Semicarbazide-sensitive amino oxidase inhibitors and use thereof

Abstract

The application relates to a compound of Formula (I') or (I): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of semicarbazide-sensitive amino oxidase(SSAO), a pharmaceutical composition comprising a compound of Formula (I') or (I), and a method of treating or preventing a disease in which SSAO plays a role.

Description

SEMICARBAZIDE-SENSITIVE AMINO OXIDASE INHIBITORS AND USE THEREOF BACKGROUND

[0001] Semicarbazide-sensitive amino oxidase / vascular adhesion protein-1 (SSAO / VAP-1) exists both as a membrane-bound isoform and a plasma soluble isoform. It is predominantly expressed in endothelial cell surface, vascular smooth muscle, and adipose cells. Both the membrane-bound VAP-1 protein and the soluble SSAO enzyme have amine oxidase enzymatic activity. SSAO catalyzes oxidative deamination of primary amines and produces aldehyde, hydrogen peroxide and ammonium. SSAO protein and activities are involved in leukocyte adhesion and migration from blood to tissue, which is often upregulated during inflammation.

[0002] SSAO / VAP-1 participates in many cellular processes including glucose disposition, inflammation responses and the associated pain, and leukocyte recruitment. High activity levels of this enzyme are associated with diabetes, atherosclerosis, stroke and complications thereof, chronic kidney disease, and Alzheimer's disease, among other disorders. SSAO / VAP-1 has also been implicated in the pathogenesis of liver diseases such as the fatty liver disease.

[0003] Nonalcoholic fatty liver disease (NAFLD) has shown an increasing prevalence, along with a global increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), can be characterized as ectopic accumulation of lipid, progressive lobular inflammation, hepatocyte degeneration and fibrosis in liver. It has a variable course but can lead to cirrhosis, liver cancer and other liver related morbidities. Therefore, there is a need for treatments for NAFLD and / or NASH.

[0004] An SSAO / VAP-1 inhibitor is believed to be able to reduce liver inflammation and fibrosis, and thereby provide a treatment for liver diseases, in particular, NAFLD and / or NASH. In addition, since activation of SSAO / VAP-1 has been implicated in inflammation and the associated pain, inhibition of SSAO / VAP-1 may also be useful in treating pain, and in particular, pain associated with osteoarthritis.

[0005] Currently, there is no approved drugs for the treatment for NASH, while the standard of care for NASH including diet control and / or life style changes often lacks effect once liver cell injury and inflammation are evident. In addition, the current standard of care for pain is dominated by nonsteroidal anti-inflammatory drugs (NSAIDS) and opioids, which are not recommended for chronic use due to adverse effect and abuse. Thus, there is a need for SSAO / VAP-1 inhibitors as therapeutic options for the treatment of chronic pain. The present application addresses the need. SUMMARY

[0006] A first aspect of the application relates to a compound of Formula (I') or (I): [Image disponible dans le document PDF, Image available in the PDF document] (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, L, X, and p are as described in detail below.

[0007] Another aspect of the application relates to a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0008] Another aspect of the application relates to a method of treating a SSAO-mediated disorder. The method comprises administering to a subject in need of a treatment for a disease or disorder associated with modulation of SSAO a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0009] Another aspect of the application relates to a method of reducing liver inflammation. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0010] Another aspect of the application relates to a method of reducing neuroinflammation. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0011] Another aspect of the application relates to a method of reducing liver fibrosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0012] Another aspect of the application relates to a method of reducing lung fibrosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0013] Another aspect of the application relates to a method of treating liver diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0014] Another aspect of the application relates to a method of treating nonalcoholic fatty liver disease (NAFLD). The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0015] Another aspect of the application relates to a method of treating nonalcoholic steatohepatitis (NASH). The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0016] Another aspect of the application relates to a method of treating cardiovascular diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0017] Another aspect of the application relates to a method of treating atherosclerosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0018] Another aspect of the application relates to a method of treating stroke and complications thereof. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0019] Another aspect of the application relates to a method of treating myocardial infarction. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0020] Another aspect of the application relates to a method of treating chronic kidney diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0021] Another aspect of the application relates to a method of treating autoimmune diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0022] Another aspect of the application relates to a method of treating metabolic diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0023] Another aspect of the application relates to a method of treating inflammation. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0024] Another aspect of the application relates to a method of treating pain. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0025] Another aspect of the application relates to a method of treating pain associated with osteoarthritis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0026] Another aspect of the application relates to a method of modulating <com:Math><semantics>(e.g.,inhibiting)<annotation encoding="application / x-tex">(e.g., inhibiting)< / annotation>< / semantics>< / com:Math> SSAO. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0027] Another aspect of the application relates to a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, for use in a method of treating a SSAO-mediated disorder or of modulating (e.g., inhibiting) SSAO.

[0028] Another aspect of the application relates to use of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, in the manufacture of a medicament for treating a SSAO-mediated disorder or for modulating (e.g., inhibiting) SSAO.

[0029] The present application further provides methods of treating a disease or disorder associated with modulation of SSAO including, but not limited to, liver diseases, nonalcoholic steatohepatitis (NASH), cardiovascular diseases, metabolic diseases, inflammation, and pain, comprising administering to a subject suffering from at least one of the diseases or disorders a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

[0030] The present application provides inhibitors of SSAO that are therapeutic agents in the treatment of diseases such as liver diseases, nonalcoholic steatohepatitis (NASH), cardiovascular diseases, metabolic diseases, inflammation, pain, and other disease associated with the modulation of SSAO.

[0031] The present application further provides compounds and compositions with an improved efficacy and safety profile relative to known SSAO inhibitors. The present application also provides agents with novel mechanisms of action toward SSAO in the treatment of various types of diseases including liver diseases, nonalcoholic steatohepatitis (NASH), cardiovascular diseases, metabolic diseases, inflammation, and pain. Ultimately the present application provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with SSAO. DETAILED DESCRIPTION Compounds of the Application

[0032] The present application relates to compounds and compositions thereof that are capable of modulating the activity of semicarbazide-sensitive amino oxidase (SSAO). The application features methods of treating, preventing, or ameliorating a disease or disorder in which SSAO plays a role by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. The compounds of the present application can be used in the treatment of a variety of SSAO-mediated diseases and disorders by inhibiting the activity of SSAO. Inhibition of SSAO provides treatment, prevention, or amelioration of diseases including, but not limited to, liver diseases, nonalcoholic steatohepatitis (NASH), cardiovascular diseases, metabolic diseases, inflammation, and pain.

[0033] In a first aspect of the application, a compound of Formula (I') or (I) is described: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: each X is independently Cl or F; p is 0, 1, 2, or 3; L is absent, -O-, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, substituted <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, -O-<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, substituted <com:Math><semantics>−O−(C1−C4)<annotation encoding="application / x-tex">-O-(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene-O-, or substituted <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene-O-, wherein the substituted <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, substituted <com:Math><semantics>−O−(C1−C4)<annotation encoding="application / x-tex">-O-(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, or substituted <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene-O- is substituted with one or more L<com:Sup>1< / com:Sup>; each <com:Math><semantics>L1<annotation encoding="application / x-tex">L^1< / annotation>< / semantics>< / com:Math> is independently (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>) alkyl, F, or CF<com:Sub>3< / com:Sub>; or two <com:Math><semantics>L1<annotation encoding="application / x-tex">L^1< / annotation>< / semantics>< / com:Math>, together with the atom to which they are attached, form a 3- to 5-membered cycloalkyl ring; each R<com:Sup>1< / com:Sup> is independently H, F, methyl, ethyl, or CF<com:Sub>3< / com:Sub>; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, NR<com:Sup>3< / com:Sup>C(O)R<com:Sup>4< / com:Sup>, C(O)NR<com:Sup>3< / com:Sup>R<com:Sup>4< / com:Sup>, phenyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>) cycloalkyl, heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O, or heteroaryl comprising one or two 5- to 6-membered rings and 1 to 3 heteroatoms selected from N and O, wherein the phenyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more R<com:Sup>5< / com:Sup>; R<com:Sup>3< / com:Sup> is H, methyl, or ethyl; R<com:Sup>4< / com:Sup> is (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>) alkyl or (C<com:Sub>3< / com:Sub>-C<com:Sub>10< / com:Sub>) cycloalkyl optionally substituted with one or more R<com:Sup>8< / com:Sup>; or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup>, together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>5< / com:Sup>; each <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is independently <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, hydroxy, cyano, oxo, <com:Math><semantics>C(O)ℝ7<annotation encoding="application / x-tex">C(O)\mathbb{R}^7< / annotation>< / semantics>< / com:Math>, C(O)NR<com:Sup>7< / com:Sup>R<com:Sup>7< / com:Sup>, NR<com:Sup>3< / com:Sup>C(O)R<com:Sup>7< / com:Sup>, NR<com:Sup>3< / com:Sup>S(O)<com:Sub>2< / com:Sub>R<com:Sup>4< / com:Sup>, S(O)<com:Sub>2< / com:Sub>R<com:Sup>4< / com:Sup>, (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>) alkyl substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>, (C<com:Sub>3< / com:Sub>-C<com:Sub>10< / com:Sub>) cycloalkyl optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>, or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>; or two R<com:Sup>5< / com:Sup>, together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated or 5- or 6- membered aromatic ring optionally comprising 1 or 2 heteroatoms selected from N and O; each R<com:Sup>6< / com:Sup> is independently NR<com:Sup>3< / com:Sup>C(O)R<com:Sup>7< / com:Sup> or C(O)NR<com:Sup>3< / com:Sup>R<com:Sup>7< / com:Sup>; each R<com:Sup>7< / com:Sup> is independently OH, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, CF<com:Sub>3< / com:Sub>, F, or (C<com:Sub>3< / com:Sub>–C<com:Sub>10< / com:Sub>) cycloalkyl, <com:Math><semantics>(C3−C10)<annotation encoding="application / x-tex">(C_3-C_{10})< / annotation>< / semantics>< / com:Math> cycloalkyl optionally substituted with one or more <com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math>, or phenyl optionally substituted with one or more <com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^{8}< / annotation>< / semantics>< / com:Math>; each R<com:Sup>7< / com:Sup> is independently H, methyl, or ethyl; or R<com:Sup>7< / com:Sup> and R<com:Sup>7< / com:Sup>, together with the atom to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>; or R<com:Sup>3< / com:Sup> and R<com:Sup>7< / com:Sup>, together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>; and each R<com:Sup>8< / com:Sup> is independently (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>) alkyl, (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>) alkoxy, CF<com:Sub>3< / com:Sub>, OH, or F.

[0034] In some embodiments, in the compounds of Formula (I') or (I), each R<com:Sup>7< / com:Sup> is independently <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, CF<com:Sub>3< / com:Sub>, F, or (C<com:Sub>3< / com:Sub>-C<com:Sub>10< / com:Sub>) cycloalkyl, <com:Math><semantics>(C3−C10)<annotation encoding="application / x-tex">(C_3-C_{10})< / annotation>< / semantics>< / com:Math> cycloalkyl optionally substituted with one or more <com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math>, or phenyl optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[0035] In some embodiments, the compounds of Formula (I') or (I) have the structure of Formula (Ia), (Ia-0), (Ia'), (Ia'-0), (Ia1), (Ia1-0), (Ia1'), (Ia1'-0), (Ia2), (Ia2-0), (Ia2'), (Ia2'-0), (Ia3), (Ia3-0), (Ia3'), or (Ia3'-0): [Image disponible dans le document PDF, Image available in the PDF document] 5 )), , Ο), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ia2), <com:Math><semantics>(Ia2−0),<annotation encoding="application / x-tex">(Ia2-0),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ia2'), <com:Math><semantics>(Ia2′−0),<annotation encoding="application / x-tex">(Ia2'-0),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ia3), <com:Math><semantics>(Ia3−0),<annotation encoding="application / x-tex">(Ia3-0),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ia3'), (Ia3'- 0), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: <com:Math><semantics>A1<annotation encoding="application / x-tex">A^1< / annotation>< / semantics>< / com:Math> is N or <com:Math><semantics>CR5<annotation encoding="application / x-tex">CR^{5}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5′<annotation encoding="application / x-tex">R^{5'}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, hydroxy, or cyano; A<com:Sup>2< / com:Sup> and A<com:Sup>2< / com:Sup> are each independently absent, CH<com:Sub>2< / com:Sub>, CHR<com:Sup>5< / com:Sup>, C(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, NH, NR<com:Sup>5< / com:Sup>, or O, provided that at least one of A<com:Sup>2< / com:Sup> and A<com:Sup>2< / com:Sup> is not absent and that A<com:Sup>2< / com:Sup>-A<com:Sup>2< / com:Sup> is not O-O, O-NH, O-NR<com:Sup>5< / com:Sup>, NH-O, NH–NH, NH–NR<com:Sup>5< / com:Sup>, NR<com:Sup>5< / com:Sup>–O, NR<com:Sup>5< / com:Sup>–NH, or NR<com:Sup>5< / com:Sup>–NR<com:Sup>5< / com:Sup>; A<com:Sup>3< / com:Sup> is CH<com:Sub>2< / com:Sub>, CHR<com:Sup>5< / com:Sup>, C(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, NH, NR<com:Sup>5< / com:Sup>, or O when m is 0, or CH or CR<com:Sup>5< / com:Sup> when m is 1 or 2, provided that A<com:Sup>2< / com:Sup>-A<com:Sup>3< / com:Sup> is not O-O, O-NH, O-NR<com:Sup>5< / com:Sup>, NH-O, NH-NH, NH-NR<com:Sup>5< / com:Sup>, NR<com:Sup>5< / com:Sup>-O, NR<com:Sup>5< / com:Sup>-NH, or <com:Math><semantics>NR5−NR5<annotation encoding="application / x-tex">NR^5 - NR^5< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] m is 0, 1, or 2; and n is 1 or 2.

[0036] In some embodiments, the compounds of Formula (I') or (I) have the structure of Formula (Ib), (Ib-0), (Ib'), or (Ib'-0): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ib), <com:Math><semantics>(Ib−0)<annotation encoding="application / x-tex">(Ib-0)< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ib'), or <com:Math><semantics>(Ib′−0),<annotation encoding="application / x-tex">(Ib'-0),< / annotation>< / semantics>< / com:Math> and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein <com:Math><semantics>R2′<annotation encoding="application / x-tex">R^{2'}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, NR<com:Sup>3< / com:Sup>C(O)R<com:Sup>4< / com:Sup>, C(O)NR<com:Sup>3< / com:Sup>R<com:Sup>4< / com:Sup>, or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O, wherein the heterocyclyl is optionally substituted with one or more R<com:Sup>5< / com:Sup>.

[0037] In some embodiments, the compounds of Formula (I') or (I) have the structure of Formula (Ic), (Ic-0), (Ic'), or (Ic'-0): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ic), <com:Math><semantics>(Ic−0),<annotation encoding="application / x-tex">(Ic-0),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ic'), or <com:Math><semantics>(Ic′−0),<annotation encoding="application / x-tex">(Ic'-0),< / annotation>< / semantics>< / com:Math> and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0038] In some embodiments, the compounds of Formula (I') or (I) have the structure of Formula (Id1), (Id1-0), (Id1'), (Id1'-0), (Id2), (Id2-0), (Id2'), or (Id2'-0): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Id1), <com:Math><semantics>(Id1−0),<annotation encoding="application / x-tex">(Id1-0),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Id1'), <com:Math><semantics>(Id1′−0),<annotation encoding="application / x-tex">(Id1'-0),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Id2), <com:Math><semantics>(Id2−0),<annotation encoding="application / x-tex">(Id2-0),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Id2'), or <com:Math><semantics>(Id2′−0),<annotation encoding="application / x-tex">(Id2'-0),< / annotation>< / semantics>< / com:Math> and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0039] For the formulae above, where applicable:

[0040] In some embodiments, L is absent, -O-, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, substituted <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene-O-, or substituted <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene-O-.

[0041] In some embodiments, L is absent, -O-, <com:Math><semantics>(C1−C2)<annotation encoding="application / x-tex">(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene, substituted <com:Math><semantics>(C1−C2)<annotation encoding="application / x-tex">(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene, <com:Math><semantics>(C1−C2)<annotation encoding="application / x-tex">(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene-O-, or substituted <com:Math><semantics>(C1−C2)<annotation encoding="application / x-tex">(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene-O-.

[0042] In some embodiments, L is absent or -O-.

[0043] In some embodiments, L is absent.

[0044] In some embodiments, L is -O-.

[0045] In some embodiments, L is <com:Math><semantics>(C1−C2)<annotation encoding="application / x-tex">(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene substituted with one or more <com:Math><semantics>L1<annotation encoding="application / x-tex">L^1< / annotation>< / semantics>< / com:Math>.

[0046] In some embodiments, L is <com:Math><semantics>(C1−C2)<annotation encoding="application / x-tex">(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene-O- or <com:Math><semantics>(C1−C2)<annotation encoding="application / x-tex">(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene-O- substituted with one or more <com:Math><semantics>L1<annotation encoding="application / x-tex">L^1< / annotation>< / semantics>< / com:Math>.

[0047] In some embodiments, each <com:Math><semantics>L1<annotation encoding="application / x-tex">L^1< / annotation>< / semantics>< / com:Math> is independently (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>–<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>) alkyl, F, or <com:Math><semantics>CF3<annotation encoding="application / x-tex">CF_3< / annotation>< / semantics>< / com:Math>.

[0048] In some embodiments, each L<com:Sup>1< / com:Sup> is independently methyl, ethyl, F, or CF<com:Sub>3< / com:Sub>.

[0049] In some embodiments, each L<com:Sup>1< / com:Sup> is independently methyl or ethyl.

[0050] In some embodiments, two L<com:Sup>1< / com:Sup>, together with the atom to which they are attached, form a cyclopropyl, cyclobutyl, or cyclopentyl ring.

[0051] In some embodiments, two <com:Math><semantics>L1<annotation encoding="application / x-tex">L^1< / annotation>< / semantics>< / com:Math>, together with the atom to which they are attached, form a cyclopropyl ring.

[0052] In some embodiments, each R<com:Sup>1< / com:Sup> is H.

[0053] In some embodiments, each R<com:Sup>1< / com:Sup> is independently F, methyl, ethyl, or CF<com:Sub>3< / com:Sub>.

[0054] In some embodiments, each R<com:Sup>1< / com:Sup> is independently methyl or ethyl.

[0055] In some embodiments, each R<com:Sup>1< / com:Sup> is independently methyl or CF<com:Sub>3< / com:Sub>.

[0056] In some embodiments, <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(ℂ1−ℂ4)<annotation encoding="application / x-tex">(\mathbb{C}_1 - \mathbb{C}_4)< / annotation>< / semantics>< / com:Math> alkyl (i.e., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, <com:Math><semantics>i<annotation encoding="application / x-tex">i< / annotation>< / semantics>< / com:Math>-propoxy, <com:Math><semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics>< / com:Math>-butoxy, <com:Math><semantics>i<annotation encoding="application / x-tex">i< / annotation>< / semantics>< / com:Math>-butoxy, <com:Math><semantics>s<annotation encoding="application / x-tex">s< / annotation>< / semantics>< / com:Math>-butoxy, or <com:Math><semantics>t<annotation encoding="application / x-tex">t< / annotation>< / semantics>< / com:Math>-butoxy).

[0057] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is methyl or ethyl substituted with methoxy or ethoxy.

[0058] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy).

[0059] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is methoxy or ethoxy.

[0060] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>NR3C(O)R4<annotation encoding="application / x-tex">NR^3C(O)R^4< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>C(O)NR3R4<annotation encoding="application / x-tex">C(O)NR^3R^4< / annotation>< / semantics>< / com:Math>.

[0061] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is phenyl optionally substituted with one or more <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>.

[0062] In some embodiments, <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(ℂ3−ℂ8)<annotation encoding="application / x-tex">(\mathbb{C}_3-\mathbb{C}_8)< / annotation>< / semantics>< / com:Math> cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or spiro-, bridged-, or fused cycloalkyl) optionally substituted with one or more R<com:Sup>5< / com:Sup>.

[0063] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is heterocyclyl (e.g., spiro-, bridged-, or fused-heterocyclyl) optionally substituted with one or more R<com:Sup>5< / com:Sup>.

[0064] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is a heterocyclyl selected from: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein W, W<com:Sup>1< / com:Sup> and W<com:Sup>2< / com:Sup> are each independently CH<com:Sub>2< / com:Sub>, CHR<com:Sup>5< / com:Sup>, C(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, O, S, NH, or NR<com:Sup>5< / com:Sup>, each optionally substituted with one or more R<com:Sup>5< / com:Sup>.

[0065] In some embodiments, R<com:Sup>2< / com:Sup> is heteroaryl optionally substituted with one or more R<com:Sup>5< / com:Sup>.

[0066] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl (i.e., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, or t-butyl) substituted with one or more (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>) alkoxy (i.e., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy).

[0067] In some embodiments, <com:Math><semantics>ℝ2*<annotation encoding="application / x-tex">\mathbb{R}^{2^{*}}< / annotation>< / semantics>< / com:Math> is methyl or ethyl substituted with methoxy or ethoxy.

[0068] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy).

[0069] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is methoxy or ethoxy.

[0070] In some embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>NR3C(O)R4<annotation encoding="application / x-tex">NR^3C(O)R^4< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>C(O)NR3R4<annotation encoding="application / x-tex">C(O)NR^3R^4< / annotation>< / semantics>< / com:Math>.

[0071] In some embodiments, <com:Math><semantics>ℝ2∘<annotation encoding="application / x-tex">\mathbb{R}^{2^{\circ}}< / annotation>< / semantics>< / com:Math> is heterocyclyl (e.g., spiro-, bridged-, or fused-heterocyclyl) optionally substituted with one or more R<com:Sup>5< / com:Sup>.

[0072] In some embodiments, <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^{2}< / annotation>< / semantics>< / com:Math> is a heterocyclyl selected from: [Image disponible dans le document PDF, Image available in the PDF document] wherein W, W<com:Sup>1< / com:Sup> and W<com:Sup>2< / com:Sup> are each independently CH<com:Sub>2< / com:Sub>, CHR<com:Sup>5< / com:Sup>, C(R<com:Sup>5< / com:Sup>)<com:Sub>2< / com:Sub>, O, S, NH, or NR<com:Sup>5< / com:Sup>, each optionally substituted with one or more R<com:Sup>5< / com:Sup>.

[0073] In some embodiments, R<com:Sup>3< / com:Sup> is H,

[0074] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is methyl or ethyl.

[0075] In some embodiments, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl.

[0076] In some embodiments, R<com:Sup>4< / com:Sup> is methyl or ethyl.

[0077] In some embodiments, R<com:Sup>4< / com:Sup> is (C<com:Sub>3< / com:Sub>-C<com:Sub>10< / com:Sub>) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or spiro-, bridged-, or fused cycloalkyl) optionally substituted with one or more R<com:Sup>8< / com:Sup>. In some embodiments, R<com:Sup>4< / com:Sup> is (C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub>) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or spiro-, bridged-, or fused cycloalkyl) optionally substituted with one or more R<com:Sup>8< / com:Sup>. In some embodiments, R<com:Sup>4< / com:Sup> is cyclopropyl or cyclobutyl optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[0078] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>5< / com:Sup>. In some embodiments, each R<com:Sup>5< / com:Sup> is independently selected from methyl, ethyl, cyclopentyl, and phenyl.

[0079] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup>, together with atom(s) to which they are attached, form a 4- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>5< / com:Sup>. In some embodiments, each R<com:Sup>5< / com:Sup> is independently selected from methyl, ethyl, cyclopentyl, and phenyl.

[0080] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup>, together with atom(s) to which they are attached, form a 3-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>5< / com:Sup>. In some embodiments, each R<com:Sup>5< / com:Sup> is independently selected from methyl, ethyl, cyclopentyl, and phenyl.

[0081] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 4-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>5< / com:Sup>. In some embodiments, each R<com:Sup>5< / com:Sup> is independently selected from methyl, ethyl, cyclopentyl, and phenyl.

[0082] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup>, together with atom(s) to which they are attached, form a 5-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>5< / com:Sup>. In some embodiments, each R<com:Sup>5< / com:Sup> is independently selected from methyl, ethyl, cyclopentyl, and phenyl.

[0083] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup>, together with atom(s) to which they are attached, form a 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>5< / com:Sup>. In some embodiments, each R<com:Sup>5< / com:Sup> is independently selected from methyl, ethyl, cyclopentyl, and phenyl.

[0084] In some embodiments, at least one <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl (i.e., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, or t-butyl), (C1-C4) alkoxy (i.e., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), hydroxy, cyano, oxo, <com:Math><semantics>C(O)R7<annotation encoding="application / x-tex">C(O)R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)NR7R7<annotation encoding="application / x-tex">C(O)NR^7R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NR3C(O)R7<annotation encoding="application / x-tex">NR^3C(O)R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NR3S(O)2R4<annotation encoding="application / x-tex">NR^3S(O)_2R^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(O)2R4<annotation encoding="application / x-tex">S(O)_2R^4< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl ((i.e., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, or t-butyl)) substituted with one or more hydroxy or <com:Math><semantics>ℝ6<annotation encoding="application / x-tex">\mathbb{R}^6< / annotation>< / semantics>< / com:Math>.

[0085] In some embodiments, at least one <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl (i.e., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, or t-butyl), (C1-C4) alkoxy ((i.e., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy)), hydroxy, cyano, oxo, or (C<com:Sub>1< / com:Sub>–C<com:Sub>4< / com:Sub>) alkyl ((i.e., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl)) substituted with one or more hydroxy or <com:Math><semantics>ℝ6<annotation encoding="application / x-tex">\mathbb{R}^6< / annotation>< / semantics>< / com:Math>.

[0086] In some embodiments, at least one <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is methyl, methoxy, hydroxy, or cyano.

[0087] In some embodiments, at least one <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C(O)R7<annotation encoding="application / x-tex">C(O)R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)NR7R7<annotation encoding="application / x-tex">C(O)NR^7R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NR3C(O)R7<annotation encoding="application / x-tex">NR^3C(O)R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NR3S(O)2R4<annotation encoding="application / x-tex">NR^3S(O)_2R^4< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>S(O)2R4<annotation encoding="application / x-tex">S(O)_2R^4< / annotation>< / semantics>< / com:Math>.

[0088] In some embodiments, at least one <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C(O)R7<annotation encoding="application / x-tex">C(O)R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)NR7R7<annotation encoding="application / x-tex">C(O)NR^7R^7< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>NR3C(O)R7<annotation encoding="application / x-tex">NR^3C(O)R^7< / annotation>< / semantics>< / com:Math>.

[0089] In some embodiments, at least one <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(ℂ3−ℂ10)<annotation encoding="application / x-tex">(\mathbb{C}_3-\mathbb{C}_{10})< / annotation>< / semantics>< / com:Math> cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or spiro-, bridged-, or fused cycloalkyl) optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>. In some embodiments, at least one R<com:Sup>5< / com:Sup> is (C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub>) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or spiro-, bridged-, or fused cycloalkyl) optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>. In some embodiments, at least one R<com:Sup>5< / com:Sup> is cyclopropyl or cyclobutyl optionally substituted with one or more hydroxy or <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math>.

[0090] In some embodiments, at least one R<com:Sup>5< / com:Sup> is heterocyclyl comprising one or two 3- to 6- membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>. In some embodiments, at least one R<com:Sup>5< / com:Sup> is heterocyclyl comprising one 3- to 6-membering ring and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>. In some embodiments, at least one R<com:Sup>5< / com:Sup> is heterocyclyl comprising one 3- to 6-membering ring and 1 to 2 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>. In some embodiments, at least one R<com:Sup>5< / com:Sup> is heterocyclyl comprising one 3- to 6-membering ring and 1 heteroatom selected from N and O and optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>. In some embodiments, at least one R<com:Sup>5< / com:Sup> is heterocyclyl comprising two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>. In some embodiments, at least one R<com:Sup>5< / com:Sup> is heterocyclyl comprising two 3- to 6-membering rings and 1 to 2 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R<com:Sup>6< / com:Sup>.

[0091] In some embodiments, at least two R<com:Sup>5< / com:Sup>, together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated or 5- or 6-membered aromatic ring optionally comprising 1 or 2 heteroatoms selected from N and O.

[0092] In some embodiments, at least two R<com:Sup>5< / com:Sup>, together with the atom or atoms to which they are attached, form a phenyl ring.

[0093] In some embodiments, at least two R<com:Sup>5< / com:Sup>, together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated ring optionally comprising 1 or 2 heteroatoms selected from N and O.

[0094] In some embodiments, at least one <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl (i.e., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, or t-butyl), <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), hydroxy, cyano, oxo, or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl substituted with one or more hydroxy or <com:Math><semantics>ℝ6<annotation encoding="application / x-tex">\mathbb{R}^6< / annotation>< / semantics>< / com:Math>.

[0095] In some embodiments, R<com:Sup>5< / com:Sup> is H.

[0096] In some embodiments, <com:Math><semantics>R5*<annotation encoding="application / x-tex">R^{5^{*}}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl (i.e., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, or t-butyl), (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>–<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>) alkoxy (i.e., methoxy, ethoxy, propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, or t-butoxy), hydroxy, or cyano.

[0097] In some embodiments, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^{5}< / annotation>< / semantics>< / com:Math> is methyl, methoxy, hydroxy, or cyano.

[0098] In some embodiments, at least one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>NR3C(O)R7<annotation encoding="application / x-tex">NR^3C(O)R^7< / annotation>< / semantics>< / com:Math>.

[0099] In some embodiments, at least one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C(O)NR3R7<annotation encoding="application / x-tex">C(O)NR^3R^7< / annotation>< / semantics>< / com:Math>.

[00100] In some embodiments, each R<com:Sup>7< / com:Sup> is independently <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>CF3<annotation encoding="application / x-tex">CF_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>F<annotation encoding="application / x-tex">F< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>(C3−C10)<annotation encoding="application / x-tex">(C_3-C_{10})< / annotation>< / semantics>< / com:Math> cycloalkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>10< / com:Sub>) cycloalkyl optionally substituted with one or more R<com:Sup>8< / com:Sup>, or phenyl optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00101] In some embodiments, at least one <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl <com:Math><semantics>(e.g.,methyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,ethyl,e<annotation encoding="application / x-tex">(e.g., methyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, ethyl, e< / annotation>< / semantics>< / com:Math> propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s- butoxy, or t-butoxy), CF<com:Sub>3< / com:Sub>, F, or (C<com:Sub>3< / com:Sub>-C<com:Sub>10< / com:Sub>) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[00102] In some embodiments, at least one <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl (e.g., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) or (C1-C6) alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t- butoxy), CF<com:Sub>3< / com:Sub>, F, or (C<com:Sub>3< / com:Sub>-C<com:Sub>10< / com:Sub>) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or spiro-, bridged-, or fused cycloalkyl).

[00103] In some embodiments, at least one <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl <com:Math><semantics>(e.g.,methyl,ethyl,propyl,<math>i<annotation encoding="application / x-tex">(e.g., methyl, ethyl, propyl, i< / annotation>< / semantics>< / com:Math>- propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) or (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>) alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkoxy (i.e., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t- butoxy), CF<com:Sub>3< / com:Sub>, F, or (C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub>) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or spiro-, bridged-, or fused cycloalkyl).

[00104] In some embodiments, at least one <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is methyl or ethyl.

[00105] In some embodiments, at least one <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C3−C10)<annotation encoding="application / x-tex">(C_3-C_{10})< / annotation>< / semantics>< / com:Math> cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or spiro-, bridged-, or fused cycloalkyl) optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00106] In some embodiments, at least one <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is phenyl optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00107] In some embodiments, each R<com:Sup>7< / com:Sup> is H,

[00108] In some embodiments, at least one <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^{7}< / annotation>< / semantics>< / com:Math> is methyl or ethyl.

[00109] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>RT<annotation encoding="application / x-tex">R^T< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00110] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7′<annotation encoding="application / x-tex">R^{7'}< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached. form a 4- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00111] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 3- or 4-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00112] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^{7}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>RT<annotation encoding="application / x-tex">R^{T}< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 3-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00113] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7′<annotation encoding="application / x-tex">R^{7'}< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 4-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00114] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>RT<annotation encoding="application / x-tex">R^T< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 5-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00115] In some embodiments, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00116] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>7< / com:Sup>, together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00117] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 4- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00118] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>7< / com:Sup>, together with atom(s) to which they are attached, form a 3- or 4-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00119] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 3-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00120] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math>, together with atom(s) to which they are attached, form a 4-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00121] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>7< / com:Sup>, together with atom(s) to which they are attached, form a 5-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00122] In some embodiments, R<com:Sup>3< / com:Sup> and R<com:Sup>7< / com:Sup>, together with atom(s) to which they are attached, form a 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R<com:Sup>8< / com:Sup>.

[00123] In some embodiments, at least one <com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl (i.e., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, or t-butyl) or (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>) alkoxy (i.e., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy).

[00124] In some embodiments, at least one <com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math> is methyl or methoxy.

[00125] In some embodiments, at least one <com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ℂ𝔽3<annotation encoding="application / x-tex">\mathbb{CF}_3< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>𝔽<annotation encoding="application / x-tex">\mathbb{F}< / annotation>< / semantics>< / com:Math>.

[00126] In some embodiments, p is 0.

[00127] In some embodiments, p is 1.

[00128] In some embodiments, X is F.

[00129] In some embodiments, X is Cl.

[00130] In some embodiments, m is 0.

[00131] In some embodiments, m is 1.

[00132] In some embodiments, m is 2.

[00133] In some embodiments, n is 1.

[00134] In some embodiments, n is 2.

[00135] Any of the moieties described herein for any one of R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>6< / com:Sup>, R<com:Sup>7< / com:Sup>, R<com:Sup>7< / com:Sup>, R<com:Sup>8< / com:Sup>, A<com:Sup>1< / com:Sup>, A<com:Sup>2< / com:Sup>, A<com:Sup>2< / com:Sup>, A<com:Sup>3< / com:Sup>, A<com:Sup>3< / com:Sup>, X, L, L<com:Sup>1< / com:Sup>, m, n, and p can be combined with any of the moieties described herein for one or more of the remainder of R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>6< / com:Sup>, R<com:Sup>7< / com:Sup>, R<com:Sup>7< / com:Sup>, R<com:Sup>8< / com:Sup>, <com:Math><semantics>A1<annotation encoding="application / x-tex">A^{1}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A2<annotation encoding="application / x-tex">A^{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A2<annotation encoding="application / x-tex">A^{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A3<annotation encoding="application / x-tex">A^{3}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A3<annotation encoding="application / x-tex">A^{3}< / annotation>< / semantics>< / com:Math>, X, L, L<com:Sup>1< / com:Sup>, m, n, and p.

[00136] Non-limiting illustrative compounds of the application include those in Table 1. Table 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00137] Due to the existence of double bonds, the compounds of the present application may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present application, the present application also encompasses the other configuration. For example, the compounds or formulae of [Image disponible dans le document PDF, Image available in the PDF document] the present application may be depicted with the group , the present application also encompasses the the componds or formulae with the other configuration which has the group <com:Math><semantics>NH2<annotation encoding="application / x-tex">^{\text{NH}_2}< / annotation>< / semantics>< / com:Math> ". In some instances, the compounds or formulae of the [Image disponible dans le document PDF, Image available in the PDF document] present application may be depicted with the group , which means that the compounds or formulae may be in cis or trans, or Z or E, configuration.

[00138] In one embodiment, a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate.

[00139] The details of the application are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. Other features, objects, and advantages of the application will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Definitions

[00140] The articles "a" and "an" are used in this application to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[00141] The term "and / or" is used in this application to mean either "and" or "or" unless indicated otherwise.

[00142] The application also includes pharmaceutical compositions comprising an effective amount of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) and a pharmaceutically acceptable carrier.

[00143] The term "alkyl," as used herein, refers to saturated, straight or branched-chain hydrocarbon radicals containing, in certain embodiments, between one and six carbon atoms. Examples of C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals. Examples of <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl radicals.

[00144] The term "alkenyl," as used herein, denotes a monovalent group derived from a hydrocarbon moiety containing, in certain embodiments, from two to six carbon atoms having at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

[00145] The term "alkoxy" refers to an -O-alkyl radical.

[00146] The terms "hal," "halo," and "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.

[00147] The term "aryl," as used herein, refers to a mono- or poly-cyclic carbocyclic ring system having one or more aromatic rings, fused or non-fused, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

[00148] The term "aralkyl," as used herein, refers to an alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.

[00149] The term "cycloalkyl," as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound (fused, bridged, or spiro rings). Examples of C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>- cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Also contemplated is a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Examples of such groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

[00150] The term "heteroaryl," as used herein, refers to a mono- or poly-cyclic (e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ring system having at least one aromatic ring, having from five to ten ring atoms of which one ring atoms is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.

[00151] The term "heteroaralkyl" as used herein, refers to an alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.

[00152] The term "heterocyclyl" or "heterocycloalkyl," as used herein, refers to a saturated or unsaturated non-aromatic 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12- membered bicyclic (fused, bridged, or spiro rings), or 11-, 12, 13, or 14- membered tricyclic ring system (fused, bridged, or spiro rings), where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, and (iv) the nitrogen heteroatom may optionally be quaternized. Representative heterocycloalkyl groups include, but are not limited to, [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4- dioxa-8-azaspiro[4.5]decanyl, 2-azaspiro[3.3]heptan-5-amine, 1-azaspiro[3.3]heptan-5-amine, 1- oxa-6-azaspiro[3.3]heptan-3-amine, 2-azaspiro[3.3]heptan-6-amine, 1-azaspiro[3.3]heptan-6- amine, 6-azaspiro[3.4]octan-2-amine, 5-azaspiro[3.4]octan-2-amine, 6-azaspiro[3.4]octan-1- amine, 5-azaspiro[3.4]octan-1-amine, 5-oxa-2-azaspiro[3.4]octan-7-amine, 7-amino-5-thia-2- azaspiro[3.4]octane 5,5-dioxide, 5-oxa-2-azaspiro[3.4]octan-8-amine, 8-amino-5-thia-2- azaspiro[3.4]octane 5,5-dioxide, and the like.

[00153] The term "alkylamino" refers to a group having the structure, <com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, NH(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl), where <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl is as previously defined.

[00154] The term "dialkylamino" refers to a group having the structure, e.g., <com:Math><semantics>N(C1−C6 alkyl)2<annotation encoding="application / x-tex">N(C_1-C_6 \text{ alkyl})_2< / annotation>< / semantics>< / com:Math>, where <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl is as previously defined.

[00155] In accordance with the application, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted.

[00156] As described herein, compounds of the application may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the application. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The terms "optionally substituted", "optionally substituted alkyl," "optionally substituted alkenyl," "optionally substituted cycloalkyl," "optionally substituted cycloalkenyl," "optionally substituted aryl", "optionally substituted heteroaryl," "optionally substituted aralkyl", "optionally substituted heteroaralkyl," "optionally substituted heterocyclyl," and any other optionally substituted group as used herein, refer to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to: -F, -CI, -Br, -I, -OH, protected hydroxy, -NO<com:Sub>2< / com:Sub>, -CN, -NH<com:Sub>2< / com:Sub>, protected amino, -NH-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, - NH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NH -C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NH-aryl, -NH -heteroaryl, -NH -heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -O-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -O-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -O-C3-C<com:Sub>12< / com:Sub>-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -C(O)- <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-heteroaryl, -C(O)-heterocycloalkyl, -CONH<com:Sub>2< / com:Sub>, -CONH-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -CONH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -CONH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -CONH-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl,-OCO<com:Sub>2< / com:Sub>-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -OCO<com:Sub>2< / com:Sub>-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -OCO<com:Sub>2< / com:Sub>-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -OCO<com:Sub>2< / com:Sub>-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -OCO<com:Sub>2< / com:Sub>-aryl, -OCO<com:Sub>2< / com:Sub>-heteroaryl, -OCO<com:Sub>2< / com:Sub>-heterocycloalkyl, -OCONH<com:Sub>2< / com:Sub>, -OCONH-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -OCONH- C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -OCONH- C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -OCONH-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkyl, -NHC(O)-<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, -NHC(O)-<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, -NHC(O)-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO<com:Sub>2< / com:Sub>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkyl, -NHCO<com:Sub>2< / com:Sub>-<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, -NHCO<com:Sub>2< / com:Sub>-<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, -NHCO<com:Sub>2< / com:Sub>-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NHCO<com:Sub>2< / com:Sub>-aryl, -NHCO<com:Sub>2< / com:Sub>-heteroaryl, -NHCO<com:Sub>2< / com:Sub>- heterocycloalkyl, -NHC(O)NH<com:Sub>2< / com:Sub>, -NHC(O)NH-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkyl, -NHC(O)NH-<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, -NHC(O)NH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NHC(O)NH-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH<com:Sub>2< / com:Sub>, -NHC(S)NH-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkyl, -NHC(S)NH-<com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>-alkenyl, -NHC(S)NH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NHC(S)NH-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH<com:Sub>2< / com:Sub>, -NHC(NH)NH- C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -NHC(NH)NH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NHC(NH)NH-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NHC(NH)NH-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NHheterocycloalkyl, -NHC(NH)-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -NHC(NH)-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NHC(NH)-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -NHC(NH)-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, [Image disponible dans le document PDF, Image available in the PDF document] -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, [Image disponible dans le document PDF, Image available in the PDF document] -S(O)-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl -SO<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, [Image disponible dans le document PDF, Image available in the PDF document] -SO<com:Sub>2< / com:Sub>NH-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -SO<com:Sub>2< / com:Sub>NH-aryl, -SO<com:Sub>2< / com:Sub>NH-heteroaryl, -SO<com:Sub>2< / com:Sub>NH-heterocycloalkyl, [Image disponible dans le document PDF, Image available in the PDF document] -NHSO<com:Sub>2< / com:Sub>-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -NHSO<com:Sub>2< / com:Sub>-aryl, -NHSO<com:Sub>2< / com:Sub>-heteroaryl, -NHSO<com:Sub>2< / com:Sub>-heterocycloalkyl, -CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, -CH<com:Sub>2< / com:Sub>SO<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, <com:Math><semantics>−C3−C12<annotation encoding="application / x-tex">-C_3-C_{12}< / annotation>< / semantics>< / com:Math>-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C<com:Sub>1< / com:Sub>-C<com:Sub>12< / com:Sub>-alkyl, -S-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -S-C<com:Sub>2< / com:Sub>-C<com:Sub>12< / com:Sub>-alkenyl, -S-C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub>-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl.

[00157] The term "carrier", as used in this application, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[00158] The compounds of the present application may form salts which are also within the scope of this application. Reference to a compound of the Formulae herein is understood to include reference to salts thereof, unless otherwise indicated.

[00159] Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[00160] The compounds of the present application, for example, including the pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers of the compounds, can exist in a solvated form with other solvent molecules or in an unsolvated form.

[00161] "Solvate" means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math>.

[00162] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this application, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the application. Individual stereoisomers of the compound of the application may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present application can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester," "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

[00163] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of the present application <com:Math><semantics>(e.g.,a)<annotation encoding="application / x-tex">(e.g., a)< / annotation>< / semantics>< / com:Math> compound of any of the formulae or any individual compounds disclosed herein) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures or as individual enantiomers or diastereomers.

[00164] In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present application includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.

[00165] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereoisomers", and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture".

[00166] The compounds of the application may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the application as well as mixtures thereof, including racemic mixtures, form part of the present application. In addition, the present application embraces all geometric and positional isomers. For example, if a compound of the application incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the application. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compound may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[00167] A carbon atom bonded to four non-identical substituents is termed a "chiral center".

[00168] "Chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture". When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[00169] "Geometric isomer" means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[00170] In another embodiment of the application, the compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is an enantiomer. In some embodiments the compound is the <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>-enantiomer. In other embodiments the compound is the <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-enantiomer. In yet other embodiments, the compounds of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) may be (+) or (-) enantiomers. The compound may contain more than one stereocenter.

[00171] In another embodiment of the application, the compounds of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) are diastereomers. In some embodiments, the compounds are the syn diastereomer. In other embodiments, the compounds are the anti-diastereomer.

[00172] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[00173] It is also possible that the compounds of the application may exist in different tautomeric forms, and all such forms are embraced within the scope of the application. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the application.

[00174] "Tautomer" is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.

[00175] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring- chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring- shaped) form as exhibited by glucose.

[00176] Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide- imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-imine.

[00177] The present application relates to a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of inhibiting SSAO, which are useful for the treatment of diseases and disorders associated with modulation of SSAO. The application further relates to compounds of the present application (<com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, a compound of any of the formulae or any individual compounds disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for inhibiting SSAO. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is a mutant SSAO.

[00178] In some embodiments, the application provides a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), wherein the compound possesses advantageous characteristics, such as decreased brain penetration, i.e., decreased penetration through the blood-brain-barrier, compared to one or more known SSAO inhibitors, including, but not limited to BI 1467335 (PXS-4728A).

[00179] In some embodiments, the application provides a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), wherein the compound is at least as potent as one or more known SSAO inhibitors, including, but not limited to BI 1467335 (PXS-4728A), at inhibiting the activity of the SSAO, and possesses additional advantageous characteristics, such as decreased brain penetration, i.e., decreased penetration through the blood-brain-barrier, compared to one or more known SSAO inhibitors, including, but not limited to BI 1467335 (PXS-4728A).

[00180] In some embodiments, the application provides a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), wherein the compound is more potent than one or more known SSAO inhibitors, including, but not limited to BI 1467335 (PXS-4728A), at inhibiting the activity of the SSAO.

[00181] In some embodiments, the application provides a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), wherein the compound is more potent than one or more known SSAO inhibitors, including, but not limited to BI 1467335 (PXS-4728A), at inhibiting the activity of the SSAO, and possesses additional advantageous characteristics, such as decreased brain penetration, i.e., decreased penetration through the blood-brain-barrier, compared to one or more known SSAO inhibitors, including, but not limited to BI 1467335 (PXS-4728A).

[00182] Potency of the inhibitor can be determined by IC<com:Sub>50< / com:Sub> value. A compound with a lower IC<com:Sub>50< / com:Sub> value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher <com:Math><semantics>IC50<annotation encoding="application / x-tex">IC_{50}< / annotation>< / semantics>< / com:Math> value. Brain penetration property can be determined by Brain Kpuu value. A compound with a lower brain Kpuu value, as determined under substantially similar conditions, is less brain penetrable

[00183] The compounds of the present application can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (<com:Math><semantics>m<annotation encoding="application / x-tex">m< / annotation>< / semantics>< / com:Math>-CPBA) and / or hydrogen peroxides) to afford other compounds of the present application. Thus, all shown and claimed nitrogen- containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N<com:Math><semantics>→<annotation encoding="application / x-tex">\rightarrow< / annotation>< / semantics>< / com:Math>O or N<com:Math><semantics>+<annotation encoding="application / x-tex">^+< / annotation>< / semantics>< / com:Math>-O<com:Math><semantics>−<annotation encoding="application / x-tex">^-< / annotation>< / semantics>< / com:Math>). Furthermore, in other instances, the nitrogens in the compounds of the present application can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compounds as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

[00184] The term "prodrug," as used in this application, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[00185] Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof can be delivered in prodrug form. Thus, the present application is intended to cover prodrugs of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present application in vivo when such prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the application wherein a hydroxyl or amino, group is bonded to any group that, when the prodrug of the present application is administered to a mammalian subject, it cleaves to form a free hydroxyl or free amino group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of each of the formulae described herein or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

[00186] The term "crystal polymorphs", "polymorphs" or "crystal forms" means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.

[00187] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[00188] The application also comprehends isotopically-labeled compounds, which are identical to those recited in the each of the formulae described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, fluorine, such as <com:Sup>3< / com:Sup>H, <com:Sup>11< / com:Sup>C, <com:Sup>14< / com:Sup>C, <com:Sup>2< / com:Sup>H and <com:Sup>18< / com:Sup>F.

[00189] Compounds of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as <com:Sup>3< / com:Sup>H, <com:Sup>14< / com:Sup>C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., <com:Sup>3< / com:Sup>H, and carbon-14, i.e., <com:Sup>14< / com:Sup>C, isotopes are useful for their ease of preparation and detectability. <com:Sup>11< / com:Sup>C and <com:Sup>18< / com:Sup>F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., <com:Sup>2< / com:Sup>H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, isotopically labeled compounds of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. In one embodiment, the compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, is not isotopically labelled.

[00190] The term "administer", "administering", or "administration" as used in this application refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug, derivative or analog of the compound or pharmaceutically acceptable salt of the compound or a composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[00191] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

[00192] An "effective amount" or "therapeutically effective amount" when used in connection with a compound or pharmaceutical composition is an amount effective for treating or preventing a disease in a subject as described herein.

[00193] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[00194] The compounds of the present application, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, can also be used to prevent a disease, condition or disorder. As used herein, "preventing" or "prevent" describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.

[00195] The term "disorder" is used in this application to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[00196] As used herein, the term "SSAO-mediated" diseases or disorders means any disease or other deleterious condition in which SSAO, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which SSAO, or a mutant thereof, is known to play a role. Specifically, the present application relates to a method of treating or lessening the severity of a disease or condition selected from a liver disease, liver inflammation, liver fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), atherosclerosis, stroke and complications thereof, chronic kidney disease, Alzheimer's disease, cardiovascular disease, metabolic disease, inflammation, pain, and pain associated with osteoarthritis, neuroinflammation, wherein said method comprises administering to a subject in need thereof a compounds of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, or a composition according to the present application. Methods for Preparing the Compounds

[00197] The compounds of the present application may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[00198] The compounds of the present application <com:Math><semantics>(e.g.,acompoundofanyoftheformulae)<annotation encoding="application / x-tex">(e.g., a compound of any of the formulae)< / annotation>< / semantics>< / com:Math> or any individual compounds disclosed herein) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of the compounds of the present application.

[00199] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present application includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

[00200] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[00201] The compounds of the present application can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present application can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. The compounds of the present application (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the steps outlined in General Scheme 1. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. General Scheme 1 [Image disponible dans le document PDF, Image available in the PDF document]

[00202] Scheme 1 depicts a generic synthesis of compounds of Formula (I') or (I). Specifically, the hydroxyl group of Compound (I)-A or Compound (I')-A can be alkylated with a suitably protected amine, typically under basic conditions, which can be deprotected to give compounds of Formula (I') or (I).

[00203] A mixture of enantiomers, diastereomers, cis / trans isomers resulting from the processes described above can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation. Analytical Methods, Materials, and Instrumentation

[00204] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker<com:Sup>TM< / com:Sup> or Varian<com:Sup>TM< / com:Sup> spectrometers at 400 MHz. Spectra are given in ppm (<com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) were collected using a SHIMADZU<com:Sup>TM< / com:Sup> LCMS-2020EV or Agilent<com:Sup>TM< / com:Sup> 1260-6125B LCMS. Purity and low resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity<com:Sup>TM< / com:Sup> UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C18 2.7 μm 4.6 X 100 mm; Flow rate 0.8 mL / min; Solvent A (100 / 0.1 water / formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C18 1.7 µm 2.1 X 50 mm; Flow rate 0.5 mL / min; Solvent A (0.1% formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min.

[00205] Abbreviations used in the following examples and elsewhere herein are: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Biological Assays

[00206] The biological activities of the compounds of the present application can be assessed with methods and assays known in the art. For example, the potency of the compounds of the present application can be evaluated with an SSAO Activity Assay. Briefly, compounds of the present application can be applied to recombinant hSSAO, hMAO-A, and hMAO-B isoforms and the amine oxidase activity of the enzymes are measured after the addition and subsequent oxidation of the luminogenic substrate (e.g., with the MAO-Glo assay kit from Promega). The IC<com:Sub>50< / com:Sub> can be calculated, for example, by fitting the dose response curve using a 4-parameter non- linear regression routine.

[00207] In addition, the compounds of the preset application possess additional advantageous biological activities, such as decreased brain penetration, which can be evaluated with methods and assays known in the art. For example, Brain Kpuu assay composed of Blood-Brain-Barrier (BBB) assay and protein binding assay, can be utilized. The protein binding assay comprises equilibrium dialysis against brain lysate and plasma to calculate <com:Math><semantics>fu(brain)<annotation encoding="application / x-tex">f_{u(brain)}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>fu(plasma)<annotation encoding="application / x-tex">f_{u(plasma)}< / annotation>< / semantics>< / com:Math>, respectively. The BBB assay can be conducted in experimental animals at Img / kg IV dosage. After dosing with the compounds of the present application, plasma and brain samples can be collected to analyze compound concentration (<com:Math><semantics>Cplasma<annotation encoding="application / x-tex">C_{plasma}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Cbrain<annotation encoding="application / x-tex">C_{brain}< / annotation>< / semantics>< / com:Math>). The Kpuu value of the tested compounds can be calculated by the equation: [Image disponible dans le document PDF, Image available in the PDF document] Methods of Using the Compounds

[00208] The compounds of the present invention are useful for modulating <com:Math><semantics>(e.g.,inhibiting)<annotation encoding="application / x-tex">(e.g., inhibiting)< / annotation>< / semantics>< / com:Math> an amine oxidase enzyme, such as membrane-bound SSAO / VAP-1 or soluble SSAO / VAP-1. The relative inhibitory potencies of the compounds can be determined by the amount needed to inhibit the amine oxidase activity of SSAO / VAP-1 in a variety of ways, e.g., in in vitro assays with recombinant human protein or with recombinant non-human enzyme, in cellular assays expressing normal enzyme, or in in vivo tests. Accordingly, the present application relates to methods of modulating <com:Math><semantics>(e.g.,inhibiting)<annotation encoding="application / x-tex">(e.g., inhibiting)< / annotation>< / semantics>< / com:Math> an amine oxidase enzyme, such as membrane-bound SSAO / VAP-1 or soluble SSAO / VAP-1, for the treatment of a disease or disorder.

[00209] The compounds of the present application are useful for the treatment of a disease or disorder associated with the SSAO (e.g., overexpression, dysregulation, or aberrant activity of SSAO). A disease or disorder associated with the SSAO includes, but is not limited to, inflammation or an inflammatory disease, fibrosis or a fibrotic disease, a liver disease, a cardiovascular disease, autoimmune disease, and a metabolic disease.

[00210] Inflammation or an inflammatory disease (e.g., inflammation or an inflammatory disease associated with the SSAO) includes, but is not limited to, arthritis, synovitis, Crohn's disease, ulcerative colitis, irritable bowel disease, asthma (e.g., eosinophilic asthma, severe asthma, virally exacerbated asthma), chronic pain, chronic pain from osteoarthritis, chronic pulmonary obstructive disease, cystic fibrosis, bronchiectasis, liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, NAFLD, NASH, neuroinflammation, cirrhosis, atherosclerosis, chronic heart failure, congestive heart failure, ischemic disease, stroke and complications thereof, myocardial infarction and complications thereof, inflammatory cell-mediated tissue destruction following stroke, psoriasis, contact dermatitis, inflammation due to diabetes, skin inflammation, pulmonary inflammation, liver inflammation, and the like.

[00211] Fibrosis or a fibrotic disease (<com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, a fibrotic disease associated with the SSAO) includes, but is not limited to, cystic fibrosis, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), liver fibrosis, kidney fibrosis, lung fibrosis, fibrosis of other organs and tissues, radiation induced fibrosis, and other diseases where excessive fibrosis contributes to disease pathology, and the like.

[00212] A liver disease (e.g., a liver disease associated with the SSAO) includes, but is not limited to, liver inflammation, liver fibrosis, NASH, NAFLD, cirrhosis, liver autoimmune diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, and alcoholic liver disease.

[00213] A respiratory disease (<com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, a respiratory disease, associated with the SSAO) includes, but is not limited to, lung fibrosis, lung inflammation, asthma (e.g., eosinophilic asthma, severe asthma, virally exacerbated asthma), chronic pulmonary obstructive disease, cystic fibrosis, and bronchiectasis.

[00214] Another aspect of the application relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of SSAO (e.g., inhibition of SSAO). The method comprises administering to a subject in need of a treatment for diseases or disorders associated with modulation of SSAO an effective amount a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof or a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein). In one embodiment, the SSAO-mediated disorder is a disease or disorder described herein. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00215] Another aspect of the application relates to a method of modulating SSAO, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application (<com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein). In one embodiment, modulating SSAO is inhibiting SSAO. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00216] Another aspect of the application relates to a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating a SSAO-mediated disorder. In one embodiment, the SSAO-mediated disorder is a disease or disorder described herein. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00217] In another aspect, the present application relates to a pharmaceutical composition of a compound of the present application <com:Math><semantics>(e.g.,a)<annotation encoding="application / x-tex">(e.g., a)< / annotation>< / semantics>< / com:Math> compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating a SSAO-mediated disorder. In one embodiment, the SSAO-mediated disorder is a disease or disorder described herein. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00218] Another aspect of the application relates to a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in modulating SSAO. In one embodiment, modulating SSAO is inhibiting SSAO. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00219] In another aspect, the present application relates to a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in modulating SSAO. In one embodiment, modulating SSAO is inhibiting SSAO. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00220] Another aspect of the application relates to the use of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a SSAO-mediated disease or disorder. In one embodiment, the SSAO-mediated disorder is a disease or disorder described herein. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00221] In another aspect, the present application relates to the use of a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a SSAO-mediated disease or disorder. In one embodiment, the SSAO-mediated disorder is a disease or disorder described herein. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00222] Another aspect of the application relates to the use of a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for modulating SSAO. In one embodiment, modulating SSAO is inhibiting SSAO. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00223] In another aspect, the present application relates to the use of a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulae) or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for modulating SSAO. In one embodiment, modulating SSAO is inhibiting SSAO. In some embodiments, the SSAO is wild-type SSAO. In other embodiments, the SSAO is mutant SSAO.

[00224] The disclosed compound of the application can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects.

[00225] The compound of the application can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., non-drug therapies. For example, synergistic effects can occur with other anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory substances. In some embodiments, a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is administered in combination with an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating lung disease, an agent for treating kidney disease, an agent for treating ocular disease, an agent for treating skin disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders. Where the compound of the application is administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

[00226] Combination therapy includes the administration of the subject compound in further combination with other biologically active ingredients (such as, but not limited to, an anti- inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, an agent for treating immunodeficiency disorders, and an agent for treating pain) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). For instance, the compound of the application can be used in combination with other pharmaceutically active compounds, preferably compounds that are able to enhance the effect of the compound of the application. The compound of the application can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy. Pharmaceutical Compositions

[00227] The present application also provides pharmaceutical compositions comprising a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in combination with at least one pharmaceutically acceptable excipient or carrier.

[00228] A "pharmaceutical composition" is a formulation containing the compound of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that are required.

[00229] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[00230] "Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

[00231] A pharmaceutical compositions of the application are formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[00232] A compound or pharmaceutical composition of the application can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. The dose chosen should be sufficient to constitute effective treatment but not as high as to cause unacceptable side effects. The state of the disease condition and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[00233] The term "therapeutically effective amount", as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In one embodiment, the disease or disorder is a disease or disorder described herein.

[00234] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED<com:Sub>50< / com:Sub> (the dose therapeutically effective in 50% of the population) and LD<com:Sub>50< / com:Sub> (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, <com:Math><semantics>LD50 / ED50<annotation encoding="application / x-tex">LD_{50} / ED_{50}< / annotation>< / semantics>< / com:Math>. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[00235] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[00236] The pharmaceutical compositions containing active compound (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) of the present application may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compound into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[00237] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL<com:Sup>TM< / com:Sup> (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[00238] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[00239] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[00240] For administration by inhalation, the compound is delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[00241] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.

[00242] The active compound can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[00243] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the application are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[00244] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the application vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. As used herein, the term "dosage effective manner" refers to amount of an active compound to produce the desired biological effect in a subject or cell.

[00245] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[00246] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compound of the present application wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non- toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc...

[00247] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present application also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[00248] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[00249] The compound of the present application can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate, propionate or other ester.

[00250] The compound of the present application can also be prepared as prodrugs, for example, pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound which releases an active parent drug in vivo. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compound of the present application can be delivered in prodrug form. Thus, the present application is intended to cover prodrugs of the presently claimed compound, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present application in vivo when such prodrug is administered to a subject. Prodrugs in the present application are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include the compound of the present application wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group is bonded to any group that may be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively.

[00251] Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters (e.g., ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) N- Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in the compound of the application, and the like, See Bundegaard, H., Design of Prodrugs, p1-92, Elsevier, New York-Oxford (1985).

[00252] The compound, or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

[00253] The dosage regimen utilizing the compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[00254] Techniques for formulation and administration of the disclosed compound of the application can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compound described herein, and the pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[00255] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present application are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present application. The examples do not limit the claimed application. Based on the present application the skilled artisan can identify and employ other components and methodology useful for practicing the present application. Examples

[00256] The application is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this application in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the application is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present application and / or scope of the appended claims. Example 1: Synthesis of Intermediate A [Image disponible dans le document PDF, Image available in the PDF document]

[00257] Intermediate A can be synthesized according to methods known in the art, such as the methods described in WO 2013 / 163675 Al. Example 2: Synthesis of Intermediate B [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Intermediate B

[00258] A mixture of B-1 (1.5 g, 5.87 mmol), NaHCO<com:Sub>3< / com:Sub> (902.48 mg, 10.74 mmol) and Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (1.38 g, 10.92 mmol) in H<com:Sub>2< / com:Sub>O (10 mL) was heated to 100 °C for 1 hr. After cooling to room temperature, the reaction mixture was diluted with H<com:Sub>2< / com:Sub>O (30ml) and acidized to pH=1 with con.HCl. The white solid was collected by filtration and washed with H<com:Sub>2< / com:Sub>O to give Intermediate B (1.2 g, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=219(M−1)<annotation encoding="application / x-tex">m / z = 219 (M-1)< / annotation>< / semantics>< / com:Math>. Example 3: Synthesis of Intermediate C [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Intermediate C

[00259] A mixture of C-1 (1.5 g, 5.48 mmol), NaHCO<com:Sub>3< / com:Sub> (843.12 mg, 10.04 mmol) and Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (1.29 g, 10.26 mmol) in H<com:Sub>2< / com:Sub>O (20 mL) was heated to 100 °C for 1 hr. After cooling to room temperature, the reaction mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (30ml) and acidized to pH=1 with con.HCl. The white solid was collected by filtration and washed with H2O to give Intermediate C (1.2 g, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=237(M−1)<annotation encoding="application / x-tex">m / z = 237 (M-1)< / annotation>< / semantics>< / com:Math>. Example 4: Synthesis of Intermediate D [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Intermediate D

[00260] To a mixture of D-1 (1.5 g, 7.93 mmol), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2- a]azepine (1.21 g, 7.93 mmol, 1.18 mL) in toluene (30 mL) was added bromo(chloro)methane (20.53 g, 158.67 mmol) at 20 °C. The reaction solution was stirred for 2 hr at 20 °C. Then, the reaction mixture was filtered, and the filtrate was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether 0 to 5%) to obtain Intermediate D (1.1 g, crude). Example 5: Synthesis of Intermediate E [Image disponible dans le document PDF, Image available in the PDF document] Step 1: E-1

[00261] To a solution of D-1 (500 mg, 2.64 mmol) in DMF (10 mL) was added NaH (126.92 mg, 3.17 mmol, 60% purity) at 20 °C. The reaction solution was stirred for 0.5 hr at 20 °C. Then, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (882.79 mg, 3.17 mmol) was added. The reaction solution was stirred further for 18 hr at 20 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether 0 to 20%) to obtain E-1 (920 mg, 2.38 mmol, 90.05% yield). MS: <com:Math><semantics>m / z=386<annotation encoding="application / x-tex">m / z = 386< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(M+1)<annotation encoding="application / x-tex">(M+1)< / annotation>< / semantics>< / com:Math>. Step 2: E-2

[00262] To a mixture of E-1 (450 mg, 1.16 mmol) in DCM (30 mL) was added 3- chlorobenzenecarboperoxoic acid (709.42 mg, 3.49 mmol, 85% purity) at 20 °C. The mixture was stirred for 1 hr at 20 °C. Then, the solution was washed with saturated aqueous Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (10 mL), saturated aqueous NaHCO<com:Sub>3< / com:Sub> (20 mL × 2) and brine (15 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated with a rotary evaporator to obtain E-2 (450 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=418(M+1)<annotation encoding="application / x-tex">m / z = 418 (M+1)< / annotation>< / semantics>< / com:Math>. Step3: Intermediate E

[00263] To a solution of E-2 (450 mg, 1.08 mmol) in DCM (20 mL) was added HCl / Dioxane (4 M, 3 mL) at 20 °C and the reaction mixture was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator to obtain Intermediate E (380 mg, crude, HCl salt). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=318<annotation encoding="application / x-tex">m / z = 318< / annotation>< / semantics>< / com:Math> (M+1). Example 6: Synthesis of Intermediate F [Image disponible dans le document PDF, Image available in the PDF document] Step 1: F-2

[00264] To a mixture of F-1 (2.0 g, 8.72 mmol), Et3N (2.65 g, 26.16 mmol) in DCM (30 mL) was added methanesulfonyl chloride (1.10 g, 9.59 mmol, 742.55 μL) at 20 °C. The reaction solution was stirred for 1 hr at 20 °C. Then, the mixture was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether 0 to 50%) to obtain F-2 (2.5 g, 8.13 mmol, 93.25% yield). MS: <com:Math><semantics>m / z=308<annotation encoding="application / x-tex">m / z = 308< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(M+1).<annotation encoding="application / x-tex">(M+1).< / annotation>< / semantics>< / com:Math> Step 2: F-3

[00265] To a solution of 4-bromobenzenethiol (500 mg, 2.64 mmol) in DMF (15 mL) was added NaH (116.35 mg, 2.91 mmol, 60% purity) at 20 °C. The reaction solution was stirred for 0.5 hr at 20 °C. Then, F-2 (975.51 mg, 3.17 mmol) was added. The reaction solution was stirred further for 18 hr at 20 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether 0 to 10%) to obtain F-3 (150 mg, 374.65 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 14.17% yield). MS: m / z = 400 (M+1). Step 3: F-4

[00266] To a mixture of F-3 (150 mg, 374.65 μmol) in DCM (20 mL) was added 3- chlorobenzenecarboperoxoic acid (228.19 mg, 1.12 mmol, 85% purity) at 20 °C. The mixture was stirred for 1 hr at 20 °C. Then, the solution was washed with saturated aqueous Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (10 mL), saturated aqueous NaHCO<com:Sub>3< / com:Sub> (20 mL × 2) and brine (15 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated with a rotary evaporator to obtain F-4 (170 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=432(M+1)<annotation encoding="application / x-tex">m / z = 432 (M+1)< / annotation>< / semantics>< / com:Math>. Step 4: Intermediate F

[00267] To a solution of F-4 (170 mg, 393.18 μmol) in DCM (15 mL) was added HCl / Dioxane (4 M, 2 mL) at 20 °C and the reaction mixture was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator to obtain Intermediate F (160 mg, crude, HCl salt). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=<annotation encoding="application / x-tex">m / z =< / annotation>< / semantics>< / com:Math> 332 (M+1). Example 7: Synthesis of Intermediate G [Image disponible dans le document PDF, Image available in the PDF document] Step 1: G-2

[00268] To a mixture of G-1 (1 g, 4.83 mmol), NaH (386.32 mg, 9.66 mmol, 60% purity) in DMF (20 mL) was added tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine- 1-carboxylate (1.61 g, 5.80 mmol) at 0 °C. The reaction solution was stirred for 12 hr at 50 °C. To the mixture, saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (100 mL) was added. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic extracts were dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography (ethyl acetate / petroleum ether 10% to 80%) to give G-2 (1.3 g, 3.22) mmol, <com:Math><semantics>66.57%<annotation encoding="application / x-tex">66.57\%< / annotation>< / semantics>< / com:Math> yield). MS: m / z = <com:Math><semantics>404.3<annotation encoding="application / x-tex">404.3< / annotation>< / semantics>< / com:Math> (M+1). Step 2: G-3

[00269] A mixture of G-2 (600 mg, 1.48 mmol) and m-CPBA (903.78 mg, 4.45 mmol, 85% purity) in DCM (20 mL) was stirred at 25 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (14 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethylacetate = <com:Math><semantics>30 / 1−3 / 1<annotation encoding="application / x-tex">30 / 1-3 / 1< / annotation>< / semantics>< / com:Math>, v / v) to obtain G-3 (500 mg, 1.15) mmol, 77.22% yield). MS: <com:Math><semantics>m / z=436.3(M+1)<annotation encoding="application / x-tex">m / z = 436.3 (M+1)< / annotation>< / semantics>< / com:Math>. Step 3: Intermediate G

[00270] A mixture of G-3 (500 mg, 1.15 mmol) in HCl / Dioxane (4 M, 4.0 mL) at 20 °C and the reaction mixture was stirred at 30 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator to obtain Intermediate G (600 mg, crude, HCl salt), which was used for the next step without further purification. MS: <com:Math><semantics>m / z=372.6(M+1)<annotation encoding="application / x-tex">m / z = 372.6 (M+1)< / annotation>< / semantics>< / com:Math>. Example 8: Synthesis of Intermediate H [Image disponible dans le document PDF, Image available in the PDF document] Step 1: H-1

[00271] To a mixture of F-1 (1.74 g, 7.58 mmol) in DMF (15 mL) was added NaH (328.33 mg, 8.21 mmol, 60% purity) at 20 °C. The reaction solution was stirred for 0.5 hr at 20 °C. Then, Intermediate D (1.5 g, 6.31 mmol) was added. The reaction solution was stirred further for 18 hr at 20 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0 to 10%) to obtain H-1 <com:Math><semantics>(420 mg,975.84μmol,15.45% yield)<annotation encoding="application / x-tex">(420 \text{ mg}, 975.84 \mu\text{mol}, 15.45\% \text{ yield})< / annotation>< / semantics>< / com:Math>. MS: m / z = 430 (M+1). Step 2: H-2

[00272] To a mixture of H-2 (420 mg, 975.84 μmol) in DCM (30 mL) was added m-CPBA (594.34 mg, 2.93 mmol, 85% purity) at 20 °C. The mixture was stirred for 1 hr at 20 °C. Then, the solution was washed with saturated aqueous Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (10 mL), saturated aqueous NaHCO<com:Sub>3< / com:Sub> (20 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 2) and brine (15 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated with a rotary evaporator to obtain H-3 (510 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=462(M+1)<annotation encoding="application / x-tex">m / z = 462 (M+1)< / annotation>< / semantics>< / com:Math>. Step 3: Intermediate H

[00273] To a mixture of H-3 (510 mg, 1.10 mmol) in DCM (20 mL) was added HCl / Dioxane (4 M, 4 mL) at 20 °C and the reaction mixture was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator to obtain Intermediate H (450 mg, crude, HCl salt). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=362(M+1)<annotation encoding="application / x-tex">m / z = 362 (M+1)< / annotation>< / semantics>< / com:Math>. Example 9: Synthesis of Intermediate I [Image disponible dans le document PDF, Image available in the PDF document] Step 1: I-2

[00274] To a mixture of I-1 (5 g, 23.56 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 °C was added a tetrahydrofuran solution of Borane-tetrahydrofuran complex (1 M, 47.12 mL) under nitrogen. The reaction mixture was stirred at 25 °C for 3 hr, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous HCl solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give I-2 (4.5 g, crude). The crude product was used directly for the next step. LC / MS: <com:Math><semantics>m / z=<annotation encoding="application / x-tex">m / z =< / annotation>< / semantics>< / com:Math> 199.2 (M+1). Step 2: I-3

[00275] To a mixture of I-2 (1.78 g, 8.98 mmol) and 1-methoxy-4-[(4- methoxyphenyl)disulfanyl]benzene (3.00 g, 10.77 mmol) in acetonitrile (20 mL) was added tributylphosphine (2.54 g, 12.57 mmol, 3.1 mL) at 25 °C under the nitrogen atmosphere. The reaction mixture was stirred for 16 hr at 80 °C. The mixture was concentrated. The residue was purified by silica gel chromatography (ethyl acetate in petroleum ether = <com:Math><semantics>0∼10%<annotation encoding="application / x-tex">0\sim10\%< / annotation>< / semantics>< / com:Math>, v / v) to afford I- 3 (2.1 g, 6.55 mmol, 72.99% yield). LC / MS: <com:Math><semantics>m / z=321.1<annotation encoding="application / x-tex">m / z = 321.1< / annotation>< / semantics>< / com:Math> (M+1). Step 3: I -4

[00276] To a mixture of I-3 (2.1 g, 6.55 mmol) in DCM (10 mL) was added m-CPBA (3.39 g, 19.66 mmol) at 20 °C. The mixture was stirred for 2 hr at 25 °C. Then, the solution was washed with saturated aqueous sodium sulfite (10 mL), saturated aqueous sodium bicarbonate (20 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 2) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated with a rotary evaporator to give the crude product. The crude product was recrystallized by dichloromethane / petroleum ether to obtain I-4 (1.94 g, 5.50 mmol, 83.86% yield). LC / MS: <com:Math><semantics>m / z=<annotation encoding="application / x-tex">m / z =< / annotation>< / semantics>< / com:Math> 353.1 (M+1). Step 4: Intermediate I

[00277] A mixture of I-4 (1.9 g, 5.39 mmol) and boron tribromide (1 M in DCM, 20 mL) was stirred at 20 °C. The mixture was poured into ice and warmed to 25 °C. The mixture was filtered. The cake was washed by petroleum ether, dried under the vacuum to afford Intermediate I (1.74) g, 5.36 mmol, 99.50% yield). LC / MS: <com:Math><semantics>m / z=325.0(M+1)<annotation encoding="application / x-tex">m / z = 325.0 (M+1)< / annotation>< / semantics>< / com:Math>. Example 10: Synthesis of Intermediate J [Image disponible dans le document PDF, Image available in the PDF document] Step 1: J-2

[00278] To a mixture of J-1 (5.9 g, 20.82 mmol) in tetrahydrofuran (30 mL) and water (30 mL) was added Lithium hydroxide monohydrate, 98% (4.37 g, 104.11 mmol) at 0 °C. The reaction solution was stirred for 2 hr at 25 °C. Then, the reaction mixture was adjusted to pH <com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math> 6 by citric acid, extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated with a rotary evaporator to obtain J-2 (5.6 g, crude). Step 2: J-3

[00279] To a mixture of J-2 (5.6 g, 20.79 mmol) in anhydrous tetrahydrofuran (50 mL) was dropwise added Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 62.38 mL) at 0 °C under the nitrogen atmosphere. The reaction mixture was stirred for 2 hr at 25 °C. To the reaction mixture was dropwise added MeOH (20 mL) at 0~25 °C. The reaction mixture was stirred at room temperature (~25 °C) for 0.5 hr. The reaction mixture was concentrated with a rotary evaporator to obtain crude J-3 (5.5 g, crude). The product was used in the next step directly without further purification. Step 3: J-4

[00280] To a mixture of J-3 (5.5 g, 21.54 mmol), triethylamine (6.54 g, 64.62 mmol, 9.01 mL) in DCM (100 mL) was added Methanesulfonic anhydride (5.63 g, 32.31 mmol, 3.56 mL) at 0 °C. The reaction solution was stirred for 2 hr at 25 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate in petroleum ether = <com:Math><semantics>0∼40%<annotation encoding="application / x-tex">0\sim40\%< / annotation>< / semantics>< / com:Math>, v / v) to obtain J-4 (6.2 g, 18.59 mmol, 86.33% yield). Step 4: J-5

[00281] To a mixture of 4-bromobenzenethiol (8.79 g, 46.48 mmol), cesium carbonate (18.17 g, 55.78 mmol) and potassium iodide (1.54 g, 9.30 mmol) in DMF (50 mL) was added J-4 (6.2 g, 18.59 mmol) under the nitrogen atmosphere. The reaction mixture was heated at 55 °C for 2 hr. Ethyl acetate (100 mL) and water (50 mL) were added, the organic layer was washed with brine (50 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated, which was purified by column chromatography on silica gel (120 g, ethyl acetate in petroleum ether = <com:Math><semantics>0∼15%<annotation encoding="application / x-tex">0\sim15\%< / annotation>< / semantics>< / com:Math>, v / v) to give J-5 (6.9 g, 16.18 mmol, 87.03% yield). Step 5: J-6

[00282] A mixture of J-5 (6.9 g, 16.18 mmol) and m-CPBA (9.85 g, 48.54 mmol, 85% purity) in DCM (100 mL) was stirred at 20 °C for 2 hr. Then, sodium sulfite (5 g) was added to the mixture and stirred for 20 min. Then, to the solution was added DCM (100 mL) and water (100 mL). The organic layer was washed with aqueous NaHCO<com:Sub>3< / com:Sub> (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3), brine (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3), dried over anhydrous sodium sulfate, filtered, concentrated to give a crude, which was purified by column chromatography on silica gel (80 g, ethyl acetate in petroleum ether = <com:Math><semantics>0∼20%<annotation encoding="application / x-tex">0\sim20\%< / annotation>< / semantics>< / com:Math>, v / v) to give J-6 (7 g, 15.27 mmol, 94.38% yield). Step 6: Intermediate J

[00283] To a mixture of J-6 (4 g, 8.73 mmol) in DCM (20 mL) was added HCl / Dioxane (15 mL, 4 M) at 20 °C and stirred at 20 °C for 1 hr. The reaction mixture was then concentrated to give Intermediate J (3.5 g, crude, HCl salt). Example 11: Synthesis of Intermediate K [Image disponible dans le document PDF, Image available in the PDF document] Step 1: K-2

[00284] To a mixture of K-1 (10 g, 78.02 mmol) in tetrahydrofuran (100 mL) was added lithium diisopropylamide (2 M in THF, 78.02 mL) dropwise at -30 °C under argon. After stirred at -30 °C for 1 hr, 2-chloroacetonitrile (7.07 g, 93.63 mmol) was added into the mixture above at -30 °C. The resulting mixture was stirred at -30 °C for 30 min, then warmed up to 25 °C and stirred for another 3 hr. After quenched with aqueous ammonia chloride (150 mL), the resulting mixture was poured into water (250 mL) and extracted with ethyl acetate (200 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 4: 1) to give K-2 (4.5 g, 34.49% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.82 – 3.74 (m, 3H), <com:Math><semantics>2.67−2.62<annotation encoding="application / x-tex">2.67 - 2.62< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.90−1.59<annotation encoding="application / x-tex">1.90 - 1.59< / annotation>< / semantics>< / com:Math> (m, 8H). Step 2: Intermediate K

[00285] To a mixture of K-2 (4.5 g, 26.91 mmol) in EtOH (50 mL) was added <com:Math><semantics>NH3.H2O<annotation encoding="application / x-tex">NH_3.H_2O< / annotation>< / semantics>< / com:Math> (5 mL) and Raney Nickel (1.5 g). The reaction mixture was stirred at 25 °C for 48 hr under the hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 2: 1) to give Intermediate K (1.20 g, 32.03% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 5.96 (s, 1H), 3.23 (t, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.99 – 1.81 (m, 4H), 1.79 – 1.68 (m, 2H), 1.64 – 1.55 (m, 2H), 1.48 (dd, <com:Math><semantics>J=11.1<annotation encoding="application / x-tex">J = 11.1< / annotation>< / semantics>< / com:Math>, 5.6 Hz, 2H). Example 12: Synthesis of Compound 1 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 1-1

[00286] To a mixture of D-1 (959.96 mg, 5.08 mmol) in DMF (10 mL) was added NaH (243.68 mg, 6.09 mmol, 60% purity) at 20 °C. The reaction solution was stirred for 0.5 hr at 20 °C. Then, 4-(bromomethyl)tetrahydropyran (1.0 g, 5.58 mmol) was added. The reaction solution was stirred for further 18 hr at 20 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0 to 10%) to obtain 1-1 (1.3 g, 4.53 mmol, 89.15% yield). Step 2: 1-2

[00287] To a mixture of 1-1 (400 mg, 1.39 mmol) in DCM (30 mL) was added m-CPBA (848.24 mg, 4.18 mmol, 85% purity) at 20 °C. The mixture was stirred for 2 hr at 20 °C. Then, the solution was washed with saturated aqueous Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (10 mL), saturated aqueous NaHCO<com:Sub>3< / com:Sub> <com:Math><semantics>(20ml×2)<annotation encoding="application / x-tex">(20\text{ml} \times 2)< / annotation>< / semantics>< / com:Math> and brine <com:Math><semantics>(15 mL)<annotation encoding="application / x-tex">(15 \text{ mL})< / annotation>< / semantics>< / com:Math>, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated with a rotary evaporator to obtain 1-2 (400 mg, crude). The crude product was used for the next step without further purification. Step 3: 1-3

[00288] To a mixture of 1-2 (300 mg, 939.81 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (286.38 mg, 1.13 mmol) and KOAc (276.70 mg, 2.82 mmol) in Dioxane (6 mL) was added Pd(dppf)Cl<com:Sub>2< / com:Sub> (68.77 mg, 93.98 μmol) at 20 °C. The reaction solution was heated to 120 °C for 0.667 hr under microwave. The mixture was filtered, and the filtrate was concentrated. The residual material was dissolved in DCM (15) mL), washed with H<com:Sub>2< / com:Sub>O (15 mL) and brine (15 mL) and concentrated with a rotary evaporator to obtain 1-3 (410 mg, crude). The crude product was used for the next step without further purification. Step 4: 1-4

[00289] To a mixture of 1-3 (410 mg, 1.12 mmol), acetic acid (525.00 mg, 8.74 mmol, 0.5 mL) in THF (15 mL) was added hydrogen peroxide (0.5 mL, 30% purity) at 20 °C. The reaction solution was stirred for 1 hr at 20 °C. Then, the solution was concentrated with a rotary evaporator to obtain 1-4 (300 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=255<annotation encoding="application / x-tex">m / z = 255< / annotation>< / semantics>< / com:Math> (M-1). Step 5: 1-5

[00290] To a mixture of 1-4 (300 mg, 1.17 mmol), Intermediate A (100 mg, 372.96 μmol) in MeCN (20 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (364.56 mg, 1.12 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 90 °C. Then, the mixture was filtered, and the filtrate was concentrated with a rotary evaporator to obtain 1-5 (210 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=444(M+1)<annotation encoding="application / x-tex">m / z = 444 (M+1)< / annotation>< / semantics>< / com:Math>. Step 6: Compound 1

[00291] To a mixture of 1-5 (210 mg, 473.48 μmol) in DCM (10 mL) was added HCl / Dioxane (4 M, 3 mL) at 20 °C and the reaction mixture was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep- HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-30% B; GT: 15 min; flow rate: 15 mL / min) to give Compound 1 (110 mg, 282.46) µmol, 59.66% yield, HCO<com:Sub>2< / com:Sub>H salt). MS: m / z = 344 (M+1). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-<com:Math><semantics>d4<annotation encoding="application / x-tex">d_4< / annotation>< / semantics>< / com:Math>) δ 8.50 (s, 1H), <com:Math><semantics>7.91−7.86<annotation encoding="application / x-tex">7.91 - 7.86< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>7.24−7.19<annotation encoding="application / x-tex">7.24 - 7.19< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>7.23<annotation encoding="application / x-tex">7.23< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=81.1<annotation encoding="application / x-tex">J = 81.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.71<annotation encoding="application / x-tex">4.71< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=81.1<annotation encoding="application / x-tex">J = 81.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.71<annotation encoding="application / x-tex">4.71< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=81.1<annotation encoding="application / x-tex">J = 81.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.71<annotation encoding="application / x-tex">4.71< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=81.1<annotation encoding="application / x-tex">J = 81.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.71<annotation encoding="application / x-tex">4.71< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=81.1<annotation encoding="application / x-tex">J = 81.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4<annotation encoding="application / x-tex">4< / annotation>< / semantics>< / com:Math> 3.6, 1.1 Hz, 2H), 3.87-3.82 (m, 2H), 3.79 (d, <com:Math><semantics>J=2.3<annotation encoding="application / x-tex">J = 2.3< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.37 (td, <com:Math><semantics>J=11.8<annotation encoding="application / x-tex">J = 11.8< / annotation>< / semantics>< / com:Math>, 2.1 Hz, 2H), <com:Math><semantics>3.15<annotation encoding="application / x-tex">3.15< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.3<annotation encoding="application / x-tex">J = 6.3< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.11−2.05<annotation encoding="application / x-tex">2.11-2.05< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.75−1.71<annotation encoding="application / x-tex">1.75-1.71< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.40−1.37<annotation encoding="application / x-tex">1.40-1.37< / annotation>< / semantics>< / com:Math> (m, 2H). MS: m / z = 344.00 (M+1, ESI+). Example 13: Synthesis of Compound 2 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 2-2

[00292] To a mixture of 2-1 (2.0 g, 16.93 mmol) in DMF (30 mL) was added NaH (713.59 mg, 17.84 mmol, 60% purity) at 20 °C. The reaction solution was stirred for 0.5 hr at 20 °C. Then, 3-bromoprop-1-ene (3.07 g, 25.40 mmol) was added. The reaction solution was stirred further for 18 hr at 20 °C. Then, the solution was quenched with H<com:Sub>2< / com:Sub>O (20 mL), and extracted by ethyl acetate (15 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 2). The combined organic layers were washed with H<com:Sub>2< / com:Sub>O (15 mL) and brine (15 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0 to 40%) to give 2- 2 (2.3 g, 14.54 mmol, 85.88% yield). MS: <com:Math><semantics>m / z=159(M+1)<annotation encoding="application / x-tex">m / z = 159 (M+1)< / annotation>< / semantics>< / com:Math>. Step 2: 2-3

[00293] To a mixture of 2-2 (2.3 g, 14.54 mmol) in THF (60 mL) was added LiAlH<com:Sub>4< / com:Sub> (201.65 mg, 5.31 mmol) at 0 °C slowly over 0.5 hr. The reaction solution was stirred for 18 hr at 20 °C. Then, the solution was cooled to 0 °C and quenched successively with H<com:Sub>2< / com:Sub>O (1.1 mL), NaOH (1.1 mL, 15% aqueous solution) and H<com:Sub>2< / com:Sub>O (3.3 mL). The mixture was stirred for 0.5 hr and then was filtered and concentrated with a rotary evaporator to obtain 2-3 (1.9 g, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=131<annotation encoding="application / x-tex">m / z = 131< / annotation>< / semantics>< / com:Math> (M+1). Step 3: 2-4

[00294] To a mixture of 2-3 (1.9 g, 14.59 mmol) in MeCN (50 mL) was added NaHCO<com:Sub>3< / com:Sub> (3.68 g, 43.78 mmol) and the mixture was cooled to 0 °C. Molecular iodine (11.11 g, 43.78 mmol) was added and the reaction mixture was allowed to warm up to 25 °C and stirred for 6 hr. The reaction mixture was diluted with saturated aqueous sodium thiosulfate solution and concentrated under reduced pressure removing most of the organic solvent. The residue was extracted with ethyl acetate (30 mL x 2) and the combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate in petroleum ether, 0 to 20%) to give 2-4 (2.3 g, 8.98 mmol, 61.54% yield). MS: <com:Math><semantics>m / z=257(M+1)<annotation encoding="application / x-tex">m / z = 257 (M+1)< / annotation>< / semantics>< / com:Math>. Step 4: 2-5

[00295] To a mixture of 4-bromobenzenethiol (1.0 g, 5.29 mmol) in DMF (30 mL) was added NaH (250.0 mg, 6.25 mmol, 60% purity) at 20 °C. The reaction solution was stirred for 0.5 hr at 20 °C. Then, 2-4 (1.23 g, 4.81 mmol) was added. The reaction solution was stirred further for 18 hr at 20 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0 to 30%) to obtain 2-5 (1.1 g, 3.47 mmol, 72.11% yield). MS: <com:Math><semantics>m / z=317<annotation encoding="application / x-tex">m / z = 317< / annotation>< / semantics>< / com:Math> (M+1). Step 5: 2-6

[00296] To a mixture of 2-5 (1.1 g, 3.47 mmol) in DCM (50 mL) was added m-CPBA (2.11 g, 10.40 mmol, 85% purity) at 20 °C. The mixture was stirred for 1 hr at 20 °C. Then, the solution was washed with saturated aqueous <com:Math><semantics>Na2SO3<annotation encoding="application / x-tex">Na_2SO_3< / annotation>< / semantics>< / com:Math> (10 mL), saturated aqueous <com:Math><semantics>NaHCO3<annotation encoding="application / x-tex">NaHCO_3< / annotation>< / semantics>< / com:Math> (20 mL × 2) and brine (15 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated with a rotary evaporator to give 2-6 (440 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=1<annotation encoding="application / x-tex">m / z = 1< / annotation>< / semantics>< / com:Math> 349 (M+1). Step 6: 2-7

[00297] To a mixture of 2-6 (440 mg, 1.26 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (383.92 mg, 1.51 mmol) and KOAc (363.32 mg, 3.78 mmol) in Dioxane (15 mL) was added Pd(dppf)Cl<com:Sub>2< / com:Sub> (46.09 mg, 62.99 µmol) at 20 °C. The reaction solution was heated to 120 °C for 0.667 hr under microwave. The mixture was filtered and evaporated to give 2-7 (550 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=397<annotation encoding="application / x-tex">m / z = 397< / annotation>< / semantics>< / com:Math> (M+1). Step 7: 2-8

[00298] To a mixture of 2-7 (550 mg, 1.39 mmol), acetic acid (1.05 g, 17.49 mmol, 1 mL) in THF (20 mL) was added hydrogen peroxide (1 mL, 30% purity) at 25 °C. The reaction solution was stirred for 1 hr at 25 °C. Then, the solution was quenched by Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub>, filtered and concentrated with a rotary evaporator to obtain 2-8 (450 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=287(M+1)<annotation encoding="application / x-tex">m / z = 287 (M+1)< / annotation>< / semantics>< / com:Math>. Step 8: 2-9

[00299] To a mixture of 2-8 (450 mg, 1.57 mmol), Intermediate A (421.37 mg, 1.57 mmol) in MeCN (50 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.54 g, 4.71 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 90 °C. Then, the mixture was filtered, and concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether 0 to 100%) to obtain 2-9 (330 mg, 696.86 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 44.34% yield). MS: m / z = 474 <com:Math><semantics>(M+1)<annotation encoding="application / x-tex">(M+1)< / annotation>< / semantics>< / com:Math>. Step 9: Compound 2

[00300] To a mixture of 2-9 (330 mg, 696.86 μmol) in DCM (20 mL) was added HCl / Dioxane (4 M, 3 mL) at 25 °C and the reaction mixture was stirred at 25 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep- HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-30% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 2 (210 mg, 500.64) µmol, 71.84% yield, HCO<com:Sub>2< / com:Sub>H salt). MS: m / z = 374 (M+1). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-<com:Math><semantics>d4<annotation encoding="application / x-tex">d_4< / annotation>< / semantics>< / com:Math>) δ 7.94-7.84 (m, 2H), 7.27-7.17 (m, 2H), 7.26 (d, <com:Math><semantics>J=81.0<annotation encoding="application / x-tex">J = 81.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.73 (dd, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math>, 1.0 Hz, 2H), <com:Math><semantics>3.89−3.84<annotation encoding="application / x-tex">3.89-3.84< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.84<annotation encoding="application / x-tex">3.84< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.2<annotation encoding="application / x-tex">J = 2.2< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.65−3.48<annotation encoding="application / x-tex">3.65-3.48< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.44−3.36<annotation encoding="application / x-tex">3.44-3.36< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.30−3.21<annotation encoding="application / x-tex">3.30-3.21< / annotation>< / semantics>< / com:Math> (m, 2H), 1.24 (s, 3H), 1.07 (s, 3H). Example 14: Synthesis of Compound 3 & 4 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Compound 3 & 4

[00301] Compound 2 (210 mg, 500.64 µmol) was separated by SFC to obtain Compound 3 & 4 (enantiomer 1, Rt = 6.220 min, 67.4 mg, 180.48 μmol, 52.05% yield. Column: Chiralpak IG 250 mm*4.6 mm 5 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, Mobile phase: MeCN: IPA: AMMN = 80:20:0.2, F: 1 mL / min, T = 30 °C) and (enantiomer 2, Rt = 8.083 min, 53.2 mg, 142.46 μmol, 41.08% yield, Column: Chiralpak IG 250 mm*4.6 mm 5 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, Mobile phase: MeCN: IPA: AMMN = 80:20:0.2, F: 1 mL / min, T = 30 °C). Enantiomer 1: <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-<com:Math><semantics>d4<annotation encoding="application / x-tex">d_4< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.91-7.81 (m, 2H), 7.23-7.15 (m, 2H), 6.96 (dt, <com:Math><semantics>J=83.2<annotation encoding="application / x-tex">J = 83.2< / annotation>< / semantics>< / com:Math>, 1.0 Hz, 1H), 4.68 (dd, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math>, 1.1 Hz, 2H), 3.86-3.83 (m, 1H), 3.63-3.51 (m, 2H), 3.49 (dd, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math>, 0.8 Hz, 2H), 3.44-3.36 (m, 2H), 3.31-3.23 (m, 2H), 1.24 (s, 3H), 1.07 (s, 3H). Enantiomer 2: <com:Math><semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>< / com:Math>H NMR (400 MHz, Methanol-<com:Math><semantics>d4<annotation encoding="application / x-tex">d_4< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.89-7.85 (m, 2H), 7.19 (d, <com:Math><semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics>< / com:Math> Hz, 2H), 6.97 (d, <com:Math><semantics>J=83.2<annotation encoding="application / x-tex">J = 83.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.68 (dd, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math>, 1.1 Hz, 2H), 3.86-3.83 (m, 1H), 3.63-3.51 (m, 2H), 3.52-3.48 (m, 2H), 3.46-3.35 (m, 2H), 3.29-3.24 (m, 2H), 1.24 (s, 3H), 1.07 (s, 3H). Example 15: Synthesis of Compound 5 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-2

[00302] To a mixture of methanesulfonic anhydride (200 mg, 1.15 mmol) and TEA (582.96) mg, 5.76 mmol, 802.98 μL) in DCM (10 mL) was added 5-1 (250 mg, 1.92 mmol) at 0 °C. The reaction solution was stirred for 2 hr at 0 °C. H<com:Sub>2< / com:Sub>O (5 mL) was added, the organic phase was separated, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated to give 5-2 (300 mg, 1.44 mmol, 75.01% yield). MS: <com:Math><semantics>m / z=208.2(M+1)<annotation encoding="application / x-tex">m / z = 208.2 (M+1)< / annotation>< / semantics>< / com:Math>. Step 2: 5-3

[00303] A mixture of 5-2 (300 mg, 1.44 mmol) and 4-bromobenzenethiol (326.81 mg, 1.73 mmol) in DMF (10 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.41 g, 4.32 mmol) at 20 °C. The reaction solution was stirred for 8 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>4 / 1<annotation encoding="application / x-tex">4 / 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 5-3 (200 mg, 663.92 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 46.09% yield). MS: m / z = 301.2 (M+1). Step 3: 5-4

[00304] A mixture of 5-3 (180 mg, 597.53 μmol) and m-CPBA (330.19 mg, 1.79 mmol, 85% purity) in DCM (20 mL) was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (4 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>5 / 1−1 / 1<annotation encoding="application / x-tex">5 / 1-1 / 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 5-4 (180 mg, 540.15) <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 90.40% yield). MS: m / z = 333.2 (M+1). Step 4: 5-5

[00305] To a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (194.32 mg, 765.21 μmol), 5-4 (170 mg, 510.14 μmol) and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (37.33 mg, 51.01 µmol) in Dioxane (8 mL) was added KOAc (154.83 mg, 1.53 mmol) at 30 °C under the nitrogen atmosphere. The reaction solution was stirred for 2 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (petroleum ether / ethyl- acetate = <com:Math><semantics>10 / 1−1 / 1<annotation encoding="application / x-tex">10 / 1-1 / 1< / annotation>< / semantics>< / com:Math>, v / v) to obtain 5-5 (150 mg, 394.42 µmol, 77.32% yield). MS: m / z = 380.3 <com:Math><semantics>(M+1).<annotation encoding="application / x-tex">(M+1).< / annotation>< / semantics>< / com:Math> Step 5: 5-6

[00306] A mixture of 5-5 (120 mg, 315.54 µmol) in THF (4 mL) and acetic acid (1 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (315.54 µmol, 1 mL, 30% purity). The mixture was stirred at 25 °C for 0.5 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.5 g) was added to the mixture and stirred for 20 min. The mixture was filtered and concentrated to give 5-6 (0.7 g, crude), which was used in the next step without purification. MS: <com:Math><semantics>m / z=270.3(M+1)<annotation encoding="application / x-tex">m / z = 270.3 (M+1)< / annotation>< / semantics>< / com:Math>. Step 6: 5-7

[00307] A mixture of 5-6 (0.7 g) and Intermediate A (138.85 mg, 517.86 µmol) in MeCN (20 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (2.53 g, 7.77 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated to obtain 5-7 (120 mg, crude), which was used in the next step without purification. MS: <com:Math><semantics>m / z=457.5<annotation encoding="application / x-tex">m / z = 457.5< / annotation>< / semantics>< / com:Math> (M+1). Step 7: Compound 5

[00308] A mixture of 5-7 (120 mg, 262.26 µmol) in HCl / Dioxane (4 M, 3 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 2-30% B; GT: 15 min; flow rate: 15 mL / min) to give Compound 5 (22 mg, 61.55 μmol, 23.47% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-d4) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.50 (s, 1H), 7.99 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.0 Hz, 2H), 7.23 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 80.0 Hz, 1H), 7.21 (d, <com:Math><semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.77-4.67 (m, 2H), 3.80 (d, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.65 (dd, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math>, 4.6 Hz, 4H), 3.26 (s, 2H), 1.79-1.75(m, 2H), 1.59-1.45 (m, 2H), 1.32 (s, 3H). ppm; MS: <com:Math><semantics>m / z=358.7<annotation encoding="application / x-tex">m / z = 358.7< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(M+1,ESI+)<annotation encoding="application / x-tex">(M+1, ESI+)< / annotation>< / semantics>< / com:Math>. 5 Example 16: Synthesis of Compound 6 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 6-1

[00309] To a mixture of Intermediate C (1.0 g, 3.82 mmol) and 4- (bromomethyl)tetrahydropyran (751.61 mg, 4.20 mmol) in DMF (20 mL) was added Na<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.21 g, 11.46 mmol). The reaction mixture was heated to 80 °C for 18 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel- chromatography (petroleum ether in ethyl acetate, 0 to 40%) to obtain 6-1 (970 mg, 2.88 mmol, 75.38% yield). Step 2: 6-2

[00310] To a mixture of 6-1 (500 mg, 1.48 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (451.84 mg, 1.78 mmol) and KOAc (436.57 mg, 4.45 mmol) in Dioxane (12 mL) was added Pd(dppf)Cl<com:Sub>2< / com:Sub> (108.50 mg, 148.28 μmol) at 20 °C. The reaction solution was heated to 120 °C for 0.667 hr under microwave. The mixture was filtered, and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0 to 40%) to obtain 6-2 (350 mg, 910.82 μmol, 61.43% yield). Step 3: 6-3

[00311] To a mixture of 6-2 (150 mg, 390.35 μmol), acetic acid (105.00 mg, 1.75 mmol, 0.1 mL) in THF (8 mL) was added hydrogen peroxide (0.2 mL, 30% purity) at 20 °C. The reaction solution was stirred for 1 hr at 20 °C. Then, the solution was concentrated with a rotary evaporator to obtain 6-3 (120 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=273<annotation encoding="application / x-tex">m / z = 273< / annotation>< / semantics>< / com:Math> (M-1). Step 4: 6-4

[00312] To a mixture of 6-3 (120 mg, 437.46 μmol), Intermediate A (60 mg, 223.78 μmol) in MeCN (20 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (218.73 mg, 671.33 μmol) at 20 °C. The reaction solution was stirred for 1 hr at 90 °C. Then, the mixture was filtered, and the filtrate was concentrated with a rotary evaporator to obtain 6-4 (110 mg, crude). The crude product was used for the next step without further purification. MS: <com:Math><semantics>m / z=462(M+1)<annotation encoding="application / x-tex">m / z = 462 (M+1)< / annotation>< / semantics>< / com:Math>. Step 5: Compound 6

[00313] To a mixture of 6-4 (110 mg, 238.34 μmol) in DCM (15 mL) was added HCl / Dioxane (4 M, 2 mL) at 20 °C and the reaction mixture was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep- HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-30% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 6 (6.0 mg, 14.73) <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 6.18% yield, HCO<com:Sub>2< / com:Sub>H salt). MS: m / z = 362 (M+1). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-<com:Math><semantics>d4<annotation encoding="application / x-tex">d_4< / annotation>< / semantics>< / com:Math>) δ 8.49 (s, 1H), 7.85 (t, <com:Math><semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.23 (d, <com:Math><semantics>J=80.9<annotation encoding="application / x-tex">J = 80.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.07-7.04 (m, 1H), 7.02 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 2.6 Hz, 1H), 4.71 (dd, <com:Math><semantics>J=3.5<annotation encoding="application / x-tex">J = 3.5< / annotation>< / semantics>< / com:Math>, 1.0 Hz, 2H), 3.93-3.83 (m, 2H), 3.79 (d, <com:Math><semantics>J=2.3<annotation encoding="application / x-tex">J = 2.3< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.37- 3.32 (m, 3H), 3.28 (d, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 3H), 2.16 (dt, <com:Math><semantics>J=11.4<annotation encoding="application / x-tex">J = 11.4< / annotation>< / semantics>< / com:Math>, 6.5 Hz, 1H), 1.79-1.70 (m, 2H), 1.50- 1.36 (m, 2H). MS: <com:Math><semantics>m / z=362.1<annotation encoding="application / x-tex">m / z = 362.1< / annotation>< / semantics>< / com:Math> (M+1, ESI+). Example 17: Synthesis of Compound 7 [Image disponible dans le document PDF, Image available in the PDF document] , Step 1: 7-1

[00314] To a mixture of 4-bromo-2-fluoro-benzenethiol (547.57 mg, 2.64 mmol) and NaH (202.66 mg, 5.29 mmol, 60% purity) in DMF (20 mL) was added 5-2 (550.78 mg, 2.64 mmol) at 0 °C. The reaction solution was stirred for 8 hr at 50 °C. To the mixture was added saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (80 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic extracts were dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography (ethyl acetate in petroleum ether, 10% to 80%) to give 7-1 (189 mg, 592.05 μmol, 22.39% yield). Step 2: 7-2

[00315] A mixture of 7-1 (150 mg, 469.88 μmol) and m-CPBA (286.18 mg, 1.41 mmol, 85% purity) in DCM (20 mL) was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.3 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>10 / 1−1 / 2<annotation encoding="application / x-tex">10 / 1-1 / 2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 7-2 (120 mg, 341.66) <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 72.71% yield). MS: m / z = 351.2 (M+1). Step 3: 7-3

[00316] To a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (108.45 mg, 427.07 µmol), 7-2 (100 mg, 284.71 µmol) and cyclopentyl(diphenyl)phosphane;dichloropalladium; iron (20.83 mg, 28.47 µmol) in Dioxane (20.83 mg, 28.47 µmol) in Dioxane (20.83 mg, 28.47 µmol) in Dioxane (20.83 mg, 28.47 µmol) in Dioxane (20.83 mg, 28.47 µmol) in Dioxa mL) was added KOAc (83.83 mg, 854.14 μmol) at 20 °C under the nitrogen atmosphere. The reaction solution was stirred for 4 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator and purified by column chromatography on silical gel (petroleum ether / ethyl- acetate = <com:Math><semantics>1 / 10−1 / 1<annotation encoding="application / x-tex">1 / 10 - 1 / 1< / annotation>< / semantics>< / com:Math>) to obtain 7-3 (80 mg, 200.86 µmol, 70.55% yield). MS: m / z = 398.3(M+1). Step 4: 7-4

[00317] To a mixture of 7-3 (80 mg, 200.86 μmol) in THF (2 mL) and acetic acid (0.5 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (0.5 mL, 30% purity). The mixture was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.2 g) was added to the mixture and stirred for 20 min. The mixture was filtered and concentrated to give 7-4 (300 mg, crude), which was used in the next step without purification. MS: <com:Math><semantics>m / z=288.3<annotation encoding="application / x-tex">m / z = 288.3< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(M+1)<annotation encoding="application / x-tex">(M+1)< / annotation>< / semantics>< / com:Math>. Step 5: 7-5

[00318] To a mixture of Intermediate A (83.69 mg, 312.14 μmol) and 7-4 (300 mg) in MeCN (50 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.02 g, 3.12 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated to obtain 7-5 (209 mg, crude). MS: <com:Math><semantics>m / z=475.5(M+1)<annotation encoding="application / x-tex">m / z = 475.5 (M+1)< / annotation>< / semantics>< / com:Math>. Step 6: Compound 7

[00319] A mixture of 7-5 (200 mg, 408.52 µmol) in HCl / Dioxane (4 M, 5.0 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-30% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 7 (20 mg, 51.35 μmol, 12.57% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.84 (t, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.22 (d, <com:Math><semantics>J=80.0<annotation encoding="application / x-tex">J = 80.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.04 (d, <com:Math><semantics>J=12.8<annotation encoding="application / x-tex">J = 12.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.71 (d, <com:Math><semantics>J=12.8<annotation encoding="application / x-tex">J = 12.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.71 (d, <com:Math><semantics>J=12.8<annotation encoding="application / x-tex">J = 12.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.71 (d, <com:Math><semantics>J=12.8<annotation encoding="application / x-tex">J = 12.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.71 (d, <com:Math><semantics>J=12.8<annotation encoding="application / x-tex">J = 12.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.71 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 3.6 Hz, 2H), 3.77 (s, 2H), 3.66 (t, <com:Math><semantics>J=5.4<annotation encoding="application / x-tex">J = 5.4< / annotation>< / semantics>< / com:Math> Hz, 4H), 3.39 (s, 2H), 1.87-1.73 (m, 2H), 1.54 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 13.6 Hz, 2H), 1.32 (s, 3H).ppm; MS: <com:Math><semantics>m / z=376.5<annotation encoding="application / x-tex">m / z = 376.5< / annotation>< / semantics>< / com:Math> (M+1, ESI+). Example 18: Synthesis of Compound 8 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 8-2

[00320] A mixture of 8-1 (1 g, 3.45 mmol), Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (812.87 mg, 6.45 mmol) and NaHCO<com:Sub>3< / com:Sub> (533.08 mg, 6.35 mmol) in H<com:Sub>2< / com:Sub>O (20 mL) is heated at 100 °C for 1 hr. Then the mixture was concentrated to give 8-2 (2.5 g, crude). MS: <com:Math><semantics>m / z=277.5<annotation encoding="application / x-tex">m / z = 277.5< / annotation>< / semantics>< / com:Math> (M+1). Step 2: 8-3

[00321] A mixture of 8-2 (1 g, 3.82 mmol) and 4-(bromomethyl)tetrahydropyran (684.72 mg, 3.82 mmol) in DMF (20 mL) was stirred at 20 °C. The reaction solution was stirred for 8 hr at 100 °C. Then ethyl acetate (100 mL) and H<com:Sub>2< / com:Sub>O (100 mL) were added, the organic was washed with brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated to give a residue, which was purified by column chromatography on silical gel (ethyl acetate / petroleum ether = <com:Math><semantics>1 / 10−1 / 1<annotation encoding="application / x-tex">1 / 10 - 1 / 1< / annotation>< / semantics>< / com:Math>) to give 8-3 <com:Math><semantics>(300 mg,848.27μmol,22.18% yield)<annotation encoding="application / x-tex">(300 \text{ mg}, 848.27 \mu\text{mol}, 22.18\% \text{ yield})< / annotation>< / semantics>< / com:Math>. MS: m / z = 353.6 (M+1). Step 3: 8-4

[00322] To a mixture of 8-3 (300.00 mg, 848.27 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (323.11 mg, 1.27 mmol) and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (62.07 mg, 84.83 mmol) in Dioxane (10 mL) was added KOAc (254.88 mg, 2.54 mmol) at 30 °C under the nitrogen atmosphere. The reaction solution was stirred for 2 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (petroleum ether / ethyl- acetate = <com:Math><semantics>10 / 1−1:1<annotation encoding="application / x-tex">10 / 1-1:1< / annotation>< / semantics>< / com:Math>, v / v) to obtain 8-4 (200 mg, 499.10 µmol, 58.84% yield). MS: m / z = 400.7(M+1). Step 4: 8-5

[00323] To a mixture of 8-4 (150 mg, 344.69 μmol) in acetic acid (1 mL) and THF (4 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (1 mL, 30% purity). The mixture was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.5 g) was added to the mixture and stirred for 20 min. The mixture was filtered and concentrated to give 8-5 (700 mg, crude), which was used in the next step without purification. <com:Math><semantics>MS:m / z=290.7(M+1).<annotation encoding="application / x-tex">MS: m / z = 290.7(M+1).< / annotation>< / semantics>< / com:Math> Step 5: 8-6

[00324] To a mixture of 8-5 (700 mg) and Intermediate A (193.65 mg, 722.24 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol) in MeCN (30 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (705.96 mg, 2.17 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated to obtain 8-6 (200 mg, crude), which was used in the next step without purification. MS: <com:Math><semantics>m / z=477.9(M+1)<annotation encoding="application / x-tex">m / z = 477.9 (M+1)< / annotation>< / semantics>< / com:Math>. Step 6: Compound 8

[00325] A mixture of 8-6 (100 mg, 195.15 µmol) in HCl / Dioxane (4 M, 1.99 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 µm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-40% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 8 (21 mg, 50.93 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 26.10% yield). MS: m / z = 377.8 (M+1, ESI+). 'H NMR (400 MHz, Methanol-d4) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.05 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.8 Hz, 1H), 7.32 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 2.4 Hz, 1H), 7.26 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 80.0 Hz, 1H), 7.16 (d, <com:Math><semantics>J=3.2<annotation encoding="application / x-tex">J = 3.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.72 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.87 (d, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.82 (s, 2H), 3.40-3.35 (m, 4H), 2.14 (s, 1H), 1.74 (d, <com:Math><semantics>J=13.2<annotation encoding="application / x-tex">J = 13.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.51-1.35 (m, 2H).ppm; MS: <com:Math><semantics>m / z=378.7(M+1,ESI+).<annotation encoding="application / x-tex">m / z = 378.7 (M+1, ESI+).< / annotation>< / semantics>< / com:Math> Example 19: Synthesis of Compound 9 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 9-2

[00326] A mixture of 9-1 (1 g, 3.66 mmol), Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (861.77 mg, 6.84 mmol), and NaHCO<com:Sub>3< / com:Sub> (565.15 mg, 6.73 mmol) in H<com:Sub>2< / com:Sub>O (30 mL) is heated at 100 °C for 1 hr. Then the mixture was concentrated to give 9-2 (4 g, crude). MS: <com:Math><semantics>m / z=261(M+1)<annotation encoding="application / x-tex">m / z = 261(M+1)< / annotation>< / semantics>< / com:Math>. Step 2: 9-3

[00327] A mixture of 9-2 (4 g, 15.32 mmol) and 4-(bromomethyl) tetrahydropyran (823.10 mg, 4.60 mmol) in DMF (50 mL) at 20 °C. The reaction solution was stirred for 8 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>10 / 1−3 / 1<annotation encoding="application / x-tex">10 / 1 - 3 / 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 9-3 (400 mg, 1.19 mmol). MS: <com:Math><semantics>m / z=337(M+1)<annotation encoding="application / x-tex">m / z = 337 (M+1)< / annotation>< / semantics>< / com:Math>. Step 3: 9-4

[00328] A mixture of 9-3 (273.22 mg, 810.24 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (246.90 mg, 972.29 μmol) in Dioxane (10 mL) was added KOAc (206.75 mg, 2.43 mmol) at 20 °C under the nitrogen atmosphere. The reaction solution was stirred for 4 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator and purified by column chromatography on silical gel(ethyl acetate / petroleum ether = <com:Math><semantics>1 / 10−1 / 1<annotation encoding="application / x-tex">1 / 10 - 1 / 1< / annotation>< / semantics>< / com:Math>) to obtain 9-4 (200 mg, 520.47 µmol, 64.24% yield). MS: m / z = 384 (M+1). Step 4: 9-5

[00329] To a mixture of 9-4 (200 mg, 520.47 μmol) in acetic acid (0.5 mL) and THF (2 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (1 mL, 30% purity). The mixture was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.5 g) was added to the mixture and stirred for 20 min. The mixture was filtered and concentrated to give 9-5 (0.8 g, crude), which was used in the next step without purification. MS: <com:Math><semantics>m / z=<annotation encoding="application / x-tex">m / z =< / annotation>< / semantics>< / com:Math> 274(M+1). Step 5: 9-6

[00330] To a mixture of 9-5 (500 mg) and Intermediate A (146.62 mg, 546.83 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol) in MeCN (80 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.78 g, 5.47 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated to obtain 9-6 (200 mg, 433.35 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol). MS: m / z = 461(M+1). Step 6: Compound 9

[00331] A mixture of 9-6 (150 mg, 325.01 µmol) in HCl / Dioxane (4 M, 3 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-30% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 9 (23 mg, 63.64 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 19.58% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-d4) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.47 (s, 1H), 7.74 (t, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 7.40 (t, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.25 (d, <com:Math><semantics>J=80.0<annotation encoding="application / x-tex">J = 80.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.79 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.88 (d, <com:Math><semantics>J=11.2<annotation encoding="application / x-tex">J = 11.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.84-3.75 (m, 2H), 3.38 (t, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.19 (d, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 2.13 (s, 1H), 1.76 (d, <com:Math><semantics>J=13.2<annotation encoding="application / x-tex">J = 13.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.45-1.41 (m, 2H).ppm; MS: m / z = 362.7 (M+1, ESI+). Example 20: Synthesis of Compound 10 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 10-1

[00332] A mixture of D-1 (3 g, 15.87 mmol) and <com:Math><semantics>Cs2CO3<annotation encoding="application / x-tex">Cs_2CO_3< / annotation>< / semantics>< / com:Math> (7.75 g, 23.80 mmol) in MeCN (50 mL) was added 1,6-dioxaspiro[2.5]octane (1.81 g, 15.87 mmol) and the mxture was heated at 80 °C for 2 hr. After cooling to room temperature, the reaction mixture was filtered and concentrated to give a residue, which was purified by column chromatography on silical gel- (ethyl acetate / petroleum ether = <com:Math><semantics>1 / 10−1 / 5<annotation encoding="application / x-tex">1 / 10 - 1 / 5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to give 10-1 (4 g, 13.19 mmol, 83.14% yield). MS: <com:Math><semantics>m / z=303(M+1)<annotation encoding="application / x-tex">m / z = 303 (M+1)< / annotation>< / semantics>< / com:Math>. Step 2: 10-2

[00333] To a mixture of 10-1 (500 mg, 1.65 mmol) and m-CPBA (1.00 g, 4.95 mmol, 85% purity) in DCM (20 mL) was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.4 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>10 / 1−1 / 2<annotation encoding="application / x-tex">10 / 1 - 1 / 2< / annotation>< / semantics>< / com:Math>, v / v) to obtain 10-2 (400 mg, 1.19) mmol, <com:Math><semantics>72.36%<annotation encoding="application / x-tex">72.36\%< / annotation>< / semantics>< / com:Math> yield). MS: m / z = 335 (M+1). Step 3: 10-3

[00334] To a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (454.52 mg, 1.79 mmol), 10-2 (400 mg, 1.19 mmol) in Dioxane (20 mL) was added cyclopentyl(diphenyl)phosphane; dichloropalladium;iron (87.31 mg, 119.33 µmol) and KOAc (351.33 mg, 3.58 mmol) at 20 °C under the nitrogen atmosphere. The reaction solution was stirred for 4 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator and purified by column chromatography on silical gel (ethyl acetate / petroleum ether = <com:Math><semantics>1 / 10−1 / 1<annotation encoding="application / x-tex">1 / 10 - 1 / 1< / annotation>< / semantics>< / com:Math>) to obtain 10-3 (300 mg, 784.77 µmol, 65.77% yield). MS; m / z = 382.2 (M+1). Step 4: 10-4

[00335] A mixture of 10-3 (300 mg, 784.77 μmol) in THF (2 mL) and acetic acid (0.5 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (0.5 mL, 30% purity). The mixture was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.3 g) was added to the mixture and stirred for 20 min. The mixture was filtered and concentrated to give 10-4 (0.6 g, crude), which was used in the next step without purification. MS: <com:Math><semantics>m / z=272<annotation encoding="application / x-tex">m / z = 272< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(M+1)<annotation encoding="application / x-tex">(M+1)< / annotation>< / semantics>< / com:Math>. Step 5: 10-5

[00336] To a mixture of 10-4 (0.5 g) and Intermediate A (147.69 mg, 550.83 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol) in MeCN (20 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.79 g, 5.51 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated to obtain 10-5 (280 mg, crude). MS: <com:Math><semantics>m / z=459(M+1)<annotation encoding="application / x-tex">m / z = 459 (M+1)< / annotation>< / semantics>< / com:Math>. Step 6: Compound 10

[00337] To a mixture of 10-5 (250 mg, 544.04 µmol) in HCl / Dioxane (4 M, 5 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-25% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 10 (19 mg, 52.86 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-d4) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.89 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 8.4 Hz, 2H), 7.23 (d, <com:Math><semantics>J=80.0<annotation encoding="application / x-tex">J = 80.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.20 (d, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.71 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.84- <Formule mathématique disponible dans le document PDF, Math available in the PDF document>3.79 \text{ (m, 2H)}, 3.78-3.71 \text{ (m, 2H)}, 3.69-3.65 \text{ (m, 2H)}, 3.40 \text{ (s, 2H)}, 1.95-1.84 \text{ (m, 2H)}, 1.72 \text{ (d, } J = 1.84 \text{ (m, 2H)}, 1.72 \text{ (d, } J = 1.84 \text{ (m, 2H)}, 1.84 \text{ (m, 2H)}, 1.84 \text{ (m, 2H)}, 1.84 \text{ 13.6 Hz, 2H).ppm; MS: <com:Math><semantics>m / z=360.6<annotation encoding="application / x-tex">m / z = 360.6< / annotation>< / semantics>< / com:Math> (M+1, ESI+). 25 Example 21: Synthesis of Compound 11 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 11-1

[00338] A mixture of 10-1 (1 g, 3.30 mmol) in DMF (10 mL) was added NaH (197.86 mg, 4.95 mmol, 60% purity) at 0 °C and stirred for 1 hr. MeI (936.22 mg, 6.60 mmol) was added. The reaction solution was stirred at 50 °C for 4 hr. To the mixture was added saturated aqueous ammonium chloride solution (150 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic extracts were dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography (ethyl acetate in petroleum ether, 10% to 80%) to give 11-1 (700 mg, 2.21 mmol, 66.91% yield). MS: <com:Math><semantics>m / z=317<annotation encoding="application / x-tex">m / z = 317< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(M+1)<annotation encoding="application / x-tex">(M+1)< / annotation>< / semantics>< / com:Math>. Step 2: 11-2

[00339] A mixture of 11-1 (700 mg, 2.21 mmol) and m-CPBA (1.34 g, 6.62 mmol, 85% purity) in DCM (20 mL) was stirred at 20 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.3 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>10 / 1−1 / 2<annotation encoding="application / x-tex">10 / 1 - 1 / 2< / annotation>< / semantics>< / com:Math>, v / v) to obtain 11-2 (680 mg, 1.95) mmol, 88.24% yield). MS: <com:Math><semantics>m / z=349(M+1)<annotation encoding="application / x-tex">m / z = 349 (M+1)< / annotation>< / semantics>< / com:Math>. Step 3: 11-3

[00340] To a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (327.20 mg, 1.29 mmol), 11-2 (300 mg, 859.01 µmol) in Dioxane (20 mL) was added cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (62.85 mg, 85.90) µmol) and KOAc (252.91 mg, 2.58 mmol) at 20 °C under the nitrogen atmosphere. The reaction solution was stirred for 4 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator and purified by column chromatography on silical gel (petroleum ether / ethylacetate=<com:Math><semantics>1 / 10−1 / 1<annotation encoding="application / x-tex">1 / 10 - 1 / 1< / annotation>< / semantics>< / com:Math>) to obtain 11-3 (200 mg, 504.66 µmol, 58.75% yield). MS: m / z = 396 (M+1). Step 4: 11-4

[00341] A mixture of 11-3 (200 mg, 504.66 μmol) in THF (2 mL) and acetic acid (0.5 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (0.5 mL, 30% purity). The mixture was stirred at 25 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.3 g) was added to the mixture and stirred for 20 min. The mixture was filtered and concentrated to give 11-4 (0.6 g, crude), which was used in the next step without purification. MS: <com:Math><semantics>m / z=286<annotation encoding="application / x-tex">m / z = 286< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(M+1)<annotation encoding="application / x-tex">(M+1)< / annotation>< / semantics>< / com:Math>. Step 5: 11-5

[00342] To a mixture of 11-4 (0.5 g) and Intermediate A (140.46 mg, 523.85 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol) in MeCN (50 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (568.93 mg, 1.75 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated to obtain 11-5 (200 mg, crude). MS: <com:Math><semantics>m / z=473<annotation encoding="application / x-tex">m / z = 473< / annotation>< / semantics>< / com:Math> (M+1). Step 6: Compound 11

[00343] A mixture of 11-5 (200 mg, 422.34 µmol) in HCl / Dioxane (4 M, 5 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-30% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 11 (25 mg, 66.95 μmol, 7.93% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.90 (d, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 7.23 (d, <com:Math><semantics>J=80.0<annotation encoding="application / x-tex">J = 80.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.20 (d, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.71 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.79 (d, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.73-3.57 (m, 4H), 3.50 (s, 2H), 2.95 (s, 3H), 1.98 (d, <com:Math><semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.86−1.82<annotation encoding="application / x-tex">1.86-1.82< / annotation>< / semantics>< / com:Math> (m, 2H).ppm; MS: <com:Math><semantics>m / z=374.6<annotation encoding="application / x-tex">m / z = 374.6< / annotation>< / semantics>< / com:Math> (M+1, ESI+). 15 Example 22: Synthesis of Compound 12 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 12-2

[00344] A mixture of 12-1 (1 g, 7.08 mmol), TEA (2.15 g, 21.25 mmol, 2.96 mL) in DCM (50 mL) was added MsCl (973.75 mg, 8.50 mmol) at 0 °C. The reaction solution was stirred for 1 hr at 0 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>4 / 1<annotation encoding="application / x-tex">4 / 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 12-2 (1.4 g, 6.39 mmol, 90.14% yield). Step 2: 12-3

[00345] A mixture of 4-bromobenzenethiol (689.87 mg, 3.65 mmol), NaH (87.56 mg, 3.65 mmol) in DMF (10 mL) was added 12-2 (400 mg, 1.82 mmol) at 0 °C. The reaction solution was stirred for 12 hr at 50 °C. To the mixture was added saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (120 mL). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (80 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic extracts were dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography (petroleum ether in ethyl acetate, 10% to 80%) to give 12-3 (150 mg, 480.42 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 26.33% yield). MS: m / z = 312 (M+1). Step 3: 12-4

[00346] A mixture of 12-3 (100 mg, 320.28 μmol) and m-CPBA (195.07 mg, 960.85 μmol, 85% purity) in DCM (20 mL) was stirred at 25 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (14 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>30 / 1−3 / 1<annotation encoding="application / x-tex">30 / 1 - 3 / 1< / annotation>< / semantics>< / com:Math>, v / v) to obtain 12-4 (80 mg, 232.41) <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 72.56% yield). MS: m / z = 344 (M+1). Step 4: 12-5

[00347] A 30 mL microwave reaction tube was charged with 12-4 (80 mg, 232.41 µmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (88.53) mg, 348.61 µmol), cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (170.05 mg, 232.41 µmol) and KOAc (158.58 mg, 697.22 μmol) in Dioxane (10 mL). After O<com:Sub>2< / com:Sub> was purged by bubbling N<com:Sub>2< / com:Sub> into the reaction solution, the tube was sealed and heated at 120 °C for 0.5 hr in a Biotage microwave reactor. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The resultant crude product was purified by flash chromatography (ethyl acetate in petroleum ether, 0-100%) to deliver 12-5 (75 mg, 191.67 µmol, 82.47% yield). MS: <com:Math><semantics>m / z=391(M+1)<annotation encoding="application / x-tex">m / z = 391(M+1)< / annotation>< / semantics>< / com:Math>. Step 5: 12-6

[00348] To a mixture of 12-5 (70 mg, 178.90 μmol) in THF (1 ml) and acetic acid (0.25 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (0.5 mL, 30% purity). The mixture was stirred at 25 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.3 g) was added to the mixture and stirred for 30 min. The reaction mixture was filtered and concentrated to give 12-6 (0.4 g, crude). MS: <com:Math><semantics>m / z=281(M+1)<annotation encoding="application / x-tex">m / z = 281(M+1)< / annotation>< / semantics>< / com:Math>. Step 6: 12-7

[00349] To a mixture of 12-6 (0.4 g) and Intermediate A (152.49 mg, 568.73 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol) in MeCN (50 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.39 g, 4.27 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered, concentrated and purified by column chromatography on silical gel (ethyl acetate / petroleum ether = <com:Math><semantics>1 / 10−5 / 1<annotation encoding="application / x-tex">1 / 10 - 5 / 1< / annotation>< / semantics>< / com:Math>) to obtain 12-7 (70 mg, 149.40 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 10.51% yield). MS: m / z = 468 (M+1). Step 7: Compound 12

[00350] A mixture of 12-7 (70 mg, 149.40 µmol) in HCl / Dioxane (4 M, 4.0 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-35% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 12 (12 mg, 32.57 μmol, 21.80% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-d4) δ 7.94 (d, <com:Math><semantics>J=8.4 Hz<annotation encoding="application / x-tex">J = 8.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 2H), 7.25 (d, <com:Math><semantics>J=80.0 Hz<annotation encoding="application / x-tex">J = 80.0 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 7.22 (d, <com:Math><semantics>J=8.4 Hz<annotation encoding="application / x-tex">J = 8.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 2H), 4.72 (d, <com:Math><semantics>J=3.6 Hz<annotation encoding="application / x-tex">J = 3.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 2H), <com:Math><semantics>3.98−3.88<annotation encoding="application / x-tex">3.98 - 3.88< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.82<annotation encoding="application / x-tex">3.82< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.66<annotation encoding="application / x-tex">3.66< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=13.9<annotation encoding="application / x-tex">J = 13.9< / annotation>< / semantics>< / com:Math> Hz, 4H), <com:Math><semantics>2.07<annotation encoding="application / x-tex">2.07< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=13.6<annotation encoding="application / x-tex">J = 13.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.88-1.85 (m 2H).ppm; MS: <com:Math><semantics>m / z=369.5<annotation encoding="application / x-tex">m / z = 369.5< / annotation>< / semantics>< / com:Math> (M+1, ESI+). Example 23: Synthesis of Compound 13 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 13-1

[00351] A mixture of 4-bromo-2-fluoro-benzenethiol (1 g, 4.83 mmol), NaH (370.10 mg, 9.66 mmol, 60% purity) in DMF (10 mL) was added 12-2 (423.56 mg, 1.93 mmol) at 0 °C. The reaction solution was stirred for 12 hr at 50 °C. To the mixture was added saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (50 ml <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic extracts were dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography (ethyl acetate in petroleum ether, 10% to 80%) to give 13-1 (200 mg, 605.67 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 12.54% yield). MS: m / z = 330 (M+1). Step 2: 13-2

[00352] To a mixture of 13-1 (200 mg, 605.67 μmol) and m-CPBA (368.88 mg, 1.82 mmol, 85% purity) in DCM (20 mL) was stirred at 25 °C for 1 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (1 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethylacetate = <com:Math><semantics>30 / 1−10 / 1<annotation encoding="application / x-tex">30 / 1-10 / 1< / annotation>< / semantics>< / com:Math>, v / v) to obtain 13-2 (120 mg, 331.30 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 54.70% yield). MS: m / z = 362 (M+1). Step 3: 13-3

[00353] To a mixture of 13-2 (110 mg, 303.69 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (115.68 mg, 455.53 μmol) in Dioxane (4 mL) was added KOAc (158.58 mg, 911.06 μmol) at 20 °C under the nitrogen atmosphere. The reaction solution was stirred for 2 hr at 100 °C. Then, the solution was concentrated with a rotary evaporator and purified by column chromatography on silical gel (petroleum ether / ethyl acetate = <com:Math><semantics>1 / 10−1 / 1<annotation encoding="application / x-tex">1 / 10 - 1 / 1< / annotation>< / semantics>< / com:Math>) to obtain 13-3 (90 mg, 219.90 µmol, 72.41% yield). MS: m / z = 409 (M+1). Step 4: 13-4

[00354] A mixture of 13-3 (90 mg, 219.90 μmol) in THF (1 mL) and acetic acid (0.25 mL) was added H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (0.5 mL, 30% purity). The mixture was stirred at 25 °C for 0.5 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (0.35 g) was added to the mixture and stirred for 30 min. The reaction mixture was filtered and concentrated to give 13-4 (0.4 g, crude). MS: <com:Math><semantics>m / z=299(M+1)<annotation encoding="application / x-tex">m / z = 299 (M+1)< / annotation>< / semantics>< / com:Math>. Step 5: 13-5

[00355] A mixture of 13-4 (0.4 g) and Intermediate A (143.33 mg, 534.55 µmol) in MeCN (5 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.31 g, 4.01 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated and purified by column chromatography on silical gel (petroleum ether / ethyl acetate <com:Math><semantics>=1 / 10−5 / 1<annotation encoding="application / x-tex">=1 / 10 - 5 / 1< / annotation>< / semantics>< / com:Math>) to obtain 13-5 (60 mg, 123.32 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 9.23% yield). MS: m / z = 486 (M+1). Step 6: Compound 13

[00356] A mixture of 13-5 (60 mg, 123.32 µmol) in HCl / Dioxane (4 M, 2.25 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-30% B; GT: 15 min; flow rate: 15 mL / min) to obtain Compound 13 (5.3 mg, 13.72 μmol, 11.12% yield). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.89 (t, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.22 (d, <com:Math><semantics>J=80.0<annotation encoding="application / x-tex">J = 80.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.10-7.00 (m, 2H), 4.72 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.20 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.20 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.20 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.10-7.00 (m, 2H), 3.6 Hz, 2H), 4.04-3.87 (m, 2H), 3.78 (d, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.74 (s, 2H), 3.63 (t, <com:Math><semantics>J=12.4<annotation encoding="application / x-tex">J = 12.4< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.07(d,J=13.6Hz,2H),1.90−1.86(m,2H).ppm;MS:m / z=387.5(M+1,ESI+).<annotation encoding="application / x-tex">2.07 (d, J = 13.6 Hz, 2H), 1.90-1.86 (m, 2H).ppm; MS: m / z = 387.5 (M+1, ESI+).< / annotation>< / semantics>< / com:Math> Example 24: Synthesis of Compound 14 & 15 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 14-2

[00357] To a mixture of 14-1 (1.55 g, 9.00 mmol) in DCM (30 mL) was added tert- butylchlorodiphenylsilane (4.95 g, 18.0 mmol), Imidazole (1.53 g, 22.5 mmol). After stirred at 25 °C for 16 hr, the reaction mixture was poured into 50 mL water, extracted with DCM (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrated was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether / ethyl acetate (20 / 1) to afford 14-2 (2.8 g, 75.77% yield). Step 2: 14-3

[00358] To a mixture of 14-2 (2.8 g, 6.82 mmol) in THF (30 mL) was added LiAlH<com:Sub>4< / com:Sub> (518.24 mg, 13.64 mmol) at 0 °C. After addition, the mixture was warmed up to 25 °C and stirred at 25 °C for 2 hr. The resulting mixture was quenched with Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>·10H<com:Sub>2< / com:Sub>O (2.0 g) and ice-water (20 mL). The aqueous mixture was extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether / ethyl acetate (10 / 1) to afford 14-3 (2.3 g, 91.51% yield). Step 3: 14-4

[00359] To a mixture of 14-3 (2.3 g, 6.24 mmol) in DCM (30 mL) was added 4- methylbenzenesulfonyl chloride (1.78 g, 9.36 mmol) and TEA (1.26 g, 12.48 mmol). After stirred at 25 °C for 16 hr, the resulting mixture was poured into ice-water (30 mL) and extracted with DCM (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether / ethyl acetate (50 / 1) to afford 14-4 (3.2 g, 98.10% yield). Step 4: 14-5

[00360] To a mixture of 14-4 (3.2 g, 6.12 mmol) in MeCN (30 mL) was added 4- Bromothiophenol (1.39 g, 7.35 mmol) and K<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.69 g, 12.24 mmol). The resulting mixture was stirred at 80 °C for 3 hr. After cooling to 25 °C, the reaction mixture was poured into ice- water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether / ethyl acetate (50 / 1) to afford 14-5 (3.2 g, 96.87% yield). Step 5: 14-6

[00361] To a mixture of 14-5 (2.0 g, 3.71 mmol) in MeOH / H<com:Sub>2< / com:Sub>O (24 mL, 4 / 1) was added Oxone (4.56 g, 7.41 mmol). After stirred at 25 °C for 2 hr, the resulting mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrate was concentrated under reduced pressure to afford 14-6 (2.05 g), which was used for next step directly without further purification. Step 6: 14-7

[00362] To a mixture of 14-6 (2.05 g, 3.59 mmol) in Dioxane / <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (30 mL, 1 / 1) was added t- Buxphos (304.57 mg, 0.72 mmol), Pd<com:Sub>2< / com:Sub>(dba)<com:Sub>3< / com:Sub> (328.14 mg, 0.36 mmol) and KOH (603.66 mg, 10.76 mmol). The resulting mixture was stirred at 100 °C for 1 hr under argon. After cooling to 25 °C, the reaction mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether / ethyl acetate (5 / 1 to 2 / 1) to afford 14-7 (1.4 g, <com:Math><semantics>76.74%<annotation encoding="application / x-tex">76.74\%< / annotation>< / semantics>< / com:Math> yield). MS: m / z = 509.3 (M+H, ESI+). Step 7: 14-8

[00363] To a mixture of 14-7 (254 mg, 0.5 mmol) in DMF (5 mL) was added Intermediate A (160.64 mg, 0.6 mmol) and <com:Math><semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics>< / com:Math> (275.60 mg, 2.00 mmol). The resulting mixture was stirred at 80 °C for 5 hr. After cooling to 25 °C, the reaction mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether / ethyl acetate (5 / 1) to afford 14-8 (330 mg, 94.97% yield). MS: <com:Math><semantics>m / z=696.5<annotation encoding="application / x-tex">m / z = 696.5< / annotation>< / semantics>< / com:Math> (M+H, ESI+). Step 8: 14-9

[00364] To a mixture of 14-8 (330 mg, 0.47 mmol) in THF (10 mL) was added TABF (1 M in THF, 0.95 mL). The resulting mixture was stirred at 40 °C for 6 hr. After cooling to 25°C, the reaction mixture was poured into ice-water (30 mL) and extracted with ethyl acetate (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluted with petroleum ether / ethyl acetate (1 / 1) to afford 14-9 (195 mg, 89.88% yield). MS: <com:Math><semantics>m / z=458.2<annotation encoding="application / x-tex">m / z = 458.2< / annotation>< / semantics>< / com:Math> (M+H, ESI+). Step 9: Compound 14 & 15

[00365] To a mixture of 14-9 (195 mg, 0.43 mmol) in DCM (10 mL) was added HCl (4 M in Dioxane, 2.13 mL). After stirred at 25 °C for 3 hr, the solvent was removed under reduced pressure. The residue was purified by prep-HPLC (column: Sunfire Prep C18 10 μm 19×250 mm; A: 0.05% HCl water, B: acetonitrile; gradient: 10-14% B; GT: 18 min; flow rate: 20 mL / min) to afford Compound 15 (35 mg, 22.98% yield) and Compound 14 (38 mg, 24.95% yield). Compound 15: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.46 (br, 3H), 7.84-7.82 (m, 2H), 7.45 (s, 1H), 7.24-7.22 (m, 2H), 4.78 (s, 2H), 3.27-3.13 (m, 3H), 1.77-1.75 (m, 4H), 1.61-1.43 (m, 2H), 1.07- 1.05 (m, 4H) ppm; MS: <com:Math><semantics>m / z=358.2<annotation encoding="application / x-tex">m / z = 358.2< / annotation>< / semantics>< / com:Math> (M+H, ESI+). Compound 14: <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.49 (br, 3H), 7.84-7.83 (m, 2H), 7.44 (s, 1H), 7.23-7.21 (m, 2H), 4.78 (s, 2H), 3.64-3.59 (m, 3H), 3.16 (d, <com:Math><semantics>J=2.8<annotation encoding="application / x-tex">J = 2.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.78-1.36 (m, 9H) ppm; MS: <com:Math><semantics>m / z=358.2<annotation encoding="application / x-tex">m / z = 358.2< / annotation>< / semantics>< / com:Math> (M+H, ESI+). Example 25: Synthesis of Compound 16 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 16-1

[00366] To a mixture of I-2 (4 g, 20.18 mmol), Triethylamine (6.12 g, 60.53 mmol, 8.44 mL) in DCM (40 mL) was added Methanesulfonic anhydride (5.27 g, 30.26 mmol, 3.34 mL) at 0 °C. The reaction solution was stirred for 2 hr at 25 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0~30%, v / v) to obtain 16-1 (4.9 g, 17.73 mmol, 87.88% yield). Step 2: 16-2

[00367] To a mixture of 4-bromobenzenethiol (5.03 g, 26.60 mmol), Potassium iodide (1.47 g, 8.87 mmol, 471.70 uL) in DMF (30 mL) was added 16-1 (4.9 g, 17.73 mmol) under the nitrogen atmosphere. The reaction mixture was heated at 55 °C for 8 hr. Ethyl acetate (150 mL) and H<com:Sub>2< / com:Sub>O (100 mL) were added, the organic layer was washed with brine (100 mL × 3), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated to a residue, which was purified by column chromatography on silical gel (ethyl acetate in petroleum ether, 0~20%, v / v) to give 16-2 (5.5 g, 14.89 mmol, 83.99% yield). Step 3: 16-3

[00368] To a mixture of 16-2 (5.5 g, 14.89 mmol) and m-CPBA (7.56 g, 37.23 mmol, 85% purity) in DCM (100 mL) was stirred at 20 °C for 2 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (1 g) was added to the mixture and stirred for 20 min. Then, to the solution was added ethyl acetate (20 mL) and water (20 mL). The organic layer was washed with aq. NaHCO<com:Sub>3< / com:Sub> (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3), brine (30 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered, concentrated to give crude, which was purified by column chromatography on silical gel (20 g, ethyl acetate in petroleum ether, <com:Math><semantics>0∼20%<annotation encoding="application / x-tex">0\sim20\%< / annotation>< / semantics>< / com:Math>) to give 16-3 (4.5 g, 11.21 mmol, 75.29% yield). Step 4: 16-4

[00369] A mixture of methyl 16-3 (1.5 g, 3.74 mmol) and lithium hydroxide monohydrate (784.24 mg, 18.69 mmol) in THF (10 mL) and water (10 mL) was stirred at 25 °C for 16 hr. Upon completion, the resulting mixture was concentrated to remove organic solvent. The residue was acidified with 1 M aqueous HCl to pH = <com:Math><semantics>5∼6<annotation encoding="application / x-tex">5 \sim 6< / annotation>< / semantics>< / com:Math> and filtered to give the filter cake as 16-4 (1.1) g, 2.84 mmol, 75.99% yield). MS: <com:Math><semantics>m / z=387<annotation encoding="application / x-tex">m / z = 387< / annotation>< / semantics>< / com:Math> (M+H) Step 5: 16-5

[00370] To a mixture of 16-4 (1.1 g, 2.84 mmol), ammonium chloride (1.52 g, 28.42 mmol, 993.62 uL) and HATU (1.62 g, 4.26 mmol) in DMF (10 mL) was added DIPEA (1.10 g, 8.52 mmol, 1.48 mL). After addition, the mixture was stirred at 25 °C for 16 hr. Upon completion, the resulting mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with H<com:Sub>2< / com:Sub>O (20 mL × 3) and brine, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated to give 16-5 (1 g, 2.59 mmol, 91.14% yield). MS: <com:Math><semantics>m / z=386<annotation encoding="application / x-tex">m / z = 386< / annotation>< / semantics>< / com:Math> (M+H) Step 6: 16-6

[00371] A mixture of 16-5 (950 mg, 2.46 mmol) and Burgess Reagent (1.17 g, 4.92 mmol) in DCM (30 mL) was stirred at 25 °C for 3 hr. Upon completion, the resulting solution was concentrated. The residue was purified by FCC (silica gel, petroleum ether / ethyl acetate <com:Math><semantics>=3 / 1<annotation encoding="application / x-tex">= 3 / 1< / annotation>< / semantics>< / com:Math>) to give 16-6 (900 mg, 2.44 mmol, 99.37% yield). MS: <com:Math><semantics>m / z=368<annotation encoding="application / x-tex">m / z = 368< / annotation>< / semantics>< / com:Math> (M+H) Step 7: 16-7

[00372] To a mixture of 16-6 (500 mg, 1.36 mmol) and Ti(OiPr)<com:Sub>4< / com:Sub> (3.09 g, 10.86 mmol) in THF (10 mL) was added bromo(ethyl)magnesium (1 M in THF, 13.6 mL) dropwise at 25 °C. After addition, the resulting mixture was stirred at 25 °C for 0.5 hr. Boron trifluoride diethyl etherate (805.0 mg, 5.67 mmol, 700 µL) was added at 25 °C. After addition, the mixture was stirred at 25 °C for 0.5 hr. Upon completion, the resulting mixture was quenched with 10% aqueous NaOH and extracted with DCM (40 mL). The seperated organic layer was washed with brine, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated. The residue was purified by FCC (silica gel, DCM / MeOH = <com:Math><semantics>100 / 1<annotation encoding="application / x-tex">100 / 1< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>20 / 1<annotation encoding="application / x-tex">20 / 1< / annotation>< / semantics>< / com:Math>) to give 16-7 (170 mg, <com:Math><semantics>426.75<annotation encoding="application / x-tex">426.75< / annotation>< / semantics>< / com:Math> µmol, <com:Math><semantics>31.43%<annotation encoding="application / x-tex">31.43\%< / annotation>< / semantics>< / com:Math> yield). MS: m / z = 398 (M+H) Step 8: 16-8

[00373] To a mixture of 16-7 (170 mg, 426.75 μmol), DIPEA (275.77 mg, 2.13 mmol, 371.66 μL) in DCM (10 mL) was added cyclopropanecarbonyl chloride (134 mg, 1.28 mmol, 116.52 μL). After addition, the mixture was stirred at 25 °C for 2 hr. Upon completion, the resulting solution was quenched with water. The separated organic layer was concentrated. The residue was purified by FCC (silica gel, DCM / MeOH = <com:Math><semantics>20 / 1<annotation encoding="application / x-tex">20 / 1< / annotation>< / semantics>< / com:Math>) to give 16-8 (160 mg, 343.03 µmol, 80.38% yield). MS: <com:Math><semantics>m / z=466(M+H)<annotation encoding="application / x-tex">m / z = 466 (M+H)< / annotation>< / semantics>< / com:Math> Step 9: 16-9

[00374] A mixture of 16-8 (160 mg, 343.03 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (131 mg, 515.87 µmol), Pd(dppf)Cl<com:Sub>2< / com:Sub> (26 mg, 35.53 µmol) and KOAc (433 mg, 1.03 mmol) in Dioxane (5 mL) was microwaved at 120 °C for 30 min. Upon completion, the resulting mixture was cooled to room temperature, filtered and concentrated to give crude 16-9 (170 mg, 331.06 µmol, 96.51% yield). Step 10: 16-10

[00375] A mixture of 16-9 (170 mg, 331.06 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol), H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (1 mL, 30% purity) and acetic acid (1 mL) in THF (4 mL) was stirred at 25 °C for 1 hr. Upon completion, the resulting solution was quenched with Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub>, filtered and concentrated. The residue was purified by FCC (silica gel, petroleum ether / ethyl acetate = <com:Math><semantics>1 / 1<annotation encoding="application / x-tex">1 / 1< / annotation>< / semantics>< / com:Math>) to give 16-10 (120 mg, 297.37 µmol, 89.82% yield). MS: <com:Math><semantics>m / z=404(M+H)<annotation encoding="application / x-tex">m / z = 404 (M+H)< / annotation>< / semantics>< / com:Math> Step 11: 16-11

[00376] A mixture of 16-10 (120 mg, 297.37 μmol), Intermediate A (88 mg, 328.21 μmol) and Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (485 mg, 1.49 mmol) in MeCN (20 mL) was stirred at 95 °C for 1 hr. Upon completion, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated. The residue was purified by FCC (silica gel, petroleum ether / ethyl acetate = <com:Math><semantics>1 / 1<annotation encoding="application / x-tex">1 / 1< / annotation>< / semantics>< / com:Math> to 1 / 4) to give 16-11 (130 mg, 220.06 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 74.00% yield). MS: m / z = 535 (M+H-56). Step 12: Compound 16

[00377] A mixture of 16-11 (130 mg, 220.06 μmol) and HCl / Dioxane (4 M, 5.0 mL) in Dioxane (2 mL) was stirred at 25 °C for 1 hr. Upon completion, the resulting mixture was filtered to obtain the filter cake as Compound 16 (70 mg, 132.80 µmol, 60.35% yield, HCl salt). <com:Sup>1< / com:Sup>H NMR (500 MHz, Methanol-<com:Math><semantics>d4<annotation encoding="application / x-tex">d_4< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.77-7.72 (m, 2H), 7.24 (s, 0.5H), 7.12-7.09 (m, 2H), 7.08 <com:Math><semantics>(s,0.5H),4.62(d,J=3.4Hz,2H),3.74(d,J=2.3Hz,2H),2.94(s,2H),1.60−1.50(m,6H),<annotation encoding="application / x-tex">(s, 0.5H), 4.62 (d, J = 3.4 Hz, 2H), 3.74 (d, J = 2.3 Hz, 2H), 2.94 (s, 2H), 1.60-1.50 (m, 6H),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.43−1.30<annotation encoding="application / x-tex">1.43-1.30< / annotation>< / semantics>< / com:Math> (m, 7H), <com:Math><semantics>0.74−0.64<annotation encoding="application / x-tex">0.74-0.64< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>0.58−0.53<annotation encoding="application / x-tex">0.58-0.53< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>0.51−0.40<annotation encoding="application / x-tex">0.51-0.40< / annotation>< / semantics>< / com:Math> (m, 2H). MS: m / z = 491 <com:Math><semantics>(M+1,ESI+)<annotation encoding="application / x-tex">(M+1, ESI+)< / annotation>< / semantics>< / com:Math>. Example 26: Synthesis of Compound 17 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 17-1

[00378] To a mixture of Intermediate I (900 mg, 2.77 mmol), N-methoxymethanamine (405.94 mg, 4.16 mmol, HCl salt) in DMF (10 mL) was added HATU (1.27 g, 3.33 mmol) and TEA (842.23 mg, 8.32 mmol, 1.16 mL) at 30 °C. The reaction solution was stirred for 1 hr at 30 °C. Then, ethyl acetate (100 mL) was added and the mixture reaction was washed with H<com:Sub>2< / com:Sub>O <com:Math><semantics>(100mL×3)<annotation encoding="application / x-tex">(100 \text{mL} \times 3)< / annotation>< / semantics>< / com:Math>, the organic phases were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>5 / 1−1 / 1<annotation encoding="application / x-tex">5 / 1 - 1 / 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 17-1 (220 mg, 598.71 μmol, 21.58% yield). Step 2: 17-2

[00379] To a mixture of 17-1 (200 mg, 544.28 μmol) and Intermediate A (145.93 mg, 544.28 µmol) in MeCN (40 mL) was added Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (532.01 mg, 1.63 mmol) at 20 °C. The reaction solution was stirred for 1 hr at 80 °C. Then, the solution was filtered and concentrated to give a residue, which was purified by column chromatography on silical (ethyl acetate / petroleum ether = <com:Math><semantics>5 / 1−1 / 1<annotation encoding="application / x-tex">5 / 1 - 1 / 1< / annotation>< / semantics>< / com:Math>) to obtain 17-2 (220 mg, 396.63 µmol, 72.87% yield). Step 3: 17-3

[00380] To a mixture of 17-2 (200 mg, 360.58 μmol) in THF (10 mL) was added bromo(methyl)magnesium (1 M in THF, 1.44 mL) at -40 °C. The reaction solution was stirred for 2 hr at 25 °C. Aq. NH<com:Sub>4< / com:Sub>Cl (10 mL) and ethyl acetate (100 mL) were added, the organic phases were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>4 / 1−1 / 1<annotation encoding="application / x-tex">4 / 1 - 1 / 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 17-3 (160 mg, 313.95 μmol, 87.07% yield). Step 4: 17-4

[00381] A mixture of 17-3 (100 mg, 196.22 μmol) and m-CPBA (79.67 mg, 392.44 μmol, 85% purity) in DCM (5 mL) was stirred at 30 °C for 12 hr. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (4 g) was added to the mixture and stirred for 20 min. Then, the solution was filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethylacetate = <com:Math><semantics>5 / 1−1 / 1<annotation encoding="application / x-tex">5 / 1 - 1 / 1< / annotation>< / semantics>< / com:Math>, v / v) to obtain 17-4 (20 mg, 37.90) <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 19.32% yield). MS: m / z = 348.4 (M+1). Step 5: 17-5

[00382] To a mixture of 17-5 (20 mg, 37.90 μmol) in MeOH (5 mL) was added K<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (15.72 mg, 113.71 μmol) at 25 °C, and the reaction solution was stirred for 2 hr at 25 °C. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = <com:Math><semantics>4 / 1−1 / 1<annotation encoding="application / x-tex">4 / 1 - 1 / 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v / v<annotation encoding="application / x-tex">v / v< / annotation>< / semantics>< / com:Math>) to obtain 17-5 (18 mg, 37.07) <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 97.79% yield). MS: m / z = 334.4 (M+1). Step 6: Compound 17

[00383] A mixture of 17-5 (18 mg, 37.07 µmol) in HCl / Dioxane (4 M, 3 mL) was stirred at 20 °C for 1 hr. Then, the solution was concentrated with a rotary evaporator. The crude product was purified by prep-HPLC (column: XBridge@ Prep C18 5 μm 19×150 mm; A: 0.1% HCO<com:Sub>2< / com:Sub>H water, B: acetonitrile; gradient: 5-95% B; GT: 25 min; flow rate: 15 mL / min) to obtain Compound 17 (4 mg, 9.27 µmol, 25.01% yield, HCO<com:Sub>2< / com:Sub>H salt). <com:Sup>1< / com:Sup>H NMR (400 MHz, Methanol- d4) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.51 (s, 1H), 7.90-7.82 (m, 2H), 7.24 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 80.0 Hz, 1H), 7.24-7.17 (m, 2H), 4.75-4.67 (m, 2H), 3.81 (d, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.07 (s, 2H), 1.84-1.80 (m, 6H), 1.66-1.63 (m, 6H), ppm; MS: m / z <com:Math><semantics>=384.5(M+1,ESI+).<annotation encoding="application / x-tex">= 384.5 (M+1, ESI+).< / annotation>< / semantics>< / com:Math> Example 27: Synthesis of Compound 18 [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 18-1

[00384] A mixture of 16-3 (590 mg, 1.47 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (560 mg, 2.21 mmol), Pd(dppf)Cl<com:Sub>2< / com:Sub> (108 mg, 147.60 μmol) and KOAc (433 mg, 4.41 mmol) in Dioxane (5 mL) was microwaved at 120 °C for 30 min. The resulting mixture was cooled to room temperature, filtered and concentrated to give crude 18-1 (650 mg, 1.45 mmol, 98.61% yield. MS: <com:Math><semantics>m / z=448<annotation encoding="application / x-tex">m / z = 448< / annotation>< / semantics>< / com:Math> (M+H) Step 2: 18-2

[00385] A mixture of 18-1 (650 mg, 1.45 mmol), H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (1 mL, 30% purity) and acetic acid (1.45 mmol, 1 mL) in THF (4 mL) was stirred at 25 °C for 1 hr. The resulting solution was quenched with Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub>, filtered and concentrated. The residue was purified by FCC (silica gel, petroleum eth...

Claims

1. A compound of Formula (Ia) or (Ib): [Image disponible dans le document PDF, Image available in the PDF document] (Ib), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: each X is independently Cl or F; p is 0, 1, 2, or 3; L is absent, -O-, ( C 1 − C 4 ) (C_1-C_4) alkylene, substituted ( C 1 − C 4 ) (C_1-C_4) alkylene, -O- ( C 1 − C 4 ) (C_1-C_4) alkylene, substituted -O- ( C 1 − C 4 ) (C_1-C_4) alkylene, ( C 1 − C 4 ) (C_1-C_4) alkylene-O-, or substituted ( C 1 − C 4 ) (C_1-C_4) alkylene-O-, wherein the substituted ( C 1 C_1 – C 4 C_4 ) alkylene, substituted -O-( C 1 C_1 – C 4 C_4 ) alkylene, or substituted ( C 1 C_1 – C 4 C_4 ) alkylene-O- is substituted with one or more L 1 L^1 ; each L 1 L^1 is independently (C 1 –C 4 ) alkyl, F, or CF 3 ; or two L 1 L^1 , together with the atom to which they are attached, form a 3- to 5-membered cycloalkyl ring; each R 1 is independently H, F, methyl, ethyl, or CF 3 ; A 1 A^1 is C or C R 5 ′ CR^{5'} ; R 5 R^{5} is H, ( C 1 − C 4 ) (C_1-C_4) alkyl, ( C 1 − C 4 ) (C_1-C_4) alkoxy, hydroxy, or cyano; A 2 and A 2 are each independently absent, CH 2 , CHR 5 , C(R 5 ) 2 , NH, NR 5 , or O, provided that at least one of A 2 and A 2 is not absent and that A 2 –A 2 is not O–O, O–NH, O–NR 5 , NH–O, NH–NH, NH–NR 5 , NR 5 –O, NR 5 –NH, or NR 5 –NR 5 ; A 3 is CH 2 , CHR 5 , C(R 5 ) 2 , NH, NR 5 , or O when m is 0, or CH or CR 5 when m is 1 or 2, provided that A 2 -A 3 is not O-O, O-NH, O-NR 5 , NH-O, NH-NH, NH-NR 5 , NR 5 -O, NR 5 -NH, or N R 5 − N R 5 NR^5-NR^5 ; m is 0, 1, or 2; n is 1 or 2; R 2 R^2 is ( C 1 − C 4 ) (C_1-C_4) alkyl substituted with one or more ( C 1 − C 4 ) (C_1-C_4) alkoxy, ( C 1 − C 4 ) (C_1-C_4) alkoxy, N R 3 C ( O ) R 4 NR^3C(O)R^4 , C ( O ) N R 3 R 4 C(O)NR^3R^4 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O, wherein the heterocyclyl is optionally substituted with one or more R 5 ; R 3 is H, methyl, or ethyl; R 4 R^4 is ( C 1 − C 4 ) (C_1-C_4) alkyl or ( C 3 − C 10 ) (C_3-C_{10}) cycloalkyl optionally substituted with one or more R 8 R^8 ; or R 3 and R 4 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one or more heteroatom selected from N and O and optionally substituted with one or more substituent selected from (C 1 –C 4 ) alkyl, (C 1 –C 4 ) alkoxy, hydroxy, cyano, oxo, C(O)R 7 , C(O)NR 7 R 7 , NRC(O)R 7 , NRS(O) 2 R 7 , S(O) 2 R 7 , (C 1 –C 4 ) alkyl substituted with one or more hydroxy, NRC(O)R 7 , or C(O)NRR 7 , (C 3 -C 10 ) cycloalkyl optionally substituted with one or more hydroxy, NRC(O)R 7 , or C(O)NRR 7 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy, NRC(O)R 7 , or C(O)NRR 7 , wherein R is H, methyl, or ethyl; and R' is ( C 1 − C 4 ) (C_1-C_4) alkyl or ( C 3 − C 10 ) (C_3-C_{10}) cycloalkyl optionally substituted with one or more ℝ 8 \mathbb{R}^8 ; each R 5 R^5 is independently (C 1 –C 4 ) alkyl, (C 1 –C 4 ) alkoxy, hydroxy, cyano, oxo, C(O) R 7 R^7 , C(O)NR 7 R 7 , NR 3 C(O)R 7 , NR 3 S(O) 2 R 4 , S(O) 2 R 4 , (C 1 –C 4 ) alkyl substituted with one or more hydroxy or R 6 R^6 , (C 3 –C 10 ) cycloalkyl optionally substituted with one or more hydroxy or R 6 R^6 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R 6 ; or two R 5 , together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated or 5- or 6- membered aromatic ring optionally comprising 1 or 2 heteroatoms selected from N and O; each R 6 is independently NR 3 C(O)R 7 or C(O)NR 3 R 7 ; each R 7 is independently OH, ( C 1 − C 4 ) (C_1-C_4) alkoxy, ( C 1 − C 6 ) (C_1-C_6) alkyl optionally substituted with one or more ( C 1 − C 4 ) (C_1-C_4) alkoxy, CF 3 , F, or (C 3 –C 10 ) cycloalkyl, ( C 3 − C 10 ) (C_3-C_{10}) cycloalkyl optionally substituted with one or more ℝ 8 \mathbb{R}^8 , or phenyl optionally substituted with one or more R 8 ; each R 7 is independently H, methyl, or ethyl; or R 7 and R 7 , together with the atom to which they are attached, form a 3- to 6-membered ring optionally comprising one or more heteroatom selected from N and O and optionally substituted with one or more R 8 ; or R 3 and R 7 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one or more heteroatom selected from N and O and optionally substituted with one or more R 8 ; and each R 8 R^8 is independently (C 1 –C 4 ) alkyl, (C 1 –C 4 ) alkoxy, CF 3 , OH, or F.

2. The compound of claim 1, wherein m is 1 or 2.

3. The compound of claim 1 or claim 2, wherein m and n are each 2. [Image disponible dans le document PDF, Image available in the PDF document]4. The compound of any one of claims 1-3, wherein is a heterocyclyl selected from: [Image disponible dans le document PDF, Image available in the PDF document] wherein W, W 1 , and W 2 are each independently CH 2 , CHR 5 , C(R 5 ) 2 , O, NH, or NR 5 , and [Image disponible dans le document PDF, Image available in the PDF document] substituted with one or more (C 1 –C 4 ) alkyl, (C 1 –C 4 ) alkoxy, hydroxy, cyano, oxo, C(O)R 7 , C(O)NR 7 R 7 , NR 3 C(O)R 7 , NR 3 S(O) 2 R 4 , S(O) 2 R 4 , (C 1 –C 4 ) alkyl substituted with one or more hydroxy or R 6 , (C 3 –C 10 ) cycloalkyl optionally substituted with one or more hydroxy or R 6 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R 6 .

5. The compound of claim 4, wherein selected from: [Image disponible dans le document PDF, Image available in the PDF document]6. The compound of any one of claims 1-5, wherein L is absent, − O -O -, ( C 1 − C 4 ) (C_1-C_4) alkylene, substituted ( C 1 − C 4 ) (C_1-C_4) alkylene, ( C 1 − C 4 ) (C_1-C_4) alkylene-O-, or substituted ( C 1 − C 4 ) (C_1-C_4) alkylene-O-.

7. The compound of any one of claims 1-6, wherein L is absent, -O-, ( C 1 − C 2 ) (C_1-C_2) alkylene, substituted ( C 1 − C 2 ) (C_1-C_2) alkylene, ( C 1 − C 2 ) (C_1-C_2) alkylene-O-, or substituted ( C 1 − C 2 ) (C_1-C_2) alkylene-O-.

8. The compound of any one of claims 1-7, wherein each L 1 L^1 is independently ( C 1 C_1 – C 4 C_4 ) alkyl, F, or CF 3 .

9. The compound of any one of claims 1-8, wherein each L 1 is independently methyl or ethyl.

10. The compound of any one of claims 1-7, wherein two L 1 , together with the atom to which they are attached, form a cyclopropyl, cyclobutyl, or cyclopentyl ring.

11. The compound of any one of claims 1-7, wherein L is absent or -O-.

12. The compound of any one of claims 1-11, wherein R 3 is H.

13. The compound of any one of claims 1-12, wherein ℝ 4 \mathbb{R}^4 is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl.

14. The compound of any one of claims 1-12, wherein R 4 R^4 is ( C 3 − C 10 ) (C_3-C_{10}) cycloalkyl optionally substituted with one or more R 8 .

15. The compound of any one of claims 1-11, wherein R 3 and R 4 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one or more heteroatom selected from N and O and optionally substituted with one or more substituent selected from ( C 1 − C 4 ) (C_1-C_4) alkyl, ( C 1 − C 4 ) (C_1-C_4) alkoxy, hydroxy, cyano, oxo, C ( O ) R 7 C(O)R^7 , C ( O ) N R 7 R 7 C(O)NR^7R^7 , N R C ( O ) R 7 NRC(O)R^7 , N R S ( O ) 2 R ′ NRS(O)_2R' , S ( O ) 2 R ′ S(O)_2R' , ( C 1 − C 4 ) (C_1-C_4) alkyl substituted with one or more hydroxy, NRC(O)R 7 , or C(O)NRR 7 , (C 3 –C 10 ) cycloalkyl optionally substituted with one or more hydroxy, NRC(O)R 7 , or C(O)NRR 7 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy, N R C ( O ) R 7 NRC(O)R^7 , or C ( O ) N R R 7 C(O)NRR^7 , wherein R is H, methyl, or ethyl and R' is ( C 1 − C 4 ) (C_1-C_4) alkyl or ( C 3 − C 10 ) (C_3-C_{10}) cycloalkyl optionally substituted with one or more R 8 .

16. The compound of any one of claims 1-15, wherein at least one R 5 R^5 is ( C 1 − C 4 ) (C_1-C_4) alkyl, ( C 1 − C 4 ) (C_1-C_4) C 4 ) alkoxy, hydroxy, cyano, oxo, C(O)R 7 , C(O)NR 7 R 7 , NR 3 C(O)R 7 , NR 3 S(O) 2 R 4 , S(O) 2 R 4 , or ( C 1 − C 4 ) (C_1-C_4) alkyl substituted with one or more hydroxy or ℝ 6 \mathbb{R}^6 .

17. The compound of any one of claims 1-16, wherein at least one R 5 R^5 is ( C 1 − C 4 ) (C_1-C_4) alkyl, ( C 1 − C 4 ) (C_1-C_4) C 4 C_4 ) alkoxy, hydroxy, cyano, oxo, or ( C 1 − C 4 ) (C_1-C_4) alkyl substituted with one or more hydroxy or R 6 R^6 .

18. The compound of any one of claims 1-17, wherein at least one R 5 is methyl, methoxy, hydroxy, or cyano.

19. The compound of any one of claims 1-16, wherein at least one R 5 R^5 is C ( O ) R 7 C(O)R^7 , C ( O ) N R 7 R 7 C(O)NR^{7}R^{7} , N R 3 C ( O ) R 7 NR^{3}C(O)R^{7} , N R 3 S ( O ) 2 R 4 NR^{3}S(O)_{2}R^{4} , or S ( O ) 2 R 4 S(O)_{2}R^{4} .

20. The compound of any one of claims 1-16 and 19, wherein at least one R 5 R^5 is C ( O ) R 7 C(O)R^7 , C ( O ) N R 7 R 7 C(O)NR^7R^7 , or N R 3 C ( O ) R 7 NR^3C(O)R^7 .

21. The compound of any one of claims 1-15, wherein at least one R 5 R^5 is ( C 3 − C 10 ) (C_3-C_{10}) cycloalkyl optionally substituted with one or more hydroxy or R 6 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R 6 R^6 .

22. The compound of any one of claims 1-15, wherein two R 5 , together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated or 5- or 6-membered aromatic ring optionally comprising 1 or 2 heteroatoms selected from N and O.

23. The compound of any one of claims 1-15 and 22, wherein two R 5 , together with the atom or atoms to which they are attached, form a phenyl ring.

24. The compound of any one of claims 1-15 and 22, wherein two R 5 , together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated ring optionally comprising 1 or 2 heteroatoms selected from N and O.

25. The compound of claim 1, wherein R 5 is H.

26. The compound of claim 1, wherein R 5 ′ R^{5'} is ( C 1 − C 4 ) (C_1-C_4) alkyl, ( C 1 − C 4 ) (C_1-C_4) alkoxy, hydroxy, or cyano.

27. The compound of any one of claims 1-26, wherein at least one R 6 R^6 is N R 3 C ( O ) R 7 NR^3C(O)R^7 .

28. The compound of any one of claims 1-26, wherein at least one R 6 R^6 is C ( O ) N R 3 R 7 C(O)NR^3R^7 .

29. The compound of any one of claims 1-28, wherein at least one R 7 R^7 is ( C 1 − C 4 ) (C_1-C_4) alkoxy, ( C 1 − C 4 ) (C_1-C_4) C 6 C_6 ) alkyl optionally substituted with one or more ( C 1 C_1 – C 4 C_4 ) alkoxy, C F 3 CF_3 , F F , or ( C 3 C_3 – C 10 C_{10} ) cycloalkyl.

30. The compound of any one of claims 1-29, wherein at least one ℝ 7 \mathbb{R}^7 is methyl or ethyl.

31. The compound of any one of claims 1-28, wherein at least one R 7 R^7 is ( C 3 − C 10 ) (C_3-C_{10}) cycloalkyl optionally substituted with one or more R 8 .

32. The compound of any one of claims 1-28, wherein at least one R 7 is phenyl optionally substituted with one or more R 8 .

33. The compound of any one of claims 1-28, wherein R 7 and R 7 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one or more heteroatom selected from N and O and optionally substituted with one or more R 8 .

34. The compound of any one of claims 1-11, wherein R 3 and R 7 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one or more heteroatom selected from N and O and optionally substituted with one or more R 8 .

35. The compound of any one of claims 1-34, wherein at least one R 8 R^8 is ( C 1 − C 4 ) (C_1-C_4) alkyl or ( C 1 − C 4 ) (C_1-C_4) C 4 ) alkoxy.

36. The compound of claim 1, wherein R 2 R^2 is ( C 1 − C 4 ) (C_1-C_4) alkyl substituted with one or more ( C 1 − C 4 ) (C_1-C_4) C 4 ) alkoxy.

37. The compound of claim 1, wherein R 2 R^{2} is ( C 1 − C 4 ) (C_1-C_4) alkoxy.

38. The compound of claim 1, wherein R 2 R^2 is N R 3 C ( O ) R 4 NR^3C(O)R^4 or C ( O ) N R 3 R 4 C(O)NR^3R^4 .

39. The compound of claim 1, wherein R 2 is heterocyclyl optionally substituted with one or more R 5 R^5 .

40. The compound of any one of claims 1-39, wherein each R 1 R^1 is H.

41. The compound of any one of claims 1-39, wherein each R 1 is independently F, methyl, ethyl, or CF 3 .

42. The compound of any one of claims 1-41, wherein p is 0 or 1.

43. The compound of any one of claims 1-42, wherein p is 0.

44. The compound of any one of claims 1-42, wherein p is 1.

45. The compound of any one of claims 1-44, wherein X is F.

46. The compound of any one of claims 1-44, wherein X is Cl.

47. The compound of claim 1, wherein the compound is of Formula (Ia') or (Ib'): [Image disponible dans le document PDF, Image available in the PDF document] (Ib') or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

48. The compound of claim 1, wherein the compound is of Formula (Ia2) or (Ia2'): [Image disponible dans le document PDF, Image available in the PDF document] (Ia2'), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

49. The compound of claim 1, wherein the compound is of Formula (Ia3) or (Ia3'): [Image disponible dans le document PDF, Image available in the PDF document] (Ia3) or [Image disponible dans le document PDF, Image available in the PDF document] (Ia3'), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

50. A compound selected from the table below: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]51. The compound of claim 50, wherein the compound is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] 1 , [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

52. A pharmaceutical composition comprising the compound as claimed in any one of claims 1-51, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

53. Use of the compound as claimed in any one of claims 1-51, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a SSAO-mediated disorder or modulating SSAO.

54. The use as claimed in claim 53, wherein the SSAO-mediated disorder is inflammation, liver inflammation, neuroinflammation, fibrosis, liver fibrosis, lung fibrosis, renal fibrosis, liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cardiovascular disease, atherosclerosis, stroke or a complication thereof, myocardial infarction, kidney disease, autoimmune disease, metabolic disease, or pain.