 mg, 2.9 mmol) in MeOH (30 mL) was added a solution of NaOH (234 mg, 5.8 mmol) in HO (6 mL). The mixture was stirred at room temperature for 4 hours. HCl (1 M) was added until the pH of the mixture reached 5. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column, C 18Purification on silica gel; mobile phase, 5-100% MeCN in water) gave 2-(1H-tetrazol-1-yl)nicotinic acid as a white solid.

[0245] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(1H-tetrazol-1-yl)nicotinamide [ka]

[0246] To a solution of 2-(1H-tetrazol-1-yl)nicotinic acid (200 mg, 1.0 mmol) in DMF (5 mL) was added 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (253 mg, 1.0 mmol, Intermediate B), EDCI (301 mg, 1.6 mmol), and HOBT (212 mg, 1.6 mmol). The mixture was stirred at 50° C. overnight. The mixture was diluted with saturated NaCl (20 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were concentrated under reduced pressure. The residue was recrystallized from DCM:MeOH (30:1) to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(1H-tetrazol-1-yl)nicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 5.50 (s, 2H), 7.47-7.56 (m, 4H), 7.82-7.93 (m, 1H), 8.39-8.49 (m, 1H), 8.83-8.88 (m, 1H), 10.21 (s, 1H), 13.05 (s, 1H) ppm. m / z 415 (M+H + ).

[0247] Synthesis Example 12: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(4-methoxyphenyl)-1H-imidazole-5-carboxamide [ka]

[0248] Step 1: Preparation of ethyl 1-(4-methoxyphenyl)-1H-imidazole-5-carboxylate [ka]

[0249] To a solution of p-anisidine (3.0 g, 24.4 mmol) and ethyl glyoxylate (5.0 g, 24.4 mmol, 50% toluene solution) in toluene (30 mL) under nitrogen, sodium sulfate (17.3 g, 122 mmol) was added. The mixture was stirred at 120 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was diluted with EtOH (30 mL) and purged with nitrogen. K2CO3 (2.2 g, 16.2 mmol) and p-toluenesulfonylmethyl isocyanide (2.4 g, 12.2 mmol) were then added. The mixture was stirred at 50 °C for 4 hours. The mixture was cooled to room temperature and quenched with water (30 mL). The mixture was extracted with EtOAc (6 × 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 2% MeOH in DCM to give ethyl 1-(4-methoxyphenyl)-1H-imidazole-5-carboxylate as a yellow solid.

[0250] Step 2: Preparation of 3-(4-methoxyphenyl)imidazole-4-carboxylic acid [ka]

[0251] To a solution of ethyl 3-(4-methoxyphenyl)imidazole-4-carboxylate (400 mg, 1.6 mmol) in THF (4 mL) and water (4 mL) was added NaOH (130 mg, 3.2 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (15 mL). The mixture was acidified to pH 6 with HOAc. The mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 3-(4-methoxyphenyl)imidazole-4-carboxylic acid as a white solid.

[0252] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(4-methoxyphenyl)-1H-imidazole-5-carboxamide [ka]

[0253] The title compound was prepared using general procedure D employing 3-(4-methoxyphenyl)imidazole-4-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was cooled to room temperature and quenched with water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure, and the residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(4-methoxyphenyl)-1H-imidazole-5-carboxamide as a brown solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.81 (s, 3H), 5.46 (s, 2H), 7.00-7.03 (m, 2H), 7.27-7.34 (m, 2H), 7.45-7.53 (m, 4H), 8.04-8.16 (m, 2H), 12.63-12.80 (br s, 1H) ppm. m / z 442 (M+H + ).

[0254] Synthesis Example 13: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinopyrimidine-5-carboxamide Step 1: Preparation of methyl 2-chloro-4-(morpholin-4-yl)pyrimidine-5-carboxylate [ka]

[0255] To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (1.0 g, 4.8 mmol) in NMP (10 mL) at 0° C. under nitrogen was added DIEA (1.25 g, 9.7 mmol). Morpholine (0.42 g, 4.8 mmol) was then added portionwise. The mixture was stirred at 0° C. for 3 hours. The mixture was diluted with EtOAc (10 mL) and washed with water (3×10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc, 2:1) to give methyl 2-chloro-4-(morpholin-4-yl)pyrimidine-5-carboxylate as a yellow solid.

[0256] Step 2: Preparation of 4-(morpholin-4-yl)pyrimidine-5-carboxylic acid [ka]

[0257] To a solution of methyl 2-chloro-4-(morpholin-4-yl)pyrimidine-5-carboxylate (400 mg, 1.6 mmol) in MeOH, 10% Pd / C (40 mg), NaOH (311 mg, 7.8 mmol), and water (4 mL) were added. The mixture was stirred at room temperature under H2 (g) for 3 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 4-(morpholin-4-yl)pyrimidine-5-carboxylic acid as a white solid.

[0258] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinopyrimidine-5-carboxamide [ka]

[0259] The title compound was prepared using general procedure D using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) and 4-(morpholin-4-yl)pyrimidine-5-carboxylic acid. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water (3x). The aqueous layer was extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH, 50:1) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinopyrimidine-5-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.48-3.50 (m, 4H), 3.61-3.64 (m, 4H), 5.51 (s, 2H), 7.48-7.51 (m, 2H), 7.54-7.56 (m, 2H), 8.47 (s, 1H), 8.61 (s, 1H), 13.01 (s, 1H) ppm. m / z 433 (M+H + ).

[0260] Synthesis Example 14: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-morpholinonicotinamide [ka]

[0261] Step 1: Preparation of 6-bromo-2-morpholinonicotinic acid [ka]

[0262] To a solution of 6-bromo-2-fluoropyridine-3-carboxylic acid (5.0 g, 22.7 mmol) in MeCN (50 mL) was added morpholine (4.0 g, 45.5 mmol) and DIEA (5.9 g, 45.4 mmol) under nitrogen. The mixture was stirred at 50° C. overnight. The mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (column, C 18The residue was purified by silica gel; mobile phase, 5-40% MeCN in water) to give 6-bromo-2-morpholinonicotinic acid as a brown solid.

[0263] Step 2: Preparation of 6-cyano-2-morpholinonicotinic acid [ka]

[0264] To a solution of 6-bromo-2-morpholinonicotinic acid (3.2 g, 11.1 mmol) in DMSO (32 mL) was added CuCN (5.0 g, 55.7 mmol) under nitrogen. The mixture was stirred at 120° C. for 4 hours. The mixture was then cooled to room temperature and diluted with EtOAc (20 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C 18 Purification on silica gel (mobile phase, 5-30% MeCN in water) gave 6-cyano-2-morpholinonicotinic acid as a yellow-green solid.

[0265] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-morpholinonicotinamide [ka]

[0266] To a solution of 6-cyano-2-morpholinonicotinic acid (170 mg, 0.73 mmol) and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (211 mg, 0.88 mmol, Intermediate B) in DMF (2 mL) under nitrogen was added EDCI (210 mg, 1.09 mmol) and HOBT (148 mg, 1.1 mmol). The mixture was stirred at 50° C. overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were concentrated under reduced pressure, and the residue was triturated with 1 mL of MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-morpholinonicotinamide as a pale yellow solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.31-3.32 (m, 4H), 3.61-3.63 (m, 4H), 5.46-5.51 (m, 2H), 7.46-7.57 (m, 5H), 8.00-8.02 (m, 1H), 13.03 (s, 1H) ppm. m / z 457 (M+H + ).

[0267] Synthesis Example 15: Synthesis of N-[5-[(5-bromopyridin-3-yl)oxy]-1,3,4-thiadiazol-2-yl]-2-(morpholin-4-yl)pyridine-3-carboxamide [ka]

[0268] Step 1: Preparation of 5-((5-bromopyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine [ka]

[0269] The title compound was prepared using a similar procedure to Intermediate C, replacing (5-chloropyridin-2-yl)methanol in Step 1 with (5-bromopyridin-2-yl)methanol.

[0270] Step 2: Preparation of N-[5-[(5-bromopyridin-3-yl)oxy]-1,3,4-thiadiazol-2-yl]-2-(morpholin-4-yl)pyridine-3-carboxamide [ka]

[0271] The title compound was prepared using general procedure A using 5-((5-bromopyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine and 2-morpholinonicotinic acid. The mixture was diluted with water and filtered. The filtrate was concentrated, and the residue was purified by preparative TLC (DCM:MeOH, 50:1) to afford N-[5-[(6-bromopyridin-3-yl)oxy]-1,3,4-thiadiazol-2-yl]-2-(morpholin-4-yl)pyridine-3-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.22-3.24 (m, 4H), 3.65-3.67 (m, 4H), 5.55 (s, 2H), 6.98-7.01 (m, 1H), 7.56-7.58 (m, 1H), 7.90-7.93 (m, 1H), 8.12-8.15 (m, 1H), 8.35-8.36 (m, 1H), 8.73-8.74 (m, 1H), 12.90 (s, 1H) ppm. m / z 479 (M+H + ).

[0272] Synthesis Example 16: Synthesis of 2-(4-acetylpiperazin-1-yl)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide [ka]

[0273] Proceeding similarly as described in Synthesis Example 9, but replacing (R)-3-methylmorpholine with 1-(piperazin-1-yl)ethan-1-one, the crude product was obtained. The crude residue was purified by preparative HPLC (column, C18 silica gel; mobile phase, 45-85% aqueous MeCN with 0.1% FA in both eluents) to give the title compound as a white solid. LC / MS [M+H] + 472.95. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 4.6 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 6.98 (dd, J = 7.4, 4.9 Hz, 1H), 5.49 (s, 2H), 3.64 - 3.45 (m, 4H), 3.30 - 3.15 (m, 4H), 2.00 (s, 3H) ppm. + ).

[0274] Synthesis Example 17: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(pyridin-3-yl)-1H-imidazole-5-carboxamide [ka]

[0275] The title compound was prepared using a procedure similar to that of Synthesis Example 12, replacing p-anisidine in step 1 with 3-aminopyridine, to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(pyridin-3-yl)-1H-imidazole-5-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 5.47 (s, 2H), 7.45-7.58 (m, 5H), 7.92-7.95 (m, 1H), 8.21-8.25 (m, 2H), 8.66-8.67 (m, 2H), 12.87-12.95 (br s, 1H) ppm. m / z 413 (M+H + ).

[0276] Synthesis Example 18: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)-1H-imidazole-5-carboxamide [ka]

[0277] Step 1: Preparation of 3-(pyridin-4-yl)imidazole-4-carboxylic acid [ka]

[0278] The title compound was prepared using a procedure similar to Steps 1 and 2 of Synthesis Example 12, replacing p-anisidine in Step 1 with 4-aminopyridine.

[0279] Step 2: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)-1H-imidazole-5-carboxamide [ka]

[0280] The title compound was prepared using general procedure A employing 3-(pyridin-4-yl)imidazole-4-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was stirred at 50° C. for 4 hours. The mixture was cooled to room temperature and diluted with water (10 mL) at room temperature. The mixture was extracted with EtOAc (2×5 mL). The combined organic layers were concentrated under reduced pressure, and the residue was triturated with MeOH (2 mL) to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)-1H-imidazole-5-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 5.47 (s, 2H), 7.45-7.57 (m, 6H), 8.15-8.25 (m, 2H), 8.69-8.71 (m, 2H), 12.81-13.15 (br s, 1H) ppm. m / z 413 (M+H + ).

[0281] Synthesis Example 19: Synthesis of N-[5-[(5-chloropyrazin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(morpholin-4-yl)pyridine-3-carboxamide [ka]

[0282] Step 1: Preparation of 5-[(5-chloropyrazin-2-yl)methoxy]-1,3,4-thiadiazol-2-amine [ka]

[0283] The title compound was prepared using a similar procedure to Intermediate C, replacing (5-chloropyridin-2-yl)methanol in Step 1 with (5-chloropyrazin-2-yl)methanol.

[0284] Step 2: Preparation of N-[5-[(5-chloropyrazin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(morpholin-4-yl)pyridine-3-carboxamide [ka]

[0285] The title compound was prepared using General Procedure A, employing 5-[(5-chloropyrazin-2-yl)methoxy]-1,3,4-thiadiazol-2-amine and 2-morpholinonicotinic acid. The mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH (1 mL) to afford N-[5-[(5-chloropyrazin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(morpholin-4-yl)pyridine-3-carboxamide as a yellow solid. 1H NMR (300 MHz; DMSO-d6): δ 3.22-3.25 (m, 4H), 3.61-3.68 (m, 4H), 5.67 (s, 2H), 6.98-7.03 (m, 1H), 7.91-7.96 (m, 1H), 8.36-8.38 (m, 1H), 8.75 (s, 1H), 8.86-8.87 (m, 1H), 12.92 (s, 1H) ppm. m / z 434 (M+H + ).

[0286] Synthesis Example 20: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(4-hydroxypiperidin-1-yl)nicotinamide [ka]

[0287] Proceeding similarly as described in Synthesis Example 22, but replacing (R)-3-methylmorpholine with 4-piperidinol, the crude product was purified by reverse-phase HPLC (water (0.1% formic acid) and MeCN (0.1% formic acid)) to give the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 8.66 (s, 1H), 8.33 (d, J = 4.7 Hz, 1H), 8.08 - 7.95 (m, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.06 - 6.81 (m, 1H), 5.57 (s, 2H), 4.71 (d, J = 4.0 Hz, 1H), 3.79 - 3.57 (m, 1H), 3.57 - 3.40 (m, 3H), 2.98 (t, J = 11.2Hz, 2H), 1.85 - 1.63 (m, 2H), 1.55 - 1.37 (m, 2H) ppm. m / z 447 (M+H + ).

[0288] Synthesis example 21:N 5 Synthesis of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-morpholinopyridine-2,5-dicarboxamide [ka]

[0289] To a solution of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-morpholinonicotinamide (55 mg, 0.12 mmol, Synthesis Example 14) in MeOH (3 mL) was added HO (1.5 mL, 30% aqueous solution), water (0.6 mL), and NaOH (3.5 mg, 0.087 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (6 mL) and extracted with EtOAc (2 × 3 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1). The residue was triturated with MeOH (1 mL) to give N 5 -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-morpholinopyridine-2,5-dicarboxamide was obtained as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.62 (s, 4H), 5.36-4.82 (m, 6H), 6.08 (s, 1H), 7.37-7.34 (m, 1H), 7.53-7.45 (m, 5H), 7.86-7.76 (m, 2H) ppm. m / z 475 (M+H + ).

[0290] Synthesis Example 22: Synthesis of (R)—N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-(3-methylmorpholino)nicotinamide [ka]

[0291] To a vial equipped with a stir bar was added 2-chloro-N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide Intermediate F (200 mg, 1 equiv.), followed by (R)-3-methylmorpholine (158 mg, 3 equiv.) and THF (2.6 mL). DIPEA (0.546 mL, 6 equiv.) was then added, and the reaction was heated to 75 °C and stirred for 8 h. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over NaSO, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (40%-80% MeCN / HO) to afford the title compound (30 mg, 12% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.50 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.32 - 7.25 (m, 1H), 5.61 (s, 2H), 4.10 - 3.98 (m 3H), 3.27 (td, J = 11.3, 10.4, 4.8 Hz, 1H), 3.15 (dd, J = 22.2, 12.2 Hz, 2H), 2.98 (t, J = 11.3 Hz, 1H), 1.23 (d, J = 6.2 Hz, 3H) ppm. m / z 447 (M+H + ).

[0292] Synthesis Example 23: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)nicotinamide [ka]

[0293] The crude product was obtained by proceeding in a similar manner as described in Synthesis Example 22 using (methylsulfonyl)piperazine, hydrogen chloride, and N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-fluoronicotinamide (Intermediate G). The residue was purified by preparative HPLC (column, C18 Purification by silica gel; mobile phase, 45%-85% MeCN in water with 0.1% FA in both eluents) gave the title compound. 1 H NMR (400 MHz; DMSO-d6): δ 12.85 (br s, 1H), 8.66 (s, 1H), 8.35 (d, 1H), 8.01 (dd, 1H), 7.91 (d, 1H), 7.62 (d, 1 H), 7.00-6.97 (m, 1 H), 5.57 (s, 2H), 3.37-3.31 (m, 4H), 3.20-3.18 (m, 4H), 2.89 (s, 3H) ppm. + ).

[0294] Synthesis Example 24: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-1-phenyl-1H-pyrazole-5-carboxamide [ka]

[0295] The title compound was prepared using general procedure D using 1-phenyl-1H-pyrazole-5-carboxylic acid and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase HPLC (column, C 18 Purification on silica; mobile phase 0-100% MeCN in water with 0.1% FA in water in both eluents) gave N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-1-phenyl-1H-pyrazole-5-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.04 - 7.94 (m, 1H), 7.85 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.44 (td, J = 15.8, 14.5, 10.2 Hz, 7H), 5.55 (s, 2H) ppm. m / z 413 (M+H + ).

[0296] Synthesis Example 25: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-1-phenyl-1H-1,2,3-triazole-5-carboxamide [ka]

[0297] The title compound was prepared using general procedure D employing 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase HPLC (column, C 18 Purification on silica; mobile phase 0-100% MeCN in water with 0.1% FA in water in both eluents) gave N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-1-phenyl-1H-pyrazole-5-carboxamide as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 7.99 (dd, J = 8.3, 2.4 Hz, 1H), 7.58 (s, 6H), 5.55 (s, 2H) ppm. m / z 414 (M+H + ).

[0298] Synthesis Example 26: Synthesis of 3-(2-chlorophenyl)-N-[5-[(5-chloropyridin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]imidazole-4-carboxamide [ka]

[0299] The title compound was prepared using a procedure similar to that of Synthesis Example 18, using 2-chloroaniline instead of 4-aminopyridine in Step 1 and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C) in Step 2. The mixture was stirred at 50° C. overnight, then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3×) and the combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 15:1) to afford 3-(2-chlorophenyl)-N-[5-[(5-chloropyridin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]imidazole-4-carboxamide as a yellow solid. 1 H NMR (400 MHz; DMSO-d6): δ 5.53 (s, 2H), 7.48-7.58 (m, 4H), 7.65-7.67 (m, 1H), 7.97-8.00 (m, 1H), 8.10 (s, 1H), 8.25 (s, 1H), 8.63-8.64 (m, 1H),12.85 (s, 1H) ppm. m / z 447 (M+H + ).

[0300] Synthesis Example 27: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-oxopiperazin-1-yl)nicotinamide [ka]

[0301] The title compound was prepared using general procedure C using piperazin-2-one, followed by general procedure D using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with brine (2x). The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by preparative TLC (DGVPMeOH, 20:1). Trituration of the residue with MeOH afforded N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-oxopiperazin-1-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.22 (s, 2H), 3.44-3.47 (m, 2H), 3.78 (s, 2H), 5.50 (s, 2H), 6.94-6.97 (m, 1H), 7.48-7.56 (m, 4H), 7.87-7.89 (m, 1H), 8.02 (s, 1H), 8.32-8.33 (m, 1H), 12.84 (s, 1H) ppm. m / z 445 (M+H + ).

[0302] Synthesis Example 28: Synthesis of 4-(3-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)pyridin-2-yl)-N,N-dimethylpiperazine-1-carboxamide [ka]

[0303] The title compound was prepared using general procedure C using N,N-dimethylpiperazine-1-carboxamide followed by general procedure A using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×). The combined organic layers were concentrated and the residue was purified by preparative TLC (DCM:MeOH, 20:1). The residue was purified by preparative HPLC [column, C 18 Purification on silica gel; mobile phase, 50-63% ACN in 0.16% NH4HCO3 in water] gave 4-(3-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)pyridin-2-yl)-N,N-dimethylpiperazine-1-carboxamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 2.76 (s, 6H), 3.19-3.26 (m, 8H), 5.51 (s, 2H), 6.98-7.02 (m, 1H), 7.49-7.57 (m, 4H), 7.91-7.93 (m, 1H), 8.35-8.37 (m, 1H),12.87 (s, 1H) ppm. m / z 502 (M+H +).

[0304] Synthesis Example 29: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-morpholinonicotinamide [ka]

[0305] Step 1: Preparation of 6-bromo-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0306] The title compound was prepared using General Procedure A, employing 6-bromo-2-morpholinonicotinic acid (Step 1 of Synthesis Example 14) and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with DCM:MeOH (10:1) to afford 6-bromo-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a white solid.

[0307] Step 2: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-morpholinonicotinamide [ka]

[0308] To a solution of 6-bromo-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide (150 mg, 0.29 mmol) in DME (5 mL) under nitrogen, 2-methyl-3-butyn-2-ol (37 mg, 0.44 mmol, 1.50), PPh3 (123 mg, 0.47 mmol), CuI (22 mg, 0.12 mmol), and 10% Pd / C (15 mg, 10%) were added. The mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:hexanes, 1:1) to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-morpholinonicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 1.47 (s, 6H), 3.21-3.23 (d, 4H), 3.63-3.65 (m, 4H), 5.50-5.62 (m, 3H), 7.00-7.03 (m, 1H), 7.47-7.56 (m, 4H), 7.84-7.87 (m, 1H), 12.84 (s, 1H) ppm. m / z 433 (M+H + ).

[0309] Synthesis Example 30: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide [ka]

[0310] The title compound was prepared using general procedure C using 4-oxa-7-azaspiro[2.5]octane followed by general procedure A using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (4x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 0.50-0.55 (m, 2H), 0.66-0.70 (m, 2H), 3.23 (s, 2H), 3.27-3.32 (m, 2H), 3.72-3.76 (m, 2H), 5.50 (s, 2H), 7.00-7.05 (m, 1H), 7.47-7.57 (m, 4H), 7.93-7.96 (m, 1H), 8.36-8.38 (m, 1H), 13.00 (s, 1H) ppm. + ).

[0311] Synthesis Example 31: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2,4-dimethoxyphenyl)-1H-imidazole-5-carboxamide [ka]

[0312] The title compound was prepared using a procedure similar to that of Synthesis Example 18, replacing 4-aminopyridine with 2,4-dimethoxyaniline in Step 1 and using (5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) in Step 2. The mixture was stirred at 50° C. overnight, then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc and the combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2,4-dimethoxyphenyl)-1H-imidazole-5-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.65 (s, 3H), 3.83 (s, 3H), 5.46 (s, 2H), 6.58-6.62 (m, 1H), 6.70-6.71 (m, 1H), 7.25-7.28 (m, 1H), 7.45-7.53 (m, 4H), 7.92 (s, 1H), 8.11 (s, 1H), 12.68 (s, 1H) ppm. m / z 472 (M+H + ).

[0313] Synthesis Example 32: Synthesis of N-{5-[(5-chloro(2-pyridyl))methoxy](1,3,4-thiadiazol-2-yl)}(6-cyano-2-morpholin-4-ylnicotinamide [ka]

[0314] The title compound was prepared using General Procedure A, employing 6-cyano-2-morpholinonicotinic acid (Step 3 of Synthesis Example 14) and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was cooled to room temperature and filtered. The solid was washed with EtOAc to give N-{5-[(5-chloro(2-pyridyl))methoxy](1,3,4-thiadiazol-2-yl)}(6-cyano-2-morpholin-4-yl(3-pyridyl))carboxamide as a tan solid. 1 H NMR (400 MHz; DMSO-d6): δ 13.04 (br s, 1H), 8.66 (s, 1H), 8.01 (d, 2H), 7.63 (d, 1H), 7.47 (d, 1H), 5.57 (s, 2H), 3.64-3.61 (m, 4H), 3.33-3.30 (m, 4H), ppm. m / z 458 (M+H + ).

[0315] Synthesis Example 33: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5-cyano-2-morpholinonicotinamide [ka]

[0316] Step 1: Preparation of methyl 5-bromo-2-morpholinonicotinate [ka]

[0317] To a solution of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.0 g, 4.0 mmol) in DMF (10 mL) was added morpholine (0.70 g, 8.0 mmol) and DIEA (1.0 g, 8.0 mmol) under nitrogen. 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×). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 9% EtOAc in PE to give methyl 5-bromo-2-morpholinonicotinate as a yellow oil.

[0318] Step 2: Preparation of methyl 5-cyano-2-morpholinonicotinate [ka]

[0319] To a solution of methyl 5-bromo-2-morpholinonicotinate (1.1 g, 3.6 mmol) in DMF (11 mL) was added Zn(CN) (0.84 g, 7.2 mmol) and Pd(PPh) (0.41 g, 0.36 mmol) under nitrogen. The mixture was stirred at 100 °C overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 33% EtOAc in PE to give methyl 5-cyano-2-morpholinonicotinate as an off-white solid.

[0320] Step 3: Preparation of 5-cyano-2-morpholinonicotinic acid [ka]

[0321] To a solution of methyl 5-cyano-2-morpholinonicotinate (770 mg, 3.1 mmol) in THF (7.7 mL) was added water (2 mL) and LiOH (179 mg, 7.5 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 10 mL). Formic acid was added to the aqueous layer until the pH reached 3. The aqueous layer was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column, C 18 Purification on silica gel; mobile phase, 0-40% MeCN in water) gave 5-cyano-2-morpholinonicotinic acid as a white solid.

[0322] Step 4: Preparation of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5-cyano-2-morpholinonicotinamide [ka]

[0323] To a solution of 5-cyano-2-morpholinonicotinic acid (460 mg, 2.0 mmol) in DMF (5 mL) under nitrogen, 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (718 mg, 3.0 mmol, Intermediate C), EDCI (567 mg, 3.0 mmol), and HOBT (400 mg, 3.0 mmol) were added. The mixture was stirred at room temperature overnight and then diluted with water (20 mL). The mixture was extracted with EtOAc (5 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was diluted with MeOH (10 mL), and the mixture was filtered. The solid was washed with MeOH (1 × 3 mL) to give N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5-cyano-2-morpholinonicotinamide as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 3.46-3.49 (m, 4H), 3.61-3.64 (m, 4H), 5.57 (s, 2H), 7.61-7.64 (m, 1H), 8.00-8.04 (m, 1H), 8.23-8.24 (m, 1H), 8.63-8.67 (m, 2H), 12.99 (s, 1H) ppm. m / z 458 (M+H + ).

[0324] Synthesis Example 34: Synthesis of N-(5-((4-chloro-3-methoxybenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0325] Step 1: Preparation of 5-[(4-chloro-3-methoxyphenyl)methoxy]-1,3,4-thiadiazol-2-amine [ka]

[0326] The title compound was prepared using a similar procedure to Intermediate C, replacing (5-chloropyridin-2-yl)methanol in Step 1 with (4-chloro-3-methoxyphenyl)methanol.

[0327] Step 2: Preparation of N-(5-((4-chloro-3-methoxybenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0328] The title compound was prepared using general procedure D using 5-[(4-chloro-3-methoxyphenyl)methoxy]-1,3,4-thiadiazol-2-amine and 2-morpholinonicotinic acid. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 35:1) to afford N-(5-((4-chloro-3-methoxybenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.22-3.25 (m, 4H), 3.66-3.69 (m, 4H), 3.89 (s, 3H), 5.50 (s, 2H), 6.98-7.03 (m, 1H), 7.10-7.13 (m, 1H), 7.33-7.34 (m, 1H), 7.46-7.49 (m, 1H), 7.91-7.94 (m, 1H), 8.36-8.38 (m, 1H), 12.88 (s, 1H) ppm. + ).

[0329] Synthesis Example 35: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-morpholinonicotinamide [ka]

[0330] Step 1: Preparation of ethyl 6-chloro-4-morpholinonicotinate [ka]

[0331] To a solution of morpholine (871 mg, 10 mmol) and EtN (1.8 g, 18 mmol) in MeCN (20 mL) under nitrogen, ethyl 4,6-dichloropyridine-3-carboxylate (2.0 g, 9.1 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was triturated with PE:EtOAc (30:1) to give ethyl 6-chloro-4-morpholinonicotinate as a white solid.

[0332] Step 2: Preparation of 6-cyano-4-(morpholin-4-yl)pyridine-3-carboxylic acid [ka]

[0333] To a solution of 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylic acid (400 mg, 1.6 mmol) in DMF (4 mL) was added Zn(CN) (387 mg, 3.3 mmol), Zn powder (323 mg, 4.9 mmol), and Pd(dppf)Cl (181 mg, 0.25 mmol) under nitrogen. The mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature and filtered. The solid was washed with DMF (2 × 2 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (column, C 18 Purification on silica gel; mobile phase, 0-100% MeCN in water) gave 6-cyano-4-(morpholin-4-yl)pyridine-3-carboxylic acid as a yellow solid.

[0334] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-morpholinonicotinamide [ka]

[0335] The title compound was prepared using general procedure A employing 6-cyano-4-(morpholin-4-yl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-morpholinonicotinamide as a yellow solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.26 (s, 4H), 3.64 (s, 4H), 5.51 (s, 2H), 7.48-7.57 (m, 4H), 7.70 (s, 1H), 8.47 (s, 1H), 13.04 (s, 1H) ppm. m / z 457 (M+H + ).

[0336] Synthesis Example 36: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methoxy-4-morpholinonicotinamide [ka]

[0337] Step 1: Preparation of 6-methoxy-4-(morpholin-4-yl)pyridine-3-carboxylic acid [ka]

[0338] To a solution of ethyl 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylate (810 mg, 3.1 mmol, Synthesis Example 35, Step 1) in MeOH (10 mL) at 0° C. under nitrogen, sodium methoxide (199 mg, 3.7 mmol) was added. The mixture was stirred at 60° C. overnight. NaOH (1.5 mL, 6.1 mmol, 4 M) was then added, and the mixture was stirred at room temperature for 5 hours. The mixture was acidified to pH 6 with HOAc. The mixture was concentrated, and the residue was purified by reverse-phase chromatography (column, C 18Purification on silica gel; mobile phase, 10-50% MeCN in water) gave 6-methoxy-4-(morpholin-4-yl)pyridine-3-carboxylic acid as a white solid.

[0339] Step 2: Preparation of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methoxy-4-morpholinonicotinamide [ka]

[0340] The title compound was prepared using general procedure A employing 6-methoxy-4-(morpholin-4-yl)pyridine-3-carboxylic acid and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was stirred at 50° C. overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH (2 mL) to afford N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methoxy-4-morpholinonicotinamide as a brown solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.02-3.05 (m, 4H), 3.66-3.69 (m, 4H), 3.88 (s, 3H), 5.57 (s, 2H), 6.37 (s, 1H), 7.62-7.65 (m, 1H), 8.00-8.04 (m, 1H), 8.26 (s, 1H), 8.66-8.67 (m, 1H), 12.65 (s, 1H) ppm. m / z 463 (M+H + ).

[0341] Synthesis Example 37: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-(1,1-dioxidethiomorpholino)nicotinamide [ka]

[0342] To a vial equipped with a stir bar was added N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-fluoronicotinamide Intermediate G (100 mg, 1 equiv.), followed by thiomorpholine 1,1-dioxide (110 mg, 3 equiv.) and DMF (1.2 mL). DIPEA (0.280 mL, 6 equiv.) was then added, and the reaction was heated to 75° C. and stirred for 48 hours. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 10 wt. % aqueous LiCl, then with brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified under reverse-phase chromatography conditions (column, C 18 Purification on silica gel; mobile phase, 40-80% aqueous MeCN with 0.1% FA in both eluents) afforded the title compound (7 mg, 5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.32 (d, J = 4.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 6.2 Hz, 1H), 5.55 (s, 2H), 3.72 (bs, 4H), 3.18 (bs, 4H) ppm. m / z 481 (M+H + ).

[0343] Synthesis Example 38: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-1-(pyridin-2-yl)-1H-imidazole-5-carboxamide [ka]

[0344] The title compound was prepared using general procedure D employing 1-(pyridin-2-yl)-1H-imidazole-5-carboxylic acid and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (column, C 18Purification by silica gel; mobile phase, 0-100% aqueous MeCN, both containing 0.1% formic acid) gave N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-1-phenyl-1H-pyrazole-5-carboxamide as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.59 - 8.44 (m, 1H), 8.34 - 8.19 (m, 1H), 8.09 - 7.87 (m, 2H), 7.66 - 7.55 (m, 2H), 7.57 - 7.43 (m, 1H), 6.52 (s, 1H), 5.52 (s, 2H) ppm. m / z 414 (M+H + ).

[0345] Synthesis Example 39: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-(4,4-difluoropiperidin-1-yl)nicotinamide [ka]

[0346] Proceeding similarly as described in Synthesis Example 22, but using N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2-fluoronicotinamide intermediate G and 4,4-difluoropiperidine, the crude product was obtained. Purification by reverse-phase chromatography (column, C18 silica gel; mobile phase, 40-80% MeCN in water containing 0.1% FA in both eluents) afforded the title compound as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.54 (d, J = 4.5 Hz, 1H), 8.48 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.32 - 7.26 (m, 1H), 5.63 (s, 2H), 3.44 (s, 4H), 2.31 (dt, J = 13.5, 7.2 Hz, 4H) ppm. m / z 467 (M+H +).

[0347] Synthesis Example 40: Synthesis of N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0348] Step 1: Preparation of 5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0349] The title compound was prepared using a procedure similar to Intermediate C, replacing (5-chloropyridin-2-yl)methanol in Step 1 with p-bromobenzyl alcohol.

[0350] Step 2: Preparation of N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0351] The title compound was prepared using general procedure A using 5-((4-bromobenzyl)-oxy)-1,3,4-thiadiazol-2-amine and 2-morpholinonicotinic acid. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a pink solid. 1H NMR (400 MHz; DMSO-d6): δ 3.22-3.25 (m, 4H), 3.66-3.68 (m, 4H), 5.45 (s, 2H), 7.00-7.02 (m, 1H), 7.48-7.52 (m, 2H), 7.62-7.65 (m, 2H), 7.91-7.93 (m, 1H), 8.36-8.37 (m, 1H),12.88 (s, 1H) ppm. m / z 476 (M+H + ).

[0352] Synthesis Example 41: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholino-6-oxo-1,6-dihydropyridine-3-carboxamide or its tautomer N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-hydroxy-4-morpholinonicotinamide [ka]

[0353] Step 1: Preparation of ethyl 4-(morpholin-4-yl)-6-oxo-1H-pyridine-3-carboxylate [ka]

[0354] A solution of ethyl 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylate (1.0 g, 3.7 mmol, Step 1 of Synthesis Example 35) in HOAc (10 mL) was stirred at 100° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with saturated NaHCO (10 mL), and the mixture was extracted with EtOAc (5×10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% MeOH in DCM to give ethyl 4-(morpholin-4-yl)-6-oxo-1H-pyridine-3-carboxylate as a white solid.

[0355] Step 2: Preparation of 4-morpholino-6-oxo-5,6-dihydropyridine-3-carboxylic acid [ka]

[0356] To a solution of ethyl 4-(morpholin-4-yl)-6-oxo-1H-pyridine-3-carboxylate (430 mg, 1.7 mmol) in MeOH (4.3 mL) was added NaOH (136 mg, 3.4 mmol) and water (1.7 mL). The mixture was stirred at 100° C. for 48 hours. The mixture was acidified to pH 6 with HCl (1 M). The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column, C 18 The residue was purified by reverse-phase chromatography (column, preparative T3 OBD column; mobile phase, 2-10% MeCN in water with 0.05% TFA in both eluents) to give 4-morpholino-6-oxo-5,6-dihydropyridine-3-carboxylic acid as a white solid.

[0357] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholino-6-oxo-1,6-dihydropyridine-3-carboxamide [ka]

[0358] The title compound was prepared using general procedure A employing 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was stirred under nitrogen at 50° C. overnight. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 25:1) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholino-6-oxo-1,6-dihydropyridine-3-carboxamide as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 2.92 (s, 4H), 3.65-3.69 (m, 4H), 5.48 (s, 2H), 5.71 (s, 1H), 7.47-7.56 (m, 4H), 7.77 (s, 1H), 11.62 (s, 1H), 12.38 (s, 1H) ppm. m / z 448 (M+H + ).

[0359] Synthesis Example 42: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-chlorophenyl)-1H-imidazole-5-carboxamide [ka]

[0360] The title compound was prepared using a procedure similar to that of Synthesis Example 18, replacing 4-aminopyridine with 2-chloroaniline in step 1 and using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) in step 2. The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 35:1) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-chlorophenyl)-1H-imidazole-5-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 5.44-5.47 (m, 2H), 7.45-7.60 (m, 7H), 7.65-7.68 (m, 1H), 8.11 (s, 1H), 8.27 (s, 1H), 12.85 (s, 1H) ppm. m / z 446 (M+H + ).

[0361] Synthesis Example 43: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-cyanophenyl)-1H-imidazole-5-carboxamide [ka]

[0362] The title compound was prepared using a procedure similar to that of Synthesis Example 12, replacing p-anisidine with 2-aminobenzonitrile in Step 2 and using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-cyanophenyl)-1H-imidazole-5-carboxamide as a pale yellow solid. 1 H NMR (300 MHz; DMSO-d6): δ 5.47 (s, 2H), 7.46-7.54 (m, 4H), 7.70-7.75 (m, 2H), 7.83-7.93 (m, 1H), 8.04-8.07 (m, 1H), 8.27-8.32 (m, 2H), 12.96-13.04 (br s, 1H) ppm. m / z 437 (M+H + ).

[0363] Synthesis Example 44: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide [ka]

[0364] Step 1: Preparation of 6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinic acid [ka]

[0365] The title compound was prepared using a procedure similar to steps 1-2 of Synthesis Example 14, replacing morpholine with 4-oxa-7-azaspiro[2.5]octane in step 1.

[0366] Step 2: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide [ka]

[0367] The title compound was prepared using general procedure A employing 6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide as a yellow-green solid. 1 H NMR (400 MHz; DMSO-d6): δ 0.53-0.56 (m, 2H), 0.66-0.69 (m, 2H), 3.31-3.32 (m, 2H), 3.35-3.37 (m, 2H), 3.68-3.70 (m, 2H), 5.51 (s, 2H), 7.47-7.50 (m, 3H), 7.54-7.56 (m, 2H), 8.00-8.02 (m, 1H), 13.04 (s, 1H) ppm. m / z 483 (M+H + ).

[0368] Synthesis Example 45: Synthesis of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(4-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxamide [ka]

[0369] To a solution of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-fluoropyridine-3-carboxamide (100 mg, 0.27 mmol, Intermediate D) in MeCN (1.0 mL) was added 1-methylpiperazin-2-one (34 mg, 0.3 mmol) and EtN (55 mg, 0.55 mmol) under nitrogen. The mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with MeOH to give N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(4-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxamide as a yellow solid. 1 H NMR (400 MHz; DMSO-d6): δ 2.82-2.85 (m, 3H), 3.32-3.34 (m, 2H), 3.54-3.57 (m, 2H), 3.83 (s, 2H), 5.51 (s, 2H), 6.95-6.98 (m, 1H), 7.48-7.56 (m, 4H), 7.88-7.90 (m, 1H), 8.32-8.34 (m, 1H), 12.74 (s, 1H) ppm. m / z 459 (M+H + ).

[0370] Synthesis Example 46: Synthesis of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methyl-5-oxopiperazin-1-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methyl-5-oxopiperazin-1-yl)nicotinamide [ka]

[0371] To a solution of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-fluoropyridine-3-carboxamide (100 mg, 0.27 mmol, Intermediate D) in NMP (1 mL) was added racemic 6-methylpiperazin-2-one (125 mg, 1.1 mmol) and DIEA (74 mg, 0.55 mmol) under nitrogen. The mixture was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc (2 mL) and washed with water (2×). The organic layer was concentrated under reduced pressure. The residue was triturated with MeOH (2 mL) to give (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methyl-5-oxopiperazin-1-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-methyl-5-oxopiperazin-1-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 1.00-1.02 (m, 3H), 3.00-3.05 (m, 1H), 3.55 (s, 1H), 3.65-3.79 (m, 3H), 5.51 (s, 2H), 6.93-6.96 (m, 1H), 7.48-7.56 (m, 4H), 7.86-7.89 (m, 1H), 8.07 (s, 1H), 8.32-8.33 (m, 1H), 12.84 (s, 1H) ppm. m / z 459 (M+H + ).

[0372] Synthesis Example 47: Synthesis of N-(5-((4-cyclopropylbenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0373] Step 1: Preparation of 5-[(4-cyclopropylphenyl)methoxy]-1,3,4-thiadiazol-2-amine [ka]

[0374] The title compound was prepared using a similar procedure to Intermediate C, replacing (5-chloropyridin-2-yl)methanol in Step 1 with (4-cyclopropylphenyl)methanol.

[0375] Step 2: Preparation of N-(5-((4-cyclopropylbenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0376] The title compound was prepared using General Procedure A, employing 5-[(4-cyclopropylphenyl)methoxy]-1,3,4-thiadiazol-2-amine and 2-morpholinonicotinic acid. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-cyclopropylbenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as an off-white solid. 1 H NMR (300 MHz; DMSO-d6): δ 0.61-0.71 (m, 2H), 0.96-0.99 (m, 2H), 1.89-1.98 (m, 1H), 3.21-3.24 (m, 4H), 3.65-3.68 (m, 4H), 5.43 m / z 438 (M+H + ).

[0377] Synthesis example 48:N 5 Synthesis of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinopyridine-2,5-dicarboxamide [ka]

[0378] The title compound was prepared using a procedure similar to Synthesis Example 21 using N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-morpholinonicotinamide (Synthesis Example 35). The mixture was stirred at room temperature for 2 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 35:1) to give N 5 -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinopyridine-2,5-dicarboxamide was obtained as a yellow solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.20 (s, 4H), 3.67 (s, 4H), 5.51 (s, 2H), 7.49-7.58 (m, 5H), 7.70-7.73 (m, 1H), 8.14-8.19 (m, 1H), 8.45 (s, 1H), 12.92-13.00 (br s, 1H) ppm. m / z 475 (M+H + ).

[0379] Synthesis Example 49: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(3-methoxyphenyl)-1H-imidazole-5-carboxamide [ka]

[0380] The title compound was prepared using a procedure similar to that of Synthesis Example 18, replacing 4-aminopyridine with 3-methoxyaniline in Step 1 and using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) in Step 2. The mixture was diluted with EtOAc and washed with water (2x). The organic layer was concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(3-methoxyphenyl)-1H-imidazole-5-carboxamide as an off-white solid. 1H NMR (300 MHz; DMSO-d6): δ 3.78 (s, 3H), 5.47 (s, 2H), 6.95-7.01 (m, 3H), 7.36-7.53 (m, 5H), 8.12-8.16 (m, 2H), 12.80 (s, 1H) ppm. m / z 442 (M+H + ).

[0381] Synthesis Example 50: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide [ka]

[0382] The title compound was prepared using a procedure similar to that of Synthesis Example 18, replacing 4-aminopyridine with 2-methoxyaniline in Step 1 and using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) in Step 2. The mixture was diluted with water and filtered. The solid was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide as an off-white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.64-3.66 (m, 3H), 5.44 (s, 2H), 7.02-7.07 (m, 1H), 7.15-7.17 (m, 1H), 7.34-7.36 (m, 1H), 7.41-7.52 (m, 5H), 7.97 (s, 1H), 8.09 (s, 1H), 12.71 (s, 1H) ppm. m / z 442 (M+H + ).

[0383] Synthesis Example 51: Synthesis of 2-(2-chlorophenyl)-N-[5-[(5-chloropyridin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]pyridine-3-carboxamide [ka]

[0384] Step 1: Preparation of methyl 2-(2-chlorophenyl)pyridine-3-carboxylate [ka]

[0385] The title compound was prepared using general procedure E using methyl 2-bromopyridine-3-carboxylate and 2-chlorophenylboronic acid. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 16% EtOAc in hexane to afford methyl 2-(2-chlorophenyl)pyridine-3-carboxylate as a yellow solid.

[0386] Step 2: Preparation of 2-(2-chlorophenyl)pyridine-3-carboxylic acid [ka]

[0387] The title compound was prepared using general procedure F using methyl 2-(2-chlorophenyl)pyridine-3-carboxylate. The mixture was diluted with water and extracted with EtOAc (5x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 50:1) to afford 2-(2-chlorophenyl)pyridine-3-carboxylic acid as a white solid.

[0388] Step 3: Preparation of 2-(2-chlorophenyl)-N-[5-[(5-chloropyridin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]pyridine-3-carboxamide [ka]

[0389] To a solution of 2-(2-chlorophenyl)pyridine-3-carboxylic acid (140 mg, 0.51 mmol) in DCM (1.4 mL) was added oxalyl chloride (98 mg, 0.77 mmol) and DMF (4 mg, 0.05 mmol) at room temperature. The mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (1.2 mL), and EtN (130 mg, 1.3 mmol) and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (149 mg, 0.62 mmol, Intermediate C) were added. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 50:1) to give 2-(2-chlorophenyl)-N-[5-[(5-chloropyridin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]pyridine-3-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 5.54 (s, 2H), 7.40-7.49 (m, 4H), 7.58-7.63 (m, 2H), 7.98-8.01 (m, 1H), 8.21-8.24 (m, 1H), 8.64-8.65 (m, 1H), 8.81-8.83 (m, 1H), 13.00 (s, 1H) ppm. m / z 458 (M+H + ).

[0390] Synthesis Example 52: Synthesis of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-3-oxopiperazin-1-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-3-oxopiperazin-1-yl)nicotinamide [ka]

[0391] Step 1: Preparation of (R) 2-(2-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxylic acid and (S) 2-(2-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxylic acid [ka]

[0392] To a solution of 2-fluoropyridine-3-carboxylic acid (1.0 g, 7.1 mmol) in MeCN (10 mL) was added racemic 3-methylpiperazin-2-one (1618 mg, 14.2 mmol) and EtN (1434 mg, 14.2 mmol). The mixture was stirred at 80 °C for 3 days. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with MeOH (5 mL) to give a racemic mixture of (R) 2-(2-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxylic acid and (S) 2-(2-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxylic acid as a yellow solid.

[0393] Step 2: Preparation of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-3-oxopiperazin-1-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-3-oxopiperazin-1-yl)nicotinamide [ka]

[0394] The title compound was prepared using general procedure A using a racemic mixture of (R) 2-(2-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxylic acid and (S) 2-(2-methyl-3-oxopiperazin-1-yl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was stirred at 50° C. for 4 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3×). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give a racemic mixture of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-3-oxopiperazin-1-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-3-oxopiperazin-1-yl)nicotinamide as a yellow solid. 1 H NMR (300 MHz; DMSO-d6): δ 1.24-1.32 (m, 3H), 3.10-3.14 (m, 1H), 3.35-3.41 (m, 2H), 3.51-3.57 (m, 1H), 4.25-4.32 (m, 1H), 5.51 (s, 2H), 6.93-6.98 (m, 1H), 7.48-7.57 (m, 4H), 7.86-7.89 (m, 2H), 8.32-8.35 (m, 1H), 12.97 (s, 1H) ppm. m / z 459 (M+H + ).

[0395] Synthesis Example 53: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)nicotinamide [ka]

[0396] Step 1: Preparation of methyl 2-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate [ka]

[0397] The title compound was prepared using general procedure E using methyl 2-chloropyridine-3-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The mixture was stirred at 100° C. for 3 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (4×). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 33% EtOAc in PE to give methyl 2-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate as a yellow oil.

[0398] Step 2: Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)nicotinic acid [ka]

[0399] The title compound was prepared using general procedure F using methyl 2-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate. The mixture was stirred at room temperature for 5 hours and then diluted with water. The mixture was extracted with EtOAc (3x). The aqueous layer was neutralized to pH 6 with HOAc and the mixture was extracted with EtOAc (5x). The combined organic layers were concentrated under reduced pressure. Preparative HPLC (column, C 18 The residue was purified using silica gel; mobile phase, 10-50% aqueous MeCN containing 0.05% TFA in both eluents) to give 2-(3,6-dihydro-2H-pyran-4-yl)nicotinic acid as a pale yellow oil.

[0400] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)nicotinamide [ka]

[0401] The title compound was prepared using General Procedure A, employing 2-(3,6-dihydro-2H-pyran-4-yl)nicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 2.51-2.54 (m, 2H), 3.75-3.78 (m, 2H), 4.06-4.07 (m, 2H), 5.50 (s, 2H), 5.92 (s, 1H), 7.39-7.43 (m, 1H), 7.46-7.57 (m, 4H), 7.93-7.96 (m, 1H), 8.66-8.69 (m, 1H), 12.89 (s, 1H) ppm. m / z 429 (M+H + ).

[0402] Synthesis Example 54: Synthesis of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(oxan-4-yl)pyridine-3-carboxamide [ka]

[0403] Step 1: Preparation of 2-(oxan-4-yl)pyridine-3-carboxylic acid [ka]

[0404] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)nicotinic acid (180 mg, 0.88 mmol, Synthesis Example 53, Step 2) in MeOH (22 mL) was added 20% Pd / C (36 mg). The mixture was stirred under hydrogen at room temperature for 9 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2-(oxan-4-yl)pyridine-3-carboxylic acid as a pale yellow oil.

[0405] Step 2: Preparation of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(oxan-4-yl)pyridine-3-carboxamide [ka]

[0406] The title compound was prepared using general procedure A employing 2-(oxan-4-yl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 100:1) to afford N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-(oxan-4-yl)pyridine-3-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 1.62-1.65 (m, 2H), 1.84-1.98 (m, 2H), 3.17-3.22 (m, 1H), 3.37-3.40 (m, 2H), 3.89-3.94 (m, 2H), 5.52 (s, 2H), 7.35-7.40 (m, 1H), 7.49-7.58 (m, 4H), 7.94-7.97 (m, 1H), 8.68-8.71 (m, 1H), 12.98 (s, 1H) ppm. m / z 431 (M+H + ).

[0407] Synthesis Example 55: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-5-carboxamide [ka]

[0408] Step 1: Preparation of 1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-5-carboxylic acid [ka]

[0409] The title compound was prepared using a procedure similar to steps 1-2 of Synthesis Example 12, replacing p-anisidine in step 1 with oxan-4-amine.

[0410] Step 2: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-5-carboxamide [ka]

[0411] To a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-5-carboxylic acid (110 mg, 0.61 mmol) in DCM (1.1 mL) was added DMF (4.5 mg, 0.06 mmol), followed by the dropwise addition of oxalyl chloride (85 mg, 0.63 mmol) at room temperature under nitrogen. After the addition, the mixture was concentrated under reduced pressure. The yellow solid was diluted with DCM (1.2 mL), and EtN (113 mg, 1.1 mmol) and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (120 mg, 0.56 mmol, Intermediate B) were added at room temperature under nitrogen. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH (1 mL) to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-5-carboxamide as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 1.89-1.98 (m, 4H), 3.40-3.49 (m, 2H), 3.95-3.99 (m, 2H), 5.05-5.10 (m, 1H), 5.50 (s, 2H), 7.47-7.56 (m, 4H), 8.10 (s, 1H), 8.23 ​​(s, 1H), 12.67-12.79 (br s, 1H) ppm. m / z 420 (M+H + ).

[0412] Synthesis Example 56: Synthesis of 2-morpholino-N-(5-((4-(oxetan-3-yl)benzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide [ka]

[0413] Step 1: Preparation of ((4-bromobenzyl)oxy)(tert-butyl)diphenylsilane [ka]

[0414] To a solution of p-bromobenzyl alcohol (5 g, 26.88 mmol) in THF (10 mL) under nitrogen, imidazole (182.0 mg, 0.2688 mmol) and TBDPSCl (8.08 g, 29.57 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with DCM (3×). The combined organic layers were concentrated under reduced pressure to give ((4-bromobenzyl)oxy)(tert-butyl)diphenylsilane as a solid. This material was used in the next step without further purification.

[0415] Step 2: Preparation of tert-butyl((4-(oxetan-3-yl)benzyl)oxy)diphenylsilane [ka]

[0416] ((4-Bromobenzyl)oxy)(tert-butyl)diphenylsilane (500 mg, 1.2 mmol), 3-iodooxetane (732 mg, 5.3 mmol), [Ir(dtbbpy)(ppy)][PF] (43 mg, 0.047 mmol), tris(trimethylsilyl)silane (532 mg, 2.4 mmol), and NaCO (450 mg, 4.2 mmol) were combined and purged with nitrogen. DME (20 mL) was then added. In a separate vial, 4,4'-di-tert-butyl-2,2-bipyridine (12 mg, 0.043 mmol), nickel(II) chloride (5 mg, 0.036 mmol), and 1,2-dimethoxyethane (9 mg, 0.039 mmol) were combined, purged with nitrogen, and diluted with DME (10 mL). The mixture was stirred at room temperature for 20 minutes and then added to the Ir solution. The mixture was degassed with bubbling nitrogen for 10 minutes and then sealed. The mixture was stirred under a 50 W blue LED lamp (7 cm away, equipped with a cooling fan to maintain 25 °C) for 3.5 days. The mixture was diluted with EtOAc (50 mL) and washed with water (20 mL × 2). The organic layer was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE: EtOAc, 4:1) to give tert-butyl((4-(oxetan-3-yl)benzyl)oxy)diphenylsilane as a pale yellow solid.

[0417] Step 3: Preparation of (4-(oxetan-3-yl)phenyl)methanol [ka]

[0418] To a solution of tert-butyl([[4-(oxetan-3-yl)phenyl]methoxy])diphenylsilane (300 mg, 0.72 mmol) in THF (6 mL) was added TBAF (564 mg, 2.2 mmol). The mixture was stirred at room temperature for 40 minutes. The mixture was diluted with EtOAc (30 mL), washed with brine (3 × 5 mL), and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc, 1:1) to give (4-(oxetan-3-yl)phenyl)methanol as a colorless oil.

[0419] Step 4: Preparation of S-methyl O-(4-(oxetan-3-yl)benzyl)carbodithioate [ka]

[0420] To a solution of (4-(oxetan-3-yl)phenyl)methanol (80 mg, 0.49 mmol) in THF (5 mL) at 0° C. was added NaH (39 mg, 0.97 mmol, 60% oil dispersion). The mixture was stirred at 0° C. for 20 min, then CS2 (45 mg, 0.59 mmol) was added. The mixture was stirred at 0° C. for 10 min, then MeI (83 mg, 0.59 mmol) was added. The mixture was diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 9% EtOAc in hexane to give S-methyl O-(4-(oxetan-3-yl)benzyl)carbonodithioate as a white solid.

[0421] Step 5: Preparation of 5-((4-(oxetan-3-yl)benzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0422] The title compound was prepared using a procedure similar to Step 2 of Intermediate B, replacing O-(4-chlorobenzyl) S-methylcarbonodithioate with S-methyl O-(4-(oxetan-3-yl)benzyl)carbonodithioate.

[0423] Step 6: Preparation of 2-morpholino-N-(5-((4-(oxetan-3-yl)benzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide [ka]

[0424] The title compound was prepared using general procedure A using 2-(morpholin-4-yl)pyridine-3-carboxylic acid and 5-((4-(oxetan-3-yl)benzyl)oxy)-1,3,4-thiadiazol-2-amine. The mixture was diluted with water and extracted with DCM (3x). The combined organic layers were purified by preparative HPLC [column, XBridge Prep OBD C 18 ; mobile phase, 20-40% MeCN in 0.05% NH4OH in water] to give 2-morpholino-N-(5-((4-(oxetan-3-yl)benzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.22-3.25 (m, 4H), 3.66-3.68 (m, 4H), 4.24-4.32 (m, 1H), 4.61-4.64 (m, 2H), 4.94-4.97 (m, 2H), 5.50 (s, 2H), 6.98-7.01 (m, 1H), 7.45-7.54 (m, 4H), 7.90-7.92 (m, 1H), 8.35-8.37 (m, 1H), 12.88 (s, 1H) ppm. + ).

[0425] Synthesis Example 57: Synthesis of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide [ka]

[0426] To a solution of racemic hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (110 mg, 0.78 mmol) and N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-fluoropyridine-3-carboxamide (200 mg, 0.55 mmol, Intermediate D) in NMP (1.5 mL) was added DIEA (202 mg, 1.6 mmol) under nitrogen. The mixture was stirred at 60° C. overnight. The mixture was diluted with water. The mixture was extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1) to give a racemic mixture of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 1.52-1.59 (m, 1H), 2.03-2.09 (m, 1H), 2.22-2.30 (m, 2H), 2.61-2.68 (m, 1H), 2.73-2.85 (m, 2H), 3.61-3.68 (m, 2H), 3.78-3.84 (m, 2H), 5.51 (s, 2H), 6.99-7.03 (m, 1H), 7.48-7.58 (m, 4H), 7.91-7.94 (m, 1H), 8.35-8.37 (m, 1H), 12.85 (s, 1H) ppm. m / z 485 (M+H + ).

[0427] Synthesis Example 58: Synthesis of 6-bromo-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide [ka]

[0428] The title compound was prepared using General Procedure A, employing 6-bromo-2-morpholinonicotinic acid (Step 1 of Synthesis Example 14) and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with DCM:MeOH (10:1) to afford 6-bromo-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-morpholinonicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.26-3.32 (m, 4H), 3.61-3.64 (m, 4H), 5.50 (s, 2H), 7.06-7.09 (m, 1H), 7.47-7.56 (m, 4H), 7.72-7.75 (m, 1H), 12.83 (s, 1H) ppm. m / z 512 (M+H + ).

[0429] Synthesis Example 59: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-morpholinoisonicotinamide [ka]

[0430] Step 1: Preparation of 3-morpholinoisonicotinic acid [ka]

[0431] To a solution of 3-fluoroisonicotinic acid (1 equiv.) and morpholine (1.2 equiv.) in THF at −78° C. was slowly added a solution of LiHMDS (3 equiv., 1 M THF solution). The mixture was slowly warmed to room temperature and stirred for an additional 18 hours. The mixture was quenched with 4 M HCl in dioxane, and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0-12% MeOH in DCM to give 3-morpholinoisonicotinic acid as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 14.11 (s, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.34 (dd, J = 4.9, 1.7 Hz, 1H), 7.53 (dd, J = 4.9, 1.7 Hz, 1H), 3.80 - 3.68 (m, 4H), 3.16 - 3.03 (m, 4H).

[0432] Step 2: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-morpholinoisonicotinamide [ka]

[0433] The title compound was prepared using general procedure D employing 3-morpholinoisonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column, C18 silica gel; mobile phase, both eluents 0-100% MeCN in water containing 0.1% FA) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-morpholinoisonicotinamide as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H), 8.65 (s, 1H), 8.54 - 8.36 (m, 1H), 7.69 - 7.60 (m, 1H), 7.56 (dd, J = 8.5, 1.9 Hz, 2H), 7.49 (dd, J = 8.6, 2.0 Hz, 2H), 5.51 (s, 2H), 3.73 (t, J = 4.3 Hz, 4H), 3.08 (t, J = 4.2 Hz, 4H) ppm. m / z 432 (M+H + ).

[0434] Synthesis Example 60: Synthesis of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-5-oxopiperazin-1-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-5-oxopiperazin-1-yl)nicotinamide [ka]

[0435] The title compound was prepared using a procedure similar to Steps 1-2 of Synthesis Example 7, replacing racemic 2-methylmorpholine with racemic 5-methylpiperazin-2-one hydrochloride in Step 1. The mixture was diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 50:1) to afford a racemic mixture of (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-5-oxopiperazin-1-yl)nicotinamide and (S)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methyl-5-oxopiperazin-1-yl)nicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 1.09-1.11 (m, 3H), 2.97-3.06 (m, 1H), 3.36-3.42 (m, 1H), 3.66-3.81 (m, 2H), 4.08-4.10 (m, 1H), 5.50 (s, 2H), 6.92-7.02 (m, 1H), 7.47-7.57 (m, 4H), 7.86-7.96 (m, 2H), 8.31-8.38 (m, 1H), 12.86 (s, 1H) ppm. + ).

[0436] Synthesis Example 61: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(5-oxo-1,4-diazepan-1-yl)nicotinamide [ka]

[0437] To a solution of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-2-fluoropyridine-3-carboxamide (200 mg, 0.55 mmol, Intermediate D) in MeCN (2.0 mL) under nitrogen, 1,4-diazepan-5-one (69 mg, 0.60 mmol) and EtN (111 mg, 1.1 mmol) were added. The mixture was stirred at 60 °C overnight. The mixture was cooled to room temperature and diluted with water. The mixture was filtered, and the solid was washed with MeOH (2 mL) to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(5-oxo-1,4-diazepan-1-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 2.56-2.58 (m, 4H), 3.20-3.25 (m, 2H), 3.51 (s, 2H), 5.50 (s, 2H), 6.87-6.91 (m, 1H), 7.45-7.57 (m, 5H), 7.83-7.88 (m, 1H), 8.28-8.30 (m, 1H), 12.84 (s, 1H) ppm. m / z 459 (M+H + ).

[0438] Synthesis Example 62: Synthesis of N-(5-((4-cyclopropylbenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide [ka]

[0439] The title compound was prepared using a procedure similar to Synthesis Example 50, using 5-[(4-cyclopropylphenyl)methoxy]-1,3,4-thiadiazol-2-amine (Step 1 of Synthesis Example 47) in Step 2. The mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-cyclopropylbenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 0.62-0.66 (m, 2H), 0.94-0.98 (m, 2H), 1.87-1.96 (m, 1H), 3.66 (s, 3H), 5.39 (s, 2H), 7.03-7.11 (m, m / z 448 (M+H + ).

[0440] Synthesis Example 63: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-oxo-1,4-diazepan-1-yl)nicotinamide [ka]

[0441] The title compound was prepared using a procedure similar to that of Synthesis Example 61, replacing 1,4-diazepan-5-one with 1,4-diazepan-2-one. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1). The residue was further triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(3-oxo-1,4-diazepan-1-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 1.90 (s, 2H), 2.96-2.97 (m, 2H), 3.36-3.39 (m, 2H), 4.02 (s, 2H), 5.49 (s, 2H), 6.82-6.86 (m, 1H), 7.41 (s, 1H), 7.47-7.56 (m, 4H), 7.78-7.84 (m, 1H), 8.22-8.27 (m, 1H), 12.74 (s, 1H) ppm. m / z 459 (M+H + ).

[0442] Synthesis example 64:N 5 Synthesis of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2-methyl-4-morpholinopyridine-2,5-dicarboxamide [ka]

[0443] Step 1: Preparation of ethyl 6-(methylcarbamoyl)-4-morpholinonicotinate [ka]

[0444] To a solution of ethyl 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylate (1.5 g, 5.5 mmol, Step 1 of Synthesis Example 35) in THF (15 mL) was added EtN (1.1 g, 11.1 mmol), methylamine (2.80 mL, 5.6 mmol, 2 M THF solution), and Pd(dppf)Cl (405 mg, 0.55 mmol). The mixture was stirred at 110 °C under CO (20 atm) for 4 h. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (5x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 50:1) to afford ethyl 6-(methylcarbamoyl)-4-morpholinonicotinate as a red solid.

[0445] Step 2: Preparation of 6-(methylcarbamoyl)-4-morpholinonicotinic acid [ka]

[0446] To a solution of ethyl 6-(methylcarbamoyl)-4-morpholinonicotinate (310 mg, 1.0 mmol) in MeOH (3 mL) and water (3 mL) was added NaOH (204 mg, 5.1 mmol). The mixture was stirred at room temperature overnight. The mixture was acidified to pH 6 with HCl (1 M). The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column, C 18Purification on silica gel; mobile phase, 10-50% MeOH in water) gave 6-(methylcarbamoyl)-4-morpholinonicotinic acid as a colorless solid.

[0447] Step 3:N 5 Preparation of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2-methyl-4-morpholinopyridine-2,5-dicarboxamide [ka]

[0448] The title compound was prepared using general procedure A using 6-(methylcarbamoyl)-4-morpholinonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH and purified by N 5 -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2-methyl-4-morpholinopyridine-2,5-dicarboxamide was obtained as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 2.81-2.82 (m, 3H), 3.18-3.21 (m, 4H), 3.60-3.69 (m, 4H), 5.52 (s, 2H), 7.49-7.58 (m, 5H), 8.46 (s, 1H), 8.80-8.82 (m, 1H), 12.93 (s, 1H) ppm. m / z 489 (M+H + ).

[0449] Synthesis Example 65: Synthesis of 2-morpholino-N-(5-((4-(oxazol-2-yl)benzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide [ka]

[0450] Step 1: Preparation of 2-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)oxazole [ka]

[0451] To a solution of ((4-bromobenzyl)oxy)(tert-butyl)diphenylsilane (1.5 g, 3.5 mmol, Step 1 of Synthesis Example 56) in toluene (15 mL) under nitrogen was added 2-(tributylstannyl)-1,3-oxazole (1.9 g, 5.3 mmol) and Pd(PPh3)4 (0.4 g, 0.35 mmol). The mixture was stirred at 110 °C overnight. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with DCM (3x), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 9% EtOAc in hexane to give 2-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)oxazole as a yellow oil.

[0452] Step 2: Preparation of 5-((4-(oxazol-2-yl)benzyl)oxy)-1,3,4-thiadiazol-2-amine [ka]

[0453] The title compound was prepared using a procedure similar to steps 3, 4, and 5 of Synthesis Example 56, replacing tert-butyl([[4-(oxetan-3-yl)phenyl]methoxy])diphenylsilane with 2-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)oxazole in step 3.

[0454] Step 3: Preparation of 2-morpholino-N-(5-((4-(oxazol-2-yl)benzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide [ka]

[0455] The title compound was prepared using general procedure A using 2-(morpholin-4-yl)pyridine-3-carboxylic acid and 5-((4-(oxazol-2-yl)benzyl)oxy)-1,3,4-thiadiazol-2-amine. The mixture was diluted with water and the mixture was filtered. The solid was triturated with MeOH to give 2-morpholino-N-(5-((4-(oxazol-2-yl)benzyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.18-3.25 (m, 4H), 3.66-3.69 (m, 4H), 5.59 (s, 2H), 6.98-7.02 (m, 1H), 7.42 (s, 1H), 7.67-7.70 (m, 2H), 7.91-7.94 (m, 1H), 8.00-8.06 (m, 2H), 8.26 (s, 1H), 8.36-8.38 (m, 1H), 12.89 (s, 1H) ppm. m / z 465 (M+H + ).

[0456] Synthesis Example 66: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)nicotinamide [ka]

[0457] The title compound was prepared according to general procedure D using intermediate B and 2-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)nicotinic acid, prepared according to general procedure C using 3,4-dihydro-2H-benzo[b][1,4]oxazine, to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)nicotinamide (14 mg, 15% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.7 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.49 (q, J = 8.2 Hz, 4H), 7.17 (t, J = 6.0 Hz, 1H), 6.73 (d, m / z 480 (M+H+).

[0458] Synthesis Example 67: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methoxyphenyl)nicotinamide [ka]

[0459] Step 1: Preparation of methyl 2-(2-methoxyphenyl)pyridine-3-carboxylate [ka]

[0460] The title compound was prepared using general procedure E using methyl 2-chloropyridine-3-carboxylate and 2-methoxyphenylboronic acid. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 17% EtOAc in PE to give methyl 2-(2-methoxyphenyl)pyridine-3-carboxylate as a white solid.

[0461] Step 2: Preparation of 2-(2-methoxyphenyl)pyridine-3-carboxylic acid [ka]

[0462] The title compound was prepared using general procedure F using methyl 2-(2-methoxyphenyl)pyridine-3-carboxylate. The mixture was stirred at 50° C. for 4 hours. The mixture was acidified to pH 6 with HCl (1M) and extracted with EtOAc (4×). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 33% EtOAc in PE to give 2-(2-methoxyphenyl)pyridine-3-carboxylic acid as a white solid.

[0463] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methoxyphenyl)nicotinamide [ka]

[0464] The title compound was prepared using general procedure A employing 2-(2-methoxyphenyl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH. The residue was further purified by preparative TLC (DCM:MeOH, 20:1) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(2-methoxyphenyl)nicotinamide (90.8 mg, 22.98%) as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.49 (s, 3H), 5.47 (s, 2H), 6.93-6.95 (m, 1H), 7.05-7.13 (m, 1H), 7.36-7.40 (m, 1H), 7.47-7.54 (m, 6H), 8.03-8.04 (m, 1H), 8.77-8.78 (m, 1H), 12.70 (s, 1H) ppm. m / z 453 (M+H + ).

[0465] Synthesis Example 68: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(4-(2-hydroxyethyl)-3-oxopiperazin-1-yl)nicotinamide [ka]

[0466] Step 1: Preparation of benzyl 4-(2-acetoxyethyl)-3-oxopiperazine-1-carboxylate [ka]

[0467] To a solution of benzyl 3-oxopiperazine-1-carboxylate (3.0 g, 12.8 mmol) in DMF (30 mL) under nitrogen, 2-bromoethyl acetate (2.1 g, 12.8 mmol) was added dropwise. NaH (1.3 g, 32 mmol, 60% dispersion in oil) was then added. The mixture was stirred at room temperature overnight. The mixture was diluted with saturated NH4Cl. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0.5% MeOH in DCM to give benzyl 4-(2-acetoxyethyl)-3-oxopiperazine-1-carboxylate as a yellow solid.

[0468] Step 2: Preparation of 1-(2-hydroxyethyl)piperazin-2-one [ka]

[0469] To a solution of benzyl 4-[2-(acetyloxy)ethyl]-3-oxopiperazine-1-carboxylate (2.4 g, 7.5 mmol) in MeOH (24 mL) and water (10 mL) was added KCO (2.1 g, 15.0 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with CHCl (24 mL).

[0470] The mixture was washed with brine (3x). The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and 10% Pd / C (100 mg) was added. The mixture was stirred under hydrogen at room temperature for 2 hours. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give 1-(2-hydroxyethyl)piperazin-2-one as a white solid.

[0471] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(4-(2-hydroxyethyl)-3-oxopiperazin-1-yl)nicotinamide [ka]

[0472] The title compound was prepared using a procedure similar to that of Synthesis Example 61, replacing 1,4-diazepan-5-one with 1-(2-hydroxyethyl)piperazin-2-one. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water (3x). The organic layer was concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(4-(2-hydroxyethyl)-3-oxopiperazin-1-yl)nicotinamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.35-3.38 (m, 2H), 3.44-3.52 (m, 4H), 3.55-3.58 (m, 2H), 3.83 (s, 2H), 4.68-4.71 (m, 1H), 5.51 (s, m / z 489 (M+H + ).

[0473] Synthesis Example 69: (R)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide or (S)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide [ka]

[0474] The racemic mixture (R)N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide and (S)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide (Synthesis Example 57) was purified using preparative HPLC (column: CHIRALPAK IF-3; mobile phase A: 25% DCM in hexane containing 0.1% EtNH, mobile phase B: EtOH, isocratic 30% B in A). The title compound was obtained as a white solid as the first eluting isomer. 1 H NMR (300 MHz; DMSO-d6): δ 1.51-1.58 (m, 1H), 2.03-2.07 (m, 1H), 2.21-2.29 (m, 2H), 2.60-2.64 (m, 1H), 2.77-2.84 (m, 2H), 3.60-3.67 (m, 2H), 3.77-3.84 (m, 2H), 5.50 (s, 2H), 6.98-7.03 (m, 1H), 7.48-7.57 (m, 4H), 7.91-7.94 (m, 1H), 8.34-8.36 (m, 1H), 12.82 (s, 1H) ppm. m / z 485 (M+H + ).

[0475] Synthesis Example 70: Synthesis of (R)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide or (S)—N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide [ka]

[0476] Further elution of Synthesis Example 69 gave the title compound as the second eluting isomer. 1H NMR (300 MHz; DMSO-d6): δ 1.52-1.59 (m, 1H), 2.03-2.07 (m, 1H), 2.21-2.30 (m, 2H), 2.60-2.68 (m, 1H), 2.73-2.84 (m, 2H), 3.61-3.68 (m, 2H), 3.77-3.84 (m, 2H), 5.51 (s, 2H), 6.99-7.03 (m, 1H), 7.48-7.58 (m, 4H), 7.91-7.94 (m, 1H), 8.35-8.37 (m, 1H), 12.82 (s, 1H) ppm. m / z 485 (M+H + ).

[0477] Synthesis Example 71: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(2-methoxyphenyl)nicotinamide [ka]

[0478] Step 1: Preparation of methyl 2-chloro-6-cyanonicotinate [ka]

[0479] To a solution of methyl 6-bromo-2-chloropyridine-3-carboxylate (1 g, 4.0 mmol) in DMF (10 mL) was added Zn(CN) (516 mg, 4.4 mmol). The solution was degassed with bubbling nitrogen for 3 minutes, and then Pd(PPh) (461 mg, 0.40 mmol) was added. The solution was degassed by bubbling nitrogen for 3 minutes. The mixture was stirred at 80 °C for 14 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine (3x) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 3-9% EtOAc in PE to give methyl 2-chloro-6-cyanonicotinate as a pale yellow oil.

[0480] Step 2: Preparation of methyl 6-cyano-2-(2-methoxyphenyl)nicotinate [ka]

[0481] The title compound was prepared using general procedure E using methyl 2-chloro-6-cyanopyridine-3-carboxylate and 2-methoxyphenylboronic acid. The mixture was stirred at 80° C. for 4 hours. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with brine (2×) and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc, 2:1) to afford methyl 6-cyano-2-(2-methoxyphenyl)nicotinate as a white solid.

[0482] Step 3: Preparation of 6-cyano-2-(2-methoxyphenyl)nicotinic acid [ka]

[0483] To a solution of methyl 6-cyano-2-(2-methoxyphenyl)pyridine-3-carboxylate (215 mg, 0.80 mmol) in THF (4 mL) was added a solution of LiOH (19 mg, 0.80 mmol) in water (0.8 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and washed with brine (2x). The combined aqueous layers were acidified to pH 3 with HCl (1 M). The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure to give 6-cyano-2-(2-methoxyphenyl)nicotinic acid as a white solid.

[0484] Step 4: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(2-methoxyphenyl)nicotinamide [ka]

[0485] The title compound was prepared using general procedure A using 6-cyano-2-(2-methoxyphenyl)nicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with brine (2x). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 80:1). The residue was further purified by trituration with MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(2-methoxyphenyl)nicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.51 (s, 3H), 5.48 (s, 2H), 6.98-7.01 (m, 1H), 7.08-7.13 (m, 1H), 7.42-7.56 (m, 6H), 8.15-8.18 (m, 1H), 8.30-8.33 (m, 1H), 13.00 (s, 1H) ppm. m / z 478 (M+H + ).

[0486] Synthesis Example 72: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-cyano-2-morpholinobenzamide [ka]

[0487] Step 1: Preparation of 4-cyano-2-morpholinobenzoic acid [ka]

[0488] The title compound was prepared using general procedure C using 4-cyano-2-fluorobenzoic acid. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column eluting with 0.9-2% MeOH in DCM containing 0.05% AcOH. The residue was further purified by trituration with DCM to give 4-cyano-2-morpholinobenzoic acid as a white solid.

[0489] Step 2: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-cyano-2-morpholinobenzamide [ka]

[0490] The title compound was prepared using General Procedure A employing 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and stirred at room temperature for 5 minutes. The mixture was filtered and the solid was washed with water (2x). The solid was triturated with MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-cyano-2-morpholinobenzamide as a pale yellow solid. 1H NMR (300 MHz; DMSO-d6): δ 3.00-3.03 (m, 4H), 3.70-3.73 (m, 4H), 5.52 (s, 2H), 7.48-7.51 (m, 2H), 7.55-7.58 (m, 2H), 7.63-7.66 (m, 1H), 7.77-7.78 (m, 1H), 7.83-7.86 (m, 1H), 13.38 (s, 1H) ppm. m / z 456 (M+H+).

[0491] Synthesis example 73:N 5 Synthesis of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2,N2-dimethyl-4-morpholinopyridine-2,5-dicarboxamide [ka]

[0492] Step 1: Preparation of 6-(dimethylcarbamoyl)-4-(morpholin-4-yl)pyridine-3-carboxylic acid [ka]

[0493] The title compound was prepared using a procedure similar to steps 1-2 of Synthesis Example 64, replacing methylamine with dimethylamine in step 1.

[0494] Step 2:N 5 Preparation of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2,N2-dimethyl-4-morpholinopyridine-2,5-dicarboxamide [ka]

[0495] To a solution of 6-(dimethylcarbamoyl)-4-(morpholin-4-yl)pyridine-3-carboxylic acid (100 mg, 0.36 mmol) in DCM (1 mL) was added DMF (5 mg, 0.72 mmol) and oxalyl chloride (68 mg, 0.54 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Then, a solution of 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (87 mg, 0.36 mmol, Intermediate B) and EtN (72 mg, 0.72 mmol) in DCM (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was triturated with MeOH (1 mL). Column: XBridge Prep OBD C 18 The residue was further purified by preparative HPLC with a mobile phase of 13-33% MeCN in 0.05% NH4OH in water to give N 5 -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2,N2-dimethyl-4-morpholinopyridine-2,5-dicarboxamide was obtained as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 2.92 (s, 3H), 2.99 (s, 3H), 3.16 (s, 4H), 3.63-3.65 (m, 4H), 5.50 (s, 2H), 7.08 (s, 1H), 7.47-7.57 (m, 4H), 8.41 (s, 1H), 12.85 (s, 1H) ppm. m / z 503 (M+H + ).

[0496] Synthesis Example 74: N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2'-hydroxy-[2,4'-bipyridine]-3-carboxamide or its tautomer N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2'-oxo-1',2'-dihydro-[2,4'-bipyridine]-3-carboxamide [ka]

[0497] Step 1: Preparation of methyl 2'-methoxy-[2,4'-bipyridine]-3-carboxylate [ka]

[0498] The title compound was prepared using general procedure D using methyl 2-chloropyridine-3-carboxylate and 2-methoxypyridin-4-ylboronic acid. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water (3x), and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 9% EtOAc in PE to give methyl 2'-methoxy-[2,4'-bipyridine]-3-carboxylate as a white solid.

[0499] Step 2: Preparation of 2'-methoxy-[2,4'-bipyridine]-3-carboxylic acid [ka]

[0500] To a solution of methyl 2'-methoxy-[2,4'-bipyridine]-3-carboxylate (1.9 g, 7.8 mmol) in DCM (20 mL) was added BBr3 (19 g, 78 mmol) at 0 °C under nitrogen. The mixture was warmed to room temperature and stirred at room temperature overnight. The mixture was diluted with saturated NaHCO3 (20 mL). The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 17% MeOH in DCM to give 2'-methoxy-[2,4'-bipyridine]-3-carboxylic acid as a white solid.

[0501] Step 3: Preparation of 2'-oxo-1',2'-dihydro-[2,4'-bipyridine]-3-carboxylic acid [ka]

[0502] To a solution of 2-methoxy-[2,4-bipyridine]-3-carboxylic acid (780 mg, 3.4 mmol) and PTSA (886 mg, 5.1 mmol) in DMF was added LiCl (218 mg, 5.1 mmol). The mixture was stirred under nitrogen at 100° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column, C 18 ; mobile phase, 0-100% MeCN in water) to give 2'-oxo-1',2'-dihydro-[2,4'-bipyridine]-3-carboxylic acid as a white solid.

[0503] Step 4: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2'-oxo-1',2'-dihydro-[2,4'-bipyridine]-3-carboxamide [ka]

[0504] The title compound was prepared using general procedure A employing 2'-oxo-1',2'-dihydro-[2,4'-bipyridine]-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with water (2x). The organic layer was concentrated under reduced pressure, and the residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2'-oxo-1',2'-dihydro-[2,4'-bipyridine]-3-carboxamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 5.49 (s, 2H), 6.30-6.37 (m, 2H), 7.41-7.61 (m, 6H), 8.10-8.13 (m, 1H), 8.79-8.81 (m, 1H), 11.58-11.73 (br s, 1H), 13.01-13.11 (br s, 1H) ppm. m / z 440 (M+H + ).

[0505] Synthesis Example 75: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-methoxy-4-morpholinonicotinamide [ka]

[0506] Step 1: Preparation of methyl 6-methoxy-4-morpholinonicotinate [ka]

[0507] To a solution of ethyl 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylate (500 mg, 1.8 mmol, Step 1 of Synthesis Example 35) in DMF (5 mL) and MeOH (3.8 mL) was added MeONa (998 mg, 18.5 mmol). The mixture was stirred at 60 °C overnight. The mixture was cooled to room temperature and diluted with saturated NH Cl (15 mL). The mixture was extracted with EtOAc (3x), and the combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc, 5:1) to afford methyl 6-methoxy-4-morpholinonicotinate as an off-white oil.

[0508] Step 2: Preparation of 6-methoxy-4-morpholinonicotinic acid [ka]

[0509] The title compound was prepared using general procedure F using methyl 6-methoxy-4-morpholinonicotinate. The mixture was acidified to pH 3 with HCl (1M). The mixture was concentrated. The residue was purified by preparative HPLC (column, C 18 Purification by elution with a mobile phase of 10-50% MeCN and water containing 0.05% TFA in both eluents gave 6-methoxy-4-morpholinonicotinic acid as an off-white oil.

[0510] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-methoxy-4-morpholinonicotinamide [ka]

[0511] The title compound was prepared using general procedure A using 6-methoxy-4-morpholinonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with water (2x). The mixture was concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-methoxy-4-morpholinonicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.02-3.05 (m, 4H), 3.64-3.69 (m, 4H), 3.88 (s, 3H), 5.50 (s, 2H), 6.37 (s, 1H), 7.48-7.57 (m, 4H), 8.26 (s, 1H), 12.62 (s, 1H) ppm. m / z 462 (M+H + ).

[0512] Synthesis Example 76: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(3-oxopiperazin-1-yl)nicotinamide [ka]

[0513] The title compound was prepared using a procedure similar to steps 1-3 of Synthesis Example 14, replacing morpholine with piperazin-2-one in step 1. The mixture was purified by preparative HPLC [column C 18 Spherical; mobile phase, 35-55% MeCN in 0.16% NH4HCO3 in water] to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(3-oxopiperazin-1-yl)nicotinamide as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 3.24 (s, 2H), 3.51-3.55 (m, 2H), 3.81 (s, 2H), 5.51 (s, 2H), 7.46-7.56 (m, 5H), 8.02-8.05 (m, 1H), 8.13 (s, 1H), 13.11 (s, 1H) ppm. m / z 470 (M+H + ).

[0514] Synthesis Example 77: Synthesis of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-(2-methoxyphenyl)pyridine-3-carboxamide [ka]

[0515] The title compound was prepared using a procedure similar to steps 1-3 of Synthesis Example 67, replacing methyl 2-chloropyridine-3-carboxylate with methyl 4-chloropyridine-3-carboxylate in step 1. The residue was purified by preparative TLC (DCM:MeOH, 15:1) to afford N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-(2-methoxyphenyl)pyridine-3-carboxamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.52 (s, 3H), 5.48 (s, 2H), 6.98-7.00 (m, 1H), 7.06-7.09 (m, 1H), 7.34-7.44 (m, 3H), 7.47-7.54 (m, 4H), 8.75-8.79 (m, 2H), 12.78 (s, 1H) ppm. m / z 453 (M+H + ).

[0516] Synthesis Example 78: Synthesis of 6-acetamido-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinonicotinamide [ka]

[0517] Step 1: Preparation of ethyl 6-acetamido-4-morpholinonicotinate [ka]

[0518] To a stirred solution of ethyl 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylate (1.0 g, 3.7 mmol, Step 1 of Synthesis Example 35) in dioxane (10 mL) was added acetamide (436 mg, 7.4 mmol), Pd(OAc) (124 mg, 0.55 mmol), dppf (204 mg, 0.37 mmol), and CsCO (2.4 g, 7.4 mmol) under nitrogen at room temperature. The mixture was stirred at 100 °C for 4 h. The mixture was diluted with EtOAc (10 mL) and washed with water (3 × 10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 3% EtOAc in PE to give ethyl 6-acetamido-4-morpholinonicotinate as an off-white solid.

[0519] Step 2: Preparation of 6-acetamido-4-morpholinonicotinic acid [ka]

[0520] To a solution of ethyl 6-acetamido-4-morpholinonicotinate (300 mg, 1.0 mmol) in DCM (3 mL) was added BBr3 (512 mg, 2.0 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 30 minutes and diluted with saturated NaHCO3. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column, C 18 Purification by silica gel; mobile phase, 0-5% MeCN in water) gave 6-acetamido-4-morpholinonicotinic acid as a white solid.

[0521] Step 3: Preparation of 6-acetamido-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinonicotinamide [ka]

[0522] The title compound was prepared using general procedure A employing 6-acetamido-4-morpholinonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with water (3x). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc, 2:1). The residue was further purified by trituration with MeOH to afford 6-acetamido-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-morpholinonicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 2.11(s, 3H), 3.05 (s, 4H), 3.69 (s, 4H), 5.50 (s, 2H), 7.47-7.57 (m, 4H), 7.79 (s, 1H), 8.31 (s, 1H), 10.61 (s, 1H), 12.59 (s, 1H) ppm. m / z 489 (M+H + ).

[0523] Synthesis Example 79: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6'-oxo-1',6'-dihydro-[2,3'-bipyridine]-3-carboxamide or its tautomer N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6'-hydroxy-[2,3'-bipyridine]-3-carboxamide [ka]

[0524] The title compound was prepared using a procedure similar to Steps 1-3 of Synthesis Example 67, replacing 2-methoxyphenylboronic acid with 6-oxo-1H-pyridin-3-ylboronic acid in Step 1. The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6'-oxo-1',6'-dihydro-[2,3'-bipyridine]-3-carboxamide as a light green solid. 1H NMR (300 MHz; DMSO-d6): δ 5.51 (s, 2H), 6.31-6.40 (m, 1H), 7.29-7.65 (m, 7H), 8.03-8.04 (m, 1H), 8.74 (s, 1H), 11.65-11.96 (br s, 1H), 12.73-13.11 (br s, 1H) ppm. m / z 440 (M+H + ).

[0525] Synthesis Example 80: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridine]-3-carboxamide [ka]

[0526] The title compound was prepared using a procedure similar to Steps 1-3 of Synthesis Example 67, replacing 2-methoxyphenylboronic acid with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in Step 1. The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridine]-3-carboxamide as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 3.48 (s, 3H), 5.50 (s, 2H), 6.38-6.40 (m, 1H), 7.45-7.48 (m, 4H), 7.50-7.56 (m, 2H), 8.05-8.07 (m, 2H), 8.73-8.74 (m, 1H), 12.94 (s, 1H) ppm. m / z 440 (M+H + ).

[0527] Synthesis Example 81: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-fluoro-5-(2-methoxyphenyl)isonicotinamide [ka]

[0528] Step 1: Preparation of methyl 5-bromo-2-fluoroisonicotinate [ka]

[0529] To a solution of 5-bromo-2-fluoropyridine-4-carboxylic acid (1.0 g, 4.5 mmol) in THF (10 mL) was added Ph3P (2.4 g, 9.1 mmol) and MeOH (0.7 g, 22.7 mmol) at 0° C. The mixture was stirred at 0° C. for 5 minutes, and then DIAD (1.8 g, 9.1 mmol) was added. The mixture was warmed to room temperature and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 3% EtOAc in PE to give methyl 5-bromo-2-fluoroisonicotinate as a white solid.

[0530] Step 2: Preparation of methyl 2-fluoro-5-(2-methoxyphenyl)isonicotinate [ka]

[0531] The title compound was prepared using general procedure E using methyl 5-bromo-2-fluoroisonicotinate and 2-methoxyphenylboronic acid. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 3% EtOAc in PE to give methyl 2-fluoro-5-(2-methoxyphenyl)isonicotinate as a white solid.

[0532] Step 3: Preparation of 2-fluoro-5-(2-methoxyphenyl)pyridine-4-carboxylic acid [ka]

[0533] The title compound was prepared using general procedure F using methyl 2-fluoro-5-(2-methoxyphenyl)isonicotinate. The mixture was acidified with HCl (1M) to pH 6. The mixture was extracted with EtOAc (3x) and the combined organic layers were concentrated under reduced pressure to give 2-fluoro-5-(2-methoxyphenyl)pyridine-4-carboxylic acid as a white solid.

[0534] Step 4: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-fluoro-5-(2-methoxyphenyl)isonicotinamide [ka]

[0535] The title compound was prepared using general procedure A employing 2-fluoro-5-(2-methoxyphenyl)pyridine-4-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was recrystallized from MeOH:water (10:1) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-fluoro-5-(2-methoxyphenyl)isonicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.51 (s, 3H), 5.48 (s, 2H), 6.97-7.08 (m, 2H), 7.34-7.41 (m, 2H), 7.46-7.55 (m, 5H), 8.27 (s, 1H), 12.97 (s, 1H) ppm. m / z 471 (M+H + ).

[0536] Synthesis Example 82: Synthesis of N-(5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-1,2,3-triazole-5-carboxamide [ka]

[0537] Step 1: Preparation of ethyl 3-(2-methoxyphenyl)-5-(trimethylsilyl)-1,2,3-triazole-4-carboxylate [ka]

[0538] To a solution of 2-methoxyaniline (3 g, 24.4 mmol) in 4 M HCl (30 mL) was added dropwise a solution of NaNO (1.9 g, 26.8 mmol) in water (10 mL) at 0 °C. The mixture was stirred for 30 min. Sodium azide (1.9 g, 29.2 mmol) was then added portionwise. The mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. The mixture was extracted with MTBE (3x). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was diluted with toluene (8 mL), and ethyl 3-(trimethylsilyl)prop-2-inoate (1.0 g, 5.9 mmol) was added under nitrogen. The mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure to give ethyl 3-(2-methoxyphenyl)-5-(trimethylsilyl)-1,2,3-triazole-4-carboxylate as a brown oil, which was used in the next step without further purification.

[0539] Step 2: Preparation of ethyl 3-(2-methoxyphenyl)-1,2,3-triazole-4-carboxylate [ka]

[0540] To a solution of ethyl 3-(2-methoxyphenyl)-5-(trimethylsilyl)-1,2,3-triazole-4-carboxylate (1.7 g, 5.3 mmol) in THF (20 mL) was added TBAF (2.1 g, 8.0 mmol) under nitrogen. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (20 mL) and extracted with DCM (3x). The combined organic layers were concentrated under reduced pressure, and the residue was purified by preparative TLC (hexane:EtOAc, 3:1) to give ethyl 3-(2-methoxyphenyl)-1,2,3-triazole-4-carboxylate as a brown oil.

[0541] Step 3: Preparation of 3-(2-methoxyphenyl)-1,2,3-triazole-4-carboxylic acid [ka]

[0542] The title compound was prepared using general procedure F using ethyl 3-(2-methoxyphenyl)-1,2,3-triazole-4-carboxylate. The mixture was diluted with water and acidified to pH 6 with HCl (1M). The mixture was extracted with EtOAc (2x) and the combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give 3-(2-methoxyphenyl)-1,2,3-triazole-4-carboxylic acid as a white solid.

[0543] Step 4: Preparation of N-(5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-1,2,3-triazole-5-carboxamide [ka]

[0544] The title compound was prepared using general procedure A employing 3-(2-methoxyphenyl)-1,2,3-triazole-4-carboxylic acid and 5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate A). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1). The residue was further purified by trituration with MeOH to afford N-(5-((4-fluorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-1,2,3-triazole-5-carboxamide as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 3.66 (s, 3H), 5.47-5.52 (m, 2H), 7.13-7.28 (m, 4H), 7.52-7.59 (m, 4H), 8.57-8.62 (m, 1H), 13.28-13.37 (br s, 1H) ppm. m / z 427 (M+H + ).

[0545] Synthesis Example 83: Synthesis of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-[4-[2-(morpholin-4-yl)ethyl]-3-oxopiperazin-1-yl]pyridine-3-carboxamide [ka]

[0546] Step 1: Preparation of benzyl 4-[2-(morpholin-4-yl)ethyl]-3-oxopiperazine-1-carboxylate [ka]

[0547] To a solution of benzyl 3-oxopiperazine-1-carboxylate (2.0 g, 8.5 mmol) in DMF (20 mL) was added NaH (0.68 g, 17.1 mmol, 60% oil dispersion) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 hour, and then 4-(2-bromoethyl)morpholine (1.7 g, 8.5 mmol) was added. The mixture was warmed to room temperature and stirred at room temperature for 3 hours. The mixture was diluted with saturated NH4Cl (60 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 25% EtOAc in PE to give 4-[2-(morpholin-4-yl)ethyl]-benzyl 3-oxopiperazine-1-carboxylate as a yellow solid.

[0548] Step 2: Preparation of 1-[2-(morpholin-4-yl)ethyl]piperazin-2-one [ka]

[0549] To a solution of benzyl 4-[2-(morpholin-4-yl)ethyl]-3-oxopiperazine-1-carboxylate (500 mg, 1.4 mmol) in MeOH (10 mL) was added 20% Pd / C (100 mg). The mixture was stirred under hydrogen at room temperature for 2 hours. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give 1-[2-(morpholin-4-yl)ethyl]piperazin-2-one as a yellow solid.

[0550] Step 3: Preparation of 4-chloro-N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]pyridine-3-carboxamide [ka]

[0551] A solution of 4-chloropyridine-3-carboxylic acid (2.0 g, 12.7 mmol) in SOCl (20 mL) was stirred at 85 °C under nitrogen for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL), and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (3.1 g, 12.7 mmol, Intermediate B) and EtN (2.6 g, 25.4 mmol) were added under nitrogen. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with EtOAc to give 4-chloro-N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]pyridine-3-carboxamide as a yellow solid.

[0552] Step 4: Preparation of N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-[4-[2-(morpholin-4-yl)ethyl]-3-oxopiperazin-1-yl]pyridine-3-carboxamide [ka]

[0553] To a solution of 1-[2-(morpholin-4-yl)ethyl]piperazin-2-one (180 mg, 0.84 mmol, Step 2) in MeCN (2 mL) was added 4-chloro-N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]pyridine-3-carboxamide (322 mg, 0.84 mmol, Step 3) and DIEA (218 mg, 1.7 mmol) under nitrogen. The mixture was stirred at 80 °C for 6 h. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH, 5:1) to give N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-[4-[2-(morpholin-4-yl)ethyl]-3-oxopiperazin-1-yl]pyridine-3-carboxamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 2.35-2.39 (m, 4H), 2.42-2.44 (m, 2H), 3.40-3.50 (m, 6H), 3.52 (s, 4H), 3.78 (s, 2H), 5.51 (s, 2H), 6.92-6.97 (m, 1H), 7.48-7.57 (m, 4H), 8.33-8.35 (m, 1H), 8.42 (s, 1H), 12.80-13.03 (br s, 1H) ppm. m / z 558 (M+H + ).

[0554] Synthesis Example 84: Synthesis of 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-morpholinopicolinic acid [ka] Step 1: Preparation of 6-chloro-N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-(morpholin-4-yl)pyridine-3-carboxamide [ka]

[0555] The title compound was prepared using General Procedure A, employing 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylic acid (Step 1 of Synthesis Example 35) and 5-((4-chlorobenzyl)-oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with water (2x). The organic layer was concentrated under reduced pressure. The residue was recrystallized from MeOH / water (10:1) to afford 6-chloro-N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-(morpholin-4-yl)pyridine-3-carboxamide as a white solid.

[0556] Step 2: Preparation of methyl 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-morpholinopicolinate [ka]

[0557] To a solution of 6-chloro-N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]-4-(morpholin-4-yl)pyridine-3-carboxamide (5.0 g, 10.7 mmol) in MeOH (300) was added EtN (2.2 g, 21.4 mmol), Xantphos (0.3 g, 0.54 mmol), and Pd(dppf)Cl (0.4 g, 0.54 mmol) at room temperature. The mixture was stirred under 30 atmospheres of carbon monoxide at 80 °C for 12 hours. The mixture was cooled to room temperature and diluted with EtOAc (500 mL). The resulting mixture was washed with water (3x). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0.3% MeOH in DCM to give methyl 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-morpholinopicolinate as a white solid.

[0558] Step 3: Preparation of 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-morpholinopicolinic acid [ka]

[0559] To a solution of methyl 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-morpholinopicolinate (1.2 g, 2.5 mmol) in MeOH (7 mL) and HO (7 mL) was added NaOH (0.2 g, 5.1 mmol). The mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 7 with HCl (1 M). The mixture was extracted with EtOAc (3×). The combined organic layers were concentrated under reduced pressure. The residue was recrystallized from MeOH:water (12:1) to give 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-morpholinopicolinate as an off-white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.24-3.26 (m, 4H), 3.65-3.68 (m, 4H), 5.49 (s, 2H), 7.47-7.56 (m, 5H), 8.44 (s, 1H) ppm. m / z 476 (M+H + ).

[0560] Synthesis Example 85: Synthesis of N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide [ka]

[0561] The title compound was prepared using General Procedure A, employing 6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinic acid (Step 1 of Synthesis Example 44) and 5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Step 1 of Synthesis Example 40). The mixture was diluted with EtOAc and washed with water (2x). The organic layer was concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide as a yellow solid. 1 H NMR (300 MHz; DMSO-d6): δ 0.48-0.55 (m, 2H), 0.60-0.69 (m, 2H), 3.35-3.38 (m, 4H), 3.68-3.71 (m, 2H), 5.49 (s, 2H), 7.47-7.49 (m, 3H), 7.61-7.64 (m, 2H), 8.00-8.02 (m, 1H), 13.03 (s, 1H) ppm. m / z 527 (M+H + ).

[0562] Synthesis Example 86: Synthesis of N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide [ka]

[0563] The title compound was prepared using a procedure similar to Synthesis Example 18, substituting 2-methoxyaniline for 4-aminopyridine in Step 1 and using 5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Step 1 of Synthesis Example 40) in Step 2. The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to give N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide as a pink solid. 1H NMR (300 MHz; DMSO-d6): δ 3.68 (s, 3H), 5.44 (s, 2H), 7.03-7.08 (m, 1H), 7.16-7.19 (m, 1H), 7.35-7.38 (m, 1H), 7.43-7.48 (m, 3H), 7.59-7.62 (m, 2H), 7.98 (s, 1H), 8.10 (s, 1H), 12.71 (s, 1H) ppm. m / z 486 (M+H + ).

[0564] Synthesis example 87:N 5 Synthesis of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2-methyl-4-(5-oxo-1,4-diazepan-1-yl)pyridine-2,5-dicarboxamide [ka]

[0565] Step 1: Preparation of ethyl 6-chloro-4-(5-oxo-1,4-diazepan-1-yl)nicotinate [ka]

[0566] The title compound was prepared using a procedure similar to Step 1 of Synthesis Example 35, replacing morpholine with 1,4-diazepan-5-one.

[0567] Step 2: Preparation of 6-(methylcarbamoyl)-4-(5-oxo-1,4-diazepan-1-yl)nicotinic acid [ka]

[0568] The title compound was prepared using a procedure similar to steps 1 and 2 of Synthesis Example 64, replacing ethyl 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylate with ethyl 6-chloro-4-(5-oxo-1,4-diazepan-1-yl)nicotinate in step 1.

[0569] Step 3:N5 Preparation of -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2-methyl-4-(5-oxo-1,4-diazepan-1-yl)pyridine-2,5-dicarboxamide [ka]

[0570] The title compound was prepared using general procedure D using 6-(methylcarbamoyl)-4-(5-oxo-1,4-diazepan-1-yl)nicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with water (3x). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH, 20:1) to give N 5 -(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-N2-methyl-4-(5-oxo-1,4-diazepan-1-yl)pyridine-2,5-dicarboxamide was obtained as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 2.62-2.68 (m, 2H), 2.80-2.82 (m, 3H), 3.29-3.34 (m, 4H), 3.50-3.51 (m, 2H), 5.51 (s, 2H), 7.49-7.61 (m, 6H), 8.42 (s, 1H), 8.79-8.81 (m, 1H), 12.96 (s, 1H) ppm. m / z 516 (M+H + ).

[0571] Synthesis Example 88: Synthesis of N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(3-oxopiperazin-1-yl)nicotinamide [ka]

[0572] Step 1: Preparation of 6-bromo-2-(3-oxopiperazin-1-yl)nicotinic acid [ka]

[0573] The title compound was prepared using a procedure similar to Step 1 of Synthesis Example 14, replacing morpholine with piperazin-2-one.

[0574] Step 2: Preparation of 6-cyano-2-(3-oxopiperazin-1-yl)pyridine-3-carboxylic acid [ka]

[0575] The title compound was prepared using a procedure similar to Step 2 of Synthesis Example 35, replacing 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylic acid with 6-bromo-2-(3-oxopiperazin-1-yl)nicotinic acid.

[0576] Step 3: Preparation of N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(3-oxopiperazin-1-yl)nicotinamide [ka]

[0577] The title compound was prepared using General Procedure A, employing 6-cyano-2-(3-oxopiperazin-1-yl)pyridine-3-carboxylic acid and 5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Step 1 of Synthesis Example 40). The mixture was diluted with EtOAc and washed with water (2x). The organic layer was concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-bromobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-2-(3-oxopiperazin-1-yl)nicotinamide as a yellow solid. 1H NMR (400 MHz; DMSO-d6): δ 3.24-3.28 (m, 2H), 3.52-3.54 (m, 2H), 3.81 (s, 2H), 5.49 (s, 2H), 7.46-7.52 (m, 3H), 7.58-7.64 (m, 2H), 8.02-8.04 (m, 1H), 8.12 (s, 1H), 13.10 (s, 1H) ppm. m / z 514 (M+H + ).

[0578] Synthesis Example 89: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0579] The title compound was prepared using a procedure similar to that of Synthesis Example 77, replacing 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) with 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). 1 H NMR (300 MHz; DMSO-d6): δ 3.52 (s, 3H), 5.54 (s, 2H), 6.98-7.01 (m, 1H), 7.05-7.10 (m, 1H), 7.34-7.44 (m, 3H), 7.59-7.62 (m, 1H), 7.98-8.02 (m, 1H), 8.65-8.66 (m, 1H), 8.74-8.79 (m, 2H), 12.82 (s, 1H) ppm. m / z 454 (M+H + ).

[0580] Synthesis Example 90: Synthesis of N-(5-(cyclopropylmethoxy)-1,3,4-thiadiazol-2-yl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0581] Step 1: Preparation of 5-(cyclopropylmethoxy)-1,3,4-thiadiazol-2-amine [ka]

[0582] The title compound was prepared using a similar procedure to Intermediate A, substituting cyclopropylmethanol for (4-fluorophenyl)methanol in step 1.

[0583] Step 2: Preparation of N-(5-(cyclopropylmethoxy)-1,3,4-thiadiazol-2-yl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0584] The title compound was prepared using General Procedure A employing 5-(cyclopropylmethoxy)-1,3,4-thiadiazol-2-amine and 4-(2-methoxyphenyl)pyridine-3-carboxylic acid (Synthesis Example 77). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1). The residue was further purified by trituration with MeOH to afford N-(5-(cyclopropylmethoxy)-1,3,4-thiadiazol-2-yl)-4-(2-methoxyphenyl)nicotinamide as a white solid. 1 H NMR (300 MHz; CD3OD): δ 0.38-0.41 (m, 2H), 0.68-0.69 (m, 2H), 1.31-1.40 (m, 1H), 3.00 (s, 1H), 3.63 (s, 3H), 4.25-4.31 (m, 2H), 6.98-7.01 (m, 1H), 7.07-7.12 (m, 1H), 7.39-7.42 (m, 2H), 7.45-7.50 (m, 1H), 8.71-8.72 (m, 1H), 8.79 (s, 1H) ppm. m / z 383 (M+H + ).

[0585] Synthesis Example 91: Synthesis of 2-(2-chlorophenyl)-N-[5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]pyridine-3-carboxamide [ka]

[0586] The title compound was prepared using a procedure similar to that of Synthesis Example 51 using 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). 1 H NMR (300 MHz; DMSO-d6): δ 5.54 (s, 2H), 7.40-7.49 (m, 8H), 7.58-7.63 (m, 1H), 8.20-8.23 (m, 1H), 8.81-8.83 (m, 1H), 13.00 (s, 1H) ppm. m / z 457 (M+H + ).

[0587] Synthesis Example 92: N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide [ka]

[0588] Step 1: Preparation of benzyl 6-bromo-4-chloropyridine-3-carboxylate [ka]

[0589] To a solution of 6-bromo-4-chloropyridine-3-carboxylic acid (1.5 g, 6.3 mmol) in DMF (20 mL) were added (bromomethyl)benzene (1.2 g, 7.0 mmol) and K2CO3 (1.8 g, 12.7 mmol). The mixture was stirred at 60 °C for 10 minutes. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 8% EtOAc in hexane to give benzyl 6-bromo-4-chloropyridine-3-carboxylate as a white solid.

[0590] Step 2: Preparation of benzyl 4-chloro-6-cyanopyridine-3-carboxylate [ka]

[0591] The title compound was prepared using a procedure similar to Step 2 of Synthesis Example 33, substituting methyl 6-bromo-4-chloropyridine-3-carboxylate for methyl 5-bromo-2-morpholinonicotinate.

[0592] Step 3: Preparation of benzyl 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylate [ka]

[0593] The title compound was prepared using a procedure similar to Step 1 of Synthesis Example 67, replacing methyl 2-chloropyridine-3-carboxylate with benzyl 4-chloro-6-cyanopyridine-3-carboxylate in Step 1.

[0594] Step 4: Preparation of 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylic acid [ka]

[0595] To a solution of benzyl 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylate (530 mg, 1.5 mmol) in THF (12 mL) was added 10% Pd / C (106 mg). The mixture was stirred under hydrogen at room temperature for 6 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylic acid as an off-white solid.

[0596] Step 5: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide [ka]

[0597] The title compound was prepared using general procedure D employing 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was stirred at room temperature overnight and diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 12:1) to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide as a pale yellow solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.54 (s, 3H), 5.48 (s, 2H), 7.02-7.13 (m, 2H), 7.42-7.55 (m, 6H), 8.14 (s, 1H), 8.96 (s, 1H), 13.07 (s, 1H) ppm. m / z 478 (M+H + ).

[0598] Synthesis Example 93: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-(2-cyclopropoxyphenyl)nicotinamide [ka]

[0599] The title compound was prepared using a procedure similar to that of Synthesis Example 77, replacing 2-methoxyphenylboronic acid with 2-(2-cyclopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1 H NMR (300 MHz; DMSO-d6): δ 0.32-0.55 (m, 4H), 3.49-3.57 (m, 1H), 5.53 (s, 2H), 7.06-7.10 (m, 1H), 7.17-7.66 (m, 8H), 8.70-8.80 (m, 2H), 12.66-12.96 (br s, 1H) ppm. m / z 479 (M+H+ ).

[0600] Synthesis Example 94: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-2-phenylnicotinamide [ka]

[0601] The title compound was prepared using a procedure similar to that of Synthesis Example 67, substituting phenylboronic acid for 2-methoxyphenylboronic acid in Step 1. 1 H NMR (400 MHz; DMSO-d6): δ 5.48 (s, 2H), 7.38 (s, 3H), 7.40-7.58 (m, 7H), 8.05-8.08 (m, 1H), 8.79-8.81 (m, 1H), 12.88 (s, 1H) ppm. m / z 423 (M+H + ).

[0602] Synthesis Example 95: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide [ka]

[0603] [ka] The title compound was prepared using General Procedure A, employing 3-(2-methoxyphenyl)pyridine-4-carboxylic acid (Intermediate H) and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide as an off-white solid. 1H NMR (300 MHz; DMSO-d6): δ 3.51 (s, 3H), 5.47 (s, 2H), 6.97-7.00 (m, 1H), 7.04-7.09 (m, 1H), 7.35-7.41 (m, 2H), 7.47-7.54 (m, 4H), 7.62-7.63 (m, 1H), 8.61 (s, 1H), 8.70-8.72 (m, 1H), 12.84 (s, 1H) ppm. m / z 453 (M+H + ).

[0604] Synthesis Example 96: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide [ka]

[0605] The title compound was prepared using general procedure D, employing 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylic acid (Step 4 of Synthesis Example 92) and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C). The mixture was stirred at room temperature overnight and diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 12:1) to afford N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-cyano-4-(2-methoxyphenyl)nicotinamide as a white solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.54 (s, 3H), 5.54 (s, 2H), 7.02-7.12 (m, 2H), 7.42-7.47 (m, 2H), 7.59-7.62 (m, 1H), 7.98-8.02 (m, 1H), 8.13 (s, 1H), 8.64-8.65 (m, 1H), 8.96 (s, 1H), 13.08 (s, 1H) ppm. m / z 479 (M+H + ).

[0606] Synthesis Example 97: Synthesis of N-(5-((5-bromopyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0607] The title compound was prepared using a procedure similar to that of Synthesis Example 77, replacing 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) with 5-((5-bromopyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Step 1 of Synthesis Example 15). 1 H NMR (300 MHz; DMSO-d6): δ 3.52 (s, 3H), 5.52 (s, 2H), 6.98-7.01 (m, 1H), 7.05-7.10 (m, 1H), 7.34-7.44 (m, 3H), 7.53-7.56 (m, 1H), 8.11-8.14 (m, 1H), 8.73-8.76 (m, 2H), 8.79 (s, 1H), 12.84 (s, 1H) ppm. m / z 498 (M+H + ).

[0608] Synthesis Example 98: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(1H-imidazol-2-yl)-4-morpholinonicotinamide [ka]

[0609] Step 1: Preparation of ethyl 6-cyano-4-(morpholin-4-yl)pyridine-3-carboxylate [ka]

[0610] The title compound was prepared using a procedure similar to Step 2 of Synthesis Example 35, replacing 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylic acid with ethyl 6-chloro-4-(morpholin-4-yl)pyridine-3-carboxylate.

[0611] Step: Preparation of methyl 6-(1H-imidazol-2-yl)-4-morpholinonicotinate [ka]

[0612] To a solution of ethyl 6-cyano-4-(morpholin-4-yl)pyridine-3-carboxylate (360 mg, 1.38 mmol) in MeOH (4 mL) was added NaOMe (15 mg, 0.28 mmol). The mixture was stirred at 50° C. for 1.5 hours, and then HOAc (147 mg, 2.4 mmol) and 2,2-dimethoxyethanamine (1289 mg, 1.2 mmol) were added. The mixture was stirred at 50° C. for 2 hours. Then, HCl (133.97 mg, 3.7 mmol, concentrated) was added. The mixture was stirred at 50° C. for 13 hours. The mixture was cooled to room temperature and diluted with saturated NaHCO (10 mL). The mixture was extracted with EtOAc (4×), and the combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 30:1) to give methyl 6-(1H-imidazol-2-yl)-4-morpholinonicotinate as a white solid.

[0613] Step 2: Preparation of 6-(1H-imidazol-2-yl)-4-morpholinonicotinic acid [ka]

[0614] The title compound was prepared using general procedure F using methyl 6-(1H-imidazol-2-yl)-4-morpholinonicotinate. The mixture was stirred at room temperature overnight and then acidified to pH 6 with HCl (1M). The mixture was concentrated and the residue was purified by reverse phase chromatography (column, C 18 Purification by silica gel; mobile phase, 0-50% MeCN in water) gave 6-(1H-imidazol-2-yl)-4-morpholinonicotinic acid as a white solid.

[0615] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(1H-imidazol-2-yl)-4-morpholinonicotinamide [ka]

[0616] The title compound was prepared using general procedure A employing 6-(1H-imidazol-2-yl)-4-morpholinonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with water (3x). The organic layer was concentrated under reduced pressure, and the residue was triturated with MeOH to afford N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(1H-imidazol-2-yl)-4-morpholinonicotinamide as a pale yellow solid. 1 H NMR (300 MHz; DMSO-d6): δ 3.17 (s, 4H), 3.69-3.70 (m, 4H), 5.51 (s, 2H), 7.19 (s, 2H), 7.48-7.61 (m, 5H), 8.51 (s, 1H), 12.81-12.93 (m, 2H) ppm. m / z 498 (M+H + ).

[0617] Synthesis Example 99: Synthesis of N-[5-[(5-chloropyridin-2-yl)methoxy]-1,3,4-thiadiazol-2-yl]-3-(2-methoxyphenyl)pyridine-4-carboxamide [ka]

[0618] The title compound was prepared using general procedure A using 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C) and 3-(2-methoxyphenyl)pyridine-4-carboxylic acid (Intermediate H). The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and Concentration under reduced pressure was carried out and the residue was triturated with EtOAc (2x) to give the title compound. 1H NMR (300 MHz; DMSO-d6): δ 12.91 (s, 1H), 8.72-8.61 (m, 3H), 8.00 (d, 1H), 7.65-7.60 (m, 2H), 7.42-7.36 (m, 2H), 7.10-6.99 (m, 2H), 5.55 (s, 2H), 3.52(s, 3H) ppm. m / z 454 (M+H+).

[0619] Synthesis Example 100: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-(difluoromethoxy)phenyl)isonicotinamide [ka]

[0620] Step 1: Preparation of methyl 3-[2-(difluoromethoxy)phenyl]pyridine-4-carboxylate [ka]

[0621] The title compound was prepared using general procedure E using methyl 3-bromopyridine-4-carboxylate and 2-(difluoromethoxy)phenylboronic acid. The mixture was stirred at 80° C. for 1 hour. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water (3×). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 50% EtOAc in PE to give the title compound as a yellow oil.

[0622] Step 2: Preparation of 3-[2-(difluoromethoxy)phenyl]pyridine-4-carboxylic acid [ka]

[0623] The title compound was prepared using general procedure F using methyl 3-[2-(difluoromethoxy)phenyl]pyridine-4-carboxylate. The mixture was stirred at 50° C. for 3 hours. The mixture was diluted with water and washed with EtOAc. 2M HCl was added to the aqueous layer to adjust the pH to 5-6. The precipitate was filtered and the solid was dried in an oven to give the title compound as a white solid. The residue was purified by preparative TLC (DCM:MeOH, 20:1) to give the title compound as a white solid.

[0624] Step 3: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-(difluoromethoxy)phenyl)isonicotinamide [ka]

[0625] The title compound was prepared using general procedure A employing 3-[2-(difluoromethoxy)phenyl]pyridine-4-carboxylic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with EtOAc and washed with water (2x). The organic layer was concentrated under reduced pressure. 1 H NMR (300 MHz; DMSO-d6): δ 13.06 (s, 1H), 8.78 (d, 1H), 8.63 (s, 1H), 7.74 (d, 1H), 7.51 - 7.42 (m, 6H), 6.80-7.35 (m, 3H), 5.47 (s, 2H) ppm. m / z 489 (M+H+).

[0626] Synthesis Example 101: Synthesis of N-[5-[(6-cyclopropylpyridin-3-yl)methoxy]-1,3,4-thiadiazol-2-yl]-3-(2-methoxyphenyl)pyridine-4-carboxamide [ka]

[0627] Step 1: Preparation of (6-cyclopropylpyridin-3-yl)methanol [ka]

[0628] To a solution of methyl 6-cyclopropylpyridine-3-carboxylate (2.0 g, 11.3 mmol) in THF (20 mL) at 0 °C was added LiAlH (0.86 g, 22.660 mmol, 2.01 equiv.). The mixture was stirred at 0 °C for 1 h. The mixture was warmed to room temperature, and aqueous NH Cl was added. The mixture was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 25% EtOAc in PE to give the title compound (1.4 g, 79% yield) as a yellow liquid.

[0629] Step 2: Preparation of [(6-cyclopropylpyridin-3-yl)methoxy](methylsulfanyl)methanethione [ka]

[0630] The title compound was prepared using a procedure similar to Step 1 of Intermediate A, substituting (6-cyclopropylpyridin-3-yl)methanol for (4-fluorophenyl)methanol.

[0631] Step 3: Preparation of 5-[(6-cyclopropylpyridin-3-yl)methoxy]-1,3,4-thiadiazol-2-amine [ka]

[0632] To a solution of [(6-cyclopropylpyridin-3-yl)methoxy](methylsulfanyl)methanethione (920 mg, 3.8 mmol) in MeOH (10 mL) at 0° C. was added hydrazine hydrate (196 mg, 3.9 mmol). The mixture was stirred at 0° C. for 0.5 h. The mixture was filtered, and the solid was washed with MeOH (2×). The filtrate was concentrated under reduced pressure to give a white solid. The solid was diluted with MeOH (7 mL) cooled to 0° C. Then, EtN (625 mg, 6.2 mmol) and BrCN (393 mg, 3.7 mmol) were added. The mixture was stirred at 0° C. for 1 h. The mixture was filtered, and the solid was washed with MeOH (2×) to give the title compound as a yellow solid.

[0633] Step 4: Preparation of N-[5-[(6-cyclopropylpyridin-3-yl)methoxy]-1,3,4-thiadiazol-2-yl]-3-(2-methoxyphenyl)pyridine-4-carboxamide [ka]

[0634] The title compound was prepared using general procedure A using 3-(2-methoxyphenyl)pyridine-4-carboxylic acid (Intermediate H) and 5-[(6-cyclopropylpyridin-3-yl)methoxy]-1,3,4-thiadiazol-2-amine. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and washed with water (2x). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1) to afford the title compound as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 12.87 (s, 1H), 8.71(d, 1H), 8.60 (s, 1H), 8.52 - 8.51 (m, 1H), 7.79-7.76 (m, 1H), 7.63 (d, 1H), 7.37-7.32 (m, 3H), 7.09-7.06 (m, 1H), 6.98 (d, 1H), 5.44 (s, 2H), 3.51 (s, 3H), 2.11-2.07 (m, 1H), 0.98 -0.90 (m, 4H) ppm. m / z 460 (M+H+).

[0635] Synthesis Example 102: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(hydroxymethyl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0636] Step 1: Preparation of 5-benzyl 2-isopropyl 4-chloropyridine-2,5-dicarboxylate [ka]

[0637] A solution of benzyl 6-bromo-4-chloropyridine-3-carboxylate (8.0 g, 24.5 mmol), EtN (5.0 g, 49.0 mmol), and Pd(dppf)Cl (2.7 g, 3.7 mmol) in propan-2-ol (1.50 L) was added to a 2 L pressure tank reactor. The mixture was purged with CO (30 atm) and stirred at 60 °C overnight under an atmosphere of CO (30 atm). The mixture was diluted with water and extracted with DCM (3x). The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography eluting with 9% EtOAc in hexane to give the title compound (6.8 g, 75% yield) as a white solid.

[0638] Step 2: Preparation of 5-benzyl 2-isopropyl 4-(2-methoxyphenyl)pyridine-2,5-dicarboxylate [ka]

[0639] The title compound was prepared using general procedure E using 5-benzyl 2-isopropyl 4-chloropyridine-2,5-dicarboxylate and 2-methoxyphenylboronic acid. The mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with 1N NaOH (2x), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 14% EtOAc in PE to give the title compound (4.4 g, 49% yield) as a pale yellow solid.

[0640] Step 3: Preparation of 6-(isopropoxycarbonyl)-4-(2-methoxyphenyl)pyridine-3-carboxylic acid [ka]

[0641] To a solution of 5-benzyl 2-isopropyl 4-(2-methoxyphenyl)pyridine-2,5-dicarboxylate (4.4 g) in THF (180 mL) was added 10% Pd / C (0.80 g). The mixture was stirred at room temperature under an atmosphere of H for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (3.6 g) as a pale yellow solid, which was used without further purification.

[0642] Step 4: Preparation of isopropyl 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-(2-methoxyphenyl)picolinate [ka]

[0643] A reaction vial was charged with 6-(isopropoxycarbonyl)-4-(2-methoxyphenyl)pyridine-3-carboxylic acid (200 mg, 0.634 mmol), THF (3 mL), 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) (153 mg, 0.634 mmol), DIEA (163 mg, 1.26 mmol), and propylphosphonic anhydride (50 wt % solution in EtOAc, 605 mg, 0.951 mmol) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic extracts were concentrated in vacuo. The crude product was triturated with MeOH (5 mL) to afford the title compound (230 mg, 63% yield) as a white solid.

[0644] Step 5: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(hydroxymethyl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0645] A round-bottom flask was charged with 5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-(2-methoxyphenyl)isopropyl picolinate (210 mg, 0.390 mmol), MeOH (2 mL, 49 mmol), and NaBH (29 mg, 0.779 mmol) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction was quenched by the addition of saturated aqueous NH Cl (25 mL) at room temperature. The aqueous layer was extracted with EtOAc (4 × 10 mL). The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (eluent: 10% MeOH in DCM) to afford the title compound (33 mg, 17% yield) as a yellow solid. 1H NMR (400 MHz; DMSO d6): δ 12.78 (s, 1H), 8.69 (s, 1H), 7.54-7.42 (m, 5H), 7.40-7.38 (m, 1H), 7.35-7.33 (m, 1H), 7.11-7.07 (m, 1H), 6.99 (d, 1H), 5.59 (d, 1H), 5.47(s, 2H), 4.66 (d, 1H), 3.51 (s, 3H). m / z 483 (M+H + ).

[0646] Synthesis Example 103: Synthesis of 3-(benzo[c][1,2,5]thiadiazol-4-yl)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide [ka]

[0647] Step 1: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole [ka]

[0648] A round-bottom flask under a nitrogen atmosphere was charged with 4-bromo-2,1,3-benzothiadiazole (1.00 g, 4.65 mmol), 1,4-dioxane (10 mL), bis(pinacolato)diboron (1.77 g, 6.97 mmol), KOAc (912 mg, 9.29 mmol), and Pd(dppf)Cl (340 mg, 0.465 mmol). The resulting solution was stirred at 80 °C for 4 h. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: 3% EtOAc in PE) to afford the title compound (850 mg, 48% yield) as a yellow solid.

[0649] Step 2: Preparation of methyl 3-(benzo[c][1,2,5]thiadiazol-4-yl)isonicotinate [ka]

[0650] Under a nitrogen atmosphere, a round-bottom flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)benzo[c][1,2,5]thiadiazole (830 mg, 3.16 mmol), 1,4-dioxane (8.30 mL), methyl 3-bromopyridine-4-carboxylate (752 mg, 3.48 mmol), HO (2.10 mL), KCO (875 mg, 6.33 mmol), and Pd(dppf)Cl (231 mg, 0.317 mmol). The resulting solution was stirred at 100 °C for 1.5 h. The resulting mixture was diluted with water (30 mL). The aqueous layer was extracted with EtOAc (40 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 25% EtOAc in PE) to give the title compound (490 mg, 54% yield) as a yellow solid.

[0651] Step 3: Preparation of 3-(benzo[c][1,2,5]thiadiazol-4-yl)isonicotinic acid [ka]

[0652] The title compound was prepared according to general procedure F using methyl 3-(benzo[c][1,2,5]thiadiazol-4-yl)isonicotinate (470 mg, 1.73 mmol), MeOH (5 mL), HO (1.25 mL), NaOH (138 mg, 3.46 mmol). The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The pH of the aqueous solution was adjusted to 5 with HCl (1 M). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were concentrated under reduced pressure to provide the title compound (330 mg, 71% yield) as a white solid.

[0653] Step 4: Preparation of 3-(benzo[c][1,2,5]thiadiazol-4-yl)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide [ka]

[0654] A reaction vial was charged with 3-(benzo[c][1,2,5]thiadiazol-4-yl)isonicotinic acid (150 mg, 0.583 mmol), DMF (1.50 mL), 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B) (140 mg, 0.583 mmol), EDCI (167 mg, 0.875 mmol), and HOBT (118 mg, 0.875 mmol). The resulting solution was stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with water (3 mL) followed by MeOH (3 mL) to afford the title compound (167 mg, 58% yield) as an off-white solid. 1 H NMR (400 MHz; DMSO d6): δ 13.19 (s, 1H), 8.91 (d, 2H), 8.15 (dd, 1H), 7.85-7.79 (m, 3H), 7.51-7.45 (m, 4H), 5.44 (s, 2H); m / z 481 [M+H + ].

[0655] Synthesis Example 104: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-(difluoromethoxy)phenyl)-6-(hydroxymethyl)nicotinamide [ka]

[0656] Step 1: Preparation of ethyl 6-chloro-4-(2-(difluoromethoxy)phenyl)nicotinate [ka]

[0657] Under a nitrogen atmosphere, a reaction vial was charged with 2(difluoromethoxy)phenylboronic acid (460 mg, 2.44 mmol), 1,4-dioxane (4.60 mL), ethyl 4,6-dichloropyridine-3-carboxylate (807 mg, 3.67 mmol), HO (1.10 mL), KCO (676 mg, 4.89 mmol), and Pd(dtbpf)Cl (159 mg, 0.245 mmol). The resulting solution was stirred at 80 °C for 4 h. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc in PE) to afford the title compound (730 mg, 60% yield) as a white solid.

[0658] Step 2: Preparation of ethyl 4-(2-(difluoromethoxy)phenyl)-6-(hydroxymethyl)nicotinate [ka]

[0659] Under a nitrogen atmosphere, a round-bottom flask was charged with ethyl 6-chloro-4-(2-(difluoromethoxy)phenyl)nicotinate (690 mg, 2.10 mmol), PhMe (7 mL), (tributylstannyl)methanol (1.01 g, 3.15 mmol), and Pd(PPh3)4 (243 mg, 0.211 mmol). The resulting solution was stirred at 80 °C for 4 h. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The residue was purified by preparative TLC (40% EtOAc in PE) to afford the title compound (160 mg, 24% yield) as a yellow oil.

[0660] Step 3: Preparation of 4-(2-(difluoromethoxy)phenyl)-6-(hydroxymethyl)nicotinic acid [ka]

[0661] A reaction vial was charged with ethyl 4-(2-(difluoromethoxy)phenyl)-6-(hydroxymethyl)nicotinate (150 mg, 0.464 mmol), EtOH (1.50 mL), HO (0.4 mL), and NaOH (37 mg, 0.928 mmol). The resulting solution was stirred at room temperature for 1.5 h. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (10 mL). The pH of the aqueous solution was adjusted to 5 using HCl (1 M). The aqueous layer was extracted with EtOAc (10 mL). The resulting mixture was concentrated under reduced pressure to provide the title compound (120 mg, 86% yield) as a white solid.

[0662] Step 4: Preparation of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-(difluoromethoxy)phenyl)-6-(hydroxymethyl)nicotinamide [ka]

[0663] A reaction vial was charged with 4-(2-(difluoromethoxy)phenyl)-6-(hydroxymethyl)nicotinic acid (100 mg, 0.339 mmol), DMF (1 mL), 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C) (82 mg, 0.339 mmol), EDCI (97 mg, 0.508 mmol), and HOBT (68 mg, 0.508 mmol). The resulting solution was stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with water (3 mL) and then MeOH (2 mL) to afford the title compound (25 mg, 14% yield) as an off-white solid. 1H NMR (400 MHz; DMSO d6): δ 12.98 (s, 1H), 8.85 (s, 1H), 8.66 (s, 1H), 8.02-8.00 (m, 1H), 7.62 (d, 1H), 7.52 (d, 2H), 7.43-7.36 (m, 2H), 7.24-6.88 (m, 2H), 5.64 (t, 1H), 5.55 (s, 2H), 4.69 (d, 2H); m / z 520 (M+H + ).

[0664] Synthesis Example 105: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(cyanomethyl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0665] Step 1: Preparation of ethyl 6-chloro-4-(2-methoxyphenyl)pyridine-3-carboxylate [ka]

[0666] The title compound was prepared using general procedure E using ethyl 4,6-dichloropyridine-3-carboxylate and 2-methoxyphenylboronic acid, substituting Pd(dppf)Cl (0.2 equiv.) with Pd(dtbpf)Cl (0.1 equiv.). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 6% EtOAc in PE to give the title compound as a yellow solid.

[0667] Step 2: Preparation of ethyl 6-(hydroxymethyl)-4-(2-methoxyphenyl)pyridine-3-carboxylate [ka]

[0668] To a stirred solution of ethyl 6-chloro-4-(2-methoxyphenyl)pyridine-3-carboxylate (480 mg, 1.6 mmol) and (tributylstannyl)methanol (792 mg, 2.5 mmol) in toluene was added Pd(dppf)Cl2 (120 mg, 0.17 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated in vacuo. The residue was purified by preparative TLC (PE:EtOAc, 1:1) to afford the title compound (300 mg, 63% yield) as a white solid.

[0669] Step 3: Preparation of 6-(hydroxymethyl)-4-(2-methoxyphenyl)pyridine-3-carboxylic acid [ka]

[0670] To a solution of ethyl 6-(hydroxymethyl)-4-(2-methoxyphenyl)pyridine-3-carboxylate (287 mg, 1.0 mmol) in EtOH (5 mL) and water (1 mL) was added LiOH (84 mg, 2.0 mmol). The mixture was stirred at room temperature overnight. The mixture was acidified to pH 5 with HCl (1 M). The mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography (column, C18 silica gel; mobile phase, 0-100% MeCN in water) to give the title compound (77 mg, 30% yield) as a white solid.

[0671] Step 4: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(hydroxymethyl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0672] The title compound was prepared according to general procedure A using 6-(hydroxymethyl)-4-(2-methoxyphenyl)pyridine-3-carboxylic acid (540 mg, 2.08 mmol) and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (2×). The residue was purified by preparative TLC (5% MeOH in DCM) to afford the title compound (300 mg, 27% yield) as a brown solid.

[0673] Step 5: Preparation of (5-((5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)carbamoyl)-4-(2-methoxyphenyl)pyridin-2-yl)methyl methanesulfonate [ka]

[0674] To a solution of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(hydroxymethyl)-4-(2-methoxyphenyl)nicotinamide (290 mg, 0.600 mmol) and EtN (121 mg, 1.20 mmol) in DCM was added MsCl (82.54 mg, 0.721 mmol) dropwise at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (110 mg, 29% yield) as an off-white solid.

[0675] Step 6: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-(cyanomethyl)-4-(2-methoxyphenyl)nicotinamide [ka]

[0676] To a solution of [5-([5-[(4-chlorophenyl)methoxy]-1,3,4-thiadiazol-2-yl]carbamoyl)-4-(2-methoxyphenyl)pyridin-2-yl]methyl methanesulfonate (100 mg, 0.178 mmol) in DMSO (2 mL) was added NaCN (34 mg, 0.713 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc (2×). The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (2% MeOH in DCM) to afford the title compound (37 mg, 40% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.79 (s, 1H), 7.59 - 7.31 (m, 7H), 7.12-7.00 (m, 2H), 5.48 (s, 2H), 4.35 (s, 2H), 3.52 (s, 3H); m / z: [M+H] + 492.

[0677] Synthesis Example 106: Synthesis of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka]

[0678] Step 1: Preparation of 5-(2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile [ka]

[0679] To a solution of 2-(2-methoxyphenyl)-2-oxoacetaldehyde (1.90 g, 11.5 mmol) in EtOH (60 mL) was added thioacetaside (1.14 g, 11.5 mmol) and Na2SO4 (3.28 g, 23.1 mmol). The mixture was stirred at room temperature under an inert atmosphere of nitrogen for 5 hours. The mixture was filtered and washed with EtOAc (3x). The mixture was concentrated to give a brown solid. The residue was dissolved in EtOH (60 mL). In a separate flask, sodium metal (2.66 g, 11.5 mmol) was added to EtOH (60 mL), and the mixture was cooled to 0 °C under a nitrogen atmosphere. The brown mixture was added dropwise to the sodium ethoxide mixture at 0 °C. The mixture was then stirred at 80 °C overnight. The mixture was cooled to room temperature and diluted with water. The mixture was concentrated to half its volume under reduced pressure. The precipitate was collected by filtration and washed with water, then with EtOAc to give the title compound (1.5 g, 56% yield) as a grey solid.

[0680] Step 2: Preparation of 3-chloro-5-(2-methoxyphenyl)pyridazine-4-carbonitrile [ka]

[0681] A round-bottom flask was charged with 5-(2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile (1.50 g, 6.60 mmol) and POCl3 (15 mL). The mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was cooled to 0 °C, and ice water was added (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 17% EtOAc in PE) to give the title compound (780 mg, 47% yield) as a brown solid.

[0682] Step 3: Preparation of 5-(2-methoxyphenyl)pyridazine-4-carbonitrile [ka]

[0683] To a solution of 3-chloro-5-(2-methoxyphenyl)pyridazine-4-carbonitrile (720 mg, 2.93 mmol) in THF (72 mL) was added 10% Pd / C (72 mg) and EtN (889 mg, 8.79 mmol). The mixture was purged with H and stirred at room temperature under an H atmosphere for 30 minutes. The mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 25% EtOAc in PE) to give the title compound (300 mg, 45% yield) as a gray solid.

[0684] Step 4: Preparation of 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid [ka]

[0685] To a solution of 5-(2-methoxyphenyl)pyridazine-4-carbonitrile (285 mg, 1.34 mmol) in HO (2 mL) was added HSO (1.20 mL, 60% w / w). The mixture was stirred at 100 °C for 5 h. The mixture was cooled to room temperature, and saturated aqueous NaHCO was added until the mixture reached pH 5. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 5% MeOH in DCM) to give the title compound (100 mg, 31%) as an off-white solid.

[0686] Step 5: Preparation of N-(5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5-(2-methoxyphenyl)pyridazine-4-carboxamide [ka]

[0687] To a solution of 5-(2-methoxyphenyl)pyridazine-4-carboxylic acid (90 mg, 0.391 mmol) in DMF (1 mL) were added EDCI (112 mg, 0.586 mmol), HOBT (79 mg, 0.586 mmol), and 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (Intermediate C) (94 mg, 0.391 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water. The aqueous layer was extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was triturated with MeOH to give the title compound (26.7 mg, 14% yield) as a white solid. 1 H NMR (300 MHz; DMSO d6): δ 13.17 (s, 1H), 9.41 (dd, 2H), 8.66 (d, 1H), 8.01 (dd, 1H), 7.62 (d, 1H), 7.51-7.46 (m, 2H), 7.16-7.06 (m, 2H), 5.56 (s, 2H), 3.55 (s, 3H); m / z 455 (M+H + ).

[0688] Synthesis Example 107: Synthesis of N-(5-((7-chloro-1-indazol-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide [ka]

[0689] Step 1: Preparation of 4-bromo-7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ka]

[0690] To a solution of 4-bromo-7-chloro-1H-indazole (1.50 g, 6.48 mmol) in DMF (32 mL), sodium hydride (60% dispersion in mineral oil, 518 mg, 12.9 mmol) was added portionwise at 0° C. The mixture was stirred for 40 minutes, and then SEM-Cl (2.16 g, 12.9 mmol) was added to the mixture and stirred for 4 hours. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: 1% EtOAc in PE) to give the title compound (1.8 g, 76% yield) as a yellow oil.

[0691] Step 2: 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-indazole [ka]

[0692] To a solution of 4-bromo-7-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (1.80 g, 4.97 mmol) in toluene (15 mL), tributyl(ethenyl)stannane (1.89 g, 5.97 mmol at room temperature) and Pd(PPh3)4 (862 mg, 0.746 mmol) were added. The mixture was stirred at 110 °C under a nitrogen atmosphere for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 100% DCM) to give the title compound (1.3 g, 84% yield) as a yellow oil.

[0693] Step 3: 1-(7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)ethane-1,2-diol [ka]

[0694] To a solution of 7-chloro-4-ethenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (1.30 g, 4.20 mmol) in THF (12 mL) was added OsO (107 mg, 0.421 mmol) at room temperature. Then, a solution of NMO (986 mg, 8.41 mmol) in HO (1 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with HO and extracted with EtOAc (3x). The combined organic extracts were concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (660 mg, 45% yield) as a yellow oil.

[0695] Step 4: Preparation of 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carbaldehyde [ka]

[0696] To a solution of 1-(7-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]indazol-4-yl)ethane-1,2-diol (650 mg, 1.89 mmol) in MeOH (5 mL) was added NaIO (810 mg, 3.79 mmol) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was diluted with water and extracted with EtOAc (5x). The combined organic extracts were concentrated in vacuo. The residue was purified by preparative TLC (eluent: 17% EtOAc in PE) to give the title compound (560 mg, 87% yield) as a yellow solid.

[0697] Step 5: (7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methanol [ka]

[0698] To a solution of 7-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-4-carbaldehyde (560 mg, 1.80 mmol) in MeOH (5 mL) was added NaBH (136 mg, 3.60 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH Cl was then added, and the mixture was extracted with EtOAc (3x). The combined organic extracts were concentrated in vacuo. The residue was purified by preparative TLC (eluent: 5% MeOH in DCM) to give the title compound (520 mg, 84% yield) as a yellow solid.

[0699] Step 6: Preparation of O-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methyl) S-methyl carbonodithioate [ka]

[0700] To a solution of (7-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]indazol-4-yl)methanol (510 mg, 1.63 mmol) in THF (0.5 mL) was added NaH (60% dispersion in mineral oil, 130 mg, 3.25 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then MeI (254 mg, 1.79 mmol) was added at 0° C. The mixture was stirred for 5 minutes, then CS2 (5 mg, 0.070 mmol) was added. The mixture was warmed to room temperature and stirred for 30 minutes. Saturated aqueous NH4Cl was added and diluted with water. The mixture was extracted with EtOAc (3×). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 20% EtOAc in PE) to give the title compound (445 mg, 67%) as a yellow solid.

[0701] Step 7: Preparation of O-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methyl)hydrazinecarbothioate [ka]

[0702] To a solution of O-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methyl)S-methylcarbonodithioate (445 mg, 1.10 mmol) in MeOH (5 mL) at 0° C. was added hydrazine hydrate (55 mg, 1.10 mmol) at 0° C. The mixture was warmed to room temperature and stirred at room temperature for 15 minutes. The mixture was diluted with EtOAc. The mixture was washed with water (5×). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 50% EtOAc in PE) to afford the title compound (370 mg, 86% yield) as a yellow oil.

[0703] Step 8: 5-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methoxy)-1,3,4-thiadiazol-2-amine [ka]

[0704] To a solution of O-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methyl)hydrazinecarbothioate (370 mg, 0.956 mmol) in MeOH (4 mL) at 0° C., EtN (193 mg, 1.91 mmol) and BrCN (111 mg, 1.05 mmol) were added at 0° C. The mixture was stirred for 30 min. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 7% MeOH in DCM) to give the title compound (210 mg, 52% yield) as a yellow oil.

[0705] Step 9: N-(5-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide [ka]

[0706] The title compound was prepared according to general procedure A using 3-(2-methoxyphenyl)pyridine-4-carboxylic acid (Intermediate H) and 5-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methoxy)-1,3,4-thiadiazol-2-amine. The mixture was diluted with EtOAc (25 mL). The mixture was washed with water (3×). The organic layer was concentrated in vacuo. The residue was purified by preparative TLC (eluent: 5% EtOAc in PE) to afford the title compound (260 mg, 81%) as an off-white solid.

[0707] Step 10: N-(5-((7-chloro-1-indazol-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide [ka]

[0708] To a solution of N-(5-((7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)isonicotinamide (150 mg, 0.241 mmol) in THF (2 mL) was added TBAF (2 M in THF, 0.722 mL, 1.44 mmol) and CsF (365 mg, 2.40 mmol) at room temperature. The mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The mixture was diluted with EtOAc. The mixture was washed with water (4×). The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 7% MeOH in DCM) to give the title compound (50 mg, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO d6): δ 13.76 (s, 1H), 12.87 (s, 1H), 8.72 (d, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 7.63 (d, 1H), 7.48 (d, 1H), 7.40-7.35 (m, 2H), 7.26 (d, 1H), 7.08-7.04 (m, 1H), 6.99-6.97 (m, 1H), 5.81 (s, 2H), 3.50 (s, 3H); m / z 493 (M+H + ).

[0709] Synthesis Example 108: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(5-cyano-2-(difluoromethoxy)phenyl)isonicotinamide [ka]

[0710] Step 1: Preparation of 3-bromo-4-(difluoromethoxy)benzonitrile [ka]

[0711] To a solution of 3-bromo-4-hydroxybenzonitrile (5.00 g, 25.2 mmol) and (bromodifluoromethyl)trimethylsilane (10.2 g, 50.4 mmol) in DCM (20 mL) was added a solution of KOH (8.50 g, 151.5 mmol) in water (35 mL) at 0° C. The mixture was stirred at room temperature overnight. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: 75% EtOAc in PE) to give the title compound (4 g, 63% yield) as a white solid.

[0712] Step 2: 4-(Difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ka]

[0713] To a solution of 3-bromo-4-(difluoromethoxy)benzonitrile (2.00 g, 8.06 mmol) and bis(pinacolato)diboron (2.46 g, 9.67 mmol) in 1,4-dioxane (20 mL) was added KOAc (1.58 g, 16.1 mmol) and Pd(dppf)Cl (1.18 g, 1.61 mmol) at room temperature. The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: 33% EtOAc in PE) to give the title compound (400 mg, 16%) as an off-white solid.

[0714] Step 3: Preparation of methyl 3-(5-cyano-2-(difluoromethoxy)phenyl)isonicotinate [ka]

[0715] The title compound was prepared according to general procedure E using 4-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and methyl 3-bromopyridine-4-carboxylate. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated in vacuo. The residue was purified by preparative TLC (eluent: 25% EtOAc in PE) to afford the title compound (143 mg, 34% yield) as an off-white solid.

[0716] Step 4: Preparation of 3-(5-cyano-2-(difluoromethoxy)phenyl)isonicotinic acid [ka]

[0717] The title compound was prepared according to general procedure F using methyl 3-(5-cyano-2-(difluoromethoxy)phenyl)isonicotinate (50 mg, 0.164 mmol) and substituting LiOH (1.5 equiv.) for NaOH (5 equiv.). The mixture was acidified to pH 5 with HCl (1 M) and extracted with EtOAc (2×). The combined organic layers were concentrated in vacuo. The residue was purified by reverse-phase chromatography (column, C18 silica gel; mobile phase, 0-100% MeCN in water) to afford the title compound as a white solid.

[0718] Step 5: N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(5-cyano-2-(difluoromethoxy)phenyl)isonicotinamide [ka]

[0719] The title compound was prepared according to general procedure A using 3-(5-cyano-2-(difluoromethoxy)phenyl)isonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were concentrated in vacuo. The residue was purified by preparative TLC (eluent: 3% MeOH in DCM) to afford the title compound (10 mg, 18%) as a white solid. 1 H NMR (300 MHz, DMSO d6): δ 13.12 (s, 1H), 8.84 (d, 1H), 8.69 (s, 1H), 8.03-7.99 (m, 2H), 7.80 (d, 1H), 7.55-7.01 (m, 6H), 5.48 (s, 2H); m / z 514 (M+H + ).

[0720] Synthesis Example 109: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-(difluoromethoxy)-6-fluorophenyl)isonicotinamide [ka]

[0721] Step 1: Preparation of 2-bromo-1-(difluoromethoxy)-3-fluorobenzene [ka]

[0722] To a solution of 2-bromo-3-fluorophenol (5 g, 26.1 mmol) and (bromodifluoromethyl)trimethylsilane (10.6 g, 52.3 mmol) in DCM (100 mL) was added a solution of KOH (8.81 g, 157.0 mmol) in water (35 mL) dropwise. The mixture was stirred at room temperature overnight. The mixture was diluted with water (300 mL). The aqueous layer was extracted with DCM (3 × 100 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% EtOAc in PE) to give the title compound (4 g, 63% yield) as a yellow oil.

[0723] Step 2: Preparation of 2-(2-(difluoromethoxy)-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0724] To a solution of 2-bromo-1-(difluoromethoxy)-3-fluorobenzene (2.00 g, 8.29 mmol) in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (3.16 g, 12.4 mmol), KOAc (1.63 g, 16.5 mmol), and Pd(dppf)Cl (0.61 g, 0.830 mmol). The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc (3x). The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% EtOAc in PE) to give the title compound (900 mg, 37% yield) as a yellow oil.

[0725] Step 3: Preparation of methyl 3-(2-(difluoromethoxy)-6-fluorophenyl)isonicotinate [ka]

[0726] To a solution of 2-(2-(difluoromethoxy)-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (840 mg, 2.91 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added methyl 3-bromopyridine-4-carboxylate (944 mg, 4.374 mmol), K2CO3 (806 mg, 5.83 mmol), and Pd(dtbpf)Cl2 (380 mg, 0.583 mmol) at room temperature. The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 10% EtOAc in PE) to give the title compound (140 mg, 16% yield) as a white solid.

[0727] Step 4: Preparation of 3-(2-(difluoromethoxy)-6-fluorophenyl)isonicotinic acid [ka]

[0728] To a solution of methyl 3-(2-(difluoromethoxy)-6-fluorophenyl)isonicotinate (130 mg, 0.437 mmol) in MeOH (2 mL) was added aqueous LiOH (2 M, 0.44 mL, 0.880 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with water and washed with EtOAc. HCl (1 M) was added to the aqueous layer until the pH reached 5. The solid was collected by filtration and washed with water (3×) to give the title compound (60 mg, 47% yield) as a white solid.

[0729] Step 5: Preparation of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-(difluoromethoxy)-6-fluorophenyl)isonicotinamide [ka]

[0730] The title compound was prepared according to general procedure A using 3-(2-(difluoromethoxy)-6-fluorophenyl)isonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic extracts were concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 5% MeOH in DCM) to afford the title compound (53 mg, 59% yield) as a pale yellow solid. 1 H NMR (300 MHz; DMSO d6): δ 13.13 (s, 1H), 8.83 (d, 1H), 8.66 (s, 1H), 7.84 (d, 1H), 7.54 -7.46 (m, 5H), 7.38-6.89 (m, 3H), 5.47 (s, 2H); m / z 507 (M+H + ).

[0731] Synthesis Example 110: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-((3S,5S)-3,5-dimethylmorpholino)isonicotinamide [ka]

[0732] Step 1: Preparation of 3-fluoro-4-(methoxycarbonyl)pyridine 1-oxide [ka]

[0733] To a solution of methyl 3-fluoropyridine-4-carboxylate (800 mg, 5.2 mmol) in chloroform (8 mL) under a nitrogen atmosphere was added m-CPBA (85%, 10474 mg, 5.2 mmol). The mixture was stirred at room temperature for 5 hours. Saturated aqueous NH4Cl was added, and the mixture was extracted with DCM (3x). The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% MdOH in DCM to give the title compound.

[0734] Step 2: Preparation of 3-((3S,5S)-3,5-dimethylmorpholino)-4-(methoxycarbonyl)pyridine 1-oxide [ka]

[0735] To a solution of 3-fluoro-4-(methoxycarbonyl)pyridine 1-oxide (770 mg, 4.50 mmol) in MeCN (7.70 mL) were added (3S,5S)-3,5-dimethylmorpholine hydrochloride (407 mg, 2.70 mmol) and DIEA (1.04 g, 8.09 mmol). The mixture was stirred at 100° C. for 3 days. The mixture was diluted with water and concentrated to half its volume under reduced pressure. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was concentrated in vacuo. The residue was purified by preparative TLC (eluent: 4% MeOH in DCM) to give the title compound (130 mg, 8% yield) as a yellow oil.

[0736] Step 3: Preparation of methyl 3-((3S,5S)-3,5-dimethylmorpholino)isonicotinate [ka]

[0737] To a solution of 3-((3S,5S)-3,5-dimethylmorpholino)-4-(methoxycarbonyl)pyridine 1-oxide (120 mg, 0.451 mmol) in MeOH (1.20 mL) were added 10% Pd / C (12 mg) and HCONH (142 mg, 2.25 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with MeOH. The solids were removed by filtration and washed with MeOH (2×). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 20% EtOAc in PE) to give the title compound (78 mg, 67%) as a colorless oil.

[0738] Step 4: Preparation of 3-((3S,5S)-3,5-dimethylmorpholino)isonicotinic acid [ka]

[0739] To a solution of methyl 3-((3S,5S)-3,5-dimethylmorpholino)isonicotinate (78 mg, 0.312 mmol) in MeOH (0.80 mL) and water (0.20 mL) was added NaOH (24 mg, 0.623 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and washed with EtOAc. HCl (1 M) was added to the aqueous layer until the pH was 5. The aqueous layer was extracted with EtOAc (8×). The combined organic layers were concentrated under reduced pressure to afford the title compound (70 mg, 94% yield) as a white solid, which was used without further purification.

[0740] Step 5: N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-((3S,5S)-3,5-dimethylmorpholino)isonicotinamide [ka]

[0741] The title compound was prepared according to general procedure A using 3-((3S,5S)-3,5-dimethylmorpholino)isonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The result was stirred at room temperature for 2 hours. The mixture was diluted with water. The solid was collected by filtration and washed with water. The solid was purified by trituration with MeOH to give the title compound (61 mg, 43% yield) as a pale pink solid. 1 H-NMR (300 MHz, DMSO-d6): δ 14.24 (s, 1H), 8.74 (s, 1H), 8.62 (d, 1H), 7.90 (d, 1H), 7.57-7.55 (m, 2H), 7.51-7.48 (m, 2H), 5.52 (s, 2H), 3.95 (s, 3H), 3.74 (s, 1H), 3.17 (s, 2H), 1.06 (s, 3H), 0.81 (s, 3H); m / z [M+H] + 460.

[0742] Synthesis Example 111: Synthesis of 3-(benzo[d]oxazol-7-yl)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide [ka]

[0743] Step 1: Preparation of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole [ka]

[0744] To a solution of 7-bromo-1,3-benzoxazole (2.00 g, 10.1 mmol) in 1,4-dioxane (20 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1,3,2-dioxaborolane (3.88 g, 15.1 mmol), KOAc (1.98 g, 20.2 mmol), and Pd(dppf)Cl2 (740 mg, 1.01 mmol) were added. The mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 2% EtOAc in PE) to give the title compound (2 g, 71% yield) as a white solid.

[0745] Step 2: Preparation of methyl 3-(benzo[d]oxazol-7-yl)isonicotinate [ka]

[0746] To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1.00 g, 4.08 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added methyl 3-bromopyridine-4-carboxylate (1.32 g, 6.12 mmol), K2CO3 (1.13 g, 8.16 mmol), and Pd(dppf)Cl2 (0.30 g, 0.408 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 3% EtOAc in PE) to give the title compound (700 mg, 64% yield) as a white solid.

[0747] Step 3: Preparation of 3-(benzo[d]oxazol-7-yl)isonicotinic acid [ka]

[0748] The title compound was prepared according to general procedure F using methyl 3-(benzo[d]oxazol-7-yl)isonicotinate. The mixture was acidified to pH 6 with AcOH. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column, C18 silica gel; mobile phase, 0-10% MeCN in water) to give the title compound (270 mg, 37% yield) as a yellow solid.

[0749] Step 4: Preparation of 3-(benzo[d]oxazol-7-yl)-N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)isonicotinamide [ka]

[0750] The title compound was prepared according to general procedure A using 3-(benzo[d]oxazol-7-yl)isonicotinic acid and 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-amine (Intermediate B). The mixture was diluted with water and extracted with EtOAc (2x). The combined organic extracts were concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: 5% MeOH in DCM) to afford the title compound (15 mg, 7% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6): δ 13.13 (s, 1H), 8.93 (s, 1H), 8.85 (d, 1H), 8.72 (s, 1H), 7.85 - 7.80 (m, 2H), 7.54 - 7.46 (m, 6H), 5.46 (s, 2H); m / z 464 (M+H + ).

[0751] Synthesis Example 112: Synthesis of N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-5-(2-(difluoromethoxy)phenyl)pyridazine-4-carboxamide [ka]

[0752] Step 1: Preparation of 2-(2-(difluoromethoxy)phenyl)-2-oxoacetaldehyde [ka]

[0753] To a solution of 1-[2-(difluoromethoxy)phenyl]ethanone (5.00 g, 26.8 mmol) in 1,4-dioxane (27 mL) and water (3 mL) was added SeO2 (4.47 g, 40.2 mmol). The mixture was stirred at 100 °C overnight. The mixture was diluted with water and extracted with EtOAc. The combined org...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, X is -N- or -C-; alk is alkylene; Ring A is phenyl or a 5-10 membered heteroaryl ring, including X, containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ar １ is phenyl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl or spiroheterocyclyl; Ar １ Each of the rings represented by R ａ , R ｂ and / or R ｃ is substituted with R ａ and R ｂ are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, acyl, acylamino, monoalkylamino, dialkylamino, alkylsulfonyl, cyano, and hydroxy; or R ａ and R ｂ If they are on adjacent vertices of a ring, they are taken together as C ３－６ forming a cycloalkyl, or R ａ and R ｂ are taken together to form an oxo when present on the same vertex of the ring; R ｃ is selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, heterocyclyloxy, aminocarbonyl; Ar ２ is phenyl, heteroaryl or cycloalkyl; Ar ２ The phenyl and the heteroaryl represented by R ｄ , R ｅ and / or R ｆ is replaced by R ｄ and R ｅ is independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano; R ｆ is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl; R ｆ The heteroaryl and heterocyclyl represented by the formula: are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from alkyl, halo, haloalkyl and hydroxy; R １ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, optionally substituted heteroaryl, hydroxyalkyl, cycloalkyl, hydroxyalkynyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, alkylsulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl or optionally substituted heterocyclylalkyl; R ２ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, or cyano. or a pharma- ceutically acceptable salt thereof.

2. The compound has the structure of formula (Ia): 【Chemistry 2】 2. The compound of claim 1 having the formula:

3. The compound according to claim 1 or 2, wherein Ring A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, 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, or a pharma- ceutically acceptable salt thereof.

4. Ring A is 【Chemistry 3】 The compound according to any one of claims 1 to 3, wherein:

5. Ring A is 【Chemistry 4】 The compound according to any one of claims 1 to 3, wherein:

6. Ring A is 【Chemistry 5】 The compound according to any one of claims 1 to 3, wherein:

7. R ２ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, cyano or fluoro.

8. Ar １ But, R ａ , R ｂ and / or R ｃ 8. The compound according to any one of claims 1 to 7, wherein R is substituted phenyl with R, or a pharma- ceutically acceptable salt thereof.

9. Ar １ but, 【Chemistry 6】 9. The compound of claim 8, which is: or a pharma- ceutically acceptable salt thereof.

10. Ar １ But, R ａ , R ｂ and / or R ｃ 8. The compound according to claim 1, wherein R is a heteroaryl substituted with R, or a pharma- ceutically acceptable salt thereof.

11. Ar １ But, R ａ , R ｂ and / or R ｃ pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl substituted with R ａ is hydrogen or alkyl; R ｂ is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy; R ｃ 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.

12. Ar ２ But, R ｄ , R ｅ and / or R ｆ 12. The compound of claim 1, wherein R is substituted with R, or a pharma- ceutically acceptable salt thereof.

13. Ar ２ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is cycloalkyl.

14. R １ is hydrogen, cyano, -CONH ２ , methylaminocarbonyl, dimethylaminocarbonyl, imidazol-2-yl, methoxy, hydroxy, bromo, carboxy or fluoro, or a pharma- ceutically acceptable salt thereof.

15. The compound is the following compound: 【Chemistry 7】 【change】 【change】 【change】 2. The compound of claim 1, selected from the group consisting of:

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and at least one pharma- ceutically acceptable excipient.

17. 17. The pharmaceutical composition of claim 16 for use in treating a homologous recombination (HR) deficient cancer in a patient.

18. The pharmaceutical composition described in claim 17, wherein the cancer is characterized by reduced or absent BRCA gene expression, absence of the BRCA gene, or reduced function of the BRCA protein.

19. The pharmaceutical composition of claim 17, wherein the cancer is selected from lymphoma, soft tissue cancer, 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, fibroblast cancer, cancer of the central nervous system, urinary tract cancer, upper aerodigestive cancer, leukemia, renal cancer, skin cancer, esophageal cancer and pancreatic cancer.

Images