Compounds and their uses as MIF inhibitors

Abstract

The present invention provides compounds of formula I that can be used as macrophage migration inhibitory factor (MIF) inhibitors, methods for preparing the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, and uses and methods for treating diseases mediated by MIF by administering the compounds of the invention. Formula I: JPEG2023538199000134.jpg33163

Description

[Technical field]

[0001] The present invention relates to novel compounds, methods for preparing the compounds of the present invention, pharmaceutical compositions containing the compounds of the present invention, and uses and methods for treating diseases mediated by macrophage migration inhibitory factor (MIF) by administering the compounds of the present invention. Specifically, the compounds of the present invention can be used as MIF inhibitors. [Background technology]

[0002] Macrophage migration inhibitory factor (MIF) is originally identified as a cytokine released by activated T cells to inhibit the random movement of macrophages. It is secreted by epithelial cells, endothelial cells, lymphocytes, monocytes and macrophages, suggesting a role in innate and adaptive immunity. In humans, the MIF gene is located on chromosome 22q11.2 and encodes an evolutionarily conserved protein of 115 amino acids. The molecular weight of the monomeric form of MIF protein is 12.5 kD. When MIF protein is activated, MIF forms a trimer composed of three identical subunits, each monomer containing two antiparallel α-helices, which pack into a four-stranded β-sheet. MIF exhibits chemokine-like functions and is identified as a ligand for CD74, which can form a complex with CXCR2 and CXCR4. Binding of MIF to these receptors enhances monocyte recruitment and leukocyte chemotaxis. The inflammatory cascade is dependent on activation of CXCR2 and CD74, suggesting that MIF acts through a functional CXCR2 / CD74 complex.

[0003] MIF has a variety of biological effects, the most important of which are inflammation and immunity. MIF counterregulates the action of glucocorticoids, natural steroid hormones produced by the adrenal gland during cellular stress, and has anti-inflammatory effects. MIF may stimulate the expression of other cytokines involved in inflammation. Inflammation is necessary for the survival of the organism, but when misregulated, can lead to tumorigenesis. MIF plays a role in both innate and adaptive immunity and is constitutively expressed by monocytes, macrophages, dendritic cells, B cells, neutrophils, eosinophils, mast cells and basophils. It functions as a regulator of the response to infection by promoting the stimulation and proliferation of T cells in response to foreign factors and increasing the expression of TLR4. Activated T cells release MIF to inhibit the production of interleukin-2 and interferon-γ mediated by glucocorticoids. Since circulating glucocorticoid levels increase during infection and inflammation, MIF exerts its immunosuppressive effect, thereby enabling the primary immune response and reducing the need for steroid therapy.It has also been reported that MIF has the enzymatic activity of converting D-dopachrome to 5,6-dihydroxy-2-indole carboxylic acid (DHICA).The identification of DHICA as a true biological MIF substrate has elucidated this mechanism of action, but the role of MIF enzymatic activity is not fully understood.

[0004] MIF is a multipotent and pleiotropic cytokine expressed in a variety of human malignancies, including glioblastoma, lung cancer, breast cancer, gastric cancer, bladder cancer, and melanoma. In multiple studies, MIF has been shown to cause many different forms of cancer. First, MIF is a regulator of the p53 signaling pathway and can physically interact with p53. MIF causes deregulation of normal cell cycle by inhibiting the activity of p53. MIF functionally inactivates p53, so it does not cause cell cycle arrest and apoptosis. Second, MIF is involved in the phosphoinositide-3-kinase (PI3K) / Akt pathway, which plays a key role in tumor development. Activation of this pathway can prevent vital cells from apoptosis. Previous studies have shown that MIF and CD74 initiate the activation of Akt, and when MIF is overexpressed, it allows vital cells to progress through the cell cycle via the PI3K / Akt pathway. Third, MIF plays a role in angiogenesis. When MIF is highly expressed, vascular endothelial growth factor (VEGF), hypoxia inducible factor 1 (HIF-1) and other angiogenic factors are involved in the generation of new blood vessels. Fourth, MIF causes metastasis of tumor cells by decreasing the expression of E-cadherin and increasing the expression of N-cadherin. Decreased expression of E-cadherin can also promote epithelial-mesenchymal transition (EMT), leading to the formation of secondary tumors. EMT is a process that regulates epithelial cells to acquire the characteristics of mesenchymal cells, leading to invasion and metastasis.

[0005] In addition to its application in oncology, MIF is also a pleiotropic proinflammatory cytokine that plays an upstream regulatory role in innate and adaptive immunity and is also involved in the pathogenesis of autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). MIF is significantly upregulated in the serum of MS, RA and SLE patients and animal models. MIF inhibition has been shown to improve ex vivo and in vivo features of autoimmune diseases.

[0006] The important role of MIF in cancer development and autoimmune diseases suggests that targeted inhibition of MIF is a potential therapeutic approach for treating cancer, autoimmune diseases and other inflammatory diseases. One of the most important strategies to target MIF is to develop small molecule inhibitors against MIF, which have demonstrated promising preclinical efficacy. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides novel compounds for use as MIF inhibitors. [Means for solving the problem]

[0008] In one aspect, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof: Formula I: JPEG0007664642000001.jpg27133

[0009] Where: A1 is a 5- or 6-membered carbocyclic or heterocyclic ring; where A1 is OH, halogen or C 1-6 optionally substituted with 0, 1, 2 or 3 substituents independently selected from alkyl groups; A2 is, Selected from JPEG0007664642000002.jpg13160, n1 is 0 or 1, If n1 is 0, R 1 and R 2 does not exist and n1 is 1, then R 1 and R 2 Each of these is H, C 1-6 alkyl group or R 1 and R 2 together with the carbon atom to which they are attached, C 3-6 Forming a cycloalkyl group, m1 is 0 or 1, m2 is 0, 1 or 2, when m1 is 0 and m2 is 1, Y is C; when m1 is 0 and m2 is 2, Y is S; when m1 is 1, Y is absent and m2 is 0; R 3 is H, methylene or C 1-6 is an alkyl group, n2 is 0 or 1,

[0010] A3 is a 5- or 6-membered carbocyclic or heterocyclic ring; Here, A3 is OH, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy groups, Optionally substituted by 0, 1, 2 or 3 substituents independently selected from:

[0011] Where: JPEG0007664642000004.jpg13160, C 1-6 Alkoxy groups are halogens, OH, CH3, OCH3, COOH, NH2, NH(C 1-6 alkyl), N(C 1-6 and optionally substituted with 0, 1, or 2 substituents independently selected from where n3 is 0, 1, 2, 3 or 4; where X is CH2, NH or O; If n2 is 0, R 3 is a methylene group, and A3 is C 1-6 When optionally substituted with an alkyl group, R 3 and C 1-6 Alkyl groups, together with the atoms to which they are attached, form a 6- to 8-membered heterocyclic ring.

[0012] In some embodiments, A3 is JPEG0007664642000005.jpg3860, OH, methylene group, F, Cl, Br, -CH3, -OMe, -OEt, OBn, -OCF3, Optionally substituted by 0, 1 or 2 substituents independently selected from:

[0013] In some embodiments, A2 is JPEG0007664642000007.jpg4794 or The image is JPEG0007664642000008.jpg4191.

[0014] In one embodiment, n1 is 1, A1 is a phenyl group, or JPEG0007664642000009.jpg11160, where A1 is optionally substituted by 0 or 1 substituent selected from OH, F, Cl or a methyl group.

[0015] In a preferred embodiment, m1 is 0, m2 is 1, and Y is C. In a further preferred embodiment, n2 is 0; A3 is selected from a phenyl group, a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group, or a piperidinyl group.

[0016] In the most preferred embodiment, A3 is selected from a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group or a piperidinyl group; Here, A3 is OH, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group or Optionally substituted with 0, 1, or 2 substituents independently selected from: 1-6 The alkyl group can be -CH3, 1-6 The alkoxy group can be -OMe.

[0017] In an alternative most preferred embodiment, A3 is a phenyl group, where A3 is OH, a methylene group, F, Cl, Br, -CH3, -OMe, -OEt, OBn, -OCF3, Optionally substituted with 0, 1, or 2 substituents independently selected from:

[0018] In another preferred embodiment, m1 is 0, m2 is 2, and Y is S; n2 is 0, A3 is selected from a phenyl group, a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group, or a piperidinyl group.

[0019] In a further preferred embodiment, A3 is selected from a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group or a piperidinyl group; Here, A3 is OH, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group or Optionally substituted with 0, 1, or 2 substituents independently selected from: 1-6 The alkyl group can be -CH3, 1-6 The alkoxy group can be -OMe.

[0020] In another embodiment, n1 is 0, A1 is a phenyl group, or JPEG0007664642000013.jpg11160, where A1 is optionally substituted by 0 or 1 substituent selected from OH, F, Cl or a methyl group.

[0021] In a preferred embodiment, m1 is 0, m2 is 1, and Y is C. In a further preferred embodiment, n2 is 0; A3 is selected from a phenyl group, a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group, or a piperidinyl group.

[0022] In the most preferred embodiment, A3 is selected from a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group or a piperidinyl group; Here, A3 is OH, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group or Optionally substituted with 0, 1, or 2 substituents independently selected from: 1-6 The alkyl group can be -CH3, 1-6 The alkoxy group can be -OMe.

[0023] In an alternative preferred embodiment, m1 is 0, m2 is 2, and Y is S; n2 is 0, A3 is selected from a phenyl group, a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group, or a piperidinyl group.

[0024] In a further preferred embodiment, A3 is selected from a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group or a piperidinyl group; Here, A3 is OH, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group or Optionally substituted with 0, 1, or 2 substituents independently selected from: 1-6 The alkyl group can be -CH3, 1-6 The alkoxy group can be -OMe.

[0025] In yet another embodiment, n1 is 0 or 1, m1 is 1, Y is not present, and m2 is 0.

[0026] In a preferred embodiment, n2 is 0, A1 is a phenyl group, or JPEG0007664642000016.jpg11160, where A1 is optionally substituted by 0 or 1 substituent selected from OH, F, Cl or a methyl group.

[0027] In a further preferred embodiment, A3 is selected from a phenyl group, a pyridinyl group, a cyclohexyl group, a pyrrolidinyl group, or a piperidinyl group.

[0028] In yet another embodiment, A1 is a phenyl group, or JPEG0007664642000017.jpg11160, where A1 is optionally substituted by 0 or 1 substituent selected from OH, F, Cl or a methyl group; n1 is 0 or 1, m1 is 0, m2 is 1, and Y is C; n2 is 0, R 3 is a methylene group, and A3 is C 1-6 a phenyl group substituted by an alkyl group, 1-6 Alkyl groups, together with the atoms to which they are attached, form a 6- to 8-membered heterocyclic ring.

[0029] In a preferred embodiment, wherein n1 is 1, R 3 is a methylene group, A3 is a phenyl group substituted by a methyl group, JPEG0007664642000018.jpg61138 is JPEG0007664642000019.jpg104140, which is halogen, Optionally substituted by 0, 1 or 2 substituents independently selected from:

[0030] In yet another embodiment, the compound is selected from the following: JPEG0007664642000021.jpg228160JPEG0007664642000022.jpg233160JPEG0007664642000023.jpg245160 JPEG0007664642000024.jpg224160JPEG0007664642000025.jpg245160JPEG0007664642000026.jpg245160 JPEG0007664642000027.jpg214160JPEG0007664642000028.jpg217160JPEG0007664642000029.jpg246160 JPEG0007664642000030.jpg235160JPEG0007664642000031.jpg230160JPEG0007664642000032.jpg192160

[0031] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I above, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable vector or excipient. In yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutical composition as defined above for treating a disease mediated by MIF. Preferably, the MIF mediated disease is A tumor selected from glioblastoma, lung cancer, breast cancer, gastric cancer, bladder cancer, and melanoma; Inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and pneumonia, The autoimmune disease is selected from rheumatoid arthritis (RA), multiple sclerosis (MS) and systemic lupus erythematosus (SLE).

[0032] In yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutical composition as defined above for the preparation of a medicament for the treatment of a disease mediated by MIF. Preferably, the MIF mediated disease is A tumor selected from glioblastoma, lung cancer, breast cancer, gastric cancer, bladder cancer, and melanoma; Inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and pneumonia, The autoimmune disease is selected from rheumatoid arthritis (RA), multiple sclerosis (MS) and systemic lupus erythematosus (SLE).

[0033] In yet another aspect, the present invention provides a method for treating a disease mediated by MIF in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I above, or a pharma- ceutically acceptable salt thereof. Preferably, the MIF mediated disease is A tumor selected from glioblastoma, lung cancer, breast cancer, gastric cancer, bladder cancer, and melanoma; Inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and pneumonia, The autoimmune disease is selected from rheumatoid arthritis (RA), multiple sclerosis (MS) and systemic lupus erythematosus (SLE). Preferably, the subject is a human.

[0034] In yet another aspect, the present invention provides a method of inhibiting MIF expression, production and / or secretion in a subject in need thereof, comprising administering to the subject a pharma- ceutical effective amount of a compound of formula I above, or a pharma- ceutical acceptable salt thereof. Preferably, the subject is a human.

[0035] In yet another aspect, the present invention provides a method of inhibiting the catalytic activity of MIF tautomerase in a subject in need thereof, comprising administering to the subject a pharma- ceutical effective amount of a compound of formula I above, or a pharma- ceutical acceptable salt thereof. Preferably, the subject is a human.

[0036] In yet another aspect, the present invention provides a method for inhibiting expression, production and / or secretion of MIF in a cell, comprising contacting said cell with a pharma- ceutical effective amount of a compound of formula I above, or a pharma- ceutical acceptable salt thereof. In yet another embodiment, the present invention provides a method of inhibiting the catalytic activity of MIF tautomerase in a cell, comprising contacting said cell with a pharma- ceutical effective amount of a compound of formula I above, or a pharma- ceutical acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] definition For the purposes of the present invention, the following definitions apply. The term "MIF inhibitors" includes all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates and prodrugs of the MIF inhibitors according to the present invention. As used herein, the article "a / an" is used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" refers to one element or to more than one element. As used herein, the term "and / or" means "and" or "or," unless otherwise stated.

[0038] The term "carbocycle" as used herein refers to a 3- to 10-membered aromatic or non-aromatic cyclic carbon chain. Examples of non-aromatic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, etc. Examples of aromatic carbocycles include benzene, naphthalene, anthracene, phenanthrene, etc.

[0039] The term "heterocycle" as used herein refers to a cyclic hydrocarbon containing 3 to 10 atoms, where at least one atom is O, N, or S, and where a monocyclic heterocycle can contain up to two double bonds. Examples of heterocycles include, but are not limited to, aziridine, ethylene oxide, ethylene sulfide, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxopentane, dithiolane, piperazine, oxazine, dithiane, and dioxane.

[0040] "C 1-6 The term "alkyl group", alone or in combination with other groups, refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, and neopentyl groups.

[0041] "C 3-6 The term "cycloalkyl group" refers to a cyclic hydrocarbon containing 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Any replaceable hydrogen on the cycloalkyl group can be replaced by halogen, C1-C3 alkyl group, hydroxyl group, alkoxy group, and cyano group.

[0042] "C 1-6 The term "alkoxy group," alone or in combination with other groups, refers to the group R'-O-, where R' is 1-6 It is an alkyl group. 1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, and hexyloxy groups.

[0043] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Preferred "halogen" groups are fluorine, chlorine or bromine. "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances when the event or circumstance occurs and instances when the event or circumstance does not occur. A "substituted" group includes embodiments in which a monovalent substituent is attached to a single atom of the substituted group (e.g., forming a branched chain), and also includes embodiments in which a substituent may be a divalent bridging group that is attached to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituent.

[0044] In the present invention, when a given group (moiety) is described as being attached to a second group and the point of attachment is ambiguous, the given group can be attached to any available position of the second group at any available position of the given group. For example, "C 1-6 "Phenyl group substituted with alkyl group" is C if the bonding position is unclear. 1-6 Any available site on the alkyl group can be bonded to any available site on the phenyl group. In this context, an "available site" is a site on the group at which a hydrogen on the group can be replaced by a substituent.

[0045] "Pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases and are obtained by reacting with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or organic acids such as sulfonic acid, carboxylic acid, organophosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g., (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or (-)-amino acids or mixtures thereof). These salts can be prepared by methods known to those skilled in the art. "Pharmaceutically acceptable salts" refers to salts which are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharma- ceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

[0046] The term "vector" as used herein includes vectors, excipients and diluents and refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is involved in carrying or transporting a drug from one organ or part of the body to another organ or part of the body. The term "effective amount" refers to an amount of the compound of the present invention that is sufficient to achieve a desired effect or result in the context of its administration or use. In some cases, the term effective amount can include a pharma- ceutically effective amount or a therapeutically effective amount or equivalents. Effective amounts can be determined by methods known to those skilled in the art.

[0047] A compound of a given formula (e.g., a compound of formula I) is meant to include the compounds of the present invention, as well as pharma- ceutically acceptable salts, pharma- ceutically acceptable esters, isomers, tautomers, solvates, isotopes, hydrates, polymorphs, and prodrugs of such compounds. Additionally, the compounds of the present invention may have one or more asymmetric centers and may be produced as racemic mixtures or as individual enantiomers or diastereomers. The number of stereoisomers present in a particular compound of a particular formula depends on the number of asymmetric centers present (2n stereoisomers may exist, where n is the number of asymmetric centers). Single stereoisomers may be obtained by resolving racemic or non-racemic mixtures of intermediates at some appropriate stage of the synthesis, or by resolving the compounds by conventional methods.

[0048] Both single stereoisomers (including single enantiomers and diastereomers) and racemic and non-racemic mixtures of stereoisomers are included within the scope of the present invention, and unless otherwise specified, they are all intended to be included within the structures herein. "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

[0049] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" is used to designate a racemic mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0050] Some compounds exist in the form of tautomers. Tautomers are in parallel with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between tautomers, those skilled in the art should understand that these compounds include amide tautomers and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0051] The term "polymorph" refers to different crystal structures of a crystalline compound. Different polymorphs may be due to differences in plasma sedimentation (sedimentary polymorphism) or differences in sedimentation between different conformers of the same molecule (conformational polymorphism). The term "solvate" refers to a complex formed by combining a compound of the invention with a solvent. The term "hydrate" refers to a complex formed by combining a compound of the invention with water.

[0052] The term "prodrug" refers to a compound of the present invention that contains a chemical group that can be converted in vivo from the remainder of the molecule and / or dissociated from the remainder of the molecule to provide an active drug, a pharma- ceutically acceptable salt thereof, or a biologically active metabolite thereof. A "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey, and the terms "subject" and "patient" are used interchangeably herein.

[0053] The term "inhibition" (inhibit) (inhibiting) refers to a significant decrease in the baseline activity of a biological activity or process. Unless otherwise stated, the term "disease" is used herein to refer to, and is used interchangeably with, the terms symptom, condition, or stage.

[0054] The term "tumor" as used herein refers to an abnormal growth of tissue. Tumors can be benign or malignant. Malignant tumors are usually referred to as cancers. The difference between cancer and benign tumors is the ability of malignant cells to invade other tissues, either by direct growth into adjacent tissues by invasion or by metastasis (i.e., transport through the blood or lymphatic system) to implant at distant sites.

[0055] The term "autoimmune disease" as used in the present invention refers to a disease caused by the body's inappropriate immune response to substances and tissues commonly present in the patient's body (self-immunity). Symptoms of autoimmune disease range from fatigue and mild rashes, such as epileptic seizures, to rare serious warning signs, such as seizures. The autoimmune disease is preferably selected from rheumatoid arthritis (RA), multiple sclerosis (MS), sarcoidosis, psoriasis, Crohn's disease, systemic lupus erythematosus (SLE) and type 1 diabetes, and the autoimmune disease is more preferably selected from rheumatoid arthritis (RA), multiple sclerosis (MS) and systemic lupus erythematosus (SLE).

[0056] The term "inflammatory disease" as used in the present invention refers to a disease caused by, resulting from, or causing inflammation. The term "inflammatory disease" can further refer to a dysregulated inflammatory response that causes macrophages, granulocytes, and / or T lymphocytes to overreact, resulting in abnormal tissue damage and / or cell death. The inflammatory disease can be an acute or chronic inflammatory condition and can be caused by infectious or non-infectious causes. The inflammatory disease is preferably chronic obstructive pulmonary disease (COPD), pneumonia.

[0057] The term "treatment," with respect to a subject, refers to improving at least one symptom of a disease in a subject. Treatment can be curing, ameliorating, or at least partially alleviating the disease. The term "administer / administering / administration" as used herein refers to administering a compound or a pharma- ceutically acceptable salt or composition of a compound directly to a subject, or administering a prodrug derivative or analog of a compound or a pharma- ceutically acceptable salt or composition of a compound to a subject, which can form an equivalent amount of the active compound in the subject's body.

[0058] Pharmaceutical Compositions and Administration The present invention further includes pharmaceutical compositions for treating diseases mediated by MIF, or inhibiting MIF expression, production and / or secretion, or inhibiting the catalytic activity of MIF tautomerase, or more than two of these activities.The compositions can be suitable for oral administration and include an effective amount of the compound of the present invention as a MIF inhibitor and a pharma- ceutical acceptable vector.MIF inhibitors are particularly useful because they have little or no systemic toxicity.

[0059] MIF inhibitors may be administered in an amount sufficient to treat or prevent, or prevent the development of, cardiovascular and cerebrovascular diseases, autoimmune diseases, inflammatory diseases, fibrotic diseases, metabolic diseases and tumors, respectively, in a subject. Administration of the MIF inhibitor can be accomplished by any of the modes of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral (intravenous), intramuscular, intrathecal, intravitreal, transdermal, subcutaneous, intravaginal, buccal, rectal, topical administration modes or drug eluting stands.

[0060] Depending on the intended mode of administration, the compositions may be in solid, semi-solid or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and the like, optionally in unit doses, consistent with conventional pharmaceutical practice. Similarly, they may be administered intravenously (bolus injection and infusion), intraperitoneally, intrathecally, intravitreal injection, subcutaneously or intramuscularly, all using formats well known to those of ordinary skill in the pharmaceutical arts.

[0061] Exemplary pharmaceutical compositions include a) diluents, such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils such as EPA or DHA or esters thereof or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine, b) lubricants, such as silicon dioxide, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol, also included in tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, glycerin, glycerol ... latin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g. glucose or β-lactose, corn sweeteners, natural and synthetic gums, e.g. gum arabic, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone (if required), d) disintegrants, e.g. starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, e) absorbents, colouring agents, flavourings and sweeteners, f) emulsifiers or dispersing agents, e.g. Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E. Tablets and gelatin capsules containing the MIF inhibitor and a pharma- ceutically acceptable vector, such as TGPS or other acceptable emulsifier, and / or g) an agent that enhances absorption of the compound, such as cyclodextrin, hydroxypropylcyclodextrin, PEG400, PEG200.

[0062] Liquids, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc. For example, the MIF inhibitor is dissolved in or mixed with a pharma- ceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. For example, proteins such as albumin, chylomicrons, or serum proteins can be used to dissolve the MIF inhibitor.

[0063] The MIF inhibitors can also be formulated as suppositories which can be prepared from fatty emulsions or suspensions, and polyalkylene glycols, such as propylene glycol, are used as the vector.

[0064] In another embodiment, the drug formulations according to the present invention include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solids, powders, immediate release formulations, sustained release formulations, fast dissolving formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations and mixed immediate and controlled release formulations.

[0065] MIF inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes are formed from various phospholipids, including cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, as described in U.S. Patent No. 5,262,564, lipid component membranes are hydrated with aqueous drug solutions to form lipid layers that encapsulate the drug.

[0066] The MIF inhibitor can also be delivered by using monoclonal antibodies as separate vectors to which the MIF inhibitor is coupled. The MIF inhibitor can also be coupled to soluble polymers as targetable drug vectors. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the MIF inhibitor can be coupled to biodegradable polymers that can be used to achieve controlled drug release, said polymers being crosslinked or amphiphilic block copolymers of polylactic acid, polyε-caprolactone, polyhydroxybutyrate, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate and hydrogels. In one embodiment, the MIF inhibitor is covalently coupled to a polymer such as a polycarboxylic acid polymer or polyacrylate.

[0067] Parenteral injection administration is usually for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for dissolving in liquids to be injectable.

[0068] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 80%, about 5% to about 60%, or about 1% to about 20% of the MIF inhibitor by weight or volume. The method of administration of the MIF inhibitor is selected based on a variety of factors, including the patient type, species, age, weight, sex, race, diet, medical condition, the severity of the medical condition being treated, the route of administration, the renal or hepatic function of the patient, and the particular MIF inhibitor being used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the animal required to prevent, control, or arrest the progression of the medical condition.

[0069] The effective dose of the present invention, when used for the indicated effect, can be administered from about 0.1 mg to about 5000 mg of active ingredient per unit dose. In one embodiment, the composition is in the form of a scored tablet. The appropriate amount of MIF inhibitor can be determined as shown in Goodman, LS, Gilman, A. The Pharmacological Basis of Therapeutics, 5th Edition; MacMillan: New York, 1975, pages 201-226.

[0070] The MIF inhibitor can be administered in a single dose per day, or the total daily dose can be administered in divided doses two, three or four times per day. Additionally, the MIF inhibitor can be administered in intranasal form by topical use of a suitable intranasal vehicle, or by transdermal route using a transdermal skin patch in a form well known to those skilled in the art. To be administered in the form of a transdermal delivery system, administration can be continuous rather than intermittent throughout the administration method. Other exemplary topical formulations include creams, ointments, lotions, aerosol sprays, and gels, in which the concentration of the MIF inhibitor is within the range of about 0.1% to about 15% w / w or w / v.

[0071] Uses of the compounds and compositions thereof The above compounds and compositions as MIF inhibitors can be used to treat or prevent MIF-related diseases. These diseases include, but are not limited to, autoimmune diseases, tumors, or chronic or acute inflammatory diseases. Examples of such diseases or conditions include: Rheumatic diseases (including but not limited to rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathy (including but not limited to ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (including but not limited to gout, pseudogout, calcium pyrophosphate deposition disease), Lyme disease, polymyalgia rheumatica,

[0072] Connective tissue diseases (including but not limited to systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome), Vasculitis (including but not limited to polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome), Inflammatory diseases, including chronic obstructive pulmonary disease (COPD), pneumonia, and the result of trauma or ischemia; ·sarcoidosis, Vascular diseases, including atherosclerotic vascular disease and infarction, atherosclerosis and vascular occlusive disease (including but not limited to atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease) and restenosis of vascular stents; Autoimmune diseases (including but not limited to diabetes, thyroiditis, myasthenia gravis, sclerosing cholangitis, primary biliary cirrhosis, rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE));

[0073] Pulmonary diseases (including but not limited to diffuse interstitial lung disease, pneumoconiosis, fibrosing alveolitis, asthma, bronchitis, bronchiectasis, chronic obstructive disease, and adult respiratory distress syndrome), Primary or metastatic tumors (including but not limited to glioblastoma, prostate cancer, colon cancer, lymphoma, lung cancer, gastric cancer, bladder cancer, melanoma, multiple myeloma, breast cancer, stomach cancer, leukemia, cervical cancer and metastatic cancer), Kidney disease, including glomerulonephritis and interstitial nephritis, Hypothalamic-pituitary-adrenal axis disorders, Neurological disorders, including multiple sclerosis and Alzheimer's disease, Diseases characterized by alterations in angiogenesis (e.g. diabetic retinopathy, rheumatoid arthritis, cancer), endometrial function (menstruation, implantation, endometriosis),

[0074] Endotoxin (septic) shock, exotoxin (septic) shock, septic (true septic) shock, complications of malaria, other infectious complications, complications of infections including pelvic inflammatory disease, Transplant rejection, graft-versus-host disease, Allergies, atopy, allergic rhinitis, and other allergic disorders Bone disorders (e.g. osteoporosis, Paget's disease), Skin disorders including psoriasis, atopic dermatitis, and UV(B)-induced activation of dermal cells (e.g. sunburn, skin cancer), Pain, testicular dysfunction, and wound healing, Bowel disorders including inflammatory bowel disease (including but not limited to ulcerative colitis and Crohn's disease), peptic ulcers, gastritis, esophagitis and liver disease (including but not limited to cirrhosis and hepatitis).

[0075] Combination therapy The compounds of the present invention may be used in combination with non-limiting examples of therapeutic agents and methods for treating and preventing these MIF-related diseases, including glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX)-2 inhibitors, licofelone (ML3000), disease-modifying antirheumatic drugs (DMARDs), methotrexate, chloroquine, hydroxychloroquine, cyclophosphamide (Cytoxan), inosine monophosphate dehydrogenase (IMPDH) inhibitors, sirolimus, everolimus (rapamycin), purine nucleoside phosphorylase inhibitors, dexamethasone, cyclosporine phosphate dehydrogenase inhibitors ... Novo purine synthesis inhibitors, dihydroorotate dehydrogenase inhibitors (malononitrile amide), prostaglandin PGE2 inhibitors, P2X7 receptor inhibitors, protease-activated receptor 2 (PAR-2) inhibitors, activated complement inhibitors, complement C3 / C5 epilepsy enzyme inhibitors, activated convertase inhibitors, complement C5aR antagonists, EP4 agonists, prostaglandin-I2 analogs, sulfasalazine (SASP), 5-aminosalicylic acid (5-ASA), immunomodulators, calcineurin inhibitors, interleukin-10 (AG011), placenta-derived cells (PDA001), mucosal addressin cell adhesion molecule (MAdCAM) inhibitors (PF-00547659 ), GLP-2 agonists, anti-CD3, CCR9 inhibitors, lenalidomide (Revlimid), recombinant human interleukin-11, CXCR2 antagonists, glucagon-like peptide-2 (GLP-2) analogs (teduglutide), insulin-like growth factor-1 (IGF-1) (Increlex), synthetic guanylhydrazone semamod (CPSI-2364), intracellular adhesion molecule-1 (ICAM-1) inhibitors (alicaforsen), stem cell therapy, activated protein C (aPC), vitamin D analogs, retinoids, phototherapy, methotrexate, cyclosporine, acitretin, CCR6 inhibitors, CCL20 inhibitors,

[0076] Deoxyspergallin, alkylating deoxyribonucleic acid (DNA) agents, tumor necrosis factor (TNF)-α inhibitors, TNF-α converting enzyme inhibitors, Janus kinase (JAK) 1, 2 and / or 3 inhibitors, spleen tyrosine kinase (SYK) inhibitors, caspase inhibitors, chemokine receptor antagonists, protein kinase C (pkc) inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitors, caspase inhibitors, NF-κB modulators, B cell inhibitors, hydroxychloroquine, B lymphocyte stimulator (BLyS) inhibitors, membrane-bound and soluble B cell activator inhibitors, BLyS and APRIL (proliferation-inducing ligand) inhibitors ) inhibitors that block cytokine binding to B cells to prevent B cell maturation and autoantibody production, anti-CD19, CD20 inhibitors, CD22 inhibitors, T cell inhibitors, interferon inhibitors, toll-like receptor inhibitors, prasterone, estrogen receptor antagonist (fulvestrant), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-Ig, v-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7-H4) agonist (AMP-110), interleukin-1 receptor antagonists (AMG108, anakinra [KINERET]), interleukin-1β antagonists, soluble IL-1 receptor, Interleukin-2R antagonists, interleukin-6 receptor antagonists, calcipotriol / betamethasone (Taclonex), fumarate (Panaclar / BG-12), interleukin-15 inhibitors, interleukin-17 inhibitors (AIN457), DHODH inhibitors (Vidofludimus), interleukin-18 inhibitors, T helper (Th) 17 cell inhibitors, interleukin-12 / interleukin-23 inhibitors, interleukin-22 inhibitors, interleukin-23 inhibitors, interleukin-12 inhibitors, interferon alpha, interferon beta [interferon beta-1a (Avonex, Rebif), interferon beta-1b (Betaseron / Betaferon), glatiramer acetate (Copaxone), selective adhesion molecule inhibitors, integrin antagonists (natalizumab [Tysabri], vedolizumab), sphingosine-1-phosphate receptor (S1P-R) agonists, fumarate derivative immunomodulators, laquinimod, anti-LFA-1, MBP-8298, cladribine, Novantrone, isoxanol dihydroorotate dehydrogenase (DHODH) and tyrosine kinase inhibitors, Revimmune (cyclophosphamide),

[0077] Fampridine SR (4-aminopyridine), Panaclar (dimethyl fumarate), MBP8298 (zircotide, a synthetic peptide version of part of human myelin basic protein), Campath (alemtuzumab), anti-CD52, purine analogs, fingolimod (sphingosine-1-phosphate receptor agonist), teriflunomide, de novo pyrimidine synthesis inhibitor, active metabolite of leflunomide, verteporfin photodynamic therapy [PDT], anti-angiogenic factors, CCR3 inhibitors, anti-CD48, β2-agonists, leukotriene modifiers, phosphodiesterase (PDE) inhibitors, selective phosphodiesterase-4 (PDE-4) inhibitors, IgE-targeted inhibitors (omalizumab), Th2 cytokine inhibitors, macrolides, ketolides, adenosine A2B antagonists, κB kinase 2 inhibitors, Prostanoid and F2-isoprostane antagonists, nitric oxide donors, inducible nitric oxide synthase inhibitors, toll-like receptor modulators, lorcaserin, phentermine, topiramate, bupropion, naltrexone, anti-CD3, antithymocyte globulin, serine protease inhibitors, tyrosine kinase inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, insulin, type 1 diabetes antigen-specific tolerance inducers, cannabinoid receptor 1 (CB1) inhibitors antagonists, long-acting glucagon-like peptide 1 (GLP1) analogues, dipeptidyl peptidase 4 (DPP4) inhibitors, vasoactive intestinal peptide-pituitary adenylate cyclase-activating polypeptide receptor 2 (VPAC2) agonists, glucokinase activators, glucagon receptor antagonists, cytosolic phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, salsalate, IκB kinase Interleukin-β (IKKβ)-inhibitors, nuclear factor κB inhibitors, interleukin-1 (IL-1) receptor antagonists, IL-1β-specific antibodies, sirtuin 1 (SIRT1) activators, selective peroxisome proliferator-activated receptor (PPAR) modulators (SPPARMs), 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibitors, PPARγ ligands, thiazolidinediones, glitazones, warfarin, coumarins, pradaxa, antithrombotic agents,Statins, hydroxymethylglutaryl CoA reductase (HMG-CoA reductase) inhibitors, ezetimibe, fenofibrate, niacin, amlodipine, vascular cell adhesion molecule (VCAM) antagonists, thromboxane A2 antagonists, prostaglandin D2 receptor 1 antagonists, G protein-coupled receptor (GPCR) modulators, cannabinoid receptor 1 (CNR, 1 CB1 receptor antagonists (rimonabant), also called

[0078] Cholesteryl ester transfer protein (CETP) inhibitors (JTT-705), chemokine (CC motif) receptor 2 (CCR2) antagonists, phospholipase A2 inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, RNA polymerase inhibitors, leukotriene synthesis inhibitors, α7 nicotinic receptor (α7 nAChR agonists, donepezil, galantamine, rivastigmine, memantine, α-secretase cleavage promoters, γ-secretase activity inhibitors, antioxidant therapy, estrogen, NO synthase inhibitors, anti-β-amyloid (Aβ) (papineuzumab), abiraterone, ActRIIA signaling inhibitor (ACE-011), doxorubicin, aldesleukin [Proleukin], alemtuzumab, alitretinoin, alkylating agents and microtubule inhibitors, allopurinol, allosteric Akt inhibitors (Akti) [MK-2206], altretamine, amifostine, anastrozole (Arimidex), triple angiokinase inhibitors (BIBFs) that inhibit VEGF receptors (VEGFRs) 1, 2 and 3, fibroblast growth factor receptor and blood platelet-derived growth factor receptor. 1120), angiopoietin 1 / 2 neutralizing peptibody (AMG386), anthracycline (amrubicin), antigen-specific cancer immunotherapy (ASCI), antimetabolite (raltitrexed), apaziquone (EOquin), aprepitant, aromatase inhibitor, arsenic trioxide, asparaginase, anaplastic lymphoma kinase (ALK) inhibitor (crizotinib, AP26113), azacitidine (Vidaza), BCG Live, Bcl-2 family inhibitors, Bcr-Abl inhibitors, bendamustine, bexarotene capsules, bexarotene gel, bleomycin, BRAF signal inhibitors, busulfan injections, oral busulfan, cabazitaxel (Jevtana), castorone, capecitabine (Xeloda), carboplatin, carmustine, carmustine and polifeprosan (Polifeprosan) 20 implant,

[0079] Caspase inhibitors, anti-CD23, anti-CD30, anti-CD32, anti-CD33, anti-CD40, chlorambucil, cisplatin, c-Met receptor tyrosine kinase inhibitor (ARQ197), clofarabine (Clolar), CS1 inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, cyclophosphamide, cytarabine, liposomal cytarabine, dacarbazine, dactinomycin, actinomycin D, darbepoetin alfa (Ara nesp), daunorubicin liposome, daunorubicin, daunomycin, histone deacetylase (HDAC) inhibitors, decitabine (Dacogen), delta-like 4 ligand (DLL4) inhibitor (OMP-21M18), denileukin, diftitox, dexrazoxane, docetaxel (Taxotere), doxorubicin, doxorubicin liposome, drotasterone propionate, DR5 agonist (LBY135), Elliott's B solution, epidermal growth factor receptor (EGFR) inhibitors, epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors, EGFR inhibitor-protein-tyrosine kinase inhibitors, dual EGFR / HER2 receptor tyrosine kinase inhibitors, elsamitrucin, endothelin-B receptor agonists, epirubicin, epoetin alpha and beta, etoposide phosphate, etoposide (VP-16), exemestane, farnesyltransferase inhibitors (FTIs), fentanyl, floxuridine (intra-arterial), fludarabine, fluorouracil (5-FU), fulvestrant (Faslodex), G2 checkpoint inhibitors (CBP501), GA101, gemcitabine (Gemzar), gemtuzumab ozogamicin, gonadotropin-releasing hormone (GnRH) agonists, goserelin acetate,

[0080] Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF) (Sargramostim), heat shock protein 90 (Hsp90) inhibitors, hedgehog pathway inhibitors (RG3616), pan-HER inhibitors (PF-00299804), Herceptin, HPV vaccine, human death receptor 5 agonists, hydroxyurea, ibritumomab (Zevalin), idarubicin, ifosfamide, imatinib mesylate (Gleevec / Glivec), immunomodulatory drugs (IMiDs), type 1 insulin-like growth factor receptor (IGF-1R) inhibitors, insulin-like growth factor Dual kinase inhibitors of insulin-1 receptor (IGF-1R) and insulin receptor (IR) (OSI-906), interleukin-2, ipilimumab, irinotecan, Istodax (romidepsin), lapatinib (Tykerb), replinin, folinic acid, levamisole, leucovorin, LOddC, lomustine (CCNU), leuprolide, luteinizing hormone releasing hormone (LHRH) agonists and antagonists, thiocanthone, MAGE-A3 inhibitors, MAPK / ERK kinase 1 / 2 inhibitors (AZD6244), nitrogen mustard (meclorethamine / nitrogenmustard, megestrol acetate, melphalan (L-PAM), mercaptopurine (6-MP), mesna, MET inhibitors (XL184), methotrexate, methoxsalen, midostaurin (PKC412), mifamotide (Mepact), mitomycin C, mitotane, mitoxantrone, mammalian target of rapamycin (mTOR) inhibitors, MEK inhibitors, microtubule inhibitors, microtubule stabilizers (patupilone [EP0906]), multikinase inhibitors, multitarget receptor tyrosine kinase inhibitors (TKI258), nandrolone phenylpropionate, necitumumab, neulasta, NK-1 receptor inhibitors, nofetumomab, noscapine (CB3304), ondansetron, oprelvekin, ero Eloxatin, PI3K inhibitors, dual PI3K / mTOR inhibitor (BEZ235), paclitaxel (Abraxane), pamidronate, platelet-derived growth factor receptor α (PDGFR-α) inhibitor (IMC-3G3), pegasine, pegaspargase, pegfilgrastim, pentostatin, pertuzumab, pipobromide, plicamycin, pole-like kinase 1 (Plk-1) inhibitors, mithramycin, poly(ADP-ribose) polymerase-1 (PARP1) inhibitors, porfimer sodium, integrin avβ3 and avβ5 inhibitor (cilengitide [EMD121974]), pemetrexed (Alimta), pralatrexate injection (Folotyn), plerixafor, dual proapoptotic receptor (PARA) DR4 and DR5 agonist, procarbazine,

[0081] Protein-tyrosine kinase inhibitors, proteasome inhibitors, quinacrine, raf and VEGFR inhibitors, receptor activator of nuclear factor-kappa B ligand (RANKL) inhibitors, rasburicase, multi-target receptor tyrosine kinase (RTK) inhibitors, romidepsin (Istodax), thiocalcitol (CB1089), polyethylene glycol-SN38 conjugates (EZN-2208), salaceplatin, dual Src and Bcr-Abl kinase inhibitors, streptozotocin, talbuvirdine (LDT), talc, tamoxifen (Nolvadex), T-DM1, temozolomide, teniposide (VM-26), testolactone, therapeutic vaccines (BiovaxID), IRX-2, Rindopepimut (C DX-110), sipuleucel-T [Provenge], TVA immunotherapy, Stimuvax [BLP25 liposomal vaccine], somatostatin analogues, taxanes (Ortataxel), Tassolan, Thalomid, thioguanine (6-TG), thiotepa, topoisomerase I and II inhibitors, topoisomerase I inhibitors (gematecan [LBQ707], irinotecan), topotecan (Hycamtin), toremifene, trabectydin (Yondelis), trastuzumab, retinoic acid (ATRA), tositumomab (Bexxar), TRPM8 agonist (D-3263), uracil mustard, recombinant urate oxidase (Elitek), valrubicin, batocitabin (monoval LDC), vascular endothelial growth factor receptor 1, 2 and 3 ("VEGFR1-3") / platelet-derived growth factor receptor ("PDGFR") / stem cell factor receptor ("c-kit") antagonist (motesanib), vascular endothelial growth factor receptor (VEGFR) / epidermal growth factor receptor (EGFR) / rearranged during transfection (RET) tyrosine kinase inhibitor (vandetanib), vascular endothelial growth factor (VEGF) inhibitors (cediranib, ramucirumab), VEGFR / EGFR / HER-2 inhibitors (AEE788), vinblastine, vinorelbine, Wnt signal inhibitors (OMP-18R5), zoledronate, zoledronic acid and combinations thereof.

[0082] General Synthesis Exemplary embodiments of the compounds of the present invention can be synthesized using the general reaction schemes described below. In view of the description herein, it will be apparent that the general schemes can be modified by replacing the starting materials with others of similar structure to produce different corresponding products. The synthetic description provides many examples of how the starting materials were modified to obtain the corresponding products. The starting materials are usually obtained from commercial sources or synthesized using published methods. The compounds of the present invention can be prepared starting from commercially available starting materials using general synthetic techniques and procedures known to those skilled in the art. The following outlines reaction schemes suitable for the preparation of such compounds. Further examples can be found in the specific examples detailed below.

[0083] The compounds disclosed in the present invention may have chiral centers, such as chiral carbon atoms. Thus, such compounds include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Furthermore, the compounds disclosed in the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, chiral centers evident from the description are provided as chiral isomers or racemic mixtures. Racemic and diastereomeric mixtures, as well as isolated or synthesized individual optical isomers substantially free of their enantiomeric or diastereomeric partners, are within the scope of the present invention. Racemic mixtures can be separated into their individual substantially optically pure isomers by well-known techniques, such as separation of diastereomeric salts with optically active auxiliaries (e.g., acids or bases), followed by conversion to optically active species. The desired optical isomers can be synthesized by stereospecific reactions starting from the appropriate stereoisomer of the desired starting material.

[0084] Scheme 1 JPEG0007664642000033.jpg24142 In Scheme 1, an amino-oxadiazole I-2 is prepared by a one-step procedure. In some embodiments, A1 is a phenyl group or a heterocycle. Aminated carboxylic acid I-3 By condensation with I-4 In some embodiments, the amide is converted to an N-methyl amide using an appropriate base and an alkyl halide under appropriate conditions such as time and temperature. 3 is the same as that described in the present invention, and R 5 and / or Z may be the same as those described for the substituents on A3 (ie, the phenyl group in this case) in the present invention.

[0085] Scheme 2 JPEG0007664642000034.jpg64136 In Scheme 2, methylamino-oxadiazole II-4 is prepared by a two-step procedure. II-3 followed by removal of the t-butoxycarbonyl protecting group to give the methylamine II-4 The amine and carboxylic acid are II-5 By condensation with II-6 In some embodiments, under appropriate conditions (e.g., time and temperature), a suitable base (e.g., NaH) and an alkyl halide (e.g., R 3 I) using II-6 of II-7 Convert to A1, R 1 , R 2 and R 3 is the same as described in the present invention, and Z can be the same as described for the substituents on A3 (ie, the phenyl group in this case) in the present invention.

[0086] Scheme 3 In Scheme 3, Z is a substituent on A (i.e., the phenyl group in this case) and can be introduced later using this method. In some embodiments, Z is attached to a nitrogen atom. In this case, the amine Z-NH2 is given III-1a In some embodiments, Z is attached to a carbon atom and is a boronic acid ZB(OH)2 and III-1a A palladium catalyzed reaction between gives an alkene. Reduction of the olefin using hydrogen gas gives the product. Alternatively, the same modification can be carried out via an organozinc reagent as a coupling partner to give the product. In some embodiments, Z is attached to an oxygen atom and is coupled to an alkyl halide (e.g., Z-halo). III-1b Alkylation of the formula gives the product. In some embodiments, Z is attached to a linking group, such as a CH2 unit. The linking group is III-1c A1, n1, R 1 and R 2 is the same as described in the present invention, and Z can be the same as described for the substituents on A3 (i.e., the phenyl group in this case) in the present invention.

[0087] Scheme 4 In some embodiments using pyridazine, IV-1 Acid chloride IV-2 and then condensed with IV-3 The product is obtained by palladium catalysis. IV-4 A1 is the same as described in the present invention, and Z can be the same as described for the substituents on A3 (i.e., the phenyl group in this case) in the present invention.

[0088] Scheme 5 In some embodiments using cyclic amides, the corresponding chloromethyl oxadiazoles V-3 teeth, V-1 and V-2 It is prepared in a two-step procedure using as the starting material followed by intramolecular cyclization. 5 was originally V-4 It will be installed in. V-4 and V-3 Coupling with V-5 A1 is the same as R 5 can be the same as those described for the substituents on A3 (i.e., the phenyl group in this case) in the present invention. EXAMPLES

[0089] The present invention can be better understood based on the following examples. However, those skilled in the art can easily understand that the contents described in the examples are only for the purpose of illustrating the present invention, and are not intended to limit the present invention described in detail in the claims.

[0090] Unless otherwise stated, the compounds of the present invention can be prepared starting from commercially available starting materials and utilizing common synthetic techniques and procedures known to those skilled in the art. Chromatographic consumables and devices can be purchased from companies such as AnaLogix, Inc, Burlington, WI, Analytical Sales and Services, Inc., Pompton Plains, NJ, Teledyne Isco, Lincoln, NE, VWR International, Bridgeport, NJ, and Rainin Instrument Company, Woburn, MA. Chemicals and reagents can be purchased from companies such as Aldrich, Argonaut Technologies, VWR and Lancaster, Invitrogen, Sigma, Promega, Solarbio, Cisbio, Signalchem, MCE. Consumables can be purchased from companies such as Corning, Labcyte, Greiner, Nunc. Equipment can be purchased from companies such as Labcyte, PerkinElmer, Eppendorf, ThermoFisher.

[0091] Example 1 JPEG0007664642000038.jpg57120 2-Chloro-N-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-4-methoxybenzamide

[0092] To a solution of 5-(2-furyl)-1,3,4-oxadiazol-2-amine (90 mg, 0.6 mmol) and DMAP (7 mg, 0.06 mmol) in pyridine (5.0 mL) is added 2-chloro-4-methoxybenzoyl chloride (369 mg, 1.8 mmol) at 10 °C. The reaction mixture is stirred overnight at 30 °C. The mixture is poured into ice water (6 mL), followed by extraction with DCM (10 mL x 2). The combined organic layer is washed with brine (6 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (DCM / EtOAc = 10 to 1:1) to give the title compound (11 mg, yield: 6%) as an off-white solid. LC-MS (ESI): m / z 320.1 [M+H]+ . 1 H NMR(400MHz,DMSO-d6):δ 12.35(s,1H),8.06(s,1H),7.84(d,J=8.8Hz,1H),7.65(d,J=8.4Hz,1H),7.27(d ,J=3.6Hz,1H),7.17(d,J=2.0Hz,1H),7.03(dd,J=2.4,8.4Hz,1H),3.85(s,3H).

[0093] Example 2 JPEG0007664642000039.jpg61135 2,4-Dimethoxy-N-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide

[0094] Following the same procedure as in Example 1, using 5-phenyl-1,3,4-oxadiazol-2-amine (186 mg, 1.16 mmol) as the amine, the title compound is obtained as a white solid (45 mg, yield: 12%). LC-MS (ESI): m / z 326.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6):δ 11.13(s,1H),7.98-7.96(m,2H),7.77(d,J=8.8Hz,1H),7.63-7.61(m,3H),6.73-6.69(m,2H),3.93(s,3H),3.87(s,3H).

[0095] Example 3 JPEG0007664642000040.jpg67148 (S)-1-Benzyl-N-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidine-3-carboxamide

[0096] To a solution of 5-(2-furyl)-1,3,4-oxadiazol-2-amine (0.31 g, 2.0 mmol) in THF (30.0 mL) is added NaH (0.29 g, 7.2 mmol) at 0° C. The mixture is stirred for 15 min. A solution of (S)-1-benzylpyrrolidine-3-carbonyl chloride (0.8 g, 3.1 mmol) in THF (20 mL) is added at 0° C. The reaction mixture is stirred for 6 h at 25° C. The mixture is poured into ice water (20 mL) and then extracted with EtOAc (50 mL×2). The combined organic layer is washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC to give the title compound as a white solid (142 mg, 98.9% purity and 178 mg, 86.6% purity, total yield: 47%) in two batches. LC-MS(ESI):m / z 339.2[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ 8.03(s,1H),7.32-7.22(m,7H),6.78(dd,J=1.6,3.2Hz,1H),3.59(s,2H), 3.35 (m, 1H), 2.83 (t, J=8.4Hz, 1H), 2.62-2.59 (m, 3H), 2.05-1.99 (m, 2H).

[0097] Example 4 JPEG0007664642000041.jpg54131 N-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2,4-dimethoxybenzamide

[0098] a) 2-(4-(benzyloxy)benzoyl)hydrazine-1-thiocarboxamide To a solution of 4-benzyloxybenzoyl chloride (1.0 g, 4.05 mmol) in THF (20 mL) at 15° C., thiosemicarbazide (554 mg, 6.07 mmol) is added in portions. The reaction mixture is stirred at room temperature for 3 h. Saturated aqueous NaHCO3 (10 mL) is added and the resulting precipitate is collected by filtration. The solid is washed with hot H2O (50° C., 100 mL) and dried to give the title compound (1.1 g, yield: 90%) as a white solid. LC-MS (ESI): m / z 302.2 [M+H] + . 1H NMR(400MHz,DMSO-d6):δ 10.25(br s,1H),9.30(br s,1H),7.86(d,J=8.8Hz,3H),7.60(br s, 1H), 7.47-7.32 (m, 5H), 7.08 (d, J=8.8Hz, 2H), 5.19 (s, 2H).

[0099] b) 5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-amine To a solution of 2-(4-(benzyloxy)benzoyl)hydrazine-1-thiocarboxamide (1.1 g, 3.65 mmol) in i-PrOH (9 mL) is added a solution of KI (182 mg, 1.1 mmol) in HO (2 mL) at room temperature. The solution is cooled to 5 °C and aqueous NaOH (5 M, 1.1 mL) is added. To the resulting mixture is added a solution of 1,3-dibromo-5,5-dimethylhydantoin (783 mg, 2.74 mmol) in acetonitrile (11 mL) dropwise at 5-10 °C. The reaction mixture is stirred for 1 h at 10 °C. The reaction is quenched with aqueous NaHSO3 (0.25 mL). EtOAc (30 mL) is added until a slurry is obtained and the precipitate is collected by filtration. The solid is washed with EtOAc (20 mL) and dried to give the title compound (0.6 g, yield: 60%) as a white solid. LC-MS(ESI):m / z 367.7[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ 7.76-7.72 (m, 2H), 7.46-7.35 (m, 5H), 7.17-7.15 (m, 4H), 5.18 (s, 2H).

[0100] c) N-(5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)-2,4-dimethoxybenzamide A solution of 2,4-dimethoxybenzoyl chloride (269 mg, 1.34 mmol) in DCM (10 mL) is added dropwise to a solution of 5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-amine (300 mg, 1.12 mmol) in pyridine (8 mL) at 10° C. The reaction mixture is stirred at room temperature for 3 h. A solution of 2,4-dimethoxybenzoyl chloride (100 mg, 0.50 mmol) in DCM (3 mL) is added and the reaction mixture is stirred at room temperature overnight. The mixture is poured into ice water (8 mL) followed by extraction with DCM (10 mL×2). The combined organic layer is washed with brine (6 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / EtOAc / DCM=3:1:1 to 0:1:1) to give the title compound as a white solid (141 mg, yield: 29%). LC-MS (ESI): m / z 432.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6):δ 11.03(s,1H),7.91(d,J=8.8Hz,2H),7.77(d,J=8.8Hz,1H),7.50-7.40(m,5H),7 .24(d,J=8.8Hz,2H),6.72-6.71(m,2H),5.22(s,2H),3.93(s,3H),3.87(s,3H).

[0101] d) N-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2,4-dimethoxybenzamide To a solution of N-(5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)-2,4-dimethoxybenzamide (70 mg, 0.16 mmol) in EtOH (150 mL) is added Pd / C (10%, 10 mg). The mixture is stirred for 12 h at room temperature under hydrogen balloon pressure. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to give the title compound (32 mg, 58%) as a grey solid. LC-MS (ESI): m / z 340.1 [MH] - . 1H NMR (400MHz, DMSO-d6): δ 10.98(s,1H),10.33(s,1H),7.80-7.76(m,3H),6.95(d,J=8.4Hz,2H),6.72-6.68(m,2H),3.93(s,3H),3.86(s,3H).

[0102] Example 5 JPEG0007664642000042.jpg75149 2,4-Dimethoxy-N-(5-(thiophen-3-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0103] a) Thiophene-3-carbohydrazide A mixture of methyl thiophene-3-carboxylate (0.5 g, 3.52 mmol, 1 eq) and hydrazine hydrate (1.85 g, 35.17 mmol, 1.80 mL, 10 eq) in ethanol (7 mL) is heated to 79° C. for 16 h. The mixture is cooled to room temperature and concentrated under vacuum to give the title compound (0.46 g, yield: 82%) as a red solid, which is used in the next step. LC-MS (ESI): m / z 143.2 [M+H] + .

[0104] b) 5-(thiophen-3-yl)-1,3,4-oxadiazol-2-amine To a mixture of thiophene-3-carbohydrazide (0.46 g, 2.91 mmol) and K2CO3 (804 mg, 5.82 mmol) in H2O (20 mL) is added dropwise BrCN (0.4 mL, 2 eq) in CH3CN (1.2 mL) at 25 °C. The mixture is stirred for 16 h at 25 °C. The mixture is filtered. The solid is washed with water (5 mL) and dried under vacuum to give the title compound (0.41 g, yield: 80%) as a white solid, which is used in the next step. LC-MS (ESI): m / z 168.1 [M+H] + .

[0105] c) 2,4-dimethoxy-N-(5-(thiophen-3-yl)-1,3,4-oxadiazol-2-yl)benzamide To a mixture of 5-(thiophen-3-yl)-1,3,4-oxadiazol-2-amine (106 mg, 0.6 mmol), 2,4-dimethoxybenzoic acid (0.1 g, 0.6 mmol) and TEA (0.3 mL, 2.20 mmol) in EtOAc (2 mL), T3P (1.3 mL, 2.20 mmol, 50% in EA, v / v) is added and the mixture is heated to 80° C. for 16 h. The reaction mixture is diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers are dried over Na2SO4, filtered and concentrated under vacuum. The crude product is triturated with CH3CN (1 mL) for 30 min at 25° C., filtered and oven dried (30 min) to give the title compound (25 mg, yield: 13%) as a white solid. LC-MS (ESI): m / z 332.1 [M+H] + . 1 H NMR(DMSO-d6,400MHz):δ 11.02(s,1H),8.30(dd,J=2.9,1.2Hz,1H),7.83(dd,J=5.0,2.9Hz,1H),7.78(d,J=8.6Hz,1H),7. 61(dd,J=5.1,1.3Hz,1H),6.66-6.77(m,2H),3.94(s,3H),3.87(s,3H),3.83(s,1H),3.81(s,1H).

[0106] The following compounds are synthesized according to the procedures described in Example 5: JPEG0007664642000043.jpg227160JPEG0007664642000044.jpg245160JPEG0007664642000045.jpg149160

[0107] Example 6 JPEG0007664642000046.jpg55129 N-(6-(furan-2-yl)pyridazin-3-yl)-2,4-dimethoxybenzamide

[0108] a) N-(6-chloropyridazin-3-yl)-2,4-dimethoxybenzamide A solution of 6-chloropyridazin-3-amine (350 mg, 2.7 mmol) in pyridine (10 mL) is added dropwise to a solution of 2,4-dimethoxybenzoyl chloride (813 mg, 4.05 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture is stirred overnight at room temperature. The mixture is poured into ice water (10 mL), followed by extraction with DCM (10 mL x 2). The combined organic layers are washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / EtOAc = 3:1 to 1:1) to give the title compound (261 mg, yield: 32%).

[0109] b) N-(6-(furan-2-yl)pyridazin-3-yl)-2,4-dimethoxybenzamide Under nitrogen gas atmosphere, Na2CO3 (173 mg, 1.64 mmol) and Pd(PPh3)4 (31 mg, 0.3 mmol) are added to a mixture of N-(6-chloropyridazin-3-yl)-2,4-dimethoxybenzamide (401 mg, 1.37 mmol) and furan-2-ylboronic acid (183 mg, 1.64 mmol) in DMF / H2O (3:2, 10 mL). The reaction mixture is stirred overnight at 90°C. Water (10 mL) is added and the resulting mixture is extracted with EtOAc (20 mL x 2). The combined organic layer is washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / EtOAc / DCM = 2:1:0.5) to give the title compound (95 mg, yield: 21%) as a white solid. LC-MS(ESI):m / z 326.1[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ 10.85(s,1H),8.55(d,J=9.2Hz,1H),8.08(d,J=9.6Hz,1H),7.98-7.95(m ,2H),7.27(d,J=3.2Hz,1H),6.80-6.74(m,3H),4.07(s,3H),3.88(s,3H).

[0110] Example 7 JPEG0007664642000047.jpg62142 4-(Benzyloxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0111] a) 4-(benzyloxy)-2-hydroxybenzoic acid methyl ester To a solution of methyl 2,4-dihydroxybenzoate (2.0 g, 11.9 mmol) in DMF (20 mL) is added K2CO3 (4.94 g, 35.7 mmol) at 5°C. The mixture is stirred at room temperature for 1 h, and BnBr (2.43 g, 14.2 mmol) is added dropwise at 5°C. The reaction mixture is stirred at room temperature overnight. The mixture is diluted with ethyl acetate (20 mL), washed with brine (50 mL x 3), and the combined organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by silica gel column chromatography (PE / EA = 100:1 to 10:1) to give the title compound (2.3 g, yield: 74%) as a white solid.

[0112] b) 4-(benzyloxy)-2-methoxybenzoic acid methyl ester To a solution of methyl 4-(benzyloxy)-2-hydroxybenzoate (2.3 g, 8.9 mmol) in anhydrous DMF (10 mL) is added NaH (60% in mineral oil, 535 mg, 13.8 mmol) in portions at 0° C., and the mixture is stirred for 10 min at 0° C. Iodomethane (3.16 g, 22.3 mmol) is added dropwise at 0° C. The reaction mixture is stirred overnight at room temperature. The reaction is quenched with ice water (50 mL) to obtain a solid. The solid is filtered and collected, washed with water, and dried under vacuum to obtain the title compound (2.4 g, yield: 97%) as a white solid.

[0113] c) 4-(benzyloxy)-2-methoxybenzoic acid To a solution of methyl 4-(benzyloxy)-2-methoxybenzoate (2.4 g, 8.8 mmol) in THF (10 mL) is added anhydrous NaOH (4 M, 7 mL, 22 mmol) at 0 °C. The reaction mixture is refluxed for 4 h. THF is evaporated and the pH of the mixture is adjusted to 3-4 with dilute aqueous HCl. The mixture is extracted with ethyl acetate (20 mL x 3). The combined organic layers are washed with 0.6 N aqueous HCl (20 mL), dried over Na2SO4, filtered and evaporated to give the title compound as a white solid (2.2 g, yield: 96%).

[0114] d) 2-Methoxy-4-((4-methoxybenzyl)oxy)benzoyl chloride To a solution of 2-methoxy-4-((4-methoxybenzyl)oxy)benzoic acid (491 mg, 1.9 mmol) in DCM (30 mL) under N2 at 0° C., add DMF (2 mL) and oxalyl chloride (4.0 g, 38 mmol). Stir the reaction mixture at room temperature for 30 min. Evaporate the solvent to give the title compound, which is used in the next step without further purification.

[0115] e) 4-(benzyloxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (200 mg, 1.19 mmol) in THF (15 mL) under N2 at 0° C., add NaH (191 mg, 4.76 mmol). Stir the reaction mixture at room temperature for 30 min, and add 4-(benzyloxy)-2-methoxybenzoyl chloride (509 mg, 1.89 mmol) to the mixture at 0° C. Stir the reaction mixture overnight at room temperature. Quench the mixture with water (15 mL) and extract with ethyl acetate (15 mL×2). Wash the combined organic layers with brine (40 mL), dry over Na2SO4, filter and evaporate. Purify the residue by preparative HPLC to give the title compound (24 mg, yield: 15%) as a white solid. LCMS (ESI): m / z 406.0 [M+H] + . 1HNMR (300MHz, DMSO-d6): δ 7.93 (d, J = 6.8 Hz, 1H), 7.77-7.74 (m, 2H), 7.50-7.28 (m, 6H), 6.82-6.76 (m, 2H), 5.23 (s, 2H), 3.91 (s, 3H).

[0116] Example 8 JPEG0007664642000048.jpg77155 4-Hydroxy-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0117] a) 2-Hydroxy-4-((4-methoxybenzyl)oxy)benzoic acid methyl ester To a solution of methyl 2,4-dihydroxybenzoate (10.0 g, 59.5 mmol) in DMF (150 mL) is added K2CO3 (9.0 g, 65.5 mmol) at 5°C. The mixture is stirred at room temperature for 1 h, and PMBCl (9.32 g, 59.5 mmol) is added dropwise at 5°C. The reaction mixture is stirred at room temperature overnight. The mixture is diluted with ethyl acetate (200 mL) and washed with brine (25 mL x 3). The organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by silica gel column chromatography (PE / EA = 100:1 to 10:1) to give the title compound (3.12 g, yield: 16%) as a grey solid. LCMS (ESI-MS): m / z 289.1 [M+H] + .

[0118] b) 2-Methoxy-4-((4-methoxybenzyl)oxy)benzoic acid methyl ester To a solution of methyl 2-hydroxy-4-((4-methoxybenzyl)oxy)benzoate (3.0 g, 10.40 mmol) in anhydrous DMF (40 mL) at 0° C., add NaH (625 mg, 15.6 mmol) in portions and stir the mixture at 0° C. for 10 min. Add iodomethane (3.7 g, 26 mmol) dropwise at 0° C. and stir the reaction mixture at room temperature overnight. Quench the reaction with ice water (50 mL) and collect the resulting solid by filtration. Wash the solid with water and dry under vacuum to give the title compound (2.6 g, yield: 86%) as a white solid. LCMS (ESI-MS): m / z 303.1 [M+H] + .

[0119] c) 2-Methoxy-4-((4-methoxybenzyl)oxy)benzoic acid To a solution of methyl 2-methoxy-4-((4-methoxybenzyl)oxy)benzoate (2.6 g, 8.6 mmol) in THF (10 mL) at 0 °C, add anhydrous NaOH (4 M, 2 mL, 34.4 mmol). Reflux the reaction mixture for 4 h. Evaporate the solvent and adjust the pH of the mixture to 5-6 with dilute aqueous HCl. Extract the mixture with ethyl acetate (50 mL x 3). Wash the combined organic layers with 0.6 N aqueous HCl (100 mL), dry over Na2SO4, filter and evaporate to give the title compound (1.6 g, yield: 65%) as a white solid. LCMS (ESI-MS): m / z 289.1 [M+H] + .

[0120] d) 2-Methoxy-4-((4-methoxybenzyl)oxy)benzoyl chloride To a solution of 2-methoxy-4-((4-methoxybenzyl)oxy)benzoic acid (200 mg, 1.03 mmol) in dichloromethane (20 mL) at 0° C. under N2, add DMF (2 μL) and oxalyl chloride (1.7 g, 13.8 mmol). The reaction mixture is stirred at room temperature for 30 min. The solvent is evaporated to give the title compound, which is used in the next step without further purification.

[0121] e) 2-Methoxy-4-((4-methoxybenzyl)oxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (116 mg, 0.69 mmol) in THF (5 mL) under N2 at 0° C., add NaH (60% in mineral oil, 110 mg, 2.76 mmol). Stir the reaction mixture at room temperature for 30 min, add 2-methoxy-4-((4-methoxybenzyl)oxy)benzoyl chloride (211 mg, 0.69 mmol) to the mixture at 0° C. Stir the reaction mixture overnight at room temperature. Quench the mixture with water (10 mL) and extract with ethyl acetate (10 mL×2). Wash the combined organic layers with brine (20 mL), dry over Na2SO4, filter and evaporate. Purify the residue by preparative HPLC to give the title compound (60 mg, yield: 20%) as a white solid. LCMS (ESI-MS): m / z 438.1 [M+H] + .

[0122] f) 4-hydroxy-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 2-methoxy-4-((4-methoxybenzyl)oxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (60 mg, 0.14 mmol) in DCM (2 mL) is added trifluoroacetic acid (2 mL) at room temperature. The reaction mixture is stirred at room temperature for 1 h. Evaporate the DCM under reduced pressure to give the title compound (18 mg, yield: 42%) as a white solid. LCMS (ESI-MS): m / z 318.1 [M+H] + . 1HNMR(300MHz,DMSO-d6):δ 10.89(s,1H),10.41(s,1H),7.94-7.92(m,1H),7.77-7.69(m,2H),7.31-7.26(m,1H),6.58-6.49(m,2H),3.89(s,3H).

[0123] Example 9 JPEG0007664642000049.jpg53144 4-(2-hydroxyethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0124] a) 4-(2-(benzyloxy)ethoxy)-2-hydroxybenzoic acid methyl ester To a solution of methyl 2,4-dihydroxybenzoate (5.0 g, 30 mmol) in DMF (100 mL) is added K2CO3 (4.3 g, 30 mmol) at 5°C. The mixture is stirred at room temperature for 1 h, and ((2-bromoethoxy)methyl)benzene (6.4 g, 30 mmol) is added dropwise at 5°C. The reaction mixture is stirred at room temperature overnight. The mixture is diluted with ethyl acetate (60 mL) and then washed with brine (200 mL x 3). The combined organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by silica gel column chromatography (PE / EA = 100:1 to 10:1) to give the title compound (2.16 g, yield: 24%) as a white solid.

[0125] b) 4-(2-(benzyloxy)ethoxy)-2-methoxybenzoate methyl To a solution of methyl 4-(2-(benzyloxy)ethoxy)-2-hydroxybenzoate (1.8 g, 5.7 mmol) in MeOH (5 mL) at room temperature, Pd / C (5%, 180 mg, 0.57 mmol) is added. The reaction mixture is stirred at room temperature under hydrogen balloon pressure for 12 h. The reaction mixture is filtered and the filtrate is collected. The solvent in the filtrate is evaporated to give the title compound (900 mg, yield: 70%) as a white solid, which is used in the next step without further purification.

[0126] c) 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxybenzoate methyl To a solution of methyl 4-(2-(benzyloxy)ethoxy)-2-methoxybenzoate (900 mg, 3.96 mmol) in anhydrous THF (30 mL) at 0° C., add imidazole (320 mg, 4.7 mmol). Add TBSCl (661 mg, 4.38 mmol) and stir the mixture at room temperature overnight. Quench the reaction with water (10 mL) and extract with EA (10 mL×2). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (680 mg, yield: 50%) as a white solid. LCMS (ESI-MS): m / z 327.1 [M+H] + .

[0127] d) 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxybenzoic acid To a solution of methyl 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxybenzoate (680 mg, 2 mmol) in THF (10 mL) at 0 °C, add anhydrous NaOH (4 M, 2 mL, 8 mmol). Reflux the reaction mixture for 4 h. Evaporate the solvent and adjust the pH of the mixture to 5-6 with dilute aqueous HCl. Extract the mixture with ethyl acetate (10 mL x 3). The combined organic layers are washed with 0.6 N aqueous HCl (20 mL), dried over Na2SO4, filtered and evaporated to give the title compound (450 mg, yield: 66%) as a white solid, which is used in the next step without further purification.

[0128] e) 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxybenzoyl chloride To a solution of 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxybenzoic acid (350 mg, 1.07 mmol) in DCM (10 mL) under N2 at 0° C., add DMF (2 mL) and oxalyl chloride (2.73 g, 21.5 mmol). Stir the reaction mixture at room temperature for 30 min. Evaporate the solvent under reduced pressure to give the title compound, which is used in the next step without further purification.

[0129] f) 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (112 mg, 0.68 mmol) in THF (5 mL) under N2 at 0° C., add NaH (60% in mineral oil, 70 mg, 2.72 mmol). Stir the reaction mixture at room temperature for 30 min, add 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxybenzoyl chloride (370 mg, 1.07 mmol) to the mixture at 0° C. Stir the reaction mixture overnight at room temperature. Quench the mixture with water (5 mL) and extract the mixture with ethyl acetate (10 mL×2). Wash the combined organic layers with brine (30 mL), dry over Na2SO4, filter and evaporate. Purify the residue by preparative HPLC to give the title compound (20 mg, yield: 17%) as a white solid.

[0130] g) 4-(2-hydroxyethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 4-(2-((t-butyldimethylsilyl)oxy)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (20 mg, 0.04 mmol) in DCM (2 mL) is added TFA (2 mL) at room temperature for 12 h. The reaction is filtered and the solvent in the filtrate is evaporated under reduced pressure to give the title compound (7 mg, yield: 46%) as a white solid. LCMS (ESI-MS): m / z 360.1 [M+H] +. 1HNMR(400MHz,DMSO-d6):δ 11.06(s,1H),7.95(s,1H),7.78-7.75(m,2H),7.31-7.29(m,1H),6.72-6.69(m,2 H),4.92(t,J=5.6Hz,1H),4.12(t,J=4.8Hz,2H),3.93(s,3H),3.77-3.74(m,2H).

[0131] Example 10 JPEG0007664642000050.jpg56160 4-(2-(benzyloxy)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0132] a) 4-(2-(benzyloxy)ethoxy)-2-hydroxybenzoic acid methyl ester To a solution of methyl 2,4-dihydroxybenzoate (5.0 g, 30 mmol) in DMF (100 mL) is added K2CO3 (4.3 g, 3 mmol) at 5 °C. The mixture is stirred at room temperature for 1 h, and ((2-bromoethoxy)methyl)benzene (6.4 g, 30 mmol) is added dropwise at 5 °C. The reaction mixture is stirred at room temperature overnight. The mixture is diluted with ethyl acetate (60 mL), then washed with brine (200 mL × 3), the combined organic layer is dried over Na2SO4, filtered, and the solvent is evaporated. The residue is purified by silica gel column chromatography (PE / EA = 100:1 to 10:1) to give the title compound (2.16 g, yield: 24%) as a white solid.

[0133] b) 4-(2-(benzyloxy)ethoxy)-2-methoxybenzoic acid To a solution of methyl 4-(2-(benzyloxy)ethoxy)-2-methoxybenzoate (2.16 g, 7.1 mmol) in THF (50 mL) at 0 °C, add anhydrous NaOH (5 mL, 1.14 g, 28.5 mmol). Reflux the reaction mixture for 4 h. Evaporate THF under reduced pressure and adjust the pH of the mixture to 5-6 with dilute HCl. Extract the mixture with EA (50 mL x 3). Wash the combined organic layers with aqueous HCl (0.6 N, 100 mL), dry over Na2SO4, filter and evaporate to give the title compound (1.8 g, yield: 63%) as a white solid. LCMS (ESI-MS): m / z 303.1 [M+H] + .

[0134] c) 4-(2-(benzyloxy)ethoxy)-2-methoxybenzoyl chloride To a solution of 4-(2-(benzyloxy)ethoxy)-2-methoxybenzoic acid (300 mg, 1.03 mmol) in DCM (20 mL) under N2 at 0° C., add DMF (2 mL) and (COCl)2 (2.5 g, 20.7 mmol). The reaction mixture is stirred at room temperature for 30 min. The DCM is evaporated to give the title compound, which is used in the next step without further purification.

[0135] d) 4-(2-(benzyloxy)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (534 mg, 1.67 mmol) in THF (20 mL) under N2 at 0° C., add NaH (60% in mineral oil, 166 mg, 4.16 mmol). Stir the reaction mixture for 30 min at room temperature, and add 4-(2-(benzyloxy)ethoxy)-2-methoxybenzoyl chloride (280 mg, 1.67 mmol) to the mixture at 0° C. After addition, stir the reaction mixture overnight at room temperature. Quench the mixture with water (10 mL) and extract with EA (20 mL×2). Wash the combined organic layers with brine (40 mL), dry over Na2SO4, filter and evaporate. Purify the residue by preparative HPLC to give the title compound (40 mg, yield: 5%) as a white solid. LCMS(ESI-MS): m / z 452.1[M+H] + . 1HNMR(300MHz,DMSO-d6):δ11.08(s,1H),7.93(d,J=4.5Hz,1H),7.78-7.75(m,2H),7.37-7.2 7(m,6H),6.74-6.68(m,2H),4.58(s,2H),4.45-4.39(m,2H),3.92(s,3H),3.82-3.76(m,2H).

[0136] Example 11 JPEG0007664642000051.jpg55152 2-(3-Methoxy-4-((5-(thiophen-2-yl)-1,3,4- Oxadiazol-2-yl)carbamoyl)phenoxy)acetic acid

[0137] a) 2-Methoxy-4-(2-oxoethoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 4-(2,3-dihydroxypropoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (47 mg, 0.12 mmol) in dichloromethane (2 mL) is added NaIO4 (34 mg, 0.16 mmol) and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate (30 mL x 3). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (60 mg, 100%) as a white solid, which is used in the next step without further purification.

[0138] b) 2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)acetic acid To a solution of 2-methoxy-4-(2-oxoethoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (60 mg, 0.17 mmol) in acetone (2 mL) is added NaClO2 (104 mg, 0.92 mmol) and NaH2PO4 (61 mg, 0.50 mmol). The mixture is stirred at room temperature for 12 h. The reaction mixture is extracted with ethyl acetate (30 mL x 3). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by preparative HPLC to give the title compound (4 mg, yield: 6%) as a white solid. LCMS (ESI-MS): m / z 376.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6):δ 13.10(s,br,1H),11.40(s,1H),7.93(d,J=8Hz,1H),7.60(d,J=8Hz,1H),7.20(d,J=8Hz ,1H),7.29(d,J=8.0Hz,1H),6.74(s,1H),6.70-.6.64(m,1H),4.80(s,2H),3.91(s,3H).

[0139] Example 12 JPEG0007664642000052.jpg59150 4-(2-(dimethylamino)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0140] To a solution of 2-methoxy-4-(2-oxoethoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (50 mg, 0.14 mmol) in DCM (2 mL) is added dimethylamine (0.4 mL, 0.70 mmol) and acetic acid (0.1 mL). The mixture is reacted at room temperature for 1 h. NaBH(OAc)3 (45 mg, 0.21 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate (30 mL x 3). The combined organic layers are washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue is purified by preparative HPLC to give the title compound (4 mg, yield: 7%) as a white solid. LCMS (ESI-MS): m / z 388.9 [M+H] + . 1 H NMR(400MHz,CD3OD):δ 8.04(d,J=8.4Hz,1H),7.85-7.79(m,2H),7.28(t,J=4.8Hz,1H),6.83-6.81(m ,2H),4.51(t,J=4.4Hz,1H),4.10(s,3H),3.68(t,J=4.4Hz,2H),3.05(s,6H).

[0141] Example 13 JPEG0007664642000053.jpg62149 2-(3-Methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)-2-methylpropionic acid

[0142] a) Ethyl 2-(4-formyl-3-methoxyphenoxy)-2-methylpropionate To a suspension of 4-hydroxy-2-methoxybenzaldehyde (0.04 mL, 0.3 mmol) and ethyl 2-bromo-2-methylpropionate (0.14 mL, 0.99 mmol) in DMF (1 mL) at 25 °C, add Cs2CO3 (321.22 mg, 0.99 mmol). The reaction is stirred at 50 °C for 16 h. The mixture is diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers are dried over MgSO4 and filtered. The filtrate is concentrated under vacuum. The residue is dissolved in DCM (1 mL), washed with NaOH (1 M, 1 mL x 3), the combined organic layers are separated and the solvent is removed under vacuum to give the title compound (50 mg, 51%) as a yellow oil. LC-MS (ESI): m / z 267.0 [M+H]+ .

[0143] b) 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-2-methoxybenzoic acid To a solution of ethyl 2-(4-formyl-3-methoxyphenoxy)-2-methylpropionate (50 mg, 0.17 mmol) in t-BuOH (1.50 mL) at 25° C., add H2O (0.67 mL) containing NaClO2 (141 mg, 1.6 mmol) and NaH2PO4 (120 mg, 1.1 mmol). The mixture is stirred at 25° C. for 16 h. The mixture is a yellow solution. The mixture is diluted with H2O (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers are dried over MgSO4, filtered and the filtrate is concentrated under vacuum to give the title compound (35 mg, yield: 66%) as a yellow solid. LC-MS (ESI): m / z 238.2 [M+H] + .

[0144] c) Ethyl 2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)-2-methylpropionate To a suspension of 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-2-methoxybenzoic acid (35 mg, 0.11 mmol), 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (28 mg, 0.17 mmol) and TEA (60 mL, 0.45 mmol) in ethyl acetate (1 mL) at 25° C., add T3P (266 mL, 0.45 mmol) and stir the reaction mixture at 80° C. for 16 h. Dilute the mixture with H2O (1 mL) and extract with ethyl acetate (2 mL×3). Dry the combined organic layers over MgSO4, filter and concentrate the filtrate under vacuum to give the title compound (65 mg, yield: 68%) as a yellow oil. LC-MS (ESI): m / z 432.2 [M+H] + .

[0145] d) 2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)-2-methylpropionic acid To a solution of ethyl 2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)-2-methylpropionate (65 mg, 0.075 mmol) in THF (0.5 mL) and HO (0.5 mL) at 25 °C, add LiOH (7.33 μL, 0.26 mmol). Stir the mixture for 16 h at 50 °C. Remove the solvent in vacuum. Dissolve the residue in HO (3 mL) and adjust the pH of the mixture to 4 with 1 N aqueous HCl. The mixture is purified by preparative HPLC (column: Phenomenex Gemini C18 250×50 mm×10 um, mobile phase: [water (0.225% FA)-ACN], B%: 38%-58%, 10 min) to give the title compound as a white solid (5 mg, yield: 16%). LC-MS (ESI): m / z 404.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.17(br s,1H),7.94(d,J=4.0Hz,1H),7.76(d,J=2.7Hz,1H),7.69(d,J=8.7Hz,1H),7.29(dd,J=3.8 ,4.9Hz,1H),6.61(d,J=2.1Hz,1H),6.48(dd,J=2.2,8.7Hz,1H),3.87(s,3H),1.59(s,6H).

[0146] Example 14 JPEG0007664642000054.jpg59155 4-((2H-tetrazol-5-yl)methoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0147] a) Methyl 4-(cyanomethoxy)-2-hydroxybenzoate To a solution of methyl 2,4-dihydroxybenzoate (5.0 g, 30 mmol) and K2CO3 (4.32 g, 31 mmol) in DMF (50 mL) at 0° C., add 2-bromoacetonitrile (3.57 g, 30 mmol). Stir the mixture for 12 h at 25° C. under nitrogen gas atmosphere. Filter the mixture and concentrate the solvent under vacuum. Purify the residue by flash silica gel chromatography (ISCO®, 80 g sepaFlash® silica gel flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give the title compound (1.6 g, yield: 26%) as a white solid. LC-MS (ESI): m / z 207.9 [M+H] + .

[0148] b) 4-(cyanomethoxy)-2-methoxybenzoic acid methyl ester To a solution of methyl 4-(cyanomethoxy)-2-hydroxybenzoate (1.0 g, 4.8 mmol) in DMF (20 mL) at 0° C., add NaH (60% in mineral oil, 0.25 g, 6.3 mmol). Stir the solution at 25° C. for 30 min and add iodomethane (0.89 g, 6.3 mmol) dropwise at 0° C. The reaction is stirred for 12 h at 25° C. under N2. Add water (60 mL) and extract the mixture with EtOAc (60 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the title compound (1.05 g, 98%) as a brown oil. LC-MS (ESI): m / z 222.1 [M+H] + .

[0149] c) 4-((2H-tetrazol-5-yl)methoxy)-2-methoxybenzoic acid methyl ester To a solution of methyl 4-(cyanomethoxy)-2-methoxybenzoate (1.0 g, 4.5 mmol) and azidotrimethylsilane (1.0 g, 9.0 mmol) in toluene (20 mL) at 0° C., dibutylstannanone (225 mg, 0.90 mmol) is added. The mixture is stirred for 12 h at 120° C. under N2. The mixture is concentrated to about 3 mL, PE (12 mL) and MTBE (3 mL) are added, and stirred for 3 h at 25° C. to give a white suspension. The solid is filtered to give the title compound (1.0 g, 84%) as a white solid. LC-MS (ESI): m / z 264.9 [M+H] + .

[0150] d) 4-((2H-tetrazol-5-yl)methoxy)-2-methoxybenzoic acid To a solution of methyl 4-((2H-tetrazol-5-yl)methoxy)-2-methoxybenzoate (100 mg, 0.38 mmol) in THF (1 mL) is added 1 M anhydrous LiOH (0.8 mL, 0.8 mmol). The reaction is stirred under N2 at 50 °C for 12 h. The mixture is concentrated and the pH of the residue is adjusted to 3-4 with 1 M aqueous HCl to give a solid. The solid is filtered to give the title compound (70 mg, 73.9%) as a white solid. LC-MS (ESI): m / z 251.1 [M+H] + .

[0151] e) 4-((2H-tetrazol-5-yl)methoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 4-((2H-tetrazol-5-yl)methoxy)-2-methoxybenzoic acid (50 mg, 0.20 mmol), 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (67 mg, 0.40 mmol) and TEA (0.11 mL, 0.8 mmol) in ethyl acetate (5 mL) is added T3P (50% in EA, 1.0 mL, 1.6 mmol) at 0 °C. The mixture is stirred for 12 h at 80 °C under N2. Water (20 mL) is added and the mixture is extracted with EtOAc (30 mL x 3). The combined organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by preparative HPLC (column: Boston Uni C18 40×150×5um, mobile phase: water (0.225% FA)-ACN, B%: 18%-58%, 10min) to give the title compound as a yellow solid (6mg, yield: 7.5%). LC-MS(ESI): m / z 400.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.99-7.91(m,1H),7.76(d,J=3.5Hz,1H),7.38(d,J=3.1Hz,1H),7.33-7.26(m,2H),7.17(d,J=9.0Hz,1H),5.45(s,2H),3.85(s,3H).

[0152] Example 15 JPEG0007664642000055.jpg47143 2-Methoxy-4-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-2H-tetrazol-5-yl)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide JPEG0007664642000056.jpg53142 2-Methoxy-4-((1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-tetrazol-5-yl)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0153] To a solution of 4-((2H-tetrazol-5-yl)methoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (20 mg, 0.05 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (5 μL, 0.045 mmol) in acetonitrile (1 mL) is added K2CO3 (8 mg, 0.06 mmol) and KI (5 mg, 0.03 mmol). The mixture is stirred for 1.5 h at 50 °C under N2. A second portion of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (5 μL, 0.045 mmol) in acetonitrile (1 mL) is added and the reaction is stirred for 1.5 h at 50 °C. A third portion of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (5 μL, 0.045 mmol) in acetonitrile (1 mL) is added and the reaction is stirred at 50 °C for 16 h. The mixture is diluted with acetonitrile (10 mL) and filtered. The solvent is removed under N2. The residue is purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 7 um, mobile phase: [water (0.225% FA)-ACN], B%: 38%-58%, 10 min) to give two isomeric products in two fractions. Isomer 1 (HPLC: RT = 3.97 min, 4 mg, yield: 15%), LC-MS (ESI): m / z 512.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.93(d,J=5.1Hz,1H),7.73(br d,J=3.1Hz,1H),7.40(d,J=2.6Hz,1H),7.33-7.23(m,2H),7.21-7.13(m,1H),5.80(s,2H),5.57( s,2H),3.84(s,3H),2.18(s,3H), and isomer 2 (HPLC: RT=4.08min, 3mg, yield 12%), white solid, LC-MS (ESI): m / z 512.2[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 7.92(br d,J=4.9Hz,1H),7.73(br s,1H),7.34(br s,1H),7.31-7.20(m,2H),7.17-7.11(m,1H),6.03(s,2H),5.41(s,2H),3.83(s,3H),2.27(s,3H).

[0154] Example 16 JPEG0007664642000057.jpg64152 4-(3-cyanopropyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0155] a) 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine To a mixture of thiophene-2-carbohydrazide (10.5 g, 66.5 mmol) in H2O (500 mL) is added dropwise BrCN (9.78 mL, 133 mmol) in acetonitrile (20 mL) at 25 °C. The mixture is stirred for 16 h at 25 °C. The mixture is filtered and the white solid is washed with water to give the title compound (4.8 g, yield: 30%) as a yellow solid. LC-MS (ESI): m / z 168.0 [M+H] + .

[0156] b) 4-Bromo-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a suspension of 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (500 mg, 2.84 mmol), 4-bromo-2-methoxybenzoic acid (984 mg, 4.26 mmol) and trimethylamine (1.58 mL, 11.4 mmol) in ethyl acetate (20 mL) at 25° C., add T3P (3.38 mL, 11.4 mmol) and stir the reaction mixture at 80° C. for 16 h. Dilute the mixture with H2O (10 mL) and extract with ethyl acetate (10 mL×3). The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue is washed with ethyl acetate (3 mL) and the solid is collected to give the title compound (730 mg, yield: 64%) as a yellow solid. LC-MS (ESI): m / z 380.0 [M+H] + .

[0157] c) 4-(3-cyanopropyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide To a mixture of 4-bromo-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (200 mg, 0.5 mmol) and (3-cyanopropyl)zinc(II) bromide (1 mL, 0.5 M solution in THF, 1.05 mmol) in THF (4 mL) at 25 °C under N2, add Pd(PPh3)4 (30 mg, 0.03 mmol). Stir the mixture in a microwave at 100 °C for 30 min. Filter the mixture through silica and remove the solvent under vacuum. Purify the residue by preparative HPLC (column: Phenomenex Gemini-NX 150 × 30 mm × 5 um, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 30%-70%, 10 min) to obtain a solid. The solid is washed with ethyl acetate (3 mL) and the solid is collected to give the title compound as a white solid (21 mg, yield: 11%). LC-MS (ESI): m / z 369.0 [M+H] + . 1 H NMR(DMSO-d6,400MHz):δ 11.40(br s,1H),7.93(d,J=4.9Hz,1H),7.74(d,J=3.0Hz,1H),7.63(d,J=8.0Hz,1H),7.28(t,J=4.3Hz,1H),7.08(s,1H),6.95(br d,J=8.3Hz,1H),3.90(s,3H),2.74(br t,J=7.7Hz,2H),2.54(br s,2H),1.84-1.99(m,2H).

[0158] Example 17 JPEG0007664642000058.jpg57151 4-(3-(2H-tetrazol-5-yl)propyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0159] To a solution of 4-(3-cyanopropyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (200 mg, 0.2 mmol) and Bu2SnO (7.21 mL, 43 mmol) in toluene (2 mL) at 25 °C, add TMSN3 (50 mg, 0.4 mmol). Stir the mixture at 120 °C for 16 h. Remove the solvent from the mixture under vacuum, dissolve in DMSO (2 mL), and purify by preparative HPLC (column: Phenomenex Gemini-NX 150 x 30 mm x 5 um, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 30%-70%, 10 min) to obtain the title compound (4.6 mg, 5.1%) as a white solid. LC-MS(ESI): m / z 412.1[M+H] + . 1 H NMR(DMSO-d6,400MHz):δ 7.93(d,J=5.0Hz,1H),7.75(d,J=3.3Hz,1H),7.64(d,J=8.0Hz,1H),7.24-7.34(m,1H),7.07(s,1H), 6.96(d,J=8.0Hz,1H),3.90(s,3H),2.90(br,t,J=7.5Hz,2H),2.64-2.76(m,2H),2.01-2.12(m,2H).

[0160] Example 18 JPEG0007664642000059.jpg61143 cis-4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid JPEG0007664642000060.jpg65150 trans-4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid

[0161] a) 4'-(ethoxycarbonyl)-3-methoxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid To a suspension of 4-bromo-2-methoxybenzoic acid (300 mg, 1.3 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (437 mg, 1.56 mmol) and K2CO3 (0.40 mL, 3.9 mmol) in dioxane (13 mL) and H2O (1.3 mL) at 25 °C under N2, add Pd(dppf)Cl2·CH2Cl2 (530 mg, 0.65 mmol). Stir the mixture for 16 h at 105 °C. Filter the mixture and wash the filter cake with ethyl acetate (5 mL x 2). Extract the filtrate with ethyl acetate (5 mL x 3) and dry the combined organic layers over MgSO4, filter and concentrate under vacuum. The residue is washed with ethyl acetate (3 mL) and the solid is filtered to give the title compound as a brown solid (200 mg, yield: 38%). LC-MS (ESI): m / z 305.2 [M+H] + .

[0162] b) 4-(4-(ethoxycarbonyl)cyclohexyl)-2-methoxybenzoic acid To a suspension of 4'-(ethoxycarbonyl)-3-methoxy-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (20 mg, 0.05 mmol) in DCM (3 mL) is added triethylsilane (74 mL, 0.46 mmol), trifluoroacetic acid (17 mL, 0.23 mmol) and Pd(OAc)2 (15 mg, 0.07 mmol) at 25° C. and stirred for 16 h at 25° C. The mixture is filtered and washed with DCM (2 mL). The solvent is removed under vacuum to give the title compound (26 mg, 92% yield) as a yellow oil. LC-MS (ESI): m / z 307.2 [M+H] + .

[0163] c) Ethyl 4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylate To a suspension of 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (20 mg, 0.12 mmol), 4-(4-(ethoxycarbonyl)cyclohexyl)-2-methoxybenzoic acid (55 mg, 0.14 mmol) and triethylamine (66 mL, 0.5 mmol) in ethyl acetate (1 mL) at 25° C., add T3P (285 mL, 0.5 mmol). Stir the reaction mixture for 16 h at 80° C. Dilute the mixture with H2O (3 mL), extract the mixture with ethyl acetate (3 mL×3), dry the combined organic layers over MgSO4, filter and concentrate under vacuum to give the title compound (80 mg, yield: 88%) as a yellow oil. LC-MS (ESI): m / z 456.2 [M+H] + .

[0164] d) 4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid To a solution of ethyl 4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylate (80 mg, 0.11 mmol) in THF (0.5 mL) and HO (0.5 mL) at 25° C., add LiOH (1 mg, 0.367 mmol). Stir the mixture for 16 h at 50° C. Remove the solvent in vacuum and dissolve the residue in HO (3 mL). The pH of the mixture was adjusted to 4-5 by adding 1N HCl aqueous solution, and the mixture was purified by preparative HPLC (column: Phenomenex Gemini-NX 150×30 mm×5 um, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 0%-40%, 10 min) to give the title compound as a white solid as a pair of separated positional isomers, white solid isomer 1 (HPLC: RT=4.06 min, 5.8 mg, yield: 11%): LC-MS (ESI): m / z 428.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ=7.84(br s,1H),7.70(br s,1H),7.62(s,1H),7.26(t,J=4.4Hz,1H),6.95(s,2H),3.87(s,3H),2.10-2.10(m,1H),2.07(br s,1H),1.91(s,1H),1.63-1.42(m,6H),1.27(s,2H), and isomer 2 (HPLC: RT=4.16min, 5mg, yield: 10%):LC-MS(ESI):m / z 428.2[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.85(s,1H),7.71(s,1H),7.64(s,1H),7.26(d,J=5.0Hz,1H),6.94(s,2H),3.90(br s,3H),2.15(br s,2H),1.79-1.63(m,6H),1.27(br s,2H).

[0165] Example 19 JPEG0007664642000061.jpg68138 3'-Methoxy-4'-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid

[0166] To a solution of ethyl 3'-methoxy-4'-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate (20 mg, 0.04 mmol) in HO (0.25 mL) and THF (0.25 mL) at 25° C., add LiOH (5.18 mg, 0.12 mmol) and stir the mixture for 16 h at 50° C. Evaporate the solvent under vacuum and dissolve the residue in HO (3 mL). The pH of the mixture is adjusted to pH=4, and the mixture is purified by preparative HPLC (column: Diamonsil C18 150×30mm×5um, mobile phase: [water (0.225% FA)-ACN], B%: 38%-78%, 10min) to give the title compound as a white solid (3.2mg, yield: 21%). LC-MS(ESI): m / z 426.0[M+H] + . 1H NMR(DMSO-d6,400MHz):δ 7.94(d,J=3.9Hz,1H),7.76(d,J=2.6Hz,1H),7.67(d,J=7.9Hz,1H),7.27-7.33(m, 1H),7.12-7.19(m,2H),6.33-6.43(m,1H),3.94(s,3H),2.56-2.65(m,1H),2.46(br s,2H),2.36-2.42(m,1H),2.11(br d,J=12.0Hz,1H),1.73(br s,1H).

[0167] Example 20 JPEG0007664642000062.jpg67133 (3-Methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)proline

[0168] To a suspension of 4-bromo-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (20 mg, 0.053 mmol) and proline (0.02 mL, 0.16 mmol) in DMSO (0.5 mL) under N2, CuI (1 mg, 0.005 mmol) and Cs2CO3 (34 mg, 0.1 mmol) are added. The mixture is stirred at 120 °C for 16 h. The mixture is diluted with H2O (2 mL) and extracted with EtOAc (3 mL × 3), and the combined organic layers are dried over MgSO4 and concentrated in vacuum. The residue is purified by preparative HPLC (column: YMC-Actus Triart C18 150×30 mm×7 um, mobile phase: [water (0.225% FA)-ACN], B%: 35%-55%, 10 min) to give the title compound as a yellow solid (3.6 mg, yield: 16%). LC-MS (ESI): m / z 415.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.37(br s,3H),8.02-7.79(m,1H),7.79-7.59(m,2H),7.28(br s,1H),6.43-5.93(m,2H),3.93(br s,3H),3.75(br s,1H),2.21-1.86(m,6H).

[0169] Example 21 JPEG0007664642000063.jpg71149 1-(3-Methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)piperidine-3-carboxylic acid

[0170] To a solution of 4-bromo-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (80 mg, 0.21 mmol), methyl piperidine-3-carboxylate (45 mg, 0.32 mmol) and CsCO (206 mg, 0.63 mmol) in t-amyl alcohol (2.5 mL) under N2 at 25° C., add RuPhos-Pd-G3 (176 mg, 0.21 mmol). The mixture is stirred at 120° C. for 16 h. The solvent is removed under vacuum and the residue is purified by preparative HPLC (column: Phenomenex Gemini-NX 150×30 mm×5 um, mobile phase: [water (0.225% FA)-ACN], B%: 26%-66%, 10 min) to give the title compound as a grey solid (6 mg, yield: 6%). LC-MS (ESI): m / z 429.0 [M+H] + . 1 H NMR(DMSO-d6,400MHz):δ 7.94(d,J=5.0Hz,1H),7.68-7.82(m,2H),7.30(t,J=4.3Hz,1H),6.65(br d,J=8.5Hz,1H),6.56(s,1H),3.96(s,3H),3.91(br d,J=12.4Hz,1H),3.75(br d,J=14.0Hz,1H),3.00-3.24(m,3H),1.94(br s,1H),1.49-1.78 ppm(m,3H).

[0171] Example 22 JPEG0007664642000064.jpg67147 2-((3-Methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)amino)-2-methylpropionic acid

[0172] To a suspension of 4-bromo-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (80 mg, 0.210 mmol) and 2-amino-2-methylpropionic acid (0.04 mL, 0.421 mmol) in DMSO (2 mL) under N2, add CuI (1.00 mg, 0.021 mmol), pyrrolidine-2-carboxylic acid (1.2 mg, 0.042 mmol) and Cs2CO3 (137.11 mg, 0.421 mmol) and stir at 110 °C for 16 h. The mixture is a yellow solution. The mixture is filtered, washed with DMSO (1 mL), and the filtrate is purified by preparative HPLC (column: YMC-Actus Triart C18 150×30 mm×7 um, mobile phase: [water (0.225% FA)-ACN], B%: 23%-63%, 10 min) to give the title compound as a white solid (19 mg, yield: 21%). LC-MS (ESI): m / z 403.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.60(br s,1H),7.93(d,J=5.1Hz,1H),7.77(d,J=3.8Hz,1H),7.64(d,J=8.9Hz,1H),7.29(t,J=4.5Hz,1H),6.28-6.14(m,2H),3.86(s,3H),1.48(s,6H).

[0173] Example 23 JPEG0007664642000065.jpg63134 4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0174] To a solution of 4-bromo-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (65 mg, 0.17 mmol), 6-oxa-3-azabicyclo[3.1.1]heptane 4-methylbenzenesulfonic acid TSOH salt (70 mg, 0.26 mmol) and Cs2CO3 (392 mg, 1.2 mmol) in t-amyl alcohol (2 mL) under N2 at 25 °C, add RuPhos-Pd-G3 (144 mg, 0.17 mmol). The mixture is stirred at 120 °C for 16 h. Remove the solvent under vacuum and purify the residue by preparative HPLC (column: Xtimate C18 100×30 mm×3 um, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN, B%: 41%-81%, 10 min) to obtain the title compound as a yellow solid (17 mg, yield: 24%). LC-MS (ESI): m / z 399.0 [M+H] + . 1 H NMR (DMSO-d6,400MHz):δ 7.65(d,J=5.0Hz,1H),7.52(d,J=8.3Hz,1H),7.45(d,J=3.6Hz,1H),7.13-7.20(m,1H),6.12-6.36(m,2H),4.71(br d,J=6.3Hz,2H),3.73(s,3H),3.57(br d,J=11.4Hz,2H),3.44(br,s,2H),3.07-3.17(m,1H),2.08(s,1H),1.93(d,J=8.8Hz,1H).

[0175] Example 24 JPEG0007664642000066.jpg61140 2-Methoxy-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0176] a) 2-Methoxy-4-morpholinobenzoic acid methyl ester Prepare a solution of methyl 4-fluoro-2-methoxybenzoate (10 g, 54 mmol) in morpholine (38 mL, 434 mmol) and NMP (30 mL) under N2 at 25 °C. Stir the mixture at 145 °C for 16 h. Freeze-dry the mixture to remove the solvent to obtain a residue. Purify the residue by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica gel flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient = 1:2) to obtain the title compound (3.5 g, yield: 18%) as a white solid. LC-MS (ESI): m / z 252.0 [M+H] + .

[0177] b) 2-Methoxy-4-morpholinobenzoic acid LiOH·H2O (12.59 mg, 0.3 mmol) is added in one portion to a solution of methyl 2-methoxy-4-morpholinobenzoate (3.0 g, 8.5 mmol) in a mixed solvent of THF (40 mL) and H2O (40 mL) at 25° C. The reaction mixture is heated to 40° C. for 16 h. The solvent is removed and the residue is acidified to pH=2 with 1N HCl. A solid is formed and collected by filtration. The solid is washed with H2O (10 mL×3) and dried under vacuum to give the title compound (1.2 g, yield: 52%) as a white solid. LC-MS (ESI): m / z 238.1 [M+H] + .

[0178] c) 2-Methoxy-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide To a suspension of 2-methoxy-4-morpholinobenzoic acid (300 mg, 1.3 mmol) and 5-(thiazol-5-yl)-1,3,4-oxadiazol-2-amine (319 mg, 1.9 mmol) in EtOAc (2 mL) at 25° C., add T3P (1.50 mL, 5.1 mmol) and TEA (0.70 mL, 5.1 mmol). Heat the reaction mixture at 80° C. for 16 h. Dilute the mixture with H2O (10 mL) and extract with EtOAc (10 mL×3). Dry the combined organic layers over MgSO4, filter and concentrate under reduced pressure. Titrate the residue with DMSO (4 mL), then filter and wash with H2O (5 mL×3) to give the crude product. Wash the crude product with MTBE (5 mL) to give the title compound as a yellow solid (110 mg, yield: 20%). LC-MS(ESI):m / z 388.1[M+H] + . 1 H NMR(DMSO-d6,400MHz):δ 10.87(s,1H),9.40(s,1H),8.56(s,1H),7.73(d,J=8.9Hz,1H),6.67(dd,J=8. 8,1.8Hz,1H),6.59(s,1H),3.96(s,3H),3.69-3.80(m,4H),3.35-3.38(m,4H).

[0179] Example 25 JPEG0007664642000067.jpg58134 2-Methoxy-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzenesulfonamide

[0180] To a suspension of 5-(thiazol-5-yl)-1,3,4-oxadiazol-2-amine (50 mg, 0.3 mmol) in THF (3 mL) at 0° C., NaH (36 mg, 0.9 mmol, 60% purity in mineral oil) is added in one portion, and the reaction mixture is stirred at 0° C. for 15 min. 2,4-Dimethoxybenzenesulfonyl chloride (120 mg, 0.5 mmol) is added in one portion, and the reaction mixture is stirred at 25° C. for 16 h. H2O (1 mL) is added to the reaction mixture at 0° C. to quench the reaction, and the reaction mixture is concentrated under reduced pressure to give a residue. The residue is purified by preparative HPLC (column: Daisogel SP ODS RPS 150×25mm×5um, mobile phase: [water (0.225% FA)-ACN], B%: 18%-58%, 11min) to give the title compound as a white solid (56mg, yield: 51%). LC-MS (ESI): m / z 369.0 [M+H] + . 1 H NMR (DMSO-d6,400MHz): δ 9.38(s,1H),8.48(s,1H),7.78(d,J=8.7Hz,1H),6.60-6.70(m,2H),3.83(s,3H),3.75(s,3H).

[0181] Example 26 JPEG0007664642000068.jpg58134 2-Methoxy-N-methyl-4-morpholino-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0182] a) 2,4-dimethoxy-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide To a suspension of 5-(thiazol-5-yl)-1,3,4-oxadiazol-2-amine (100 mg, 0.60 mmol) in EtOAc (0.6 mL) at 25° C., 2,4-dimethoxybenzoic acid (162.48 mg, 0.90 mmol) and TEA (0.33 mL, 2.38 mmol) are added in one portion, stirred for 10 min, then T3P (1.51 g, 2.38 mmol, 1.41 mL, 50% purity) is added, then the reaction mixture is heated to 80° C. and stirred for 16 h at 80° C., the reaction mixture is a brown solution. The reaction mixture is cooled to 25° C., water (2 mL) is added to the reaction mixture, and extracted with EtOAc (1 mL×2). The combined organic layer is separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by preparative HPLC (column: Daisogel SP ODS RPS 150×25mm×5um, mobile phase: [water (0.225% FA)-ACN], B%: 28%-68%, 30min) to give the title compound as a white solid (0.1g, yield: 51%). LC-MS (ESI): m / z 333.1 [M+H] + .

[0183] b) 2,4-dimethoxy-N-methyl-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide To a solution of 2,4-dimethoxy-N-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)benzamide (10 mg, 0.030 mmol) in DMF (0.3 mL) at 25° C., K2CO3 (16.59 mg, 0.120 mmol) is added in one portion and stirred for 10 min, then CHI (3.75 μL, 0.060 mmol) is added and the reaction mixture is heated to 55° C. and stirred for 30 min at 55° C. The reaction mixture is filtered and the filtrate is purified by preparative HPLC (column: YMC-Triart Prep C18 150×40 mm×7 um, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN, B%: 25%-65%, 11 min) to give the title compound (1.5 mg, yield: 14%) as a white solid. LC-MS(ESI):m / z 347.1[M+H] + . 1H NMR(CDCl3,400MHz)δ 8.92(s,1H),8.03(s,1H),7.56(d,J=8.4Hz,1H),6.62(dd,J=8.4,1.8Hz,1H),6.35(s,1H),3.87(s,3H),3.66(s,3H),3.59 ppm(s,3H).

[0184] Example 27 JPEG0007664642000069.jpg62144 2-Methoxy-4-morpholino-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[0185] To a suspension of 2-methoxy-4-morpholinobenzoic acid (40 mg, 0.17 mmol) and 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine (42 mg, 0.25 mmol) in ethyl acetate (0.4 mL) at 25° C., add T3P (75 mL, 0.25 mmol) and TEA (35 mL, 0.25 mmol) and stir the reaction mixture for 16 h at 80° C. The mixture is diluted with H2O (3 mL) and extracted with ethyl acetate (3 mL×3). The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC (column: Phenomenex Gemini-NX 150×30 mm×5 um, mobile phase: [water (0.225% FA)-ACN], B%: 26%-66%, 10 min) to give the title compound as a yellow solid (17 mg, yield: 25%). LC-MS (ESI): m / z 387.0 [M+H] + . 1 H NMR (DMSO-d6,400MHz):δ 10.79(br s,1H),7.92(br d,J=4.8Hz,1H),7.71-7.82(m,2H),7.29(t,J=4.3Hz,1H),6.66(br d,J=8.5Hz,1H),6.57(s,1H),3.95(s,3H),3.73(br d,J=4.5Hz,4H),3.55-3.57(m,4H).

[0186] Example 28 JPEG0007664642000070.jpg67131 2,4-Dimethoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0187] a) t-Butyl (2-oxo-2-(2-(thiophene-2-carbonyl)hydrazino)ethyl)carbamate To a suspension of thiophene-2-carboxylic acid (0.50 g, 3.90 mmol) and t-butyl (2-oxo-2-(2-(thiophene-2-carbonyl)hydrazino)ethyl)carbamate (0.96 g, 5.07 mmol) in DMF (40 mL) at 25° C., HATU (1.93 g, 5.07 mmol) and DIEA (1.94 mL, 11.7 mmol) are added, and the reaction mixture is stirred for 16 h at 25° C. The solvent in the mixture is removed under vacuum to give the title compound (2.7 g, 81%) as a yellow oil, which is used in the next step without purification. LC-MS (ESI): m / z 244.1 [M+H] + .

[0188] b) t-Butyl ((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate To a solution of t-butyl (2-oxo-2-(2-(thiophene-2-carbonyl)hydrazino)ethyl)carbamate (2.7 g, 3.16 mmol) and PPh3 (2.48 g, 9.47 mmol) in acetonitrile (50 mL), triethylamine (1.31 mL, 9.47 mmol) is added and stirred at 25 °C for 20 min. Carbon tetrachloride (0.92 mL, 9.47 mmol) is added to the mixture and stirred at 25 °C for 16 h. The solvent is removed under vacuum. The residue is purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica gel flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient) to give the title compound (800 mg, 81%) as a pale yellow solid. LC-MS (ESI): m / z 282.1 [M+H] + .

[0189] c) (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine TFA salt To a solution of t-butyl ((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (150 mg, 0.48 mmol) in DCM (1.5 mL) at 25° C., add TFA (1.5 mL) dropwise. The mixture is stirred for 2 h at 25° C. The solvent is removed under vacuum and N2 to give the title compound (130 mg, 0.47 mmol, 94%) as a pale yellow solid. LC-MS (ESI): m / z 182.2 [M+H] + .

[0190] d) 2,4-Dimethoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a suspension of (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine TFA salt (65 mg, 0.25 mmol) and 2,4-dimethoxybenzoic acid (68.61 mg, 0.38 mmol) in EtOAc (2 mL) at 25° C., add T3P (0.6 mL, 1.0 mmol) and TEA (0.3 mL, 2.0 mmol). Stir the mixture at 80° C. for 16 h. Dilute the mixture with H2O (3 mL), extract with ethyl acetate (5 mL×3), dry the combined organic layer over MgSO4, filter and concentrate under vacuum. The residue is purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 um, mobile phase: [water (0.225% FA)-ACN], B%: 26%-66%, 10 min) to give the title compound as a white solid (17.8 mg, 21%). LC-MS (ESI): m / z 346.1 [M+H] + . 1 H NMR(DMSO-d6,400MHz):δ 8.77(t,J=5.7Hz,1H),7.93(dd,J=5.0,1.1Hz,1H),7.85(d,J=8.6Hz,1H),7.78(dd,J=3.7,1.1Hz,1 H),7.28(dd,J=4.9,3.8Hz,1H),6.58-6.73(m,2H),4.76(d,J=5.6Hz,2H),3.94(s,3H),3.83(s,3H).

[0191] The following compounds are synthesized according to the procedure described in Example 28. JPEG0007664642000071.jpg237160JPEG0007664642000072.jpg245160JPEG0007664642 000073.jpg245160JPEG0007664642000074.jpg245160JPEG0007664642000075.jpg30160

[0192] Example 29 JPEG0007664642000076.jpg93154 2-Methoxy-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0193] a) (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine HBF 4 salt To a solution of t-butyl ((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (50 mg, 0.16 mmol) in TFE (0.5 mL) at 0° C., add HBF4 (0.02 mL, 0.16 mmol) dropwise. The mixture is stirred for 15 min at 0° C. The mixture is dissolved in H2O (2 mL) at 0° C. and lyophilized to give the title compound (43 mg, yield: 73%) as a pale yellow solid. LC-MS (ESI): m / z 182.2 [M+H] + .

[0194] b) 2-Methoxy-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a suspension of 2-methoxy-4-morpholinobenzoic acid (19 mg, 0.083 mmol) and (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine (45 mg, 0.12 mmol) in ethyl acetate (0.5 mL) at 25 °C, add T3P (0.2 mL, 0.33 mmol) and TEA (0.1 mL, 0.66 mmol) and stir the reaction mixture at 80 °C for 16 h. Dilute the mixture with H2O (2 mL) and extract with ethyl acetate (3 mL x 3). Dry the combined organic layers over MgSO4, filter, and concentrate in vacuo to give a residue. The residue is purified by preparative HPLC (column: YMC-Actus Triart C18 150×30mm×7um, mobile phase: [water (0.225% FA)-ACN], B%: 23%-63%, 10min) to obtain the title compound as a white solid (4.7mg, yield: 14%). LC-MS (ESI): m / z 401.0 [M+H] + . 1 H NMR(DMSO-d6,400MHz):δ 8.69(t,J=5.4Hz,1H),7.94(dd,J=5.0,1.0Hz,1H),7.71-7.85(m,2H),7.28(dd,J=4.9,3.8H z,1H),6.47-6.73(m,2H),4.75(d,J=5.6Hz,2H),3.95(s,3H),3.70-3.81(m,4H),3.22-3.30 ppm(m,4H).

[0195] Example 30 JPEG0007664642000077.jpg85142 2-Methoxy-N-methyl-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0196] To a solution of 2-methoxy-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (100 mg, 0.25 mmol) in THF (1.5 mL) under N2 at 0° C., add NaH (60%, 15.0 mg, 0.38 mmol) and stir for 30 min. Under N2 at 0° C., add iodomethane (78 mL, 1.25 mmol) to the mixture. Stir the mixture at 25° C. for 1 h. Dilute the mixture with H2O (5 mL) and extract with EtOAc (5 mL×3). Separate the organic layer, dry over MgSO4, filter and concentrate the filtrate under vacuum. The residue is purified by preparative HPLC (column: YMC Triart C18 150×25mm×5um, mobile phase: [water (0.225% FA)-ACN], B%: 35%-55%, 10min) to give the title compound as a white solid (14.1mg, 13.6%). LC-MS(ESI): m / z 415.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.97(d,J=4.8Hz,1H),7.86-7.73(m,1H),7.35-7.24(m,1H),7.06(d,J=8.3Hz,1H),6.56(d,J=11 .5Hz,2H),4.94(s,1H),4.64(s,1H),3.81-3.64(m,7H),3.19(d,J=3.5Hz,4H),3.09-2.86(m,3H).

[0197] The following compounds are synthesized according to the procedure described in Example 30. JPEG0007664642000078.jpg100160

[0198] Example 31 JPEG0007664642000079.jpg66144 2-Methoxy-3-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0199] a) 2-Methoxy-3-morpholinobenzoic acid methyl ester A mixture of methyl 3-bromo-2-methoxybenzoate (1.10 g, 4.49 mmol), morpholine (0.79 mL, 8.98 mmol), Pd2(dba)3 (411 mg, 0.45 mmol), Cs2CO3 (4.39 g, 13.5 mmol), BINAP (559 mg, 0.898 mmol) and toluene (30 mL) is degassed with argon gas three times and heated to 100 °C for 6 h. The mixture is mixed with water (100 mL) and extracted with EA (50 mL x 2). The organic layers are combined, washed with brine (50 mL x 3), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE / EA = 100 / 1-4 / 1) to give the title compound (303 mg, yield: 26.9%) as a yellow oil. LC-MS(ESI):m / z 252.1[M+H] + .

[0200] b) 2-Methoxy-3-morpholinobenzoic acid To a solution of methyl 2-methoxy-3-morpholinobenzoate (331 mg, 1.32 mmol) in MeOH (15 mL) and HO (15 mL), add LiOH·HO (442 mg, 10.6 mmol) and heat the resulting mixture to 80 °C for 2 h. Concentrate the mixture under reduced pressure to remove most of the MeOH and adjust the resulting mixture to pH 1-2 with aqueous HCl (1.0 M). Filter the resulting suspension under vacuum. Slurry the residue (EA / PE=1 / 10, 44 mL) to give the title compound (89 mg, yield: 29%) as a white solid. LC-MS (ESI): m / z 238.2 [M+H] + .

[0201] c) 2-Methoxy-3-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 2-methoxy-3-morpholinobenzoic acid (52 mg, 0.22 mmol) in DMF (20 mL) is added (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine (20 mg, 0.11 mmol), DIEA (0.06 mL, 0.39 mmol) and HATU (44 mg, 0.12 mmol). The reaction mixture is stirred at room temperature for 30 min. The resulting mixture is diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers are combined, washed with brine (50 mL x 3), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by preparative HPLC (Method: Waters 2767 / 2545 / 2489 / Qda, Waters Xbridge C18 10um OBD 19×150mm, Mobile phase A: water with 0.1% NH4HCO3, Mobile phase B: CH3CN, Flow rate: 20mL / min, Column temperature: room temperature) to give the title compound as a white solid (15mg, Yield: 34%). LC-MS(ESI): m / z 401.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.98(t,J=5.4Hz,1H),7.94(d,J=4.8Hz,1H),7.79(d,J=3.0Hz,1H),7.27-7.32(m,1H),7.25(d,J= 5.8Hz,1H),7.08-7.17(m,2H),4.76(d,J=5.6Hz,2H),3.86(s,3H),3.77(s,4H),3.00-3.07(m,4H).

[0202] Example 32 JPEG0007664642000080.jpg94140 4-(2,6-Dimethylmorpholino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0203] a) Methyl 4-(2,6-dimethylmorpholino)-2-methoxybenzoate A suspension of methyl 4-fluoro-2-methoxybenzoate (500 mg, 2.715 mmol), 2,6-dimethylmorpholine (0.50 mL, 4.07 mmol) and K2CO3 (563 mg, 4.07 mmol) in DMSO (10 mL) is heated at 120°C for 16 h. The resulting mixture is diluted with water (40 mL) and extracted with EtOAc (20 mL x 3). The organic layers are combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (PE / EA = 20 / 1-5 / 1) to give the title compound (115 mg, 15% yield) as a white solid. LC-MS (ESI): m / z 280.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.62(d,J=8.8Hz,1H),6.55(dd,J=8.9,2.1Hz,1H),6.51(s,1H),2.42-2.31(m,2H),1.17(d,J=6.2Hz,6H).

[0204] b) 4-(2,6-dimethylmorpholino)-2-methoxybenzoic acid A mixture of methyl 4-(2,6-dimethylmorpholino)-2-methoxybenzoate (115 mg, 0.412 mmol), LiOH·H2O (34.6 mg, 0.823 mmol), THF (5.0 mL) and water (2.5 mL) is heated at 70 °C for 8 h. The resulting mixture is adjusted to pH 5-6 with dilute HCl (1.0 M) and extracted with EtOAc (10 mL x 3). The organic layers are combined, washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered under vacuum. The filtrate is concentrated under reduced pressure to give the title compound (100 mg, yield: 91%) as a pale yellow solid. LC-MS (ESI): m / z 266.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.69(d,J=8.7Hz,1H),6.60(d,J=9.0Hz,1H),6.57(s,1H),3.88(s,3H),3.83(d,J= 12.1Hz, 3H), 3.71 (d, J = 6.7Hz, 3H), 2.42 (t, J = 11.3Hz, 2H), 1.23 (d, J = 6.1Hz, 5H).

[0205] c) 4-(2,6-dimethylmorpholino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide A mixture of 4-(2,6-dimethylmorpholino)-2-methoxybenzoic acid (100 mg, 0.377 mmol), DIEA (72.9 mg, 0.565 mmol) and HATU (172 mg, 0.452 mmol) in DMF (3.0 mL) is stirred at room temperature for 30 min, followed by the addition of (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine TFA salt (68.3 mg, 0.377 mmol). The resulting reaction mixture is stirred at room temperature for 1 h. The resulting mixture is diluted with water (15 mL) and extracted with EA (30 mL x 3). The organic layers are combined, washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography (PE / EA=10 / 1 to 1 / 1) to give the title compound as a white solid (138 mg, yield: 85% yield). LC-MS (ESI): m / z 429.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.66(d,J=5.5Hz,1H),7.93(d,J=4.9Hz,1H),7.76(d,J=8.7Hz,2H),7.31-7.25(m,1H),6.61(d,J=8.9Hz,1H),6.56(s,1H) ),4.75(d,J=5.5Hz,2H),3.95(s,3H),3.78(d,J=11.9Hz,2H),3.66(s,2H),2.36(t,J=11.3Hz,2H),1.17(d,J=6.1Hz,6H).

[0206] Example 33 JPEG0007664642000081.jpg87138 2-Methoxy-4-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0207] a) 4-Bromo-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a suspension of 4-bromo-2-methoxybenzoic acid (92.0 mg, 0.40 mmol) and (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine (100 mg, 0.331 mmol) in pyridine (2 mL) at 25 °C, add EDC·HCl (95.2 mg, 0.50 mmol) and DMAP (4.0 mg, 0.033 mmol) and stir the reaction mixture at 50 °C for 2 h. Concentrate the mixture in vacuum. Slurry the residue with acetonitrile (3 mL) and H2O (0.5 mL) to give the title compound (80 mg, 0.18 mmol, 55.4%) as a white solid. LC-MS (ESI): m / z 394.0 [M+H] + .

[0208] b) 2-Methoxy-4-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 4-bromo-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (50 mg, 0.12 mmol), piperidine (10 mL, 0.1 mmol), Cs2CO3 (65.4 mg, 0.20 mmol) in t-amyl alcohol (5 mL) at 25° C. under N2, add RuPhos-Pd-G3 (42.0 mg, 0.05 mmol). Stir the mixture at 120° C. for 16 h. Dilute the mixture with H2O (5 mL) and extract with EtOAc (5 mL×3). Separate the organic layer, dry over MgSO4, filter and concentrate the filtrate under vacuum. The residue is purified by preparative HPLC (column: YMC Triart C18 150×25 mm×5 um, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 43%-63%, 10 min) to give the title compound as a white solid (9 mg, 21%). LC-MS (ESI): m / z 399.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.93(d,J=5.0Hz,1H),7.81-7.70(m,2H),7.32-7.22(m,1H),6.93(s,1H) ,6.61-6.46(m,2H),4.75(s,2H),3.94(s,3H),3.30(s,4H),1.59(s,6H).

[0209] The following compounds are synthesized according to the procedure described in Example 33. JPEG0007664642000082.jpg234160JPEG0007664642000083.jpg93160

[0210] Example 34 JPEG0007664642000084.jpg93155 2-Methoxy-4-morpholino-N-((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0211] a) t-Butyl (2-oxo-2-(2-(thiazole-5-carbonyl)hydrazino)ethyl)carbamate To a suspension of thiazole-5-carbohydrazide (0.2 g, 1.4 mmol) in THF (5.6 mL) and DMF (1.4 mL) at 25° C., add HOBt (0.09 g, 0.698 mmol), EDC (0.35 g, 1.816 mmol) and (t-butoxycarbonyl)glycine (0.88 g, 4.396 mmol) and stir for 16 h. The mixture is diluted with 1 N NaOH (18 mL) and extracted with DCM (15 mL×3). The aqueous layer is lyophilized to give the title compound (4 g, 95%) as a yellow solid. LC-MS (ESI): m / z 301.1 [M+H] + .

[0212] b) t-Butyl ((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate To a solution of t-butyl (2-oxo-2-(2-(thiazole-5-carbonyl)hydrazino)ethyl)carbamate (3.3 g, 1.1 mmol) and PPh3 (0.86 g, 3.3 mmol) in acetonitrile (6 mL) is added TEA (0.5 mL, 3.3 mmol). The reaction is stirred for 20 min at 25 °C. CCl4 (0.3 mL, 3.3 mmol) is added to the mixture and stirred for 16 h at 25 °C. The solvent is removed under vacuum. The residue is diluted with H2O (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined layers are dried over MgSO4, filtered and the filtrate is concentrated under vacuum. The residue is purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica gel flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient) to give the title compound as a white solid (0.6 g, 97%). LC-MS (ESI): m / z 283.1 [M+H] + .

[0213] c) t-Butyl ((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate HBF 4 salt To a solution of t-butyl ((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (0.6 g, 1.1 mmol) in TFE (6 mL) at 0° C., add HBF4 (0.14 mL, 1.06 mmol) dropwise. The mixture is stirred for 2 h at 25° C. The white suspension mixture is dissolved in H2O (5 mL) at 0° C. and lyophilized. The solid is slurried with DCM (1 mL) to give the title compound (47 mg, 17%) as a yellow solid. LC-MS (ESI): m / z 183.1 [M+H] + .

[0214] d) 2-Methoxy-4-morpholino-N-((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a suspension of t-butyl ((5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate HBF4 salt (57.12 mg, 0.217 mmol) and 2-methoxy-4-morpholinobenzoic acid (47 mg, 0.181 mmol) in pyridine (1 mL) at 25° C., add EDC.HCl (52 mg, 0.27 mmol) and DMAP (2.21 mg, 0.018 mmol). Stir the reaction mixture at 50° C. for 2 h. The mixture is a yellow solution. Remove the solvent from the mixture under vacuum. The residue is purified by preparative HPLC (column: YMC Triart C18 150×25 mm×5 mm, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 25%-45%, 10 min) to give the title compound as a white solid (36 mg, 49%). LC-MS (ESI): m / z 402.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),8.69(t,J=5.5Hz,1H),8.56(s,1H),7.78(d,J=8.8Hz,1H),6.69-6.51 (m,2H),4.77(d,J=5.5Hz,2H),3.95(s,3H),3.78-3.70(m,4H),3.29-3.25(m,4H).

[0215] The following compounds are synthesized according to the procedure described in Example 34. JPEG0007664642000085.jpg238160JPEG0007664642000086.jpg39160

[0216] Example 35 JPEG0007664642000087.jpg79148 N-((5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-methoxy-4-morpholinobenzamide

[0217] a) t-Butyl ((5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate To a mixture of t-butyl ((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (50 mg, 0.18 mmol) in DMF (0.8 mL) is added NCS (36 mg, 0.3 mmol). The mixture is stirred at 20 °C under N2 for 16 h. The mixture is diluted with 1 M NaOH (3 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers are dried over MgSO4, filtered and concentrated to give the title compound (56 mg, yield: 99%) as a yellow oil. LC-MS (ESI): m / z 316.1 [M+H] + .

[0218] b) (5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine HBF 4 salt To a solution of t-butyl ((5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (87 mg, 0.28 mmol) in TFE (1 mL) at 0° C., add HBF4 (37 μL, 0.28 mmol) dropwise. The mixture is stirred at 25° C. for 2 h. The mixture is a white suspension. The mixture is dissolved in H2O (2 mL) at 0° C. and lyophilized to give the title compound (60 mg, yield: 91%) as a pale yellow solid. LC-MS (ESI): m / z 216.0 [M+H] + .

[0219] c) N-((5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-methoxy-4-morpholinobenzamide To a suspension of 2-methoxy-4-morpholinobenzoic acid (79 mg, 0.3 mmol) and (5-(5-chlorothiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine (60 mg, 0.3 mmol) in pyridine (1.2 mL) at 25 °C, add EDC·HCl (72 mg, 0.38 mmol) and DMAP (3 mg, 0.03 mmol) and stir the reaction mixture at 50 °C for 2 h. Remove the solvent under vacuum. Slurry the residue with MeCN (3 mL) and DMSO (1 mL). Collect the solid by filtration to give the title compound (47 mg, 41% yield) as a white solid. LC-MS (ESI): m / z 435.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.68(t,J=5.6Hz,1H),7.77(d,J=8.8Hz,1H),7.66(d,J=4.0Hz,1H),7.34(d,J=4.0Hz,1H),6.65- 6.50(m,2H),4.80-4.65(m,2H),3.94(s,3H),3.77-3.70(m,4H),3.30-3.25(m,4H),1.99(s,1H).

[0220] Example 36 JPEG0007664642000088.jpg91152 2-Methoxy-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide

[0221] a) t-Butyl (2-methyl-1-oxo-1-(2-(thiophene-2-carbonyl)hydrazino)propan-2-yl)carbamate To a suspension of thiophene-2-carbohydrazide (0.5 g, 3.5 mmol) in THF (14 mL) and DMF (4 mL) at room temperature, add HOBt (0.24 g, 1.8 mmol), EDC (0.84 g, 4.4 mmol) and 2-((t-butoxycarbonyl)amino)-2-methylpropionic acid (0.88 g, 4.4 mmol). The reaction is stirred for 16 h. The mixture is diluted with 1 M NaOH (18 mL) and extracted with DCM (15 mL x 3). The combined organic layers are dried over MgSO4, filtered and the solvent removed under vacuum to give the title compound (1.1 g, 48%) as a yellow oil. LC-MS (ESI): m / z 328.1 [M+H] + .

[0222] b) t-Butyl (2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)carbamate To a solution of t-butyl (2-methyl-1-oxo-1-(2-(thiophene-2-carbonyl)hydrazino)propan-2-yl)carbamate (500 mg, 0.76 mmol) and PPh3 (600 mg, 2.3 mmol) in acetonitrile (5 mL) is added triethylamine (318 μL, 2.3 mmol). The reaction is stirred for 20 min at 25 °C. CCl4 (221 μL, 2.3 mmol) is added to the mixture and stirred for 16 h at 25 °C. The solvent is removed in vacuum and the residue is purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica gel flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient) to give the title compound (100 mg, 35%) as a pale yellow solid. LC-MS (ESI): m / z 310.0 [M+H] + .

[0223] c) 2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-amine To a solution of t-butyl (2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)carbamate (100 mg, 0.32 mmol) in TFE (1 mL) at 0° C., HBF4 (44 μL, 0.33 mmol) is added dropwise. The mixture is stirred for 2 h at 25° C. The mixture is dissolved in H2O (2 mL) and lyophilized to give the title compound (90 mg, 93%) as a yellow solid. LC-MS (ESI): m / z 210.0 [M+H] + .

[0224] d) 2-Methoxy-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide To a suspension of 2-methoxy-4-morpholinobenzoic acid (63 mg, 0.241 mmol) and 2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-amine (60 mg, 0.20 mmol) in pyridine (1.2 mL) at room temperature, add EDC·HCl (58 mg, 0.30 mmol) and DMAP (2.5 mg, 0.02 mmol). Stir the reaction mixture at 50 °C for 2 h. Remove the solvent under vacuum. Slurry the residue with acetonitrile (3 mL) and DMSO (1 mL) and collect the solid by filtration to give the title compound (18 mg, 20% yield) as a white solid. LC-MS (ESI): m / z 429.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),7.91(dd,J=1.1,5.0Hz,1H),7.72(dd,J=1.1,3.6Hz,1H),7.63(d,J=9.4Hz,1H),7.25(dd, J=3.8,4.9Hz,1H),6.62-6.55(m,2H),3.99(s,3H),3.77-3.71(m,4H),3.28-3.24(m,4H),1.76(s,6H).

[0225] The following compounds are synthesized according to the procedure described in Example 36. JPEG0007664642000089.jpg223160

[0226] Example 37 JPEG0007664642000090.jpg84140 2-Methoxy-N-methyl-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide

[0227] To a solution of 2-methoxy-4-morpholino-N-(2-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)benzamide (400 mg, 0.14 mmol) in THF (1 mL) under N2 at 0° C., add NaH (60% in mineral oil, 8.40 mg, 0.21 mmol) and stir for 30 min. To the mixture under N2 at 0° C., add iodomethane (44 μL, 0.7 mmol). Stir the mixture at 25° C. for 1 h. Dilute the mixture with H2O (1 mL) and extract with ethyl acetate (1 mL×3). The combined organic layers are dried over MgSO4, filtered and concentrated under vacuum. The residue is purified by preparative HPLC (column: YMC Triart C18 150×25mm×5mm, mobile phase: [water (0.225% FA)-ACN], B%: 35%-55%, 10min) to give the title compound as a white solid (4.74mg, 6.6%). LC-MS (ESI): m / z 443.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.43(br s,1H),7.92(dd,J=1.2,5.1Hz,1H),7.73(dd,J=1.2,3.7Hz,1H),7.29(dd,J=3.7,5.0Hz,1H),6.97(d,J=8. 4Hz, 1H), 6.64-6.44 (m, 2H), 3.83 (s, 3H), 3.77-3.68 (m, 4H), 3.26-3.11 (m, 4H), 2.92 (s, 3H), 1.72 (s, 6H).

[0228] Example 38 JPEG0007664642000091.jpg67160 2-Methoxy-4-(2-morpholinoethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0229] a) 4-hydroxy-2-methoxybenzoic acid To a solution of 4-hydroxy-2-methoxybenzaldehyde (4.9 g, 32.2 mmol) in DMSO (100 mL) and water (75 mL) at 0 °C, add NaH2PO4 (394 mg, 161.025 mmol), NaClO2 (11.7 g, 129 mmol). Then stir the reaction mixture at room temperature for 3 h. Mix the mixture with water (400 mL) and then adjust pH to 8-9 with NaHCO3 powder. Wash the whole with EA (300 mL). Adjust the aqueous phase to 3-4 with aqueous HCl (1.0 M) and extract the resulting mixture with ethyl acetate (100 mL x 3). Wash the combined organic layers with brine (200 mL), dry over anhydrous Na2SO4 and filter. Concentrate the filtrate under reduced pressure to give the title compound (5.39 g, yield: 97.1%) as a yellow oil. LC-MS(ESI):m / z 168.8[M+H] + .

[0230] b) 4-hydroxy-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 4-hydroxy-2-methoxybenzoic acid (1.00 g, 5.95 mmol) in DMF (20 mL), add BOP (3.95 g, 8.92 mmol), DIEA (3.94 mL, 23.8 mmol) and (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine (1.82 g, 6.54 mmol) and stir the reaction at room temperature for 1.5 h. Dilute the reaction mixture with water (20 mL). Extract the mixture with ethyl acetate (20 mL x 2). Combine the organic phases, wash with brine (30 mL x 2), dry over anhydrous Na2SO4 and filter. Concentrate the filtrate under reduced pressure to give the title compound (1.8 g, yield: 63.9% yield) as a yellow solid. LC-MS (ESI): m / z 332.0 [M+H] + .

[0231] c) 2-Methoxy-4-(2-morpholinoethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 4-hydroxy-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (200 mg, 0.42 mmol) in acetonitrile (3.0 mL) is added 4-(2-chloroethyl)morpholine hydrochloride (70.8 mg, 0.381 mmol), K2CO3 (175 mg, 1.27 mmol) and KI (7.0 mg, 0.042 mmol). The resulting mixture is heated to 90 °C for 2 h. The reaction mixture is purified by preparative HPLC (Method: Waters 2767 / 2545 / 2489, Inertsil ODS-3 10um20×250nm, Mobile phase A: Water with 0.1% FA, Mobile phase B: CH3CN, Flow rate: 20mL / min, Column temperature: RT) to give the title compound as a white solid (13mg, Yield: 6.3%). LC-MS (ESI): m / z 445.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.76(t,J=5.5Hz,1H),7.93(d,J=4.3Hz,1H),7.83(d,J=8.6Hz,1H),7.77(d,J=2.8Hz,1H),7.26-7.30(m,1H),6.63-6.70(m, 2H), 4.75(d,J=5.5Hz,2H),4.17(t,J=5.6Hz,2H),3.94(s,3H),3.55-3.61(m,4H),2.70(t,J=5.6Hz,2H),2.45-2.49(m,4H).

[0232] The following compounds are synthesized according to the procedures described in Example 38. JPEG0007664642000092.jpg238160JPEG0007664642000093.jpg22160

[0233] Example 39 JPEG0007664642000094.jpg75148 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one

[0234] a) N'-(2-chloroacetyl)thiophene-2-carbohydrazide To a mixture of thiophene-2-carbohydrazide (5.00 g, 35 mmol), NaHCO3 (8.86 g, 106 mmol), H2O (40 mL) and THF (60 mL) is added dropwise a solution of 2-chloroacetyl chloride (4.20 mL, 52.8 mmol) in THF (10 mL). The resulting mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with ethyl acetate (50 mL) and washed with brine (10 mL). The organic layer is separated and concentrated under reduced pressure to give the title compound (2.10 g, yield: 27%). LC-MS (ESI): m / z 219.0 [M+H] + .

[0235] b) 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole A mixture of N'-(2-chloroacetyl)thiophene-2-carbohydrazide (1.00 g, 4.57 mmol) and POCl3 (8.50 mL, 91.5 mmol) is heated to 100°C for 2 h. The reaction mixture is then concentrated under reduced pressure. The residue is mixed with DCM (10 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer is separated, dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to give the title compound (700 mg, yield: 76%). LC-MS (ESI): m / z 201.0 [M+H] + .

[0236] c) 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (250 mg, 1.25 mmol) in DMF (15 mL) at 0° C., NaH (74.8 mg, 1.87 mmol, 60% in oil) is added, the resulting mixture is stirred at this temperature for 30 min, and 3,4-dihydroisoquinolin-1(2H)-one (250 mg, 1.25 mmol) is added. The reaction mixture is heated to room temperature and stirred for 1 h. The resulting mixture is mixed with EA (100 mL) and brine (100 mL). The organic layer is separated, dried over anhydrous Na2SO4 and filtered under vacuum. The filtrate is concentrated under reduced pressure. The residue is purified by preparative HPLC (System: Waters 2767 / 2545 / 2489 / Qda, Column name: Inertsil ODS-3 10um 20×250nm, Mobile phase A: Water containing 0.1% FA, Mobile phase B: CH3CN, Wavelength: 254nm / 214nm, Flow rate: 20mL / min, Column temperature: RT) to obtain the title compound (43.1mg, Yield: 11%). LC-MS(ESI): m / z 312.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.94(d,J=4.9Hz,1H),7.77-7.85(m,2H),7.54-7.64(m,2H),7.17-7.36(m,1H),5.02(s,2H),3.75(t,J=6.5Hz,2H),3.07(t,J=6.4Hz,2H).

[0237] Example 40 JPEG0007664642000095.jpg68160 6-Bromo-2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one

[0238] To a solution of 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (676 mg, 2.99 mmol) in DMF (15 mL) at 0° C., add NaH (178 mg, 4.49 mmol, 60% in oil), stir the reaction for 30 min at 0° C., and add 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (600 mg, 3.0 mmol). Allow the mixture to warm to room temperature and stir for 1 h. Dilute the reaction mixture with ethyl acetate (20 mL) and brine (20 mL), separate the organic layer, dry over anhydrous Na2SO4, and filter. Concentrate the filtrate under reduced pressure to give the crude product (400 mg). The crude product (100 mg) is purified by preparative HPLC (Method: Waters 2767 / 2545 / 2489 / Qda, Column name: Inertsil ODS-3 10um 20×250nm, Mobile phase A: Water containing 0.1% FA, Mobile phase B: CH3CN, Flow rate: 20mL / min, Column temperature: Room temperature) to obtain the title compound as a white solid (25 mg, Yield: 6.5%). LC-MS (ESI): m / z 392.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.94(d,J=4.9Hz,1H),7.77-7.85(m,2H),7.54-7.64(m,2H),7.17-7.36(m,1H),5.02(s,2H),3.75(t,J=6.5Hz,2H),3.07(t,J=6.4Hz,2H).

[0239] Example 41 JPEG0007664642000096.jpg81155 6-Morpholino-2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one

[0240] A mixture of 6-bromo-2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (300 mg, 0.77 mmol), morpholine (0.14 mL, 1.54 mmol), Cs2CO3 (749 mg, 2.30 mmol), BINAP (47.9 mg, 0.08 mmol), Pd2(dba)3 (70.3 mg, 0.080 mmol) and toluene (10 mL) is degassed three times with argon gas and then heated to 115 °C for 36 h. The resulting mixture is filtered and the filtrate is concentrated under vacuum. The residue is purified by preparative HPLC (System: Waters 2767 / 2545 / 2489 / Qda, Waters Xbridge C18 10um OBD 19×150 mm, Mobile phase A: Water containing 0.1% NH4OH, Mobile phase B: CH3CN, Flow rate: 20mL / min, Column temperature: Room temperature) to give the title compound as a white solid (17.0mg, Yield: 5.6%). LC-MS (ESI): m / z 397.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.94(d,J=4.5Hz,1H),7.79(d,J=2.9Hz,1H),7.73(d,J=8.8Hz,1H),7.24-7.32(m,1H),6.9 0(d,J=7.2Hz,1H),6.80(s,1H),4.97(s,1H),3.61-3.80(m,6H),3.24(s,2H),2.97(s,1H).

[0241] Example 42 JPEG0007664642000097.jpg87159 N-(2-Methoxy-4-morpholinophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carboxamide

[0242] a) 4-(3-methoxy-4-nitrophenyl)morpholine To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (8.00 g, 47 mmol) in acetonitrile (100 mL), add morpholine (4.07 g, 467 mmol) and potassium carbonate (7 mg, 51 mmol) and stir the reaction at 75° C. for 3 h. Concentrate the reaction under reduced pressure. Mix the residue with water (30 mL) and filter the suspension. Collect the filter cake, wash with water (30 mL) and dry under vacuum to give the title compound (10.0 g, yield: 90%). LC-MS (ESI): m / z 239.1 [M+H] + .

[0243] b) 2-Methoxy-4-morpholinoaniline To a solution of 4-(3-methoxy-4-nitrophenyl)morpholine (3.00 g, 12.6 mmol) in ethyl acetate (30 mL), add Pd / C (10%, 500 mg) and degas the reaction mixture with N2 three times. Stir the reaction mixture under H2 balloon pressure at room temperature for 3 h. Filter the resulting mixture and concentrate the filtrate under reduced pressure to give the title compound (2.30 g, yield: 88%). LC-MS (ESI): m / z 209.0 [M+H] + .

[0244] c) 2-oxo-2-(2-(thiophene-2-carbonyl)hydrazino)acetic acid methyl ester To a mixture of thiophene-2-carbohydrazide (3.00 g, 21.1 mmol), NaHCO3 (5.32 g, 63.3 mmol), H2O (15 mL) and THF (15 mL) is added dropwise a solution of methyl 2-chloro-2-oxoacetate (3.9 mg, 32 mmol) in THF (2.0 mL). The reaction mixture is stirred at room temperature for 2 h. The resulting mixture is concentrated under reduced pressure to remove most of the THF. The residue is extracted with EA (20 mL x 3). The organic layers are combined, washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (5.30 g, 100% yield). LC-MS (ESI): m / z 229.1 [M+H] + .

[0245] d) 5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carboxylate methyl To a solution of methyl 2-oxo-2-(2-(thiophene-2-carbonyl)hydrazino)acetate (1.4 g, 6.13 mmol) in DCM (20 mL), add TEA (2.56 mL, 18.4 mmol) and toluene tosyl chloride (1.40 g, 7.36 mmol). Stir the resulting mixture at room temperature for 2 h. Concentrate the reaction mixture under reduced pressure. Purify the residue by silica gel column chromatography, eluting with petroleum ether containing ethyl acetate (PE / EA=1 / 10 to 1 / 1) to obtain the title compound (650 mg, yield: 50%). LC-MS (ESI): m / z 221.0 [M+H] + .

[0246] e) N-(2-methoxy-4-morpholinophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carboxamide To a solution of methyl 5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carboxylate (130 mg, 0.62 mmol) in methanol (5 mL), add 2-methoxy-4-morpholinoaniline (772 mg, 3.71 mmol) and TEA (0.86 mL, 6.18 mmol) and stir the reaction at 65° C. for 5 h. Concentrate the reaction mixture under reduced pressure. Mix the residue with ethanol (10 mL) and filter under vacuum. Dry the filter cake under vacuum to give the title compound (27 mg, yield: 11%). LC-MS (ESI): m / z 387.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.87(s,1H),8.05(d,J=4.8Hz,1H),7.97(d,J=2.9Hz,1H),7.66(d,J=8.7Hz,1H),7.44- 7.27(m,1H),6.70(s,1H),6.55(d,J=8.5Hz,1H),3.87(s,3H),3.75(s,4H),3.15(s,4H).

[0247] Example 43 JPEG0007664642000098.jpg77162 2-Methoxy-4-((1-methylpyrrolidin-3-yl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0248] a) t-Butyl 3-((3-methoxy-4-(methoxycarbonyl)phenyl)amino)pyrrolidine-1-carboxylate To a solution of methyl 4-bromo-2-methoxybenzoate (5.0 g, 20 mmol) in 1,4-dioxane (50 mL), Pd2(dba)3 (1.87 g, 2.04 mmol), BINAP (1.27 g, 2.04 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (4.18 g, 22.44 mmol) and Cs2CO3 (20 g, 61 mmol) are added and the reaction is stirred overnight at 105 °C. The mixture is cooled to room temperature and diluted with ethyl acetate (200 mL) and brine (200 mL). The organic layer is separated and concentrated under vacuum. The residue is purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (EA / PE=1 / 100-1 / 2) to give the title compound (7.0 g, yield: 93%) as a yellow oil. LC-MS(ESI):m / z 351.5[M+H] + .

[0249] b) 2-Methoxy-4-(pyrrolidin-3-ylamino)benzoic acid methyl ester hydrochloride A mixture of tert-butyl 3-((3-methoxy-4-(methoxycarbonyl)phenyl)amino)pyrrolidine-1-carboxylate (7.0 g, 20 mmol) in HCl (4 M in dioxane, 10 mL) solution is stirred at room temperature for 18 h. The mixture is concentrated and dried under vacuum at 50° C. to give the title compound (5.3 g, yield: 92.5%) as a yellow solid. LC-MS (ESI): m / z 251.1 [M-HCl+H] + .

[0250] c) 2-Methoxy-4-((1-methylpyrrolidin-3-yl)amino)benzoic acid methyl ester To a solution of methyl 2-methoxy-4-(pyrrolidin-3-ylamino)benzoate hydrochloride (1.0 g, 3.49 mmol) in methanol (20 mL), add formaldehyde (0.21 g, 6.97 mmol, 30% in water) and sodium cyanoborohydride (0.26 g, 4.18 mmol) and stir the reaction at room temperature for 2 h. Concentrate the reaction under vacuum and purify the residue by silica gel column chromatography eluting with dichloromethane containing methanol (MeOH / DCM=0 / 1 to 1 / 15, v / v) to obtain the title compound as a yellow solid (430 mg, yield: 46.8%). LC-MS (ESI): m / z 264.9 [M+H]+ .

[0251] d) 2-Methoxy-4-((1-methylpyrrolidin-3-yl)amino)benzoic acid A mixture of methyl 2-methoxy-4-((1-methylpyrrolidin-3-yl)amino)benzoate (600.00 mg, 1.63 mmol), LiOH (684 mg, 16.28 mmol), MeOH (20 mL), and HO (10 mL) is heated to 70° C. and the mixture is stirred at this temperature for 18 h. The reaction is cooled to room temperature. The pH of the mixture is adjusted to 6-7. The mixture is concentrated under vacuum to give a residue. EtOH (50 mL) is added, the mixture is stirred at room temperature for 20 min, and filtered. The filtrate is concentrated under vacuum to give the title compound as a white foam (400 mg, yield: 88%). LC-MS (ESI): m / z 250.9 [M+H] + .

[0252] e) 2-Methoxy-4-((1-methylpyrrolidin-3-yl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 2-methoxy-4-((1-methylpyrrolidin-3-yl)amino)benzoic acid (400 mg, 1.60 mmol) in DMF (20 mL), add DIEA (524 mg, 4.06 mmol) and BOP (539 mg, 1.22 mmol) and stir the reaction at room temperature for 5 min. Add (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine TFA salt (300 mg, 1.02 mmol) in DMF (20 mL) in one portion. Stir the reaction at room temperature for 30 min. Purify the mixture by silica gel column chromatography eluting with DCM containing methanol (MeOH / DCM=0 / 1 to 1 / 10, v / v) and further purify by preparative HPLC (basic method) to give the title compound (0.16 g, yield: 38%) as a white solid. LC-MS(ESI): m / z 414.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.55(t,J=5.6Hz,1H),7.93(dd,J=5.0,1.1Hz,1H),7.77(dd,J=3.7,1.1Hz,1H),7.67(d, J=8.4Hz,1H),7.27(dd,J=5.0,3.8Hz,1H),6.50(d,J=6.9Hz,1H),6.21(d,J=8.5Hz,2H), 4.73(d,J=5.6Hz,2H),3.96(s,1H),3.88(s,3H),2.73(dd,J=9.2,6.7Hz,1H),2.58(dd,J =13.8,8.2Hz,1H),2.37(dt,J=9.7,6.0Hz,2H),2.29-2.19(m,4H),1.59(d,J=6.5Hz,1H).

[0253] Example 44 JPEG0007664642000099.jpg75152 2-Methoxy-4-((2-(methylamino)ethyl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0254] a) t-Butyl (2-((3-methoxy-4-(((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)amino)ethyl)(methyl)carbamate To a solution of 4-bromo-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (300 mg, 0.761 mmol) in dioxane (6 mL), add t-butyl(2-aminoethyl)(methyl)carbamate (199 mg, 1.1 mmol), Pd2(dba)3 (69.68 mg, 0.076 mmol), BINAP (47.38 mg, 0.076 mmol) and Cs2CO3 (991 mg, 3.04 mmol) and degas the mixture with N2 three times. Stir the reaction at 105 °C for 18 h. Filter the reaction, dilute the filtrate with water (15 mL) and extract the mixture with ethyl acetate (20 mL x 3). The organic layers are combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (PE:EA=4:1 to 1:4) to give the title compound (200 mg, yield: 27%). LC-MS (ESI): m / z 488.2 [M+H] + .

[0255] b) 2-Methoxy-4-((2-(methylamino)ethyl)amino)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of t-butyl (2-((3-methoxy-4-(((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenyl)amino)ethyl)(methyl)carbamate (200 mg, 0.41 mmol) in dichloromethane (8 mL) is added TFA (2 mL). The reaction is stirred at room temperature for 2 h. The reaction is concentrated under vacuum. The residue is purified by preparative HPLC to give the title compound (17 mg, yield: 21%). LC-MS (ESI): m / z 388.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.54(d,J=5.4Hz,1H),8.01-7.87(m,1H),7.77(d,J=2.6Hz,1H),7.67(d,J=9.2Hz,1H),7.27(dd,J=4.9,3.8Hz,1H),6.2 5(t,J=6.1Hz,3H),4.73(d,J=5.7Hz,2H),3.88(s,3H),3.16(dd,J=11.8,6.0Hz,3H),2.68(t,J=6.2Hz,2H),2.31(s,3H).

[0256] The following compounds are synthesized according to the procedure described in Example 44. JPEG0007664642000100.jpg234160JPEG0007664642000101.jpg89160

[0257] Example 45 JPEG0007664642000102.jpg63152 2-Methoxy-4-(2-(methylamino)ethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0258] a) 2-((t-butoxycarbonyl)(methyl)amino)ethyl methanesulfonate Add a solution of triethylamine (693 mg, 6.8 mmol) and methanesulfonyl chloride (719 mg, 6.3 mmol) in DCM (2 mL) dropwise to a solution of (2-hydroxyethyl)(methyl)carbamate t-butyl ester (1.0 g, 5.7 mmol) in DCM (10 mL) at 0 °C and allow the reaction to warm to room temperature. Stir the reaction at this temperature for 1.5 h. Wash the reaction with water (10 mL) and separate the organic layer. Concentrate the organic layer under vacuum. Purify the residue by silica gel column chromatography eluting with petroleum ether containing ethyl acetate (PE:EA = 10:1 to 1:1) to give the title compound (1.16 g, yield: 80%) as a yellow oil.

[0259] b) t-Butyl (2-(3-methoxy-4-(((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenoxy)ethyl)(methyl)carbamate To a solution of 2-((t-butoxycarbonyl)(methyl)amino)ethyl methanesulfonate (458 mg, 1.81 mmol) in DMF (5 mL), add 4-hydroxy-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (300 mg, 0.91 mmol) and Cs2CO3 (589 mg, 1.81 mmol) and stir the reaction at 90 °C for 5 h. Dilute the reaction with water (20 mL) and extract the mixture with ethyl acetate (20 mL x 3), combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, filter and concentrate under vacuum. Purify the residue by silica gel column chromatography eluting with petroleum ether containing ethyl acetate (PE:EA = 10:1 to 1:4) to give the title compound (53 mg, yield: 6.0%). LC-MS(ESI):m / z 489.0[M+H] + .

[0260] c) 2-Methoxy-4-(2-(methylamino)ethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of t-butyl (2-(3-methoxy-4-(((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)carbamoyl)phenoxy)ethyl)(methyl)carbamate (53 mg, 0.11 mmol) in DCM (5 mL) is added TFA (1 mL) and the reaction is stirred at room temperature for 1 h. The reaction is concentrated under vacuum. The residue is purified by preparative HPLC to give the title compound (9.94 mg, yield: 24%). LC-MS (ESI): m / z 389.1 [MH] - . 1 H NMR(400MHz,DMSO-d6)δ 8.76(t,J=5.5Hz,1H),7.93(d,J=4.9Hz,1H),7.84(d,J=8.7Hz,1H),7.77(d,J=3.3Hz,1H),7.32-7.18(m,1H),6.74-6.57 (m,2H),4.75(d,J=5.6Hz,2H),4.10(t,J=5.5Hz,2H),3.93(s,3H),3.32-3.28(m,1H),2.87(t,J=5.3Hz,2H),2.35(s,3H).

[0261] The following compounds are synthesized according to the procedure described in Example 45. JPEG0007664642000103.jpg153160

[0262] Example 46 JPEG0007664642000104.jpg69144 2-Methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0263] To a solution of 2-methoxy-4-(pyrrolidin-3-yloxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (240 mg, 0.6 mmol) in methanol (10 m), add acetic acid (22 mg, 0.12 mmol), formaldehyde (126 mg, 4.20 mmol) and 2-picoline borane (641 mg, 6.0 mmol) and stir the reaction at 80 °C for 2 h. Concentrate the reaction under vacuum. Purify the residue by silica gel column chromatography eluting with DCM containing methanol (MeOH:DCM = 1:100 to 1:10, v / v) to give the crude product. The crude product is further purified by preparative HPLC to give the title compound (2.18 mg, yield: 0.8%) as a white solid. LC-MS(ESI): m / z 415.5[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.75(t,J=5.4Hz,1H),7.93(dd,J=5.0,1.1Hz,1H),7.81(s,1H),7.77(dd,J=3.7,1.1Hz,2H),7.28(dd,J=5.0,3.7Hz,1H),6.60(m,2H),4.9 7(s,1H),4.75(d,J=5.6Hz,2H),3.92(s,3H),2.86-2.73(m,1H),2.72-2.60(m,2H),2.41-2.31(m,2H),2.27(s,3H),1.76(d,J=7.1Hz,1H).

[0264] Example 47 JPEG0007664642000105.jpg80139 4-(2-hydroxypropan-2-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0265] a) 4-(2-hydroxypropan-2-yl)-2-methoxybenzoic acid A solution of 4-bromo-2-methoxybenzoic acid (400 mg, 1.73 mmol) in THF (5 mL) is cooled to -65 °C and n-BuLi (3.3 mL, 0.48 mmol, 1.6 M) is added. The reaction is stirred at this temperature for 30 min. Acetone (0.19 mL, 2.5 mmol) is added dropwise to the mixture, and the mixture is slowly warmed to 0 °C and stirred for 30 min. The mixture is diluted with ethyl acetate (5 mL) and saturated aqueous NH4Cl (5 mL). The organic layer is separated, washed with brine (5 mL), filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography, eluting with dichloromethane containing methanol (MeOH:DCM = 0:1 to 1:7) to give the title compound (50 mg, yield: 14%) as a colorless oil. LC-MS (ESI): m / z 211.0 [M+H] + .

[0266] b) 4-(2-hydroxypropan-2-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 4-(2-hydroxypropan-2-yl)-2-methoxybenzoic acid (50 mg, 0.24 mmol) in DMF (5 mL) is added BOP (210 mg, 0.48 mmol), DIEA (0.12 mL, 0.71 mmol) and [5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl]methanamine (43 mg, 0.24 mmol). The reaction is stirred at room temperature for 1.5 h. The reaction is purified by preparative HPLC (Waters 2767 / 2545 / 2489, Waters Xbridge C18 10 um OBD 19×250 mm, mobile phase A: water with 0.1% NH4HCO3, mobile phase B: CH3CN, 20 mL / min, RT) to give the title compound (7 mg, yield: 7.6%) as a white solid. LC-MS(ESI):m / z 374.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.88(t,J=5.7Hz,1H),7.94(d,J=4.0Hz,1H),7.76(t,J=6.1Hz,2H),7.27(dd,J=9.5,4.6Hz ,2H),7.11(d,J=8.1Hz,1H),5.18(s,1H),4.77(d,J=5.6Hz,2H),3.93(s,3H),1.44(s,6H).

[0267] Example 48 JPEG0007664642000106.jpg71136 4-(2-hydroxy-2-methylpropyl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0268] a) Methyl 4-(2-hydroxy-2-methylpropyl)-2-methoxybenzoate At -70°C, LDA (8.3 mL, 0.2 mmol, 2M in THF) is added to a solution of 1,3-dimethyl-1,3-diazinan-2-one (7.8 mL, 64 mmol) in THF (30 mL), followed by methyl 2-methoxy-4-methylbenzoate (2.91 g, 16 mmol). The reaction is stirred at -70°C for 2 hours and acetone (1.78 mL, 24.224 mmol) is added. The reaction is warmed to 0°C and stirred at said temperature for 1 hour. The mixture is diluted with brine (20 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purify the residue by silica gel column chromatography, eluting with petroleum ether containing ethyl acetate (PE / EA=1 / 0-1.5 / 1) to obtain the title compound as a yellow oil (900 mg, yield: 19.2%). LC-MS (ESI): m / z 238.8 [M+H] + .

[0269] b) 4-(2-hydroxy-2-methylpropyl)-2-methoxybenzoic acid To a solution of methyl 4-(2-hydroxy-2-methylpropyl)-2-methoxybenzoate (1.7 g, 7.13 mmol) in MeOH (20 mL) is added HO (20 mL) and LiOH·HO (3.00 g, 71 mmol). The reaction is stirred at 60 °C for 2 h. The mixture is cooled to room temperature and the pH is adjusted to 7-8 with aqueous HCl (1.0 M). The organic solvents are removed under vacuum and water (20 mL) is added. The mixture is acidified with hydrochloric acid (5 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to give the title compound (1.4 g, yield: 72%) as a yellow oil. LC-MS (ESI): m / z 225.1 [M+H] + .

[0270] c) 4-(2-hydroxy-2-methylpropyl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine TFA salt (2.19 g, 5.563 mmol) in DMF (15 mL) is added DIEA (2.51 mL, 15.171 mmol), BOP (2.68 g, 6.068 mmol) and 4-(2-hydroxy-2-methylpropyl)-2-methoxybenzoic acid (1.4 g, 5.057 mmol). The reaction is stirred at room temperature for 1 h. The reaction is diluted with ethyl acetate (30 mL) and brine (50 mL). The organic layer is separated, dried over Na2SO4, filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (PE:EA=1:0-1 / 2) to give the title compound (1.0 g, 2.59 mmol, yield: 51%) as an off-white solid. LC-MS(ESI):m / z 388.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.87(t,J=5.6Hz,1H),7.93(dd,J=5.0,1.2Hz,1H),7.78(dd,J=3.7,1.2Hz,1H),7.73(d,J=7.9Hz,1H),7.28(dd,J=5.0,3.7H z,1H),7.02(s,1H),6.90(dd,J=7.9,1.1Hz,1H),4.77(d,J=5.7Hz,2H),4.39(s,1H),3.91(s,3H),2.70(s,2H),1.09(s,6H).

[0271] Example 49 JPEG0007664642000107.jpg61140 2-Methoxy-4-(piperidin-1-ylmethyl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

[0272] a) 4-formyl-2-methoxybenzoic acid A solution of 4-bromo-2-methoxybenzoic acid (4.0 g, 17 mmol) in THF (50 mL) is cooled to -65 °C and n-butyllithium (15.2 mL, 0.16 mmol, 2.5 M in THF) is added. The reaction is stirred at this temperature for 30 min. DMF (1.62 mL, 21 mmol) is added dropwise to the mixture, and then the whole mixture is slowly warmed to 0 °C and stirred for 30 min. The mixture is diluted with ethyl acetate (30 mL) and washed with saturated aqueous NH4Cl (50 mL) and brine (50 mL). The organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The residue is dissolved in dichloromethane with methanol (MeOH:DCM = 0:1 to 1:20) and purified by silica gel column chromatography to give the title compound (2.3 g, yield: 55%) as a yellow solid. LC-MS (ESI): m / z 179.1 [MH] - .

[0273] b) 4-formyl-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 4-formyl-2-methoxybenzoic acid (300 mg, 1.249 mmol) in DMF (10 mL) is added BOP (828 mg, 1.9 mmol), DIEA (0.62 mL, 3.7 mmol) and (5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanamine TFA salt (347.19 mg, 1.249 mmol). The reaction is stirred at room temperature for 2 h. The reaction is diluted with ethyl acetate (20 mL) and brine (40 mL). The organic layer is separated, washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography eluting with methanol in dichloromethane (MeOH / DCM=0 / 1 to 1 / 20) to give the title compound (120 mg, yield: 26%) as a white solid. LC-MS(ESI):m / z 344.1[M+H] + .

[0274] c) 2-Methoxy-4-(piperidin-1-ylmethyl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide To a solution of 4-formyl-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (50 mg, 0.15 mmol) in MeOH (5 mL), piperidine (0.2 mL, 2.02 mmol) and acetic acid (0.01 mL, 0.175 mmol) are added and the reaction is stirred at room temperature for 1 h. To this mixture, sodium cyanoborohydride (18 mg, 0.291 mmol) is added and the reaction is stirred at said temperature for 2 h. After completion of the reaction, the mixture is purified by preparative HPLC (Waters 2767 / 2545 / 2489, Waters Xbridge C18 10um OBD 19×250mm, Mobile phase A: water containing 0.1% NH4OH, Mobile phase B: CH3CN, Flow rate: 20mL / min, Column temperature: RT) to give the title compound as a white solid (18mg, Yield: 30%). LC-MS(ESI): m / z 413.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.89(t,J=5.7Hz,1H),7.94(dd,J=5.0,1.2Hz,1H),7.79-7.75(m,2H),7.28(dd,J=5.0,3.7Hz,1H),7.08(s,1H),6. 99(d,J=7.3Hz,1H),4.77(d,J=5.7Hz,2H),3.91(s,3H),3.46(s,2H),2.33(s,4H),1.53-1.47(m,4H),1.39(s,2H).

[0275] The following compounds are synthesized according to the procedure described in Example 49. JPEG0007664642000108.jpg147160

[0276] Bioanalysis and Data As described above, the compounds of formula I are MIF inhibitors and can be used to treat diseases mediated by MIF. The biological activity of the compounds can be determined by any assay method suitable for determining the activity of a candidate compound as a MIF inhibitor.

[0277] MIF enzyme analysis Tautomerase assay using pHPP as a substrate This assay measures MIF tautomerase activity by measuring the MIF-catalyzed initial rate of conversion of the keto-enol tautomer of pHPP in a cell-free system. This is achieved by spectrophotometric quantification of the complex between borate and the reaction product (enol pHPP). The substrate is prepared by converting the enol pHPP to its keto form, for which 0.5 M pHPP in methanol is diluted 10-fold with 50 mM sodium acetate buffer at pH 6.0, then the suspension is shaken in the dark at room temperature for 24 hours, and finally it is recommended to store it at 4 °C for no more than one week and sonicate for 5 minutes before use.

[0278] The assay is performed in small volume 96 or 384 well polystyrene plates (Greiner Bio-One) with black clear bottom. First, 2 μL of enzyme solution containing 6 nM MIF in D-PBS, 0.025% w / v BSA and 300 μM CHAPS is dispensed into sample and negative control wells using a dispenser - Multidrop Combi (Thermo Fisher Scientific) with a metal straw cassette pretreated with siliconizing agent Sigmacote. Then, 2 μL of the same buffer without MIF is dispensed into the positive control well. The reaction is started by adding to all wells: 2 μL of substrate solution, containing 200 mM boric acid, 25 mM sodium phosphate, 0.025% w / v BSA and 300 μM CHAPS, 3 mM ketone pHPP in pH 6.0. The plate is centrifuged at 1000 rpm for 2 minutes in an Allegra 25R centrifuge (Beckman Coulter, Inc., Brea, CA) at room temperature to remove air bubbles. The plate is then read on an EnVision. The final concentrations of enzyme and substrate are 3 nM and 1.5 mM, respectively. The initial velocity of each well is calculated as the slope of the absorbance progress curve.

[0279] All exemplified compounds (Examples 1-85) are tested in the MIF tautomerase assay described above or a similar assay. The data below show the average pIC50 It is understood that the data presented below may reasonably vary depending on the particular conditions and procedures used by those conducting the tests.

[0280] Analysis data Assay results pIC measuring the inhibitory effect of compounds on MIF 50 The data is shown in Table 1 below.

[0281] JPEG0007664642000109.jpg226161JPEG0007664642000110.jpg243161JPEG00076646420 00111.jpg243161JPEG0007664642000112.jpg243161JPEG0007664642000113.jpg105161

[0282] Cell proliferation analysis The assay detects the ability of compounds to inhibit cell proliferation using the Cell Counting Kit-8 (CCK-8), which uses a sensitive colorimetric assay to determine cell viability in cell proliferation and cytotoxicity assays. The highly water-soluble tetrazolium salt WST-8 is reduced by intracellular dehydrogenase activity to produce a yellow formazan dye that is soluble in tissue culture medium. The amount of formazan dye produced by intracellular dehydrogenase activity is directly proportional to the number of viable cells.

[0283] The assay is performed according to the manufacturer's instructions (Dojindo Molecular Technologies Inc., Rockville, MD, USA). To initiate the assay, 2 × 10 BV2 cells were cultured at 4 °C for 1 h. 6Cells are seeded into 96-well plates at a density of 1000 cells / well and treated with the compound to be tested, the highest final assay concentration of the compound to be tested being 33.3 μM, and diluted 1:3 with assay medium to generate a 10-point concentration response for 48 hours. After incubation, CCK-8 solution (10 μl) is added to each well of the cell culture plate, and the cell culture plate is incubated in a 37° C. incubator for 3 hours. The absorbance is recorded three times independently at a wavelength of 450 nm using a microplate reader (Bio-Rad Laboratories, Richmond, CA, USA).

[0284] Selected examples are tested in BV2 cell proliferation. The data below shows the average pIC of multiple test results. 50 It is to be understood that the data presented below may reasonably vary depending on the particular conditions and procedures used by the person conducting the tests. Analysis of compounds for MIF inhibitory effect pIC 50 The data is shown in Table 2 below.

[0285] JPEG0007664642000114.jpg226161JPEG0007664642000115.jpg128161

Claims

1. A compound selected from the following: or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof: 4-(benzyloxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 15), 4-hydroxy-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 16), 4-(2-hydroxyethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 17), 4-(2-(benzyloxy)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 18), 2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)acetic acid (compound 19), 4-(2-(dimethylamino)ethoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 20), 2-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenoxy)-2-methylpropionic acid (compound 21), 4-((2H-tetrazol-5-yl)methoxy)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 22), 2-Methoxy-4-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-2H-tetrazol-5-yl)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 23), 2-Methoxy-4-((1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-tetrazol-5-yl)methoxy)-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 24), 4-(3-cyanopropyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 25), 4-(3-(2H-tetrazol-5-yl)propyl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 26), cis-4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid (compound 27), trans-4-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)cyclohexane-1-carboxylic acid (compound 28), 3'-Methoxy-4'-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (compound 29), (3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)proline (compound 30), 1-(3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)piperidine-3-carboxylic acid (compound 31), 2-((3-methoxy-4-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)carbamoyl)phenyl)amino)-2-methylpropionic acid (compound 32), 4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methoxy-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 33), 2-Methoxy-4-morpholino-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 37), 2,4-dimethoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 38), 2-Methoxy-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 51), 4-(2,6-dimethylmorpholino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 55), 2-Methoxy-4-(piperidin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 56), 4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 57), 2-Methoxy-4-(piperazin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 58), 2-Methoxy-4-(4-methylpiperazin-1-yl)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 59), 2-Methoxy-4-(2-morpholinoethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 69), 4-(2-hydroxyethoxy)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 70), 2-Methoxy-4-(2-methoxyethoxy)-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 71), 4-(3-hydroxypyrrolidin-1-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 78), 4-((2-hydroxyethyl)amino)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 79), and 4-(2-hydroxypropan-2-yl)-2-methoxy-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 83).

2. The compound according to claim 1, wherein the compound is 2-methoxy-4-morpholino-N-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (compound 37), or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof.

3. The compound according to claim 1, wherein the compound is 2-methoxy-4-morpholino-N-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide (compound 51), or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof.

4. A pharmaceutical composition for treating a disease comprising a compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, and a pharma- ceutically acceptable excipient, The disease is a tumor selected from glioblastoma, lung cancer, breast cancer, gastric cancer, bladder cancer, and melanoma; an inflammatory disease selected from chronic obstructive pulmonary disease and pneumonia, or The pharmaceutical composition is an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

5. Use of a compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, in the preparation of a medicament for treating a disease, comprising: The disease is a tumor selected from glioblastoma, lung cancer, breast cancer, gastric cancer, bladder cancer, and melanoma; an inflammatory disease selected from chronic obstructive pulmonary disease and pneumonia, or The use wherein the disease is an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

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