Heteroaryl compounds, processes for their preparation and uses thereof

Abstract

Provided herein are novel compounds, e.g., compounds of Formula I, or a pharmaceutically acceptable salt thereof. Also provided herein are methods of making the compounds and methods of using the compounds, e.g., to inhibit the function of TYK2 and / or IL-12, IL-23, and / or INF-a, and / or to treat various associated diseases or disorders.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to international application No. PCT / CN2020 / 138305, filed on December 22, 2020, and PCT / CN2021 / 086083, filed on April 9, 2021, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] In various embodiments, this disclosure generally relates to novel heteroaryl compounds, compositions comprising the same, methods of their preparation, and methods of using them, for example, for inhibiting kinases and / or for treating various diseases or conditions, such as autoimmune diseases, as described herein. Background Technology

[0004] Cytokines play a crucial role 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, produced by activated antigen-presenting cells, are essential for the differentiation and proliferation of Th1 and Th17 cell lineages, two key effector T cell lines in autoimmunity. IL-23 is required for the survival and expansion of Th17 cells, which produce pro-inflammatory cytokines such as IL-17A, IL-17F, IL-6, and TNF-α. IL-12 is essential for Th1 cell development and the secretion of IFNg, a cytokine that plays a key role in immunity by stimulating MHC expression, B cell class switching to IgG subclasses, and macrophage activation. Genome-wide association studies have identified numerous gene loci associated with chronic inflammation and autoimmune diseases that encode factors acting 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 effects of IL-12 and IL-23 are expected to have therapeutic benefits in human autoimmune diseases.

[0005] The type I interferon group (IFNs), including IFNα members as well as IFNβ, IFNε, IFNκ, and IFNω, acts via the heterodimeric IFNα / β receptor (IFNAR). Type I interferons play multiple roles in the innate and adaptive immune systems, including activating cellular and humoral immune responses and enhancing the expression and release of autoantigens. Genome-wide association studies have identified gene loci associated with lupus that encode factors acting in the type I interferon pathway, including IRF5, IKBKE, TYK2, and STAT4. Besides lupus, there is evidence that aberrant activation of the type I interferon-mediated pathway 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.

[0006] The Janus kinase (JAK) family is a small family of receptor-associated tyrosine kinases essential for downstream signaling cascades of type I and type II cytokine receptors. Type I and type II cytokine receptors—a family of receptors binding to more than 50 cytokines, interleukins, interferons (IFNs), colony-stimulating factors (CSFs), and hormones—share a unique intracellular signaling pathway 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 without binding to other types of cytokine receptors. JAK-dependent cytokines are major contributors to immunopathology. JAK dependence on type I and type II cytokines has been established in various genetic models ranging from mutagenic cell lines and gene knockout mice to humans. Polymorphisms in JAK and signal transduction and activating transcription factor (STAT) genes are associated with autoimmunity, and loss of function due to the inability of type I and type II cytokines to transmit signals through their receptors leads to immunodeficiency. The crucial role of JAK in type I and type II cytokine signaling strongly suggests that interfering with the activity of these kinases could lead to a new class of immunomodulatory drugs.

[0007] Tyrosine kinase 2 (TYK2), a member of the JAK non-receptor tyrosine kinase family, has been shown to play a crucial role in regulating downstream signal transduction cascades of IL-12, IL-23, and type I interferon receptors in both mice and humans. TYK2 is the only signaling messenger shared by IL-12 and IL-23. TYK2 mediates receptor-induced phosphorylation of members of the STAT transcription factor family, an essential signaling pathway leading to STAT protein dimerization and STAT-dependent pro-inflammatory gene transcription. Experimental models of TYK2-deficient mice resisting colitis, psoriasis, and multiple sclerosis demonstrate the importance of TYK2-mediated signaling in autoimmunity and related diseases. In humans, individuals expressing inactive variants of TYK2 are protected against multiple sclerosis and potentially other autoimmune diseases. Genome-wide 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.

[0008] Treatment has significantly altered outcomes for a range of allergic, inflammatory, and autoimmune diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). However, even with substantial progress in diseases such as rheumatoid arthritis, most patients do not fully respond to currently available therapies, and cases of long-term remission after discontinuation of treatment are relatively rare. Therefore, despite substantial progress, there remains a great need for new treatment strategies targeting immune and inflammatory diseases or conditions.

[0009] Novel compounds that inhibit the activity of TYK2, which can regulate cytokines and / or interferons (e.g., IL-12, IL-23, and / or IFNα), should provide a pharmacological response favorable for the treatment of one or more of the conditions described herein and could provide substantial therapeutic benefits to a variety of patients in need. Summary of the Invention

[0010] In various embodiments, this disclosure provides novel compounds, pharmaceutical compositions, and methods of preparation and use thereof. Typically, the compounds herein are TYK2 inhibitors that modulate the function of IL-12, IL-23, and / or IFN-α. The compounds and compositions herein can be used to treat a variety of 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.

[0011] In some embodiments, this disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof:

[0012]

[0013] 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, this disclosure also provides compounds of formula I, such as 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, or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure also provides specific compounds selected from compound numbers 1-133 or pharmaceutically acceptable salts thereof.

[0014] Some embodiments of this disclosure relate to a pharmaceutical composition comprising one or more compounds of this disclosure (e.g., formula I, e.g., 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 ... The pharmaceutical compositions described herein are compounds of the numbers 1-133 (or their pharmaceutically acceptable salts) and optionally pharmaceutically acceptable excipients. These compounds are available in the form of compounds 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. The pharmaceutical compositions described herein can be formulated for various routes of administration, such as oral or parenteral administration.

[0015] Some embodiments relate to methods for treating diseases or conditions associated with TYK2, such as those mediated by IL-12, IL-23, and / or interferon-α (INF-α). In some embodiments, the method includes administering a therapeutically effective amount of a compound of the present disclosure (e.g., formula I, e.g., formulas 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- Compounds of the following compounds (I-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 the pharmaceutical composition described herein. Diseases or conditions related to TYK2 that can be treated by the methods described herein include any of those known in the art and any of those described herein.

[0016] In some embodiments, methods for treating proliferative, metabolic, allergic, autoimmune, and / or inflammatory diseases or conditions are provided. In some embodiments, the method includes administering a therapeutically effective amount of a compound of the present disclosure (e.g., formula I, e.g., formulas 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-) to a subject in need. Compounds of the following numbers (I-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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition described herein. Suitable proliferative, metabolic, allergic, autoimmune, and / or inflammatory diseases or conditions that can be treated by the methods described herein include any of those diseases or conditions described herein.

[0017] In some embodiments, a method for treating autoimmune and / or inflammatory diseases or conditions is provided. In some embodiments, the method includes administering a therapeutically effective amount of a compound of the present disclosure (e.g., formula I, e.g., formulas 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-) to a subject in need. Compounds of the following compounds (I-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 the pharmaceutical composition described herein. Suitable autoimmune and / or inflammatory diseases or conditions that can be treated by the methods described herein include any of those diseases or conditions described herein.

[0018] In some embodiments, methods for treating metabolic diseases or conditions such as type 2 diabetes or atherosclerosis, as described herein, are provided. In some embodiments, the method includes administering a therapeutically effective amount of a compound of the present disclosure (e.g., formula I, e.g., formulas 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-) to a subject in need. The compound of I-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 the pharmaceutical composition described herein.

[0019] In some embodiments, a method for treating cancer is provided. In some embodiments, the method includes administering a therapeutically effective amount of a compound of the present disclosure (e.g., formula I, e.g., formulas 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-) to a subject in need. The compound of I-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 the pharmaceutical composition described herein.

[0020] In some embodiments, methods for 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 a therapeutically effective amount of a compound of the present disclosure (e.g., formula I, e.g., formulas 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- The compound of I-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 the pharmaceutical composition described herein.

[0021] The administration methods described herein are not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, pulmonary, inhalation, oral, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. The compounds disclosed herein may be used as monotherapy or in combination therapy.

[0022] It should be understood that the above brief description and the following detailed description are merely exemplary and explanatory, and not intended to limit the invention described herein. Detailed Implementation

[0023] In various embodiments, this document provides novel heteroaryl compounds, pharmaceutical compositions, methods of preparation, and methods of use. The compounds described herein are generally TYK2 inhibitors and can be used to treat a variety of diseases or conditions, such as those described herein, including 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.

[0024] compound

[0025] In some embodiments, this disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof:

[0026]

[0027] in:

[0028] X 1 It is CR 10 Or N;

[0029] Y is CR 10 Or N;

[0030] L 1 It is NR 11 , Or it may not exist;

[0031] L 2 C is an optional substitute 1-4 Alkylene, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-6 membered heterocyclic alkylene or NH;

[0032] X 2 For O or NR 13 ;

[0033] This indicates an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl ring.

[0034] in:

[0035] J 1 It is CR 14 Or N;

[0036] J 2 It is CR 15 Or N;

[0037] J 3 It is CR 16 Or N;

[0038] J 4 It is CR17 Or N; and

[0039] J 5 It is C;

[0040] or This indicates a 5-membered heteroaryl ring with optional substitution.

[0041] in:

[0042] J 1 It is CR 18 NR 19 , O, S or N;

[0043] J 4 It is CR 20 NR 21 , O, S or N;

[0044] J 5 It is C or N; and

[0045] J 2 and J 3 One of them does not exist, and J 2 and J 3 The other one is O, S, N, NR. 22 or CR 23 ;

[0046] in:

[0047] R 1 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclic ring, optionally substituted 4-10 membered heterocycle, optionally substituted phenyl or optionally substituted heteroaryl;

[0048] R 2 It is hydrogen, CD3, or an optional substituted C. 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl;

[0049] R 3 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or nitrogen-protected groups;

[0050] R 4 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or optionally substituted C 1-6 Heteroalkyl;

[0051] in:

[0052] R 10 Each occurrence is hydrogen, halogen, CN, OH, or C optionally substituted with F. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 alkoxy group, or C group optionally substituted with one or more substituents independently selected from F, methyl, and OH. 3-6 cycloalkyl;

[0053] R 11 R 12 and R 13 Each is independently hydrogen, and each of the optionally substituted C atoms is a carbon atom. 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 intermediate atom, they form optional substituted 5-8 membered ring structures;

[0054] R 14 R 15 R 16 R 17 R 18 R 20 and R 23 Each independently constitutes 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,

[0055] R 19 R 21 and R 22 Each independently as R A COR A COOR A S(O)2R A S(O)2NR B R C or CONR B R C ,

[0056] Where R A Each time it appears, it is independently hydrogen, with optional substituted C. 1-6Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 Carbocyclic group, optionally substituted C 1-4 Heteroalkyl, optionally substituted 4-8 membered heterocyclic, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted phenyl,

[0057] Where R B and R C Each occurrence is independently assigned the value R. A -C(O)-R A -COOR A S(O)2R A CONR B 'R C ', where R B 'and R C Each of the terms in ' is independently R A ;

[0058] Or R B and R C Together with the nitrogen atoms that are all connected to them, they form optionally substituted 4-8 membered ring structures;

[0059] Or R 4 and R 13 (If applicable) It is linked with the intermediate atom to form an optionally substituted 5-8 membered ring structure;

[0060] 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, they connect together with their respective intermediate atoms to form optionally substituted 5-8 membered ring structures; or

[0061] 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, they connect together with their respective intermediate atoms to form optional substituted 5-8 membered ring structures.

[0062] Those skilled in the art should understand that when " "In the formula, it is used to connect two atoms. It should be understood that, as long as the valence allows, the bond between the two atoms can be a single bond or a double bond."

[0063] For clarity, when R is mentioned 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, a 5-8 membered ring structure is formed by connecting with its respective intermediate atom to form an optionally substituted ring structure, it should be understood that only one pair of the pairs present in the structural formula according to Formula I can form an optionally substituted ring structure. For example, when R 13 and R 14 When R is linked with an intermediate atom to form an optionally substituted 5-8 membered ring structure, it should be understood that 4 and R 14 R 14 and R 15 R 15 and R 16 and R 16 and R 17 If applicable, a ring structure is not formed; rather, in such an implementation, R 15 R 16 and R 17 If applicable, and R 4 It should be understood to have the definition described herein, without involving the possibility of it forming a cycle with another variable. For example, in such an implementation, it should be understood that R, when present, 15 R 16 and R 17 Independently for halogens, R as defined herein 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. Furthermore, when R... 4 and R 13 When the links form optional substituted 5-8 member ring structures, R 4 and R 14 Typically, it does not form 5-8 membered ring structures with optional substitution, and vice versa. Similarly, in Equation I of this paper, when R is mentioned... 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 connecting with their respective intermediate atoms to form an optionally substituted 5-8 membered ring structure, it should be understood that only one of the pairs present in the structural formula according to Formula I can form an optionally substituted ring structure.

[0064] Compounds of Formula I (including any applicable sub-formulas as described herein) may exist as individual enantiomers, diastereomers, and / or geometric isomers, if applicable, or mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. In some embodiments, when applicable, compounds of Formula I (including any applicable sub-formulas as described herein) may contain separable 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.

[0065] Typically, X in Equation I 1 Let N be the number of elements in the array.

[0066] In some implementations, X in Formula I 1 It can also be CR 10 , where R 10 As defined in this article. For example, R10 It can be hydrogen, F, Cl, CN, OH, or C arbitrarily substituted with F. 1-4 Alkyl, or C substituted with F, by choice 1-4 Alkyl group. In some embodiments, X in Formula I... 1 It is CH.

[0067] In some implementations, Y in Equation I is N.

[0068] In some implementations, Y in Equation I is CR 10 , where R 10 As defined in this article. For example, R 10 It can be hydrogen, F, Cl, CN, OH, or C arbitrarily substituted with F. 1-4 Alkyl, or C substituted with F, by choice 1-4 Alkyl group.

[0069] Typically, Y in Equation I represents CH.

[0070] Typically, X 1 For N and Y, CH, compounds of formula I can be characterized as having formula I-1:

[0071]

[0072] Where 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 Any combination thereof includes any of those described herein.

[0073] In some implementation schemes, X 1 Both Y and CH can be CH, and compounds of formula I are characterized by having formula I-2:

[0074]

[0075] Where 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 Any combination thereof includes any of those described herein.

[0076] In some implementation schemes, X 1 Both Y can be N, and compounds of formula I are characterized by having formula I-3:

[0077]

[0078] Where 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 Any combination thereof includes any of those described herein.

[0079] In Equation I (e.g., Equation I-1, I-2, or I-3) The part (also referred to herein as M-10) typically represents an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl ring. In such embodiments, J 1 It can be CR 14 Or N; J 2 It can be CR 15 Or N; J 3 It can be CR 16 Or N; J 4 It can be CR 17 Or N; and J 5 It is C, where R 14 R 15 R 16 and R 17 Any combination thereof includes any of those described herein.

[0080] In embodiments where 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 implementations, J 1 It is CR 14 And R 14 It can be hydrogen, halogen, OH, CN or R A , where RA As defined herein, for example, in some implementations, R 14 C can be arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-4 Heteroalkyl groups, or optionally substituted 4-8 membered heterocyclic groups having 1-2 independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, J 1 It is 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 G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, J 1 It is CR 14 And R 14 It can be G as defined in this article. E In some implementation schemes, J 1 It is CR 14 And R 14 It is hydrogen, F, Cl, CN, C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4 Alkyl groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorinated C groups 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), cyclopropoxy groups, or cyclobutoxy groups. As used herein, hydroxyl-substituted C... 1-4 Alkyl refers to a C that has been substituted with one or two hydroxyl groups. 1-4Alkyl groups, such as -CH2-OH, -CH(CH3)-OH, or -CH2CH2OH. Fluorine-substituted C-molecules, as used herein. 1-4 Alkyl refers to a carbon atom substituted with 1-3 fluorine atoms. 1-4 Alkyl groups, such as -CF3, -CH2F, -CHF2, etc. Fluorine-substituted C... 1-4 Alkoxy groups refer to C atoms that are substituted with 1-3 fluorine atoms. 1-4 Alkyl groups, such as CF3O-, CF3CH2O-, etc. In some embodiments, J 1 It is CR 14 And R 14 Can be used with R 4 X 2 Or R 15 Together with their respective intermediate atoms, they connect to form optionally substituted 5-8 membered ring structures, such as 5-8 membered monocyclic carbocyclic rings or monocyclic heterocyclic rings, which are optionally substituted by one or more permitted substituents as described herein. In any embodiment described herein, unless otherwise stated or contrary to the context, when J 1 It is CR 14 At that time, R 14 It can be hydrogen, F, CH3, CH2OH, OCH3, or cyclopropyl.

[0081] In embodiments where 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 implementations, J 2 It is CR 15 And R 15 It can be hydrogen, halogen, OH, CN or R A , where R A As defined herein, for example, in some implementations, R 15 C can be arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-4 Heteroalkyl groups, or optionally substituted 4-8 membered heterocyclic groups having 1-2 independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, J 2 It is 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 G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, J 2 It is CR 15 And R 15 It can be G as defined in this article. E In some implementation schemes, J 2 It is CR 15 And R 15 It can be a 4-6 membered heterocyclic group with optional substitution of 1-2 independently selected cyclic heteroatoms chosen from N, O, and S, such as oxobutyryl, morpholino, or azirrobutyryl, which is optionally substituted by one or more (e.g., 1, 2, or 3) independently selected from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, J 2 It is CR 15 And R 15 It can be OG E G E It is C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), or 4-6 membered heterocyclic groups having 1-2 cyclic heteroatoms independently selected from N, O, and S, such as oxetane, optionally having one or more (e.g., 1, 2, or 3) independently selected from F, C 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, J 2 It is CR 15 And R 15 It can be O-(C 1-4 (alkylene)-G F G F It is OH, NH2, or C with optional substitution.1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, or a 4-6 membered heterocyclic group having 1-2 independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, J 2 It is CR 15 And R 15 It can be O-(C 1-4 (alkylene)-G F G F It is OH, NH2, NH(C) 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), C 1-4 Alkoxy groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy groups (e.g., CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl-substituted C 1-4 Alkoxy groups (e.g., -O-CH2CH2OH), alkoxy-substituted C 1-4 Alkyl groups (e.g., -O-CH2CH2OMe), O-acyl groups (e.g., O-CH(O), OC(O)CH3), NH-acyl groups, N(C 1-4 Alkyl)-acyl, or a 4-6 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, such as oxetyl, optionally having one or more (e.g., 1, 2, or 3) cyclic heteroatoms independently selected from F, C 1-4 Alkyl groups (e.g., methyl) and OH substituents. As used herein, it should be understood that in the expression "N(C 1-4 Alkyl)(C 1-4 The two Cs in "alkyl") 1-4 The alkyl groups can be the same or different. In some embodiments, J 2 It is CR 15 And R 15 It can be O-(C 1-4 (alkylene)-G F C 1-4 Alkylenes (from left (O) to right (G) F The connection of ) 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 groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4Alkoxy groups (e.g., CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl-substituted C 1-4 Alkoxy groups (e.g., -O-CH2CH2OH), or C groups substituted with alkoxy groups 1-4 Alkyl groups (e.g., -O-CH2CH2OMe). In some embodiments, J 2 It is CR 15 And R 15 For hydrogen, F, Cl, CN, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (such as hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (such as fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4 Alkoxy groups (such as methoxy, ethoxy, isopropoxy, etc.), fluorinated C groups 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 Alkyl thiols (e.g., CH3S-), fluorinated C 1-4 Alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy. As those skilled in the art will understand, alkylthio refers to a group having the general formula RS-, where R is an alkyl group. As used herein, fluorinated C 1-4 Alkylthio group refers to the group in which C 1-4 C10 with alkyl moiety replaced by 1-3 fluorine atoms 1-4 Alkylthio groups, such as CF3S-. In some embodiments, J 2 It is CR 15 And R 15 Can be used with R 14 Or R 16 The links, together with their respective intermediate atoms, form optionally substituted 5-8 membered ring structures, such as 5-8 membered monocyclic carbon rings or monocyclic heterocycles, which are optionally substituted by one or more permitted substituents as described herein. For example, in some embodiments, J 2 It is CR 15 And R 15 Can be used with R 16 Together with intermediate atoms, they form

[0082] In any of the embodiments described herein, unless otherwise stated or contrary to the context, when J 2 It is CR 15 At that time, R 15 It can be hydrogen, F, Cl, CN, CH3, CH2CH3, CHF2, CF3, OCH3, OCH2CH3, O-CH(CH3)2, OCF3, SCF3, cyclopropyl or In any of the embodiments described herein, unless otherwise stated or contrary to the context, when J 2 For CR 15 At that time, R 15 You can choose from: In any of the embodiments described herein, unless otherwise stated or contrary to the context, when J 2 For CR 15 At that time, R 15 You can choose from: In any of the embodiments described herein, unless otherwise stated or contrary to the context, when J 2 For CR 15 At that time, R 15 You can choose from: When R 15 When containing one or more chiral centers, this disclosure covers all potential stereoisomers and mixtures thereof (e.g., racemic mixtures). For example, in some embodiments, J 2 It is CR 15 R 15 It can be selected from the following stereoisomers: In some embodiments, with respect to the chiral center drawn above, the compound may exist primarily as the drawn enantiomer, for example, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other corresponding enantiomers by weight, by HPLC area, or both.

[0083] In embodiments where 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 implementations, J 3 It is CR 16 And R 16 It can be hydrogen, halogen, OH, CN or R A , where R A Defined herein, for example, in some implementations, R 16 C can be arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-4 Heteroalkyl groups, or optionally substituted 4-8 membered heterocyclic groups having 1-2 independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, J 3 It is CR 16 And R16 It 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 G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, J 3 It is CR 16 And R 16 It can be G as defined in this article. E In some implementation schemes, J 3 It can be CR 16 And R 16 It can be hydrogen, F, Cl, CN, C 1-4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), C 1-4 Alkoxy groups (e.g., methoxy, ethoxy, etc.), fluorine-substituted C 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), cyclopropoxy groups, or cyclobutoxy groups. In some embodiments, J 3 It is CR 16 And R 16 Can be used with R 15 Or R 17 And their respective intermediate atoms are linked to form optionally substituted 5-8 membered ring structures, such as 5-8 membered monocyclic carbocyclic rings or monocyclic heterocyclic rings, which are optionally substituted by one or more of the permitted substituents described herein. In any embodiment described herein, unless otherwise stated or contrary to the context, when J 3 It is CR 16 At that time, R 16 It can be hydrogen, F, Cl, CN, C 1-4 Alkyl, C 1-4 Alkoxy, cyclopropyl, or cyclobutyl.

[0084] In the embodiment where M-10 represents an optionally substituted 6-membered heteroaryl ring, J 4 Typically, N is used. 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 in this article, for example, hydrogen.

[0085] In embodiments where 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 [variables] is not particularly limited. For example, in some embodiments, [variables] in Formula I The phenyl group may be optionally substituted. In some embodiments, the phenyl group in Formula I... The pyridine may be optionally substituted.

[0086] In some preferred embodiments, in Formula I The portion may be an optionally substituted pyridinyl group, wherein J 4 It is N. For example, in some embodiments, the compound of formula I may be characterized by having formula I-1-A:

[0087]

[0088] Where variable L 1 R 1 L 2 R 2 R 3 R 14 R 15 R 16 X 2 and R 4 Any combination thereof includes any of those described herein.

[0089] For example, in some implementations, in formula I-1-A, R 14 It can be hydrogen. In some embodiments, in formula I-1-A, R 15 It can be hydrogen. In some embodiments, in formula I-1-A, R 16 It can be hydrogen. In some embodiments, in formula I-1-A, R 14 and R 15 One of them is hydrogen and R 14 and R 15 The other one is not hydrogen; for example, in some implementations, R 14 It is hydrogen and R 15It is not hydrogen. In some implementations, in formula I-1-A, R 14 and R 15 Neither of them are hydrogen. In some implementations, in formula I-1-A, R 14 and R 15 Both are hydrogen. In some implementations, in formula I-1-A, R 14 and R 16 They are all hydrogen, and R 15 It is not hydrogen. In some implementations, in formula I-1-A, all R... 14 R 15 and R 16 Both are hydrogen. In some implementations, in formula I-1-A, R 14 and R 15 Together with the intermediate atom, they form optionally substituted 5-8 membered rings, such as 5-8 membered carbon rings or heterocycles. In some embodiments, in formula I-1-A, R 15 and R 16 Together with the intermediate atom, they form optionally substituted 5-8 membered rings, such as 5-8 membered carbon rings or heterocycles. In some embodiments, in formula I-1-A, X 2 It is NR 13 And R 14 and R 13 They are linked together with intermediate atoms to form optional substituted 5-8 membered heterocycles.

[0090] For example, in some embodiments, the compound of formula I-1-A may be characterized by 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:

[0091]

[0092] in:

[0093] In Formula I-1-A-4, ring A is a 5-8 membered ring, which, in addition to the ring S and N atoms shown therein, optionally contains one or more cyclic heteroatoms independently selected from N, O, or S.

[0094] In Formula I-1-A-5, ring B is a 5-8 membered ring, optionally containing one or more cyclic heteroatoms independently selected from N, O, or S.

[0095] In formula I-1-A-6, ring C is a 5-8 membered ring, optionally containing one or more cyclic heteroatoms independently selected from N, O, or S.

[0096] in:

[0097] Where valence allows, n is an integer from 0 to 6 (e.g., 0, 1, or 2);

[0098] R D Each time it appears, it is independently of halogen, G. A OG A OH, CN or NG B G C , or two R D Forming bonds, oxidized or cyclic structures;

[0099] Among them G A Independently substitutes C for each occurrence. 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted 4-8 membered heterocyclic groups,

[0100] Among them G B and G C Each time it appears, it is independently hydrogen, G A COG A or S(O)2G A ,

[0101] Where variable L 1 R 1 L 2 R 2 R 3 R 14 R 15 R 16 X 2 and R 4 Any combination thereof includes any of those described herein. In some embodiments, ring A in Formula I-1-A-4 is a 5, 6, or 7-membered ring that does not contain an additional cyclic heteroatom or contains an additional cyclic nitrogen atom or epoxy atom. In some embodiments, ring B in Formula I-1-A-5 is a 5, 6, or 7-membered ring that may be an aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring, which may not contain a cyclic heteroatom in the case of an aryl or carbocyclic ring, or contain 1 to 3 cyclic heteroatoms independently selected from N, O, and S in the case of a heteroaryl or heterocyclic ring. In some embodiments, ring C in Formula I-1-A-6 is a 5, 6, or 7-membered ring that may be an aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring, which may not contain a cyclic heteroatom in the case of an aryl or carbocyclic ring, or contain 1 to 3 cyclic heteroatoms independently selected from N, O, and S in the case of a heteroaryl or heterocyclic ring. In some implementations, n is 0 in formulas I-1-A-4, I-1-A-5, or I-1-A-6, meaning that rings A, B, or C are not R. DReplacement. In some embodiments, in formulas I-1-A-4, I-1-A-5, or I-1-A-6, n is 1 or 2, where R D Each of these is as defined herein. In some embodiments, in formula I-1-A-4, I-1-A-5, or I-1-A-6, R D Each time it appears, it is independently F, Cl, OH, NH2, CN, or G. A (For example, those described in this article), or two R D Formation of bonds or oxidation. In some embodiments, in formula I-1-A-4, I-1-A-5, or I-1-A-6, R D Each time it appears, it is independently F, Cl, OH, NH2, CN, or C arbitrarily replaced by 1-3 F atoms. 1-4 Alkyl groups, or C groups optionally substituted with 1-3 F atoms. 1-4 Heteroalkyl, or two R D Formation of bonds or oxidation. For clarity, it should be noted that ring B or ring C are drawn in formula I-1-A-5 or I-1-A-6 respectively, and it is not required that the two ring atoms directly attached 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 cyclic heteroatoms, said one or two cyclic heteroatoms may be directly bonded to the pyridine ring in formula I-1-A-5.

[0102] In some embodiments, the compounds of formula I-1-A may be characterized by having formulas 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:

[0103]

[0104]

[0105] in:

[0106] Where valence allows, m is an integer between 0 and 4 (e.g., 0, 1, or 2);

[0107] R E Each time it appears, it is independently F, Cl, G. D OG D OH or CN, or two R E Forming bonds, oxidized or cyclic structures;

[0108] Among them G D Independently substitutes C for each occurrence. 1-4 Alkyl, optionally substituted C 3-6cycloalkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted 4-8 membered heterocyclic groups,

[0109] Where variable L 1 R 1 L 2 R 2 R 3 R 14 R 15 R 16 X 2 and R 4 Any combination thereof includes any of those described herein. In some embodiments, m is 0 in formulas I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, or I-1-A-13. In some embodiments, m is 1 or 2 in formulas I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, or I-1-A-13, where R E Each of these is defined herein. In some embodiments, in formulas I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, or I-1-A-13, R E Each time it appears, it is independently F, Cl, OH, NH2, CN, or G. D (For example, those described in this article), or two R E Formation of bonds or oxidation. In some embodiments, in formulas I-1-A-9, I-1-A-10, I-1-A-11, I-1-A-12, or I-1-A-13, R E Each time it appears, it is independently F, Cl, OH, NH2, CN, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups, or C groups optionally substituted with 1-3 F atoms. 1-4 Heteroalkyl, or two R E Formation of bonds or oxidation. For clarity, when referring to two Rs... 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 atoms form a double bond, the two R atoms form a double bond. E Bonds are formed, and rings can have, for example... The structure can be further defined by one or more R as defined in this paper. E Replacement. When referring to two Rs E When an oxo group is formed, it means that one ring atom is replaced by an oxo group. Again, taking formula I-1-A-13 as an example, when two R... E When an oxygen is formed, the ring can have, for example... The structure can be further defined by one or more R as defined in this paper. EReplacement. Other similar expressions in this article should be understood similarly.

[0110] In some embodiments, in addition to the pyridinyl group in Formula I-1-A, the group in Formula I... The portion may also be 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:

[0111]

[0112] Where variable L 1 R 1 L 2 R 2 R 3 R 14 R 15 R 16 R 17 X 2 and R 4 Any combination thereof includes any of those described herein.

[0113] As discussed in this article, for compounds of formula I, various groups are suitable R 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 (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 G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G EIt is a C that is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from F and OH. 1-4 Alkyl group. In some embodiments, G E It is C 1-4 Heteroalkyl groups, such as C1 heteroalkyl groups (e.g., CH2OH or CH2NH2), optionally selected independently by one or more (e.g., 1, 2, or 3) from F, C 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is C 3-6 Cycloalkyl groups, such as cyclopropyl groups, are optionally selected independently by one or more (e.g., 1, 2, or 3) groups from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is a 4-6 membered heterocyclic group having 1-2 independently selected cyclic heteroatoms chosen from N, O, and S, such as aza-butane, which is optionally composed of one or more (e.g., 1, 2, or 3) independently selected from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH. In some embodiments, R is substituted 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. 14 It can be hydrogen, F, Cl, OH, CN, or G. E (For example, 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 It can be hydrogen, F, Cl, CN, C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (such as fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4 Alkoxy groups (such as methoxy, ethoxy, isopropoxy, etc.), fluorinated C groups 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), cyclopropoxy groups, or cyclobutoxy groups. In some preferred embodiments, R is present 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-1.14 It can be hydrogen. 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.

[0114] Typically, in formula I-1-A (especially formulas 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 G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is a C that is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from F and OH. 1-4 Alkyl group. In some embodiments, G E It is C 1-4 Heteroalkyl groups, such as C1 heteroalkyl groups (e.g., CH2OH or CH2NH2), which are optionally selected independently by one or more (e.g., 1, 2, or 3) groups from F, C 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is C 3-6 Cycloalkyl groups, such as cyclopropyl groups, optionally composed of one or more (e.g., 1, 2, or 3) independently selected from F, C 1-4Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is a 4-6 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, such as aza-butane, which is optionally composed of one or more (e.g., 1, 2, or 3) independently selected from F, C. 1-4 Substitution of alkyl groups (e.g., methyl) and OH groups.

[0115] In some implementations, in formula I-1-A (especially 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 a 4-6 membered heterocyclic group with optional substitution of 1-2 independently selected cyclic heteroatoms chosen from N, O, and S, such as oxobutyryl, morpholino, or azirrobutyryl, which is optionally substituted by one or more (e.g., 1, 2, or 3) independently selected from F, C 1-4 Alkyl (e.g., methyl) and OH substituents.

[0116] In some implementations, in formula I-1-A (especially 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 OG E G E It is C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), or 4-6 membered heterocyclic groups having 1-2 cyclic heteroatoms independently selected from N, O, and S, such as oxetane, optionally by one or more (e.g., 1, 2, or 3) independently selected from F, C 1-4 Substitution of alkyl groups (e.g., methyl) and OH groups.

[0117] In some implementations, in formula I-1-A (especially 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 G FIt is OH, NH2, or C with optional substitution. 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, or a 4-6 membered heterocyclic group having 1-2 independently substituted cyclic heteroatoms selected from N, O, and S. For example, in some embodiments, R 15 It can be O-(C 1-4 (alkylene)-G F G F It is OH, NH2, NH(C) 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), C 1-4 Alkoxy groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkoxy groups (e.g., CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl-substituted C 1-4 Alkoxy groups (e.g., -O-CH2CH2OH), alkoxy-substituted C 1-4 Alkyl groups (e.g., -O-CH2CH2OMe), O-acyl groups (e.g., O-CH(O), OC(O)CH3), NH-acyl groups, N(C 1-4 Alkyl)-acyl or a 4-6 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, such as oxetyl, optionally having one or more (e.g., 1, 2, or 3) cyclic heteroatoms independently selected from F, C 1-4 Substituents of alkyl (e.g., methyl) and OH. In some embodiments, R is substituted in formula I-1-A (especially 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. 15 It can be O-(C 1-4 (alkylene)-G F C 1-4 Alkylenes (from left (O) to right (G) F The connection of ) is -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2C(CH3)2-, and G F For 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 groups (e.g., CF3O-, CHF2O-, CF3CH2O-, etc.), hydroxyl-substituted C 1-4 Alkoxy groups (e.g., -O-CH2CH2OH), or C groups substituted with alkoxy groups 1-4 Alkyl groups (e.g., -O-CH2CH2OMe).

[0118] In some implementations, in formula I-1-A (especially 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, F, Cl, OH, CN or G E (such as any of those described in this article).

[0119] In some implementations, in formula I-1-A (especially 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, F, Cl, CN, C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), hydroxyl-substituted C 1-4 Alkyl groups (e.g., hydroxymethyl, hydroxyethyl, etc.), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, cyclopropyl, cyclobutyl, aziridine, C 1-4 Alkoxy groups (e.g., methoxy, ethoxy, isopropoxy, etc.), fluorine-substituted C 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), C 1-4 Alkyl thiols (e.g., CH3S-), fluorinated C 1-4 Alkylthio (e.g., CF3S-), cyclopropoxy, or cyclobutoxy.

[0120] In some implementations, in formula I-1-A (especially 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 15It can be hydrogen. In some embodiments, in formula I-1-A (especially 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's not hydrogen.

[0121] In some preferred embodiments, in formula I-1-A (especially 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 It can be In some preferred embodiments, R 15 It can be In some preferred embodiments, R 15 It can be selected from the following stereoisomers: In some embodiments, with respect to the chiral center plotted above, the compound may exist primarily as the plotted enantiomer, for example, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other corresponding enantiomers by weight, by HPLC area, or both.

[0122] 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 It 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 G E It is C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen from N, O and S, wherein C1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is a C that is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from F and OH. 1-4 Alkyl group. In some embodiments, G E It is C 1-4 Heteroalkyl groups, such as C1 heteroalkyl groups (e.g., CH2OH or CH2NH2), which are optionally selected independently by one or more (e.g., 1, 2, or 3) groups from F, C 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is C 3-6 Cycloalkyl groups, such as cyclopropyl groups, optionally composed of one or more (e.g., 1, 2, or 3) independently selected from F, C 1-4 Alkyl groups (e.g., methyl) and OH groups are substituents. In some embodiments, G E It is a 4-6 membered heterocyclic group having 1-2 independently selected cyclic heteroatoms chosen from N, O, and S, such as aza-butane, which is optionally composed of one or more (e.g., 1, 2, or 3) independently selected from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH. In some embodiments, R is substituted 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. 16 It can be hydrogen, F, Cl, OH, CN or G E (For example, any of those described herein). In some embodiments, 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 It can be hydrogen, F, Cl, CN, C 1-4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), fluorinated C 1-4 Alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), OH, C 3-6 cycloalkyl groups (such as cyclopropyl, cyclobutyl, etc.), C 1-4Alkoxy groups (such as methoxy, ethoxy, etc.), fluorine-substituted C 1-4 Alkyl groups (e.g., CF3O-, CF3CH2O-, etc.), cyclopropoxy groups, or cyclobutoxy groups. In some preferred embodiments, R is 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. 16 It can be hydrogen, F, Cl, CN, C 1-4 Alkyl, C 1-4 Alkoxy, cyclopropyl, or cyclobutyl. For example, in some preferred embodiments, 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, or formula I-1-D or formula I-1-H-1, R 16 It could be hydrogen.

[0123] When present, R in equation I (e.g., equation I-1-B, I-1-C, or I-1-D) 17 It is usually hydrogen.

[0124] In some implementations, in the applicable formula I (e.g., 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.

[0125] In some implementations, in applicable formula I (e.g., formula I-1-A or I-1-H-1), R 14 and R 16 They are all hydrogen, and R 15 It's not hydrogen.

[0126] In some implementations, in applicable formula I (e.g., formula I-1-A or I-1-H-1), R 14 R 15 and R 16 They're all hydrogen.

[0127] In some implementations, Formula I (e.g., Formula I-1, I-2, or I-3) The term (also referred to herein as M-10) can also represent a 5-membered heteroaryl ring having 1-3 independently substituted cyclic heteroatoms selected from S, O, and N, such as substituted pyrazoles, substituted thiazoles, substituted isothiazoles, substituted oxazoles, substituted isoxazoles, substituted imidazoles, etc. In such embodiments, J 1 It can be CR 18 NR 19 O, S, or N can be CR 14 Or N; J 4 It is CR 20 NR 21 O, S or N; J 5 It 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 Any combination thereof includes any of those described herein.

[0128] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (e.g., those described herein), J 4 Typically, it is N. However, in some implementations, J 4 It can also be CR 20 NR 21 , O or S, where R 20 and R 21 As defined in this article.

[0129] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (e.g., those described herein), J 1 It can be CR 18 , where R 18 As defined herein. In some preferred embodiments, R 18 It is hydrogen, halogens (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH groups. In some embodiments, R 18 Together with their respective intermediate atoms, they can interact with R. 13 R 22 Or R 23 The links form optional 5-8 membered ring structures.

[0130] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (e.g., those described herein), J 1 It can also be NR 19 , where R 19 As defined herein. For example, in some implementations, R 19 It can be hydrogen, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH groups. In some embodiments, R 19 Together with their respective intermediate atoms, they can interact with R. 13 R 22 Or R 23 The links form optional 5-8 membered ring structures.

[0131] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (e.g., those described herein), J 1 It can also be O or S.

[0132] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (e.g., those described herein), J 2 It can be CR 23 And J 3 It does not exist, where R 23 As defined herein. For example, in some implementations, R 23 It can be hydrogen, halogens (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or a 4-6 membered heterocycle having 1-2 independently selected cyclic heteroatoms chosen from N, O, and S, wherein C 1-6Alkyl, C 1-4 Heteroalkyl, C 3-6 Each of the cycloalkyl or 4-6 membered heterocyclic groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH groups. In some embodiments, R 23 Together with their respective intermediate atoms, they can interact with R. 18 R 19 R 20 Or R 21 The links form optional 5-8 membered ring structures.

[0133] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (e.g., those described herein), J 2 It can be NR 22 And J 3 It does not exist, where R 22 As defined herein. For example, in some implementations, R 22 It can be hydrogen, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH groups. In some embodiments, R 22 Together with their respective intermediate atoms, they can interact with R. 18 R 19 R 20 Or R 21 Connect to form optional 5-8 membered ring structures.

[0134] In embodiments where M-10 represents an optionally substituted 5-membered heteroaryl ring (e.g., those described herein), J 2 It can also be O or S, and J 3 It does not exist.

[0135] In some more specific embodiments, the compounds of formula I may be characterized by having formula I-1-E, I-1-F, or I-1-G:

[0136]

[0137] Where variable L 1 R 1 L2 R 2 R 3 R 18 R 22 R 23 X 2 and R 4 Any combination thereof may include any of those described herein. For example, in some embodiments, R in formula I-1-E or I-1-G 18 It can be hydrogen, halogens (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH. In some embodiments, R in formula I-1-E... 22 It can be hydrogen, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Substituents of alkyl groups (e.g., methyl) and OH. In some embodiments, R in formula I-1-F 23 It can be hydrogen, halogens (e.g., F, Cl), CN, C 1-6 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups having 1-2 independently selected cyclic heteroatoms chosen 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 groups is optionally selected independently by one or more (e.g., 1, 2 or 3) groups from F, C. 1-4 Substitution of alkyl groups (e.g., methyl) and OH groups.

[0138] 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 It is usually O.

[0139] In some implementations, X in Equation I (e.g., any applicable sub-equation) 2 It can also be NR 13 , where R 13 As defined herein. For example, in some embodiments, X in Equation I (e.g., any applicable sub-equation) 2 It can be NH. In some implementations, X in Formula I (e.g., any applicable sub-formula) 2 It can be NR 13 , where R 13 It is C 1-4 Alkyl groups, such as methyl groups. As those skilled in the art will understand, when X in formula I... 2 For NR 13 At this time, the sulfur atom is an asymmetric center. In some implementations, X... 2 For NR 13 The compounds disclosed herein can exist in racemic mixtures or mixtures rich in stereoisomers having any configuration relative to the 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:

[0140]

[0141] Where variable L 1 R 1 L 2 R 2 R 3 J 1J 2 J 3 J 4 J 5 R 13 and R 4 Any combination thereof includes any of those described herein, such as those described herein in combination with formula I-1-A and its subformulas I-1-A-1 to I-1-A-15. For example, in some embodiments, where X 2 For NR 13 The compound of formula I-1 may be rich in the stereoisomer of formula I-1-J-E1, and 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 For NR 13 The compound of formula I-1 may be rich in the stereoisomer of formula I-1-J-E2, or 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 For NR 13 The compound of formula I-1 can 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.

[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-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 selected independently by one or more elements, F, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl. For example, in any embodiment described herein, unless otherwise stated or contrary to the context, R in Formula I (e.g., any applicable sub-formula) 4 It can be methyl.

[0143] In some implementations, when X 2 It is NR 13 When, R in equation I (e.g., any applicable sub-equation) 4 and R 13 It can be linked with intermediate atoms to form optionally substituted 5-8 membered ring structures. For example, in some embodiments, the rings in Formula I (including any applicable subformulas) Part can be

[0144] M-10, X 2 and R 4 There are no particular limitations on the combination of formulas. For example, unless otherwise stated or contrary to the context, in any embodiment herein, formula I (including any applicable sub-formulas, such as formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some of the selections can be chosen from:

[0145]

[0146] Unless otherwise stated or contrary to the context, in any embodiment herein, Formula I (including any applicable sub-formulas, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some parts can also be selected from:

[0147]

[0148]

[0149] Where Cbz represents

[0150] Unless otherwise stated or contrary to the context, in any embodiment herein, Formula I (including any applicable sub-formulas, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some parts can also be selected from: For example, in some implementations, Formula I (including any applicable sub-formulas) Part can be Its chiral center relative to the plotted structure can be substantially enantiomerically pure, for example, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other corresponding enantiomers by weight, by HPLC area, or by both. In some embodiments, the chiral center in Formula I (including any applicable sub-formulas) Part can be Its chiral center relative to the plotted chiral center can be substantially enantiomerically pure, for example, by weight, by HPLC area or both, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other corresponding enantiomers.

[0151] Unless otherwise stated or contrary to the context, in any embodiment herein, Formula I (including any applicable sub-formulas, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some parts can also be selected from:

[0152]

[0153] Unless otherwise stated or contrary to the context, in any embodiment herein, Formula I (including any applicable sub-formulas, such as Formula I-1 (e.g., I-1-A or I-1-H), I-2 or I-3) Some parts can also be selected from:

[0154]

[0155] In some embodiments, with respect to the chiral center plotted above, the compound may exist primarily as the plotted stereoisomer, for example, by weight, by HPLC area, or by both, having other stereoisomers in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts.

[0156] Unless otherwise stated or contrary to the context, in any embodiment herein, Formula I (including any applicable sub-formulas, such as Formula I-1 (e.g., I-1-A, I-1-H, or I-1-J-E2), I-2, or I-3) refers to... Some parts can also be selected from:

[0157]

[0158] In some embodiments, with respect to the chiral center plotted above, the compound may exist primarily as the plotted stereoisomer, for example, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other stereoisomers by weight, by HPLC area, or by both.

[0159] Unless otherwise stated or contrary to the context, in any embodiment herein, Formula I (including any applicable sub-formulas, such as Formula I-1 (e.g., I-1-A, I-1-H, or I-1-J-E1), I-2, or I-3) Some parts can also be selected from:

[0160]

[0161] In some embodiments, with respect to the chiral center drawn above, the compound may exist primarily as the drawn stereoisomer, for example, by weight, by HPLC area, or by both, having other stereoisomers in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts.

[0162] Unless otherwise stated or contrary to the context, in any embodiment of this document, Formula I (including any applicable sub-formulas) Some parts can also be selected from:

[0163]

[0164] 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 is hydrogen.

[0165] 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:

[0166]

[0167] Where 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 combination thereof includes any of those described herein, such as those described in combination with formula I-1 and its sub-formulas. In some specific embodiments, compounds of formula I-1-H may be characterized by having the sub-formula I-1-H-1:

[0168]

[0169] Where variable R 1 L 2 R 2 R 14 R 15 R 16 X 2 and R 4 Any combination thereof includes any of those described herein, such as those described in combination with formula I-1-A (including any of sub-formulas I-1-A-1 to I-1-A-15). For example, in some embodiments, in formula I-1-H-1, R 14 It can be hydrogen. In some embodiments, in formula I-1-H-1, R 15 It can be hydrogen. In some embodiments, in formula I-1-H-1, R 16 It can be hydrogen. In some embodiments, in formula I-1-H-1, R 14 and R 15 One of them is hydrogen, and R 14 and R 15The other one is not hydrogen; for example, in some implementations, R 14 It is hydrogen and R 15 It is not hydrogen. In some embodiments, in formula I-1-H-1, R 14 and R 15 Neither of them are hydrogen. In some embodiments, in formula I-1-H-1, R 14 and R 15 Both are hydrogen. In some embodiments, in formula I-1-H-1, R 14 and R 16 They are all hydrogen, and R 15 It is not hydrogen. In some embodiments, in formula I-1-H-1, R 14 R 15 and R 16 Both are hydrogen. In some embodiments, in formula I-1-H-1, R 14 and R 15 Together with the intermediate atom, they form optionally substituted 5-8 membered rings, such as 5-8 membered carbon rings or heterocycles. In some embodiments, in formula I-1-H-1, X 2 It is NR 13 And R 14 and R 13 Together with the intermediate atom, they form 5-8 membered heterocycles that can be optionally substituted. Typically, X in formula I-1-H-1... 2 It is O, NH, or NCH3. Typically, R in formula I-1-H-1... 4 It is CH3. Other suitable definitions of the variables in equation I-1-H-1 include any of those described herein.

[0170] 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 It is NR 11 , where R 11 As defined herein. For example, in some implementations, L 1 It is NH. In some implementations, L 1 It is NR 11 , where R 11 It is hydrogen, C 1-4 Alkyl or C3-6 cycloalkyl, wherein C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally selected independently from F, C by one or more (e.g., 1, 2 or 3). 1-4 Substitution of alkyl groups (e.g., methyl) and OH groups.

[0171] 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 could also be Where R 11 As defined herein. For example, in some implementations, L 1 It can be

[0172] 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 could also be Where R 11 and R 12 As defined herein. For example, in some implementations, L 1 It can be

[0173] 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 may also not exist. For example, in some embodiments, the compound of formula I-1 may have a subformula of formula I-1-I, where R 1 Directly connected to the pyridazine ring:

[0174]

[0175] Where 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 combination thereof includes any of those described herein, such as those described by combination I-1 and its sub-formulas.

[0176] Various groups are suitable as R in Formula I 1 In some implementations, R 1 It can be hydrogen. In some implementations, R 1 C can be arbitrarily replaced 1-6 Alkyl group. In some embodiments, R 1 C can be arbitrarily replaced 3-10 The carbon ring can be a monocyclic ring, or a fused, bridged, or helical bicyclic carbon ring. Typically, the carbon ring is fully saturated. However, in some embodiments, the carbon ring can also be partially unsaturated. In some embodiments, R... 1 It can be an optionally substituted 4-10 member heterocycle, which can be a monocyclic, fused, bridged, or spirocyclic bicyclic heterocycle. The heterocycle can be fully saturated or partially unsaturated. In some embodiments, R 1 It can be an optionally substituted phenyl group. In some embodiments, R 1 It can be an optionally substituted heteroaryl group, such as a 5-10 membered monocyclic or bicyclic heteroaryl group. In some embodiments, R 1It can be a 5- or 6-membered heteroaryl group with 1-3 independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, R 1 It can be an 8-10 membered bicyclic heteroaryl group with 1-3 independently substituted cyclic heteroatoms selected from N, O and S.

[0177] 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 It can be selected from: 1) monocyclic C 3-6 1) Cycloalkyl groups; 2) Spirolinked, fused, or bridged bicyclic C 4-10 3) Cycloalkyl groups; 4) Monocyclic 4-8-membered heterocyclic groups having 1-3 heteroatoms independently selected from O, N, and S; 5) Spirolated, fused, or bridged bicyclic 5-10-membered heterocyclic groups having 1-3 heteroatoms independently selected from O, N, and S; 6) Phenyl groups; 7) 6-membered heteroaryl groups having 1 or 2 cyclic nitrogen atoms; 8) 5-membered heteroaryl groups having 1-3 cyclic heteroatoms independently selected from N, O, and S; 9) C 1-6 Alkyl groups, wherein each of 1)-9) is optionally substituted, for example, by one or more independently selected Gs as described herein. 1 Replacement. In some implementations, G 1 Each time it appears, it is independently a halogen (e.g., 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 Gs 1 Forming bonds, oxidized or cyclic structures, wherein:

[0178] G 1A Each occurrence is independent:

[0179] i)C 1-6 alkyl,

[0180] ii)C 3-6 cycloalkyl,

[0181] iii)C 1-4 Heteroalkyl,

[0182] iv) 4-8 membered heterocyclic groups having 1-3 independent cyclic heteroatoms selected from O, N, and S.

[0183] v) Phenyl, or

[0184] vi) 5-10 membered heteroaryl groups having 1-3 independent cyclic heteroatoms selected from O, N, and S.

[0185] Each of i)-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 heterocyclic group having 1 or 2 cyclic heteroatoms independently selected from O, N, and S, phenyl, or 5-6 membered heteroaryl group having 1-3 cyclic 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 heterocyclic, phenyl, or 5-6 membered heteroaryl groups are independently and optionally substituted by one or more (e.g., 1, 2, or 3) substituents, each independently selected from F, Cl, CN, OH, oxo (if valence permits), and optionally substituted by one or more (e.g., 1-3) G groups. 1D Substituted C1-4 alkyl groups, optionally with one or more (e.g., 1-3) G 1D Replacement C 1-4 Heteroalkyl groups and optionally one or more (e.g., 1-3) G 1D Replacement C 3-6 cycloalkyl, wherein G 1D Each time it appears, it is F, OH, or C. 1-4 alkyl,

[0186] G 1B and G 1C Each time it appears, it 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)-G1A G 1A As defined above.

[0187] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a single-ring C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, or cyclopentyl, which are unsubstituted or independently selected by one or more (usually 1 or 2) G groups 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 Alkyl groups, etc. In some preferred embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be cyclopropyl.

[0188] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a spiral double ring C 5-8 cycloalkyl, for example It is not replaced or selected by one or more (usually 1 or 2) independent G as described herein 1 Substitution, such as F, methyl, methoxy, etc.

[0189] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a bridge connecting two rings C 5-8 cycloalkyl, for example It is not replaced or independently selected by one or more (usually one or two) G as described herein 1 replace.

[0190] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a fused bicyclic C 5-8Cycloalkyl groups, which are unsubstituted or independently selected by one or more (usually one or two) G as described herein. 1 replace.

[0191] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a monocyclic 4-6-membered heterocyclic group having 1-3 heteroatoms independently selected from O, N, and S, such as azahexacyclic butyl, pyrrolidinyl, etc., which is unsubstituted or independently selected by one or more (usually 1 or 2) G atoms as described herein. 1 Substitution, such as F or methyl.

[0192] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a fused 6-8 membered heterocyclic group having 1-3 independent heteroatoms selected from O, N, and S, for example... It is not replaced or independently selected by one or more (usually one or two) G as described herein 1 Substitution, such as F, OH or methyl.

[0193] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a bridged or spirocyclic 5-8 membered heterocyclic group having 1-3 heteroatoms independently selected from O, N, and S, which is unsubstituted or independently selected by one or more (usually 1 or 2) G atoms as described herein. 1 replace.

[0194] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 a phenyl group, which is optionally selected by one or more (usually 1 or 2) independently chosen G as described herein. 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy, fluorine-substituted C 1-4 Alkyl groups, etc.

[0195] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a 6-membered heteroaryl group having one or two cyclic nitrogen atoms, such as pyridine, pyrimidine, etc., which is optionally independently selected by one or more (usually one or two) Gs as described herein. 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy, fluorine-substituted C 1-4 Alkyl groups, etc.

[0196] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can be a 5-membered heteroaryl group having 1-3 independently selected cyclic heteroatoms chosen from N, O, and S, such as pyrazole, which is optionally surrounded by one or more (usually 1 or 2) independently selected G atoms as described herein. 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy, fluorine-substituted C 1-4 Alkyl groups, etc.

[0197] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 can also be an 8-10 membered bicyclic heteroaryl group having 1-3 independently selected cyclic heteroatoms chosen from N, O, and S, optionally with one or more (usually 1 or 2) independently selected G atoms as described herein. 1 Substitution, such as F, OH, Cl, CN, C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy, fluorine-substituted C 1-4 Alkyl groups, etc.

[0198] In some embodiments, R in formula I (e.g., formula I-1 and its sub-formulas, 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 could also be C 3-6 Alkyl groups, such as isopropyl groups, which are optionally distinguished by one or more (usually one or two) independently selected G groups as described herein. 1 Substitution, such as F, OH, C 1-4 alkoxy, fluorine-substituted C 1-4 Alkyl groups, etc.

[0199] When L 1 When not present, for example, those compounds of formula I-1-I, R 1 Typically, it is a heteroaryl group, such as a 5- or 6-membered heteroaryl group. For example, in some embodiments, R 1 It can be a 5-membered heteroaryl group with 1-3 independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, R 1 It can be a 5-membered heteroaryl group having 1-3 independent cyclic heteroatoms selected from N, O, and S, such as those 5-membered heteroaryl groups described herein, such as pyrazoles, which are optionally surrounded by one or more G atoms. 2 Replace, where G 2 Each time it appears, it is independently a halogen (e.g., 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 Gs 2 A ring structure is formed, wherein:

[0200] G 2A It is C independently each time it appears. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-4 Heteroalkyl groups or 4-8 membered heterocyclic groups 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 heterocyclic group is optionally surrounded by one or more (e.g., 1, 2 or 3) groups, 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 Substitution of heteroalkyl groups, and

[0201] G 2B and G 2C Each time it appears, it 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 G 2A The definition is as above.

[0202] In some implementations, L 1 It does not exist, for example, those compounds of formula I-1-I, R 1 It is a pyrazole, which is optionally selected by one or more (e.g., 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 Alkyl groups, etc.

[0203] For L of equation I 1 and R 1 There are no particular limitations on suitable combinations. For example, unless otherwise stated or contrary to the context, in any embodiment herein, L in formula I (e.g., formulas 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 Optional from:

[0204]

[0205] 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 Alternatively, you can select from:

[0206]

[0207] 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 could be:

[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 choose from:

[0210]

[0211] 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 is NH.

[0212] In some implementations, in formula I (e.g., formula I-1 and its sub-formulas), L 2 It can be C 1-4 Alkylene, such as CH2. In some embodiments, in formula I (e.g., formula I-1 and its sub-formulas), L 2 It can be C 1-4 Heteroalkylene. In some embodiments, in formula I (e.g., formula I-1 and its sub-formulas), L 2 It can be C 3-6 Cycloalkylene, such as cyclopropylene. In some embodiments, in formula I (e.g., formula I-1 and its sub-formulas), L 2 It can be a 4-6 membered heterocyclic group having one or two independent cyclic heteroatoms selected from N, O and S, which may optionally be substituted, for example, by F and / or methyl.

[0213] 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.

[0214] In some implementations, in formula I (e.g., formula I-1 and its sub-formulas), R 2 It could also be C 1-4Heteroalkyl groups.

[0215] Unless otherwise stated or contrary to the context, in any embodiment herein, L in Formula I (e.g., Formula I-1 and its sub-formulas) 2 -R 2 You can choose from:

[0216]

[0217] 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 could be:

[0218]

[0219] In some embodiments, this disclosure also provides compounds selected from the following compound numbers 1-133 or pharmaceutically acceptable salts thereof:

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] In some embodiments, to the extent applicable, the types of compounds in this disclosure also exclude any compounds specifically prepared and disclosed prior to this disclosure.

[0227] Synthesis method

[0228] In view of the contents of this disclosure, those skilled in the art can readily synthesize the compounds disclosed herein. Exemplary synthesis is also shown in the Examples section.

[0229] The synthetic method of Formula I-1-H-1 below is illustrative. According to this disclosure, those skilled in the art can similarly apply this synthetic method to synthesize other compounds of Formula I by using suitable starting materials and / or intermediates. In some embodiments, this disclosure also provides synthetic methods for preparing compounds of Formula I and synthetic intermediates, as shown in the reaction formulas herein.

[0230] As shown in reaction formula 1, compounds of formula I-1-H-1 can typically be synthesized via 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 can 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 basic conditions, for example by using an alkali metal bis(trimethylsilyl)amine (e.g., LiHMDS). Compound S-3 can then be converted to S-5 by reacting with S-4. Typically, the reaction between 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) via one or two oxidation reaction steps (e.g., using the oxidants and / or conditions described herein). 2) Optional also includes X 2 and R 14 A ring is formed between them, thereby converting compound S-5 into a compound of formula I-1-H-1. Exemplary reaction conditions for converting compound S-1 into compound 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 This includes any of those defined above in conjunction with Formula I (e.g., any subformulation of Formula I) and their protected derivatives.

[0231] Reaction 1

[0232]

[0233] It will be apparent to those skilled in the art that conventional protecting groups may be necessary to prevent undesirable reactions of certain functional groups. Suitable protecting groups for various functional groups, and suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis," 4 th The reagents used in the reactions described herein are described in ed. PGM Uts; TW Greene, John Wiley, 2007, and the 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. Furthermore, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others can be prepared using the processes described in standard reference books or their obvious modifications, 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), and March's Advanced Organic Chemistry (Wiley, 7). th The references are to the edition of Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999) and any available updates up to this application.

[0234] Pharmaceutical Composition

[0235] Some embodiments involve pharmaceutical compositions comprising one or more compounds disclosed herein.

[0236] The pharmaceutical composition may optionally contain pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises compounds of the present disclosure (e.g., formula I, e.g., 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. 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, I-1-A-15, or I-1-H-1, any one of compound numbers 1-133, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives, such as absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's *The Science and Practice of Pharmacy*, 21st Edition, ARGennaro (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.

[0237] The pharmaceutical composition may include any one or more compounds disclosed herein. For example, in some embodiments, the pharmaceutical composition comprises, for example, a therapeutically effective amount of formula I (e.g., formulas 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, ... Compounds selected from compound numbers 1-133, or pharmaceutically acceptable salts thereof, are included in the formulation of this document. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from compound numbers 1-133 or pharmaceutically acceptable salts thereof.

[0238] The pharmaceutical composition may also be formulated for delivery via any known route of delivery, including but not limited to oral, parenteral, and inhalation.

[0239] In some embodiments, the pharmaceutical composition may be formulated for oral administration. Oral formulations may be in the form of: discrete units, such as capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of the active compound; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil emulsions. Excipients used to prepare oral administration compositions are known in the art. Suitable excipients, without limitation, include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, 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 carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearic fumarate, sucrose, surfactants, talc, tragacanth gum, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0240] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulation may be, for example, an aqueous solution, suspension, or emulsion. Excipients used in the preparation of the parenteral formulation are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, glucose, wheat 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.

[0241] In some embodiments, the pharmaceutical composition is formulated for inhalation administration. For example, the inhalable formulation may be formulated as a nasal spray, a dry powder, or an aerosol that can be administered via a metered-dose inhaler. Excipients used to prepare the inhaled formulation are known in the art. Suitable, non-limiting excipients include, for example, lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, as well as mixtures of these substances. The spray may also contain a propellant, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0242] Pharmaceutical compositions may include various amounts of the compounds disclosed herein, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein (e.g., formula I, e.g., formulas 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...). Compounds of the following compounds (I-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. 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 the compounds disclosed herein is an amount that is effective in treating diseases or conditions 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. This may depend 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 (e.g., its potency in inhibiting TYK2), its clearance rate, and whether it is co-administered with another drug.

[0243] For veterinary use, the compounds disclosed herein can be administered in appropriately acceptable formulations according to normal veterinary practice. Veterinarians can readily determine the dosing regimen and route of administration best suited for a particular animal.

[0244] In some embodiments, all the necessary components for treating such diseases with the compounds of the present invention, alone or in combination with another agent or intervention conventionally used to treat TYK2-related diseases or conditions (e.g., those mediated by IL-12, IL-23, and / or interferon-α (INF-α)), can be packaged into a kit. Specifically, in some embodiments, the present invention provides a kit for a therapeutic intervention for a disease comprising a packaged group of drugs including the compounds disclosed herein, buffers and other components for preparing said drugs in a deliverable form, and / or a means for delivering such drugs, and / or any agent for treatment in combination with the compounds disclosed herein, and / or instructions for use for treating the disease packaged with the drugs. The instructions for use may be affixed to 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.

[0245] Treatment methods / uses

[0246] The compounds disclosed herein can be used as therapeutically active substances for the treatment and / or prevention of diseases or conditions associated with TYK2. In particular, the compounds disclosed herein, by acting on Tyk2 to mediate signal transduction, can be used to treat conditions related to the regulation of the function of IL-23, IL-12, and / or IFN-α, especially the inhibition of the function of IL-23, IL-12, and / or IFN-α. Such conditions include those 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.

[0247] In some embodiments, this disclosure provides a method for inhibiting TYK2-mediated cell signaling, comprising reacting cells with an effective amount of one or more compounds of this disclosure (e.g., formula I, e.g., 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...). Compounds of the following compounds: 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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, this disclosure provides a method for inhibiting the function of IL-23, IL-12, and / or IFN-α in a subject of need, the method comprising administering to the subject an effective amount of one or more compounds of this 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)). Compounds of the following types: -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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, this disclosure provides a method for treating or preventing a TYK2-mediated disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this disclosure (e.g., formula I (e.g., formulas 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. Compounds of 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. Suitable TYK2-mediated diseases or conditions treatable by the methods described 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 herein by reference in their entirety. Exemplary TYK2-mediated diseases or conditions that can be treated with the methods described herein include, but are not limited to, those proliferative, metabolic, allergic, autoimmune, and / or inflammatory diseases or conditions described herein.

[0250] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition associated with IL-23, IL-12, and / or IFN-α in a subject of need, the method comprising administering to the subject an effective amount of one or more compounds of this 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, ...). Compounds of 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. Suitable diseases or conditions associated with IL-23, IL-12, and / or IFN-α that can be treated by the methods described 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 herein by reference in their entirety. Exemplary diseases or conditions related to IL-23, IL-12, and / or IFN-α that can be treated using the methods described herein include, but are not limited to, those proliferative, metabolic, allergic, autoimmune, and / or inflammatory diseases or conditions described herein.

[0251] In some embodiments, this disclosure provides a method for treating or preventing, in a subject of need, a proliferative, metabolic, allergic, autoimmune, and / or inflammatory disease or condition, such as those described herein, comprising administering to the subject an effective amount of one or more compounds of this 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-)). Compounds of 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.

[0252] In some embodiments, this disclosure provides a method for treating or preventing, for example, autoimmune and / or inflammatory diseases or conditions described herein, in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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-...). Compounds of the following compounds (I-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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, this disclosure provides a method for treating or preventing metabolic diseases or conditions, such as type 2 diabetes or atherosclerosis, in a subject in need, comprising administering to the subject an effective amount of one or more compounds of this 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). Compounds of the following compounds: 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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, this disclosure provides a method of treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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). Compounds of the following compounds (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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, this disclosure provides a method of treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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...). Compounds of the following compounds (I-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 may be one or more selected from the following: inflammatory diseases, such as Crohn's disease. Diseases including: ulcerative colitis, asthma, graft-versus-host disease, allogeneic graft rejection, and chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, and psoriasis; autoinflammatory diseases including CAPS, TRAPS, FMF, adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, and gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, and myocardial infarction; and destructive bone diseases such as bone resorption diseases, osteoarthritis, and osteoporosis. Bone diseases associated with multiple myeloma; proliferative disorders such as acute myeloid leukemia and chronic myeloid leukemia; angiogenesis disorders, including solid tumors, ocular neovascularization, and infantile hemangiomas; infectious diseases such as sepsis, septic shock, and Shigella; 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, and AIDS.

[0256] In some embodiments, this disclosure provides a method of treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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 Any one of the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof), wherein the diseases or conditions treatable 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, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome. Syndrome, gout, traumatic arthritis, urticaria, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritis diseases, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, allogeneic graft rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, heartburn, influenza, osteoporosis, bone joint Arthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigella infection; Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or trauma; angiogenic diseases, including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases, including acute hepatitis infections (including hepatitis A, hepatitis B, and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC, or malignant tumors, and herpes.Stroke, myocardial ischemia, ischemia during stroke-induced cardiac arrest, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions related to prostaglandin endothelial oxidase synthase-2, and pemphigus vulgaris.

[0257] In some preferred embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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- The disease or condition is one or more of the following compounds: I-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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is one or more of the following diseases or conditions: Crohn's disease, ulcerative colitis, allogeneic transplant rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris.

[0258] In some preferred embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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- The compounds of I-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 due to stroke and cardiac ischemia-reperfusion injury due to myocardial infarction.

[0259] In some preferred embodiments, this disclosure provides a method for treating or preventing multiple myeloma in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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 preferred embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this 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...). Compounds of 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 selected from one or more of the following: multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and scleroderma.

[0261] In some preferred embodiments, this disclosure provides a method of treating multiple sclerosis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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...). Compounds of the following compounds (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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0262] In some preferred embodiments, this disclosure provides a method of treating rheumatoid arthritis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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).

[0263] In some preferred embodiments, this disclosure provides a method of treating inflammatory bowel disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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...). Compounds of the following compounds (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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0264] In some preferred embodiments, this disclosure provides a method of treating systemic lupus erythematosus in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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, this disclosure provides a method of treating psoriasis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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-...). Compounds of the following compounds: I-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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0266] In some preferred embodiments, this disclosure provides a method of treating psoriatic arthritis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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...). Compounds of the following compounds (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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0267] In some preferred embodiments, this disclosure provides a method of treating Crohn's disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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-...). Compounds of the following compounds: I-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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0268] In some preferred embodiments, this disclosure provides a method of treating Sjögren's syndrome in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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...). Compounds of the following compounds (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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0269] In some preferred embodiments, this disclosure provides a method of treating scleroderma in a subject in need, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this 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-...). Compounds of the following compounds: I-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 the compounds numbered 1-133, or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, this disclosure also provides one or more compounds of this 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. The use of any of the compounds (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 the compounds numbered 1-133, or pharmaceutically acceptable salts thereof, for the treatment or prevention of any of the diseases or conditions 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.

[0271] In some embodiments, this disclosure also provides one or more compounds of this 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- The use of compounds of the numbers 1-A-9, 1-A-10, 1-A-11, 1-A-12, 1-A-13, 1-A-14, 1-A-15 or 1-H-1, any one of the compound numbers 1-133, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of any of the diseases or conditions 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.

[0272] The compounds disclosed herein can be used as monotherapy or in combination therapy. In some embodiments, treatment for IL-23-, IL-12-, and / or IFNα-related diseases or conditions may include administration of the compounds disclosed herein 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-suppressing anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyguanidine (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents, such as abacavir; and antiproliferative agents, such as methotrexate, leflunomide, and 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 rapamycin (sirolimus or...). ) or its derivatives.

[0273] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, pulmonary, inhaled, oral, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, administration is oral.

[0274] Dosing regimens, including dosage, can vary and 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 administered concurrently.

[0275] definition

[0276] It should be understood that all parts and their combinations maintain the appropriate valence.

[0277] It should also be understood that the specific implementation of the variable section in this paper may be the same as or different from another specific implementation with the same identifier.

[0278] The appropriate atoms or groups used for the variables in this paper are chosen independently. The definitions of variables can 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 can be related to 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 combination of other variables defined in the document. Such combinations are expected and within the scope of this disclosure.

[0279] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table on the inner cover of the 75th edition of the Handbook of Chemistry and Physics (CAS), and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following: 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;

[0280] 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. This disclosure is not intended to be limited in any way to the list of exemplary substituents described herein.

[0281] The compounds disclosed herein may contain one or more asymmetric centers and / or axial chirality, and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, transisomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be separated from mixtures 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 (Ellie Liel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure also includes the compounds described herein as single isomers substantially free of other isomers, or as mixtures of various isomers, including racemic mixtures. In the embodiments described herein, unless otherwise apparent from the context, when specifically plotting stereochemistry, it should be understood that the compound may exist primarily as the plotted stereoisomer with respect to that particular chiral center or axial chirality, for example, having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other stereoisomers by weight, by HPLC area, or by both. In view of this disclosure, including through the use of chiral HPLC, those skilled in the art can determine the presence and / or content of stereoisomers.

[0282] When listing a series of values, the aim is to cover every value within that range and every subrange. 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 2-3C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 .

[0283] 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 the following formulas: I-1-A-12, I-1-A-13, I-1-A-14, I-1-A-15, or I-1-H-1; any compound numbered 1-133; its isotopically labeled compounds (e.g., deuterated analogs, wherein one or more hydrogen atoms are replaced by deuterium atoms of higher abundance than native abundance); its possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures); its geometric isomers; its transisomers; its tautomers; its conformational isomers; and / or its pharmaceutically acceptable salts (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). For the avoidance of doubt, compounds 1-133 or compound numbers 1-133 refer to the compounds described herein marked with integers 1, 2, 3, ..., 133, see, for example, the title compounds of the examples and Table 1. For ease of description, starting materials or intermediates for synthesis may be designated with an integer (compound number) followed by a "-" and an additional numerical value, such as 1-1, 1-2, etc., as detailed in the examples. Such designation of starting materials or intermediates should not be confused with compounds designated only with integers. Hydrates and solvates of the compounds disclosed herein are considered compositions of this disclosure, wherein the compounds are respectively bound to water or a solvent.

[0284] The compounds disclosed herein may exist in isotopically labeled or enriched forms, comprising one or more atoms whose atomic mass or mass number differs from the most abundant atomic mass or mass number found in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, those... 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 this invention.

[0285] As used herein, the phrase "compound for administration," "administered compound," or other variations thereof refers to the provision of a compound or a prodrug of a compound to an individual in need of treatment.

[0286] As used herein, the term "alkyl" alone or as part of another group refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, an alkyl group may comprise one to twelve carbon atoms (i.e., C64 ... 1-12 Alkyl group (or a specified number of carbon atoms, i.e., C1 alkyl group of methyl, C2 alkyl group of ethyl, C3 alkyl group of propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight-chain C1 alkyl group. 1-10 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-10 Alkyl group. In another embodiment, the alkyl group is a straight-chain C14 group. 1-6 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain C14 group. 1-4 Alkyl group. In one embodiment, the alkyl group is a C10 group selected from 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 alkylenes include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc.

[0287] As used herein, unless otherwise stated, the term "heteroalkyl" alone or in combination with another term refers to a stable straight-chain or branched alkyl group, for example, having 2 to 14 carbons in the chain, such as 2 to 10 carbons, wherein one or more of these carbons have been replaced by heteroatoms selected from S, O, P, and N, and wherein nitrogen, phosphine, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms S, O, P, and N may be located at any internal position of the heteroalkyl group or at the position where 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" 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, the heteroatom may also occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the chemical formula of the linking group is written does not imply the orientation of the linking group. When referring to "heteroalkyl," followed by a specific heteroalkyl group, such as "-NR'R," it should be understood that the terms heteroalkyl and "-NR'R" are not redundant or mutually exclusive. Rather, listing specific heteroalkyl groups enhances the descriptiveness. Therefore, the term "heteroalkyl" in this document should not be interpreted as excluding specific heteroalkyl groups, such as "-NR'R."

[0288] As used herein, the term "alkenyl," whether used alone or as part of another group, refers to a straight-chain or branched aliphatic hydrocarbon containing one or more, such as one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2-6 Alkenyl group. In another embodiment, the alkenyl group is C. 2-4 Alkenyl. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0289] As used herein, the term "alkynyl" when used alone or as part of another group refers to a straight-chain or branched 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 Alkyne group. In another embodiment, the alkynyl group is C. 2-4 Alkyne group. Non-limiting exemplary alkyne groups include ethynyl, propynyl, butynyl, 2-butynyl, pentylyl, and hexynyl.

[0290] As used herein, the term "alkoxy" used alone or as part of another group refers to the formula OR a1 The group, wherein R a1 It is an alkyl group.

[0291] 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, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl is a C18-28-3 ... 1-4 Halogenated alkyl groups.

[0292] When used alone or as part of another group, "carbocyclic" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms in a non-aromatic ring system. 3-10 The carbocyclic group can be monocyclic (“monocyclic carbocyclic”), bicyclic, or polycyclic, and can comprise fused ring, bridged ring, or spirocyclic systems and can be saturated or partially unsaturated. As used herein, a bicyclic or polycyclic carbocyclic group can have one or more aromatic rings, provided that the bicyclic or polycyclic carbocyclic group as a whole is not an aromatic ring system, and the linking point can be on any ring of the bicyclic or polycyclic carbocyclic group. For example, a fused bicyclic carbocyclic group can comprise those fused ring systems in which one of the two rings is phenyl, wherein the linking point can be on either of the two rings. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, naphthane, adamantyl, cyclopentenyl, and cyclohexenyl.

[0293] In some embodiments, the "carbocyclic group" is fully saturated, and is also referred to as a cycloalkyl group. In some embodiments, the cycloalkyl group may have 3 to 10 cyclic carbon atoms ("C..."). 3-10 (Cycloalkyl). 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 spirocyclic bicyclic ring.

[0294] Unless otherwise stated or contrary to the context, the terms "heterocyclic group" or "heterocyclic" used alone or as part of another group refer to a group having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 cyclic group"). Heterocyclic groups or heterocycles having ring sizes different from 3-10 cyclic groups are designated with different ring size names where applicable. Those skilled in the art will understand that such heterocyclic groups with different ring sizes are also non-aromatic systems having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the bonding point may be a carbon atom or a nitrogen atom, if the valence allows. Heterocyclic groups can be monocyclic (“monocyclic heterocyclic groups”), bicyclic, or polycyclic, including fused, bridged, or spirocyclic systems, such as fused, bridged, or spirocyclic bicyclic systems (“bicyclic heterocyclic groups”), and can be saturated or partially unsaturated. A heterocyclic bicyclic system can contain one or more cyclic heteroatoms in one or both rings, with the bonding point located on either of the two rings. For example, fused heterocyclic bicyclic systems include those where one ring is a monocyclic carbocyclic ring as defined herein, where the bonding point can be on the carbocyclic ring or a ring having one or more cyclic heteroatoms. As used herein, bicyclic or polycyclic heterocyclic groups can have one or more rings that are aryl or heteroaryl rings, provided that the bicyclic or polycyclic heterocyclic group as a whole is not a heteroaryl ring system, and the bonding point can be on any ring of the bicyclic or polycyclic heterocyclic group. For example, fused heterocyclic ring systems also include those fused ring systems 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 connection point can be on any ring.

[0295] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, ethylene oxide, and cyclothioethane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrobutyl, oxetyl, and thiobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxetyl, oxetyl, dithiophenyl, 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 tetrahydrothiaranyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazineyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (i.e., 5,6-bicyclic heterocyclic groups herein) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with a benzene ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0296] "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 a ring array), having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C”). 14 "Aromatic"; for example, anthracene.

[0297] When used alone or as part of another group, "aralkyl" 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, etc. When aralkyl is optionally substituted, either the alkyl portion or the aryl portion of the aralkyl group may be optionally substituted.

[0298] Unless otherwise stated or contrary to the context, "heteroaryl" used alone or as part of another group refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array), having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). Heteroaryls with ring sizes different from 5-10 membered heteroaryls are designated with different ring size names where applicable. Those skilled in the art will understand that such heteroaryls with different ring sizes are also 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared in a cyclic array), having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryls containing one or more nitrogen atoms, the bonding point may be a carbon atom or a nitrogen atom, if the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings, with the bonding site located on either ring. For example, in a bicyclic heteroaryl system (e.g., indole, quinolinyl, etc.) where one ring does not contain a heteroatom, the bonding site may be located on the ring containing the heteroatom (e.g., 2-indole) or the ring without the heteroatom (e.g., 5-indole).

[0299] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups 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, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0300] "Heteroarylene" as 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 a heteroarylene is optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroarylene may be optionally substituted.

[0301] As commonly understood by those skilled in the art, alkylene, alkenylene, ynylene, carbocyclic, heterocyclic, aryl, and heteroaryl refer to the corresponding divalent groups of alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, respectively.

[0302] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the various groups that are either unsubstituted or substituted. Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permitted substituent, such as a substituent that, upon substitution, produces a stable compound, for example, a compound that does not spontaneously transform through, for example, rearrangement, cyclization, elimination, or other reactions. Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position can be the same or different. Typically, when substituted, an optionally substituted group herein can be substituted by 1 to 5 substituents. In some embodiments, the two substituents may, together with the intermediate atom, form an optionally substituted ring system, such as an optionally substituted 3-8 membered carbon ring, an optionally substituted 3-8 membered heterocycle, an optionally substituted aryl ring, or an optionally substituted heteroaryl ring. Where applicable, the substituents may be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents, or sulfur atom substituents.

[0303] Unless explicitly stated otherwise, combinations of substituents and / or variables are permitted only if they are chemically permissible and produce stable compounds. A “stable” compound is one that can be prepared and isolated and whose structure and properties can be maintained or caused to remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0304] In some embodiments, the “optionally substituted” alkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic groups described herein may be unsubstituted or substituted with 1, 2, 3, or 4 substituents, said substituents being independently selected from: F, Cl, -OH, protected hydroxyl, oxo (if applicable), NH2, protected amino, NH(C 1-4 alkyl groups or their protected derivatives, N(C) 1-4 Alkyl ((C) 1-4 Alkyl) and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclic groups containing 1 or 2 cyclic heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3, wherein the substituents are independently selected from: F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 alkoxy and fluorine-substituted C 1-4 Alkyl group. In some embodiments, the “optionally substituted” aryl or heteroaryl group referred to herein may be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from: F, Cl, -OH, -CN, NH2, protected amino, NH(C 1-4 alkyl groups or their protected derivatives, 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 group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclic groups containing 1 or 2 cyclic heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 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 Alkyl group.

[0305] Exemplary carbon atom substituents include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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 SO2R aa -NR bb SO2R 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 group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion; or two hydrogen atoms on a carbon atom are surrounded by =O, =S, =NN(R) groups. 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 Substitute;

[0306] R aa Each instance is independently selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0307] R bb Each instance 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 group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion;

[0308] R cc Each instance is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0309] R dd Each instance is independently selected from halogens, -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 SO2R 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 group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. ggGroup substitution, or two geminal radicals dd Substituents can be linked to form =O or =S; where X - It is a counter ion;

[0310] R ee Each instance is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 Aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0311] R ff Each instance is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and

[0312] R gg Each instance is independently a 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 groups, -NH(OH), -SH, -SC 1-6Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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 groups, -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 group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two geminal Rs gg Substituents can be linked to form =O or =S; where X - It is a counter ion.

[0313] A "counterion" or "anionic counterion" is a negatively charged group bonded to a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., comprising one negative charge). They can also be polyvalent (i.e., comprising more than one negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (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-sulfonate-5-sulfonate, ethane-1-sulfonate-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) - Examples of multivalent counterions 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, adipic acid, pimelic acid, octanoic acid, azelaic acid, sebacic acid, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.

[0314] "Halogen" or "halogen" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

[0315] "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 SO2R aa -C(=S)N(R) bb )2、-C(=O)SR aa or -C(=S)SR aa The part in which R aa and R bb As defined in this article.

[0316] Nitrogen atoms may be substituted or unsubstituted, depending on their valence, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, hydrogen, -OH, and -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 group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, or two R groups bonded to a nitrogen atom cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd The definition is as above.

[0317] In some 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, TWGreene and PGMWuts, 3 rd Those described in detail in edition, John Wiley & Sons, 1999, are incorporated herein by reference. Exemplary nitrogen-protecting groups include, but are not limited to, those that form urethane esters, such as carboxybenzyloxy (Cbz) groups, p-methoxybenzyl carbonyl (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 tosyl, nosyl, etc.; and others, such as p-methoxyphenyl.

[0318] Exemplary oxygen 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 some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxyl protecting group). Oxyprotecting groups are well known in the art and are included in Protective Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd Those described in detail in edition, John Wiley & Sons, 1999, are 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 formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., carbonates, sulfonates, such as methanesulfonate (methanesulfonate), benzylsulfonate, toluenesulfonate (Ts), etc.

[0319] The term "leaving group" is given its general meaning in the field of synthetic organic chemistry; for example, it can refer to an atom or group that can be replaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogens (e.g., F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxyamino, 9-phenyloxanthyl (pixyl), and halocarboxylate esters.

[0320] The term "pharmaceutically acceptable salt" refers to a salt that, within reasonable medical judgment, is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0321] The term "tautomer" or "tautomer" refers to two or more interconvertible compounds resulting from at least one formal migration of hydrogen atoms and at least one change in valence (e.g., single to double, triple to single, or vice versa). The exact proportions of tautomers depend on a variety of factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactamimide, enamine-imide, and enamine-(different enamines) tautomerization reactions.

[0322] As used herein, the term “subject” (or “patient” as used herein) refers to an animal, preferably a mammal, and most preferably a human, as a subject of treatment, observation or experimentation.

[0323] As used herein, the term "treatment" ("treat", "treating", "treatment", etc.) means the elimination, reduction, or improvement of a disease or condition, and / or associated symptoms. While not excluding the possibility that treatment of a disease or condition does not require the complete elimination of the disease, condition, or associated symptoms, it is not necessary. As used herein, the term "treatment" ("treat", "treating", "treatment", etc.) may include "preventive treatment," which refers to reducing the likelihood of the development of a disease or condition, or the likelihood of recurrence of a previously controlled disease or condition, in subjects who do not have the disease or condition but are at risk of its recurrence or are prone to its recurrence or recurrence. The term "treatment" and its synonyms are considered in the context of administering a therapeutically effective amount of the compound described herein to a subject in need of such treatment.

[0324] As used in this article, the singular forms “a,” “an,” and “the” include plural references unless explicitly stated or clearly understood from the context not to mean so.

[0325] The term "and / or" as used in phrases such as "A and / or B" herein 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).

[0326] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject matter, and are not associated with an interpretation of the subject matter description. In various embodiments, features described under one heading or subheading of this disclosure may be combined with features described under other headings or subheadings. Furthermore, all features under a single heading or subheading are not necessarily used together in all embodiments.

[0327] Example

[0328] The various starting materials, intermediates, and compounds of the preferred embodiments can be separated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods, for example, by melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of the steps for performing the synthesis of the products described herein are described in more detail below.

[0329] Example 1: Synthesis of Compound 1

[0330]

[0331] Step 1: At 0°C, oxalyl chloride (21 g, 165 mmol) was added to a solution of spiro[2,2]pentane-1-carboxylic acid (6.16 g, 55 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under vacuum. The residue was dissolved in dichloromethane, and a 7 M 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 under vacuum to give 1-1.

[0332] Step 2: At room temperature, a solution of lithium hydroxide (7.57 g, 315 mmol) in water (90 mL) was added to a solution of ethyl 4,6-dihydroxypyridazine-3-carboxylate (23.2 g, 126 mmol) in tetrahydrofuran (230 mL) and methanol (130 mL). The reaction mixture was stirred for 4 hours. Volatile substances were removed under vacuum. The residue was acidified with 6N hydrochloric acid solution (pH < 1) at 0 °C and stirred for 30 minutes at room temperature. 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 for 30 minutes at room temperature. The mixture was filtered and washed with dichloromethane / methanol (3 / 1) to give 1-2.

[0333] 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 phosphoric acid chloride (200 mL) at room temperature. The mixture was stirred at 110 °C for 2 hours. The phosphoric acid chloride 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 aqueous sodium bicarbonate 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 1-3.

[0334] Step 4: Triethylamine (24.4 g, 242 mmol) and neopentanoyl 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 give 1-4.

[0335] Step 5: Under a nitrogen atmosphere and at -78°C, tert-butyllithium (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 mixture at -78°C. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction was quenched 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 = 4 / 1) to give 1-5.

[0336] Step 6: The mixture of 1-5 (3.3 g, 13 mmol) and 2N HCl (65 mL, 130 mmol) was stirred overnight at 100 °C. The mixture was cooled to room temperature and extracted with methyl tert-butyl ether. The aqueous layer was adjusted to pH 7 with a saturated 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.

[0337] Step 7: Under a nitrogen atmosphere and at 0 °C, add dropwise a 1 M solution (6.2 mL, 6.2 mmol) of lithium bis(trimethylsilyl)amino in tetrahydrofuran (25 mL). Heat the reaction mixture to room temperature and stir for 1 hour. Dilute the mixture with water and then filter. Pulp the coarse filter cake with acetonitrile, filter, and dry to obtain 1-7.

[0338] Step 8: To the mixture of 1-7 (230 mg, 0.67 mmol) in dioxane (3 mL), add 1-1 (112 mg, 1 mmol), cesium carbonate (434 mg, 1.34 mmol), tris(dibenzylacetone)dipalladium (184 mg, 0.2 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (116 mg, 0.2 mmol). Stir the reaction mixture at 145 °C for 1 hour under N2 atmosphere and microwave. Dilute the mixture with dichloromethane and wash with water. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (dichloromethane to dichloromethane / ethyl acetate = 1 / 1) to give 1-8.

[0339] Step 9: Sodium tungstate (86 mg, 0.29 mmol) and 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 mixture was diluted with water and quenched with saturated sodium thiosulfate solution. The mixture was adjusted to pH ~8 with saturated 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 aqueous solution: 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).

[0340] Example 2: Synthesis of Compound 2

[0341]

[0342] Step 1: Triphenylphosphine (8.14 g, 31.1 mmol) and di-tert-butyl azodicarbonate (7.15 g, 31.1 mmol) were added to a solution of spiro[2,2]pentane-1-carboxylic acid (2.9 g, 25.9 mmol) and naphthyl-2-ylmethanol (4.91 g, 31.1 mmol) in tetrahydrofuran (80 mL). 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. This was obtained by preparative SFC ( IG, using supercritical CO2 / MeOH, separates the racemic products to obtain 2-1 and 2-2.

[0343] 2-1: Optical rotation: [α] D 20 77.3 (c 0.8, MeOH). Chiral SFC analysis: 99.46% ee. Retention time on Reprosil Chiral-AM (similar to Daicel chiralpak AD) 100×3mm 3μm (35℃) was 1.578 min; mobile phase: EtOH (+0.1% DEA) in CO2, 1800 psi, 1.5 mL / min.

[0344] 2-2: Optical rotation: [α] D 20 -78.4 (c 0.8, MeOH). Chiral SFC analysis: 98.2% ee. Retention time of Reprosil Chiral-AM (similar to Daicel chiralpak AD) on 100×3mm 3μm (35℃) was 1.841 min; mobile phase: EtOH (+0.1% DEA) in CO2, 1800 psi, 1.5 mL / min.

[0345] Step 2: At 0°C, add 34.5 mL of 1N lithium hydroxide aqueous solution (34.5 mmol) to a solution of 2-2 (2.9 g, 11.5 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL). Heat the mixture to room temperature and stir for 3 hours. Remove volatiles under vacuum and dilute the residue with water. Wash the aqueous layer with dichloromethane, acidify with 1N hydrochloric acid, and then extract with dichloromethane. Dry the combined organic layers with anhydrous sodium sulfate, filter, and concentrate to give 2-3.

[0346] Step 3: Add oxaloyl chloride (1.47 g, 1.16 mmol) to a solution of 2-3 (1.0 g, 8.9 mmol) in dichloromethane (30 mL) at room temperature. Stir the mixture for 3 hours. Remove volatiles under vacuum. Dissolve the resulting mixture in dichloromethane, and then add a 7M solution of ammonia in methanol (30 mL) at 0 °C. Stir the reaction mixture at room temperature for 16 hours. Remove the solvent under vacuum to give 2-4.

[0347] Compound 2 was prepared from components 2-4 according to the synthetic procedure for compound 1 in Example 1. 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).

[0348] Example 3: Synthesis of Compound 3

[0349]

[0350] Step 1: Under a nitrogen atmosphere at 40°C, tert-butyl nitrite (15.5 g, 150 mmol) was added dropwise over 1 hour 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). 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 give 3-1.

[0351] 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(dibenzylacetone)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 under a 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.

[0352] Step 3: Add 24 mL of 4N HCl solution (96.3 mmol) to the suspension of 3-2 (3.1 g, 9.63 mmol) in dioxane (24 mL). Stir the reaction mixture at room temperature for 1 hour. Concentrate the mixture and dilute with ethyl acetate. Adjust the pH of the mixture to approximately 8 with a saturated aqueous sodium bicarbonate solution. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 3-3.

[0353] Step 4: Under a nitrogen atmosphere at 0°C, a 1M solution (8 mL, 8 mmol) of bis(trimethylsilyl)aminolithium in tetrahydrofuran was added dropwise to a mixture of 1-3 (628 mg, 3 mmol) and 3-3 (501 mg, 3.15 mmol) in tetrahydrofuran (25 mL). 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.

[0354] Synthesize 3 following similar steps to those 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).

[0355] Example 4 Synthesis of Compound 5

[0356]

[0357] Step 1: At 0°C, a 1N solution of lithium hydroxide in water (32 mL, 32.1 mmol) was added to a solution of 2-1 (2.7 g, 10.7 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL). The mixture was then heated to room temperature and stirred for 3 hours. Volatile substances were removed under vacuum and the mixture was diluted with water. The aqueous layer was washed with dichloromethane, acidified with 1N hydrochloric acid, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-1.

[0358] Step 2: Oxaloyl chloride (1.47 g, 1.16 mmol) was added to a solution of 5-1 (1.0 g, 8.9 mmol) in dichloromethane (30 mL) at room temperature, and the mixture was stirred for 3 hours. Volatile substances 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 under vacuum to obtain 5-2.

[0359] Step 3: At room temperature, sodium methanethiol (111 g, 317 mmol, 20% aqueous solution) was added dropwise to a solution of 3-fluoro-2-nitropyridine (30 g, 211.3 mmol) in dimethylformamide (300 mL). 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.

[0360] Step 4: Add water (125 mL) to the mixture of 5-3 (42 g, 211.3 mmol) in methanol (500 mL), and add ammonium chloride (56.5 g, 1057 mmol) and iron powder (60.9 g, 1057 mmol) in portions. Stir the reaction mixture at 65 °C for 1 hour. Dilute the mixture with ethyl acetate and filter. Wash the organic layer with water and brine, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 5-4.

[0361] Step 5: Add N-bromosuccinimide (2.14 g, 12 mmol) to a solution of 5-4 (1.4 g, 10 mmol) in dichloromethane (30 mL). Stir the mixture at room temperature for 1 hour. Dilute the mixture with water and extract with dichloromethane. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10 / 1) to give 5-5.

[0362] Step 6: Add tripotassium phosphate (3.71 g, 17.5 mmol) to a mixture of 5-5 (766 mg, 3.5 mol), cyclopropylboronic acid (1.2 g, 14 mmol), tricyclohexylphosphine (196 mg, 0.7 mmol), and tris(dibenzylacetone)palladium (320 mg, 0.35 mmol) in toluene / water (25 mL / 4 mL). Stir the mixture at 100 °C for 6 hours under N2 atmosphere. Extract the mixture with ethyl acetate. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 5 / 1) to give 5-6.

[0363] Step 7: At 0°C, add a 1M solution (2.5 mL, 2.5 mmol) of bis(trimethylsilyl)aminolithium in tetrahydrofuran to a mixture of 1-3 (209 mg, 1 mmol) and 5-6 (189 mg, 1.05 mmol) in tetrahydrofuran (10 mL). Heat the mixture to room temperature and stir for 1 hour. Dilute the mixture with water, acidify to pH ~9 with 1N hydrochloric acid at 0°C, filter, and wash with water. Dry the precipitate to obtain 5-7.

[0364] Step 8: To a mixture of 5-7 (127 mg, 0.36 mmol) and dioxane (5 mL), add 5-2 (60 mg, 0.54 mmol), tris(dibenzylacetone)dipalladium (50 mg, 0.054 mmol), cesium carbonate (235 mg, 0.72 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (63 mg, 0.108 mmol). Stir the reaction mixture at 145 °C for 1 hour under N2 atmosphere and microwave. Dilute the mixture with dichloromethane and wash with water. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (dichloromethane to dichloromethane / ethyl acetate = 1:1) to give 5-8.

[0365] 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 mixture was diluted with water, quenched with saturated sodium thiosulfate solution, adjusted to pH ~9 with sodium carbonate, and 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 (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).

[0366] Example 5: Synthesis of Compound 6

[0367]

[0368] Step 1: At 0°C, 20% sodium methanethiol aqueous solution (98.9 g, 282.5 mmol) was added dropwise to a solution of 2-bromo-3-fluoroisonicotinic acid (24.8 g, 113 mmol) in dimethylacetamide (150 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, adjusted to pH ~2 with 1 M hydrochloric acid aqueous solution, and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-1.

[0369] Step 2: N,N'-carbonyldiimidazole (22.6 g, 139.5 mmol) was added to a solution of 6-1 (23 g, 93 mmol) in tetrahydrofuran (200 mL) at room temperature. The mixture was stirred for 3 hours. The mixture was then 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 2 M hydrochloric acid, the pH was adjusted to ~8 with saturated sodium carbonate aqueous solution, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-2.

[0370] Step 3: Under a nitrogen atmosphere and at 0°C, tert-butylchlorodiphenylsilane (23 g, 83.6 mmol) was added dropwise to a solution of 6-2 (17.8 g, 43 mmol) and imidazole (6.2 g, 91.2 mmol) in dichloromethane (200 mL). The mixture was heated to room temperature and stirred for 1 hour. The mixture was washed with water, saturated sodium bicarbonate 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.

[0371] 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(dibenzylacetone)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 under a nitrogen 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 3 M hydrochloric acid aqueous solution. The mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH ~8 with saturated sodium carbonate aqueous 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.

[0372] Compound 6-6 was prepared from 6-4 according to the synthesis procedure of compounds 1-8 in Example 1.

[0373] Compound 6-7 was prepared from 6-6 according to the synthesis procedure of compound 1 in Example 1.

[0374] Step 5: At room temperature, add dropwise a 1M solution (0.03 mL, 0.03 mmol) of tetrabutylammonium fluoride in tetrahydrofuran to a solution of 6-7 (20 mg, 0.029 mmol) in tetrahydrofuran (0.5 mL). Stir the mixture for 1 hour. Dilute the mixture with water and stir for 10 minutes, filter and wash with water. Purify the residue by preparative HPLC (acetonitrile / 0.05% formic acid aqueous solution: 5%–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).

[0375] Example 6 Synthesis of Compound 7

[0376]

[0377] Compound 7-1 was prepared from 20-1 according to the synthesis procedure of compounds 1-8 in Example 1.

[0378] Step 1: Add (diacetoxyiodine)benzene (83 mg, 0.258 mmol) and ammonium carbamate (20 mg, 0.258 mmol) to a suspension of 7-1 (40 mg, 0.103 mmol) in methanol (100 mL) and dichloromethane (5 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture and purify it by preparative HPLC (acetonitrile / 0.05% formic acid aqueous solution: 5%–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).

[0379] Example 7 Synthesis of Compound 8

[0380]

[0381] Step 1: Add 3.2 mL of 1 M solution of tetrabutylammonium fluoride in THF to a solution of 6-6 (2.1 g, 3.2 mmol) in tetrahydrofuran (20 mL) at room temperature. Stir the mixture for 1 hour. Dilute the reaction mixture with water, filter, and wash with water. Slurry the filter cake with methanol, filter, and dry to obtain 8-1.

[0382] Step 2: 1,8-diazabicyclo[5.4.0]undecyl-7-ene (1.22 g, 8 mmol) and diphenylphosphoazide (1.1 g, 4 mmol) were added to a suspension of 8-1 (834 mg, 2 mmol) in tetrahydrofuran (100 mL) at room temperature. The mixture was stirred for 3 hours under a nitrogen atmosphere. The mixture was diluted with water, filtered, and washed with water. The filter cake was slurried with methanol, filtered, and dried to obtain 8-2.

[0383] Step 3: At room temperature, sodium tungstate (147 mg, 0.5 mmol) and 30% hydrogen peroxide aqueous solution (1.13 g, 10 mmol) were added dropwise to a mixture of 8-2 (221 mg, 0.5 mmol) in acetic acid (20 mL), and the mixture was stirred for 0.5 hours. The mixture was diluted with water, adjusted to pH ~8 with sodium carbonate, and quenched with saturated sodium thiosulfate aqueous solution. The crude product was filtered and washed with water. The filter cake was slurried with methanol to obtain 8-3.

[0384] Step 4: The 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 a 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).

[0385] Example 8 Synthesis of Compound 9

[0386]

[0387] Step 1: 6-Chlorobenzo[d]thiazol-2-amine (10.0 g, 54.1 mmol) was added to a solution of potassium hydroxide (60.5 g, 1.08 mol) in water (100 mL). The mixture was stirred at 100 °C for 6 hours. The mixture was cooled to room temperature. Then, methyl iodide (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 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 = 5 / 1) to give 9-1.

[0388] Compound 9 was prepared from step 9-1 according to the synthetic procedure for 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).

[0389] Example 9 Synthesis of Compound 10

[0390]

[0391] Step 1: At 0°C, potassium tert-butoxide (4.93 g, 44 mmol) was added to a solution of 2-amino-4-chlorobenzylthiol (6.4 g, 40 mmol) in ethanol (80 mL). The mixture was stirred for 75 minutes. Then methyl iodide (11.36 g, 80 mmol) was 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.

[0392] Compound 10 was prepared from 10⁻¹ according to the synthetic procedure for compound 5 in Example 4. 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).

[0393] Example 10 Synthesis of Compound 11

[0394]

[0395] Step 1: N,N-diisopropylethylamine (503 mg, 3.9 mmol) was added to a mixture of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (702 mg, 3 mmol) and 2-(methanesulfonyl)aniline (567 mg, 3.3 mmol) in acetonitrile (15 mL) at 25 °C. The mixture was stirred for 2 minutes under a N2 atmosphere and then purified by preparative HPLC (acetonitrile / 0.05% TFA aqueous solution: 5%–95%) to obtain 11-1.

[0396] Step 2: Add 3-chloroperoxybenzoic acid (621 mg, 3.0 mmol) to a solution of 11-1 (450 mg, 1.2 mmol) in dichloromethane (10 mL). Stir the reaction mixture at 25 °C for 30 min. Concentrate the mixture and then dissolve it in ethanol and water. Add sodium hydroxide (240 mg, 6 mmol) to the above mixture at 0 °C. Stir the mixture at 25 °C for 30 min. Dilute the mixture with water and wash with dichloromethane. Neutralize the aqueous layer to pH ~7 with acetic acid and purify by preparative HPLC (acetonitrile / 0.05% TFA aqueous solution: 5%–95%) to obtain 11-2.

[0397] Step 3: A mixture of 11-2 (104 mg, 0.33 mmol) and N,N-diethylaniline (50 mg, 0.33 mmol) in phosphoric acid chloride (2 mL) was stirred at 80 °C under a nitrogen 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 25 °C under a nitrogen atmosphere for 30 minutes. 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 preparative HPLC (acetonitrile / 0.05% TFA aqueous solution: 5%–95%) to obtain 11-3.

[0398] Compound 11 was prepared from 11-3 according to the synthetic procedure for compounds 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).

[0399] Example 11 Synthesis of Compound 12

[0400]

[0401] Step 1: To a solution of 4,6-dichloronicotinic acid (5 g, 26 mmol) in acetonitrile (50 mL), 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'-tetramethylureon hexafluorophosphate (10.4 g, 27.4 mmol) were added. 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 12-1.

[0402] Step 2: Under a nitrogen atmosphere and at -15°C, a 1M solution (73 mL, 73 mmol) of cyclopropylmagnesium bromide in THF was added dropwise to a solution of 12-1 (5.68 g, 24.2 mmol) in tetrahydrofuran (25 mL). The mixture was heated to room temperature and stirred for 0.5 hours. The mixture was then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were 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 = 10 / 1) to give 12-2.

[0403] Step 3: At 0°C, sodium hydride (1.74 g, 43.5 mmol, 60% in mineral oil) was added in portions 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 h, 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 h. The mixture was then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were 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 12-3.

[0404] Compound 12 was prepared from 12-3 according to the synthetic procedure for compound 1 in Example 1. 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).

[0405] Example 12 Synthesis of Compound 13

[0406]

[0407] Step 1: Under a nitrogen atmosphere and at -78°C, n-butyllithium (39 mL, 98 mmol) was added dropwise to a suspension of N-(pyridin-4-yl)neopentamide (7 g, 39 mmol) in tetrahydrofuran (150 mL). The mixture was heated to 0°C and stirred for 3 hours. Dimethyl disulfide (11 g, 118 mmol) was added dropwise to the mixture at -78°C. The mixture was heated to room temperature and stirred for 0.5 hours. The reaction 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. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 5 / 1) to give 13-1.

[0408] Step 2: The mixture of 13-1 (2 g, 8.9 mmol) in 3N hydrochloric acid aqueous 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 sodium hydroxide aqueous solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 13-2.

[0409] Compound 13 was prepared from 13-2 according to the synthetic procedure for 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).

[0410] Example 13 Synthesis of Compound 16

[0411]

[0412] At 0 °C, oxalyl chloride (762 mg, 6.0 mmol) was added to a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (224 mg, 2.0 mmol) in dichloromethane (4 mL). 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 7 M solution of ammonia in methanol (6 mL, 42 mmol) was added at 0 °C. The reaction mixture was heated to room temperature and stirred for 0.5 hours. The solvent was removed under vacuum to give 16-1.

[0413] Compound 16 was prepared from 16-1 according to the synthetic procedure for 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).

[0414] Example 14 Synthesis of Compound 20

[0415]

[0416] Compound 20-1 was prepared from 1-3 according to the synthetic procedure of compounds 1-7 in Example 1.

[0417] Step 1: Bicyclo[1.1.1]pentane-1-amine hydrochloride (4.04 g, 33.4 mmol) was added 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) at room temperature. The mixture was stirred in a sealed tube at 150 °C for 24 hours. The mixture was cooled, diluted with ethyl acetate, and 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.

[0418] Compound 20 was prepared from 20-2 according to the synthetic procedure for 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).

[0419] Example 15 Synthesis of compounds 21 and 22

[0420]

[0421] Step 1: Cyclopropylamine (2.2 g, 38.3 mmol) was added to a solution of phenyl carbamate (2.1 g, 15.3 mmol) in dioxane (30 mL). 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.

[0422] Step 2: To a mixture of 20-1 (156 mg, 0.5 mmol) in dioxane (5 mL), add 21-1 (125 mg, 1.25 mmol), tris(dibenzylacetone)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 a nitrogen atmosphere. The mixture was diluted with ethyl acetate and 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 aqueous solution: 10%–95%) to give 21-2 / 22-2 (20%).

[0423] Step 3: Sodium tungstate (122 mg, 0.41 mmol) and a 30% aqueous solution of hydrogen peroxide were added dropwise to a mixture of 21-2 (160 mg, 0.41 mmol, mixed with ~20% of 22-2) in acetic acid (10 mL) at room temperature. The reaction mixture was stirred for 1 hour. The mixture was diluted with water, quenched with a saturated aqueous solution of 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% aqueous solution of formic acid: 10%–95%) to give 2.0 equivalents of formate form 21 and 2.0 equivalents of formate form 22.

[0424] 2.0 equivalent of formate in 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).

[0425] 2.0 equivalent of formate at 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).

[0426] Example 16 Synthesis of Compound 25

[0427]

[0428] Compound 25-1 was prepared from 20-1 according to the synthesis procedure of compound 1 in Example 1.

[0429] Step 1: To a mixture of 25-1 (173 mg, 0.5 mmol) in dimethyl sulfoxide (4 mL) / water (0.4 mL), (3-methyl-1H-pyrazol-5-yl)boronic acid (157.5 mg, 1.25 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(I) (73 mg, 0.1 mmol), and potassium carbonate (207 mg, 1.5 mmol) were added. The reaction mixture was stirred at 130 °C for 1 hour under N2 atmosphere and microwave. 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 aqueous solution: 15%–95%) to give 25, as a 2.0 equivalent formate. 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).

[0430] Example 17 Synthesis of Compound 37

[0431]

[0432] 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) over 0.5 hours. A solution of ethyl 2-diazoacetate (1.5 mL, 14.2 mmol) in dichloromethane (7 mL) was added dropwise 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.

[0433] Step 2: Stir the mixture of 37-1 (200 mg, 1.28 mmol) and ammonia (10 mL) at room temperature for 72 hours. Concentrate the mixture to obtain 37-2.

[0434] Compound 37 was prepared from 37-2 according to the synthetic procedure for compound 1 in Example 1. LCMS (ESI, m / z): [M+H] + =466.2; 1 H-NMR (400MHz, DMSO-d6, 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=2.8Hz,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).

[0435] Example 18 Synthesis of compounds 39-41

[0436]

[0437] Step 1: Benzyl chloroformate (11.29 g, 66 mmol) was added to a suspension of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthylidine 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 and 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.

[0438] 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(dibenzylacetone)dipalladium (1.83 g, 2 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (2.3 g, 4 mmol) in dimethyl sulfoxide (200 mL) was stirred at 110 °C under a N2 atmosphere for 24 hours. The mixture was diluted with ethyl acetate and 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.

[0439] Step 3: N-iodosuccinimide (4.05 g, 18 mmol) was added to a solution of 39-2 (4.25 g, 15 mmol) in acetic acid (50 mL) at room temperature. The reaction was then stirred for 16 hours. The mixture was diluted with water, adjusted to pH ~8 with saturated sodium carbonate aqueous 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.

[0440] Step 4: To a mixture of 39-3 (4.9 g, 12 mmol) in dioxane (50 mL), methyl 3-mercaptopropionate (2.16 g, 18 mmol), tris(dibenzylacetone)dipalladium (550 mg, 0.6 mmol), ethyl diisopropylamine (3.1 g, 24 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (694 mg, 1.2 mmol) were added. The mixture was stirred at 100 °C for 5 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and 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.

[0441] Step 5: Potassium tert-butoxide (3.36 g, 30 mmol) was added to a mixture of 39-4 (4 g, 10 mmol) in tetrahydrofuran (40 mL) 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, and the mixture was stirred for 1 hour. The mixture was diluted with ethyl acetate and 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.

[0442] Compound 39 was prepared from 39-5 according to the synthetic procedure for 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).

[0443] Step 6: Under a nitrogen atmosphere, 39 (152 mg, 0.25 mmol) of iodotrimethylsilane (300 mg, 1.5 mmol) was added to a solution of 39 (152 mg, 0.25 mmol) in acetonitrile (10 mL). The reaction was then stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous sodium bicarbonate solution 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 aqueous solution: 5%–95%) to give 2.0 equivalents of 40 in the form of formate. 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).

[0444] Step 7: To a solution of 40 (47 mg, 0.1 mmol) in 1,2-dichloroethane (3 mL) and N,N-dimethylacetamide (3 mL), acetic acid (12 mg, 0.2 mmol), 36% formaldehyde solution (83 mg, 1 mmol), and sodium triacetoxyborohydride (106 mg, 0.5 mmol) were added. The reaction was then stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate aqueous solution 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 aqueous solution: 5%–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).

[0445] Example 19 Synthesis of Compound 42

[0446]

[0447] Step 1: 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) in an ice bath. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum. 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.

[0448] Step 2: Add 42-1 (10 g, 40.8 mmol) in portions to a mixture of concentrated sulfuric acid (35 mL, 609 mmol) and fuming nitric acid (23.5 mL, 487 mmol) at 0 °C. After stirring overnight at room temperature, pour the mixture into ice water. Filter the precipitate, wash with water, and dry to obtain 42-2.

[0449] Step 3: Under a nitrogen atmosphere, sodium ethoxide (3.87 g, 56.881 mmol) was added to a mixture of 42-2 (3 g, 10.342 mmol) and ethanol (60 mL) with stirring. The reaction mixture 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 under vacuum. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2:3) to give 42-3.

[0450] Compound 42-4 was prepared from 42-3 according to the synthetic procedure of compound 3-1 in Example 3.

[0451] Compound 42-5 was prepared from 42-4 according to the synthetic procedure of compound 5-4 in Example 4.

[0452] Compound 42 was prepared from 42-5 according to the synthetic procedure for 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).

[0453] Example 20 Synthesis of Compound 43

[0454]

[0455] Step 1: Tribromoborane (35.2 mL, 35.2 mmol) was added to a solution of 1-6 (2 g, 11.7 mmol) in dichloromethane (20 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed under vacuum 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.

[0456] 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 complete, the mixture was quenched with ice water. The aqueous 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.

[0457] Compound 43 was prepared from 43-2 according to the synthetic procedure for compound 5 in Example 4. 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).

[0458] Example 21 Synthesis of Compound 44

[0459]

[0460] Step 1: A mixture of 5-5 (2.7 g, 12.3 mmol), potassium vinyltrifluoroborate (2.49 g, 18.5 mmol), sodium carbonate (2.6 g, 24.6 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (0.9 g, 1.23 mmol) in dioxane (48 mL) and water (12 mL) was stirred at 110 °C for 2 hours 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.

[0461] Step 2: Add platinum oxide (IV) (85 mg) to a solution of 44-1 (850 mg, 5.1 mmol) in methanol (10 mL). Stir the reaction mixture at room temperature for 2 hours under a H2 atmosphere. Filter the suspension and wash with methanol. Concentrate the filtrate to obtain 44-2.

[0462] Compound 44 was prepared from 44-2 according to the synthetic procedure for 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).

[0463] Example 22 Synthesis of Compound 49

[0464]

[0465] Compound 49-1 was prepared from step 20-1 according to the synthetic procedure of compound 44-1 in Example 21.

[0466] 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 the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by rapid column chromatography (dichloromethane / methanol = 20 / 1) to obtain 49-2.

[0467] 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. The mixture was stirred 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.

[0468] Compound 49 was prepared from 49-3 according to the synthetic procedure for 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).

[0469] Example 23 Synthesis of Compound 50

[0470]

[0471] Step 1: Add methyl magnesium bromide (4.347 mL, 1 M hexane solution) to a solution of methyl 2-chloropyrimidine-5-carboxylate (250 mg, 1.449 mmol) in tetrahydrofuran (5 mL) at -78 °C. Stir the solution at 0 °C for 30 minutes. Stir the reaction mixture at room temperature for another 1 hour. Quench the mixture with a saturated aqueous ammonium chloride solution and dilute with diethyl ether. Wash the organic layer with water, dry with sodium sulfate, and concentrate to give 50-1.

[0472] 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.

[0473] Step 3: The 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 with a 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 solution) to give 50-3.

[0474] Compound 50 was prepared from 50-3 and 50-1 according to the synthetic procedure for compound 1 in Example 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).

[0475] Example 24 Synthesis of Compound 51

[0476]

[0477] Step 1: To a solution of cyclopropylamine (2 g, 35 mmol) in acetonitrile (70 mL), add 4-nitrobenzene chloroformate (7 g, 35 mmol) and triethylamine (5.3 g, 52.5 mmol). Stir the reaction mixture at 20 °C for 2 hours. Dilute the resulting mixture with dichloromethane and water. Concentrate the organic layer and purify by silica gel column chromatography (0-10% ethyl acetate in petroleum ether solution) to give 51-1.

[0478] Compound 51-2 was prepared from 50-3 and 51-1 according to the synthesis procedure of compound 12-3 in Example 11.

[0479] Compound 51 was prepared from 51-2 according to the synthetic procedure for compound 1 in Example 1. 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).

[0480] Example 25 Synthesis of Compound 52

[0481]

[0482] Compound 52-1 was prepared from 2-amino-5-chloropyridine according to the synthesis procedure of compounds 1-7 in Example 1.

[0483] Compound 52 was prepared from 52-1 and cyclopropaneformamide according to the synthetic procedure of compound 1 in Example 1. 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).

[0484] Example 26 Synthesis of Compound 53

[0485]

[0486] Step 1: Under a nitrogen atmosphere, 2,2-dimethylpropionamide (4.860 mL, 43.390 mmol), tris(dibenzylacetone)dipalladium (0.79 g, 0.868 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (1.00 g, 1.736 mmol), and cesium carbonate (8.48 g, 26.034 mmol) were added to a solution of 2-bromo-5-(trifluoromethoxy)pyridine (2.1 g, 8.678 mmol) in dioxane (160 mL), and the mixture was heated to 110 °C overnight. The mixture was concentrated and purified by column chromatography (petroleum ether) to give 53-1.

[0487] Step 2: Under a nitrogen atmosphere and at -65°C, tert-butyllithium (33 mL, 2.5 equivalents) was added dropwise to a mixture of 53-1 (4 g, 15.254 mmol) in diethyl ether (150 mL), and the mixture was stirred for 3 hours. Then, dimethyl disulfide (2.028 mL, 22.881 mmol) was added to the mixture at -65°C and the mixture was 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.

[0488] Step 3: Add concentrated hydrochloric acid (36 wt%, 40 mL) to a solution of 53-2 (3 g, 9.730 mmol) in water (40 mL) and heat to 110 °C for 3 hours. Pour the mixture into a saturated aqueous sodium bicarbonate solution and extract with ethyl acetate. Wash the organic phase with brine, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography (ethyl acetate / petroleum ether = 1:1) to give 53-3.

[0489] Compound 53 was prepared from 53-3 and 1-3 according to the synthetic procedure for compound 1 in Example 1. 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).

[0490] Example 27 Synthesis of Compound 54

[0491]

[0492] 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, then extracted with ethyl acetate. The combined organic layers were 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.

[0493] 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 h under microwave and N2 atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 5 / 1) to give 54-2.

[0494] Compound 54-3 was prepared from 54-2 according to the synthesis procedure of compound 1 in Example 1.

[0495] Compound 54 was prepared from 54-3 according to the synthetic procedure for compounds 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).

[0496] Example 28 Synthesis of Compound 55

[0497]

[0498] Step 1: Oxaloyl chloride (18.5 g, 146 mmol) and N,N-dimethylformamide (1 mL) were added to a mixture of 4,6-dichloronicotinic acid (7.0 g, 36.4 mmol) in chloroform (150 mL) at room temperature, and the mixture was stirred at 60 °C for 2 hours. The volatiles were removed under vacuum and co-evaporated with chloroform. Tetrahydrofuran (100 mL), 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, and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate 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.

[0499] Compound 55 was prepared from 55-1 and 3-3 according to the synthetic procedure for compounds 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).

[0500] Example 29 Synthesis of Compound 58

[0501]

[0502] Compound 58-1 was prepared from 44-1 and 1-3 according to the synthesis procedure of compounds 1-8 in Example 1.

[0503] Compound 58-2 was prepared from 58-1 according to the synthesis procedure of compound 49-2 in Example 22.

[0504] Step 1: To a solution of 58-2 (60 mg, 0.148 mmol) in dichloromethane (10 mL), add bis(2-methoxyethyl)aminosulfur trifluoride (0.136 mL, 0.740 mmol). Stir the mixture at 20 °C for 16 hours. Pour the reaction mixture into ice water, wash the organic layer with brine, dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to dryness. Purify the crude product by preparative TLC (dichloromethane / methanol = 15 / 1) to obtain 58-3.

[0505] Compound 58 was prepared from 58-3 according to the synthetic procedure for 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).

[0506] Example 30 Synthesis of Compound 59

[0507]

[0508] 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 then cooled to 0 °C. The mixture was quenched with methanol. The resulting mixture was adjusted to pH ~9 with lithium hydroxide (1 M 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.

[0509] Step 2: Triphenylphosphine (2.02 g, 7.7 mmol) and N,N,N',N'-tetramethylazodicarbonamide (1.32 g, 7.7 mmol) were added 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). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by preparative HPLC (acetonitrile / 0.05% TFA aqueous solution: 10%–95%) to give 59-2.

[0510] Compound 59 was prepared from 59-2 according to the synthetic procedure for 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).

[0511] Example 31 Synthesis of Compound 60

[0512]

[0513] Step 1: At 10–20 °C, a solution of sodium hydroxide (1.64 g, 40.9 mmol) in water (10.0 ml) was added dropwise to a mixture of 59-1 (2.00 g, 12.8 mmol) in 1,2-dimethoxyethane (20.0 ml). The mixture was then bubbled with difluorochloromethane for 30 minutes and stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were 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 give 60-1.

[0514] Compound 60-2 was prepared from 60-1 according to the synthetic procedure of compound 1 in Example 1.

[0515] Compound 60 was prepared from 60-2 according to the synthetic procedure for compounds 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).

[0516] Example 32 Synthesis of Compound 65

[0517]

[0518] Compound 65-1 was prepared from 5-5 according to the synthetic procedure of compounds 1-4 in Example 1.

[0519] Step 1: To a mixture of 65-1 (5 g, 22.820 mmol) in dioxane (250 mL), (3R)-3-methylmorpholine (6.92 g, 68.459 mmol), 2-(dicyclohexylphosphine)-2',4',6'-triisopropylbiphenyl (2.18 g, 4.564 mmol), bis(trimethylsilyl)aminolithium (38 mL, 38.3 mmol, 1 M tetrahydrofuran solution), and tris(dibenzylideneacetone)dipalladium (2.09 g, 2.282 mmol) were added. The mixture was then stirred at 110 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and 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.

[0520] Compound 65-3 was prepared from 65-2 according to the synthesis procedure of compounds 1-6 in Example 1.

[0521] Compound 65-4 was prepared from 65-3 according to the synthesis procedure of compound 1 in Example 1.

[0522] Step 2: Add sodium thiosulfate (187 mg, 1.18 mmol) to a solution of 65-4 (60 mg, 0.11 mmol) in methanol (20 mL). Stir the mixture at 20 °C for 24 hours. Dilute the resulting mixture with water and extract with dichloromethane / methanol = 10 / 1. Dry the combined organic layers with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by preparative HPLC (acetonitrile / 0.1% formic acid aqueous solution = 44-56%) to obtain 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).

[0523] Example 33 Synthesis of compounds 73 and 74

[0524]

[0525] 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-dioxolane-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 product).

[0526] Step 2: At 0 °C, tert-butylchlorodiphenylsilane (4.13 g, 15 mmol) was added to a mixture of 73-1 (crude, 10 mmol) and imidazole (2.04 g, 30 mmol) in N,N-dimethylformamide (40 mL), and the mixture was stirred 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.

[0527] Compound 73-3 was prepared from 73-2 according to the synthesis procedure of compounds 1-8 in Example 1.

[0528] 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 saturated sodium thiosulfate solution, and adjusted to pH ~9 with sodium carbonate solid. The mixture was extracted with dichloromethane / methanol = 10 / 1. The combined organic layers were 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 the mixture was 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 solid was dried to give 73-4.

[0529] Compound 73-5 was prepared from 73-4 according to the synthetic procedure for compound 6 in Example 5.

[0530] 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 the mixture was stirred at 60 °C for 1 hour. The resulting mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane / methanol = 20 / 1. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% FA aqueous solution: 10%–95%) to give 73 and 74.

[0531] 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).

[0532] 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).

[0533] Example 33 Synthesis of compounds 86 and 87

[0534]

[0535] Step 1: To a solution of [(4-methoxyphenyl)methyl](methyl)amine (2.34 g, 15.477 mmol) in dichloroethane (30 mL), ethyl 3-oxocyclobutanecarboxylate (2 g, 14.070 mmol) and acetic acid (0.806 mL, 14.070 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (5.93 g, 28.139 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The residue was purified by silica gel column chromatography (0-6% methanol in dichloromethane solution) to give 86-1.

[0536] Step 2: Lithium hydroxide (0.581 mL, 20.911 mmol) was added to a solution of 86-1 (2.9 g, 10.456 mmol) in tetrahydrofuran (20 mL) and water (20 mL), and the mixture was stirred 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 under vacuum to give 86-2.

[0537] Step 3: A solution of 86-2 (1000 mg, 4.011 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.28 g, 6.016 mmol), and ethylbis(prop-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 the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC (acetonitrile / ammonium bicarbonate aqueous solution) to obtain 86-3.

[0538] Step 4: Add palladium on carbon (10%, 80 mg) to a solution of 86-3 (400 mg, 1.611 mmol) in methanol (30 mL). Stir the mixture at 50 °C for 17 hours under hydrogen atmosphere. Filter and concentrate the mixture to obtain 86-4.

[0539] 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 / ammonium bicarbonate aqueous solution) to obtain 86-5.

[0540] Compound 86-6 was prepared from 86-5 according to the synthetic procedure of compound 5 in Example 4.

[0541] Step 6: Add 2 mL of trifluoroacetic acid to a solution of 86-6 (97 mg, 0.168 mmol) in dichloromethane (4.5 mL), and stir for 1 hour at room temperature. Dilute the reaction mixture with dichloromethane and concentrate under vacuum. The residue is then processed via chiral preparative SFC (…). The sample was purified by IG (eluting with supercritical CO2 / MeOH) to obtain 86 and crude product 87. Crude product 87 was further purified by preparative HPLC (acetonitrile / 0.1% trifluoroacetic acid aqueous solution = 22%).

[0542] 86: Chiral SFC analysis: >99% de. Retention time: Incubation time: 5.231 min on IG 100*3mm 3μm (35℃); mobile phase: MeOH (0.1% DEA) in CO2, 1800psi 2.0mL / min.

[0543] 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).

[0544] 87: Chiral SFC analysis: 96.94% de. Retention time: Incubation time: 3.814 min on 100*3mm 3μm (35℃); Mobile phase: MeOH (0.1% DEA) in CO2, 1800psi 2.0mL / min.

[0545] 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).

[0546] Example 34 Synthesis of compounds 94 and 95

[0547]

[0548] Step 1: In a 1 L flask, add 2-chloro-3-iodopyridine (10 g, 41.764 mmol), heptane-3-yl 3-mercaptopropionate (11.40 g, 52.205 mmol), tris(dibenzylacetone)dipalladium (3.82 g, 4.176 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (4.83 g, 8.353 mmol), N,N-diisopropylethylamine (13.49 g, 104.410 mmol), and dioxane (300 mL). Stir the mixture at 100 °C under N2 atmosphere for 18 hours. Dilute the reaction mixture with water and extract with ethyl acetate; concentrate the combined organic layers under vacuum. Purify the residue by column chromatography (0–20% ethyl acetate / petroleum ether) to give 94-1.

[0549] Step 2: At 0°C, add 94-1 (500 mg, 1.516 mmol), tetrahydrofuran (10 mL), and sodium methoxide (122.79 mg, 2.273 mmol) to a 100 mL flask. Stir the mixture at room temperature for 4 hours. 94-2 is used for the next step without purification.

[0550] Step 3: Add 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) to a 250 mL flask. Stir the mixture at room temperature for 18 hours. Dilute the reaction mixture with water and extract with ethyl acetate. Concentrate the combined organic layers under vacuum. Purify the residue by column chromatography (0–30% ethyl acetate / petroleum ether) to give 94-3.

[0551] Step 4: Add 94-3 (3.20 g, 14.405 mmol) and methanol (100 mL), iodophenyl 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 under vacuum. Purify the residue by column chromatography (0–100% ethyl acetate / petroleum ether) to give 94-4.

[0552] Step 5: The solution of 94-4 (2.6 g, 10.271 mmol) in ammonium hydroxide solution (55 mL, 0.1 wt%) was stirred in a sealed tube at 80 °C for 4 hours. The cooled reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane:methanol = 20:1) to obtain 94-5.

[0553] Step 6: The 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 concentrated filtrate yielded 94-6.

[0554] Compound 94-7 was prepared by steps 1-3 and 5-2 according to a synthetic procedure similar to that of compounds 5-8 in Example 4.

[0555] Compounds 94 and 95 were prepared from 94-7 and 94-6 according to the synthetic procedure for compounds 5-8 in Example 4.

[0556] Enantiomer 1:94 chiral SFC analysis: 98.04% ee. Reprosil Chiral-AM (similar to Daicel) Retention time on 100*3mm 3μm (35℃) optical fiber (AD) was 6.188 min; mobile phase: MeOH (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).

[0557] Enantiomer 2: 95% chiral SFC analysis: 98.88% ee. Reprosil Chiral-AM (similar to Daicel) Retention time on 100*3mm 3μm (35℃) optical fiber (AD) was 7.186 min; mobile phase: MeOH (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).

[0558] Example 35 Synthesis of Compound 96

[0559]

[0560] Step 1: N,N-diisopropylethylamine (25.3 g, 195.48 mmol) and lithium bromide (17 g, 195.48 mmol) were added to a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (14.4 g, 65.16 mmol) in acetonitrile (75 mL) and water (11 mL) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered and washed with acetonitrile to give 96-1.

[0561] 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, and the mixture was stirred at room temperature for 16 hours. Then, sodium methoxide (2.44 g, 45.24 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 2–3 with 2 M hydrochloric acid aqueous solution and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% trifluoroacetic acid aqueous solution: 0%–95%) to obtain 96-2 (crude product, directly used in the next step).

[0562] 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 at 0 °C to a pre-stirred mixture of potassium 3-ethoxy-3-oxopropionate (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), and stirred at room temperature for 16 hours. The mixture was quenched with methanol, adjusted to pH ~4 with 2 M hydrochloric acid aqueous solution, and extracted with ethyl acetate. The combined organic layers were 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.

[0563] Step 4: Trideuterated (iodo)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 washed 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.

[0564] Step 5: The 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. It was then cooled to room temperature and concentrated. The residue was diluted with water and filtered. The filter cake was pulped with acetonitrile and filtered to obtain 96-5.

[0565] Step 6: N,N-Diethylaniline (985 mg, 6.61 mmol) was added to a mixture of 96-5 (1.13 g, 6.61 mmol) and phosphorus oxychloride (10 mL) at room temperature, and the mixture was stirred at 100 °C for 1 hour. The mixture was 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 give 96-6.

[0566] Compound 96-7 was prepared from 96-6 and 5-2 according to the synthesis procedure of compounds 5-8 in Example 4.

[0567] Compound 96 was prepared from 96-7 and 5-4 according to the synthesis procedure of compound 5 in Example 4.

[0568] 96 represents 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).

[0569] Example 36 Synthesis of compounds 97 and 98

[0570]

[0571] Step 1: In a 100 mL flask, add 94-2 (from Example 34, 2.666 mmol), methyl iodoform (0.166 mL, 2.666 mmol), triethylamine (0.371 mL, 2.666 mmol), and tetrahydrofuran (20 mL). Stir the mixture at room temperature for 18 hours. Dilute the reaction mixture with water and extract with ethyl acetate. Concentrate the combined organic layers under vacuum. Purify the residue by column chromatography (0–30% ethyl acetate / petroleum ether) to give 97-1.

[0572] Compound 97-2 was prepared from 97-1 according to the synthetic procedure of compound 94-4 in Example 34.

[0573] Step 2: At 0°C, 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) and stirred for 15 minutes. Then, methyl iodoform (0.418 mL, 6.719 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. After the reaction was complete, the mixture 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 under vacuum. The residue was purified by silica gel column chromatography (0-75% ethyl acetate in petroleum ether solution) to give 97-3.

[0574] Step 3: The 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 obtain 97-4.

[0575] Compounds 97 and 98 were prepared from 94-7 and 97-4 according to the synthesis procedure of compounds 5-8 in Example 4.

[0576] Enantiomer 1:97 chiral SFC analysis: 98.62% ee. Retention time on OJ 100*3mm 3μm (35℃): 3.490 min; 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).

[0577] Enantiomer 2: 98 chiral SFC analysis: >99.5% ee. Retention time on OJ 100*3mm 3μm (35℃): 3.862 min; 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).

[0578] Example 37 Synthesis of Compound 100

[0579]

[0580] Step 1: N-bromosuccinimide (8.10 g, 45.524 mmol) was added fractionally to a solution of 5-methoxy-2-nitropyridine-3-amine (7.7 g, 45.524 mmol) in N,N-dimethylformamide (80 mL) at 0 °C. The reaction mixture was stirred at 20–25 °C for 3 hours. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100-1.

[0581] 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 the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate = 1:0 to 1:10) to obtain 100-2.

[0582] Step 3: Dimethyl disulfide (3.387 mL, 38.216 mmol) was added to a solution of tert-butyl nitrite (3.437 mL, 28.662 mmol) in dichloromethane (360 mL) at 0 °C. Then, a solution of 100-2 (3.5 g, 19.108 mmol) in dichloromethane (20 mL) was added dropwise to this solution, and the mixture was heated to room temperature and maintained for 4 hours. Petroleum ether was then added to the solution, and the mixture was filtered by silica gel column chromatography, eluted with dichloromethane, to obtain 100-3.

[0583] Step 4: Add ammonium chloride (3 g, 56.009 mmol) and iron powder (0.94 g, 16.803 mmol) to a solution of 100-3 (1.2 g, 5.601 mmol) in ethanol (12 mL) and water (6 mL). Heat the mixture at 90 °C for 2 hours. Concentrate the reaction mixture and purify it by silica gel column chromatography to obtain 100-4.

[0584] Compound 100 was prepared from 100-4 according to the synthetic procedure for 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).

[0585] Example 38 Synthesis of Compound 103

[0586]

[0587] Step 1: Under ice-cooled conditions, p-toluenesulfonyl chloride (13.74 g) was added to a solution of (E)-2-cyano-2-(hydroxyimino)ethyl acetate (1 g, 7.037 mmol) and triethylamine (1.09 g) in ethyl acetate (7.2 mL). 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 off and dried under reduced pressure to give 10³⁻¹.

[0588] Step 2: Pyridine (6.94 mL) was added dropwise to a mixture of 10³⁻¹ (18.3 g, 61.76 mmol) and methyl mercaptoacetate (8.4 mL, 93.931 mmol) in ethanol (54 mL). The reaction mixture was stirred for 30 minutes. The reaction mixture was then partitioned between cold diethyl ether and ice water. The aqueous layer was extracted with cold diethyl 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 this substance in anhydrous ethanol (20 mL). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was filtered and dried to provide 10³⁻².

[0589] Step 3: Heat 103-2 (18 g, 78.176 mmol) in concentrated hydrochloric acid (100 mL) under reflux for 16 hours. Cool the mixture to 0 °C and filter. Wash the filter cake with ether and dry under vacuum to obtain 103-3 (crude product).

[0590] Step 4: Add thionyl chloride (10 mL) to a solution of 10³⁻³ (13.35 g, 92.605 mmol) in methanol (70 mL) at 0 °C for 5 minutes. Stir the solution at 70 °C for 1 hour. Concentrate the mixture to obtain 10³⁻⁴.

[0591] Compound 103-5 was prepared from 103-4 according to the synthesis procedure of compound 100-3 in Example 37.

[0592] Step 5: Lithium hydroxide (0.319 g, 9.510 mmol) was added to a solution of 10³⁻⁵ (1.2 g, 6.340 mmol) in tetrahydrofuran (20 mL) and water (10 mL) 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.

[0593] Step 6: Under a nitrogen atmosphere at 20°C, add 0.405 mL of diphenylphosphine azide and 0.404 mL of triethylamine dropwise to a solution of 103-6 (254 mg, 1.450 mmol) in tert-butanol (5 mL). Stir the mixture at 100°C for 5 hours under a nitrogen atmosphere. Quench the mixture with a saturated aqueous sodium bicarbonate solution and dilute with ether. Dry the organic layer with magnesium sulfate and concentrate. Purify the residue by silica gel chromatography (ethyl acetate:petroleum ether = 1:10) to give 103-7.

[0594] Compound 103-8 was prepared from 103-7 according to the synthetic procedure of compound 5 in Example 4.

[0595] Step 7: Add 3M hydrochloric acid / methanol (40 mL) to a solution of 10³⁻⁸ (2 g, 7.185 mmol) in methanol (40 mL). Then stir the reaction at 50 °C for 3 hours under a nitrogen atmosphere. Cool the mixture to room temperature and filter to obtain 10³⁻⁹.

[0596] Compound 103 was prepared from 103-9 according to the synthetic procedure for compounds 5-8 in Example 4. 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).

[0597] Example 39 Synthesis of Compound 109

[0598]

[0599] Step 1: Butyllithium (17.6 mL, 2.5 M hexane solution, 43.93 mmol) was added dropwise to a mixture of 5-5 (2.75 g, 12.55 mmol) in tetrahydrofuran (100 mL) at -60 °C under a N2 atmosphere. The mixture was then stirred for 0.5 h. Oxybutane-3-one (3.16 g, 43.93 mmol) in tetrahydrofuran (10 mL) was added dropwise to the above mixture at -60 °C, and the mixture was stirred for 1 h. The mixture was quenched with a saturated ammonium chloride aqueous 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.

[0600] 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-butyldimethylsilicon chloride (923 mg, 6.12 mmol) in dichloromethane (20 mL) at 0 °C and under a N2 atmosphere, and the mixture was 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.

[0601] Compound 109-3 was prepared from 109-2 and 1-3 according to the synthesis procedure of compounds 1-7 in Example 1.

[0602] Step 3: To a solution of 10⁹⁻³ (570 mg, 1.14 mmol) in tetrahydrofuran (15 mL), add tetrabutylammonium fluoride (1.26 mL, 1.26 mmol, 1 M THF solution) and stir for 1 hour. Dilute the mixture with water and stir for 5 minutes. Filter the mixture and wash with water and acetonitrile to obtain 10⁹⁻⁴.

[0603] Step 4: Under a nitrogen atmosphere and at -70°C, 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), and the mixture was stirred for 2 hours. The mixture was then heated to -10°C and stirred for 2 hours. The mixture was stirred at 5°C for 16 hours. The resulting mixture was quenched with a saturated aqueous sodium bicarbonate 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 give 109-5.

[0604] Compound 109 was prepared from 109-5 according to the synthetic procedure for compound 5 in Example 4. 109 was a 2.0 equivalent 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).

[0605] Example 40 Synthesis of Compound 120

[0606]

[0607] Step 1: Under a nitrogen atmosphere, 1.3 g (5.96 mmol) of 5-5 in 60 mL tetrahydrofuran was added dropwise with 13 mL (3.5 equivalents, 1.3 M), and the mixture was stirred at -65 °C for 10 min. Acetone (2 g, 6.0 equivalents) was added to the resulting mixture at -65 °C, and the mixture was stirred at -65 °C for 5 min. The reaction was quenched with brine and extracted with tetrahydrofuran. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated under vacuum. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol at a ratio of 100:0 to 50:1 to give 120-1.

[0608] Compound 120 was prepared from 120-1 according to the synthetic procedure for 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).

[0609] Example 41 Synthesis of Compound 123

[0610]

[0611] Step 1: To a solution of 2-cyclopropylthiazole (2 g, 15.974 mmol) in tetrahydrofuran (50 mL) at -65 °C, n-butyllithium (7.688 mL, 19.169 mmol, 2.5 M hexane solution) was added, followed by stirring at -78 °C for 30 min. Then, hexachloroethane (2.170 mL, 19.169 mmol) was added in portions over 30 min. The reaction mixture was stirred at -78 °C for 30 min, then warmed to room temperature. The mixture was quenched with a 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.

[0612] 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 brought to room temperature and stirred for 2 hours. The mixture was then poured into ice water and stirred for 1 hour. The organic phase was washed with 1 M sodium bicarbonate aqueous solution and brine. The organic phase was concentrated to give 123-2.

[0613] Compound 123-3 was prepared from 123-2 according to the synthetic procedure of compound 5-4 in Example 4.

[0614] Compound 123 was prepared from 123-3 according to the synthetic procedure for compound 5 in Example 4. 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).

[0615] Example 42 Synthesis of Compound 124

[0616]

[0617] 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 layers were 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.

[0618] Step 2: A solution of 124-1 (1.8 g, 7.168 mmol), 3,3-difluoroazacyclobutane (2.79 g, 21.505 mmol), tris(dibenzylacetone)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 a nitrogen 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 rapid column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 124-2.

[0619] 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 solution, water, and brine, dried over anhydrous sodium sulfate, and concentrated to give 124-3.

[0620] Compound 124 was prepared from 124-3 according to the synthetic procedure for compounds 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).

[0621] Example 43 Synthesis of Compound 126

[0622]

[0623] Step 1: The 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 solution of ammonium chloride (50 mL) 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 / ethyl acetate = 1 / 1) to give 126-1.

[0624] Step 2: To a solution of 126-1 (200 mg, 1.211 mmol) in dibromomethane (5 mL), tetrabutylammonium bromide (1560.92 mg, 4.842 mmol) and tert-butyl nitrite (1.440 mL, 12.105 mmol) were added, and the mixture was stirred for 4 hours. The mixture was diluted with ethyl acetate and 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.

[0625] Step 3: Add 4-methoxybenzylamine (7.32 g, 53.391 mmol) and potassium fluoride (8.46 g, 145.611 mmol) to a solution of 1-3 (10 g, 48.537 mmol) in dimethyl sulfoxide (100 mL). Stir the reaction mixture at 120 °C for 3 hours, cool the mixture to room temperature, and pour it into water. Filter to collect the solid, and dry it under vacuum to obtain 126-3.

[0626] Compound 126-4 was prepared from 126-3 and 5-2 according to the synthesis procedure of compound 5-8 in Example 4.

[0627] Compound 126-5 was prepared from 126-4 according to the synthesis procedure of compound 50-3 in Example 23.

[0628] Compound 126 was prepared from 126-5 and 126-2 according to the synthetic procedure for compound 5 in Example 4. 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).

[0629] Example 44 Synthesis of compounds 129 and 130

[0630]

[0631] Compound 129-1 was prepared from 5-2 according to the synthetic procedure of compound 8-3 in Example 7.

[0632] Compounds 129 and 130 were prepared from 129-1 according to the synthetic procedure for compound 8 in Example 7. Compounds 129 and 130 were synthesized via preparative SFC (using MeOH / CO2). AD) purification.

[0633] 129: Chiral SFC analysis: 99.44% ee. The retention time on the AD-3 100*3mm 3μm column (35℃) was 2.420 min; mobile phase: MeOH (0.1% DEA) in CO2, 1800 psi, 1.5 mL / min.

[0634] 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).

[0635] 130: Chiral SFC analysis: >99.5% ee. The retention time on the AD-3 100*3mm 3μm column (35℃) was 3.892 min; the mobile phase was MeOH (0.1% DEA) in CO2, 1800 psi, 1.5 mL / min.

[0636] 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).

[0637] The compounds disclosed herein can be prepared according to similar procedures and methods described above. Table 1 shows the characterization of representative compounds prepared.

[0638] Table 1. Characterization of representative compounds of this disclosure

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] HEK-Blue IL-23STAT3 reporter gene assay

[0653] HEK-Blue IL23 cells (InvivoGen catalog #HKB-IL23) are designed to detect the biological activity of IL-23 by monitoring the activation of the STAT3 pathway. They are generated by stably introducing the human IL-23 receptor gene STAT3 and the SEAP (secretory embryonic alkaline phosphatase) reporter gene into the human HEK293 cell line.

[0654] In summary, approximately 50,000 cells were seeded into each well in DMEM medium supplemented with 10% heat-inactivated FBS (approximately 180 μL) and incubated at 37°C with 5% CO2 in air for 48 hours. On day 3, 1 μL of the compound and 20 μL of IL-23 were transferred separately to the assay plate. The assay plate was left in an incubator at 37°C overnight. 2 μL of cell supernatant was transferred to a 384-well plate, and 18 μL of resuspended QUANTI-Blue solution was added to each well. The cells were then analyzed using Tecan Spark at OD... 655 Measure SEAP levels.

[0655] Cells without IL-23 were used as a low control. Cells stimulated with IL-23 were used as a high control. The inhibition rate was calculated using the formula: %inhibition = 100 * (high control - treated wells) / (high control - low control). IL-23 reporter gene assay showed an IC50 inhibition rate. 50 Calculate using the following equation: Y = bottom + (top - bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope)).

[0656] Table 2. Inhibition of HEK-Blue IL23 reporter gene by representative compounds

[0657]

[0658]

[0659]

[0660] The brief description and summary section may illustrate one or more exemplary embodiments of the invention as conceived by the inventors, but not all exemplary embodiments, and is therefore not intended to limit the invention and the appended claims in any way.

[0661] The invention has been described above using 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 here. Alternative boundaries can be defined as long as the specified functions and their relationships are properly executed.

[0662] Regarding aspects of the invention described as belonging to a genus, all individual species are considered separately as independent aspects of the invention. If an aspect of the invention is described as "comprising" a feature, the embodiment is also contemplated as "consisting of" or "substantially consisting of" that feature.

[0663] The above description of the specific embodiments will fully reveal the general nature of the invention, enabling others to easily modify and / or adapt it to various applications, such as the specific embodiments, by applying knowledge of the art, without excessive 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 fall within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology used herein is for descriptive purposes and not for limitation, and that the terminology or terminology of this specification will be interpreted by those skilled in the art based on the teachings and guidance.

[0664] The breadth and scope of this invention should not be limited by any of the exemplary embodiments described above.

[0665] All aspects, implementation schemes, and options described herein can be combined in any and all variations.

[0666] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is 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 any document incorporated by reference, the meaning or definition given to that term in this document shall prevail.

Claims

1. The following intermediate compounds: 。 2. The compound according to claim 1, characterized in that, The compound is 。 3. The compound according to claim 1, characterized in that, The compound is 。 4. The compound according to claim 1, characterized in that, The compound is 。 5. The compound according to claim 1, characterized in that, The compound is 。 6. The compound according to claim 1, characterized in that, The compound is 。 7. The compound according to claim 1, characterized in that, The compound is 。 8. The compound according to claim 1, characterized in that, The compound is 。 9. The compound according to claim 1, characterized in that, The compound is 。

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