Heteroaryl compound as well as preparation method and application thereof

Abstract

The invention relates to a heteroaryl compound as well as a preparation method and application thereof. In particular, provided herein are novel compounds, such as compounds of Formula I or pharmaceutically acceptable salts thereof. Also provided herein are methods of making the compounds and methods of using the compounds, e.g., inhibiting the function of TYK2 and / or IL-12, IL-23 and / or INF-alpha, and / or treating various related diseases or conditions. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202180007811.2, application date December 22, 2021, and invention name “Heteroaryl compounds, preparation methods and uses thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to international application numbers PCT / CN2020 / 138305 filed on December 22, 2020 and PCT / CN2021 / 086083 filed on April 9, 2021, the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0004] In various embodiments, the present disclosure is generally directed to novel Heteroaryl Compounds, compositions comprising the same, methods of making the same, and methods of using the same, for example, for inhibiting kinases and / or for treating various diseases or conditions described herein, such as autoimmune diseases. Background Art

[0005] Cytokines are critical in mediating the pathobiology of many autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. The heterodimeric cytokines interleukins IL-12 and IL-23 are produced by activated antigen-presenting cells and are essential for the differentiation and proliferation of two effector T-cell lineages, Th1 and Th17 cells, which play a key role in autoimmunity. IL-23 is required for the survival and expansion of Th17 cells, which produce proinflammatory cytokines such as IL-17A, IL-17F, IL-6, and TNF-α. IL-12 is required for Th1 cell development and secretion of IFNg, a cytokine that plays a key role in immunity by stimulating MHC expression, class switching of B cells to the IgG subclass, and activation of macrophages. Genome-wide association studies have identified a number of genetic loci associated with chronic inflammatory and autoimmune diseases that encode factors that function in the IL-23 and IL-12 pathways. These genes include IL23A, IL12A5, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2, STAT3, and STAT4. Agents that inhibit the action of IL-12 and IL-23 may be expected to have therapeutic benefit in human autoimmune diseases.

[0006] The type I interferon group (IFN), including IFNα members as well as IFNβ, IFNε, IFNκ, and IFNω, acts through the heterodimeric IFNα / β receptor (IFNAR). Type I interferons have multiple roles in the innate and adaptive immune systems, including activation of cellular and humoral immune responses and enhancement of the expression and release of self-antigens. Genome-wide association studies have identified lupus-associated genetic loci that encode factors that function in the type I interferon pathway, including IRF5, IKBKE, TYK2, and STAT4. In addition to lupus, there is evidence that aberrant activation of type I interferon-mediated pathways is also important in the pathobiology of other autoimmune diseases, such as Sjogren's syndrome and scleroderma. Agents that inhibit the type I interferon response can be expected to have therapeutic benefits in human autoimmune diseases.

[0007] The Janus kinase (JAK) family is a family of small receptor-associated tyrosine kinases that are essential for signaling cascades downstream of type I and type II cytokine receptors. Type I and type II cytokine receptors—composed of a family of receptors bound by more than 50 cytokines, interleukins, interferons (IFNs), colony stimulating factors (CSFs), and hormones—share unique intracellular signaling pathways mediated by JAKs (JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)), which bind directly to the intracellular domains of type I and type II cytokine receptors but not to other types of cytokine receptors. JAK-dependent cytokines are major contributors to immunopathology. The dependence of type I and type II cytokines on JAKs is established in a variety of genetic models ranging from mutagenic cell lines and knockout mice to humans. Polymorphisms in the JAK and signal transducer and activator of transcription (STAT) genes are associated with autoimmunity, and loss of function mutations cause immunodeficiency due to the inability of type I and type II cytokines to signal through their receptors. The critical role of JAKs in type I and II cytokine signaling provides strong evidence that interfering with the activity of these kinases could lead to a new class of immunomodulatory drugs.

[0008] Tyrosine kinase 2 (TYK2) is a member of the JAK non-receptor tyrosine kinase family and has been shown to be crucial in regulating the signal transduction cascade downstream of IL-12, IL-23 and type I interferon receptors in both mice and humans. TYK2 is the only signal messenger shared by IL12 and IL-23. TYK2 mediates receptor-induced phosphorylation of members of the STAT transcription factor family, which is an essential signal for STAT protein dimerization and STAT-dependent pro-inflammatory gene transcription. TYK2-deficient mice resist experimental models of colitis, psoriasis and multiple sclerosis, demonstrating the importance of TYK2-mediated signaling in autoimmunity and related diseases. In humans, individuals expressing TYK2 inactive variants are protected from multiple sclerosis and possible other autoimmune diseases. Whole genome association studies have shown that variants of the active form of TYK2 are associated with autoimmune diseases such as Crohn's disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis, further demonstrating the importance of TYK2 in autoimmunity.

[0009] Treatment has significantly changed the outcome of a range of allergic, inflammatory and autoimmune diseases, including rheumatoid arthritis, psoriasis and inflammatory bowel disease (IBD). However, even though great progress has been made for diseases such as rheumatoid arthritis, most patients do not fully respond to currently available therapies, and examples of long-term remission after cessation of treatment are relatively rare. Therefore, despite substantial progress, new therapeutic strategies for immune and inflammatory diseases or conditions are still greatly needed.

[0010] New compounds that inhibit the activity of TYK2 capable of regulating cytokines and / or interferons (e.g., IL-12, IL-23 and / or IFNα) should provide a pharmacological response that is beneficial for treating one or more of the conditions described herein and may provide substantial therapeutic benefit to a variety of patients in need thereof. Summary of the invention

[0011] In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, and methods of preparation and use thereof. Typically, the compounds herein are TYK2 inhibitors that can modulate the function of IL-12, IL-23, and / or IFN-α. The compounds and compositions herein can be used to treat various diseases or conditions, such as autoimmune and / or inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and / or scleroderma.

[0012] In some embodiments, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0013]

[0014] Where L 1 , R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 1 , Y, X 2 and R 4 Defined in this article. In some embodiments, the disclosure also provides compounds of sub-formulas of Formula I, such as Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1 as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure also provides a specific compound selected from Compound Nos. 1-133 or a pharmaceutically acceptable salt thereof.

[0015] Certain embodiments of the present disclosure are directed to a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- -1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound Nos. 1-133, or a pharmaceutically acceptable salt thereof) and an optional pharmaceutically acceptable excipient. The pharmaceutical composition described herein can be formulated for a variety of administration routes, such as oral administration or parenteral administration, etc.

[0016] Certain embodiments relate to methods of treating diseases or conditions associated with TYK2, such as diseases or conditions mediated by IL-12, IL-23 and / or interferon-α (INF-α). In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- The invention relates to a compound of any one of the compounds of the invention, i-1-A-4, i-1-A-5, i-1-A-6, i-1-A-7, i-1-A-8, i-1-A-9, i-1-A-10, i-1-A-11, i-1-A-12, i-1-A-13, i-1-A-14, i-1-A-15 or i-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. Diseases or conditions associated with TYK2 that can be treated with the methods herein include any of those diseases or conditions known in the art and those described herein.

[0017] In some embodiments, methods of treating proliferative, metabolic, allergic, autoimmune and / or inflammatory diseases or conditions are provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- The invention relates to a compound of any one of the compounds of the invention, i-1-A-4, i-1-A-5, i-1-A-6, i-1-A-7, i-1-A-8, i-1-A-9, i-1-A-10, i-1-A-11, i-1-A-12, i-1-A-13, i-1-A-14, i-1-A-15 or i-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. Suitable proliferative, metabolic, allergic, autoimmune and / or inflammatory diseases or conditions that can be treated with the methods herein include any of those diseases or conditions described herein.

[0018] In some embodiments, a method for treating an autoimmune and / or inflammatory disease or condition is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- The invention relates to a compound of any one of the compounds of the invention, i-1-A-4, i-1-A-5, i-1-A-6, i-1-A-7, i-1-A-8, i-1-A-9, i-1-A-10, i-1-A-11, i-1-A-12, i-1-A-13, i-1-A-14, i-1-A-15 or i-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. Suitable autoimmune and / or inflammatory diseases or conditions that can be treated with the methods herein include any of those diseases or conditions described herein.

[0019] In some embodiments, a method for treating a metabolic disease or condition such as described herein, such as type 2 diabetes or atherosclerosis is provided. In some embodiments, the method comprises administering a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- 1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound Nos. 1-133 or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

[0020] In some embodiments, a method for treating cancer is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- 1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

[0021] In some embodiments, methods of treating multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and / or scleroderma are provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- 1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

[0022] Administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, oral, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. The compounds of the present disclosure can be used as a monotherapy or a combination therapy.

[0023] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention herein. DETAILED DESCRIPTION

[0024] In various embodiments, novel heteroaryl compounds, pharmaceutical compositions, methods of preparation and methods of use are provided herein. The compounds herein can generally be TYK2 inhibitors and can be used to treat various diseases or conditions, such as those described herein, such as autoimmune and / or inflammatory diseases, for example, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and / or scleroderma.

[0025] Compound

[0026] In some embodiments, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0027]

[0028] in:

[0029] X 1 Yes CR 10 or N;

[0030] Y is CR 10 or N;

[0031] L 1 YesNR 11 , or does not exist;

[0032] L 2 is an optionally substituted C 1-4 Alkylene, optionally substituted C 1-4 Heteroalkylene, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-6 membered heterocyclylene or NH;

[0033] X 2 O or NR 13 ;

[0034] represents an optionally substituted phenyl group or an optionally substituted 6-membered heteroaryl ring,

[0035] in:

[0036] J 1 Yes CR 14 or N;

[0037] J 2 Yes CR 15 or N;

[0038] J 3 Yes CR 16 or N;

[0039] J 4 Yes CR17 or N; and

[0040] J 5 It is C;

[0041] or represents an optionally substituted 5-membered heteroaryl ring,

[0042] in:

[0043] J 1 Yes CR 18 NR 19 , O, S or N;

[0044] J 4 Yes CR 20 NR 21 , O, S or N;

[0045] J 5 is C or N; and

[0046] J 2 and J 3 One of the does not exist, and J 2 and J 3 The other one is O, S, N, NR 22 or CR 23 ;

[0047] in:

[0048] R 1 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 carbocycle, optionally substituted 4-10 membered heterocycle, optionally substituted phenyl or optionally substituted heteroaryl;

[0049] R 2 is hydrogen, CD3, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl;

[0050] R 3 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 heteroalkyl or nitrogen protecting groups;

[0051] R 4 is hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 heteroalkyl;

[0052] in:

[0053] R 10 At each occurrence, hydrogen, halogen, CN, OH, C optionally substituted by F 1-4 Alkyl, optionally substituted by F 1-4 alkoxy, or C optionally substituted by one or more substituents independently selected from F, methyl and OH 3-6 Cycloalkyl;

[0054] R 11 , R 12 and R 13 are each independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 Cycloalkyl; or R 11 and R 12 Together with the middle atom, they are linked to form an optionally substituted 5-8 membered ring structure;

[0055] R 14 , R 15 , R 16 , R 17 , R 18 , R 20 and R 23 are independently halogen, R A , OR A , SR A 、S(O)R A 、S(O)2R A , COR A 、COOR A 、CN、NR B R C ,CONR B R C 、S(O)2NR B R C , or NO2,

[0056] R 19 , R 21 and R 22 Each independently is R A , COR A 、COOR A 、S(O)2R A 、S(O)2NR B R C or CONR B R C ,

[0057] Where R A is independently at each occurrence hydrogen, optionally substituted C 1-6Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-8 Carbocyclic group, optionally substituted C 1-4 heteroalkyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted phenyl,

[0058] Where R B and R C Each time it occurs, it is independently R A 、-C(O)-R A 、-COOR A 、S(O)2R A ,CONR B 'R C ', where R B ' and R C Each of ' is independently R A ;

[0059] or R B and R C Joined together with the nitrogen to which they are both attached to form an optionally substituted 4-8 membered ring structure;

[0060] or R 4 and R 13 (if applicable) together with the intermediate atoms to form an optionally substituted 5-8 membered ring structure;

[0061] or R 4 and R 13 , R 4 and R 14 , R 13 and R 14 , R 14 and R 15 , R 15 and R 16 , or R 16 and R 17 , if applicable, together with respective intermediate atoms to form an optionally substituted 5-8 membered ring structure; or

[0062] R 13 and R 18 , R 13 and R 19 , R 18 and R 22 , R 18 and R 23 , R 19 and R 22 , R 19 and R 23 , R 20 and R22 , R 20 and R 23 , R 21 and R 22 , or R 21 and R 23 , if applicable, together with respective intermediate atoms, are joined to form an optionally substituted 5-8 membered ring structure.

[0063] It should be clear to those skilled in the art that In the formula used to connect two atoms, it should be understood that as long as the valence permits, the bond between the two atoms can be a single bond or a double bond.

[0064] For the sake of clarity, when referring to R 4 and R 14 , R 13 and R 14 , R 14 and R 15 , R 15 and R 16 or R 16 and R 17 When, if applicable, R is linked to the respective intermediate atoms to form an optionally substituted 5-8 membered ring structure, it is understood that only one of the pairs present in the structural formula according to Formula I can form an optionally substituted ring structure. 13 and R 14 When joined together with the intermediate atoms to form an optionally substituted 5-8 membered ring structure, it is understood that R 4 and R 14 , R 14 and R 15 , R 15 and R 16 and R 16 and R 17 , if applicable, do not form a ring structure; rather, in such embodiments, R 15 , R 16 and R 17 , if applicable, and R 4 It is understood to have the definitions described herein without regard to its possibility of forming a ring with another variable, for example, in such embodiments, it is understood that when present, R 15 , R 16 and R 17 are independently halogen, R A , OR A , SR A 、S(O)R A 、S(O)2R A , COR A 、COORA 、CN、NR B R C ,CONR B R C 、S(O)2NR B R C or NO2. In addition, when R 4 and R 13 When connected to form an optionally substituted 5-8 membered ring structure, R 4 and R 14 Typically, optionally substituted 5-8 membered ring structures are not formed, and vice versa. Similarly, in Formula I herein, when referring to R 13 and R 18 , R 13 and R 19 , R 18 and R 22 , R 18 and R 23 , R 19 and R 22 , R 19 and R 23 , R 20 and R 22 , R 20 and R 23 , R 21 and R 22 or R 21 and R 23 , if applicable, when joined together with respective intermediate atoms to form an optionally substituted 5-8 membered ring structure, it is to be understood that only one of said pairs present in the structural formula according to Formula I can form an optionally substituted ring structure.

[0065] The compounds of Formula I (including any applicable subformula as described herein) can exist as individual enantiomers, diastereomers and / or geometric isomers, if applicable, or mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, when applicable, the compounds of Formula I (including any applicable subformula as described herein) can exist as isolated enantiomers that are substantially free of (e.g., less than 20%, less than 10%, less than 5%, less than 1% or undetectable amounts by weight, by HPLC area, or both) other enantiomers.

[0066] Typically, X in Formula I 1 is N.

[0067] In some embodiments, X in Formula I 1 It can also be CR 10 , where R 10 As defined herein. For example, R10 It can be hydrogen, F, Cl, CN, OH, C optionally substituted by F 1-4 Alkyl, or C optionally substituted by F 1-4 In some embodiments, X in Formula I 1 It is CH.

[0068] In some embodiments, Y in Formula I is N.

[0069] In some embodiments, Y in Formula I is CR 10 , where R 10 As defined herein. For example, R 10 It can be hydrogen, F, Cl, CN, OH, C optionally substituted by F 1-4 Alkyl, or C optionally substituted by F 1-4 Alkoxy.

[0070] Typically, Y in formula I is CH.

[0071] Usually, X 1 is N, Y is CH, and the compound of formula I can be characterized as having formula I-1:

[0072]

[0073] The variable L 1 , R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 2 and R 4 Include any of those described herein in any combination.

[0074] In some embodiments, X 1 and Y may both be CH and the compound of Formula I may be characterized as having Formula I-2:

[0075]

[0076] The variable L 1 , R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 2and R 4 Include any of those described herein in any combination.

[0077] In some embodiments, X 1 and Y may both be N and the compound of Formula I may be characterized as having Formula I-3:

[0078]

[0079] The variable L 1 , R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 2 and R 4 Include any of those described herein in any combination.

[0080] In Formula I (e.g., Formula I-1, I-2 or I-3) The moiety (also referred to herein as M-10) typically represents an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl ring. In such an embodiment, J 1 Can be CR 14 or N; J 2 Can be CR 15 or N; J 3 Can be CR 16 or N; J 4 Can be CR 17 or N; and J 5 is C, where R 14 , R 15 , R 16 and R 17 Include any of those described herein in any combination.

[0081] In the embodiment wherein M-10 represents an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl ring, J 1 Usually CR 14 , where R 14 As defined herein. However, in some embodiments where M-10 represents an optionally substituted 6-membered heteroaryl ring, J 1 It can also be N. In some embodiments, J 1 Yes CR 14 , and R 14 Can be hydrogen, halogen, OH, CN or R A , where RA As defined herein, for example, in some embodiments, R 14 It may be an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 or an optionally substituted 4-8 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S. In some embodiments, J 1 Yes CR 14 , and R 14 It can be hydrogen, halogen (e.g., F or Cl), G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E or O-(C 1-4 Alkylene)-G E , where G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, J 1 Yes CR 14 , and R 14 It can be G defined in this paper E In some embodiments, J 1 Yes CR 14 , and R 14 It is hydrogen, F, Cl, CN, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxy substituted C 1-4 Alkyl (such as hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 Alkoxy (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (e.g., CF3O-, CF3CH2O-, etc.), cyclopropyloxy or cyclobutyloxy. As used herein, hydroxy-substituted C 1-4 Alkyl refers to a C substituted with one or two hydroxyl groups. 1-4As used herein, fluorine-substituted C 1-4 Alkyl refers to a C substituted with 1 to 3 fluorine groups. 1-4 Alkyl, such as -CF3, -CH2F, -CHF2, etc. As used herein, fluorine-substituted C 1-4 Alkoxy refers to a C substituted with 1 to 3 fluorine groups. 1-4 Alkoxy, such as CF3O-, CF3CH2O-, etc. In some embodiments, J 1 Yes CR 14 , and R 14 Can be used with R 4 , X 2 or R 15 and respective intermediate atoms are joined together to form an optionally substituted 5-8 membered ring structure, such as a 5-8 membered monocyclic carbocyclic ring or a monocyclic heterocyclic ring, which is optionally substituted with one or more permissible substituents described herein. In any embodiment described herein, unless otherwise indicated or contrary to the context, when J 1 Yes CR 14 When R 14 It can be hydrogen, F, CH3, CH2OH, OCH3 or cyclopropyl.

[0082] In the embodiment wherein M-10 represents an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl ring, J 2 Usually CR 15 , where R 15 As defined herein. However, in some embodiments where M-10 represents an optionally substituted 6-membered heteroaryl ring, J 2 It can also be N. In some embodiments, J 2 Yes CR 15 , and R 15 Can be hydrogen, halogen, OH, CN or R A , where R A As defined herein, for example, in some embodiments, R 15 It may be an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 or an optionally substituted 4-8 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S. In some embodiments, J 2 Yes CR 15 And R 15 It can be hydrogen, halogen (e.g., F or Cl), G E 、-(C 1-4 Alkylene)-G E , OH, CN, OGE 、O-(C 1-4 Alkylene)-G E SG E 、S(O)-G E or S(O)2-G E , where G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, J 2 Yes CR 15 , and R 15 It can be G defined in this paper E In some embodiments, J 2 Yes CR 15 , and R 15 It may be an optionally substituted 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as oxetanyl, morpholinyl or azetidinyl, which is optionally substituted by one or more (e.g., 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, J 2 Yes CR 15 , and R 15 It could be OG E , where G E It is C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as oxetanyl, which is optionally substituted by one or more (e.g., 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, J 2 Yes CR 15 , and R 15 It can be O-(C 1-4 Alkylene)-G F , where G F is OH, NH2, optionally substituted C1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S. In some embodiments, J 2 Yes CR 15 , and R 15 It can be O-(C 1-4 Alkylene)-G F , where G F It is OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-4 Alkoxy (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (such as CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl substituted C 1-4 Alkoxy (e.g. -O-CH2CH2OH), alkoxy-substituted C 1-4 Alkoxy (e.g. -O-CH2CH2OMe), O-acyl (e.g. O-CH(O), OC(O)CH3), NH-acyl, N(C 1-4 alkyl)-acyl, or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as oxetanyl, which is optionally substituted by one or more (e.g. 1, 2 or 3) independently selected from F, C 1-4 As used herein, it is understood that in the expression "N(C 1-4 Alkyl)(C 1-4 The two C 1-4 The alkyl groups may be the same or different. 2 Yes CR 15 , and R 15 It can be O-(C 1-4 Alkylene)-G F , where C 1-4 Alkylene (from left (O) to right (G F ) is -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2C(CH3)2-, and G F It is OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-4 Alkoxy (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4Alkoxy (such as CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl substituted C 1-4 Alkoxy (e.g., -O-CH2CH2OH), or alkoxy-substituted C 1-4 In some embodiments, J 2 Yes CR 15 , and R 15 For hydrogen, F, Cl, CN, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxy substituted C 1-4 Alkyl (such as hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 Alkyl (such as fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 Alkoxy (such as methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (such as CF3O-, CF3CH2O-, etc.), C 1-4 Alkylthio (e.g. CH3S-), fluorine-substituted C 1-4 As will be appreciated by those skilled in the art, alkylthio refers to a group having the general structure of RS-, wherein R is an alkyl group. As used herein, fluorine-substituted C 1-4 Alkylthio refers to a group in which C 1-4 The alkyl part is substituted by 1-3 fluorine groups. 1-4 In some embodiments, J 2 Yes CR 15 , and R 15 Can be used with R 14 or R 16 are connected, together with their respective middle atoms, to form an optionally substituted 5-8 membered ring structure, such as a 5-8 membered monocyclic carbocyclic ring or a monocyclic heterocyclic ring, which is optionally substituted with one or more permissible substituents described herein. For example, in some embodiments, J 2 Yes CR 15 , and R 15 Can be used with R 16 and the intermediate atoms together to form

[0083]

[0084] In any embodiment described herein, unless otherwise indicated or contradicted by context, when J 2 Yes CR 15 When R 15It can be hydrogen, F, Cl, CN, CH3, CH2CH3, CHF2, CF3, OCH3, OCH2CH3, O-CH(CH3)2, OCF3, SCF3, cyclopropyl or In any embodiment described herein, unless otherwise indicated or contradicted by context, when J 2 CR 15 When R 15 Can be selected from:

[0085] In any embodiment described herein, unless otherwise indicated or contradicted by context, when J 2 CR 15 When R 15 Can be selected from: In any embodiment described herein, unless otherwise indicated or contradicted by context, when J 2 CR 15 When R 15 Can be selected from: When R 15 When one or more chiral centers are included, the present disclosure encompasses all potential stereoisomers and mixtures thereof (e.g., racemic mixtures). For example, in some embodiments, J 2 Yes CR 15 , R 15 The following stereoisomers may be selected:

[0086] In some embodiments, with respect to the aforementioned drawn chiral centers, the compound may be present predominantly as the drawn enantiomer, e.g., with less than 20%, less than 10%, less than 5%, less than 1%, or no detectable amount of the other corresponding enantiomer, by weight, by HPLC area, or both.

[0087] In the embodiment wherein M-10 represents an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl ring, J 3 Usually CR 16 , where R 16 As defined herein. However, in some embodiments where M-10 represents an optionally substituted 6-membered heteroaryl ring, J 16 It can also be N. In some embodiments, J 3 Yes CR 16 , and R 16 Can be hydrogen, halogen, OH, CN or R A , where R A As defined herein, for example, in some embodiments, R 16 It may be an optionally substituted C 1-6 Alkyl, optionally substituted C3-6 Cycloalkyl, optionally substituted C 1-4 or an optionally substituted 4-8 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S. In some embodiments, J 3 Yes CR 16 , and R 16 Can be hydrogen, F, Cl, G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E or O-(C 1-4 Alkylene)-G E , where G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, J 3 Yes CR 16 , and R 16 It can be G defined in this paper E In some embodiments, J 3 Can be CR 16 And R 16 Can be hydrogen, F, Cl, CN, C 1-4 Alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), fluorine-substituted C 1-4 Alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, C 3-6 Cycloalkyl (e.g. cyclopropyl, cyclobutyl, etc.), C 1-4 Alkoxy (such as methoxy, ethoxy, etc.), fluorine-substituted C 1-4 In some embodiments, J 3 Yes CR 16 , and R 16 Can be used with R 15 or R 17 , and each intermediate atom is connected to form an optionally substituted 5-8 membered ring structure, such as a 5-8 membered monocyclic carbocyclic ring or a monocyclic heterocyclic ring, which is optionally substituted with one or more permissible substituents described herein. In any embodiment described herein, unless otherwise indicated or contrary to the context, when J3 Yes CR 16 When R 16 Can be hydrogen, F, Cl, CN, C 1-4 Alkyl, C 1-4 Alkoxy, cyclopropyl or cyclobutyl.

[0088] In the embodiment wherein M-10 represents an optionally substituted 6-membered heteroaryl ring, J 4 Typically N. However, in some embodiments where M-10 represents an optionally substituted 6-membered heteroaryl ring, J 4 It can also be CR 17 , where R 17 As defined herein, for example, hydrogen.

[0089] In the embodiment wherein M-10 represents an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl ring, J 1 , J 2 , J 3 and J 4 The combination of is not particularly limited. For example, in some embodiments, The moiety may be an optionally substituted phenyl. In some embodiments, The moiety may be an optionally substituted pyridine.

[0090] In some preferred embodiments, in Formula I The moiety may be an optionally substituted pyridyl group, wherein J 4 is N. For example, in some embodiments, the compound of Formula I can be characterized as having Formula I-1-A:

[0091]

[0092] The variable L 1 , R 1 , L 2 , R 2 , R 3 , R 14 , R 15 , R 16 , X 2 and R 4 Include any of those described herein in any combination.

[0093] For example, in some embodiments, in Formula I-1-A, R 14 In some embodiments, in Formula I-1-A, R 15 In some embodiments, in Formula I-1-A, R 16 In some embodiments, in Formula I-1-A, R14 and R 15 One is hydrogen and R 14 and R 15 The other of is not hydrogen. For example, in some embodiments, R 14 is hydrogen and R 15 is not hydrogen. In some embodiments, in Formula I-1-A, R 14 and R 15 In some embodiments, in Formula I-1-A, R 14 and R 15 In some embodiments, in Formula I-1-A, R 14 and R 16 are all hydrogen, and R 15 In some embodiments, in Formula I-1-A, all R 14 , R 15 and R 16 In some embodiments, in Formula I-1-A, R 14 and R 15 Together with the intermediate atom, they are connected to form an optionally substituted 5-8 membered ring, such as a 5-8 membered carbocyclic ring or heterocyclic ring. In some embodiments, in Formula I-1-A, R 15 and R 16 Together with the intermediate atom, they are connected to form an optionally substituted 5-8 membered ring, such as a 5-8 membered carbocyclic ring or heterocyclic ring. In some embodiments, in Formula I-1-A, X 2 YesNR 13 , and R 14 and R 13 Together with the middle atom, they are linked to form an optionally substituted 5-8 membered heterocyclic ring.

[0094] For example, in some embodiments, the compound of formula I-1-A can be characterized as having formula I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, or I-1-A-6:

[0095]

[0096]

[0097] in:

[0098] Ring A in formula I-1-A-4 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S, in addition to the ring S and N atoms shown therein,

[0099] Ring B in formula I-1-A-5 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S,

[0100] Ring C in formula I-1-A-6 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S,

[0101] in:

[0102] Where valence permits, n is an integer from 0 to 6 (e.g., 0, 1 or 2);

[0103] R D is independently halogen, G A , OG A , OH, CN or NG B G C , or two R D forming bonds, oxo or ring structures;

[0104] Among them G A is independently at each occurrence an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 4-8 membered heterocyclic group,

[0105] Among them G B and G C is independently hydrogen, G A , COG A or S(O)2G A ,

[0106] The variable L 1 , R 1 , L 2 , R 2 , R 3 , R 14 , R 15 , R 16 , X 2 and R 4In some embodiments, the ring A in formula I-1-A-4 is a 5-, 6-, or 7-membered ring, does not contain additional ring heteroatoms or contains an additional ring nitrogen atom or ring oxygen atom. In some embodiments, the ring B in formula I-1-A-5 is a 5-, 6-, or 7-membered ring, which can be an aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring, which may not contain ring heteroatoms in the case of an aryl or carbocyclic ring, or contains 1-3 ring heteroatoms independently selected from N, O, and S in the case of a heteroaryl or heterocyclic ring. In some embodiments, the ring C in formula I-1-A-6 is a 5-, 6-, or 7-membered ring, which can be an aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring, which may not contain ring heteroatoms in the case of an aryl or carbocyclic ring, or contains 1-3 ring heteroatoms independently selected from N, O, and S in the case of a heteroaryl or heterocyclic ring. In some embodiments, in formula I-1-A-4, I-1-A-5 or I-1-A-6, n is 0, that is, ring A, B or C is not R D In some embodiments, in formula I-1-A-4, I-1-A-5 or I-1-A-6, n is 1 or 2, wherein R D In some embodiments, in Formula I-1-A-4, I-1-A-5 or I-1-A-6, R D is independently at each occurrence F, Cl, OH, NH2, CN or G A (e.g., those described herein), or two R D In some embodiments, in Formula I-1-A-4, I-1-A-5 or I-1-A-6, R D is independently at each occurrence F, Cl, OH, NH2, CN, C optionally substituted with 1-3 F 1-4 Alkyl, or C optionally substituted by 1-3 F 1-4 heteroalkyl, or two R D Form a bond or oxo. For clarity, it should be noted that drawing Ring B or Ring C in Formula I-1-A-5 or I-1-A-6, respectively, does not require that the two ring atoms directly connected to the pyridine ring be carbon atoms. For example, in some embodiments, when Ring B in Formula I-1-A-5 contains one or more ring heteroatoms, the one or two ring heteroatoms can be directly bonded to the pyridine ring in Formula I-1-A-5.

[0107] In some embodiments, the compound of formula I-1-A can be characterized as having formula I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14 or I-1-A-15:

[0108]

[0109] in:

[0110] Where valence permits, m is an integer from 0 to 4 (e.g., 0, 1 or 2);

[0111] R E F, Cl, G independently at each occurrence D , OG D , OH or CN, or two R E forming bonds, oxo or ring structures;

[0112] Among them G D is independently at each occurrence an optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 4-8 membered heterocyclic group,

[0113] The variable L 1 , R 1 , L 2 , R 2 , R 3 , R 14 , R 15 , R 16 , X 2 and R 4 In some embodiments, in formula I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-13, m is 0. In some embodiments, in formula I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-13, m is 1 or 2, wherein R E In some embodiments, in Formula I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-13, R E Each occurrence is independently F, Cl, OH, NH2, CN or G D (e.g., those described herein), or two R E In some embodiments, in Formula I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-13, R E Each occurrence is independently F, Cl, OH, NH2, CN, C optionally substituted with 1-3 F 1-4 Alkyl, or C optionally substituted by 1-3 F 1-4 heteroalkyl, or two RE For clarity, when referring to two R E When a bond is formed, it means that two adjacent ring atoms are connected by an additional bond, usually a double bond; taking formula I-1-A-13 as an example, when two R E To form bonds, the rings can have e.g. The structure may be further represented by one or more R as defined herein. E Replace. When two R E When an oxo group is formed, it means that a ring atom is replaced by an oxo group. E When an oxo group is formed, the ring may have, for example The structure may be further represented by one or more R as defined herein. E Other similar expressions in this article should be understood similarly.

[0114] In some embodiments, in addition to the pyridyl group in Formula I-1-A, The moiety may also be an optionally substituted phenyl or 6-membered heteroaryl. For example, in some embodiments, the compound of Formula I may be characterized by having Formula I-1-B, Formula I-1-C, or Formula I-1-D:

[0115]

[0116] The variable L 1 , R 1 , L 2 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 2 and R 4 Include any of those described herein in any combination.

[0117] As discussed herein, various groups are suitable R for compounds of Formula I. 14 , R 15 , R 16 or R 17 Typically, in Formula I-1-A (e.g., Formula I-1-A-2, I-1-A-3, I-1-A-5, I-1-A-8 or I-1-A-13), Formula I-1-B, Formula I-1-C or Formula I-1-D or Formula I-1-H-1 as described below, R 14 It can be hydrogen, halogen (such as F or Cl), G E 、-(C 1-4 Alkylene)-G E, OH, CN, OG E or O-(C 1-4 Alkylene)-G E , where G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E is C optionally substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from F and OH 1-4 In some embodiments, G E It is C 1-4 Heteroalkyl, such as C1 heteroalkyl (such as CH2OH or CH2NH2), optionally substituted by one or more (such as 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E It is C 3-6 Cycloalkyl, such as cyclopropyl, optionally substituted by one or more (e.g. 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E is a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as azetidinyl, which is optionally substituted by one or more (e.g. 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, in Formula I-1-A (e.g., Formula I-1-A-2, I-1-A-3, I-1-A-5, I-1-A-8, or I-1-A-13), Formula I-1-B, Formula I-1-C, Formula I-1-D, or Formula I-1-H-1, R 14 Can be hydrogen, F, Cl, OH, CN, or G E (e.g., any of those described herein). In some embodiments, in Formula I-1-A (e.g., Formula I-1-A-2, I-1-A-3, I-1-A-5, I-1-A-8, or I-1-A-13), Formula I-1-B, Formula I-1-C, Formula I-1-D, or Formula I-1-H-1, R 14 Can be hydrogen, F, Cl, CN, C1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxy-substituted C 1-4 Alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 Alkyl (such as fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 Alkoxy (such as methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 In some preferred embodiments, in Formula I-1-A (e.g., Formula I-1-A-2, I-1-A-3, I-1-A-5, I-1-A-8 or I-1-A-13), Formula I-1-B, Formula I-1-C, Formula I-1-D or Formula I-1-H-1, R 14 In some preferred embodiments, in Formula I-1-A (e.g., Formula I-1-A-2, I-1-A-3, I-1-A-5, I-1-A-8 or I-1-A-13), Formula I-1-B, Formula I-1-C, Formula I-1-D or Formula I-1-H-1, R 14 It can also be F, CH3, CH2OH, OCH3 or cyclopropyl.

[0118] Typically, in Formula I-1-A (particularly Formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), Formula I-1-B, Formula I-1-C or Formula I-1-H-1, R 15 It can be hydrogen, halogen (e.g., F or Cl), G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E 、O-(C 1-4 Alkylene)-G E SG E 、S(O)-G E or S(O)2-G E , where G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4In some embodiments, G E is C optionally substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from F and OH 1-4 In some embodiments, G E It is C 1-4 heteroalkyl, such as C1 heteroalkyl (such as CH2OH or CH2NH2), which is optionally substituted by one or more (such as 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E It is C 3-6 Cycloalkyl, such as cyclopropyl, optionally substituted with one or more (e.g. 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E is a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as azetidinyl, which is optionally substituted by one or more (e.g. 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0119] In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C or formula I-1-H-1, R 15 It may be an optionally substituted 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as oxetanyl, morpholinyl or azetidinyl, which is optionally substituted by one or more (e.g., 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0120] In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C or formula I-1-H-1, R 15 It could be OG E , where G E It is C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as oxetanyl, which is optionally substituted by one or more (e.g., 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0121] In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C or formula I-1-H-1, R 15 It can be O-(C 1-4 Alkylene)-G F , where G F is OH, NH2, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S. For example, in some embodiments, R 15 It can be O-(C 1-4 Alkylene)-G F , where G F It is OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-4 Alkoxy (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (such as CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl substituted C 1-4 Alkoxy (e.g. -O-CH2CH2OH), alkoxy-substituted C 1-4 Alkoxy (e.g. -O-CH2CH2OMe), O-acyl (e.g. O-CH(O), OC(O)CH3), NH-acyl, N(C 1-4 alkyl)-acyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as oxetanyl, which is optionally substituted by one or more (e.g., 1, 2 or 3) independently selected from F, C 1-4In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C or formula I-1-H-1, R 15 It can be O-(C 1-4 Alkylene)-G F , where C 1-4 Alkylene (from left (O) to right (G F ) is -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2C(CH3)2-, and G F OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-4 Alkoxy (e.g., methoxy, ethoxy), isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (such as CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl substituted C 1-4 Alkoxy (e.g., -O-CH2CH2OH), or alkoxy-substituted C 1-4 Alkoxy (eg, -O-CH2CH2OMe).

[0122] In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C or formula I-1-H-1, R 15 Can be hydrogen, F, Cl, OH, CN or G E (such as any of those described herein).

[0123] In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C or formula I-1-H-1, R 15 Can be hydrogen, F, Cl, CN, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxy substituted C 1-4 Alkyl (such as hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4Alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 Alkoxy (such as methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (such as CF3O-, CF3CH2O-, etc.), C 1-4 Alkylthio (e.g. CH3S-), fluorine-substituted C 1-4 Alkylthio (eg CF3S-), cyclopropyloxy or cyclobutyloxy.

[0124] In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, or formula I-1-C, R 15 In some embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C or formula I-1-H-1, R 15 Not hydrogen.

[0125] In some preferred embodiments, in formula I-1-A (particularly formula I-1-A-1, I-1-A-3, I-1-A-4, I-1-A-7, I-1-A-9, I-1-A-10, I-1-A-11 or I-1-A-12), formula I-1-B, formula I-1-C, or formula I-1-H-1, R 15 It can be F, Cl, CN, CH3, CH2CH3, CHF2, CF3, OCH3, OCH2CH3, O-CH(CH3)2, OCHF2, OCF3, SCF3, cyclopropyl, or In some preferred embodiments, R 15 Can be In some preferred embodiments, R 15 Can be In some preferred embodiments, R 15 The following stereoisomers may be selected: In some embodiments, for a previously drawn chiral center, the compound may be present predominantly as the drawn enantiomer, e.g., with less than 20%, less than 10%, less than 5%, less than 1%, or no detectable amount of the other corresponding enantiomer, by weight, by HPLC area, or both.

[0126] Generally, in formula I-1-A (especially I-1-A-1, I-1-A-2, I-1-A-4, I-1-A-6, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-14), formula I-1-B, formula I-1-D, or formula I-1-H-1, R 16 Can be hydrogen, F, Cl, G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E or O-(C 1-4 Alkylene)-G E , where G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E is C optionally substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from F and OH 1-4 In some embodiments, G E It is C 1-4 heteroalkyl, such as C1 heteroalkyl (such as CH2OH or CH2NH2), which is optionally substituted by one or more (such as 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E It is C 3-6 Cycloalkyl, such as cyclopropyl, optionally substituted with one or more (e.g. 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, G E is a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, such as azetidinyl, which is optionally substituted by one or more (e.g. 1, 2 or 3) independently selected from F, C 1-4In some embodiments, in formula I-1-A (particularly I-1-A-1, I-1-A-2, I-1-A-4, I-1-A-6, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-14), formula I-1-B, formula I-1-D or formula I-1-H-1, R 16 Can be hydrogen, F, Cl, OH, CN or G E (e.g., any of those described herein). In some embodiments, in Formula I-1-A (particularly I-1-A-1, I-1-A-2, I-1-A-4, I-1-A-6, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, or I-1-A-14), Formula I-1-B, Formula I-1-D, or Formula I-1-H-1, R 16 Can be hydrogen, F, Cl, CN, C 1-4 Alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), fluorine-substituted C 1-4 Alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, C 3-6 Cycloalkyl (such as cyclopropyl, cyclobutyl, etc.), C 1-4 Alkoxy (such as methoxy, ethoxy, etc.), fluorine-substituted C 1-4 In some preferred embodiments, in formula I-1-A (particularly I-1-A-1, I-1-A-2, I-1-A-4, I-1-A-6, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-14), formula I-1-B, formula I-1-D or formula I-1-H-1, R 16 Can be hydrogen, F, Cl, CN, C 1-4 Alkyl, C 1-4 For example, in some preferred embodiments, in formula I-1-A (particularly I-1-A-1, I-1-A-2, I-1-A-4, I-1-A-6, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12 or I-1-A-14), formula I-1-B, or formula I-1-D or formula I-1-H-1, R 16 It may be hydrogen.

[0127] When present, R in Formula I (e.g., Formula I-1-B, I-1-C, or I-1-D) 17 Typically hydrogen.

[0128] In some embodiments, in an applicable Formula I (eg, Formula I-1-A, such as Formula I-1-A-3 or I-1-H-1), R 14 and R 15 At least one of them is not hydrogen.

[0129] In some embodiments, in applicable Formula I (eg, Formula I-1-A or I-1-H-1), R 14 and R 16 are all hydrogen, and R 15 Not hydrogen.

[0130] In some embodiments, in applicable Formula I (eg, Formula I-1-A or I-1-H-1), R 14 , R 15 and R 16 It's all hydrogen.

[0131] In some embodiments, in Formula I (eg, Formula I-1, I-2, or I-3) The moiety (also referred to herein as M-10) may also represent an optionally substituted 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from S, O and N, such as optionally substituted pyrazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted oxazole, optionally substituted isoxazole, optionally substituted imidazole, etc. In such an embodiment, J 1 Can be CR 18 NR 19 , O, S or N can be CR 14 or N; J 4 Yes CR 20 NR 21 , O, S or N; J 5 is C or N; and J 2 and J 3 One of them does not exist, J 2 and J 3 The other one is O, S, N, NR 22 or CR 23 ; where R 18 , R 19 , R 20 , R 21 , R 22 and R 23 Include any of those described herein in any combination.

[0132] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (eg, those described herein), J 4 Typically, N. However, in some embodiments, J 4 It can also be CR 20 NR21 , O or S, where R 20 and R 21 As defined herein.

[0133] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (eg, those described herein), J 1 Can be CR 18 , where R 18 As defined herein. In some preferred embodiments, R 18 is hydrogen, halogen (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, R 18 Together with the respective intermediate atoms, they can be 13 , R 22 or R 23 The groups are linked to form an optionally substituted 5-8 membered ring structure.

[0134] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (eg, those described herein), J 1 It can also be NR 19 , where R 19 As defined herein. For example, in some embodiments, R 19 It can be hydrogen, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, R 19 Together with the respective intermediate atoms, they can be 13 , R 22 or R 23 The groups are linked to form an optionally substituted 5-8 membered ring structure.

[0135] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (eg, those described herein), J 1 It can also be O or S.

[0136] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (eg, those described herein), J 2 Can be CR 23 , and J 3 does not exist, where R 23 As defined herein. For example, in some embodiments, R 23 It can be hydrogen, halogen (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, R 23 Together with the respective intermediate atoms, they can be 18 , R 19 , R 20 or R 21 The groups are linked to form an optionally substituted 5-8 membered ring structure.

[0137] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (eg, those described herein), J 2 It can be NR 22 , and J 3 does not exist, where R 22 As defined herein. For example, in some embodiments, R 22 It can be hydrogen, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, R 22 Together with the respective intermediate atoms, they can be18 , R 19 , R 20 or R 21 Connected to form an optionally substituted 5-8 membered ring structure.

[0138] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (eg, those described herein), J 2 It can also be O or S, and J 3 Does not exist.

[0139] In some more specific embodiments, the compound of Formula I can be characterized as having Formula I-1-E, I-1-F or I-1-G:

[0140]

[0141] The variable L 1 , R 1 , L 2 , R 2 , R 3 , R 18 , R 22 , R 23 , X 2 and R 4 Any combination of any of those described herein is included. For example, in some embodiments, R in Formula I-1-E or I-1-G 18 It can be hydrogen, halogen (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 In some embodiments, R in Formula I-1-E is substituted with an alkyl group (e.g., methyl) and an OH group. 22 It can be hydrogen, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4In some embodiments, R in Formula I-1-F is substituted with an alkyl group (e.g., methyl) and an OH group. 23 It can be hydrogen, halogen (such as F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0142] Unless otherwise stated or contrary to context, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I- The 2 Usually O.

[0143] In some embodiments, X in Formula I (eg, any applicable subformula) 2 It can also be NR 13 , where R 13 As defined herein. For example, in some embodiments, X in Formula I (eg, any applicable subformula) 2 In some embodiments, X in Formula I (eg, any applicable subformula) is 2 It can be NR 13 , where R 13 It is C 1-4 As will be appreciated by those skilled in the art, when X in Formula I 2 NR 13 In some embodiments, wherein X 2 NR 13The compounds of the present disclosure may exist as a racemic mixture or as a mixture enriched in a stereoisomer having either configuration about an asymmetric sulfur center. For example, in some embodiments, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-5, I- 1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1 -A-13, I-1-A-14, I-1-A-15 or I-1-H-1) may be characterized by having the formula I-1-J-E1 or I-1-J-E2:

[0144]

[0145] The variable L 1 , R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , R 13 and R 4 In any combination, any of those described herein, such as those described herein in conjunction with Formula I-1-A and its subformulas I-1-A-1 to I-1-A-15. For example, in some embodiments, wherein X 2 NR 13 The compound of formula I-1 may be enriched in the stereoisomer of formula I-1-J-E1, which may be substantially free of the stereoisomer of formula I-1-J-E2, for example, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of the stereoisomer of formula I-1-J-E2 by weight, by HPLC area, or both. In some embodiments, wherein X 2 NR 13 The compound of formula I-1 may be enriched in the stereoisomer of formula I-1-J-E2, which may be substantially free of the stereoisomer of formula I-1-J-E1, for example, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of the stereoisomer of formula I-1-J-E1 by weight, by HPLC area, or both. In some embodiments, wherein X 2 NR 13The compound of formula I-1 may be a mixture of stereoisomers of formula I-1-J-E1 and formula I-1-J-E2 in a 1:1 molar ratio or any other ratio.

[0146] Unless otherwise stated or contrary to context, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2 , I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1- R in A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1) 4 Typically, it is optionally one or more independently selected from F, OH and C 1-4 Substituents of heteroalkyl substituted C 1-4 For example, in any embodiment described herein, unless otherwise indicated or contradicted by context, R in Formula I (eg, any applicable subformula) is 4 It may be methyl.

[0147] In some embodiments, when X 2 YesNR 13 When R in Formula I (e.g., any applicable subformula) is 4 and R 13 Can be linked together with the intermediate atom to form an optionally substituted 5-8 membered ring structure. For example, in some embodiments, Formula I (including any applicable subformulas) Part can be

[0148] M-10, X 2 and R 4 For example, unless otherwise specified or contrary to the context, in any embodiment herein, Formula I (including any applicable subformulae, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some can be selected from:

[0149]

[0150] Unless otherwise indicated or contrary to the context, in any embodiment herein, Formula I (including any applicable subformulae, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some may also be selected from:

[0151]

[0152]

[0153] Where Cbz represents

[0154] Unless otherwise indicated or contrary to the context, in any embodiment herein, Formula I (including any applicable subformulae, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some may also be selected from: For example, in some embodiments, in Formula I (including any applicable subformulae) Part can be It can be substantially enantiomerically pure relative to the drawn chiral center, e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or no detectable amount of the other corresponding enantiomer by weight, by HPLC area, or both. In some embodiments, the Part can be It can be substantially enantiomerically pure relative to the drawn chiral center, e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or no detectable amount of the other corresponding enantiomer by weight, by HPLC area, or both.

[0155] Unless otherwise indicated or contrary to the context, in any embodiment herein, Formula I (including any applicable subformulae, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some may also be selected from:

[0156]

[0157] Unless otherwise indicated or contrary to the context, in any embodiment herein, Formula I (including any applicable subformulae, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some may also be selected from:

[0158]

[0159] In some embodiments, for the chiral centers drawn above, the compounds may be present predominantly as the drawn stereoisomer, e.g., with less than 20%, less than 10%, less than 5%, less than 1%, or no detectable amounts of other stereoisomers, by weight, by HPLC area, or both.

[0160] Unless otherwise indicated or contrary to the context, in any embodiment herein, Formula I (including any applicable subformulae, such as Formula I-1 (e.g., I-1-A, I-1-H or I-1-J-E2), I-2 or I-3) Some may also be selected from:

[0161]

[0162] In some embodiments, for the chiral centers drawn above, the compounds may be present predominantly as the drawn stereoisomer, e.g., with less than 20%, less than 10%, less than 5%, less than 1%, or no detectable amount of other stereoisomers, by weight, by HPLC area, or both.

[0163] Unless otherwise indicated or contrary to the context, in any embodiment herein, Formula I (including any applicable subformulae, such as Formula I-1 (e.g., I-1-A, I-1-H or I-1-J-E1), I-2 or I-3) Some may also be selected from:

[0164]

[0165] In some embodiments, for the chiral centers drawn above, the compounds may be present predominantly as the drawn stereoisomer, e.g., with less than 20%, less than 10%, less than 5%, less than 1%, or no detectable amounts of other stereoisomers, by weight, by HPLC area, or both.

[0166] Unless otherwise indicated or contrary to the context, in any embodiment herein, the Some may also be selected from:

[0167]

[0168] Generally, in formula I (for example, formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I R 3 It's hydrogen.

[0169] Generally, in formula I (for example, formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A- 3. I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14 or I-1-A-15), L 1 yes Where R 11 As defined herein. In some preferred embodiments, L 1 yes For example, in some embodiments, Formula I-1 (e.g., Formula I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, Compounds of I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14 or I-1-A-15) may be characterized by having the formula I-1-H:

[0170]

[0171] The variable R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 2 and R 4 Any of those described herein are included in any combination, such as those described in conjunction with Formula I-1 and its subformulae. In some specific embodiments, the compound of Formula I-1-H can be characterized as having the subformula of I-1-H-1:

[0172]

[0173] The variable R 1 , L 2 , R 2 , R 14 , R 15 , R 16 , X2 and R 4 Any combination includes any of those described herein, such as those described in conjunction with Formula I-1-A (including any of Subformulae I-1-A-1 to I-1-A-15). For example, in some embodiments, in Formula I-1-H-1, R 14 In some embodiments, in Formula I-1-H-1, R 15 In some embodiments, in Formula I-1-H-1, R 16 In some embodiments, in Formula I-1-H-1, R 14 and R 15 One of them is hydrogen, and R 14 and R 15 The other of is not hydrogen. For example, in some embodiments, R 14 is hydrogen and R 15 is not hydrogen. In some embodiments, in Formula I-1-H-1, R 14 and R 15 In some embodiments, in Formula I-1-H-1, R 14 and R 15 In some embodiments, in Formula I-1-H-1, R 14 and R 16 are all hydrogen, and R 15 is not hydrogen. In some embodiments, in Formula I-1-H-1, R 14 , R 15 and R 16 In some embodiments, in Formula I-1-H-1, R 14 and R 15 Together with the intermediate atom, they are connected to form an optionally substituted 5-8 membered ring, such as a 5-8 membered carbocyclic ring or heterocyclic ring. In some embodiments, in Formula I-1-H-1, X 2 YesNR 13 , and R 14 and R 13 Together with the intermediate atom, they form an optionally substituted 5-8 membered heterocyclic ring. 2 is O, NH or NCH3. Generally, R in formula I-1-H-1 4 is CH3. Suitable additional definitions for the variables of formula I-1-H-1 also include any of those described herein.

[0174] In some embodiments, in Formula I (e.g., Formula I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I- L 1 YesNR 11 , where R 11 As defined herein. For example, in some embodiments, L 1 is NH. In some embodiments, L 1 YesNR 11 , where R 11 It is hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0175] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1- L 1 It can also be Where R 11 As defined herein. For example, in some embodiments, L 1 Can be

[0176] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1- L 1 It can also be Where R 11 and R 12 As defined herein. For example, in some embodiments, L 1 Can be

[0177] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1- L 1 For example, in some embodiments, the compound of formula I-1 may have a subformula of formula I-1-I, wherein R 1 Directly attached to the pyridazine ring:

[0178]

[0179] The variable R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 2 and R 4 Any of those described herein are included in any combination, such as those described in conjunction with Formula 1-1 and subformulae thereof.

[0180] Various groups are suitable as R in formula I 1 In some embodiments, R 1Can be hydrogen. In some embodiments, R 1 It may be an optionally substituted C 1-6 In some embodiments, R 1 It may be an optionally substituted C 3-10 A carbocyclic ring, which may be a monocyclic ring, or a fused, bridged or spiro-linked bicyclic carbocyclic ring. Typically, the carbocyclic ring is fully saturated. However, in some embodiments, the carbocyclic ring may also be partially unsaturated. In some embodiments, R 1 It can be an optionally substituted 4-10 membered heterocyclic ring, which can be a monocyclic ring, or a fused, bridged or spiro-linked bicyclic heterocyclic ring. The heterocyclic ring can be fully saturated or partially unsaturated. In some embodiments, R 1 It may be an optionally substituted phenyl. 1 It may be an optionally substituted heteroaryl, such as a 5-10 membered monocyclic or bicyclic heteroaryl. 1 It may be an optionally substituted 5- or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S. In some embodiments, R 1 It may be an optionally substituted 8-10 membered bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S.

[0181] In some embodiments, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I- 1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A R in -10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1) 1 Can be selected from: 1) monocyclic C 3-6 Cycloalkyl; 2) Spiro-linked, fused or bridged bicyclic C 4-10 cycloalkyl; 3) monocyclic 4-8 membered heterocyclyl having 1-3 heteroatoms independently selected from O, N and S; 4) spiro-, fused- or bridged bicyclic 5-10 membered heterocyclyl having 1-3 heteroatoms independently selected from O, N and S; 5) phenyl; 6) 6 membered heteroaryl having 1 or 2 ring nitrogen atoms; 7) 5 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S; 8) 8-10 membered bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S; and 9) C 1-6Alkyl, wherein each of 1)-9) is optionally substituted, for example, by one or more independently selected G as described herein 1 In some embodiments, G 1 is independently at each occurrence a halogen (eg, F or Cl), G 1A , OG 1A , (C 1-4 Alkylene)-G 1A 、O-(C 1-4 Alkylene)-G 1A , OH, CN or NG 1B G 1C , or two G 1 to form a bond, oxo or ring structure wherein:

[0182] G 1A Each occurrence is independently:

[0183] i)C 1-6 alkyl,

[0184] ii) C 3-6 Cycloalkyl,

[0185] iii) C 1-4 Heteroalkyl,

[0186] iv) a 4-8 membered heterocyclyl group having 1-3 ring heteroatoms independently selected from O, N and S,

[0187] v) phenyl, or

[0188] vi) 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from O, N and S,

[0189] wherein each of i) to vi) is optionally substituted, for example, by one or more (e.g., 1, 2, or 3) substituents, each of which is independently selected from F, Cl, CN, OH, oxo (if valence permits), C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, N and S, phenyl or 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from O, N and S, wherein C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 The cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are independently optionally substituted with one or more (e.g., 1, 2 or 3) substituents, each of which is independently selected from F, Cl, CN, OH, oxo (if valence permits), optionally with one or more (e.g., 1-3) G 1DSubstituted C1-4 alkyl, optionally substituted with one or more (e.g. 1-3) G 1D Substituted C 1-4 Heteroalkyl and optionally substituted by one or more (eg 1-3) G 1D Substituted C 3-6 Cycloalkyl, where G 1D F, OH, or C at each occurrence 1-4 alkyl,

[0190] G 1B and G 1C is independently hydrogen, G 1A , (C 1-4 Alkylene)-G 1A , COG 1A 、CO-(C 1-4 Alkylene)-G 1A 、S(O)2G 1A or S(O)2-(C 1-4 Alkylene)-G 1A , where G 1A As defined above.

[0191] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 Can be a single ring C 3-6 Cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, which is unsubstituted or substituted by one or more (usually 1 or 2) independently selected radicals as described herein. 1 Substitution, such as F, OH, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkoxy, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 In some preferred embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) 1 It may be cyclopropyl.

[0192] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It can be a spiro-bicyclic C 5-8 Cycloalkyl groups, such as which is unsubstituted or replaced by one or more (usually 1 or 2) independently selected G as described herein 1 Substitution, such as F, methyl, methoxy, etc.

[0193] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 Can be a bridged bicyclic C 5-8 Cycloalkyl groups, such as which is unsubstituted or replaced by one or more (usually 1 or 2) independently selected G as described herein 1 replace.

[0194] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It can be a fused bicyclic C 5-8 Cycloalkyl, which is unsubstituted or substituted with one or more (usually 1 or 2) independently selected G as described herein 1 replace.

[0195] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It may be a monocyclic 4-6 membered heterocyclic group having 1-3 heteroatoms independently selected from O, N and S, such as azetidinyl, pyrrolidinyl, etc., which is unsubstituted or substituted with one or more (usually 1 or 2) independently selected G as described herein. 1 Substitution, for example F or methyl.

[0196] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It may be a fused 6-8 membered heterocyclic group having 1-3 heteroatoms independently selected from O, N and S, for example which is unsubstituted or replaced by one or more (usually 1 or 2) independently selected G as described herein 1 Substitution, for example, F, OH or methyl.

[0197] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is1 It may be a bridged or spiro-linked 5-8 membered heterocyclic group having 1-3 heteroatoms independently selected from O, N and S, which is unsubstituted or substituted with one or more (usually 1 or 2) independently selected G as described herein. 1 replace.

[0198] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 may be phenyl, optionally replaced by one or more (usually 1 or 2) independently selected G as described herein 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkoxy, etc.

[0199] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It may be a 6-membered heteroaryl group having 1 or 2 ring nitrogen atoms, such as pyridine, pyrimidine, etc., which may be optionally substituted with one or more (usually 1 or 2) independently selected G as described herein. 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkoxy, etc.

[0200] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It may be a 5-membered heteroaryl group having 1-3 ring heteroatoms independently selected from N, O and S, such as pyrazole, etc., which is optionally replaced by one or more (usually 1 or 2) independently selected G as described herein. 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkoxy, etc.

[0201] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It may also be an 8-10 membered bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, which is optionally replaced by one or more (usually 1 or 2) independently selected G as described herein. 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkoxy, etc.

[0202] In some embodiments, R in Formula I (e.g., Formula I-1 and its subformulae, such as Formula I-1-A (e.g., I-1-A-1 to I-1-A-15) or I-1-H (e.g., I-1-H-1)) is 1 It can also be C 3-6 Alkyl, such as isopropyl, optionally replaced by one or more (usually 1 or 2) independently selected G as described herein 1 Substitution, such as F, OH, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkoxy, etc.

[0203] When L 1 When absent, such as those compounds of formula I-1-I, R 1 Typically, R is a heteroaryl group, such as a 5- or 6-membered heteroaryl group. 1 It may be an optionally substituted 5-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S. In some embodiments, R 1 It may be a 5-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, such as those described herein, for example pyrazole, which is optionally substituted by one or more G 2 Replacement, where G 2 is independently at each occurrence a halogen (eg, F or Cl), G 2A , OG 2A , (C 1-4 Alkylene)-G 2A 、O-(C 1-4 Alkylene)-G 2A , OH, CN or NG 2B G 2C , or two G 2A ring structure is formed, in which:

[0204] G 2A C independently at each occurrence 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-4 heteroalkyl or a 4-8 membered heterocyclyl having 1-3 heteroatoms independently selected from O, N and S, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-4 The heteroalkyl or 4-8 membered heterocyclyl is optionally substituted by one or more (e.g. 1, 2 or 3) each independently selected from F, Cl, OH, C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Heteroalkyl or fluorine-substituted C 1-4 The substituents of the heteroalkyl group are substituted, and

[0205] G 2B and G 2C is independently hydrogen, G 2A , (C 1-4 Alkylene)-G 2A , COG 2A 、CO-(C 1-4 Alkylene)-G 2A 、S(O)2G 2A or S(O)2-(C 1-4 Alkylene)-G 2A , where G 2A As defined above.

[0206] In some embodiments, L 1 does not exist, such as those compounds of formula I-1-I, R 1 is pyrazole, which is optionally replaced by one or more (eg, 1 or 2) independently selected G as described herein 2 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkoxy, etc.

[0207] For L of Formula I 1 and R 1There is no particular limitation on suitable combinations of. For example, unless otherwise specified or contrary to the context, in any embodiment herein, L in Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14 or I-1-A-15) 1 -R 1 You can choose from:

[0208]

[0209] Unless otherwise stated or contrary to context, in any embodiment herein, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1- A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I- L in 1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1) 1 -R 1 You can also choose from:

[0210]

[0211] Unless otherwise stated or contrary to context, in any embodiment herein, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1- A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I- L in 1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1) 1 -R 1 It can be:

[0212]

[0213] Unless otherwise stated or contrary to context, in any embodiment herein, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1- A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I- L in 1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1) 1 -R 1 Can be selected from:

[0214]

[0215] Generally, in formula I (for example, formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A -3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-1 0. I-1-A-11, I-1-A-12, I-1-A-13, I-in 1-A-14, I-1-A-15 or I-1-H-1), L 2 It's NH.

[0216] In some embodiments, in Formula I (eg, Formula I-1 and subformulae thereof), L 2 Can be C 1-4 In some embodiments, in Formula I (eg, Formula I-1 and its subformulae), L 2 Can be C 1-4 In some embodiments, in Formula I (eg, Formula I-1 and its subformulae), L 2 Can be C 3-6 In some embodiments, in Formula I (eg, Formula I-1 and its subformulae), L 2 It may be a 4-6 membered heterocyclylene having 1 or 2 ring heteroatoms independently selected from N, O and S, which is optionally substituted, for example by F and / or methyl.

[0217] Generally, in formula I (for example, formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A R 2 It is hydrogen, C 1-4 Alkyl or CD3.

[0218] In some embodiments, in Formula I (eg, Formula I-1 and subformulae thereof), R 2 It can also be C 1-4 Heteroalkyl.

[0219] Unless otherwise indicated or contrary to the context, in any embodiment herein, L in Formula I (eg, Formula I-1 and its subformulae) is 2 -R 2 Can be selected from:

[0220]

[0221] Unless otherwise stated or contrary to context, in any embodiment herein, Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I -1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I -L in 1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1) 2 -R 2 It can be:

[0222]

[0223] In some embodiments, the present disclosure also provides a compound selected from the following compound numbers 1-133 or a pharmaceutically acceptable salt thereof:

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] In some embodiments, the genus of compounds in the present disclosure also excludes, to the extent applicable, any compounds specifically prepared and disclosed prior to the present disclosure.

[0232] Synthesis method

[0233] Given the present disclosure, one skilled in the art can readily synthesize the compounds of the present disclosure. Exemplary syntheses are also shown in the Examples section.

[0234] The synthesis method of the following formula I-1-H-1 is illustrative, and according to the present disclosure, by using appropriate synthetic starting materials and / or intermediates, those skilled in the art can similarly apply the synthesis method to synthesize other compounds of formula I. In some embodiments, the present disclosure also provides synthetic methods and synthetic intermediates for preparing compounds of formula I, as shown in the reaction formulas herein.

[0235] As shown in Reaction Scheme 1, compounds of Formula I-1-H-1 can generally be synthesized through a series of coupling reactions and functional group transformations. In some embodiments, S-1 can be coupled with pyridazine S-2 to form compound S-3, wherein Lg 1 and Lg 2 Each independently may be a leaving group as described herein, such as a halogen (e.g., Cl). Typically, the reaction between S-1 and S-2 can be carried out under alkaline conditions, such as by using an alkali metal bis(trimethylsilyl)amide (e.g., LiHMDS). Compound S-3 can then be converted to S-5 by reaction with S-4. Typically, the reaction of S-3 and S-4 can be carried out in the presence of a transition metal catalyst, such as a palladium catalyst. The thioether functional group is then typically converted to S(O)(X) by one or two oxidation steps (e.g., using an oxidant and / or conditions as described herein). 2) , optionally also including in X 2 and R 14A ring is formed between the two, thereby compound S-5 can be converted to a compound of formula I-1-H-1. Exemplary reaction conditions for converting a compound of S-1 to a compound of formula I-1-H-1 are shown in the Examples section. When applicable, the variable R in formulas S-1, S-2, S-3, S-4, and S-5 of reaction formula 1 1 , L 2 , R 2 , R 4 , R 14 , R 15 , R 16 and X 2 Included are any of those defined above in conjunction with Formula I (eg, any subformula of Formula I) and protected derivatives thereof.

[0236] Reaction 1

[0237]

[0238] It will be apparent to those skilled in the art that conventional protecting groups may be required to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis", 4 thed. PGM Wuts; TW Greene, John Wiley, 2007 and references cited therein. The reagents used in the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, some reagents suitable for the reactions described herein can be prepared by following the corresponding procedures described in WO2019 / 103952, the contents of which are incorporated herein by reference in their entirety. In addition, many reagents are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference books, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 1997), or obvious modifications thereof. th Edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any available updates as of the present application.

[0239] Pharmaceutical composition

[0240] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0241] The pharmaceutical composition may optionally include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition includes a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A- The invention relates to a compound of the invention comprising: ... See also Remington's The Science and Practice of Pharmacy, 21st Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients for formulating pharmaceutical compositions and known techniques for preparing pharmaceutical compositions.

[0242] The pharmaceutical composition may include any one or more compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises, for example, a therapeutically effective amount of Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound No. 1-133, or a pharmaceutically acceptable salt thereof. In any embodiment described herein, the pharmaceutical composition may contain a therapeutically effective amount of a compound selected from compound No. 1-133 or a pharmaceutically acceptable salt thereof.

[0243] The pharmaceutical compositions may also be formulated for delivery by any known delivery route, including but not limited to oral, parenteral, inhalation, and the like.

[0244] In some embodiments, the pharmaceutical composition can be formulated for oral administration. Oral formulations can be presented as discrete units such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of active compound; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil emulsions. Excipients for preparing compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropyl alcohol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0245] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral preparations can be, for example, aqueous solutions, suspensions, or emulsions. Excipients for preparing parenteral preparations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, glucose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0246] In some embodiments, the pharmaceutical composition is formulated for inhalation administration. For example, the inhalable formulation can be formulated into a nasal spray, a dry powder or an aerosol that can be administered by a metered dose inhaler. Excipients for preparing inhalation formulations are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, and mixtures of these substances. Sprays can also include propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0247] Pharmaceutical compositions can include various amounts of compounds of the present disclosure, depending on various factors, such as the intended use and potency and selectivity of the compound. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or condition as described herein, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and / or scleroderma, which may depend on the recipient of the treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound (e.g., potency for inhibiting TYK2), its clearance rate, and whether it is co-administered with another drug.

[0248] For veterinary use, the compounds of the present disclosure can be administered in a suitably acceptable formulation according to normal veterinary practice. A veterinarian can readily determine the dosing regimen and route of administration most suitable for a particular animal.

[0249] In some embodiments, all necessary ingredients for treating diseases or conditions associated with TYK2, such as those mediated by IL-12, IL-23 and / or interferon-α (INF-α), using the compounds of the present invention alone or in combination with another agent or intervention that is traditionally used to treat such diseases or conditions can be packaged into a kit. Specifically, in some embodiments, the present invention provides a kit for therapeutic intervention of a disease, which comprises a set of packaged drugs, the drug set including the compounds disclosed herein and a buffer and other components for preparing a deliverable form of the drug, and / or a device for delivering such drugs, and / or any agent for combined treatment with the compounds of the present disclosure, and / or instructions for use for treating the disease packaged with the drug. The instructions can be fixed in any tangible medium, such as printed paper, or computer-readable magnetic or optical media, or indicate a reference to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0250] Treatment methods / uses

[0251] The compounds of the present disclosure can be used as therapeutically active substances for treating and / or preventing diseases or conditions associated with TYK2. In particular, the compounds of the present disclosure can be used to treat conditions associated with regulating the function of IL-23, IL-12 and / or IFN-α, particularly inhibiting the function of IL-23, IL-12 and / or IFN-α, by acting on Tyk2 to mediate signal transduction. Such conditions include diseases associated with these cytokines in which the pathogenic mechanism is mediated by IL-23-, IL-12- and / or IFN-α, including any of those diseases known in the art and those described herein.

[0252] In some embodiments, the present disclosure provides a method of inhibiting TYK2-mediated cell signaling, comprising treating a cell with an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-E2, I-1-A-2, I-1-A-3, I-1-A-4, I-1-B-5, I-1-C-6, I-1-D-7, I-1-E-8, I-1-F-9, I-1-G-10, I-1-H-11, I-1-I-12, I-1-I-13, I-1-I-14, I-1-I-15 -1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15, or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0253] In some embodiments, the present disclosure provides a method of inhibiting IL-23, IL-12 and / or IFN-α function in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J -E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0254] In some embodiments, the present disclosure provides a method of treating or preventing a disease or condition mediated by TYK2 in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E 2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any of compound numbers 1-133, or a pharmaceutically acceptable salt thereof). Suitable TYK2-mediated diseases or conditions that can be treated with the methods herein include any of those diseases or conditions known in the art, such as those described in WO2019 / 103952 and WO2020 / 185755, the contents of each of which are incorporated by reference in their entirety. Exemplary TYK2-mediated diseases or conditions that can be treated using the methods herein also include, but are not limited to, those proliferative, metabolic, allergic, autoimmune, and / or inflammatory diseases or conditions described herein.

[0255] In some embodiments, the present disclosure provides a method of treating or preventing a disease or condition associated with IL-23, IL-12 and / or IFN-α in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any of compound numbers 1-133, or a pharmaceutically acceptable salt thereof). Suitable diseases or conditions associated with IL-23, IL-12 and / or IFN-α that can be treated with the methods herein include any of those diseases or conditions known in the art, such as those described in WO2019 / 103952 and WO2020 / 185755, the contents of each of which are incorporated by reference in their entirety. Exemplary diseases or conditions associated with IL-23, IL-12 and / or IFN-α that can be treated using the methods herein also include, but are not limited to, those proliferative, metabolic, allergic, autoimmune and / or inflammatory diseases or conditions described herein.

[0256] In some embodiments, the present disclosure provides a method of treating or preventing a proliferative, metabolic, allergic, autoimmune and / or inflammatory disease or condition, such as described herein, in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J- E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0257] In some embodiments, the present disclosure provides a method of treating or preventing an autoimmune and / or inflammatory disease or condition, such as described herein, in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-J-E3, I-1-J-E4, I-1-J-E5, I-1-J-E6, I-1-J-E7, I-1-J-E8, I-1-J-E9, I-1-J-E10, I-1-J-E111, I-1-J-E12, I-1-J-E2, I-1-J-E3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E10, I-1-J-E2, I-1-J-E3, I-1-J-E4, I-1-J-E5, I-1-J-E6, I-1-J- 1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0258] In some embodiments, the present disclosure provides a method of treating or preventing a metabolic disease or condition, such as described herein, such as type 2 diabetes or atherosclerosis, in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1 , I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0259] In some embodiments, the present disclosure provides a method for treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A -1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0260] In some embodiments, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1 -A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound Nos. 1-133, or a pharmaceutically acceptable salt thereof), wherein the disease or condition may be one or more selected from the following diseases or conditions: inflammatory diseases, such as Crohn's disease disease), ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases, such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, psoriasis; autoinflammatory diseases, including CAPS, TRAPS, FMF, adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases, including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone diseases, such as bone resorption diseases, osteoarthritis, osteoporosis proliferative diseases, such as acute myeloid leukemia, chronic myeloid leukemia; angiogenesis disorders, such as angiogenesis disorders, including solid tumors, ocular neovascularization and infantile hemangioma; infectious diseases, such as sepsis, septic shock and Shigellosis; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or trauma, tumors and viral diseases, such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, as well as HIV infection and CMV retinitis, AIDS.

[0261] In some embodiments, the present disclosure provides a method of treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1 , I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I - Compounds of -1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), chemical compounds The method is preferably any one of the compound numbers 1-133, or a pharmaceutically acceptable salt thereof, wherein the diseases or conditions that can be treated by the method include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, inflammatory response caused by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome (Reiter's syndrome), gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic B-cell diseases; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic diseases, cerebral malaria, chronic inflammatory lung diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, heartburn, influenza, osteoporosis, bone joint disease, Arthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and shigellosis; Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or trauma; angiogenic diseases, including solid tumors, ocular neovascularization, and infantile hemangioma; viral diseases, including acute hepatitis infection (including hepatitis A, B, and C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes;Stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endothelial oxidase synthase-2, and pemphigus vulgaris.

[0262] In some preferred embodiments, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1- The invention relates to a compound of the invention comprising: a compound of any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is one or more selected from the group consisting of Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris.

[0263] In some preferred embodiments, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1- 1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof), wherein the disease or condition is ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and cardiac ischemia-reperfusion injury caused by myocardial infarction.

[0264] In some preferred embodiments, the present disclosure provides a method for treating or preventing multiple myeloma in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I- 1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0265] In some preferred embodiments, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5 ...6, I-1-J-E3, I-1-J-E4, I-1-J-E5, I-1-J-E6, I-1-J-E7, I-1-J-E8, I-1-J-E9, I-1-J-I10, I-1-J-I111, I-1-J-I12 -1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof), wherein the disease or condition is one or more diseases or conditions selected from the following: multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and scleroderma.

[0266] In some preferred embodiments, the present disclosure provides a method of treating multiple sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1- -1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0267] In some preferred embodiments, the present disclosure provides a method of treating rheumatoid arthritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I- 1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0268] In some preferred embodiments, the present disclosure provides a method for treating inflammatory bowel disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1- -1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0269] In some preferred embodiments, the present disclosure provides a method for treating systemic lupus erythematosus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I- 1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0270] In some preferred embodiments, the present disclosure provides a method of treating psoriasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1- 1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0271] In some preferred embodiments, the present disclosure provides a method of treating psoriatic arthritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1- -1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0272] In some preferred embodiments, the present disclosure provides a method for treating Crohn's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1- 1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0273] In some preferred embodiments, the present disclosure provides a method for treating Sjögren's syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1- -1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0274] In some preferred embodiments, the present disclosure provides a method of treating scleroderma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1- 1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof).

[0275] In some embodiments, the present disclosure also provides one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15, I-1-A-16, I-1-A-17, I-1-A-18, I-1-A-19, I-1-A-20, I-1-A-21, I-1-A-22, I-1-A-23, I-1-A-24, I-1-A-25, I-1-A-26, I-1-A-27, I-1-A-28, I-1-A-29, I-1-A-30, I-1-A-31, I-1-A-32, I-1-A-33, I-1-A-34, I-1-A-35, I-1-A-36, I-1-A-37, I-1-A-38, I-1-A-39, I-1-A-40, I-1-A-41, I-1-A-42, I-1-A-43, I-1-A-44, I-1-A-45 8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof) for use in treating or preventing any disease or condition described herein, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and / or scleroderma.

[0276] In some embodiments, the present disclosure also provides one or more compounds of the present disclosure (e.g., Formula I (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J-E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1- The invention relates to a compound of any one of compound Nos. 1-1-9, 1-1-A-10, 1-1-A-11, 1-1-A-12, 1-1-A-13, 1-1-A-14, 1-1-A-15 or 1-1-H-1), any one of compound Nos. 1-133, or a pharmaceutically acceptable salt thereof) for the preparation of a medicament for treating or preventing any disease or condition described herein, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and / or scleroderma.

[0277] The compounds of the present disclosure can be used as monotherapy or combination therapy. In some embodiments, the treatment methods of IL-23-, IL-12 and / or IFNα-related diseases or conditions may include administering the compounds of the present disclosure alone or in combination with one or more other suitable therapeutic agents that can be used to treat the condition. Examples of such other suitable therapeutic agents include corticosteroids, rolipram, calphostin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents, such as abacavir; antiproliferative agents, such as methotrexate, leflunomide, FK506 (tacrolimus, ); antimalarial drugs, such as hydroxychloroquine; cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycins (sirolimus or ) or its derivatives.

[0278] Administration herein is not limited to any specific route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhaled, oral, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. In some embodiments, administration is oral administration.

[0279] The dosing regimen, including dosage, may vary and may be adjusted depending on the recipient of treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0280] definition

[0281] It is to be understood that all moieties and combinations thereof retain appropriate valences.

[0282] It is also to be understood that a specific embodiment of a variable moiety herein may be the same as or different than another specific embodiment having the same identifier.

[0283] Suitable atoms or groups for the variables herein are independently selected. The definitions of the variables may be combined. For example, L in Formula I 1 , R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 1 , Y, X 2 and R 4 Any definition of one or more variables in L 1 , R 1 , L 2 , R 2 , R 3 , J 1 , J 2 , J 3 , J 4 , J 5 , X 1 , Y, X 2 and R 4 Any defined combination of other variables in . Such combinations are contemplated and within the scope of the present disclosure.

[0284] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. It is not intended that the present disclosure be limited in any way to the list of exemplary substituents described herein.

[0285] The compounds disclosed herein may contain one or more asymmetric centers and / or axial chirality and may therefore exist in various isomeric forms, for example, enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, atropisomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure also includes the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers, including racemic mixtures. In the embodiments herein, unless otherwise clearly contrary to the context, when stereochemistry is specifically drawn, it is understood that with respect to that particular chiral center or axial chirality, the compound may be present primarily as the drawn stereoisomer, e.g., by weight, by HPLC area, or both, with less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other stereoisomers. In view of the present disclosure, including by using chiral HPLC, one skilled in the art can determine the presence and / or content of stereoisomers.

[0286] When a range of values ​​is listed, it is intended that every value and subrange within that range be included. For example, “C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3, C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 .

[0287] As used herein, the term "compound of the present disclosure" refers to a compound according to Formula I described herein (e.g., Formula I-1, I-2, I-3, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-J -E1, I-1-J-E2, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I Any compound of I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15 or I-1-H-1), any one of compound numbers 1-133, isotope-labeled compounds thereof (e.g., deuterated analogs in which one or more hydrogen atoms are replaced by deuterium atoms with an abundance higher than the natural abundance), possible stereoisomers thereof (including diastereomers, enantiomers and racemic mixtures), geometric isomers thereof, atropisomers thereof, tautomers thereof, conformational isomers thereof and / or pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). For the avoidance of doubt, compound No. 1-133 or compound No. 1-133 refers to compounds labeled as integers 1, 2, 3, ..., 133 as described herein, see, for example, the title compounds of the Examples and Table 1. For ease of description, the starting materials or intermediates of the synthesis may be labeled with an integer (compound number) followed by "-" and an additional numerical value, such as 1-1, 1-2, etc., as shown in the examples. The labels of such starting materials or intermediates of the synthesis should not be confused with compounds labeled only with integers. Hydrates and solvates of the compounds of the present disclosure are considered to be compositions of the present disclosure, in which the compounds are combined with water or solvents, respectively.

[0288] The compounds of the present disclosure may exist in isotopically labeled or enriched form, which contains one or more atoms having an atomic mass or mass number different from the atomic mass or mass number found most abundantly in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 32 P. 35 S.18 F. 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of the invention.

[0289] As used herein, the phrases "administration" of a compound, "administering" a compound, or other variations thereof, means providing the compound or a prodrug of the compound to a subject in need of treatment.

[0290] As used herein, the term "alkyl" used alone or as part of another group refers to a straight or branched aliphatic saturated hydrocarbon. In some embodiments, an alkyl group may include one to twelve carbon atoms (i.e., C 1-12 In one embodiment, the alkyl group is a straight chain C 1-10 In another embodiment, the alkyl group is a branched C 3-10 In another embodiment, the alkyl group is a straight chain C 1-6 In another embodiment, the alkyl group is a branched C 3-6 In another embodiment, the alkyl group is a straight chain C 1-4 In one embodiment, the alkyl group is a C alkyl group selected from the group consisting of methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl and isobutyl. 1-4 Alkyl. As used herein, the term "alkylene," used alone or as part of another group, refers to a divalent group derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, and the like.

[0291] As used herein, unless otherwise indicated, the term "heteroalkyl" alone or in combination with another term refers to a stable straight or branched chain alkyl group, for example, having 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of which have been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom S, O, P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the rest of the molecule. 1-4Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups, such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl groups, such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, or -CH2-CH2-S(O)2-CH3, C2 heteroalkyl groups, such as -O-CH2-CH3, and C1 heteroalkyl groups, such as -O-CH3. Similarly, the term "heteroalkylene" by itself or as part of another substituent refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). In addition, for alkylene and heteroalkylene linking groups, the direction in which the chemical formula of the linking group is written does not imply a direction of the linking group. When referring to "heteroalkyl", followed by reference to a specific heteroalkyl group, such as -NR'R", etc., it is understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Instead, specific heteroalkyl groups are listed to enhance illustrativeness. Therefore, the term "heteroalkyl" should not be interpreted herein to exclude specific heteroalkyl groups, such as -NR'R", etc.

[0292] As used herein, the term "alkenyl" when used alone or as part of another group refers to a straight or branched chain aliphatic hydrocarbon containing one or more, for example one, two or three, carbon-carbon double bonds. In one embodiment, alkenyl is C 2-6 In another embodiment, alkenyl is C 2-4 Alkenyl. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0293] As used herein, the term "alkynyl" when used alone or as part of another group refers to a straight or branched chain aliphatic hydrocarbon containing one or more, for example one to three, carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-6 In another embodiment, alkynyl is C 2-4 Alkynyl. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

[0294] As used herein, the term "alkoxy" used alone or as part of another group refers to a radical of the formula OR a1 A group in which R a1 It is an alkyl group.

[0295] As used herein, the term "haloalkyl" used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In a preferred embodiment, a haloalkyl group is an alkyl group substituted with one, two or three fluorine atoms. In one embodiment, a haloalkyl group is C 1-4 Halogenated alkyl.

[0296] "Carbocyclyl" or "carbocyclic" when used alone or as part of another group refers to a non-aromatic cyclic hydrocarbon radical having 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system ("Carbocyclyl" or "carbocyclic"). 3-10 A carbocyclyl group may be monocyclic (a "monocyclic carbocyclyl"), bicyclic or polycyclic, may contain fused, bridged or spiro ring systems and may be saturated or may be partially unsaturated. As used herein, a bicyclic or polycyclic carbocyclyl group may have one or more rings that are aromatic, provided that the bicyclic or polycyclic carbocyclyl group as a whole is not an aromatic ring system, and the point of attachment may be on any ring of the bicyclic or polycyclic carbocyclyl group. For example, a fused bicyclic carbocyclyl group may include those fused ring systems in which one of the two rings is phenyl, in which the point of attachment may be on either of the two rings. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

[0297] In some embodiments, a "carbocyclyl" is fully saturated, which is also referred to as a cycloalkyl. In some embodiments, a cycloalkyl may have 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the cycloalkyl group is a monocyclic ring. In some embodiments, the cycloalkyl group can be a bicyclic ring, which can be a fused, bridged, or spiro-linked bicyclic ring.

[0298] Unless otherwise indicated or contrary to the context, "heterocyclyl" or "heterocyclic" used alone or as part of another group refers to a group having a 3- to 10-membered non-aromatic ring system with ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). Heterocyclyls or heterocycles having a ring size different from that of a 3-10 membered heterocyclyl are designated with a different ring size designation when applicable. It will be understood by those skilled in the art that such heterocyclyls of different ring sizes are also non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom if valence permits. The heterocyclyl group may be monocyclic ("monocyclic heterocyclyl"), bicyclic or polycyclic, including fused, bridged or spiro ring systems, such as fused, bridged or spiro bicyclic ring systems ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. The heterocyclyl bicyclic ring system may contain one or more ring heteroatoms in one or both rings, wherein the point of attachment is on either of the two rings. For example, fused heterocyclyl bicyclic ring systems include those fused bicyclic ring systems in which one ring is a monocyclic carbocycle as defined herein, wherein the point of attachment may be on the carbocycle or on a ring having one or more ring heteroatoms. As used herein, the bicyclic or polycyclic heterocyclyl may have one or more rings that are aryl or heteroaryl rings, provided that the bicyclic or polycyclic heterocyclyl as a whole is not a heteroaryl ring system, and the point of attachment may be on any ring of the bicyclic or polycyclic heterocyclyl. For example, fused heterocyclyl ring systems also include those having one or more rings that are aryl or heteroaryl rings, provided that the fused ring system as a whole is not a heteroaryl ring, wherein the point of attachment may be on any ring.

[0299] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thioethane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothiopyranyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepane, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxocanyl, and thiecanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (that is, 5,6-bicyclic heterocyclic groups herein) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to a benzene ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0300] "Aryl" used alone or as part of another group refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms (a "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (a "C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "aryl"; e.g., anthracenyl).

[0301] "Aralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more aryl groups, preferably, an alkyl group substituted with one aryl group. Examples of aralkyl groups include benzyl, phenethyl, and the like. When an aralkyl group is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl group may be optionally substituted.

[0302] Unless otherwise indicated or contrary to the context, "heteroaryl" used alone or as part of another group refers to the following groups: a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). Heteroaryl groups with ring sizes different from 5-10 membered heteroaryl groups are designated with different ring size designations when applicable. It should be understood by those skilled in the art that such heteroaryl groups of different ring sizes are also 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared in the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom if valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings, wherein the point of attachment may be on either ring. For example, in bicyclic heteroaryl groups where one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, etc.), the point of attachment may be on the ring with the heteroatoms (e.g., 2-indolyl) or the ring without the heteroatoms (e.g., 5-indolyl).

[0303] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0304] "Heteroaralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more heteroaryl groups, preferably, an alkyl group substituted with one heteroaryl group. When the heteroaralkyl group is referred to as optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl group may be optionally substituted.

[0305] As generally understood by those skilled in the art, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, respectively.

[0306] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic radical, optionally substituted heterocyclic radical, optionally substituted aryl and optionally substituted heteroaryl, refer to each group that is unsubstituted or substituted. In general, the term "substituted", whether or not there is the term "optional" in front, refers to at least one hydrogen present in a group (such as a carbon or nitrogen atom) being replaced by an allowed substituent, the allowed substituent being able to produce a substituent of a stable compound after, for example, a compound that will not spontaneously transform by, for example, rearrangement, cyclization, elimination or other reactions. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent at each position may be the same or different. Typically, when substituted, the optionally substituted group herein may be substituted by 1-5 substituents. In some embodiments, the two substituents can be taken together with the middle atom to form an optionally substituted ring system, such as an optionally substituted 3-8 membered carbocyclic ring, an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted aryl or an optionally substituted heteroaryl ring. If applicable, the substituents can be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents or sulfur atom substituents.

[0307] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if they are chemically permitted and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties are or can be caused to remain substantially unchanged for a period of time sufficient to permit the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0308] In some embodiments, the "optionally substituted" alkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy or heterocyclic groups herein may be unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: F, Cl, -OH, protected hydroxy, oxo (if applicable), NH2, protected amino, NH(C 1-4 Alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 Alkyl)), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from O, S and N, 3-7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyloxy, phenyl, heteroaryl and heterocyclyl is optionally substituted with 1, 2 or 3 substituents independently selected from: F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl (such as CF3), C 1-4 Alkoxy and fluorine substituted C 1-4 In some embodiments, the "optionally substituted" aryl or heteroaryl groups herein may be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: F, Cl, -OH, -CN, NH2, protected amino, NH(C 1-4 Alkyl) or its protected derivative, N(C 1-4 Alkyl ((C 1-4 alkyl), -S(=O)(C 1-4 Alkyl), -SO2(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from O, S and N, 3-7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyloxy, phenyl, heteroaryl and heterocyclyl is optionally substituted with 1, 2 or 3 substituents independently selected from: F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C1-4 Alkyl, C 1-4 Alkoxy and fluorine substituted C 1-4 Alkoxy.

[0309] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb , -SH, -SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc 2. -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2, -OC(=O)N(R bb )2.-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2, -C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2.-NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb S02R aa 、-NR bb S02R aa 、-SO2N(R bb 2. -SO2R aa 、-SO2OR aa 、-OSO2Raa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb)2 )2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc )、C1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is a counterion; or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN (R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or = NOR cc Replacement;

[0310] R aa Each instance of is independently selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0311] R bb Each instance of is independently selected from hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SORaa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc ,-P(=O)(R aa )2.-P(=O)(OR cc )2、-P(=O)(N(R cc) 2)2、C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is the counter ion;

[0312] R cc Each instance of is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0313] R dd Each instance of is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2、-N(R ff )3 + X - 、-N(OR ee )R ff , -SH, -SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(＝ O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2, -OC(=O)N(R ff )2.-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2.-NR ff C(=NR ff )N(R ff )2.-NR ff S02R ee 、-SO2N(R ff 2. -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3.-OSi(R ee )3. -C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)(OR ee )2. -P(=O)(R ee )2.-OP(=O)(R ee )2.-OP(=O)(OR ee 2. C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R ggGroup substitution, or two geminal R dd Substituents may be linked to form =O or =S; where X - is the counter ion;

[0314] R ee Each instance of is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0315] R ff Each instance of is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution; and

[0316] R gg Each instance of is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6Alkyl)2, -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - It is a counter ion.

[0317] A "counterion" or "anionic counterion" is a negatively charged group that is combined with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., include one negative formal charge). Anionic counterions can also be multivalent (i.e., include more than one negative formal charge), such as divalent or trivalent. Exemplary counterions include halides (e.g., F - , Cl - Br - ,I - )、NO3 - 、ClO4 - OH - 、H2PO4 - 、HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - PF4 - PF6 - 、AsF6 - 、SbF6 - 、B[3,5-(CF3)2C6H3]4] - ,BPh4 - 、Al(OC(CF3)3)4 - and carborane anions (e.g. CB 11 H 12 - or (HCB 11 Me5Br6) - ). Exemplary counterions that may be multivalent include CO3 2- 、HPO4 2- PO43- 、B4O7 2- 、SO4 2- 、S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carborane.

[0318] "Halo" or "halogen" refers to fluorine (F, -F), chlorine (Cl, -Cl), bromine (Br, -Br) or iodine (I, -I).

[0319] "Acyl" refers to a group selected from -C(=O)R aa 、-CHO、-CO2R aa 、-C(=O)N(R bb )2, -C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2, -C(=O)NR bb S02R aa 、-C(=S)N(R bb )2, -C(=O)SR aa or -C(=S)SR aa The part of R aa and R bb As defined herein.

[0320] The nitrogen atoms may be substituted or unsubstituted where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SORaa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)(OR cc )2. -P(=O)(R aa )2、-P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R groups connected to the nitrogen atom cc The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc and R dd As defined above.

[0321] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups are well known in the art and are included in Protective Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those that form carbamates, such as carboxybenzyloxy (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butoxycarbonyl (BOC) groups, Troc, 9-fluorenylmethoxycarbonyl (Fmoc) groups, etc., those that form amides, such as acetyl, benzoyl, etc., those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc., those that form sulfonamides, such as toluenesulfonyl (tosyl), nitrobenzenesulfonyl (Nosyl), etc., and others, such as p-methoxyphenyl.

[0322] Exemplary oxygen atom substituents include, but are not limited to, -R aa 、-C(=O)SR aa 、-C(=O)R aa 、-CO2R aa、-C(=O)N(R bb )2, -C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2, -S(=O)R aa 、-SO2R aa 、-Si(R aa )3. -P(R cc )2. -P(R cc )3 + X - 、-P(OR cc )2、-P(OR cc )3 + X - ,-P(=O)(R aa )2.-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - , R aa , R bb and R cc As defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxy protecting group). Oxygen protecting groups are well known in the art and are included in Protective Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Those described in detail in , edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl (e.g., 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc., silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc., acetals or ketals, such as tetrahydropyran (THP), esters, such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, etc., carbonates, sulfonates, such as methanesulfonate (mesylate), benzylsulfonate, tosylate (Ts), etc.

[0323] The term "leaving group" is given its common meaning in the field of synthetic organic chemistry, for example, it can refer to an atom or group that can be replaced by a nucleophilic reagent. For example, see Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arylsulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxylamino, 9-phenylxanthracene (pixyl) and haloformate.

[0324] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art.

[0325] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one valence change (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on a variety of factors, including temperature, solvent, and pH. Tautomerism reactions (i.e., reactions that provide tautomeric pairs) can be catalyzed by acids or bases. Exemplary tautomerism reactions include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerism reactions.

[0326] As used herein, the term "subject" (or "patient" herein) refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.

[0327] As used herein, the terms "treat", "treating", "treatment", etc. refer to the elimination, reduction, or amelioration of a disease or condition, and / or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition, or symptoms associated therewith. As used herein, the terms "treat", "treating", "treatment", etc. may include "prophylactic treatment," which refers to reducing the likelihood of redevelopment of a disease or condition, or the likelihood of recurrence of a previously controlled disease or condition, in a subject who does not have the disease or condition but is at risk of redeveloping the disease or condition or recurring the disease or condition or is susceptible to redeveloping the disease or condition or recurring the disease or condition. The terms "treatment" and synonyms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0328] As used herein, the singular forms "a," "an," and "the" include plural references unless expressly stated or unambiguously clear from the context that a different intention is intended.

[0329] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0330] The titles and subtitles are used only for convenience and / or formal compliance, do not limit the subject technology, and are not associated with the interpretation of the subject technology description. In various embodiments, the features described under one title or one subtitle of the present disclosure can be combined with the features described under other titles or subtitles. In addition, all features under a single title or a single subtitle are not necessarily used together in an embodiment.

[0331] Example

[0332] The various starting materials, intermediates and compounds of the preferred embodiments can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography when appropriate. The characterization of these compounds can be carried out using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance and various other spectral analyses. Exemplary embodiments of the steps for carrying out the synthesis of the products described herein are described in more detail below.

[0333] Example 1 Synthesis of Compound 1

[0334]

[0335] Step 1: To a solution of spiro[2.2]pentane-1-carboxylic acid (6.16 g, 55 mmol) in dichloromethane (100 mL) was added oxalyl chloride (21 g, 165 mmol) at 0°C. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane and a 7M solution of ammonia in methanol was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to afford 1-1.

[0336] Step 2: To a solution of ethyl 4,6-dihydroxypyridazine-3-carboxylate (23.2 g, 126 mmol) in tetrahydrofuran (230 mL) and methanol (130 mL) was added a solution of lithium hydroxide (7.57 g, 315 mmol) in water (90 mL) at room temperature. The reaction mixture was stirred for 4 hours. The volatiles were removed under vacuum. The residue was acidified with 6N hydrochloric acid solution at 0°C (pH <1) and stirred at room temperature for 30 minutes. The precipitate was filtered, washed with 1N hydrochloric acid, and dried under vacuum for 2 hours. The substance was dissolved in dichloromethane / methanol (3 / 1) and stirred at room temperature for 30 minutes. The mixture was filtered and washed with dichloromethane / methanol (3 / 1) to give 1-2.

[0337] Step 3: N, N-diethylaniline (13.8 g, 92.3 mmol) was added to a mixture of 1-2 (14.4 g, 92.3 mmol) in phosphorus oxychloride (200 mL) at room temperature. The mixture was stirred at 110 ° C for 2 hours. The phosphorus oxychloride was removed in a rotary evaporator and the remaining crude product was co-evaporated with 1,2-dichloroethane. The reaction mixture was dissolved in tetrahydrofuran (200 mL), and deuterated methylamine hydrochloride (methan-d3-amine) (6.51 g, 92.3 mmol) and N, N-diisopropylethylamine (29.8 g, 230.7 mmol) were added at 0 ° C. The mixture was stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and brine (brine), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 1-3.

[0338] Step 4: Triethylamine (24.4 g, 242 mmol) and pivaloyl chloride (25.6 g, 212 mmol) were added dropwise to a solution of 5-methoxypyridine-2-amine (25 g, 202 mmol) in dichloromethane (500 mL) at 0 ° C. The reaction was stirred at room temperature for 1 hour. The mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 1-4.

[0339] Step 5: At -78 ° C and N2 atmosphere, tert-butyl lithium (38 mL, 50 mmol) was added dropwise to a solution of 1-4 (4.16 g, 20 mmol) in diethyl ether (120 mL), and the reaction was stirred at -78 ° C for 3 hours. 1,2-dimethyl disulfide (2.82 g, 30 mmol) was added dropwise to the above mixture at -78 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to give 1-5.

[0340] Step 6: A mixture of 1-5 (3.3 g, 13 mmol) and 2N HCl (65 mL, 130 mmol) was stirred at 100 °C overnight. The mixture was cooled to room temperature and extracted with methyl tert-butyl ether. The aqueous layer was adjusted to pH 7 with saturated aqueous sodium carbonate solution and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 1-6.

[0341] Step 7: To a mixture of 1-3 (518 mg, 2.5 mmol) and 1-6 (447 mg, 2.6 mmol) in tetrahydrofuran (25 mL) was added dropwise a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (6.2 mL, 6.2 mmol) at 0°C under N2 atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with water and then filtered. The crude filter cake was slurried with acetonitrile, filtered and dried to give 1-7.

[0342] Step 8: 1-1 (112 mg, 1 mmol), cesium carbonate (434 mg, 1.34 mmol), tris(dibenzylideneacetone)dipalladium (184 mg, 0.2 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (116 mg, 0.2 mmol) were added to a mixture of 1-7 (230 mg, 0.67 mmol) in dioxane (3 mL). The reaction mixture was stirred at 145 ° C for 1 hour under N2 atmosphere and microwave conditions. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / ethyl acetate = 1 / 1) to give 1-8.

[0343] Step 9: Sodium tungstate (86 mg, 0.29 mmol), 30% aqueous hydrogen peroxide solution (657 mg, 5.8 mmol) were added dropwise to a mixture of 1-8 (122 mg, 0.29 mmol) in acetic acid (15 mL) at room temperature. The reaction mixture was stirred for 3 hours. The reaction was diluted with water and quenched with saturated aqueous sodium thiosulfate solution. The mixture was adjusted to pH~8 with saturated aqueous sodium carbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% formic acid in water: 5%~95%) to give 1. LCMS (ESI, m / z): [M+H] + =450.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.80 (s, 1H), 11.12 (s, 1H), 9.11-9.08 (m, 2H), 8.35 (d, J = 2.8Hz, 1H), 7.76 (d,J=3.2Hz,1H),3.89(s,3H),3.30-3.29(m,3H),2.42-2.39(m,1H),1.37-1.31(m,2H),0.88-0.70(m,4H).

[0344] Example 2 Synthesis of Compound 2

[0345]

[0346] Step 1: To a solution of spiro[2.2]pentane-1-carboxylic acid (2.9 g, 25.9 mmol) and naphthalene-2-ylmethanol (4.91 g, 31.1 mmol) in tetrahydrofuran (80 mL) was added triphenylphosphine (8.14 g, 31.1 mmol) and di-tert-butyl azodicarboxylate (7.15 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=10 / 1) to give 2-0. By preparative SFC ( IG, separation of the racemic products using supercritical CO2 / MeOH) afforded 2-1 and 2-2.

[0347] 2-1: Optical rotation: [α] D 20 77.3 (c 0.8, MeOH). Chiral SFC analysis: 99.46% ee. Retention time on ReprosilChiral-AM (similar to Daicel chiralpak AD) 100×3 mm 3 μm (35° C.) 1.578 min; mobile phase: EtOH (+0.1% DEA) in CO 2 , 1800 psi, 1.5 mL / min.

[0348] 2-2: Optical rotation: [α] D 20 -78.4 (c 0.8, MeOH). Chiral SFC analysis: 98.2% ee. Retention time on ReprosilChiral-AM (similar to Daicel chiralpak AD) 100×3 mm 3 μm (35° C.) 1.841 min; mobile phase: EtOH (+0.1% DEA) in CO 2 , 1800 psi, 1.5 mL / min.

[0349] Step 2: To a solution of 2-2 (2.9 g, 11.5 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL) was added 1N aqueous lithium hydroxide solution (34.5 mL, 34.5 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 3 hours. The volatiles were removed under vacuum and the residue was diluted with water. The aqueous layer was washed with dichloromethane, acidified with 1N hydrochloric acid, and then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2-3.

[0350] Step 3: To a solution of 2-3 (1.0 g, 8.9 mmol) in dichloromethane (30 mL) was added oxalyl chloride (1.47 g, 1.16 mmol) at room temperature. The mixture was stirred for 3 hours. The volatiles were removed under vacuum. The resulting mixture was dissolved in dichloromethane and then a 7M solution of ammonia in methanol (30 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum to give 2-4.

[0351] According to the synthetic procedure of compound 1 in Example 1, compound 2 was prepared from 2-4. LCMS (ESI, m / z): [M+H] + =450.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.80(s,1H),11.12(s,1H),9.10(s,1H),9.09(s,1H),8.36(d,J=3.2Hz,1H),7.76(d ,J=3.2Hz,1H),3.89(s,3H),3.30(s,3H),2.44-2.39(m,1H),1.39-1.31(m,2H),0.89-0.79(m,3H),0.76-0.68(m,1H).

[0352] Example 3 Synthesis of Compound 3

[0353]

[0354] Step 1: Under N2 atmosphere at 40°C, tert-butyl nitrite (15.5 g, 150 mmol) was added dropwise to a solution of 3-amino-2-bromo-5-fluoropyridine (19.1 g, 100 mmol) and dimethyl disulfide (18.8 g, 200 mmol) in dichloroethane (300 mL) within 1 hour. The reaction mixture was stirred for 1 hour. The mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to obtain 3-1.

[0355] Step 2: A mixture of 3-1 (3.7 g, 6.7 mmol), benzophenone imine (3.63 g, 20 mmol), sodium tert-butoxide (2.4 g, 25 mmol), tris(dibenzylideneacetone)dipalladium (1.53 g, 1.67) mmol) and 1,1'-binaphthyl-2.2'-diphenylphosphine (1.04 g, 1.67 mmol) in toluene (50 mL) was stirred at 100 ° C. and N2 atmosphere for 3 hours. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=10 / 1) to give 3-2.

[0356] Step 3: 4N HCl solution (24 mL, 96.3 mmol) was added to a suspension of 3-2 (3.1 g, 9.63 mmol) in dioxane (24 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and diluted with ethyl acetate. The mixture was adjusted to pH ~ 8 with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 3-3.

[0357] Step 4: To a mixture of 1-3 (628 mg, 3 mmol) and 3-3 (501 mg, 3.15 mmol) in tetrahydrofuran (25 mL) was added dropwise a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (8 mL, 8 mmol) at 0°C under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and filtered. The filter cake was slurried with acetonitrile, filtered and dried to give 3-4.

[0358] 3 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): [M+H] + =438.1; 1H-NMR (400MHz, DMSO-d6, ppm): δ12.02(s,1H),11.19(s,1H),9.26(s,1H),9.14(s,1H),8.67(d,J=2.8Hz ,1H),8.13(dd,J=7.6,2.8Hz,1H),3.35(s,3H),2.43-2.41(m,1H),1.38-1.32(m,2H),0.88-0.65(m,4H). 19 F-NMR (376MHz, DMSO-d6, ppm): δ-133.11 (1F).

[0359] Example 4 Synthesis of Compound 5

[0360]

[0361] Step 1: To a solution of 2-1 (2.7 g, 10.7 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL) was added a 1 N solution of lithium hydroxide in water (32 mL, 32.1 mmol) at 0°C, then warmed to room temperature and stirred for 3 hours. The volatiles were removed in vacuo and diluted with water. The aqueous layer was washed with dichloromethane, then acidified with 1 N hydrochloric acid and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 5-1.

[0362] Step 2: To a solution of 5-1 (1.0 g, 8.9 mmol) in dichloromethane (30 mL) was added oxalyl chloride (1.47 g, 1.16 mmol) at room temperature and then stirred for 3 hours. The volatiles were removed under vacuum. The resulting mixture was dissolved in dichloromethane (10 mL) and then a 7M solution of ammonia in methanol (30 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo to give 5-2.

[0363] Step 3: To a solution of 3-fluoro-2-nitropyridine (30 g, 211.3 mmol) in dimethylformamide (300 mL) was added sodium thiomethoxide (111 g, 317 mmol, 20% aqueous solution) dropwise at room temperature. The mixture was stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 5-3.

[0364] Step 4: To a mixture of 5-3 (42 g, 211.3 mmol) in methanol (500 mL) was added water (125 mL), and ammonium chloride (56.5 g, 1057 mmol) and iron powder (60.9 g, 1057 mmol) were added in batches. The reaction mixture was stirred at 65 ° C for 1 hour. The mixture was diluted with ethyl acetate and filtered. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to obtain 5-4.

[0365] Step 5: To a solution of 5-4 (1.4 g, 10 mmol) in dichloromethane (30 mL) was added N-bromosuccinimide (2.14 g, 12 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=10 / 1) to give 5-5.

[0366] Step 6: To a mixture of 5-5 (766 mg, 3.5 mol), cyclopropylboronic acid (1.2 g, 14 mmol), tricyclohexylphosphine (196 mg, 0.7 mmol), tri(dibenzylideneacetone)dipalladium (320 mg, 0.35 mmol) in toluene / water (25 mL / 4 mL) was added tripotassium phosphate (3.71 g, 17.5 mmol). The mixture was stirred at 100 ° C for 6 hours under N2 atmosphere. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 5 / 1) to give 5-6.

[0367] Step 7: To a mixture of 1-3 (209 mg, 1 mmol) and 5-6 (189 mg, 1.05 mmol) in tetrahydrofuran (10 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.5 mL, 2.5 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with water, acidified to pH ˜9 with 1N hydrochloric acid at 0°C, filtered and washed with water. The precipitate was dried to give 5-7.

[0368] Step 8: 5-2 (60 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.054 mmol), cesium carbonate (235 mg, 0.72 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.108 mmol) were added to a mixture of 5-7 (127 mg, 0.36 mmol) in dioxane (5 mL). The reaction mixture was stirred at 145 ° C for 1 hour under N2 atmosphere and microwave conditions. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / ethyl acetate = 1: 1) to give 5-8.

[0369] Step 9: Sodium tungstate (69 mg, 0.234 mmol) and 30% aqueous hydrogen peroxide solution (531 mg, 4.68 mmol) were added dropwise to a mixture of 5-8 (100 mg, 0.234 mmol) in acetic acid (4 mL) at room temperature. The reaction mixture was stirred for 1 hour. The reaction was diluted with water, quenched with saturated aqueous sodium thiosulfate solution, adjusted to pH ~ 9 with sodium carbonate, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol = 40: 1) to give 5. LCMS (ESI, m / z): [M+H] + =460.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.94(s,1H),11.17(s,1H),9.33(s,1H),9.12(s,1H),8.43(d,J=1.6Hz,1H),7.81(d,J= 2.0Hz,1H),3.28(s,3H),2.45-2.39(m,1H),2.13-2.02(m,1H),1.40-1.31(m,2H),1.04-0.95(m,2H),0.89-0.70(m,6H).

[0370] Example 5 Synthesis of Compound 6

[0371]

[0372] Step 1: To a solution of 2-bromo-3-fluoroisonicotinic acid (24.8 g, 113 mmol) in dimethylacetamide (150 mL) was added dropwise 20% aqueous sodium thiomethoxide solution (98.9 g, 282.5 mmol) at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, adjusted to pH ˜2 with 1 M aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 6-1.

[0373] Step 2: To a solution of 6-1 (23 g, 93 mmol) in tetrahydrofuran (200 mL) was added N,N'-carbonyldiimidazole (22.6 g, 139.5 mmol) at room temperature. The mixture was stirred for 3 hours. The mixture was added dropwise to a solution of sodium borohydride (17.67 g, 465 mmol) in water (200 mL) at 0°C. After stirring for 1 hour, the reaction was quenched with 2M hydrochloric acid, the pH was adjusted to 8 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 6-2.

[0374] Step 3: To a solution of 6-2 (17.8 g, 43 mmol) and imidazole (6.2 g, 91.2 mmol) in dichloromethane (200 mL) was added dropwise tert-butylchlorodiphenylsilane (23 g, 83.6 mmol) under N2 atmosphere and 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was washed with water, saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=4 / 1) to give 6-3.

[0375] Step 4: A solution of 6-3 (23.9 g, 50.5 mmol), benzophenone imine (10 g, 55.6 mmol), sodium tert-butoxide (6.3 g, 65.15 mmol), tris(dibenzylideneacetone)dipalladium (1.39 g, 1.52 mmol) and 1.1'-binaphthyl-2.2'-diphenylphosphine (1.88 g, 3.03 mmol) in toluene (200 mL) was stirred at 100 ° C. and N2 atmosphere for 3 hours. The mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in dioxane and 3M aqueous hydrochloric acid solution. The mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH~8 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=1 / 1) to give 6-4.

[0376] Compound 6-6 was prepared from 6-4 according to the synthetic procedure of compound 1-8 in Example 1.

[0377] Compound 6-7 was prepared from 6-6 according to the synthetic procedure of compound 1 in Example 1.

[0378] Step 5: To a solution of 6-7 (20 mg, 0.029 mmol) in tetrahydrofuran (0.5 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.03 mL, 0.03 mmol) at room temperature. The mixture was stirred for 1 hour. The mixture was diluted with water and stirred for 10 minutes, filtered and washed with water. The residue was purified by preparative HPLC (acetonitrile / 0.05% formic acid in water: 5% to 95%) to give 6. LCMS (ESI, m / z): [M+H] + =450.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.86 (s, 1H), 11.15 (s, 1H), 9.08 (s, 1H), 9.06 (s, 1H), 8.51 (d, J = 5.2Hz, 1H), 7.55 (d,J=4.8Hz,1H),5.61(s,1H),4.93(s,2H),3.30(s,3H),2.42-2.39(m,1H),1.39-1.28(m,2H),0.91-0.65(m,4H).

[0379] Example 6 Synthesis of Compound 7

[0380]

[0381] Compound 7-1 was prepared from 20-1 according to the synthetic procedure of compound 1-8 in Example 1.

[0382] Step 1: To a suspension of 7-1 (40 mg, 0.103 mmol) in methanol (100 mL) and dichloromethane (5 mL) was added (diacetoxyiodo)benzene (83 mg, 0.258 mmol) and ammonium carbamate (20 mg, 0.258 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC (acetonitrile / 0.05% formic acid in water: 5% to 95%) to give 7. LCMS (ESI, m / z): [M+H] + =419.1; 1H-NMR (400MHz, DMSO-d6, ppm): δ11.96(s,1H),11.19(s,1H),9.45(s,1H),9.09(s,1H),8.54(dd,J=4.8,1.6Hz,1H),8.29(dd,J=8.0,1.6H z,1H),7.30(dd,J=8.0,4.8Hz,1H),4.81(s,1H),3.20(s,3H),2.48-2.44(m,1H),1.45-1.32(m,2H),0.98-0.83(m,3H),0.80-0.68(m,1H).

[0383] Example 7 Synthesis of Compound 8

[0384]

[0385] Step 1: To a solution of 6-6 (2.1 g, 3.2 mmol) in tetrahydrofuran (20 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (3.2 mL, 3.2 mmol) at room temperature. The mixture was stirred for 1 hour. The reaction was diluted with water, filtered and washed with water. The filter cake was slurried with methanol, filtered and dried to give 8-1.

[0386] Step 2: To a suspension of 8-1 (834 mg, 2 mmol) in tetrahydrofuran (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8 mmol) and diphenylphosphoryl azide (1.1 g, 4 mmol) at room temperature. The mixture was stirred under N2 atmosphere for 3 hours. The mixture was diluted with water, filtered and washed with water. The filter cake was slurried with methanol, filtered and dried to give 8-2.

[0387] Step 3: To a mixture of 8-2 (221 mg, 0.5 mmol) in acetic acid (20 mL) was added sodium tungstate (147 mg, 0.5 mmol), 30% aqueous hydrogen peroxide solution (1.13 g, 10 mmol) at room temperature, and then stirred for 0.5 hours. The mixture was diluted with water, adjusted to pH ~ 8 with sodium carbonate, and quenched with saturated aqueous sodium thiosulfate solution. The crude product was filtered and washed with water. The filter cake was slurried with methanol to give 8-3.

[0388] Step 4: A suspension of 8-3 (115 mg, 0.25 mmol) and iron phthalocyanine (14 mg, 0.025 mmol) in dioxane (30 mL) was stirred at 100 ° C. under N2 atmosphere for 3 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol=10 / 1) to give 8. LCMS (ESI, m / z): [M+H] +=431.2; 1 H-NMR (400MHz, CDCl3, ppm): δ12.63(s,1H),10.07(s,1H),8.94(s,1H),8.56(d,J=5.2Hz,1H),8.22(s,1H),7.06(d,J=5.2 Hz,1H),4.92-4.69(m,2H),3.68-3.66(m,3H),2.22-2.18(m,1H),1.69-1.64(m,1H),1.53-1.49(m,1H),1.16-0.94(m,4H).

[0389] Example 8 Synthesis of Compound 9

[0390]

[0391] Step 1: To a solution of potassium hydroxide (60.5 g, 1.08 mol) in water (100 mL) was added 6-chlorobenzo[d]thiazole-2-amine (10.0 g, 54.1 mmol). The mixture was stirred at 100 ° C for 6 hours. The mixture was cooled to room temperature. Then iodomethane (8.4 g, 59.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with tert-butyl methyl ether. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=5 / 1) to obtain 9-1.

[0392] Compound 9 was prepared from 9-1 according to the synthetic procedure of compound 5 in Example 4. LCMS (ESI, m / z): [M+H] + =453.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.20(s,1H),11.10(s,1H),9.09(s,1H),8.06(s,1H),7.91-7.78(m,2H),7. 73(d,J=8.4Hz,1H),3.20(s,3H),2.41-2.35(m,1H),1.35-1.27(m,2H),0.88-0.76(m,3H),0.74-0.65(m,1H).

[0393] Example 9 Synthesis of Compound 10

[0394]

[0395] Step 1: At 0°C, potassium tert-butoxide (4.93 g, 44 mmol) was added to a solution of 2-amino-4-chlorobenzenethiol (6.4 g, 40 mmol) in ethanol (80 ml). The mixture was stirred for 75 minutes. Iodomethane (11.36 g, 80 mmol) was then added and the reaction mixture was stirred for 16 hours. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=5 / 1) to give 10-1.

[0396] According to the synthetic procedure of compound 5 in Example 4, compound 10 was prepared from 10-1. LCMS (ESI, m / z): [M+H] + =453.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.21(s,1H),11.15(s,1H),9.09(s,1H),8.12(s,1H),7.91(d,J=8.4Hz,1H),7.82(s ,1H),7.48(d,J=8.0Hz,1H),3.17(s,3H),2.41-2.37(m,1H),1.36-1.28(m,2H),0.88-0.78(m,3H),0.73-0.66(m,1H).

[0397] Example 10 Synthesis of Compound 11

[0398]

[0399] Step 1: To a mixture of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (702 mg, 3 mmol) and 2-(methylsulfonyl)aniline (567 mg, 3.3 mmol) in acetonitrile (15 mL) was added N,N-diisopropylethylamine (503 mg, 3.9 mmol) at 25° C. The mixture was stirred under N2 atmosphere for 2 minutes and then purified by preparative HPLC (acetonitrile / 0.05% TFA in water / : 5% to 95%) to give 11-1.

[0400] Step 2: 3-chloroperoxybenzoic acid (621 mg, 3.0 mmol) was added to a solution of 11-1 (450 mg, 1.2 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 25 ° C for 30 minutes. The mixture was concentrated and then dissolved in ethanol and water. Sodium hydroxide (240 mg, 6 mmol) was added to the above mixture at 0 ° C. The mixture was stirred at 25 ° C for 30 minutes. The mixture was diluted with water and washed with dichloromethane. The aqueous layer was neutralized with acetic acid to pH ~ 7 and purified by preparative HPLC (acetonitrile / 0.05% TFA in water / : 5% ~ 95%) to obtain 11-2.

[0401] Step 3: A mixture of 11-2 (104 mg, 0.33 mmol) and N,N-diethylaniline (50 mg, 0.33 mmol) in phosphoryl chloride (2 mL) was stirred at 80 ° C under N2 atmosphere for 2 hours. After removing the solvent, the residue was dissolved in tetrahydrofuran (2 mL). Deuterated methylamine hydrochloride (23.6 mg, 0.33 mmol) and N,N-diisopropylethylamine (213 mg, 1.65 mmol) were added to the above mixture at 0 ° C. The reaction mixture was stirred at N2 atmosphere and 25 ° C for 30 minutes. The mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% TFA in water: 5% to 95%) to give 11-3.

[0402] Compound 11 was prepared from 11-3 according to the synthetic procedure of compound 1-8 in Example 1. LCMS (ESI, m / z): [M+H] + =420.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.70(s,1H),11.02(s,1H),9.13(s,1H),8.65-8.54(m,1H),7.93-7.82(m,1H),7.72-7.59(m,1H) ),7.42-7.28(m,1H),3.19(s,3H),2.52-2.44(m,1H),1.41-1.37(m,1H),1.31-1.25(m,1H),0.88-0.76(m,3H),0.73-0.66(m,1H).

[0403] Example 11 Synthesis of Compound 12

[0404]

[0405] Step 1: To a solution of 4,6-dichloronicotinic acid (5 g, 26 mmol) in acetonitrile (50 mL) was added N,O-dimethylhydroxylamine hydrochloride (3.8 g, 39 mmol), N,N-diisopropylethylamine (10 g, 77.5 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.4 g, 27.4 mmol). The mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to give 12-1.

[0406] Step 2: Under N2 atmosphere and -15 ° C, a 1M solution of cyclopropylmagnesium bromide in THF (73 ml, 73 mmol) was added dropwise to a solution of 12-1 (5.68 g, 24.2 mmol) in tetrahydrofuran (25 ml). The mixture was allowed to warm to room temperature and stirred for 0.5 hours. The mixture was then poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=10 / 1) to give 12-2.

[0407] Step 3: At 0°C, sodium hydride (1.74 g, 43.5 mmol, 60% in mineral oil) was added in batches to a solution of 5-4 (1.2 g, 8.7 mmol) in dimethylformamide (30 ml). The mixture was stirred at 0°C for 0.5 hours, and then a solution of 12-2 (1.7 g, 7.9 mmol) in dimethylformamide (10 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was then poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to give 12-3.

[0408] According to the synthetic procedure of compound 1 in Example 1, compound 12 was prepared from 12-3. LCMS (ESI, m / z): [M+H] + =427.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.70(s,1H),10.77(s,1H),9.12(s,1H),9.01(s,1H),8.56(dd,J=4.8,2.0Hz,1H),8.22(dd,J=8.0,2.0Hz,1 H),7.28(dd,J=7.6,4.8Hz,1H),3.24(s,3H),2.94-2.90(m,1H),2.37-2.34(m,1H),1.35-1.28(m,2H),1.06-0.97(m,4H),0.86-0.68(m,4H).

[0409] Example 12 Synthesis of Compound 13

[0410]

[0411] Step 1: At -78 ° C and N2 atmosphere, n-butyl lithium (39 mL, 98 mmol) was added dropwise to a suspension of N- (pyridin-4-yl) pivalamide (7 g, 39 mmol) in tetrahydrofuran (150 mL). The mixture was warmed to 0 ° C and stirred for 3 hours. Dimethyl disulfide (11 g, 118 mmol) was added dropwise to the above mixture at -78 ° C. The mixture was warmed to room temperature and stirred for 0.5 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 5 / 1) to give 13-1.

[0412] Step 2: A mixture of 13-1 (2 g, 8.9 mmol) in 3N aqueous hydrochloric acid solution (30 mL) was stirred under reflux for 4 hours. After cooling to room temperature, the mixture was diluted with water and washed with tert-butyl methyl ether. The aqueous layer was adjusted to pH ~ 8 with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 13-2.

[0413] Compound 13 was prepared from 13-2 according to the synthetic procedure of compound 5 in Example 4. LCMS (ESI, m / z): [M+H] + =420.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.48(s,1H),11.36(s,1H),9.18(s,1H),8.92-8.58(m,2H),8.46-8.35(m,1H ),7.76-7.61(m,1H),3.26(s,3H),2.43-2.37(m,1H),1.40-1.28(m,2H),0.88-0.79(m,3H),0.74-0.66(m,1H).

[0414] Example 13 Synthesis of Compound 16

[0415]

[0416] To a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (224 mg, 2.0 mmol) in dichloromethane (4 mL) was added oxalyl chloride (762 mg, 6.0 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum. The resulting mixture was dissolved in dichloromethane (4 mL), and then a 7M solution of ammonia in methanol (6 mL, 42 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 0.5 hours. The solvent was removed in vacuo to give 16-1.

[0417] Compound 16 was prepared from 16-1 according to the synthetic procedure of compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + =450.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.83(s,1H),10.82(s,1H),9.14(s,1H),9.10(s,1H),8.37 (d,J=2.8Hz,1H),7.76(d,J=2.8Hz,1H),3.89(s,3H),3.30(s,3H),2.40(s,1H),2.10(s,6H).

[0418] Example 14 Synthesis of Compound 20

[0419]

[0420] Compound 20-1 was prepared from 1-3 according to the synthetic procedure of compound 1-7 in Example 1.

[0421] Step 1: To a mixture of 20-1 (700 mg, 2.24 mmol) and N,N-diisopropylethylamine (5.8 g, 44.9 mmol) in 1-methyl-2-pyrrolidone (5 mL) was added bicyclo[1.1.1]pentane-1-amine hydrochloride (4.04 g, 33.4 mmol) at room temperature. The mixture was stirred at 150 ° C for 24 hours in a sealed tube. The mixture was cooled, diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol=15 / 1) to give 20-2.

[0422] Compound 20 was prepared from 20-2 according to the synthetic procedure of compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + =392.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.99(s,1H),9.04(s,1H),8.55(dd,J=4.8,2.0Hz,1H),8.21(dd,J=7.6,1.6 Hz,1H),8.16(s,1H),7.97(s,1H),7.22(dd,J=8.0,4.8Hz,1H),3.32(s,3H),2.47-2.45(m,1H),2.09(s,6H).

[0423] Example 15 Synthesis of Compounds 21 and 22

[0424]

[0425] Step 1: To a solution of phenyl carbamate (2.1 g, 15.3 mmol) in dioxane (30 mL) was added cyclopropylamine (2.2 g, 38.3 mmol). The mixture was stirred at room temperature for 16 hours and concentrated. The residue was suspended in dichloromethane and sonicated. The resulting precipitate was collected by filtration to give 21-1.

[0426] Step 2: To a mixture of 20-1 (156 mg, 0.5 mmol) in dioxane (5 mL) was added 21-1 (125 mg, 1.25 mmol), tris(dibenzylideneacetone)dipalladium (68 mg, 0.075 mmol), sodium tert-butoxide (286 mg, 3.0 mmol) and 1.1'-binaphthyl-2.2'-diphenylphosphine (46 mg, 0.10 mmol). The reaction mixture was then stirred at 110°C for 1 hour under N2 atmosphere. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% TFA in water: 10% to 95%) to give 21-2 / 22-2 (20%).

[0427] Step 3: To a mixture of 21-2 (160 mg, 0.41 mmol, mixed with 22-2 at 20% of 22-2) in acetic acid (10 mL) was added sodium tungstate (122 mg, 0.41 mmol), 30% aqueous hydrogen peroxide solution at room temperature. The reaction mixture was stirred for 1 hour. The mixture was diluted with water, quenched with saturated aqueous sodium thiosulfate, adjusted to pH 9 with sodium carbonate, and extracted with dichloromethane / methanol (10 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% formic acid in water: 10% to 95%) to give 2.0 equivalents of 21 in the form of a formate salt and 2.0 equivalents of 22 in the form of a formate salt.

[0428] 2.0 equivalents of formate salt of 21: LCMS (ESI, m / z): [M+H] + =409.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.02(s,1H),9.62(s,1H),9.12(s,1H),-9.06(s,1H),8.58(d,J=3.2Hz,1H),8.42(s,2H),8 .23(d,J=7.6Hz,1H),7.68(s,1H),7.30-7.26(m,1H),3.30(s,3H),2.59-2.51(m,1H),0.66-0.59(m,2H),0.40-0.38(s,2H).

[0429] 2.0 equivalents of formate salt of 22: CMS (ESI, m / z): [M+H] + =366.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.00(s,1H),8.94(s,1H),8.58-8.55(m,1H),8.42(s,2H),8.22-8.18(m,2H),7 .62(s,1H),7.22(dd,J=8.0,J=4.8Hz,1H),3.32(s,3H),2.61-2.53(m,1H),0.75-0.70(m,2H),0.50-0.44(m,2H).

[0430] Example 16 Synthesis of Compound 25

[0431]

[0432] Compound 25-1 was prepared from 20-1 according to the synthetic procedure of compound 1 in Example 1.

[0433] Step 1: To a mixture of 25-1 (173 mg, 0.5 mmol) in dimethyl sulfoxide (4 mL) / water (0.4 mL) was added (3-methyl-1H-pyrazol-5-yl)boronic acid (157.5 mg, 1.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(I) (73 mg, 0.1 mmol) and potassium carbonate (207 mg, 1.5 mmol). The reaction mixture was stirred at 130 °C for 1 hour under N2 atmosphere and microwave conditions. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% formic acid in water: 15% to 95%) to give 25 as 2.0 equivalents of formate salt. LCMS (ESI, m / z): [M+H] + =391.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ13.00(s,1H),12.07(s,1H),9.34(s,1H),9.16(s,1H),8.64(d,J=3.6 Hz, 1H), 8.40 (s, 2H), 8.25 (d, J = 7.6Hz, 1H), 7.34-7.25 (m, 1H), 6.74 (s, 1H), 3.30 (s, 3H), 2.29 (s, 3H).

[0434] Example 17 Synthesis of Compound 37

[0435]

[0436] Step 1: Rhodium (II) acetate dimer (31.53 mg, 0.071 mmol) was added to a solution of 2,5-dihydrofuran (1.08 mL, 14.2 mmol) in dichloromethane (15 mL). A solution of ethyl 2-diazoacetate (1.5 mL, 14.2 mmol) in dichloromethane (7 mL) was added dropwise to the above solution over 0.5 hours. The reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10 / 1) to give 37-1.

[0437] Step 2: A mixture of 37-1 (200 mg, 1.28 mmol) and aqueous ammonia (10 mL) was stirred at room temperature for 72 hours. The mixture was concentrated to give 37-2.

[0438] Compound 37 was prepared from 37-2 according to the synthetic procedure of compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + =466.2; 1 H-NMR (400 MHz, DMSO-d 6, ppm): δ11.85(s,1H),11.30(s,1H),9.16(s,1H),9.12(s,1H),8.38(d,J=2.8Hz,1H),7.80(d,J=2.8 Hz, 1H), 3.93 (s, 3H), 3.83 (d, J = 8.4Hz, 2H), 3.66 (d, J = 8.4Hz, 2H), 3.34 (s, 3H), 2.25-1.97 (m, 3H).

[0439] Example 18 Synthesis of Compounds 39-41

[0440]

[0441] Step 1: Benzyl chloroformate (11.29 g, 66 mmol) was added to a suspension of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (12.3 g, 60 mmol) in dioxane (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL) at 0 ° C. The reaction was then stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 39-1.

[0442] Step 2: A mixture of 39-1 (12.1 g, 40 mmol), benzophenone imine (8.7 g, 48 mmol), cesium carbonate (19.6 g, 60 mmol), tris(dibenzylideneacetone)dipalladium (1.83 g, 2 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (2.3 g, 4 mmol) in dimethyl sulfoxide (200 mL) was stirred at 110 ° C. under N2 atmosphere for 24 hours. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was dissolved in dioxane (69 mL) and 3M hydrochloric acid (69 mL, 207 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was adjusted to pH ~ 8 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to ethyl acetate) to give 39-2.

[0443] Step 3: To a solution of 39-2 (4.25 g, 15 mmol) in acetic acid (50 mL) was added N-iodosuccinimide (4.05 g, 18 mmol) at room temperature. The reaction was then stirred for 16 hours. The mixture was diluted with water, adjusted to pH ~ 8 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to ethyl acetate) to give 39-3.

[0444] Step 4: To a mixture of 39-3 (4.9 g, 12 mmol) in dioxane (50 mL) was added methyl 3-mercaptopropionate (2.16 g, 18 mmol), tris(dibenzylideneacetone)dipalladium (550 mg, 0.6 mmol), ethyldiisopropylamine (3.1 g, 24 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (694 mg, 1.2 mmol). The mixture was stirred at 100 ° C for 5 hours under N2 atmosphere. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 4) to give 39-4.

[0445] Step 5: To a mixture of 39-4 (4 g, 10 mmol) in tetrahydrofuran (40 mL) was added potassium tert-butoxide (3.36 g, 30 mmol) at 0 ° C. The reaction was then stirred at room temperature for 1 hour. A solution of sodium hydroxide (800 mg, 20 mmol) in methanol (40 mL) and iodomethane (2.84 g, 20 mmol) were added to the above mixture, followed by stirring for 1 hour. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 3) to give 39-5.

[0446] Compound 39 was prepared from 39-5 according to the synthetic procedure of compound 5 in Example 4. LCMS (ESI, m / z): [M+H] + =609.3; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.06(s,1H),11.19(s,1H),9.72(s,1H),9.15(s,1H),8.14(s,1H),7.50-7.29(m,5H),5.13(s,2H ),4.77-4.59(m,2H),3.85-3.72(m,2H),3.30(s,3H),2.96-2.92(m,2H),2.49-2.43(m,1H),1.45-1.35(m,2H),0.95-0.70(m,4H).

[0447] Step 6: To a solution of 39 (152 mg, 0.25 mmol) in acetonitrile (10 mL) was added iodotrimethylsilane (300 mg, 1.5 mmol) at 0 ° C. under a nitrogen atmosphere. The reaction was then stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.1% formic acid in water: 5% to 95%) to give 2.0 equivalents of 40 in the form of a formate salt. LCMS (ESI, m / z): [M+H] + =475.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.98(s,1H),11.16(s,1H),9.66(s,1H),9.14(s,1H),8.33(s,2H),7.94(s,1H),3.8 8(s,2H),3.28(s,3H),3.06-3.02(m,2H),2.84-2.80(m,2H),2.49-2.43(m,1H),1.43-1.34(m,2H),0.92-0.70(m,4H).

[0448] Step 7: To a solution of 40 (47 mg, 0.1 mmol) in 1,2-dichloroethane (3 mL) and N,N-dimethylacetamide (3 mL) was added acetic acid (12 mg, 0.2 mmol), 36% formaldehyde solution (83 mg, 1 mmol) and sodium triacetoxyborohydride (106 mg, 0.5 mmol). The reaction was then stirred for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.1% formic acid in water: 5% to 95%) to give 41. LCMS (ESI, m / z): [M+H] + =489.3; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.00(s,1H),11.18(s,1H),9.66(s,1H),9.15(s,1H),7.96(s,1H),3.54(s,2H),3.29(s ,3H),2.93(t,J=5.6Hz,2H),2.72(t,J=5.6Hz,2H),2.47-2.42(m,1H),2.37(s,3H),1.43-1.34(m,2H),0.92-0.70(m,4H).

[0449] Example 19 Synthesis of Compound 42

[0450]

[0451] Step 1: In an ice bath, ethyl chloroformate (15.05 g, 138.72 mmol) was added dropwise to a solution of 5-bromopyridine-3-amine (20 g, 115.6 mmol) in pyridine (200 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=7 / 3) to give 42-1.

[0452] Step 2: To a mixture of concentrated sulfuric acid (35 mL, 609 mmol) and fuming nitric acid (23.5 mL, 487 mmol) was added 42-1 (10 g, 40.8 mmol) in portions at 0°C. After stirring overnight at room temperature, the mixture was poured into ice water. The precipitate was filtered, washed with water and dried to give 42-2.

[0453] Step 3: Under N2 atmosphere, sodium ethoxide (3.87 g, 56.881 mmol) was added to a mixture of 42-2 (3 g, 10.342 mmol) in ethanol (60 mL) under stirring. The reaction was stirred at 50 ° C for 17 hours. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2:3) to give 42-3.

[0454] Compound 42-4 was prepared from 42-3 according to the synthetic procedure of compound 3-1 in Example 3.

[0455] Compound 42-5 was prepared from 42-4 according to the synthetic procedure of compound 5-4 in Example 4.

[0456] Compound 42 was prepared from 42-5 according to the synthetic procedure of compound 5 in Example 4. LCMS (ESI, m / z): [M+H] + =464.0; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.83(s,1H),11.17(s,1H),9.14(s,1H),9.12(s,1H),8.38(d,J=3.2Hz,1H),7.78(d,J=2 .8Hz,1H),4.21(q,J=6.8Hz,2H),3.33(s,3H),2.45-2.42(m,1H),1.41-1.35(m,5H),0.92-0.85(m,3H),0.79-0.72(m,1H).

[0457] Example 20 Synthesis of Compound 43

[0458]

[0459] Step 1: To a solution of 1-6 (2 g, 11.7 mmol) in dichloromethane (20 mL) was added tribromoborane (35.2 mL, 35.2 mmol) at 0 ° C. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed in vacuo and ethyl acetate was added. The mixture was quenched with ice water and an aqueous sodium hydroxide solution was added to adjust the pH to 12. The aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methane=10 / 1) to give 43-1.

[0460] Step 2: Sodium hydride (436.34 mg, 10.9 mmol, 60% in mineral oil) was added to a solution of 43-1 (1.42 g, 9.1 mmol) in N, N-dimethylformamide (15 mL) at 0 ° C, and the mixture was stirred for 15 minutes. Then 2-iodopropane (1.7 g, 10.0 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. After the reaction was completed, the mixture was quenched with ice water. The water layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 43-2.

[0461] According to the synthetic procedure of compound 5 in Example 4, compound 43 was prepared from 43-2. ​​LCMS (ESI, m / z): [M+H] + =478.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.83(s,1H),11.17(s,1H),9.14(s,1H),9.11(s,1H),8.36(d,J=2.8Hz,1H),7.76(d,J=3.2Hz,1H) ,4.81-4.74(m,1H),3.34(s,3H),2.46-2.42(m,1H),1.42-1.35(m,2H),1.32(d,J=6.0Hz,6H),0.94-0.82(m,3H),0.79-0.73(m,1H).

[0462] Example 21 Synthesis of Compound 44

[0463]

[0464] Step 1: A mixture of 5-5 (2.7 g, 12.3 mmol), potassium vinyl trifluoroborate (2.49 g, 18.5 mmol), sodium carbonate (2.6 g, 24.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.9 g, 1.23 mmol) in dioxane (48 mL) and water (12 mL) was stirred for 2 hours at 110 ° C. under N2 atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 44-1.

[0465] Step 2: To a solution of 44-1 (850 mg, 5.1 mmol) in methanol (10 mL) was added platinum (IV) oxide (85 mg). The reaction mixture was stirred at room temperature for 2 hours under H2 atmosphere. The suspension was filtered and washed with methanol. The filtrate was concentrated to give 44-2.

[0466] Compound 44 was prepared from 44-2 according to the synthetic procedure of compound 5 in Example 4. LCMS (ESI, m / z): [M+H] + =448.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.01(s,1H),11.21(s,1H),9.42(s,1H),9.17(s,1H),8.51(d,J=2.4Hz,1H),8.11(d,J=2.4Hz,1H),3 .32(s,3H),2.71(q,J=7.6Hz,2H),2.47-2.44(m,1H),1.41-1.35(m,2H),1.21(t,J=7.6Hz,3H),0.91-0.83(m,3H),0.78-0.74(m,1H).

[0467] Example 22 Synthesis of Compound 49

[0468]

[0469] Compound 49-1 was prepared from 20-1 according to the synthetic procedure of compound 44-1 in Example 21.

[0470] Step 1: Ozone was bubbled into a solution of 49-1 (1.05 g, 3.5 mmol) in dichloromethane (30 mL) at -78 ° C for 1 hour. Dimethyl sulfide (2 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give 49-2.

[0471] Step 2: Triethylamine trihydrofluoric acid (0.5 mL, 3.0 mmol) and diethylaminosulfur trifluoride (1.2 g, 7.5 mmol) were added to a solution of 49-2 (248 mg, 0.75 mmol) in dichloromethane (20 mL) at 0 ° C. Stir at room temperature for 1 hour. The reaction mixture was added dropwise to ice water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol=20 / 1) to give 49-3.

[0472] Compound 49 was prepared from 49-3 according to the synthetic procedure of compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + =361.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.33 (s, 1H), 9.49 (s, 1H), 9.01 (s, 1H), 8.71-8.66 (m, 1H), 8.32 (d, J = 7.6Hz, 1H), 7.44-7.15 (m, 2H), 3.37 (s, 3H).

[0473] Example 23 Synthesis of Compound 50

[0474]

[0475] Step 1: To a solution of methyl 2-chloropyrimidine-5-carboxylate (250 mg, 1.449 mmol) in tetrahydrofuran (5 mL) was added methylmagnesium bromide (4.347 mL, 1 M in hexane) at -78 °C. The solution was stirred at 0 °C for 30 minutes. The reaction mixture was stirred at room temperature for another hour. The mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ether. The organic layer was washed with water, dried over sodium sulfate and concentrated to give 50-1.

[0476] Step 2: A mixture of 1-7 (5 g, 14.6 mmol), 4-methoxybenzylamine (10 g, 72.9 mmol) and potassium fluoride (2.5 g, 43.7 mmol) in dimethyl sulfoxide (50 mL) was stirred at 120 ° C for 16 hours. The reaction solution was poured into water. The precipitate was filtered, washed with water and dried to give 50-2.

[0477] Step 3: A mixture of 50-2 (5 g, 11.3 mmol) in trifluoroacetic acid (30 mL) was stirred at 60 ° C for 3 hours. The mixture was concentrated to remove trifluoroacetic acid. The resulting mixture was adjusted to pH ~ 9 by saturated sodium bicarbonate aqueous solution. The resulting solution was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 50-3.

[0478] According to the synthetic procedure of compound 1 in Example 1, compound 50 was prepared from 50-3 and 50-1. LCMS (ESI, m / z): [M+H] + =492.1; 1H-NMR (400MHz, DMSO-d6, ppm): δ11.91(s,1H),10.49(s,1H),9.63(s,1H),9.09(s,1H),8.69(s, 2H),8.52-8.51(m,1H),7.83-7.82(m,1H),5.27(s,1H),3.94(s,3H),3.37(s,3H),1.48(s,6H).

[0479] Example 24 Synthesis of Compound 51

[0480]

[0481] Step 1: To a solution of cyclopropylamine (2 g, 35 mmol) in acetonitrile (70 mL) was added 4-nitrophenyl chloroformate (7 g, 35 mmol) and triethylamine (5.3 g, 52.5 mmol). The reaction mixture was stirred at 20 ° C for 2 hours. The resulting mixture was diluted with dichloromethane and water. The organic layer was concentrated and purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give 51-1.

[0482] According to the synthetic procedure of compound 12-3 in Example 11, compound 51-2 was prepared from 50-3 and 51-1.

[0483] According to the synthetic procedure of compound 1 in Example 1, compound 51 was prepared from 51-2. LCMS (ESI, m / z): [M+H] + =439.6; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.82(s,1H),9.47(s,1H),9.12(s,1H),8.77(s,1H),8.40(d,J=2.8Hz,1H),7.81 (d,J=2.8Hz,1H),7.56(s,1H),3.94(s,3H),3.34(s,3H),2.62-2.58(m,1H),0.71-0.62(m,2H),0.46-0.37(m,2H).

[0484] Example 25 Synthesis of Compound 52

[0485]

[0486] According to the synthetic procedure of compound 1-7 in Example 1, compound 52-1 was prepared from 2-amino-5-chloropyridine.

[0487] According to the synthetic procedure of compound 1 in Example 1, compound 52 was prepared from 52-1 and cyclopropanecarboxamide. LCMS (ESI, m / z): [M+H] + =428.0; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.17(s,1H),11.47(s,1H),9.38(s,1H),9.22(s, 1H),8.67(s,1H),8.25(s,1H),3.40(s,3H),2.17-2.08(m,1H),0.91-0.82(m,4H).

[0488] Example 26 Synthesis of Compound 53

[0489]

[0490] Step 1: To a solution of 2-bromo-5-(trifluoromethoxy)pyridine (2.1 g, 8.678 mmol) in dioxane (160 mL) was added 2,2-dimethylpropionamide (4.860 mL, 43.390 mmol), tris(dibenzylideneacetone)dipalladium (0.79 g, 0.868 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.00 g, 1.736 mmol), cesium carbonate (8.48 g, 26.034 mmol) under nitrogen atmosphere and heated to 110° C. overnight. The mixture was concentrated and purified by column chromatography (petroleum ether) to give 53-1.

[0491] Step 2: To a mixture of 53-1 (4 g, 15.254 mmol) in ether (150 mL) was added tert-butyl lithium (33 mL, 2.5 equivalents) at -65 ° C and under a nitrogen atmosphere, followed by stirring for 3 hours. Then, dimethyl disulfide (2.028 mL, 22.881 mmol) was added to the mixture at -65 ° C and stirred for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 53-2.

[0492] Step 3: To a solution of 53-2 (3 g, 9.730 mmol) in water (40 mL) was added concentrated hydrochloric acid (36 wt%, 40 mL) and heated to 110 ° C for 3 hours. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether=1:1) to give 53-3.

[0493] According to the synthetic procedure of compound 1 in Example 1, compound 53 was prepared from 53-3 and 1-3. LCMS (ESI, m / z): [M+H] + =478.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.27(s,1H),11.49(s,1H),9.45(s,1H),9.25(s,1H),8.76 (d,J=2.4Hz,1H),8.23(d,J=2.0Hz,1H),3.45(s,3H),2.18-2.08(m,1H),0.93-0.82(m,4H). 19 F-NMR (376MHz, DMSO-d6, ppm): δ-57.62 (3F).

[0494] Example 27 Synthesis of Compound 54

[0495]

[0496] Step 1: A mixture of 5-4 (4.5 g, 32 mmol), p-toluenesulfonic acid (553 mg, 3.2 mmol) and N-iodosuccinimide (10.8 g, 48 mmol) in dimethyl sulfoxide (30 mL) was stirred at room temperature for 2 hours under N2 atmosphere. The resulting mixture was quenched with water and adjusted to pH 8, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 5 / 1) to give 54-1.

[0497] Step 2: A mixture of 54-1 (500 mg, 1.88 mmol) and trifluoromethylthio (2,2-bipyridine) copper (I) (724 mg, 2.06 mmol) in diethylene glycol dimethyl ether (6 mL) was stirred at 140 ° C for 1.5 hours under microwave conditions and N2 atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 5 / 1) to give 54-2.

[0498] According to the synthetic procedure of compound 1 in Example 1, compound 54-3 was prepared from 54-2.

[0499] Compound 54 was prepared from 54-3 according to the synthetic procedure of compound 1-8 in Example 1. LCMS (ESI, m / z): [M+H] + =494.1; 1H-NMR (400MHz, DMSO-d6, ppm): δ12.42(s,1H),11.53(s,1H),9.56(s,1H),9.27(s,1H),8.80 (d,J=2.4Hz,1H),8.40(d,J=2.4Hz,1H),3.43(s,3H),2.15-2.03(m,1H),0.90-0.83(m,4H). 19 F-NMR (376MHz, DMSO-d6, ppm): δ-42.49 (3F).

[0500] Example 28 Synthesis of Compound 55

[0501]

[0502] Step 1: To a mixture of 4,6-dichloronicotinic acid (7.0 g, 36.4 mmol) in chloroform (150 mL) was added oxalyl chloride (18.5 g, 146 mmol) and N,N-dimethylformamide (1 mL) at room temperature, followed by stirring at 60 ° C for 2 hours. The volatiles were removed under vacuum and co-evaporated with chloroform. Tetrahydrofuran (100 mL), deuterated methylamine (methan-d3-amine) hydrochloride (3.1 g, 43 mmol) and N,N-diisopropylethylamine (14.1 g, 109 mmol) were added to the resulting mixture at 0 ° C, followed by stirring for 3 hours. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 55-1.

[0503] Compound 55 was prepared from 55-1 and 3-3 according to the synthetic procedure of compound 1-8 in Example 1. LCMS (ESI, m / z): [M+H] + =411.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.43(s,1H),10.82(s,1H),8.83(s,1H),8.63(s,1H),8.60(d,J=2.8H z,1H),8.56(s,1H),8.10(dd,J=7.6Hz,2.8Hz,1H),3.34(s,3H),2.00-1.96(m,1H),0.79-0.75(m,4H).

[0504] Example 29 Synthesis of Compound 58

[0505]

[0506] According to the synthetic procedure of compound 1-8 in Example 1, compound 58-1 was prepared from 44-1 and 1-3.

[0507] According to the synthetic procedure of compound 49-2 in Example 22, compound 58-2 was prepared from 58-1.

[0508] Step 1: To a solution of 58-2 (60 mg, 0.148 mmol) in dichloromethane (10 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (0.136 mL, 0.740 mmol). The mixture was stirred at 20 ° C for 16 hours. The reaction mixture was poured into ice water, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by preparative TLC (dichloromethane / methanol=15 / 1) to give 58-3.

[0509] Compound 58 was prepared from 58-3 according to the synthetic procedure of compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + =444.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.34(s,1H),11.50(s,1H),9.58(s,1H),9.25(s,1H),8.80 (s,1H),8.40(s,1H),7.40-7.08(m,1H),3.42(s,3H),2.19-2.03(m,1H),0.89-0.82(m,4H). 19 F-NMR (376MHz, DMSO-d6, ppm): δ-110.08 (2F).

[0510] Example 30 Synthesis of Compound 59

[0511]

[0512] Step 1: Boron tribromide (90 mL, 90 mmol, 1.0 M dichloromethane solution) was added to a mixture of 1-6 (5.1 g, 30 mmol) in dichloromethane (50 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 3 hours and cooled to 0 ° C. The mixture was quenched with methanol. The resulting mixture was adjusted to pH ~ 9 with lithium hydroxide (1M aqueous solution) and extracted with dichloromethane / methanol = 20 / 1. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol = 20: 1) to give 59-1.

[0513] Step 2: To a solution of 59-1 (1.0 g, 6.4 mmol) and 2-methoxyethane-1-ol (585 mg, 7.7 mmol) in tetrahydrofuran (40 mL) were added triphenylphosphine (2.02 g, 7.7 mmol)) and N,N,N',N'-tetramethylazodicarbonamide (1.32 g, 7.7 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by preparative HPLC (acetonitrile / 0.05% TFA in water: 10% to 95%) to give 59-2.

[0514] Compound 59 was prepared from 59-2 according to the synthetic procedure of compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + =468.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.84(s,1H),11.39(s,1H),9.17(s,1H),9.13(s,1H),8.38(d,J=3.2Hz,1H),7.81(d,J=2 .8Hz,1H),4.29(t,J=4.0Hz,2H),3.68(t,J=4.0Hz,2H),3.33(s,3H),3.32(s,3H),2.15-2.07(m,1H),0.86-0.82(m,4H).

[0515] Example 31 Synthesis of Compound 60

[0516]

[0517] Step 1: To a mixture of 59-1 (2.00 g, 12.8 mmol) in 1,2-dimethoxyethane (20.0 ml) was added a solution of sodium hydroxide (1.64 g, 40.9 mmol) in water (10.0 ml) at 10-20 ° C, then bubbled with difluorochloromethane for 30 minutes, and then stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 60-1.

[0518] Compound 60-2 was prepared from 60-1 according to the synthetic procedure of compound 1 in Example 1.

[0519] Compound 60 was prepared from 60-2 according to the synthetic procedure of compound 1-8 in Example 1. LCMS (ESI, m / z): [M+H] + =460.2, 1H-NMR (400MHz, DMSO-d6, ppm): δ12.14(s,1H),11.46(s,1H),9.38(s,1H),9.22(s,1H),8.56 (s,1H),8.07(s,1H),7.55-7.15(m,1H),3.40(s,3H),2.14-2.08(m,1H),0.90-0.82(m,4H). 19 F-NMR (376MHz, DMSO-d6, ppm): δ-82.62 (2F).

[0520] Example 32 Synthesis of Compound 65

[0521]

[0522] Compound 65-1 was prepared from 5-5 according to the synthetic procedure of compound 1-4 in Example 1.

[0523] Step 1: To a mixture of 65-1 (5 g, 22.820 mmol) in dioxane (250 mL) was added (3R)-3-methylmorpholine (6.92 g, 68.459 mmol), 2-(dicyclohexylphosphine)-2',4',6'-triisopropylbiphenyl (2.18 g, 4.564 mmol), bis(trimethylsilyl) lithium amide (38 mL, 38.3 mmol, 1 M in tetrahydrofuran) and tris(dibenzylideneacetone)dipalladium (2.09 g, 2.282 mmol). The mixture was then stirred at 110 ° C for 18 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, water and brine. The ethyl acetate layer was concentrated and purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether 1:4 to give 65-2.

[0524] According to the synthetic procedure of compound 1-6 in Example 1, compound 65-3 was prepared from 65-2.

[0525] According to the synthetic procedure of compound 1 in Example 1, compound 65-4 was prepared from 65-3.

[0526] Step 2: Sodium thiosulfate (187 mg, 1.18 mmol) was added to a solution of 65-4 (60 mg, 0.11 mmol) in methanol (20 mL). The mixture was stirred at 20 ° C for 24 hours. The resulting mixture was diluted with water and extracted with dichloromethane / methanol = 10 / 1. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.1% formic acid in water = 44-56%) to give 65. LCMS (ESI, m / z): [M+H] + =493.6;1 H-NMR (400MHz, DMSO-d6, ppm): δ11.73(s,1H),11.33(s,1H),9.12(s,1H),9.08(s,1H),8.31(d,J=3.2Hz,1H),7.66(d,J=3.2Hz,1H),4.01-3. 90(m,2H),3.75-3.67(m,2H),3.59-3.55(m,1H),3.30(s,3H),3.17-3. 08(m,2H),2.14-2.05(m,1H),1.06(d,J=6.4Hz,3H),0.87-0.81(m,4H).

[0527] Example 33 Synthesis of Compounds 73 and 74

[0528]

[0529] Step 1: A mixture of 59-1 (1.56 g, 10 mmol), cesium carbonate (6.52 g, 20 mmol) and (S)-4-methyl-1,3-dioxolan-2-one (1.53 g, 15 mmol) in N,N-dimethylformamide (40 mL) was stirred at 100° C. for 1 hour. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 73-1 (crude).

[0530] Step 2: To a mixture of 73-1 (crude, 10 mmol) and imidazole (2.04 g, 30 mmol) in N,N-dimethylformamide (40 mL) was added tert-butylchlorodiphenylsilane (4.13 g, 15 mmol) at 0°C, followed by stirring at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 4 / 1) to give 73-2.

[0531] According to the synthetic procedure of compound 1-8 in Example 1, compound 73-3 was prepared from 73-2.

[0532] Step 3: Sodium tungstate (1.03 g, 3.5 mmol) and 30% aqueous hydrogen peroxide solution (5.93 g, 52.3 mmol) were added dropwise to a mixture of 73-3 (2.35 g, 3.5 mmol) in acetic acid (50 mL) at room temperature. The reaction mixture was stirred for 3 hours. The resulting mixture was diluted with water, quenched with a saturated aqueous sodium thiosulfate solution, and adjusted to pH~9 with solid sodium carbonate. The mixture was extracted with dichloromethane / methanol = 10 / 1. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Dioxane (50 mL) and bis(pinacol)diboron (5.1 g, 20 mmol) were added to the residue, and then stirred at 100°C for 3 hours. The resulting mixture was concentrated and diluted with petroleum ether, filtered and washed with petroleum ether. The collected solids were dried to obtain 73-4.

[0533] Compound 73-5 was prepared from 73-4 according to the synthetic procedure of compound 6 in Example 5.

[0534] Step 4: 2,2-difluoro-2-(fluorosulfonyl)acetic acid (229 mg, 1.28 mmol) was added to a mixture of 73-5 (200 mg, 0.43 mmol) and cuprous iodide (41 mg, 0.21 mmol) in acetonitrile (5 mL), and then stirred at 60 ° C for 1 hour. The resulting mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane / methanol = 20 / 1. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% FA in water: 10% to 95%) to give 73 and 74.

[0535] 73: LCMS (ESI, m / z): [M+H] + =518.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.86 (s, 1H), 11.38 (s, 1H), 9.24-9.05 (m, 2H), 8.38 (d, J = 2.8Hz, 1H), 7.81 (d, J = 3.2Hz, 1H), 7. 03-6.55(m,1H),4.63-4.48(m,1H),4.28-4.12(m,2H),3.32(s,3H),2.16-2.05(m,1H),1.30(d,J=6.8Hz,3H),0.86-0.79(m,4H); 19 F-NMR (376MHz, DMSO-d6, ppm): δ-79.10 (2F).

[0536] 74: LCMS (ESI, m / z): [M+H] + =496.2; 1H-NMR (400MHz, DMSO-d6, ppm): δ11.85(s,1H),11.38(s,1H),9.19-9.08(m,2H),8.37(d,J=2.8Hz,1H),8.27(s,1H),7.79(d,J =2.8Hz,1H),5.33-5.14(m,1H),4.36-4.17(m,2H),3.32(s,3H),2.15-2.00(m,1H),1.30(d,J=6.4Hz,3H),0.87-0.79(m,4H).

[0537] Example 33 Synthesis of Compounds 86 and 87

[0538]

[0539] Step 1: To a solution of [(4-methoxyphenyl)methyl](methyl)amine (2.34 g, 15.477 mmol) in dichloroethane (30 mL) was added ethyl 3-oxocyclobutanecarboxylate (2 g, 14.070 mmol) and acetic acid (0.806 mL, 14.070 mmol) and then stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (5.93 g, 28.139 mmol) was added and stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (0-6% methanol in dichloromethane) to give 86-1.

[0540] Step 2: To a solution of 86-1 (2.9 g, 10.456 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide (0.581 mL, 20.911 mmol), followed by stirring at room temperature for 2 hours. The mixture was concentrated and poured into water. The aqueous phase was washed with ethyl acetate and the aqueous layer was acidified with saturated citric acid solution. The aqueous layer was extracted with chloroform and isopropanol (3:1). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give 86-2.

[0541] Step 3: A solution of 86-2 (1000 mg, 4.011 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.28 g, 6.016 mmol), and ethylbis(propan-2-yl)amine (1.989 mL, 12.033 mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature for 5 minutes. Then ammonium chloride (0.282 mL, 8.022 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC (acetonitrile / ammonium bicarbonate aqueous solution) to give 86-3.

[0542] Step 4: To a solution of 86-3 (400 mg, 1.611 mmol) in methanol (30 mL) was added palladium on carbon (10%, 80 mg). The mixture was stirred at 50° C. under hydrogen for 17 hours. The mixture was filtered and concentrated to give 86-4.

[0543] Step 5: A mixture of 86-4 (200 mg, 1.560 mmol), di-tert-butyl dicarbonate (0.501 mL, 2.340 mmol) and triethylamine (0.651 mL, 4.681 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC (acetonitrile / aqueous ammonium bicarbonate solution) to give 86-5.

[0544] Compound 86-6 was prepared from 86-5 according to the synthetic procedure of compound 5 in Example 4.

[0545] Step 6: To a solution of 86-6 (97 mg, 0.168 mmol) in dichloromethane (4.5 mL) was added trifluoroacetic acid (2 mL) and then stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and concentrated in vacuo. The residue was purified by chiral preparative SFC ( IG, eluted with supercritical CO2 / MeOH) to give 86 and crude 87. Crude 87 was further purified by preparative HPLC (acetonitrile / 0.1% trifluoroacetic acid in water = 22%).

[0546] 86: Chiral SFC analysis: >99% de. Retention time: 5.231 min on IG 100*3mm 3μm (35°C); mobile phase: MeOH (0.1% DEA) in CO2, 1800psi 2.0mL / min.

[0547] LCMS (ESI, m / z): [M+H] + =477.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.99(s,1H),11.07(s,1H),9.41(s,1H),9.16(s,1H),8.48(d,J=2.0Hz,1H),7.87(d,J=2.0Hz,1H),3.3 3(s,3H),3.11-2.92(m,2H),2.42-2.26(m,2H),2.18(s,3H),2.15-2.08(m,1H),1.96-1.80(m,2H),1.11-1.01(m,2H),0.90-0.77(m,2H).

[0548] 87: Chiral SFC analysis: 96.94% de. Retention time: 3.814 min on IG 100*3mm 3μm (35°C); mobile phase: MeOH (0.1% DEA) in CO2, 1800psi 2.0mL / min.

[0549] LCMS (ESI, m / z): [M+H] + =477.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.02(s,1H),11.15(s,1H),9.45(s,1H),9.17(s,1H),8.91-8.61(m,2H),8.48(d,J=2.0Hz,1H),7.88(d,J= 2.4Hz,1H),3.79-3.74(m,1H),3.48-3.41(m,1H),3.35(s,3H),2.47- 2.35(m,7H),2.19-2.07(m,1H),1.10-1.03(m,2H),0.86-0.77(m,2H).

[0550] Example 34 Synthesis of Compounds 94 and 95

[0551]

[0552] Step 1: 2-chloro-3-iodopyridine (10 g, 41.764 mmol), 3-mercaptopropionic acid heptane-3-yl ester (11.40 g, 52.205 mmol), tris(dibenzylideneacetone)dipalladium (3.82 g, 4.176 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (4.83 g, 8.353 mmol), N,N-diisopropylethylamine (13.49 g, 104.410 mmol) and dioxane (300 mL) were added to a 1 L flask. The mixture was stirred at 100 ° C under N2 atmosphere for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was purified by phase column chromatography (0-20% ethyl acetate / petroleum ether) to give 94-1.

[0553] Step 2: 94-1 (500 mg, 1.516 mmol), tetrahydrofuran (10 mL), and sodium methoxide (122.79 mg, 2.273 mmol) were added to a 100 mL flask at 0° C. The mixture was stirred at room temperature for 4 hours. 94-2 was used in the next step without purification.

[0554] Step 3: 94-2 (3.6 g, 31.989 mmol), 1-bromo-3-chloropropane (5.54 g, 35.188 mmol), triethylamine (2.27 g, 22.400 mmol) and tetrahydrofuran (50 ml) were added to a 250 mL flask. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated under vacuum. The residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to give 94-3.

[0555] Step 4: Add 94-3 (3.20 g, 14.405 mmol) and methanol (100 mL), iodobenzene diacetate (11.60 g, 36.013 mmol), and ammonium carbamate (2.81 g, 36.013 mmol) to a 250 mL flask. Stir the mixture at room temperature for 2 hours. Concentrate the reaction mixture in vacuo. Purify the residue by column chromatography (0-100% ethyl acetate / petroleum ether) to give 94-4.

[0556] Step 5: A solution of 94-4 (2.6 g, 10.271 mmol) in ammonium hydroxide solution (55 mL, 0.1 wt%) was stirred at 80 ° C. in a sealed tube for 4 hours. The cooled reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (dichloromethane: methanol = 20: 1) to give 94-5.

[0557] Step 6: A solution of 94-5 (1.5 g, 6.922 mmol) in ammonium hydroxide solution (25 mL, 28 wt%) was stirred in a sealed tube at 120°C for 18 hours. The mixture was concentrated. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated to give 94-6.

[0558] Compound 94-7 was prepared from 1-3 and 5-2 according to a synthetic procedure similar to that of compound 5-8 in Example 4.

[0559] Compounds 94 and 95 were prepared from 94-7 and 94-6 according to the synthetic procedure of compound 5-8 in Example 4.

[0560] Enantiomer 1: 94 chiral SFC analysis: 98.04% ee. Reprosil Chiral-AM (similar to Daicel AD) retention time on 100*3mm 3μm (35℃) 6.188 minutes; mobile phase: (0.1% DEA) in CO2, 1800 psi, 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =445.2; 1H-NMR (400MHz, DMSO-d6, ppm): δ11.86(s,1H),11.21(s,1H),9.41(s,1H),9.14(s, 1H),8.59(dd,J=4.8Hz,1.6Hz,1H),8.31(dd,J=8.0Hz,1.6Hz,1H),7.32(dd,J=8.0H z,4.8Hz,1H),3.84-3.73(m,2H),3.67-3.55(m,1H),3.54-3.43(m,1H),2.50-2.44( m,1H),2.36-2.24(m,1H),2.20-2.08(m,1H),1.45-1.35(m,2H),0.96-0.75(m,4H).

[0561] Enantiomer 2: 95 chiral SFC analysis: 98.88% ee. Reprosil Chiral-AM (similar to Daicel AD) retention time on 100*3mm 3μm (35°C) 7.186 minutes; mobile phase: (0.1% DEA) in CO2, 1800 psi, 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =445.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.89(s,1H),11.21(s,1H),9.41(s,1H),9.14 (s,1H),8.60-8.57(m,1H),8.29(dd,J=8.0Hz,1.2Hz,1H),7.31(dd,J=7.6,4.8H z,1H),3.86-3.69(m,2H),3.65-3.56(m,1H),3.55-3.46(m,1H),2.48-2.44(m,1 H),2.35-2.23(m,1H),2.22-2.07(m,1H),1.46-1.34(m,2H),0.96-0.74(m,4H).

[0562] Example 35 Synthesis of Compound 96

[0563]

[0564] Step 1: To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (14.4 g, 65.16 mmol) in acetonitrile (75 mL) and water (11 mL) was added N,N-diisopropyl-ethylamine (25.3 g, 195.48 mmol) and lithium bromide (17 g, 195.48 mmol) at 0°C, then stirred at room temperature for 16 hours. The mixture was filtered and rinsed with acetonitrile to give 96-1.

[0565] Step 2: Sodium methoxide (3.66 g, 67.86 mmol) was added in portions to a solution of 96-1 (9 g, 45.24 mmol) in methanol (100 ml) at 0°C, followed by stirring at room temperature for 16 hours. Sodium methoxide (2.44 g, 45.24 mmol) was then added and stirred at room temperature for 3 hours. The mixture was adjusted to pH = 2-3 with 2M aqueous hydrochloric acid solution and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% trifluoroacetic acid in water: 0%-95%) to give 96-2 (crude product, used directly in the next step).

[0566] Step 3: A mixture of 96-2 (10.08 g, 53.62 mmol) and N,N'-carbonyldiimidazole (13.03 g, 80.43 mmol) in tetrahydrofuran (200 mL) was stirred at 60 ° C for 4 hours. The resulting mixture was added dropwise to a pre-stirred mixture of potassium 3-ethoxy-3-oxopropanoate (21.88 g, 128.69 mmol), triethylamine (19.5 g, 193.03 mmol) and magnesium chloride (15.3 g, 160.86 mmol) in acetonitrile (400 mL) at 0 ° C, and then stirred at room temperature for 16 hours. The mixture was quenched with methanol, adjusted to pH ~ 4 with 2M aqueous hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 2) to give 96-3.

[0567] Step 4: Trideuterated (iodine) methane (5.72 g, 39.43 mmol) was added dropwise to a solution of 96-3 (10.2 g, 39.43 mmol) and potassium carbonate (5.44 g, 39.43 mmol) in acetone (120 mL) at 0 ° C, and then stirred at 30 ° C for 16 hours. The mixture was filtered and rinsed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 96-4.

[0568] Step 5: A mixture of 96-4 (3.2 g, 11.61 mmol) in acetic acid (20 mL) and concentrated hydrochloric acid (10 mL) was stirred at 100 °C for 16 hours. Then cooled to room temperature and concentrated. The residue was diluted with water and filtered. The filter cake was slurried with acetonitrile and filtered to give 96-5.

[0569] Step 6: N, N-diethylaniline (985 mg, 6.61 mmol) was added to a mixture of 96-5 (1.13 g, 6.61 mmol) in phosphorus oxychloride (10 mL) at room temperature, and then stirred at 100 ° C for 1 hour. Then cooled to room temperature and concentrated. The residue was dissolved in dichloromethane and slowly poured into ice water. The organic layer was washed with brine and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10 / 1) to obtain 96-6.

[0570] According to the synthetic procedure of compound 5-8 in Example 4, compound 96-7 was prepared from 96-6 and 5-2.

[0571] According to the synthetic procedure of compound 5 in Example 4, compound 96 was prepared from 96-7 and 5-4.

[0572] 96 is 1.0 equivalent of formate. LCMS (ESI, m / z): [M+H] + =419.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.61(s,1H),11.38(s,1H),9.44(s,1H),8.63(s,1H),8.43(s,1H),8.28( d,J=6.4Hz,1H),7.36(s,1H),3.32-3.24(m,5H),2.47-2.43(m,1H),1.45-1.36(m,2H),0.94-0.71(m,4H).

[0573] Example 36 Synthesis of Compounds 97 and 98

[0574]

[0575] Step 1: In a 100 mL flask, 94-2 (from Example 34, 2.666 mmol), iodomethane (0.166 mL, 2.666 mmol), triethylamine (0.371 mL, 2.666 mmol) and tetrahydrofuran (20 mL) were added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate, and the combined organic layers were concentrated in vacuo. The residue was purified by phase column chromatography (0-30% ethyl acetate / petroleum ether) to give 97-1.

[0576] Compound 97-2 was prepared from 97-1 according to the synthetic procedure of compound 94-4 in Example 34.

[0577] Step 2: Sodium hydride (179 mg, 7.458 mmol) was added to a stirred solution of 97-2 (427 mg, 2.240 mmol) in 1,2-dimethoxyethane (6 mL) at 0 ° C and stirred for 15 minutes. Then iodomethane (0.418 mL, 6.719 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with ice water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (0-75% ethyl acetate in petroleum ether) to give 97-3.

[0578] Step 3: A solution of 97-3 (1.3 g, 6.351 mmol) in ammonium hydroxide (25 ml) was stirred in a sealed tube at 120° C. for 18 hours. The solid was collected by filtration and washed with water to give 97-4.

[0579] According to the synthetic procedure of compound 5-8 in Example 4, compounds 97 and 98 were prepared from 94-7 and 97-4.

[0580] Enantiomer 1: 97 chiral SFC analysis: 98.62% ee. Retention time on OJ 100*3mm 3μm (35°C) 3.490 minutes; Mobile phase: MeOH (0.1% DEA) in CO2, 1800 bar, 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =433.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.88(s,1H),11.20(s,1H),9.47(s,1H),9.08(s,1H),8.57(dd,J=4.8,1.6Hz,1H),8.24(dd,J=8.0,1.6H z,1H),7.31(dd,J=8.0,4.8Hz,1H),3.23(s,3H),2.69(s,3H),2.47-2.43(m,1H),1.45-1.36(m,2H),0.95-0.82(m,3H),0.78-0.72(m,1H).

[0581] Enantiomer 2: 98 Chiral SFC analysis: >99.5% ee. Retention time on OJ 100*3mm 3μm (35°C) 3.862 minutes; Mobile phase: MeOH (0.1% DEA) in CO2, 1800 bar, 1.5 mL / min. LCMS (ESI, m / z): [M+H] + =433.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.88(s,1H),11.20(s,1H),9.48(s,1H),9.08(s,1H),8.57(d,J=4.0Hz,1H),8.24(d,J=7 .2Hz,1H),7.30(dd,J=7.6,4.8Hz,1H),3.24(s,3H),2.68(s,3H),2.48-2.44(m,1H),1.45-1.35(m,2H),0.96-0.77(m,4H).

[0582] Example 37 Synthesis of Compound 100

[0583]

[0584] Step 1: To a solution of 5-methoxy-2-nitropyridine-3-amine (7.7 g, 45.524 mmol) in N,N-dimethylformamide (80 ml) was added N-bromosuccinimide (8.10 g, 45.524 mmol) in portions at 0°C. The reaction mixture was stirred at 20-25°C for 3 hours. The aqueous phase was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100-1.

[0585] Step 2: Under N2 protection, methylboric acid (10.02 g, 167.312 mmol), potassium carbonate (13.87 g, 100.387 mmol) and tetrakis(triphenylphosphine)palladium (3.87 g, 3.346 mmol) were added to a solution of 100-1 (8.3 g, 33.462 mmol) in dioxane (332 mL), and then heated to reflux for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 1:0 to 1:10) to obtain 100-2.

[0586] Step 3: To a solution of tert-butyl nitrite (3.437 mL, 28.662 mmol) in dichloromethane (360 mL) was added dimethyl disulfide (3.387 mL, 38.216 mmol) at 0°C, and then a solution of 100-2 (3.5 g, 19.108 mmol) in dichloromethane (20 mL) was added dropwise to the solution and allowed to warm to room temperature for 4 hours. Petroleum ether was then added to the solution, filtered by silica gel column chromatography, eluted with dichloromethane to give 100-3.

[0587] Step 4: To a solution of 100-3 (1.2 g, 5.601 mmol) in ethanol (12 mL) and water (6 mL) was added ammonium chloride (3 g, 56.009 mmol) and iron powder (0.94 g, 16.803 mmol). The mixture was heated at 90 °C for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography to give 100-4.

[0588] Compound 100 was prepared from 100-4 according to the synthetic procedure of compound 5 in Example 4. LCMS (ESI, m / z): [M+H] + =464.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.88(s,1H),11.14(s,1H),9.57(s,1H),9.13(s,1H),7.70(s,1H),3.91(s ,3H),3.31(s,3H),2.47(s,3H),2.46-2.43(m,1H),1.43-1.35(m,2H),0.98-0.83(m,3H),0.80-0.70(m,1H).

[0589] Example 38 Synthesis of Compound 103

[0590]

[0591] Step 1: To a solution of (E)-2-cyano-2-(hydroxyimino)acetic acid ethyl ester (1 g, 7.037 mmol) and triethylamine (1.09 g) in ethyl acetate (7.2 mL) was added p-toluenesulfonyl chloride (13.74 g) under ice cooling. The reaction was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was stirred for 15 minutes. The precipitate was filtered and dried under reduced pressure to obtain 103-1.

[0592] Step 2: Pyridine (6.94 mL) was added dropwise to a mixture of 103-1 (18.3 g, 61.76 mmol) and methyl thioglycolate (8.4 mL, 93.931 mmol) in ethanol (54 mL). The reaction was stirred for 30 minutes. The reaction mixture was then partitioned between cold ether and ice water. The aqueous layer was extracted with cold ether. The combined ether layers were dried over anhydrous sodium sulfate, filtered and concentrated. Triethylamine (1.858 mL, 13.33 mmol) was added dropwise to a solution of the substance in anhydrous ethanol (20 mL). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered and dried to provide 103-2.

[0593] Step 3: 103-2 (18 g, 78.176 mmol) in concentrated hydrochloric acid (100 mL) was heated to reflux for 16 hours. The mixture was cooled to 0°C and filtered, and the filter cake was washed with ether and dried in vacuo to give 103-3 (crude product).

[0594] Step 4: To a solution of 103-3 (13.35 g, 92.605 mmol) in methanol (70 mL) was added thionyl chloride (10 mL) at 0° C. over 5 min. The solution was stirred at 70° C. for 1 h. The mixture was concentrated to give 103-4.

[0595] According to the synthetic procedure of compound 100-3 in Example 37, compound 103-5 was prepared from 103-4.

[0596] Step 5: To a solution of 103-5 (1.2 g, 6.340 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added lithium hydroxide (0.319 g, 9.510 mmol) at 0°C. The solution was stirred at room temperature for another 30 minutes. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, and recrystallized from ethyl acetate: petroleum ether (10 mL: 5 mL) to give 103-6.

[0597] Step 6: Under nitrogen atmosphere at 20 ° C, diphenylphosphoryl azide (0.405 mL) and triethylamine (0.404 mL) were added dropwise to a solution of 103-6 (254 mg, 1.450 mmol) in tert-butanol (5 mL). The mixture was stirred at 100 ° C for 5 hours under nitrogen atmosphere. The mixture was quenched with saturated sodium bicarbonate aqueous solution and diluted with ether. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 10) to give 103-7.

[0598] Compound 103-8 was prepared from 103-7 according to the synthetic procedure of compound 5 in Example 4.

[0599] Step 7: To a solution of 103-8 (2 g, 7.185 mmol) in methanol (40 mL) was added 3M hydrochloric acid / methanol (40 mL). The reaction was then stirred at 50° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered to give 103-9.

[0600] According to the synthetic procedure of compound 5-8 in Example 4, compound 103 was prepared from 103-9. LCMS (ESI, m / z): [M+H] + =426.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.45(s,1H),11.26(s,1H),9.72(s,1H),9.69(s,1H ),9.21(s,1H),3.38(s,3H),2.49-2.45(m,1H),1.48-1.37(m,2H),0.94-0.74(m,4H).

[0601] Example 39 Synthesis of Compound 109

[0602]

[0603] Step 1: To a mixture of 5-5 (2.75 g, 12.55 mmol) in tetrahydrofuran (100 mL) was added butyl lithium (17.6 mL, 2.5 M hexane solution, 43.93 mmol) at -60 ° C under N2 atmosphere. Then stirred for 0.5 hours. A solution of oxetane-3-one (3.16 g, 43.93 mmol) in tetrahydrofuran (10 ml) was added dropwise to the above mixture at -60 ° C, and then stirred for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride solution, diluted with brine and extracted with tetrahydrofuran. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol / ammonium hydroxide = 10 / 1 / 0.05) to give 109-1.

[0604] Step 2: 1,8-diazabicyclo[5.4.0]undec-7-ene (932 mg, 6.12 mmol) was added to a mixture of 109-1 (1 g, 4.71 mmol) and tert-butyldimethylsilyl chloride (923 mg, 6.12 mmol) in dichloromethane (20 mL) at 0 ° C. under N2 atmosphere, and then stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 109-2.

[0605] According to the synthetic procedure of compound 1-7 in Example 1, compound 109-3 was prepared from 109-2 and 1-3.

[0606] Step 3: To a solution of 109-3 (570 mg, 1.14 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1.26 mL, 1.26 mmol, 1M in THF) at room temperature and then stirred for 1 hour. The mixture was diluted with water and stirred for 5 minutes. The mixture was filtered and rinsed with water and acetonitrile to give 109-4.

[0607] Step 4: Diethylaminosulfur trifluoride (403 mg, 2.50 mmol) was added dropwise to a mixture of 109-4 (390 mg, 1.01 mmol) in dichloromethane (20 mL) at -70 ° C and N2 atmosphere, and then stirred for 2 hours. The mixture was warmed to -10 ° C and then stirred for 2 hours. The mixture was stirred at 5 ° C for 16 hours. The resulting mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / ethyl acetate = 2 / 1) to obtain 109-5.

[0608] Compound 109 was prepared from 109-5 according to the synthetic procedure of compound 5 in Example 4. 109 was 2.0 equivalents of formate salt. LCMS (ESI, m / z): [M+H] + =494.2; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.25(s,1H),11.27(s,1H),9.55(s,1H),9.21(s,1H),8.90-8.67(m,1H),8.42(s,2H),8.3 6-8.23(m,1H),5.07-4.93(m,4H),3.38(s,3H),2.47-2.42(m,1H),1.44-1.35(m,2H),0.93-0.82(m,3H),0.78-0.73(m,1H). 19 F-NMR (376MHz, DMSO-d6, ppm): δ-143.83 (1F).

[0609] Example 40 Synthesis of Compound 120

[0610]

[0611] Step 1: At -65 ° C and nitrogen atmosphere, n-butyl lithium (13 mL, 3.5 equivalents, 1.3 M) was added dropwise to a mixture of 5-5 (1.3 g, 5.96 mmol) in tetrahydrofuran (60 mL), and then stirred at -65 ° C for 10 minutes. Acetone (2 g, 6.0 equivalents) was added to the resulting mixture at -65 ° C, and then stirred at -65 ° C for 5 minutes. The reaction was quenched with brine and extracted with tetrahydrofuran. The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol = 100: 0 ~ 50: 1 to give 120-1.

[0612] Compound 120 was prepared from 120-1 according to the synthetic procedure of compound 5 in Example 4. LCMS (ESI, m / z): [M+H] + =478.4; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.08(s,1H),11.21(s,1H),9.50(s,1H),9.18(s,1H),8.70(d,J=2.4Hz,1H),8.34 (d,J=2.4Hz,1H),5.46(s,1H),3.36(s,3H),2.50-2.45(m,1H),1.51(s,6H),1.47-1.36(m,2H),1.00-0.73(m,4H).

[0613] Example 41 Synthesis of Compound 123

[0614]

[0615] Step 1: To a -78°C solution of 2-cyclopropylthiazole (2 g, 15.974 mmol) in tetrahydrofuran (50 mL) was added n-butyl lithium (7.688 mL, 19.169 mmol, 2.5 M in hexane) at -65°C, then stirred at -78°C for 30 minutes, after which hexachloroethane (2.170 mL, 19.169 mmol) was added in portions over 30 minutes. The reaction mixture was stirred at -78°C for 30 minutes and then warmed to room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate. The mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 123-1.

[0616] Step 2: A solution of 123-1 (2 g, 12.528 mmol) in sulfuric acid (10 mL) was slowly added to a mixture of sulfuric acid (15 mL) and nitric acid (7 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was poured into ice water and stirred for 1 hour. The organic phase was washed with 1M sodium bicarbonate aqueous solution and brine. The organic phase was concentrated to give 123-2.

[0617] Compound 123-3 was prepared from 123-2 according to the synthetic procedure of compound 5-4 in Example 4.

[0618] According to the synthetic procedure of compound 5 in Example 4, compound 123 was prepared from 123-3. LCMS (ESI, m / z): [M+H] + =466.1; 1 H-NMR (400MHz, CDCl3, ppm): δ12.33(s,1H),9.45(s,1H),8.88(s,1H),8.10(s,1H),3.21(s,3H),2.26-2. 18(m,2H),1.64-1.61(m,1H),1.58-1.44(m,3H),1.28-1.27(m,2H),1.15-1.09(m,1H),1.07-0.97(m,3H).

[0619] Example 42 Synthesis of Compound 124

[0620]

[0621] Step 1: 3-Chloroperoxybenzoic acid (11.54 g, 57.05 mmol) was added to a solution of 5-5 (5 g, 22.820 mmol) in dichloromethane (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with aqueous sodium hydroxide solution (1 N) and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane) to give 124-1.

[0622] Step 2: A solution of 124-1 (1.8 g, 7.168 mmol), 3,3-difluoroazetidine (2.79 g, 21.505 mmol), tris(dibenzylideneacetone)dipalladium (0.66 g, 0.717 mmol), cesium carbonate (389.03 mg, 1.194 mmol) and 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl (75.94 mg, 0.159 mmol) in dioxane (150 mL) was stirred at 110 ° C. for 6 hours under N2 atmosphere. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 124-2.

[0623] Step 3: A solution of 124-2 (1.5 g, 5.698 mmol) in dibromomethane (50 mL) was treated with tetrabutylammonium bromide (2446.16 mg, 7.597 mmol) and tert-butyl nitrite (6.769 mL, 56.976 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated to give 124-3.

[0624] Compound 124 was prepared from 124-3 according to the synthetic procedure of compound 5-8 in Example 4. LCMS (ESI, m / z): [M+H] + =511.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ11.78 (s, 1H), 11.15 (s, 1H), 9.14-9.11 (m, 2H), 8.06 (d, J = 3.2Hz, 1H), 7.46 (d ,J=3.2Hz,1H),4.47(t,J=12.0Hz,4H),3.30(s,3H),2.47-2.41(m,1H),1.47-1.32(m,2H),0.95-0.71(m,4H). 19 F-NMR (376MHz, DMSO-d6, ppm): δ-98.27 (2F).

[0625] Example 43 Synthesis of Compound 126

[0626]

[0627] Step 1: A suspension of 5-5 (1 g, 219.1 mmol) and copper cyanide (820 mg, 89.56 mmol) in N,N-dimethylformamide (10 mL) was stirred at 155 ° C for 12 hours. The mixture was poured into an aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 126-1.

[0628] Step 2: Tetrabutylammonium bromide (1560.92 mg, 4.842 mmol) and tert-butyl nitrite (1.440 mL, 12.105 mmol) were added to a solution of 126-1 (200 mg, 1.211 mmol) in dibromomethane (5 mL) at room temperature and then stirred for 4 hours. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-50%) to give 126-2.

[0629] Step 3: To a solution of 1-3 (10 g, 48.537 mmol) in dimethyl sulfoxide (100 mL) was added 4-methoxybenzylamine (7.32 g, 53.391 mmol) and potassium fluoride (8.46 g, 145.611 mmol). The reaction mixture was stirred at 120 ° C for 3 hours, the mixture was cooled to room temperature and poured into water. The solid was collected by filtration and dried in vacuo to give 126-3.

[0630] According to the synthetic procedure of compound 5-8 in Example 4, compound 126-4 was prepared from 126-3 and 5-2.

[0631] According to the synthetic procedure of compound 50-3 in Example 23, compound 126-5 was prepared from 126-4.

[0632] According to the synthetic procedure of compound 5 in Example 4, compound 126 was prepared from 126-5 and 126-2. LCMS (ESI, m / z): [M+H] + =445.1; 1 H-NMR (400MHz, DMSO-d6, ppm): δ12.49(s,1H),11.36(s,1H),9.54(s,1H),9.28(s,1H),9.03 (s,1H),8.61(s,1H),3.42(s,3H),2.50-2.46(m,1H),1.46-1.39(m,2H),0.98-0.74(m,4H).

[0633] Example 44 Synthesis of Compounds 129 and 130

[0634]

[0635] Compound 129-1 was prepared from 5-2 according to the synthetic procedure of compound 8-3 in Example 7.

[0636] Compounds 129 and 130 were prepared from 129-1 according to the synthetic procedure of compound 8 in Example 7. Compounds 129 and 130 were prepared by preparative SFC (using MeOH / CO2 AD) purification.

[0637] 129: Chiral SFC analysis: 99.44% ee. The retention time on an AD-3 100*3mm 3μm column (35°C) was 2.420 minutes; mobile phase: MeOH (0.1% DEA) in CO2, 1800psi, 1.5mL / min.

[0638] 129: LCMS (ESI, m / z): [M+H] + =431.2; 1 H-NMR (400MHz, CDCl3, ppm): δ12.76(s,1H),10.14(s,1H),9.32(br s,1H),8.60(d,J=4.4Hz,1H),8.19(s,1H),7.11(d,J=5.2Hz,1H),4.95-4.74(m,2H),3.71(s,3H) ,2.27-2.17(m,1H),1.73-1.65(m,1H),1.61-1.52(m,1H),1.20-1.12(m,1H),1.10-0.96(m,3H).

[0639] 130: Chiral SFC analysis: >99.5% ee. Retention time on AD-3 100*3mm 3μm column (35°C) was 3.892 minutes; mobile phase: MeOH (0.1% DEA) in CO2, 1800psi, 1.5mL / min.

[0640] 130:LCMS(ESI,m / z):[M+H] + =431.2; 1H-NMR (400MHz, CDCl3, ppm): δ12.71(s,1H),10.12(s,1H),9.33(br s,1H),8.59(d,J=5.2Hz,1H),8.21(s,1H),7.10(d,J=5.2Hz,1H),4.95-4.73(m,2H),3.69(s,3H) ,2.28-2.25(m,1H),1.74-1.65(m,1H),1.57-1.49(m,1H),1.17-1.08(m,1H),1.07-0.94(m,3H).

[0641] The compounds of the present disclosure can be prepared following similar procedures and methods described above. Table 1 shows the characterization of representative compounds prepared.

[0642] Table 1. Characterization of representative compounds of the present disclosure

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654] HEK-Blue IL-23 STAT3 reporter gene assay

[0655] HEK-Blue IL23 cells (InvivoGen catalog #HKB-IL23) are designed to detect biologically active IL-23 by monitoring activation of the STAT3 pathway. They are generated by stably introducing the human IL-23 receptor gene STAT3 and the SEAP (secreted embryonic alkaline phosphatase) reporter gene into the human HEK293 cell line.

[0656] Briefly, approximately 50,000 cells in DMEM medium supplemented with 10% heat-inactivated FBS (approximately 180 ul) were seeded into each well and incubated at 37°C and 5% CO2 in air for 48 hours. On day 3, 1 μl of compound and 20 μl of IL-23 were transferred to the assay plate separately. The assay plate was left in a 37°C incubator overnight. 2 μl of cell supernatant was transferred to a 384-well plate and 18 ul of resuspended QUANTI-Blue solution was added to each well. The plate was measured using a Tecan Spark at OD 655 SEAP levels were measured.

[0657] Cells without IL23 were used as low control. Cells stimulated with IL23 were used as high control. The inhibition rate was calculated as: % inhibition = 100*(high control - treated well) / (high control - low control). IL-23 reporter gene assay inhibition IC 50 Calculate using the following equation: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)).

[0658] Table 2. Inhibition of HEK-Blue IL23 reporter gene by representative compounds

[0659]

[0660]

[0661] The Brief Description and Abstract sections may set forth one or more, but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.

[0662] The present invention has been described above with the aid of functional building blocks, which illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined as long as the specified functions and their relationships are properly performed.

[0663] With respect to aspects of the invention described as a genus, all individual species are considered separately as independent aspects of the invention. If aspects of the invention are described as "comprising" a feature, embodiments are also contemplated as "consisting of" or "consisting essentially of" the feature.

[0664] The above description of the specific embodiments will fully reveal the general nature of the invention so that others can easily modify and / or adapt various applications, such as specific embodiments, by applying knowledge within the art without undue experimentation and without departing from the general concept of the invention. Therefore, based on the teachings and guidance presented herein, such modifications and adaptations are intended to be within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the words or terms herein are for the purpose of description rather than limitation, so that the terms or words of this specification will be interpreted by those skilled in the art based on the teachings and guidance.

[0665] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0666] All of the various aspects, embodiments and options described herein may be combined in any and all variations.

[0667] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

[0668] The present invention includes the following embodiments:

[0669] 1. A compound of formula I or a pharmaceutically acceptable salt thereof:

[0670]

[0671] in:

[0672] X 1 Yes CR 10 or N;

[0673] Y is CR 10 or N;

[0674] L 1 YesNR 11 , or does not exist;

[0675] L 2 is an optionally substituted C 1-4 Alkylene, optionally substituted C 1-4 Heteroalkylene, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-6 membered heterocyclylene or NH;

[0676] X 2 O or NR 13 ;

[0677] represents an optionally substituted phenyl group or an optionally substituted 6-membered heteroaryl ring,

[0678] in:

[0679] J 1 Yes CR 14 or N;

[0680] J 2 Yes CR 15 or N;

[0681] J 3 Yes CR 16 or N;

[0682] J 4 Yes CR 17 or N; and

[0683] J 5 It is C;

[0684] or represents an optionally substituted 5-membered heteroaryl ring,

[0685] in:

[0686] J 1 Yes CR 18 NR 19 , O, S or N;

[0687] J 4 Yes CR 20 NR 21 , O, S or N;

[0688] J 5 is C or N; and

[0689] J 2 and J 3 One of the does not exist, and J 2 and J 3 The other one is O, S, N, NR 22 or CR 23 ;

[0690] in:

[0691] R 1 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10carbocycle, optionally substituted 4-10 membered heterocycle, optionally substituted phenyl or optionally substituted heteroaryl;

[0692] R 2 is hydrogen, CD3, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl;

[0693] R 3 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 heteroalkyl or nitrogen protecting groups;

[0694] R 4 is hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 heteroalkyl;

[0695] in:

[0696] R 10 At each occurrence, hydrogen, halogen, CN, OH, C optionally substituted by F 1-4 Alkyl, optionally substituted by F 1-4 alkoxy, or C optionally substituted by one or more substituents independently selected from F, methyl and OH 3-6 Cycloalkyl;

[0697] R 11 , R 12 and R 13 are each independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 Cycloalkyl; or R 11 and R 12 Together with the middle atom, they are linked to form an optionally substituted 5-8 membered ring structure;

[0698] R 14 , R 15 , R 16 , R 17 , R 18 , R 20 and R 23 are independently halogen, R A , OR A , SR A 、S(O)R A 、S(O)2R A , COR A 、COOR A 、CN、NR B R C ,CONR B RC 、S(O)2NR B R C , or NO2,

[0699] R 19 , R 21 and R 22 Each independently is R A , COR A 、COOR A 、S(O)2R A 、S(O)2NR B R C or CONR B R C ,

[0700] Where R A is independently at each occurrence hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-8 Carbocyclic group, optionally substituted C 1-4 heteroalkyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted phenyl,

[0701] Where R B and R C Each time it occurs, it is independently R A 、-C(O)-R A 、-COOR A 、S(O)2R A ,CONR B 'R C ', where R B ' and R C Each of ' is independently R A ;

[0702] or R B and R C Joined together with the nitrogen to which they are both attached to form an optionally substituted 4-8 membered ring structure;

[0703] or R 4 and R 13 , if applicable, together with the intermediate atoms, are joined to form an optionally substituted 5-8 membered ring structure;

[0704] or R 4 and R 14 , R 13 and R 14 , R 14 and R 15 , R 15and R 16 , or R 16 and R 17 , if applicable, together with respective intermediate atoms to form an optionally substituted 5-8 membered ring structure; or

[0705] R 13 and R 18 , R 13 and R 19 , R 18 and R 22 , R 18 and R 23 , R 19 and R 22 , R 19 and R 23 , R 20 and R 22 , R 20 and R 23 , R 21 and R 22 , or R 21 and R 23 , if applicable, together with respective intermediate atoms, are joined to form an optionally substituted 5-8 membered ring structure.

[0706] 2. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, characterized in that it has Formula I-1, Formula I-2 or Formula I-3:

[0707]

[0708] 3. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1 or 2, characterized in that it has Formula I-1-A, I-1-B, I-1-C, or Formula I-1-D:

[0709]

[0710]

[0711] 4. The compound according to Embodiment 3 or a pharmaceutically acceptable salt thereof, characterized in that it has formula I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5 or I-1-A-6:

[0712]

[0713] in:

[0714] Ring A in formula I-1-A-4 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S, in addition to the ring S and N atoms shown therein,

[0715] Ring B in formula I-1-A-5 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S,

[0716] Ring C in formula I-1-A-6 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S,

[0717] in:

[0718] Where valence permits, n is an integer from 0 to 6 (e.g., 0, 1 or 2);

[0719] R D is independently halogen, G A , OG A , OH, CN or NG B G C , or two R D forming bonds, oxo or ring structures;

[0720] Among them G A is independently at each occurrence an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 4-8 membered heterocyclic group,

[0721] Among them G B and G C is independently hydrogen, G A , COG A or S(O)2G A .

[0722] 5. The compound according to Embodiment 3 or a pharmaceutically acceptable salt thereof, characterized in that it has formula I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14 or I-1-A-15:

[0723]

[0724]

[0725] in:

[0726] Where valence permits, m is an integer from 0 to 4 (e.g., 0, 1 or 2);

[0727] R E F, Cl, G independently at each occurrence D , OG D, OH or CN, or two R E forming bonds, oxo or ring structures;

[0728] Among them G D is independently at each occurrence an optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 4-8 membered heterocyclyl.

[0729] 6. The compound according to any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that J 1 Yes CR 14 , and R 14 is hydrogen, halogen (e.g., F or Cl), G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E or O-(C 1-4 Alkylene)-G E ,

[0730] Among them G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0731] 7. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1-5, characterized in that J 1 Yes CR 14 , and R 14 It is hydrogen, F, Cl, CN, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxy substituted C 1-4 Alkyl (such as hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 Alkoxy (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (e.g., CF3O-, CF3CH2O-, etc.), cyclopropyloxy or cyclobutyloxy.

[0732] 8. The compound according to any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that J 1 Yes CR 14 , and R 14 It is hydrogen, F, CH3, CH2OH, OCH3 or cyclopropyl.

[0733] 9. The compound according to any one of embodiments 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that J 2 Yes CR 15 , and R 15 is hydrogen, halogen (e.g., F or Cl), G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E 、O-(C 1-4 Alkylene)-G E SG E 、S(O)-G E or S(O)2-G E ,

[0734] Among them G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0735] 10. The compound according to any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, characterized in that J 2 Yes CR 15 , and R 15 For hydrogen, F, Cl, CN, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxy substituted C 1-4 Alkyl (such as hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 Alkyl (such as fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 Alkoxy (such as methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (such as CF3O-, CF3CH2O-, etc.), C1-4 Alkylthio (e.g. CH3S-), fluorine-substituted C 1-4 Alkylthio (eg CF3S-), cyclopropyloxy or cyclobutyloxy.

[0736] 11. The compound according to any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, characterized in that J 2 Yes CR 15 , and R 15 is hydrogen, F, Cl, CN, CH3, CH2CH3, CHF2, CF3, OCH3, OCH2CH3, O-CH(CH3)2, OCF3, SCF3 or cyclopropyl, or R 15 Selected from:

[0737]

[0738] 12. The compound according to any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, characterized in that J 3 Yes CR 16 , and R 16 Hydrogen, F, Cl, G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E or O-(C 1-4 Alkylene)-G E ,

[0739] Among them G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0740] 13. The compound according to any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, characterized in that J 3 Yes CR 16 , and R 16 For hydrogen, F, Cl, CN, C 1-4 Alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), fluorine-substituted C 1-4 Alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, C 3-6Cycloalkyl (e.g. cyclopropyl, cyclobutyl, etc.), C 1-4 Alkoxy (such as methoxy, ethoxy, etc.), fluorine-substituted C 1-4 Alkoxy (e.g., CF3O-, CF3CH2O-, etc.), cyclopropyloxy or cyclobutyloxy.

[0741] 14. The compound according to any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, characterized in that J 3 Yes CR 16 , and R 16 For hydrogen, F, Cl, CN, C 1-4 Alkyl, C 1-4 Alkoxy, cyclopropyl or cyclobutyl.

[0742] 15. The compound according to any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, characterized in that J 1 Yes CR 14 , J 2 Yes CR 15 , and R 14 and R 15 At least one of is not hydrogen.

[0743] 16. The compound according to any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, characterized in that J 1 Yes CR 14 , J 2 Yes CR 15 , J 3 Yes CR 16 , and R 14 , R 15 and R 16 All are hydrogen.

[0744] 17. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1-3 and 6-16, characterized in that when J 4 Yes CR 17 When R 17 For hydrogen.

[0745] 18. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: The moiety represents an optionally substituted 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from S, O and N.

[0746] 19. The compound according to embodiment 18 or a pharmaceutically acceptable salt thereof, characterized in that it has formula I-1-E, I-1-F or I-1-G:

[0747]

[0748] 20. The compound according to embodiment 18 or 19 or a pharmaceutically acceptable salt thereof, characterized in that J 1 Yes CR 18 , and R 18 is hydrogen, halogen (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0749] 21. The compound according to any one of embodiments 18-20 or a pharmaceutically acceptable salt thereof, characterized in that J 2 Yes CR 23 , J 3 does not exist, and R 23 is hydrogen, halogen (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0750] 22. The compound according to any one of embodiments 18-20 or a pharmaceutically acceptable salt thereof, characterized in that J 2 YesNR 22 , J 3 does not exist, and R 22 It is hydrogen, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0751] 23. The compound according to any one of embodiments 1-22 or a pharmaceutically acceptable salt thereof, characterized in that X 2 is O.

[0752] 24. The compound according to any one of embodiments 1-22 or a pharmaceutically acceptable salt thereof, characterized in that X 2 NR 13 .

[0753] 25. The compound according to embodiment 24 or a pharmaceutically acceptable salt thereof, characterized in that R 13 It is hydrogen or methyl.

[0754] 26. The compound according to any one of embodiments 1-25 or a pharmaceutically acceptable salt thereof, characterized in that R 4 is optionally one or more independently selected from F, OH and C 1-4 Substituents of heteroalkyl substituted C 1-4 Alkyl, or, when applicable, R 4 and R 13 and the intermediate atoms are linked together to form an optionally substituted 5-8 membered ring structure, for example

[0755]

[0756] 27. The compound according to any one of embodiments 1-25 or a pharmaceutically acceptable salt thereof, characterized in that R 4 It's methyl.

[0757] 28. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that Some selected from:

[0758]

[0759]

[0760] 29. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that Some selected from:

[0761] 30. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that Some selected from:

[0762]

[0763]

[0764] 31. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that Some selected from:

[0765]

[0766] 32. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that Some selected from:

[0767]

[0768] 33. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that Some selected from:

[0769]

[0770] 34. The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 NR 11 .

[0771] 35. The compound according to embodiment 34 or a pharmaceutically acceptable salt thereof, characterized in that R 11 It is hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

[0772] 36. The compound according to embodiment 34 or a pharmaceutically acceptable salt thereof, characterized in that R 11 It's hydrogen.

[0773] 37. The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 for

[0774] 38. The compound according to embodiment 37 or a pharmaceutically acceptable salt thereof, characterized in that R 11 It's hydrogen.

[0775] 39. The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 for

[0776] 40. The compound according to embodiment 39 or a pharmaceutically acceptable salt thereof, characterized in that R 11 It's hydrogen.

[0777] 41. The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 for

[0778] 42. The compound according to embodiment 41 or a pharmaceutically acceptable salt thereof, characterized in that R 11 is hydrogen and R 12 It's hydrogen.

[0779] 43. The compound according to any one of embodiments 1-42 or a pharmaceutically acceptable salt thereof, characterized in that R 1 Selected from: 1) Monocyclic C 3-6 Cycloalkyl; 2) spiro, fused or bridged bicyclic C 4-10 cycloalkyl; 3) monocyclic 4-8 membered heterocyclyl having 1-3 heteroatoms independently selected from O, N and S; 4) spirocyclic, fused or bridged bicyclic 5-10 membered heterocyclyl having 1-3 heteroatoms independently selected from O, N and S; 5) phenyl; 6) 6 membered heteroaryl having 1 or 2 ring nitrogen atoms; 7) 5 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S; 8) 8-10 membered bicyclic heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S; and 9) C 1-6 Alkyl, wherein each of the groups 1) to 9) is optionally substituted with one or more G 1 Replacement, where G 1 is independently at each occurrence a halogen (eg, F or Cl), G 1A , OG 1A , (C 1-4 Alkylene)-G 1A 、O-(C 1-4 Alkylene)-G 1A , OH, CN or NG 1B G 1C or two G 1 to form a bond, oxo or ring structure wherein:

[0780] G 1A Each occurrence is independently:

[0781] i)C1-6 alkyl,

[0782] ii) C 3-6 Cycloalkyl,

[0783] iii) C 1-4 Heteroalkyl,

[0784] iv) a 4-8 membered heterocyclyl group having 1-3 ring heteroatoms independently selected from O, N and S,

[0785] v) phenyl, or

[0786] vi) 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from O, N and S,

[0787] wherein each of i) to vi) is optionally substituted, for example, by one or more (e.g., 1, 2, or 3) substituents, each of which is independently selected from F, Cl, CN, OH, oxo (if valence permits), C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, N and S, phenyl or 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from O, N and S, wherein C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are independently optionally substituted with one or more (e.g. 1, 2 or 3) substituents independently selected from F, Cl, CN, OH, oxo (as valence permits), optionally with one or more (e.g. 1-3) G 1D Substituted C1-4 alkyl, optionally substituted with one or more (e.g. 1-3) G 1D Substituted C 1-4 Heteroalkyl and optionally substituted by one or more (eg 1-3) G 1D Substituted C 3-6 Cycloalkyl, where G 1D F, OH, or C at each occurrence 1-4 alkyl,

[0788] Among them G 1B and G 1C is independently hydrogen, G 1A , (C 1-4 Alkylene)-G 1A , COG 1A 、CO-(C 1-4 Alkylene)-G 1A 、S(O)2G 1A or S(O)2-(C1-4 Alkylene)-G 1A .

[0789] 44. The compound according to any one of embodiments 1-33 or 43, or a pharmaceutically acceptable salt thereof, characterized in that L 1 Does not exist.

[0790] 45. The compound according to embodiment 44 or a pharmaceutically acceptable salt thereof, characterized in that R 1 is a 5-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein the 5-membered heteroaryl is optionally substituted by one or more G 2 Replacement, where G 2 is independently at each occurrence a halogen (eg, F or Cl), G 2A , OG 2A , (C 1-4 Alkylene)-G 2A 、O-(C 1-4 Alkylene)-G 2A , OH, CN or NG 2B G 2C , or two G 2 Forming a ring structure,

[0791] Among them G 2A C independently at each occurrence 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-4 heteroalkyl or a 4-8 membered heterocyclyl having 1-3 heteroatoms independently selected from O, N and S, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-4 The heteroalkyl or 4-8 membered heterocyclyl is optionally substituted by one or more (e.g. 1, 2 or 3) each independently selected from F, Cl, OH, C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Heteroalkyl or fluorine-substituted C 1-4 Substituents of heteroalkyl groups are substituted,

[0792] Among them G 2B and G 2C is independently hydrogen, G 2A , (C 1-4 Alkylene)-G 2A , COG 2A 、CO-(C 1-4 Alkylene)-G 2A 、S(O)2G 2A or S(O)2-(C 1-4 Alkylene)-G2A .

[0793] 46. ​​The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 -R 1 Selected from:

[0794]

[0795] 47. The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 -R 1 Selected from:

[0796]

[0797] 48. The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 -R 1 yes:

[0798]

[0799] 49. The compound according to any one of embodiments 1-33 or a pharmaceutically acceptable salt thereof, characterized in that L 1 -R 1 Selected from:

[0800]

[0801] 50. The compound according to any one of embodiments 1-49 or a pharmaceutically acceptable salt thereof, characterized in that L 2 It's NH.

[0802] 51. The compound according to any one of embodiments 1-49 or a pharmaceutically acceptable salt thereof, characterized in that L 2 It is C 1-4 Alkylene or cyclopropylene.

[0803] 52. The compound according to any one of embodiments 1-51 or a pharmaceutically acceptable salt thereof, characterized in that R 2 It is hydrogen, C 1-4 Alkyl or CD3.

[0804] 53. The compound according to any one of embodiments 1-49 or a pharmaceutically acceptable salt thereof, characterized in that L 2 -R 2 Selected from:

[0805]

[0806] 54. The compound according to any one of embodiments 1-49 or a pharmaceutically acceptable salt thereof, characterized in that L 2 -R 2 yes:

[0807]

[0808] 55. The compound according to any one of embodiments 1-54 or a pharmaceutically acceptable salt thereof, characterized in that R 3 It's hydrogen.

[0809] 56. A compound selected from Compound Nos. 1-133 or a pharmaceutically acceptable salt thereof.

[0810] 57. A pharmaceutical composition comprising a compound according to any one of embodiments 1-56 or a pharmaceutically acceptable salt thereof.

[0811] 58. A method of inhibiting Tyk2-mediated signal transduction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 57.

[0812] 59. A method for modulating the function of IL-12, IL-23 and / or interferon-α in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 57.

[0813] 60. A method for treating or preventing a disease or condition mediated by Tyk2 (e.g., mediated by IL-12, IL-23 and / or interferon-α) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 57.

[0814] 61. A method for treating or preventing a proliferative, metabolic, allergic, autoimmune and / or inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 57.

[0815] 62. A method for treating or preventing an autoimmune and / or inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 57.

[0816] 63. A method for treating or preventing a metabolic disease or condition, such as type 2 diabetes or atherosclerosis, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 57.

[0817] 64. A method for treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 57.

[0818] 65. A method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 57, wherein the disease or condition is one or more diseases or conditions selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and scleroderma.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: X 1 Yes CR 10 or N; Y is CR 10 or N; L 1 YesNR 11 , or does not exist; L 2 is an optionally substituted C 1-4 Alkylene, optionally substituted C 1-4 Heteroalkylene, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-6 membered heterocyclylene or NH; X 2 O or NR 13 ; represents an optionally substituted phenyl group or an optionally substituted 6-membered heteroaryl ring, in: J 1 Yes CR 14 or N; J 2 Yes CR 15 or N; J 3 Yes CR 16 or N; J 4 Yes CR 17 or N; and J 5 It is C; or represents an optionally substituted 5-membered heteroaryl ring, in: J 1 Yes CR 18 NR 19 , O, S or N; J 4 Yes CR 20 NR 21 , O, S or N; J 5 is C or N; and J 2 and J 3 One of the does not exist, and J 2 and J 3 The other one is O, S, N, NR 22 or CR 23 ; in: R 1 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 carbocycle, optionally substituted 4-10 membered heterocycle, optionally substituted phenyl or optionally substituted heteroaryl; R 2 is hydrogen, CD3, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl; R 3 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 heteroalkyl or nitrogen protecting groups; R 4 is hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 heteroalkyl; in: R 10 At each occurrence, hydrogen, halogen, CN, OH, C optionally substituted by F 1-4 Alkyl, optionally substituted by F 1-4 alkoxy, or C optionally substituted by one or more substituents independently selected from F, methyl and OH 3-6 Cycloalkyl; R 11 , R 12 and R 13 are each independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 Cycloalkyl; or R 11 and R 12 Together with the middle atom, they are linked to form an optionally substituted 5-8 membered ring structure; R 14 , R 15 , R 16 , R 17 , R 18 , R 20 and R 23 are independently halogen, R A , OR A , SR A 、S(O)R A 、S(O)2R A , COR A 、COOR A 、CN、NR B R C ,CONR B R C 、S(O)2NR B R C , or NO2, R 19 , R 21 and R 22 Each independently is R A , COR A 、COOR A 、S(O)2R A 、S(O)2NR B R C or CONR B R C , Where R A is independently at each occurrence hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-8 Carbocyclic group, optionally substituted C 1-4 heteroalkyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted phenyl, Where R B and R C Each time it occurs, it is independently R A 、-C(O)-R A 、-COOR A 、S(O)2R A ,CONR B 'R C ', where R B ' and R C Each of ' is independently R A ; or R B and R C Joined together with the nitrogen to which they are both attached to form an optionally substituted 4-8 membered ring structure; or R 4 and R 13 , if applicable, together with the intermediate atoms, are joined to form an optionally substituted 5-8 membered ring structure; or R 4 and R 14 , R 13 and R 14 , R 14 and R 15 , R 15 and R 16 , or R 16 and R 17 , if applicable, together with respective intermediate atoms to form an optionally substituted 5-8 membered ring structure; or R 13 and R 18 , R 13 and R 19 , R 18 and R 22 , R 18 and R 23 , R 19 and R 22 , R 19 and R 23 , R 20 and R 22 , R 20 and R 23 , R 21 and R 22 , or R 21 and R 23 , if applicable, together with respective intermediate atoms, are joined to form an optionally substituted 5-8 membered ring structure.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Having formula I-1, formula I-2 or formula I-3:

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: Having formula I-1-A, I-1-B, I-1-C, or formula I-1-D:

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that: Having the formula I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5 or I-1-A-6: in: Ring A in formula I-1-A-4 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S, in addition to the ring S and N atoms shown therein, Ring B in formula I-1-A-5 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S, Ring C in formula I-1-A-6 is a 5- to 8-membered ring, optionally containing one or more ring heteroatoms independently selected from N, O or S, in: Where valence permits, n is an integer from 0 to 6 (e.g., 0, 1 or 2); R D is independently halogen, G A , OG A , OH, CN or NG B G C , or two R D forming bonds, oxo or ring structures; Among them G A is independently at each occurrence an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 4-8 membered heterocyclic group, Among them G B and G C is independently hydrogen, G A , COG A or S(O)2G A .

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that: Having the formula I-1-A-7, I-1-A-8, I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, I-1-A-13, I-1-A-14 or I-1-A-15: in: Where valence permits, m is an integer from 0 to 4 (e.g., 0, 1 or 2); R E F, Cl, G independently at each occurrence D , OG D , OH or CN, or two R E forming bonds, oxo or ring structures; Among them G D is independently at each occurrence an optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-4 heteroalkyl or an optionally substituted 4-8 membered heterocyclyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that: J 1 Yes CR 14 , and R 14 is hydrogen, halogen (e.g., F or Cl), G E 、-(C 1-4 Alkylene)-G E , OH, CN, OG E or O-(C 1-4 Alkylene)-G E , Among them G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, wherein C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from F, C 1-4 The alkyl group (eg, methyl group) and the OH group are substituted with substituents.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: J 1 Yes CR 14 , and R 14 It is hydrogen, F, Cl, CN, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxy substituted C 1-4 Alkyl (such as hydroxymethyl, hydroxyethyl, etc.), fluorine-substituted C 1-4 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, azetidinyl, C 1-4 Alkoxy (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy (e.g., CF3O-, CF3CH2O-, etc.), cyclopropyloxy or cyclobutyloxy.

8. A compound selected from Compound Nos. 1-133 or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. A method for inhibiting Tyk2-mediated signal transduction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9.

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