Dipeptidyl peptidase 1 inhibitors and uses thereof

Abstract

Provided herein are compounds of Formula (I) or pharmaceutically acceptable salts or deuterated forms thereof, wherein ring A, R 1 、 R 2 、 R 3 、 R 4 、 and m are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of Formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, for example, in the treatment of a disease that can be treated by administration of a DPP1 inhibitor.(I)

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 538,521, filed September 15, 2023, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] Dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine ​​protease belonging to the papain family, with a molecular weight of 200 kDa. DPP1 was first discovered by Gutman and Fruton in 1948 (J Biol Chem, 174, 851-858); however, the human enzyme's cDNA was first described in 1995 (Paris et al. 1995, FEBS Lett, 369, 326-330). DPP1 is the only member of the papain family to function as a tetramer, composed of four identical subunits. Each subunit consists of an N-terminal fragment, a heavy chain, and a light chain (Dolenc et al. 1995, J Biol Chem, 270, 21626-21631).

[0004] DPP1 is constitutively expressed in many tissues, with the highest expression levels in the lung, kidney, liver, and spleen. DPP1 catalyzes the removal of dipeptides from the N-terminus of polypeptide substrates with broad specificity. Recent data suggest that, in addition to being an important enzyme in lysosomal protein degradation, DPP1 also functions as a key enzyme in activating granular serine proteases in cytotoxic T lymphocytes and natural killer cells (granulases A and B), mast cells (chymotrypsin and trypsin-like proteins), and neutrophils (cathepsin G, neutrophil elastase, and protease-3).

[0005] Mast cells are present in many tissues, but are most abundant in the epithelial lining of the human body, such as the skin, respiratory tract, and gastrointestinal tract. In humans, two types of mast cells have been identified: the T-type, which expresses only trypsin, and the MC-type, which expresses both trypsin and chymotrypsin. In humans, T-type mast cells are mainly located in alveolar tissue and intestinal mucosa, while TC-type cells are mainly found in the skin and conjunctiva. Trypsin and chymotrypsin appear to be important mediators of allergic diseases, involved in processes such as inflammation, bronchoconstriction, and mucus secretion.

[0006] Neutrophils play a crucial role in the host's defense against invading pathogens. Neutrophils are produced in the bone marrow and fully mature upon release into the bloodstream to function as the first line of cellular defense. Pro-inflammatory mediators and chemotactic attractors activate neutrophils and pull them to the site of infection, where they engulf bacteria through phagocytosis and attack them using a library of antimicrobial compounds employing oxidative and non-oxidative attack methods. Neutrophil elastase, a potent serine protease, is one of the antimicrobial compounds significantly involved in bacterial elimination. Neutrophil elastase is released into phagolysosomes surrounding microorganisms, thereby eliminating them. Neutrophil elastase can attack the outer membrane protein OmpA in Gram-negative bacteria, thereby facilitating the direct killing of pathogens by degrading their membranes and enabling other antimicrobial compounds to penetrate the pathogen. Furthermore, neutrophil elastase can aid in the processing of other antimicrobial compounds, converting them from inactive propeptides to their active state, such as in the case of cathelicidin.

[0007] However, neutrophil elastase can also cause problems for its host. Neutrophil elastase is one of the most destructive enzymes in the human body, capable of degrading extracellular matrix proteins (including collagen, proteoglycans, fibronectin, platelet receptors, complement receptors, thrombomodulin, lung surfactant, and cadherin) and key plasma proteins (including coagulation factors and complement factors, immunoglobulins, several proteases, and protease inhibitors). Under physiological conditions, endogenous protease inhibitors, such as α1-antitrypsin, strictly regulate neutrophil elastase activity. However, at sites of inflammation, neutrophil elastase can evade regulation, and once unregulated, it can induce the release of pro-inflammatory cytokines such as interleukin-6 and interleukin-8, leading to acute lung injury. Neutrophil elastase can even impair the host's defenses against infection by degrading phagocyte surface receptors and opsonins. The negative effects of the neutrophil elastase are illustrated by its involvement in tissue destruction and inflammation, which are characteristic of a variety of diseases including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemia-reperfusion injury, and rheumatoid arthritis.

[0008] Therefore, there is a need in the art to provide novel DPP1 inhibitors for the treatment of the aforementioned diseases, as well as other diseases associated with DPP1 and neutrophil elastase. Summary of the Invention

[0009] In an embodiment, this disclosure provides a compound of formula (I):

[0010] (I),

[0011] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0012] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0013] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0014] R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0015] R 3 It is H, halogen, -OH, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, SC 1-6 Alkyl, SOC 1-6 Alkyl or SO2C 1-6 Alkyl; or R 3 Can be used with R 6 Together, they form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally connected by 1, 2, 3, or 4 R atoms. 10 replace;

[0016] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0017] Each R 5 Independently, it is C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0018] R 6Each of the following can be independently H, halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0019] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0020] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0021] R 10 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8-C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic; and

[0022] m is 0, 1, 2, or 3; where:

[0023] (i) R 1 The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom;

[0024] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0025] (iii) Combinations of (i) and (ii).

[0026] In an embodiment, this disclosure provides a compound of formula (IA):

[0027] (IA),

[0028] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0029] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0030] R 3 It is H;

[0031] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0032] Each R 5 Independently, it is C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), heterocyclic;

[0033] R 6 It is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0034] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0035] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0036] m is 0, 1, 2, or 3; where:

[0037] (i) R 1 The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom;

[0038] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0039] (iii) Combinations of (i) and (ii).

[0040] In an embodiment, this disclosure provides a compound of formula (IB):

[0041] (IB),

[0042] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0043] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0044] R 3 It is H;

[0045] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0046] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8-S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0047] Each R 6 Independently, it is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0048] R 6a It is H, C 1-6 Alkyl, C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0049] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0050] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0051] m is 0, 1, 2, or 3; and

[0052] p is 0; where:

[0053] (i) R 1 The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom;

[0054] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0055] (iii) Combinations of (i) and (ii).

[0056] In an embodiment, this disclosure provides a compound of formula (IC):

[0057] (IC),

[0058] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0059] Ring B is a 5- to 8-membered ring that optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O;

[0060] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0061] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0062] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR7 R 8 -S(=NH)(O)(C1-C6 alkyl), heterocyclic;

[0063] Each R 6 and R 10 Independently, it is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0064] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0065] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0066] m is 0, 1, 2, or 3;

[0067] p is 0, 1, 2, or 3; and

[0068] q is 0, 1, 2, or 3; where:

[0069] (i) R 1The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom;

[0070] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0071] (iii) Combinations of (i) and (ii).

[0072] In an embodiment, this disclosure provides a compound of formula (ID):

[0073] (ID),

[0074] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0075] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0076] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0077] R 3 It is H;

[0078] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0079] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8-S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0080] Each R 6 H and C independently 1-6 Alkyl, C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0081] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0082] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0083] m is 0, 1, 2, or 3; where:

[0084] (i) R 1 The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom;

[0085] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0086] (iii) Combinations of (i) and (ii).

[0087] In an embodiment, this disclosure provides a compound of formula (IE):

[0088] (IE),

[0089] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0090] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0091] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0092] R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0093] R 3 It is H;

[0094] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0095] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0096] Each R 6 Independently, it is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0097] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0098] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0099] m is 0, 1, 2, or 3; where:

[0100] (i) R 1 The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom;

[0101] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0102] (iii) Combinations of (i) and (ii).

[0103] In the embodiments, this disclosure provides the compounds of Table A or their pharmaceutically acceptable salts, stereoisomers or deuterated forms.

[0104] In embodiments, this disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or a compound of Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof) and a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0105] In an embodiment, this disclosure provides a method for treating airway obstructive disease in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0106] In an embodiment, this disclosure provides a method for treating cystic fibrosis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0107] In an embodiment, this disclosure provides a method for treating chronic sinusitis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0108] In an embodiment, this disclosure provides a method for treating hidradenitis suppurativa in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0109] In an embodiment, this disclosure provides a method for treating cancer in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0110] In an embodiment, this disclosure provides a method for treating lupus nephritis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0111] In an embodiment, this disclosure provides a method for treating rheumatoid arthritis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0112] In an embodiment, this disclosure provides a method for treating inflammatory bowel disease in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0113] In an embodiment, this disclosure provides a method for treating antineutrophil cytoplasmic antibody-associated vasculitis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0114] In embodiments, this disclosure provides a method for treating a disease in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof), wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpassuia), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, obstructive bronchiolitis, atopic dermatitis, pyoderma gangrenosa, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatitis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

[0115] In an embodiment, this disclosure provides a method for treating heart failure in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof). Detailed Implementation

[0116] Throughout this disclosure, various patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes in order to provide a more comprehensive description of the state of the prior art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0117] definition

[0118] The following lists the definitions of various terms used in the specification and claims to describe the contents of this disclosure.

[0119] Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0120] When immediately preceding a numerical value, the term "about" means a range covering the numerical value ± an amount of variation acceptable in the art (e.g., the value ± 10%). For example, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc., unless the context of this disclosure otherwise indicates or is inconsistent with such interpretation. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range extending to less than half the interval between a previous value and a subsequent value, such as greater than 49.5 to less than 50.5. Furthermore, given the definition of the term "about" provided herein, the phrases "less than about" or "greater than about" should be understood. Similarly, when preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30" or "about 10-30"), the term "about" refers to the endpoints of all values ​​or ranges in the series, respectively.

[0121] Unless otherwise stated, the following terms as used herein have the following meanings:

[0122] "Cyano" refers to the -CN group.

[0123] "Hydroxyl" or "hydroxyl" refers to the -OH group.

[0124] "Oxyto" refers to the =O substituent.

[0125] "alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched hydrocarbon chain group having one to twelve carbon atoms, and which is connected to the rest of the molecule by a single bond. This includes alkyl groups containing any number of carbon atoms from 1 to 12. Alkyl groups containing up to 12 carbon atoms are C1-C1. 12 Alkyl groups, which contain up to 10 carbon atoms, are C1-C6. 10 Alkyl groups, specifically those containing up to six carbon atoms (C1-C6 alkyl groups) and those containing up to five carbon atoms (C1-C5 alkyl groups), are further categorized. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups encompass all the portions described above for C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C 10 Alkyl groups include all the portions described above regarding C1-C5 and C1-C6 alkyl groups, but also include C7, C8, C9, and C6 alkyl groups. 10 Alkyl group. Similarly, C1-C 12 Alkyl groups include all of the above-mentioned portions, but also include C4 groups. 11 and C 12 Alkyl group. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified in the specification, the alkyl group may optionally be substituted.

[0126] "alkylene" or "alkylene chain" refers to a fully saturated, straight-chain or branched divalent hydrocarbon chain group having one to twelve carbon atoms. C1-C 12 Non-limiting examples of alkylene groups include methylene, ethylene, propylene, n-butene, vinylene, propenylene, n-butenylene, propynylene, n-butynylene, etc. The alkylene chain is connected to the rest of the molecule by single bonds and to functional groups by single bonds. The connection points of the alkylene chain to the rest of the molecule and to functional groups can be one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkylene chain may optionally be substituted.

[0127] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to the rest of the molecule by a single bond. This includes alkenyl groups containing any number of carbon atoms from 2 to 12. Alkenyl groups containing up to 12 carbon atoms are C2-C. 12 Alkenyl groups, which contain up to 10 carbon atoms, are C2-C. 10Alkenyl groups, specifically C2-C6 alkenyl groups containing up to six carbon atoms, and C2-C5 alkenyl groups containing up to five carbon atoms, are also included. C2-C5 alkenyl groups include C5, C4, C3, and C2 alkenyl groups. C2-C6 alkenyl groups include all the portions described above for C2-C5 alkenyl groups, but also include C6 alkenyl groups. C2-C 10 Alkenyl groups include all the parts described above regarding C2-C5 and C2-C6 alkenyl groups, but also include C7, C8, C9, and C6 alkenyl groups. 10 Alkenyl. Similarly, C2-C 12 Alkenyl groups include all the aforementioned portions, but also include C. 11 and C 12 Alkenyl. C2-C 12 Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4 -Nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise specified in the specification, the alkenyl group may be optionally substituted.

[0128] "Alkenyl" or "alkenyl chain" refers to a straight-chain or branched divalent hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon double bonds. (C2-C) 12 Non-limiting examples of alkenyl groups include ethylene, propylene, butene, etc. The alkenyl chain is connected to the remainder of the molecule by a single bond and to a group by a single bond. The connection points between the alkenyl chain and the remainder of the molecule and to the group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkenyl chain may optionally be substituted.

[0129] "Alkynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. This includes alkynyl groups containing any number of carbon atoms from 2 to 12. Alkynyl groups containing up to 12 carbon atoms are C2-C. 12 The alkynyl group, which contains up to 10 carbon atoms, is C2-C. 10 The alkynyl group, containing up to 6 carbon atoms, is C2-C6 alkynyl, and containing up to 5 carbon atoms, is C2-C5 alkynyl. C2-C5 alkynyl groups include C5, C4, C3, and C2 alkynyl groups. C2-C6 alkynyl groups include all the parts described above regarding C2-C5 alkynyl groups, but also include C6 alkynyl groups. C2-C 10 The alkynyl group includes all the parts described above regarding C2-C5 and C2-C6 alkynyl groups, but also includes C7, C8, C9, and C6 alkynyl groups. 10 Alkyne group. Similarly, C2-C 12 The alkynyl group includes all the aforementioned parts, but also includes C. 11 and C 12 Alkyne group. C2-C 12 Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, and pentyynyl. Unless otherwise specified in the specification, the ethynyl group may optionally be substituted.

[0130] "Imyynyl" or "Imyynyl chain" refers to a straight-chain or branched divalent hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon triple bonds. (C2-C) 12 Non-limiting examples of ynylenes include ethynylenes, propynylenes, etc. The ynylene chain is connected to the rest of the molecule by a single bond and to a group by a single bond. The connection points between the ynylene chain and the rest of the molecule and to the group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the ynylene chain may optionally be substituted.

[0131] "Alkoxy" refers to the formula -OR a The group, wherein R a It is an alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, the alkoxy group may optionally be substituted.

[0132] "alkylamino" refers to the formula -NHR a or -NR a R a The groups, wherein each R aIndependently, it is an alkyl, alkenyl, or ynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, the alkylamino group may optionally be substituted.

[0133] "Aryl" refers to a hydrocarbon cyclic group comprising hydrogen, 6 to 18 carbon ring atoms, and at least one aromatic ring. For the purposes of this disclosure, the aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused, bridged, or spirocyclic systems. Aryl groups include, but are not limited to, aryl groups derived from anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, chrysoprase, fluorene, asymmetric indarene, symmetric indarene, indene, indene, naphthalene, phenanthracene, heptamethrin, pyrene, and benzo[a]phenanthrene. In embodiments where "L" is aryl, the aryl group is bimethyl. Unless otherwise specifically stated in the specification, the term "aryl" means including optionally substituted aryl groups.

[0134] "Arylalkyl" or "arylalkyl" refers to the formula -R b -R c The group, wherein R b It is an alkylene group as defined above and R c It is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified in the specification, the aryl group may optionally be substituted.

[0135] "Carbocyclic group," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon. A carbocyclic ring can contain 3 to 20 carbon atoms. Carbocyclic rings include cycloalkyl, cycloalkenyl, and cycloynyl groups as defined herein. Unless otherwise specified in the specification, the carbocyclic group may optionally be substituted.

[0136] "Cycloalkyl" refers to a stable, non-aromatic, fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused, bridged, or spirocyclic systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms), and is connected to the rest of the molecule by a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, cycloalkyl groups may optionally be substituted.

[0137] "Cycloalkenyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds. It may include fused, bridged, or spirocyclic systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms), and is connected to the rest of the molecule by single bonds. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, for example, bicyclic [2.2.1]hept-2-enyl, etc. Unless otherwise specifically stated in the specification, cycloalkenyl groups may optionally be substituted.

[0138] "Cycloynyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds. It can include fused, bridged, or spirocyclic systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms), and is connected to the rest of the molecule by single bonds. Monocyclic cycloynyl groups include, for example, cycloheptynyl, cyclooctyynyl, etc. Unless otherwise specified in the specification, the cycloynyl group may optionally be substituted.

[0139] "Cycloalkylalkyl" refers to the formula -R b -R d The group, wherein R b It is an alkylene, alkenylene, or ynylene group as defined above, and R d These are cycloalkyl, cycloalkenyl, and cycloynyl groups as defined above. Unless otherwise specified in the specification, cycloalkyl groups may optionally be substituted.

[0140] "Haloalkyl" refers to an alkyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified in the specification, haloalkyl may optionally be substituted.

[0141] "Haloalkenyl" refers to an alkenyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless otherwise specified in the specification, the haloalkenyl group may optionally be substituted.

[0142] "Haloalkynyl" refers to an alkynyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless otherwise specified in the specification, the haloalkynyl group may optionally be substituted.

[0143] "Heterocyclic group," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered non-aromatic, saturated, or partially unsaturated cyclic group consisting of two to twelve carbon ring atoms and one to six heteroatoms selected from nitrogen, oxygen, or sulfur as ring atoms, wherein at least one non-aromatic, saturated, or partially unsaturated ring contains at least one heteroatom as a ring atom. Unless otherwise specified in the specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, bridged, or spirocyclic systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolane, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecyclo, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In examples where "L" is a heterocyclic group, the heterocyclic group is a bimolecular group. Unless otherwise specifically stated in the specification, the heterocyclic group may optionally be substituted.

[0144] "Heterocyclic alkyl" refers to the formula -R b -R e The group, wherein R b It is an alkylene group as defined above, and R e It is a heterocyclic group as defined above. Unless otherwise specified in the specification, heterocyclic alkyl groups may optionally be substituted.

[0145] "N-Heterocyclic group" refers to a heterocyclic group as defined above containing at least one nitrogen atom, wherein the connection point between the heterocyclic group and the rest of the molecule is through a nitrogen atom in the heterocyclic group. Unless otherwise specified in the specification, the N-heterocyclic group may optionally be substituted.

[0146] "Heteroaryl" refers to a 5- to 20-membered ring group comprising one to thirteen carbon ring atoms, one to six heteroatoms selected from nitrogen, oxygen, and sulfur as ring atoms, and at least one aromatic ring containing at least one heteroatom as a ring atom. For the purposes of this disclosure, the heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, bridged, or spirocyclic systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, acrylonitrile, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptyl, 1,4-benzodioxyl, benzonaphthuryl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophene (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanoneyl, isothiazolyl, Imidazolyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoacetyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and phenylthioyl (i.e., thiophene). In examples where "L" is a heteroaryl group, the heteroaryl group is a dimethyl group. Unless otherwise specified in the specification, heteroaryl groups may optionally be substituted.

[0147] "N-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the connection point between the heteroaryl group and the rest of the molecule is through a nitrogen atom in the heteroaryl group. Unless otherwise specified in the specification, the N-heteroaryl group may optionally be substituted.

[0148] "Heteroarylalkyl" refers to the formula -R b -R f The group, wherein R b It is an alkylene chain as defined above, and R f It is a heteroaryl group as defined above. Unless otherwise specified in the specification, the heteroaryl alkyl group may optionally be substituted.

[0149] "Thioalkyl" refers to the formula -SR a The group, wherein Ra It is an alkyl, alkenyl, or ynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, thioalkyl groups may optionally be substituted.

[0150] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkyne, alkyne, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) in which at least one hydrogen atom is replaced by a bond with a non-hydrogen atom, such as, but not limited to: halogen atoms, such as F, Cl, Br and I; such as Oxygen atoms in hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups.

[0151] "Substituted" also means that one or more hydrogen atoms in any of the above groups are replaced by a higher-order bond (e.g., a double or triple bond) with a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by -NR. g R h -NR g C(=O)R h -NR g C(=O)NR g R h -NR g C(=O)OR h -NR g SO2R h -OC(=O)NR g R h -OR g -SR g -SOR g -SO2R g -OSO2R g -SO2OR g =NSO2R g and -SO2NR g R hSubstitution. "Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g R h Replace. In the above text, R g and R h The groups may be identical or different, and independently comprise hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further includes any of the above groups in which one or more hydrogen atoms are replaced by the following bonds: amino, cyano, hydroxyl, imino, nitro, oxo, thiooxy, halogen, alkyl, alkenyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. Additionally, each of the above substituents may optionally be substituted by one or more of the above substituents.

[0152] As used in this article, the symbol " "or" "(Hereinafter referred to as a "connection point bond")" indicates a bond that serves as a connection point between two chemical entities, one of which is depicted as being connected to the connection point bond, and the other is not depicted as being connected to the connection point bond. For example, " "or" The symbol “XY” indicates that chemical entity “XY” is bonded to another chemical entity via a tie point bond. In addition, the specific tie point with a chemical entity that is not depicted can be specified by inference.

[0153] Unless otherwise stated, in this specification, the term "pharmaceuticalally acceptable" is used to characterize a portion (e.g., salt, dosage form, or excipient) suitable for use based on reasonable medical judgment. Generally, a pharmaceutically acceptable portion has one or more benefits that outweigh any potentially harmful effects that portion may have. Harmful effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0154] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid using any of a variety of known methods.

[0155] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers, which may be defined according to absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms, whether or not specifically described herein. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise stated, it is intended that these compounds include both E-geometric isomers and Z-geometric isomers. Similarly, it aims to include all tautomer forms.

[0156] "Stereoisomers" are compounds formed by identical atoms bonded by identical bonds but having different, non-interchangeable, three-dimensional structures. This disclosure covers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0157] As used herein, the term "treatment" in relation to a patient refers to the improvement of at least one symptom of the patient's condition. Treatment may be the improvement or at least partial improvement of the condition or related symptoms.

[0158] "Effective amount" means the amount of compound or pharmaceutical formulation that is sufficient to affect such treatment when administered to a patient in a therapeutic state, condition or symptom.

[0159] The term "therapeuticly effective" applied to dosage or amount refers to an amount of compound or pharmaceutical formulation sufficient to produce the desired clinical benefit when administered to a patient in need. In some embodiments, "therapeuticly effective amount" is a dose or amount of compound or pharmaceutical formulation sufficient to achieve a preventive effect when administered to a patient in need.

[0160] The terms “subject,” “individual,” and “patient” are used interchangeably in this document to refer to vertebrates, such as mammals. Mammals can be, for example, mice, rats, rabbits, cats, dogs, pigs, sheep, horses, non-human primates (e.g., cynomolgus monkeys, chimpanzees), or humans.

[0161] compound

[0162] In one aspect of this disclosure, a DPP1 inhibitor is provided, and the DPP1 inhibitor is a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

[0163] In an embodiment, this disclosure provides a compound of formula (I):

[0164] (I),

[0165] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0166] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0167] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0168] R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0169] R 3 It is H, halogen, -OH, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, SC 1-6 Alkyl, SOC 1-6 Alkyl or SO2C 1-6 Alkyl; or R 3 Can be used with R 6 Together, they form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally connected by 1, 2, 3, or 4 R atoms. 10 replace;

[0170] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0171] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0172] R 6 Each of the following can be independently H, halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0173] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0174] R 9It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0175] R 10 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic; and

[0176] m is 0, 1, 2, or 3; where:

[0177] (i) R 1 The heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle. 5 Substituted nitrogen atom;

[0178] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0179] (iii) Combinations of (i) and (ii).

[0180] In one embodiment of the compound of formula (I), R 1 It is a 5-12 membered monocyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle is via 1 or 2 R atoms. 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0181] In one embodiment of the compound of formula (I), R 1 It is a 5-12 membered polycyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle is via 1 or 2 R atoms. 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0182] In one embodiment of the compound of formula (I), wherein:

[0183] R 1 yes , , or ;

[0184] X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -, where X 2 and X 3 At least one of them is -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; wherein:

[0185] (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-;

[0186] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0187] (iii) Combinations of (i) and (ii);

[0188] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0189] R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl;

[0190] k is 0 or 1; and

[0191] g 0, 1, 2 or 3.

[0192] In one embodiment of the compound of formula (I), wherein:

[0193] R 1 yes , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace;

[0194] X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR11 R 12 -, where X 2 and X 3 At least one of them is -NH- or -N(C1-C6 alkyl)-;

[0195] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0196] R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl;

[0197] k is 0 or 1; and

[0198] g 0, 1, 2 or 3.

[0199] In one embodiment of the compound of formula (I), wherein:

[0200] R 1 yes , , or ;

[0201] X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -, where X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-;

[0202] R 9It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0203] R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl;

[0204] k is 0 or 1; and

[0205] g 0, 1, 2 or 3.

[0206] In one embodiment of the compound of formula (I), wherein:

[0207] R 1 yes , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace;

[0208] X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -, where X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-;

[0209] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0210] R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl;

[0211] k is 0 or 1; and

[0212] g 0, 1, 2 or 3.

[0213] In one embodiment of the compound of formula (I), wherein:

[0214] R 1 yes ,in:

[0215] (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-;

[0216] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0217] (iii) Combinations of (i) and (ii);

[0218] k is 0 or 1; and

[0219] g is 2 or 3.

[0220] In one embodiment of the compound of formula (I), wherein R 1 yes ,in:

[0221] (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; or

[0222] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace.

[0223] In one embodiment of the compound of formula (I), wherein R 1 yes And R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl). In one embodiment, R 1 yes And R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl).

[0224] In one embodiment of the compound of formula (I), R 1 The carbon atom of the heterocycle is selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), or -SO2NR. 7 R 8 An R5 Replacement. In one embodiment, R 1 The carbon atom of the heterocycle is selected from an R atom of -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -S (=NH)(O)(C1-C6 alkyl). 5 Replacement. In one embodiment, R 1 The carbon atom of the heterocyclic ring is selected from an R atom of -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. 5 Replacement. In one embodiment, R 1 The carbon atom of the heterocyclic ring is selected from an R atom of -SCH3. 5 replace.

[0225] In one embodiment of the compound of formula (I), R 1 yes , , , , , or ;R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1. In one embodiment, R 5 It is CH3, -CF3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In one embodiment, R 5 It is -C(O)CH3, or In one embodiment, R 9 It is an -OC1-C6 alkyl group. In one embodiment, k is 0.

[0226] In one embodiment of the compound of formula (I), R 1 yes or ;R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1. In one embodiment, R 5 It is CH3, -CF3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In one embodiment, R 5 It is -C(O)CH3, or In one embodiment, R 9 It is an -OC1-C6 alkyl group. In one embodiment, k is 0.

[0227] In one embodiment of the compound of formula (I), R1 yes , , , , , , , , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 Replacement. In one embodiment, R 1 Further through 1, 2 or 3 R 9 Replacement. In one embodiment, where R 1 Further through 1 R 9 Replacement. In one embodiment, R 1 Further through 2 R 9 Replacement. In one embodiment, R 1 Further through 3 R 9 replace.

[0228] In one embodiment of the compound of formula (I), R 1 yes , , , , , , , , , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1Optionally further via 1, 2, or 3 R 9 Replacement. In one embodiment, R 1 Further through 1, 2 or 3 R 9 Replacement. In one embodiment, R 1 Further through 1 R 9 Replacement. In one embodiment, R 1 Further through 2 R 9 Replacement. In one embodiment, R 1 Further through 3 R 9 replace.

[0229] In one embodiment of the compound of formula (I), R 1 yes And R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl). In one embodiment, R 5 It is -NH (C1-C6 alkyl) or -N (C1-C6 alkyl)2. In one embodiment, R 5 It is -NHCH3 or -N(CH3)2.

[0230] In one embodiment of the compound of formula (I), wherein:

[0231] R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 replace;

[0232] X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -;

[0233] X 4 It is O, S, NH or N (C1-C6 alkyl);

[0234] R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl;

[0235] RA It is H, -C1-C6 alkyl, -C1-C6 alkylene-carbocycloyl or -C1-C6 alkylene-heteroaryl; and

[0236] R B It is -C1-C6 alkyl, -C2-C6 alkenyl, -C1-C6 alkylene-carbocycloyl, or -C1-C6 alkylene-heteroaryl; or

[0237] R A and R B Together they form a heterocyclic group; wherein:

[0238] (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-;

[0239] (ii-a) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace;

[0240] (ii-b) -X 4 -R A R is selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl) or -S(=NH)(O)(C1-C6 alkyl). 5 ;or

[0241] (iii) Any combination of (i), (ii-a), and (ii-b).

[0242] In one embodiment of the compound of formula (I), R 1 It is a 5-12 membered spiroheterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein the spiroheterocycle is via 1 or 2 R atoms. 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0243] In one embodiment of the compound of formula (I), R 1It is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein the fused heterocycle is connected by 1 or 2 R atoms. 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0244] In one embodiment of the compound of formula (I), R 1 It is a 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein the bridged heterocycle is connected by 1 or 2 heteroatoms. 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0245] In one embodiment of the compound of formula (I), wherein:

[0246] R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 replace;

[0247] R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic;

[0248] g1 and g2 are each independently 0, 1, or 2, provided that neither g1 nor g2 is 0, or neither g1 nor g2 is 2; and

[0249] g3 is 1 or 2.

[0250] In one embodiment of the compound of formula (I), R 1 yes , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic.

[0251] In one embodiment of the compound of formula (I), wherein:

[0252] R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 replace;

[0253] g1 is 0, 1, 2, or 3;

[0254] g3 is 1, 2, 3, or 4;

[0255] X 2 Each can be independently -O-, -S-, -NH-, -N(C1-C6 alkyl)-, or -CR 11 R 12 -;

[0256] R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic;

[0257] R 11 Selected from H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, or halo-OC1-C6 alkyl; and

[0258] R 12 It is independently H, F, Cl, Br, I or -C1-C6 alkyl.

[0259] In one embodiment of the compound of formula (I), wherein:

[0260] R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 replace;

[0261] g1 is 0, 1, 2, or 3;

[0262] g3 is 1, 2, 3, or 4;

[0263] X 2 Each can be independently -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -;

[0264] R 11 It is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, or halo-OC1-C6 alkyl; and

[0265] R 12It is H, F, Cl, Br, I or -C1-C6 alkyl; wherein

[0266] (i) X 2 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-;

[0267] (ii) R 1 The carbon atoms of the fused heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0268] (iii) Combinations of (i) and (ii).

[0269] In one embodiment of the compound of formula (I), wherein:

[0270] R 1 yes , , or , where R 1 Optionally further via 1, 2, or 3 R 9 replace;

[0271] X 2 It is -O-, -S-, -NH-, -NR 5 -or-CR 11 R 12 -;

[0272] R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic;

[0273] R 11 It is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl or halo-OC1-C6 alkyl;

[0274] R 12 It is H, F, Cl, Br, I or C1-C6 alkyl; and

[0275] Each g1 and g2 is independently 0, 1, 2 or 3, and the sum of g1 and g2 is less than or equal to 3.

[0276] In one embodiment of the compound of formula (I), R 1 , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic.

[0277] In one embodiment of the compound of formula (I), R 1 yes , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 Each is independently a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic.

[0278] In one embodiment of the compound of formula (I), R 1 yes , , , , , , , , , , , , , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 Each is independently a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic.

[0279] In one embodiment of the compound of formula (I), R 1 Selected from , , , , , , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 Each is independently a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic.

[0280] In one embodiment of the compound of formula (I), each R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

[0281] In one embodiment of the compound of formula (I), ring A is aryl or heteroaryl. In one embodiment, ring A is phenyl.

[0282] In one embodiment of the compound of formula (I), ring A is a monocyclic or bicyclic ring.

[0283] In one embodiment of the compound of formula (I), R 2 It is a single ring, double ring, or triple ring, where R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replacement. In one embodiment, R 2 It is a monocyclic carbocyclic, monocyclic aryl, monocyclic heterocyclic, or monocyclic heteroaryl, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replacement. In one embodiment, R 2 It can be chosen to pass through 1, 2, 3 or 4 Rs. 6 Substituted phenyl groups.

[0284] In one embodiment of the compound of formula (I), R 2 It is a bicyclic carbocyclic ring, a bicyclic aryl ring, a bicyclic heterocyclic ring, or a bicyclic heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replacement. In some embodiments, R 2 It is a fused ring or a spiro ring.

[0285] In one embodiment of the compound of formula (I), wherein:

[0286] R 2 yes , , or ;

[0287] Each X 1a Independently is -NR 6a -、-O-、-CR 13 R 14 -、-C(O)-、-S-、-S(O)- or -S(O)2-;

[0288] Each R 6a Independently, it is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0289] R 13 and R 14 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl; and

[0290] p is 0, 1, 2 or 3.

[0291] In one embodiment of the compound of formula (I), R 2 yes ; , or And p is 0 or 1. In one embodiment, R 2 yes , , or .

[0292] In one embodiment of the compound of formula (I), R 2 It is phenyl and R 3 With R 6 One of them, together with ring A, forms a tricycle, wherein the tricycle optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O, and the tricycle optionally passes through 1, 2, 3, or 4 R atoms. 10 replace.

[0293] In an embodiment, this disclosure provides a compound of formula (IA):

[0294] (IA),

[0295] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0296] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0297] R 3 It is H;

[0298] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0299] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0300] R 6 It is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0301] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0302] R 9It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0303] m is 0, 1, 2, or 3; where:

[0304] (i) R 1 The heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle. 5 Substituted nitrogen atom;

[0305] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0306] (iii) Combinations of (i) and (ii).

[0307] In one embodiment of the compound of formula (I) or formula (IA), R 6 Yes - CN.

[0308] In one embodiment of the compound of formula (I) or formula (IA), m is 0.

[0309] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle is via 1 or 2 R atoms. 5 Replace and optionally further via 1, 2 or 3 R 9 Substitution. In some embodiments, a 6-membered monocyclic heterocycle containing one or two heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle is via one or two R...5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0310] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replacement. In some embodiments, R 1 It is a 6-membered monocyclic heterocycle containing one or two heteroatoms selected from N, S, and O, wherein R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace.

[0311] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The carbon atom of the monocyclic heterocycle is selected from an R atom of -NH (C1-C6 alkyl) or -N (C1-C6 alkyl)2. 5 Substitution. In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The carbon atom of the monocyclic heterocycle is selected from an R atom of -NH (C1-C3 alkyl) or -N (C1-C3 alkyl)2. 5 Substitution. In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 6-membered monocyclic heterocycle containing one or two heteroatoms selected from N, S, and O, wherein R 1 The carbon atom of the monocyclic heterocycle is selected from an R atom of -NH (C1-C3 alkyl) or -N (C1-C3 alkyl)2. 5 replace.

[0312] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace.

[0313] In one embodiment of the compound of formula (I) or formula (IA), R 1 yes , , , , , , , , , ... , , , , , , , , , , , or ;where R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 replace.

[0314] In one embodiment of the compound of formula (I) or formula (IA), wherein:

[0315] R 1 yes ;

[0316] R5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 or -S(=NH)(O)(C1-C6 alkyl); and

[0317] R 1 Optionally further via 1, 2, or 3 R 9 replace.

[0318] In one embodiment of the compound of formula (I) or formula (IA), R 5 It is -NH (C1-C6 alkyl) or -N (C1-C6 alkyl)2. In some embodiments, R 5 It is -NHCH3 or -N(CH3)2.

[0319] In one embodiment of the compound of formula (I) or formula (IA), wherein:

[0320] R 1 yes or ,

[0321] R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic;

[0322] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0323] k is 0 or 1.

[0324] In one embodiment of the compound of formula (I) or formula (IA), R 5 Is -CH3, CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

[0325] In one embodiment of the compound of formula (I) or formula (IA), R 9 It is an -OC1-C6 alkyl group.

[0326] In one embodiment of the compound of formula (I) or formula (IA), k is 0.

[0327] In one embodiment of the compound of formula (I) or formula (IA), wherein: R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl). In some embodiments, R 5 It is -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl). In some embodiments, R 5 It is -S (C1-C6 alkyl), -SO (C1-C6 alkyl), or -S(=NH)(O)(C1-C6 alkyl). In some embodiments, R 5 It is -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. In some embodiments, R 5 It is -SCH3.

[0328] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5-12 membered spiroheterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Spiral heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0329] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Fused heterocyclic rings via 1 or 2 R 5Replace and optionally further via 1, 2 or 3 R 9 replace.

[0330] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 6-12-membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Bridge connecting heterocyclic loops via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0331] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 7-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein the fused heterocycle is connected by 1 or 2 R atoms. 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0332] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5,5-fused heterocycle, a 5,6-fused heterocycle, a 6,5-fused heterocycle, or a 6,6-fused heterocycle, wherein R 1 After 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0333] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5,5-fused heterocycle, a 5,6-fused heterocycle, a 6,5-fused heterocycle, or a 6,6-fused heterocycle, wherein R 1 The carbon atoms of the fused heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 replace.

[0334] In one embodiment of the compound of formula (I) or formula (IA), R 1 It is a 5,5-fused heterocycle, a 5,6-fused heterocycle, a 6,5-fused heterocycle, or a 6,6-fused heterocycle, wherein R 1The fused heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle. 5 Substituted nitrogen atom. In one embodiment, R 1 It is a 5,5-fused heterocycle, a 5,6-fused heterocycle, a 6,5-fused heterocycle, or a 6,6-fused heterocycle, wherein R 1 The fused heterocycle contains at least one R atom of a 4-5 membered heterocycle selected from -C1-C3 alkyl, -C1-C3 haloalkyl, -C(O)(C1-C3 alkyl), or having one cyclic heteroatom selected from O, S, or N. 5 Substituted nitrogen heteroatoms.

[0335] In one embodiment of the compound of formula (I) or formula (IA), R 1 yes , , , , , , , , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic. In one embodiment, R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

[0336] In one embodiment of the compound of formula (I) or formula (IA), R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic. In one embodiment, R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

[0337] In one embodiment of the compound of formula (I) or formula (IA), R 1 yes , , , , , , , , , , , , , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 Each is independently a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic. In one embodiment, R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

[0338] In one embodiment of the compound of formula (I) or formula (IA), R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic. In one embodiment, R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

[0339] In an embodiment, this disclosure provides a compound of formula (IB):

[0340] (IB),

[0341] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0342] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0343] R 3 It is H;

[0344] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0345] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0346] Each R 6 Independently, it is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0347] R 6a It is H, C 1-6 Alkyl, C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0348] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0349] R 9It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0350] m is 0, 1, 2, or 3; and

[0351] p is 0; where:

[0352] (i) R 1 The heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle. 5 Substituted nitrogen atom;

[0353] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0354] (iii) Combinations of (i) and (ii).

[0355] In one embodiment of a compound of formula (I), formula (IA) or formula (IB), m is 0 or 1.

[0356] In one embodiment of the compound of formula (I), formula (IA) or formula (IB), at least one R 4 It is halogen.

[0357] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), m is 1 and R 4 It is a halogen. In one embodiment, m is 1 and R 4 It is F.

[0358] In one embodiment of the compound of formula (IB), R 6a It is a C1-C6 alkyl group, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, -CH2CH2N(CH3)2 or In one embodiment, R 6a It is -CH3.

[0359] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Monocyclic heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0360] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace, and R 1 The monocyclic heterocyclic ring may be further processed by 1, 2 or 3 R... 9 Replacement. In one embodiment, R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replacement. In one embodiment, R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1The carbon atom of the monocyclic heterocyclic ring may optionally be further fused with an R atom selected from -SCH3, -S(O)CH3 or -S(=O)(=NH)CH3. 5 Replacement. In one embodiment, R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The carbon atom of the monocyclic heterocycle may optionally be further fused with an R atom selected from -SCH3. 5 replace.

[0361] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The monocyclic heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle. 5 Substituted nitrogen atom, and R 1 The monocyclic heterocyclic ring may be further processed by 1, 2 or 3 R... 9 Replacement. In one embodiment, R 1 It is a 5-8 membered monocyclic heterocycle containing one or two heteroatoms selected from N, S, and O, wherein R 1 The monocyclic heterocycle contains at least one R atom of a 4-5 membered heterocycle selected from C1-C3 alkyl, -C1-C3 haloalkyl, -C(O)(C1-C3 alkyl), or having one cyclic heteroatom selected from O, S, or N. 5 Substituted nitrogen atom, and R 1 The monocyclic heterocyclic ring may be further processed by one R 9 Replacement. In one embodiment, R 1 It is a 5-8 membered monocyclic heterocycle containing one or two heteroatoms selected from N, S, and O, wherein R 1 The monocyclic heterocycle contains at least one R atom of a 4-5 membered heterocycle selected from C1-C3 alkyl, -C1-C3 haloalkyl, -C(O)(C1-C3 alkyl), or having one cyclic heteroatom selected from O, S, or N. 5 Substituted nitrogen atom, and R 1 The monocyclic heterocycle may optionally be further fused with one R selected from -OH or -OCH3. 9 replace.

[0362] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 yes , , , , , , , , , , , , , , , , , , , , , , or , where R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 Replacement. In one embodiment, R 5 It is -SH, -S (C1-C6 alkyl), SO (C1-C6 alkyl), or -S(=NH)(O)(C1-C6 alkyl). In one embodiment, R 5 It is -SH, -SCH3, -S(O)CH3 or -S(=NH)(O)CH3.

[0363] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 yes , , , or .

[0364] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 For 1 R 5 and 1 or 2 R 9 Replacement , , , or ;R 5 It is -SH, SCH3, -S(O)CH3 or -S(=NH)(O)CH3; and R 9It is a halogen or a -C1-C3 alkyl group.

[0365] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), wherein:

[0366] R 1 yes or ;

[0367] R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic;

[0368] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0369] k is 0 or 1.

[0370] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), wherein:

[0371] R 1 yes or ;

[0372] R 5 It is a C1-C3 alkyl group;

[0373] R 9 It is a halogen, hydroxyl, -OC1-C6 alkyl, or halo-OC1-C6 alkyl; and

[0374] k is 0 or 1.

[0375] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 yes In one embodiment, R 1 yes In one embodiment, R 9It is a halogen, hydroxyl group, -OC1-C6 alkyl group, or a halogenated -OC1-C6 alkyl group. In one embodiment, R 1 yes In one embodiment, R 1 yes In one embodiment, R 1 yes .

[0376] In the embodiments of compounds of formula (I), formula (IA) or formula (IB), R 1 yes In one embodiment, R 1 yes In one embodiment, R 1 yes In one embodiment, R 9 It is a halogen, hydroxyl group, -OC1-C6 alkyl group, or a halogenated -OC1-C6 alkyl group. In one embodiment, R 1 yes In one embodiment, R 1 yes In one embodiment, R 1 yes .

[0377] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), wherein:

[0378] R 1 yes , , , , , or ;

[0379] R 5 It is a C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic;

[0380] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8-S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0381] k is 0 or 1.

[0382] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), wherein:

[0383] R 1 yes , , , , , or ;

[0384] R 5 It is a C1-C3 alkyl, C1-C3 haloalkyl, -C(O)(C1-C3 alkyl) or a 4-5 membered heterocycle having a heteroatom selected from O, S or N;

[0385] R 9 It is a halogen, hydroxyl, -OC1-C6 alkyl, or halo-OC1-C6 alkyl; and

[0386] k is 0 or 1.

[0387] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), wherein:

[0388] R 1 yes or ;

[0389] R 5 It is a C1-C3 alkyl, C1-C3 haloalkyl, -C(O)(C1-C3 alkyl) or a 4-5 membered heterocycle having a heteroatom selected from O, S or N;

[0390] R 9 It is a halogen, hydroxyl, -OC1-C6 alkyl, or halo-OC1-C6 alkyl; and

[0391] k is 0 or 1.

[0392] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 5 It is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 5 It is -CH3.

[0393] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 5 It is -C(O)CH3, or .

[0394] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 9 It is an -OC1-C6 alkyl group. In some embodiments, R 9 It is a hydroxyl group. In some embodiments, R 9 It is halogen.

[0395] In one embodiment of the compound of formula (I), formula (IA) or formula (IB), k is 0.

[0396] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), wherein:

[0397] R 1 yes , where R 1 Further, optionally, via 1, 2, or 3 R... 9 Replace; and

[0398] R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), or -SO2NR. 7 R 8 .

[0399] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 5 It is -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -S(=NH)(O)(C1-C6 alkyl). In one embodiment, R 5 It is -S (C1-C3 alkyl), SO (C1-C3 alkyl), or -S(=NH)(O)(C1-C3 alkyl). In one embodiment, R 5 It is -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. In one embodiment, R 5 It is -SCH3.

[0400] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 5 It is -SO (C1-C6 alkyl). In one embodiment, R 5 It is -S(O)CH3.

[0401] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 5 It is -S(=NH)(O)(C1-C6 alkyl). In one embodiment, R 5 It is -S(=NH)(O)CH3.

[0402] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 yes , , , , , , , , , , , , , , , or .

[0403] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 yes , , or .

[0404] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 5-12 membered spiroheterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Spiral heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0405] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Fused heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0406] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R1 The fused heterocycle contains at least one R selected from C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom, and R 1 The fused heterocycle may optionally be further processed by 1, 2 or 3 R... 9 Replacement. In one embodiment, R 1 It is a 5,5-, 5,6-, or 6,5-fused heterocycle containing one or two heteroatoms selected from N, S, or O, wherein R 1 The fused heterocycle contains at least one R atom of a 4-5 membered heterocycle selected from C1-C3 alkyl, -C1-C3 haloalkyl, -C(O)(C1-C3 alkyl), or having one cyclic heteroatom selected from O, S, or N. 5 Substituted nitrogen atom, and R 1 The fused heterocycle may optionally be further processed by one or two R... 9 replace.

[0407] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 6-12-membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Bridge connecting heterocyclic loops via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0408] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 6-12-membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 The bridged heterocycle contains at least one R selected from C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom, and R 1 The bridge connects to the heterogeneous loop, which can be further connected via 1, 2, or 3 R... 9 Replacement. In one embodiment, R 1 It is a 7-10 bridging heterocycle containing one or two heteroatoms selected from N, S, and O, wherein R 1 The bridged heterocycle contains at least one R atom of a 4-5 membered heterocycle selected from C1-C3 alkyl, -C1-C3 haloalkyl, -C(O)(C1-C3 alkyl), or having one cyclic heteroatom selected from O, S, or N. 5 Substituted nitrogen atom, and R 1 The bridge connects to the heterogeneous loop, which can be further connected by 1 or 2 R... 9 replace.

[0409] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 , , , , , , , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic. In one embodiment, R 1 yes .

[0410] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 It is a 6-12-membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Bridge connecting heterocyclic loops via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

[0411] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 yes , , , , , , , , , , , , , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 Each is independently a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic. In some embodiments, R5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

[0412] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is a -C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic. In some embodiments, R 5 It is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(O)CH3. In one embodiment, R 1 yes .

[0413] In an embodiment, this disclosure provides a compound of formula (IC):

[0414] (IC),

[0415] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0416] Ring B is a 5- to 8-membered ring that optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O;

[0417] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0418] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0419] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8-S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0420] Each R 6 and R 10 Independently, it is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0421] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0422] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0423] m is 0, 1, 2, or 3;

[0424] p is 0, 1, 2, or 3; and

[0425] q is 0, 1, 2, or 3; where:

[0426] (i) R 1 The heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle.5 Substituted nitrogen atom;

[0427] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0428] (iii) Combinations of (i) and (ii).

[0429] In one embodiment of the compound of formula (IC), the tricyclic ring containing ring B is... , or ;X 1a It is -NH-, -NR 10 -、-O-、-CR 13 R 14 -、-C(O)-、-S-、-S(O)- or -S(O)2-; R 13 and R 14 Each is independently selected from H, deuterium, halogen, or C. 1-6 Alkyl group; q is 0, 1, or 2. In one embodiment, X 1a It is -NH-, -NCH3-, -O-, or -CH2-.

[0430] In one embodiment of the compound of formula (IC), the tricyclic ring containing ring B is... , , , , , , , or Where m is 0 or 1 and p is 0, 1 or 2.

[0431] In one embodiment of the compound of formula (IC), each R 4 Independently, it is a halogen, a -C1-C3 alkyl group, or a -CN group. In one embodiment, R 4 It is a halogen and p is 1.

[0432] In one embodiment of a compound of formula (I), formula (IA), or formula (IC), each R 6Independently, it is a halogen, -OH, -CN, -C1-C3 alkyl, -C1-C3 haloalkyl, -S (C1-C3 alkyl), -SO (C1-C3 alkyl), -SO2 (C1-C3 alkyl), -SO2N (C1-C3 alkyl), -SO2NR 7 R 8 Or 4-6-membered heterocyclic rings. In one embodiment, each R 6 Independently, it is a halogen, -OH, -CN, -SO2CH3, , , or In one embodiment, each R 6 Halogen independently or And m is 1 or 2.

[0433] In some embodiments of the compound of formula (IC), the tricyclic ring containing ring B is... or ;R 4 It is a halogen; and at least one R 6 It is a 4-6 membered heterocyclic ring. In some embodiments, R 4 It is a halogen; and at least one R 6 It is a 4-5 membered heterocycle having a cyclic heteroatom selected from O, S, or N. In some embodiments, R 4 It is a halogen; and at least one R 6 It is a 4-5 membered heterocycle having a cyclic heteroatom selected from O. In some embodiments, R 4 It is a halogen; and at least one R 6 yes or In some embodiments, R 4 It is F; and at least one R 6 yes or In some embodiments, m is 1, R 4 It is F, p is 2, and an R 6 yes or And another R 6 It is halogen.

[0434] In some embodiments of the compound of formula (IC), the tricyclic ring containing ring B is... In some embodiments, R 4 It is halogen and R 6 It is a halogen. In some embodiments, the tricyclic ring containing ring B is... .

[0435] In an embodiment, this disclosure provides a compound of formula (ID):

[0436] (ID),

[0437] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0438] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0439] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0440] R 3 It is H;

[0441] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0442] Each R 5 Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0443] Each R 6 H and C independently 1-6 Alkyl, C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0444] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0445] R 9It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0446] m is 0, 1, 2, or 3; where:

[0447] (i) R 1 The heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle. 5 Substituted nitrogen atom;

[0448] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0449] (iii) Combinations of (i) and (ii).

[0450] In one embodiment of the compound of formula (I) or formula (ID), ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 5,6-fused heteroaryl, a 6,5-fused heteroaryl, or a 6,6-fused heteroaryl. In one embodiment, ring A comprises one or two heteroatoms selected from N, S, or O.

[0451] In one embodiment of the compound of formula (I) or formula (ID), ring A is , , or .

[0452] In one embodiment of the compound of formula (I) or formula (ID), ring A is , , or .

[0453] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), or formula (ID), each R 4 It is independently a halogen, a -C1-C3 alkyl group, or a -CN group. In some embodiments, m is 0 or 1.

[0454] In one embodiment of the compound of formula (ID), R 6 It is a C1-C6 alkyl group, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, -CH2CH2N(CH3)2 or In one embodiment, R 6 It is a C1-C3 alkyl group.

[0455] In an embodiment, this disclosure provides a compound of formula (IE):

[0456] (IE),

[0457] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0458] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0459] R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles;

[0460] R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0461] R 3 It is H;

[0462] Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN;

[0463] Each R 5Independently, -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings;

[0464] Each R 6 Independently, it is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0465] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0466] R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic, or -(C1-C6 alkylene)-heteroaryl; and

[0467] m is 0, 1, 2, or 3; where:

[0468] (i) R1 The heterocycle contains at least one R selected from -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or a heterocycle. 5 Substituted nitrogen atom;

[0469] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or

[0470] (iii) Combinations of (i) and (ii).

[0471] In one embodiment of the compound of formula (I) or formula (IE), wherein:

[0472] R 2 yes or , where R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0473] -DE-is-N(R 6a -C(O)-, -CH2CH2-, -C(O)-O-, or -CH2-O-;

[0474] W, Y, and Z are each independently CH or N, provided that at most two of W, Y, and Z can be N;

[0475] X 1a Yes -NR 6b -、-O-、-CR 13 R 14 -、-C(O)-、-S-、-S(O)- or -S(O)2-;

[0476] R 6a It is an H or C1-C6 alkyl group;

[0477] R 6b It is H, C1-C6 alkyl, C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8Heterocyclic or -(C1-C6 alkylene)-heterocyclic;

[0478] R 13 and R 14 Each is independently selected from H, deuterium, halogen, or C1-C6 alkyl;

[0479] s is 1, 2, or 3; and

[0480] t is 1, 2, or 3;

[0481] The condition is that the sum of s and t is 2, 3 or 4.

[0482] In one embodiment of the compound of formula (I) or formula (IE),

[0483] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), or formula (ID), R 2 yes , , , , , , or , where R 2 Choose either 1 or 2 R 6 Replace; and R 6a It is H or C1-C6 alkyl.

[0484] In one embodiment of the compound of formula (IE), W and Z are both CH or W is CH and Z is N.

[0485] In one embodiment of the compound of formula (IE), X 1a Yes -NR 6b -

[0486] In one embodiment of the compound of formula (IE), R 6b It is H, C 1-6 Alkyl or 4-6 membered heterocyclic compounds. In some embodiments, R 6b Is it H, methyl or .

[0487] In one embodiment of the compound of formula (IE), s is 2 and t is 2. In some embodiments, s is 1 and t is 3 or s is 3 and t is 1. In some embodiments, s is 1 and t is 2 or s is 2 and t is 1. In some embodiments, s is 1 and t is 1.

[0488] In one embodiment of the compound of formula (I) or formula (IE), R 2 yes , , , , , , , , , , , , , , or , where R 2 Choose either 1 or 2 R 6 replace.

[0489] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), wherein:

[0490] R 1 yes ,in:

[0491] (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-;

[0492] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and

[0493] (iii) Combinations of (i) and (ii); and

[0494] g is 2 or 3.

[0495] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 yes ,in:

[0496] (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; or

[0497] (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace.

[0498] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 yes And R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl). In some embodiments, R 1 yes And R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl).

[0499] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replacement. In one embodiment, R 1 The carbon atom of the heterocycle is selected from an R atom of -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -S (=NH)(O)(C1-C6 alkyl).5 Replacement. In one embodiment, R 1 The carbon atom of the heterocyclic ring is selected from an R atom of -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. 5 Replacement. In one embodiment, R 1 The carbon atom of the heterocyclic ring is selected from an R atom of -SCH3. 5 replace.

[0500] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 yes or And k is 0 or 1. In some embodiments, R 5 It is -CH3, -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(O)CH3. In some embodiments, R 9 It is an -OC1-C6 alkyl group. In some embodiments, k is 0.

[0501] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 yes , , , , , , , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 Replacement. In some embodiments, R 1 Further through 1 R 9 Replacement. In some embodiments, R 1 Further through 2 R 9 Replacement. In some embodiments, R1 is further processed by 3 R... 9 replace.

[0502] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 The carbon atom of the heterocycle is connected by at least one R selected from -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl) or -S (=NH)(O)(C1-C6 alkyl). 5 Substitution. In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 The carbon atom of the heterocycle is connected by at least one R selected from -S (C1-C3 alkyl), -SO (C1-C3 alkyl), -SO2 (C1-C3 alkyl) or -S (=NH)(O)(C1-C3 alkyl). 5 Substitution. In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 The carbon atom of the heterocycle is connected by at least one R atom selected from -S (C1-C3 alkyl), -SO (C1-C3 alkyl), or -S (=NH)(O)(C1-C3 alkyl). 5 Substitution. In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 The carbon atom of the heterocyclic ring is connected to at least one R atom selected from SCH3, -S(O)CH3 or -S(=O)(=NH)CH3. 5 replace.

[0503] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 The carbon atom of the heterocycle is connected to at least one R atom selected from -SCH3, -OCH3, -OCH2CH3, -OCD3, -OCF3, or -OCHF2. 5 Replacement. In some embodiments, R 5 It is -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. In some embodiments, R 5 It is -SCH3

[0504] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 1 The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocycle. 5Substituted nitrogen atom. In one embodiment of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE), R 1 The heterocycle contains at least one R selected from -C1-C3 alkyl, -C1-C3 haloalkyl, -C(O)(C1-C3 alkyl) or 4-6 membered heterocycles. 5 Substituted nitrogen atom. In one embodiment of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE), R 1 The heterocycle contains at least one R-membered heterocycle selected from at least one 4- or 5-membered heterocycle having one cyclic heteroatom selected from O, S, or N. 5 Substituted nitrogen atom. In one embodiment of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE), R 1 The heterocycle contains at least one R selected from -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3. 5 Substituted nitrogen atom. In one embodiment of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE), R 1 The heterocycle contains at least one R selected from a 4- or 5-membered heterocycle having one cyclic heteroatom selected from O. 5 Substituted nitrogen atom. In one embodiment of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE), R 1 The heterocycle contains at least one selected from or at least one R 5 Substituted nitrogen heteroatoms.

[0505] Another embodiment is the product that can be obtained by any of the methods or examples disclosed herein.

[0506] In the embodiments, this document provides compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or their stereoisomers or pharmaceutically acceptable salts thereof.

[0507] In the embodiments, pharmaceutically acceptable salts of compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) are provided herein. Further embodiments of this disclosure relate to deuterated compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), or pharmaceutically acceptable salts thereof.

[0508] In the examples of compounds of formula (I) or (IA), the compound is compound 1, 2 or 3, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

[0509] In the examples of compounds of formula (I) or (IB), the compound is compound 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

[0510] In the examples, this document provides the compounds in Table A or their pharmaceutically acceptable salts, their racemic forms or their stereoisomers.

[0511] In the embodiments, this document provides the compounds in Table A or their pharmaceutically acceptable salts or stereoisomers.

[0512] In the examples, the compounds in Table A or their pharmaceutically acceptable salts are provided herein.

[0513] In one embodiment, the compounds listed in Table A are provided herein.

[0514] In some embodiments, pharmaceutically acceptable salts of the compounds in Table A are provided herein.

[0515] Unless otherwise stated herein, the names of the diastereomers of the compounds in Table A may be assumed.

[0516] Table A. Various compounds of the present invention

[0517]

[0518] Composition

[0519] Compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts or the aforementioned deuterated forms, may be used alone, but are usually administered as pharmaceutical compositions in which a compound / salt (active ingredient) of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A is combined with a pharmaceutically acceptable adjuvant, diluent, or carrier. Routine procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs”, ME Aulton, Churchill Livingstone, 2nd edition 2002.

[0520] Depending on the administration method, the pharmaceutical composition will preferably contain 0.05 to 99% w (weight percentage), more preferably 0.05 to 80% w, even more preferably 0.10 to 70% w, and even more preferably 0.10 to 50% w of the active ingredient, all weight percentages being based on the total composition.

[0521] In embodiments, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier. This disclosure further provides a method for preparing the pharmaceutical compositions of this disclosure, comprising mixing a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A as defined above, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0522] The pharmaceutical composition may be administered topically (e.g., to the skin or lungs and / or airways) in the form of creams, solutions, suspensions, sevoflurane (HFA) aerosols, and dry powder formulations (e.g., formulations in inhalation devices called Turbuhaler®); or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules; or by parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) in the form of sterile solutions, suspensions, or emulsions for injection; or by rectal administration in the form of suppositories.

[0523] For oral administration, the compounds of this disclosure can be mixed with adjuvants, diluents, or carriers, such as lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; disintegrants, such as cellulose derivatives; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, etc., and then compressed into tablets. If coated tablets are required, the tablet core prepared as described above can be coated with a suitable polymer dissolved or dispersed in water or a volatile organic solvent. Alternatively, the tablets can be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide.

[0524] For the preparation of soft gelatin capsules, the compounds of this disclosure can be mixed with, for example, vegetable oils or polyethylene glycol. Hard gelatin capsules can contain particles of compounds using pharmaceutical excipients (such as the excipients used in tablets described above). Additionally, liquid or semi-solid formulations of the compounds of this disclosure can be filled into hard gelatin capsules.

[0525] Liquid formulations for oral administration may be in the form of syrups, solutions, or suspensions. Solutions may, for example, contain compounds disclosed herein, with the remainder being sugar and a mixture of ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain colorants, flavoring agents, saccharin, and / or carboxymethyl cellulose as thickeners. Furthermore, other excipients known to those skilled in the art may be used when preparing formulations for oral use.

[0526] Therapeutic uses

[0527] In the embodiments, compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, and their pharmaceutically acceptable salts, are DPP1 inhibitors and are therefore applicable to any disease area where DPP1 is active. Therefore, in one aspect of this disclosure, a treatment method is provided. In one embodiment, the treatment method comprises administering to a subject in need a composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt of (I), (IA), (IB), (IC), (ID), or (IE) or Table A. In the embodiments, the composition is administered to the patient for a continuous period.

[0528] In embodiments, in methods for treating the following diseases, the compound or composition of this disclosure is administered to a patient: obstructive airway disease; chronic sinusitis (CRS); hidradenitis suppurativa (HS); cancer (e.g., metastatic cancer); granulomatous polyangiitis (GPA); microscopic polyangiitis (MPA); giant cell arteritis; polyarteritis nodosa; anti-GBM disease (Goodpassuia disease); rheumatoid arthritis; lupus nephritis; systemic lupus erythematosus; systemic scleroderma; inflammatory bowel disease (IBD) (e.g., ulcerative colitis; Crohn's disease); diabetic nephropathy; diabetic neuropathy; diabetic retinopathy; diabetic ulcer; Duchenne muscular dystrophy; bronchiolitis obliterans; long-term COVID-19) – Prevention of ILD; atopic dermatitis; pyoderma gangrenosa; Sweet's syndrome; dermatomyositis / polymyositis; neutrophilic dermatitis; uveitis; Behçet's disease; thrombosis; bronchopulmonary dysplasia; amyotrophic lateral sclerosis; sickle cell anemia; psoriasis; ventilator-associated lung injury.

[0529] In an embodiment, the compound or composition of this disclosure is administered to a patient in a method for treating an airway obstructive disease. In one embodiment, the airway obstructive disease is asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (including aspirin and NSAID-induced asthma and dust-induced asthma, intermittent and persistent and of all severity), airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis (e.g., infectious bronchitis, eosinophilic bronchitis), emphysema, cystic fibrosis (CF), bronchiectasis (e.g., non-CF bronchiectasis (NCFBE) and CF-associated bronchiectasis), cystic fibrosis; sarcoidosis; α-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonia, interstitial lung disease, pulmonary fibrosis (including idiopathic pulmonary fibrosis, cryptogenic pulmonary fibrosis) Fibrosis, idiopathic interstitial pneumonia, fibrosis associated with antitumor therapy or chronic infections, including tuberculosis and aspergillosis as well as other fungal infections, complications of lung transplantation, vasculitis and thrombotic conditions of the pulmonary vasculature, pulmonary hypertension (e.g., pulmonary hypertension); cough suppression activities, including treatment of chronic cough associated with inflammatory and secretory symptoms of the airways, iatrogenic cough; acute and chronic rhinitis, including drug-induced rhinitis and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including neurogenic rhinitis (hay fever), nasal polyposis; acute viral infections, including the common cold and infections caused by respiratory viruses (e.g., respiratory syncytial virus, influenza, coronaviruses (including SARS) and adenovirus), acute lung injury, acute respiratory distress syndrome (ARDS), and exacerbations of each of the aforementioned respiratory disease states.

[0530] In embodiments, in a method for treating pulmonary hypertension, a compound or composition of the present disclosure is administered to a patient. In some embodiments, pulmonary hypertension is pulmonary arterial hypertension. In some embodiments, pulmonary hypertension is pulmonary hypertension caused by left ventricular disease. In some embodiments, pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

[0531] Cystic fibrosis (CF) is caused by abnormalities in CF transmembrane transport regulators, leading to chronic lung infections (especially those caused by Pseudomonas aeruginosa) and excessive inflammation, resulting in bronchiectasis, decreased lung function, respiratory failure, and reduced quality of life. The inflammatory process is dominated by neutrophils, which produce NE and other disruptive NSPs, including CatG and PR3, which act directly on extracellular matrix proteins and play a role in the host's response to inflammation and infection (Dittrich et al., *Eur Respir J*. 2018;51(3)). The method presented in this paper utilizes a reversible inhibitor of DPP1. It is not intended to be theoretically construed that compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts, stereoisomers, or deuterated forms, administered via the methods provided herein, have beneficial effects by inhibiting NSP activation and reducing inflammation, which in turn leads to a reduction in lung deterioration, a lower rate of lung deterioration, and / or an improvement in lung function (e.g., forced expiratory volume in one second [FEV1]) in patients with CF.

[0532] In one embodiment, a method for treating CF is provided, comprising administering to a CF patient requiring treatment a composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

[0533] In one treatment method for CF, a continuous administration period is provided to a CF patient requiring treatment, comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. The method comprises improving the patient's lung function during the administration period compared to lung function prior to the administration period. In one embodiment, the improvement in lung function is measured by spirometry.

[0534] In one embodiment, improving the patient's lung function includes increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of FVC, compared to the corresponding values ​​before the administration cycle. (25-75%) In one embodiment, the increase is an increase of approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, or approximately 50% in the corresponding value. In one embodiment, the increase is an increase of at least approximately 5%, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, or at least approximately 50%. In yet another embodiment, the increase is an increase of approximately 5% to approximately 50%, approximately 5% to approximately 40%, approximately 5% to approximately 30%, or approximately 5% to approximately 20%. In even another embodiment, the increase is an increase of approximately 10% to approximately 50%, approximately 15% to approximately 50%, approximately 20% to approximately 50%, or approximately 25% to approximately 50%.

[0535] In one embodiment of the method provided herein, a continuous administration of a composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is administered to a patient requiring treatment for bronchiectasis. Bronchiectasis is considered a pathological endpoint resulting from a variety of disease processes and is a persistent or progressive disease characterized by dilated, thick-walled bronchi. Symptoms range from intermittent expectoration and localized lung infection to persistent, copious amounts of purulent sputum daily. Bronchiectasis may be accompanied by other nonspecific respiratory symptoms. Without wishing to be bound by theory, it has been reported that the basic pathological process of bronchiectasis is airway damage resulting from one or more events centered on inflammation (Guideline for non-CF Bronchiectasis, Thorax, July 2010, Vol. 65 (Supplement 1), which is incorporated herein by reference in its entirety for all purposes).

[0536] Bronchiectasis is considered a pathological endpoint resulting from a variety of disease processes and is a persistent or progressive disease characterized by dilated, thick-walled bronchi. Symptoms range from intermittent expectoration and localized lung infection to persistent, copious amounts of purulent sputum daily. Bronchiectasis may be accompanied by other nonspecific respiratory symptoms. Without wishing to be bound by theory, it has been reported that the basic pathological process of bronchiectasis is airway damage resulting from one or more events centered on inflammation (Guideline for non-CF Bronchiectasis, Thorax, July 2010, Vol. 65 (Supplement 1), which is incorporated herein by reference in its entirety for all purposes).

[0537] The methods described herein employ reversible inhibitors of DPP1. It is not intended to be theoretically binding, but it is believed that compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts, stereoisomers, or deuterated forms, administered via the methods described herein, have beneficial effects by reducing inflammation and excessive mucus secretion, which in some embodiments resulted in reduced lung deterioration, a lower rate of lung deterioration, and / or improved lung function (cough, sputum secretion, and forced expiratory volume in one second [FEV1]) in patients with bronchiectasis. It is not intended to be theoretically binding, but it is believed that the methods described herein alter the course of bronchiectasis by slowing the rate of decline in lung function or lung tissue destruction.

[0538] In one embodiment, the bronchodilator is a non-CF bronchodilator.

[0539] In one embodiment, a method for treating bronchiectasis includes improving the patient's lung function during the administration cycle compared to the patient's lung function before the administration cycle.

[0540] In one embodiment, lung deterioration is characterized by the patient exhibiting three or more of the following symptoms for at least 48 hours: (1) increased cough; (2) increased sputum volume or altered sputum consistency; (3) increased purulent sputum; (4) worsening dyspnea and / or decreased exercise tolerance; (5) fatigue and / or lethargy; (6) hemoptysis. In another embodiment, the three or more symptoms lead the physician to decide to prescribe antibiotics to the patient exhibiting the symptoms.

[0541] In one embodiment of a method for treating bronchiectasis, the method includes reducing the rate of lung deterioration experienced by the subject compared to a rate of lung deterioration prior to a period of administration of the composition, or compared to a control subject with bronchiectasis who did not receive the treatment. In another embodiment, the bronchiectasis is non-CF bronchiectasis.

[0542] On the other hand, a method is provided for treating chronic sinusitis (CRS) in a subject of need. In one embodiment, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, for a period of time.

[0543] Chronic sinusitis refers to chronic sinusitis without nasal polyps (CRSsNP) or chronic sinusitis with nasal polyps (CRSwNP). In some embodiments, chronic sinusitis is chronic sinusitis without nasal polyps (CRSsNP). In some embodiments, chronic sinusitis is chronic sinusitis with nasal polyps (CRSwNP). In some embodiments, chronic sinusitis is refractory chronic sinusitis. In some embodiments, refractory chronic sinusitis is refractory chronic sinusitis without nasal polyps (CRSsNP). In some embodiments, refractory chronic sinusitis is refractory chronic sinusitis with nasal polyps (CRSwNP).

[0544] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) postnasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) decreased sense of smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (l) middle meatus obstruction; (m) mucosal changes in the ostiomeatal complex and sinuses; (n) nasal discharge; or (o) any combination thereof. In some embodiments, middle meatus obstruction is mucosal obstruction, edematous obstruction, or a combination thereof.

[0545] In some embodiments, the pharmaceutical composition is administered to alleviate CRS, reduce its severity, delay its onset, or eliminate one or more of its symptoms. In some embodiments, one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) postnasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) decreased sense of smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (l) middle nasal meatus obstruction; (m) mucosal changes in the ostiomeatal complex and within the sinuses; (n) nasal discharge; (o) or any combination thereof. In some embodiments, the pharmaceutical composition is administered to enhance sinus drainage.

[0546] In some embodiments, the method includes a comprehensive severity score that reduces one or more symptoms of CRS. As used herein, a “comprehensive severity score” is a quantitative measure of all CRS symptoms exhibited by the subject. In some embodiments, the comprehensive severity score is the sum of all daily symptoms exhibited by the subject. In some embodiments, the comprehensive severity score decreases during or after the administration period compared to a comprehensive severity score measured before the administration period. In some embodiments, one or more symptoms of CRS exhibited by the subject can be any CRS-related symptom described herein or known in the art. In some embodiments, the one or more symptoms of CRS are: nasal congestion, decreased sense of smell, nasal discharge, or any combination thereof. In some embodiments, the nasal discharge is anterior nasal discharge. In some embodiments, the nasal discharge is posterior nasal discharge.

[0547] In some embodiments, the method includes reducing the subject's SNOT-22 score during or after the application cycle, compared to the subject's SNOT-22 score before the application cycle. As used herein, "SNOT-22" is a patient-reported measure of CRS outcomes for patients with or without nasal polyps and comprises 22 separate questions. These questions cover a wide range of health and health-related quality-of-life issues, including physical problems, functional limitations, and emotional consequences. The theoretical range for SNOT-22 scores is 0-110, with lower scores indicating higher health-related quality of life. Further details of SNOT-22 are provided in Hopkins et al., Clinical Otorhinolaryngol. Otolaryngol. 2009, 34, 447–454, and Kennedy et al., Ann Allergy Asthma Immunol. Oct. 2013; 111(4): 246–251, the contents of which are incorporated herein by reference in their entirety.

[0548] Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory condition. Symptoms include skin lesions that are typically associated with hair follicles and may be painful, inflamed, and / or swollen. In some cases, recurrences may occur as the lesions heal, potentially leading to subcutaneous tunneling and progressive scarring. Because HS is a chronic condition that can last for years and worsen over time, it significantly impacts quality of life, mental and emotional health. In fact, people with HS have a higher incidence of anxiety and depression, and their suicide risk is two and a half times that of the general population.

[0549] Patients with hepatitis B (HS) are classified into mild (Stage I), moderate (Stage II), or severe (Stage III) based on the severity of the disease, known as the Hurley classification. Although more than 200,000 cases of HS are diagnosed annually in the United States, the disease can be difficult to diagnose and requires specialized care. HS can be misdiagnosed as an infection, ingrown hairs, or other conditions. Furthermore, current treatment options are limited and often ineffective.

[0550] On one hand, a method for treating HS in a subject in need is provided. In one embodiment, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, for a sustained period. In another embodiment, the method of treating HS comprises reducing neutrophil inflammation in the subject.

[0551] In one embodiment, HS is a Hurley Phase I HS, a Hurley Phase II HS, or a Hurley Phase III HS. In some embodiments, HS is a Hurley Phase I HS. In some embodiments, HS is a Hurley Phase II HS. In some embodiments, HS is a Hurley Phase III HS.

[0552] This disclosure provides a method for treating cancer in a subject of need, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein. This disclosure also provides a method for treating cancer-induced pain in a subject with cancer, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein for a continuous administration period. In some embodiments, the cancer-induced pain is cancer-induced bone pain. This disclosure further provides a method for treating cancer-induced bone pain in a subject with cancer, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein for a continuous administration period.

[0553] In some embodiments, cancer includes primary solid tumors. In some embodiments, cancer is bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibrous carcinoma, lymphoma, viral cancer, oropharyngeal cancer, testicular cancer, thymic cancer, thyroid cancer, melanoma, or bone cancer.

[0554] In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibrocarcinoma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is a virus-induced cancer. In some embodiments, the cancer is oropharyngeal cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is thymic carcinoma. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, fibrocarcinoma is leiomyosarcoma.

[0555] In some embodiments, breast cancer includes ductal carcinoma, lobular carcinoma, medullary carcinoma, colloidal carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, breast cancer includes ductal carcinoma. In some embodiments, breast cancer includes lobular carcinoma. In some embodiments, breast cancer includes medullary carcinoma. In some embodiments, breast cancer includes colloidal carcinoma. In some embodiments, breast cancer includes tubular carcinoma. In some embodiments, breast cancer includes inflammatory breast cancer.

[0556] In some embodiments, the breast cancer is inflammatory breast cancer. In some embodiments, the breast cancer does not respond to hormone therapy or treatment targeting the HER2 protein receptor.

[0557] In some embodiments, the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, natural killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma, or Kaposi's sarcoma. In some embodiments, the lymphoma is Hodgkin's lymphoma. In some embodiments, the lymphoma is non-Hodgkin's lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the lymphoma is B-cell immunoblastic lymphoma. In some embodiments, the lymphoma is natural killer cell lymphoma. In some embodiments, the lymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma. In some embodiments, the lymphoma is Kaposi's sarcoma.

[0558] In some embodiments, brain cancer is an astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. In some embodiments, brain cancer is an astrocytoma. In some embodiments, brain cancer is an anaplastic astrocytoma. In some embodiments, brain cancer is a glioblastoma multiforme. In some embodiments, brain cancer is an oligodendroglioma. In some embodiments, brain cancer is an ependymoma. In some embodiments, brain cancer is a meningioma. In some embodiments, brain cancer is a schwannoma. In some embodiments, brain cancer is a medulloblastoma.

[0559] In some embodiments, the cancer is a liquid tumor. In some embodiments, the liquid tumor is acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorder, natural killer cell leukemia, blastic plasmacytoid dendritic cell vegetations, chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), or myelodysplastic syndrome (MDS). In some embodiments, the liquid tumor is acute myeloid leukemia (AML). In some embodiments, the liquid tumor is acute lymphoblastic leukemia. In some embodiments, the liquid tumor is acute lymphoblastic leukemia. In some embodiments, the liquid tumor is acute promyelocytic leukemia. In some embodiments, the liquid tumor is chronic myeloid leukemia. In some embodiments, the liquid tumor is hairy cell leukemia. In some embodiments, the liquid tumor is myeloproliferative disorder. In some embodiments, the liquid tumor is natural killer cell leukemia. In some embodiments, the liquid tumor is a blastic plasmacytoid dendritic cell proliferation. In some embodiments, the liquid tumor is chronic myeloid leukemia (CML). In some embodiments, the liquid tumor is mastocytosis. In some embodiments, the liquid tumor is chronic lymphocytic leukemia (CLL). In some embodiments, the liquid tumor is multiple myeloma (MM). In some embodiments, the liquid tumor is myelodysplastic syndrome (MDS).

[0560] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer is neuroblastoma, Wilms' tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, or Ewing's sarcoma. In some embodiments, the pediatric cancer is neuroblastoma. In some embodiments, the pediatric cancer is Wilms' tumor. In some embodiments, the pediatric cancer is rhabdomyosarcoma. In some embodiments, the pediatric cancer is retinoblastoma. In some embodiments, the pediatric cancer is osteosarcoma. In some embodiments, the pediatric cancer is Ewing's sarcoma.

[0561] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the subject is at risk of having metastatic cancer. In some embodiments, metastatic cancer includes breast cancer metastasized to the brain, bone, pancreas, lymph nodes, and / or liver. In some embodiments, metastatic cancer includes bone cancer metastasized to the lungs. In some embodiments, metastatic cancer includes colorectal cancer metastasized to the peritoneum, pancreas, stomach, lungs, liver, kidneys, and / or spleen. In some embodiments, metastatic cancer includes gastric cancer metastasized to the mesentery, spleen, pancreas, lungs, liver, adrenal glands, and / or ovaries. In some embodiments, metastatic cancer includes leukemia metastasized to lymph nodes, lungs, liver, hind limbs, brain, kidneys, and / or spleen. In some embodiments, metastatic cancer includes liver cancer metastasized to the intestines, spleen, pancreas, stomach, lungs, and / or kidneys. In some embodiments, metastatic cancer includes lymphoma metastasized to the kidneys, ovaries, liver, bladder, and / or spleen.

[0562] In some embodiments, metastatic cancer includes hematopoietic cancer metastasized to the intestine, lung, liver, spleen, kidney, and / or stomach. In some embodiments, metastatic cancer includes melanoma metastasized to lymph nodes and / or lung. In some embodiments, metastatic cancer includes pancreatic cancer metastasized to the mesentery, ovary, kidney, spleen, lymph nodes, stomach, and / or liver. In some embodiments, metastatic cancer includes prostate cancer metastasized to the lung, pancreas, kidney, spleen, intestine, liver, bone, and / or lymph nodes. In some embodiments, metastatic cancer includes ovarian cancer metastasized to the diaphragm, liver, intestine, stomach, lung, pancreas, spleen, kidney, lymph nodes, and / or uterus. In some embodiments, metastatic cancer includes myeloma metastasized to bone.

[0563] In some embodiments, metastatic cancer includes lung cancer metastasized to bone, brain, lymph nodes, liver, ovary, and / or intestine. In some embodiments, metastatic cancer includes kidney cancer metastasized to liver, lung, pancreas, stomach, brain, and / or spleen. In some embodiments, metastatic cancer includes bladder cancer metastasized to bone, liver, and / or lung. In some embodiments, metastatic cancer includes thyroid cancer metastasized to bone, liver, and / or lung.

[0564] In some embodiments, the methods disclosed herein include treating cancer-induced bone pain (CIBP) in a subject with cancer metastasized to the bone. In some embodiments, the subject has prostate cancer, breast cancer, lung cancer, or myeloma that has metastasized to the bone. In some embodiments, the subject is determined to have metastases to the bone by using any of the following methods: plain radiography, computed tomography, technetium-99m bone scan, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, fluorine positron emission tomography, and / or choline positron emission tomography, but has not yet experienced cancer-induced bone pain. In some embodiments, the subject experiences cancer-induced bone pain, indicating that a previously treated or untreated primary tumor has metastasized to the bone. In some embodiments, the cancer has metastasized to the vertebrae, pelvis, long bones, or ribs.

[0565] In some embodiments, the composition is applied to reduce the severity of cancer, delay the onset of cancer, or eliminate cancer symptoms. In some embodiments, the symptom of cancer is cancer-induced bone pain (CIBP). In some embodiments, CIBP is neuropathic pain. In some embodiments, CIBP is inflammatory pain. In some embodiments, CIBP is spontaneous pain. In some embodiments, the symptom of cancer is hyperalgesia. In some embodiments, the symptom of cancer is anomalous pain. In some embodiments, anomalous pain is tactile anomalous pain. In some embodiments, tactile anomalous pain is static mechanical anomalous pain. In some embodiments, hyperalgesia is dynamic mechanical anomalous pain. In some embodiments, the subject has bone cancer or metastasis to the bone.

[0566] In yet another embodiment of this disclosure, a method for treating lupus nephritis (LN) in a subject of need is provided. The method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, for a period of time.

[0567] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, and its impact on the underlying bone and cartilage. Currently, the etiology of RA is unknown, and there is no satisfactory treatment. While many therapeutic agents have been developed and used to relieve pain and inflammation associated with the disease, such as disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs), these agents often produce intolerable side effects. To address this and other needs, in one embodiment, this disclosure provides a method for treating RA using a reversible inhibitor of DPP1 of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. In one embodiment, a method for treating RA in a subject of need is provided, and the method includes administering to the subject a continuous administration cycle of a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. In another embodiment, the method includes reducing neutrophil inflammation in the subject.

[0568] Inflammatory bowel disease (IBD) is a group of inflammatory conditions affecting the colon and small intestine. The most common IBDs are Crohn's disease and ulcerative colitis. In one embodiment, this disclosure addresses the need for novel IBD therapies. Specifically, in one embodiment, a method of treating an IBD patient in need is provided. The method comprises administering to the patient a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

[0569] In another embodiment, IBD is Crohn's disease or ulcerative colitis. In even further embodiments, the method includes reducing neutrophil inflammation in the subject.

[0570] In embodiments, in a method for treating heart failure, the compounds or compositions of this disclosure are administered to a patient. In some embodiments, heart failure is heart failure with a reduced ejection fraction. In some embodiments, heart failure is heart failure with a preserved ejection fraction.

[0571] The length of the administration cycle in any given case can depend on the nature and severity of the symptoms to be treated and / or prevented, and is determined by the physician. In one embodiment, the administration cycle begins approximately at the time of diagnosis of the symptoms / disease and continues for the patient's entire life.

[0572] In some embodiments, the application period is about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 36 months, about 4 years, about 5 years, about 10 years, about 15 years, or about 20 years. In some embodiments, the compounds or compositions disclosed herein may be applied for a period of about 24 weeks. In some embodiments, the compounds or compositions disclosed herein may be applied for a period of about 52 weeks. In yet another embodiment, the application period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, or at least about 20 years.

[0573] In some embodiments, the application period of the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, or at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. In another embodiment, the application period of the methods provided herein is from about 30 days to about 180 days. In another embodiment, the application period is from about 30 days to about 36 months, or from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months.

[0574] In one embodiment, the application period is from about 1 year to about 30 years. For example, in one embodiment, the application period is from about 1 year to about 25 years, from 1 year to about 20 years, from about 1 year to about 15 years, from about 1 year to about 10 years, from about 1 year to about 5 years, from about 1 year to about 3 years, from about 1 year to about 2 years, from about 2 years to about 15 years, from about 2 years to about 10 years, from about 2 years to about 8 years, from about 2 years to about 5 years, from about 2 years to about 4 years, or from about 2 years to about 3 years.

[0575] In one embodiment of the method, the composition is administered to the subject once daily during the administration period. In another embodiment, the composition is administered to the patient twice daily, every other day, or once weekly during the administration period. In yet another embodiment, the composition is administered every other day, every three days, three times a week, or four times a week during the administration period.

[0576] In one embodiment, the oral dosage form is administered once daily during the administration period. In a further embodiment, the oral dosage form is administered at approximately the same time each day, for example, before breakfast. In another embodiment, during the administration period, a composition comprising an effective amount of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is administered once daily or twice daily. In yet another embodiment, during the administration period, a composition comprising an effective amount of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is administered once weekly, every other day, every three days, twice weekly, three times weekly, four times weekly, or five times weekly.

[0577] In one embodiment, administration is via oral route. In a further embodiment, the composition is administered once daily.

[0578] The administered dose will vary depending on the compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, the administration method, and the desired therapeutic outcome. For example, in one embodiment, if inhaled, the daily dose of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, may range from 0.05 μg / kg body weight (μg / kg) to 100 μg / kg body weight (μg / kg). Alternatively, in one embodiment, if the compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A or its pharmaceutically acceptable salt, stereoisomer, or deuterated form is administered orally, the daily dose of the compound disclosed herein may be in the range of 0.01 μg / kg body weight (μg / kg) to 100 mg / kg body weight (mg / kg).

[0579] Compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts, stereoisomers, or deuterated forms, may be used alone, but are usually administered in the form of pharmaceutical compositions in combination with pharmaceutically acceptable adjuvants, diluents, or carriers. Routine procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs”, ME Aulton, Churchill Livingstone, 2nd edition 2002.

[0580] Example

[0581] The present disclosure is further illustrated by reference to the following examples. However, it should be noted that, similar to the embodiments described above, these examples are illustrative and should not be construed as limiting the scope of the present disclosure in any way.

[0582] In the embodiments, the compounds of this disclosure can be synthesized using the following methods. General reaction conditions are given, and the reaction products can be purified by generally known methods, including silica gel chromatography or preparative reversed-phase high-performance liquid chromatography using various organic solvents (such as hexane, dichloromethane, ethyl acetate, methanol, etc.).

[0583] Example 1: Synthesis of (S)-N-(1-cyano-2-(4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)-4-(methylamino)tetrahydro-2H-pyran-4-carboxamide (Compound 1)

[0584] Step 1. Synthesis of methyl 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylate

[0585]

[0586] Under a nitrogen atmosphere, a solution of 4-[(tert-butoxycarbonyl)amino]oxane-4-carboxylic acid (1.0 g, 4.07 mmol, 1.0 equivalent) in DMF (10 mL) was treated with NaH (0.5 g, 12.23 mmol, 3.0 equivalent, 60% in mineral oil). The mixture was stirred at 0 °C for 30 min, followed by dropwise addition of MeI (1.7 g, 12.25 mmol, 3.0 equivalent) at 0 °C. The resulting mixture was stirred at room temperature for another 5 h. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded methyl 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid (1 g, crude) as a colorless oil. LCMS (ES, m / z): [M+H] + : 274.

[0587] Step 2.4 Synthesis of [(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid

[0588]

[0589] A solution of methyl 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid (1.0 g, 3.65 mmol, 1.0 equivalent) in MeOH (9 mL) and NaOH (0.4 g, 11.00 mmol, 3.0 equivalent) in H₂O (3 mL) was stirred at 60 °C for 36 h. The mixture was cooled to 0 °C and acidified to pH = 3 with HCl (1 M). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid (520 mg, 54.8%) as a colorless oil. LCMS (ES, m / z): [M+H] + : 260.

[0590] Step 3. Synthesis of N-(4-{[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}oxane-4-yl)-N-methylcarbamate tert-butyl

[0591]

[0592] A solution of 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid (520 mg, 2.00 mmol, 1.2 equivalences) in DMF (2 mL) was treated with HOAT (341 mg, 2.50 mmol, 1.5 equivalences) and HATU (953 mg, 2.50 mmol, 1.5 equivalences) at 0 °C under a nitrogen atmosphere for 30 min. Subsequently, 4'-[(2S)-2-amino-2-cyanoethyl]-[1,1'-biphenyl]-4-carboxynitrile (413 mg, 1.67 mmol, 1.0 equivalences) and DIEA (648 mg, 5.01 mmol, 3.0 equivalences) were added dropwise at room temperature. The resulting mixture was stirred at room temperature for another 36 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give N-(4-{(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}oxane-4-yl)-N-methylcarbamate tert-butyl ester (120 mg, 14.7%) as a yellow oil. LCMS (ES, m / z): [M+H] + : 489.

[0593] Step 4. Synthesis of (S)-N-(1-cyano-2-(4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)-4-(methylamino)tetrahydro-2H-pyran-4-carboxamide

[0594]

[0595] A solution of N-(4-{[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}oxane-4-yl)-N-methylcarbamate tert-butyl ester (120 mg, 0.24 mmol, 1.0 equivalent) in ACN (3 mL) and TsOH·H2O (140 mg, 0.73 mmol, 3.0 equivalent) was added to a 25 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (S)-N-(1-cyano-2-(4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)-4-(methylamino)tetrahydro-2H-pyran-4-carboxamide (16.9 mg, 17.7%) as a white solid. LCMS (ES, m / z): [M+H] + : 389.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.6Hz, 2H), 7.75 – 7.68 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 5.11 – 5.04 (m, 1H), 3.65 – 3.42 (m, 3H), 3.29 – 3.14 (m, 3H), 2.20 (br, 1H), 1.95 (s, 3H), 1.82(ddd, J = 13.0, 8.6, 3.9 Hz, 1H), 1.66 (ddd, J = 12.9, 8.7, 3.8 Hz, 1H), 1.41–1.30(m, 2H).

[0596] Example 2: Synthesis of N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-4-(dimethylamino)oxane-4-carboxamide (Compound 2)

[0597]

[0598] A solution of N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-4-(methylamino)oxane-4-carboxamide (180 mg, 0.46 mmol, 1.0 equivalent), HCHO (366 mg, 4.63 mmol, 10.0 equivalent, 38% in H2O), NaBH(OAc)3 (196 mg, 0.92 mmol, 2.0 equivalent), and HOAc (0.1 mL) in THF (3 mL) was stirred at room temperature for 1 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-4-(dimethylamino)oxane-4-carboxamide (20.5 mg, 11%) as a white solid. LCMS (ES, m / z): [M+H] + : 403.1. 1 H NMR (400 MHz, DMSO-d6) δ8.45 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H),7.74 – 7.67 (m, 2H), 7.48 – 7.41 (m, 2H), 5.22 – 5.12 (m, 1H), 3.67 (dt, J =11.4, 4.0 Hz, 1H), 3.54 (dt, J = 11.7, 3.8 Hz, 1H), 3.29 – 3.14 (m, 3H), 2.84(td, J = 11.2, 2.2 Hz, 1H), 2.05 (s, 6H), 1.87 – 1.80 (m, 1H), 1.80 – 1.72(m, 1H), 1.62 – 1.55 (m, 1H), 1.52 – 1.45 (m, 1H).

[0599] Example 3: Synthesis of (2S,3aS,6aS)-N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-1-methyl-hexahydro-2H-cyclopentano[b]pyrrole-2-carboxamide (compound 3)

[0600]

[0601] Under a nitrogen atmosphere at room temperature, HCHO (260 mg, 2.60 mmol, 10.0 equivalent, 30% in water) and HOAc (0.05 mL) were added dropwise to a stirred solution of (2S,3aS,6aS)-N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-octahydrocyclopentano[b]pyrrole-2-carboxamide (100 mg, 0.26 mmol, 1.0 equivalent) in MeOH (3 mL). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 0.5 h. NaBH(OAc)3 (275 mg, 1.30 mmol, 5.0 equivalent) was added in portions to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for another 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 70% gradient over 10 min; detector, UV 254 nm. This yielded (2S,3aS,6aS)-N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-1-methyl-hexahydro-2H-cyclopentano[b]pyrrole-2-carboxamide (20 mg, 19%) as a grayish-white solid. LCMS (ES, m / z): [M+H] + : 399.4. 1 H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.97 – 7.82 (m, 4H), 7.68 (d, J = 8.2Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 5.10 (q, J = 8.0 Hz, 1H), 3.26 (d, J = 8.0Hz, 2H), 2.82 – 2.72 (m, 1H), 2.68 (dd, J = 10.3, 6.5 Hz, 1H), 2.44 – 2.37(m, 1H), 2.07 (s, 3H), 2.05 – 1.95 (m, 1H), 1.71 – 1.60 (m, 2H), 1.51 – 1.40 (m, 2H), 1.29 – 1.18 (m, 2H), 0.87 – 0.77 (m, 1H).

[0602] Example 4: Synthesis of (2S,3aS,6aS)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1-methyl-hexahydro-2H-cyclopentano[b]pyrrole-2-carboxamide (compound 4)

[0603]

[0604] Under a nitrogen atmosphere at room temperature, HCHO (223 mg, 2.23 mmol, 10.0 equivalent, 30% in H2O) and HOAc (0.05 mL) were added dropwise to a stirred solution of (2S,3aS,6aS)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-octahydrocyclopentano[b]pyrrole-2-carboxamide (100 mg, 0.22 mmol, 1.0 equivalent) in MeOH (2 mL). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 3 h. NaBH(OAc)3 (142 mg, 0.67 mmol, 3.0 equivalent) was added in portions to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for another 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S,3aS,6aS)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1-methyl-hexahydro-2H-cyclopentano[b]pyrrole-2-carboxamide (20 mg, 19.4%) as a white solid. LCMS (ES, m / z): [M+H] + : 421.2. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.51 – 7.36 (m, 3H), 5.09 (q, J =8.4 Hz, 1H), 3.41 (s, 3H), 3.28 (d, J = 8.0 Hz, 2H), 2.84 – 2.66 (m, 2H), 2.47 – 2.40 (m, 1H), 2.13 – 2.07 (m, 4H), 1.78 – 1.59 (m, 2H), 1.51 – 1.37(m, 2H), 1.32 – 1.24 (m, 2H), 0.98 – 0.87 (m, 1H).

[0605] Example 5: Synthesis of (3R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxy-1-methylpyrrolidine-3-carboxamide (compound 5A)

[0606] Step 1. Synthesis of (3R)-3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester and (3S)-3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0607]

[0608] A solution of (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionitrile (130 mg, 0.44 mmol, 1.0 equivalent) in DCM (5 mL) was treated with 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-3-carboxylic acid (102 mg, 0.44 mmol, 1.0 equivalent) and DIEA (172 mg, 1.32 mmol, 3.0 equivalent). HATU (202 mg, 0.53 mmol, 1.2 equivalent) was then added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (3R)-3-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (90 mg 20%) and (3S)-3-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (90 mg 20%) as white solids. LCMS (ES, m / z): [M+H] + : 507.

[0609] Step 2. Synthesis of (3R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxypyrrolidine-3-carboxamide

[0610]

[0611] At room temperature, (3R)-3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 0.17 mmol, 1.0 equivalent), ACN (3 mL), and TsOH·H2O (101 mg, 0.53 mmol, 3.0 equivalent) were added to a 25 mL round-bottom flask. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (3R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxypyrrolidine-3-carboxamide (70 mg, 97%) as a white solid. LCMS (ES, m / z): [M+H] + : 406.

[0612] Step 3. Synthesis of (3R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxy-1-methylpyrrolidine-3-carboxamide

[0613]

[0614] A solution of (3R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxypyrrolidine-3-carboxamide (70 mg, 0.17 mmol, 1.0 equivalent) in THF (3 mL) was treated with HCHO (136 mg, 1.72 mmol, 10 equivalent, 38% in water) and HOAc (0.1 mL). The mixture was stirred at room temperature for 1 hour. NaBH(OAc)3 (73 mg, 0.34 mmol, 2.0 equivalent) was then added in portions at room temperature. The resulting mixture was stirred at room temperature for another 1 hour. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 50% gradient over 10 minutes; detector, UV 254 nm. This yielded (3R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxy-1-methylpyrrolidine-3-carboxamide (17.3 mg, 24%) as a white solid. LCMS (ES, m / z): [M+H] + : 421.5. 1 H NMR(400 MHz, DMSO-d6) δ 8.68 (d, J = 8.6 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.57 (s,1H), 7.45 – 7.35 (m, 4H), 5.84 (s, 1H), 5.07 – 4.97 (m, 1H), 3.41 (s, 3H), 3.23 – 3.20 (m, 2H), 2.79 – 2.73 (m, 1H), 2.37 – 2.33 (m, 2H), 2.27 – 2.14(m, 4H), 1.78 – 1.71 (m, 1H).

[0615] Example 6: Synthesis of (3S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxy-1-methylpyrrolidine-3-carboxamide (compound 5B)

[0616] Step 1. Synthesis of (3S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxypyrrolidine-3-carboxamide

[0617]

[0618] At room temperature, a solution of (3S)-3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 0.17 mmol, 1.0 equivalent) in ACN (3 mL) and TsOH·H2O (101 mg, 0.53 mmol, 3.0 equivalent) were added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (3S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxypyrrolidine-3-carboxamide (70 mg, 96.9%) as a white solid. LCMS (ES, m / z): [M+H] + : 406.

[0619] Step 2. Synthesis of (3S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxy-1-methylpyrrolidine-3-carboxamide

[0620]

[0621] A solution of (3S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxypyrrolidine-3-carboxamide (70 mg, 0.17 mmol, 1.0 equivalent) in THF (3 mL) was treated with HCHO (136 mg, 1.72 mmol, 10 equivalent, 38% in water) and HOAc (0.1 mL). The reaction was stirred at room temperature for 1 h, followed by the addition of NaBH(OAc)3 (73 mg, 0.34 mmol, 2.0 equivalent) in portions at room temperature. The resulting mixture was stirred at room temperature for another 1 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (3S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-3-hydroxy-1-methylpyrrolidine-3-carboxamide (17.3 mg, 24%) as a white solid. LCMS (ES, m / z): [M+H] + : 421.5. 1 H NMR(400 MHz, DMSO-d6) δ 8.67 (d, J = 8.3 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.58 (s,1H), 7.45 – 7.35 (m, 4H), 5.83 (s, 1H), 5.00 (q, J = 8.0 Hz, 1H), 3.41 (s,3H), 3.22 (d, J = 7.9 Hz, 2H), 2.77 – 2.69 (m, 1H), 2.67 (d, J = 9.7 Hz, 1H), 2.56 (d, J = 9.6 Hz, 1H), 2.33 – 2.25 (m, 1H), 2.23 (s, 3H), 1.97 – 1.91 (m,1H), 1.72 – 1.65 (m, 1H).

[0622] Example 7: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-methyl-1,4-oxazheptan-2-carboxamide (compound 7)

[0623]

[0624] HOAc (1 mg, 0.024 mmol, 0.1 equivalence) was added to a stirred solution of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazetane-2-carboxamide (100 mg, 0.238 mmol, 1.0 equivalence) and HCHO (71 mg, 2.380 mmol, 10.0 equivalence) in MeOH (2 mL). The resulting mixture was stirred at room temperature for 1 h. NaBH(OAc)3 (151 mg, 0.714 mmol, 3.0 equivalence) was added in portions to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for another 1 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19*150mm 5µm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-methyl-1,4-oxazheptan-2-carboxamide (50 mg, 48.3%) as a white solid. LCMS (ES) [M+1] + m / z:435. 1 H NMR (300 MHz, DMSO-d6) δ8.66 (d, J = 8.6 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.57 (t, J = 1.2 Hz, 1H), 7.39(d, J = 8.5 Hz, 4H), 5.12 – 4.97 (m, 1H), 4.14 (dd, J = 8.3, 2.9 Hz, 1H),3.88 – 3.71 (m, 2H), 3.40 (s, 3H), 3.30 – 3.11 (m, 2H), 2.88 – 2.76 (m, 1H),2.67 – 2.52 (m, 1H), 2.45 – 2.25 (m, 2H), 2.19 (s, 3H), 1.85 – 1.72 (m, 2H).

[0625] Example 8: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-4-methyl-1,4-oxazetane-2-carboxamide (compound 8)

[0626]

[0627] Add (2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidinyl heptane-2-carboxamide (60.00 mg, 0.14 mmol, 1.00 equivalent), THF (3.00 mL), HCHO (136.96 mg, 1.37 mmol, 10.00 equivalent, 30%), and AcOH (0.08 mg, 0.001 mmol, 0.01 equivalent) to an 8 mL vial. Stir the resulting mixture at room temperature for 1 h. Add NaBH(OAc)3 (87.01 mg, 0.41 mmol, 3.00 equivalent) to the mixture in portions at room temperature. Stir the resulting mixture at room temperature for another 30 min. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: C18-120g column, mobile phase, MeCN aqueous solution (0.1% NH3). . H2O), gradient 20% to 50% over 8 minutes; detector, UV 254 nm. The target fraction was freeze-dried to give (2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-methyl-1,4-oxazetane-2-carboxamide (35.40 mg, 57.17%) as a pale yellow solid. LCMS (ES, m / z): [M+H] + : 453. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 1.8Hz, 1H), 7.63-7.52 (m, 2H), 7.52-7.44 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 5.08(q, J = 8.2 Hz, 1H), 4.15 (dd, J = 8.2, 2.9 Hz, 1H), 3.88-3.70 (m, 2H), 3.41(s, 3H), 3.32-3.13 (m, 2H), 2.84 (dd, J = 13.7, 2.9 Hz, 1H), 2.66-2.52 (m,1H), 2.46-2.29 (m, 2H), 2.19 (s, 3H), 1.90-1.67 (m, 2H).

[0628] Example 9: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-4-methyl-1,4-oxazetane-2-carboxamide (compound 9)

[0629] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0630]

[0631] DIEA (126 mg, 0.981 mmol, 3.0 equivalent) and HATU (149 mg, 0.392 mmol, 1.2 equivalent) were added in portions to a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (90 mg, 0.327 mmol, 1.0 equivalent) and (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionitrile (105 mg, 0.360 mmol, 1.1 equivalent) in DCM (1 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (170 mg, 94.4%) as a white solid. LCMS (ES) [M+H + m / z:551.

[0632] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide

[0633]

[0634] TsOH (150 mg, 0.873 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazolidinyl heptane-4-carboxylic acid tert-butyl ester (160 mg, 0.291 mmol, 1.0 equivalent) in ACN (3 mL). The resulting mixture was stirred at room temperature for 3 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19*150mm 5µm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide (90 mg, 68.7%) as a white solid. LCMS (ES) [M+H] + m / z: 451.

[0635] Step 3. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-4-methyl-1,4-oxazetane-2-carboxamide

[0636]

[0637] HOAc (1 mg, 0.020 mmol, 0.1 equivalent) was added to a stirred solution of (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide (90 mg, 0.200 mmol, 1.0 equivalent) and HCHO (59 mg, 2.000 mmol, 10.0 equivalent) in MeOH (2 mL). The resulting mixture was stirred at room temperature for 1 h. NaBH(OAc)3 (127 mg, 0.600 mmol, 3.0 equivalent) was added in portions to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for another 1 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19*150mm 5µm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-4-methyl-1,4-oxazheptan-2-carboxamide (30 mg, 32.3%) as a white solid. LCMS (ES) [M+1] + m / z: 465. 1 HNMR (300 MHz, DMSO-d6)δ 8.67 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.57 (t, J = 1.2 Hz, 1H), 7.39 (d, J = 9.2 Hz, 4H), 5.11 – 4.97 (m, 1H), 4.12(dd, J = 8.2, 3.5 Hz, 1H), 3.97 (dd, J = 12.4, 4.8 Hz, 1H), 3.58 (dd, J =12.4, 7.3 Hz, 1H), 3.53 – 3.42 (m, 1H), 3.40 (s, 3H), 3.25 (s, 3H), 3.20 (dd,J = 8.0, 4.3 Hz, 2H), 2.85 (dd, J = 13.4, 3.5 Hz, 1H), 2.68 (dd, J = 13.6,4.8 Hz, 1H), 2.62 – 2.51 (m, 1H), 2.29 (dd, J = 13.6, 8.4 Hz, 1H), 2.23 (s,3H).

[0638] Example 10: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-ethyl-1,4-oxazetane-2-carboxamide (compound 11)

[0639]

[0640] A mixture of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidinyl heptane-2-carboxamide (110 mg, 0.26 mmol, 1.0 equivalent), CH3CH2I (45 mg, 0.28 mmol, 1.1 equivalent), and K2CO3 (72 mg, 0.52 mmol, 2.0 equivalent) in ACN (3 mL) was stirred at room temperature for 16 h. The mixture was filtered, and the filtrate was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10-minute gradient from 10% to 80%; detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-ethyl-1,4-oxazetane-2-carboxamide (24.4 mg, 20.8%) as a white solid. LCMS (ES, m / z): [M+H] + : 449.2. 1 HNMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.4 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.57(t, J = 1.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 4H), 5.04 (q, J = 8.1 Hz, 1H), 4.10(dd, J = 7.7, 3.2 Hz, 1H), 3.84 – 3.72 (m, 2H), 3.41 (s, 3H), 3.28 – 3.13 (m,2H), 2.85 (dd, J = 14.0, 3.2 Hz, 1H), 2.66 – 2.60 (m, 1H), 2.49 – 2.33 (m,4H), 1.82 – 1.71 (m, 2H), 0.85 (t, J = 7.1 Hz, 3H).

[0641] Example 11: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-isopropyl-1,4-oxazetane-2-carboxamide (compound 12)

[0642]

[0643] A solution of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidinyl heptane-2-carboxamide (100 mg, 0.23 mmol, 1.0 equivalent) in THF (3 mL) was treated with acetone (41 mg, 0.71 mmol, 3.0 equivalent) and HOAc (0.1 mL). The mixture was stirred at room temperature for 1 hour. NaBH(OAc)3 (100 mg, 0.47 mmol, 2.0 equivalent) was then added in portions at room temperature. The resulting mixture was stirred at room temperature for another 1 hour. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 minutes; detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-isopropyl-1,4-oxazetane-2-carboxamide (20.0 mg, 18%) as a white solid. LCMS (ES, m / z): [M+H] + : 463.2. 1 HNMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.5 Hz, 1H), 7.67 – 7.62 (m, 2H), 7.56 (t, J = 1.2 Hz, 1H), 7.41 – 7.36 (m, 4H), 5.06 – 4.99 (m, 1H), 4.00 (dd, J =6.9, 3.2 Hz, 1H), 3.87 – 3.67 (m, 2H), 3.41 (s, 3H), 3.28 – 3.14 (m, 2H), 2.81 – 2.67 (m, 2H), 2.62 – 2.55 (m, 1H), 2.48 – 2.39 (m, 2H), 1.79 – 1.65(m, 2H), 0.80 (dd, J = 19.4, 6.5 Hz, 6H).

[0644] Example 12: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-propyl-1,4-oxazetane-2-carboxamide (compound 13)

[0645]

[0646] At room temperature, iodopropane (49 mg, 0.29 mmol, 1.2 equivalent) was added dropwise to a stirred mixture of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidinyl heptane-2-carboxamide (100 mg, 0.24 mmol, 1.0 equivalent) and K2CO3 (99 mg, 0.71 mmol, 3.0 equivalent) in ACN (3 mL). The resulting mixture was stirred at 60 °C for 3 h. The mixture was filtered, and the filtrate was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yields (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-propyl-1,4-oxazetane-2-carboxamide (20 mg, 18%) as a white solid. LCMS (ES, m / z): [M+H] + : 463.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.5 Hz, 1H), 7.69– 7.63 (m, 2H), 7.58 (t, J = 1.2 Hz, 1H), 7.45 – 7.36 (m, 4H), 5.06 – 5.00(m, 1H), 4.09 (dd, J = 7.8, 3.1 Hz, 1H), 3.86 – 3.69 (m, 2H), 3.41 (s, 3H), 3.28 – 3.13 (m, 2H), 2.83 (dd, J = 14.1, 3.2 Hz, 1H), 2.70 – 2.59 (m, 1H),2.49 – 2.39 (m, 2H), 2.37 – 2.23 (m, 2H), 1.83 – 1.72 (m, 2H), 1.34 – 1.19(m, 2H), 0.73 (t, J = 7.3 Hz, 3H).

[0647] Example 13: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-(oxetane-3-yl)-1,4-oxazetane-2-carboxamide (compound 14)

[0648]

[0649] A solution of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidinyl heptane-2-carboxamide (100 mg, 0.23 mmol, 1.0 equivalent) in THF (3 mL) was treated with 3-oxazolidinyl ketone (51 mg, 0.71 mmol, 3.0 equivalent) and HOAc (0.1 mL). The mixture was stirred at room temperature for 1 h, followed by the addition of NaBH(OAc)3 (100 mg, 0.47 mmol, 2.0 equivalent) in portions at room temperature. The resulting mixture was stirred at room temperature for another 1 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-(oxetane-3-yl)-1,4-oxazolidinyl-heptane-2-carboxamide (17.3 mg, 15.3%) as a white solid. LCMS (ES, m / z): [M+H] + : 477.3. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.5 Hz, 1H), 7.70 –7.63 (m, 2H), 7.57 (t, J = 1.2 Hz, 1H), 7.46 – 7.37 (m, 4H), 5.10 – 5.00 (m,1H), 4.51 – 4.35 (m, 2H), 4.30 – 4.20 (m, 2H), 4.15 – 4.14 (m, 1H), 3.86 –3.74 (m, 2H), 3.60 – 3.54 (m, 1H), 3.41 (s, 3H), 3.24 – 3.20 (m, 2H), 2.74(d, J = 14.2 Hz, 1H), 2.39 – 2.30 (m, 3H), 1.81 –1.73 (m, 2H).

[0650] Example 14: Synthesis of (2S)-4-acetyl-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazheptan-2-carboxamide (compound 16)

[0651]

[0652] Acetyl chloride (25 mg, 0.31 mmol, 1.2 equivalent) was added dropwise to a stirred solution of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidinyl heptane-2-carboxamide (110 mg, 0.26 mmol, 1.0 equivalent) and TEA (79 mg, 0.78 mmol, 3.0 equivalent) in DCM (3 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (20 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S)-4-acetyl-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazheptan-2-carboxamide (17.3 mg, 14%) as a white solid. LCMS (ES, m / z): [M+H] + : 463.2. 1 H NMR (400MHz, DMSO-d6) δ 8.87-8.76 (m, 1H), 7.70 – 7.64 (m, 2H), 7.59 (dd, J = 4.6,1.6 Hz, 1H), 7.46 – 7.36 (m, 4H), 5.04 (dq, J = 12.5, 8.2 Hz, 1H), 4.35 –3.77 (m, 3H), 3.76 – 3.50 (m, 2H), 3.41 (d, J = 1.4 Hz, 3H), 3.33 – 2.89 (m,4H), 2.04-1.86 (m, 3H), 1.86 –1.71 (m, 2H).

[0653] Example 15: Synthesis of (1R,3S,4S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-2-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide (compound 17)

[0654] Step 1.2 Synthesis of methyl {[(1R)-1-phenylethyl]imino}acetate

[0655]

[0656] A solution of methyl 2-hydroxy-2-methoxyacetate (8 g, 66.61 mmol, 1.0 equivalent) and D-α-methylbenzylamine (8.07 g, 66.61 mmol, 1.0 equivalent) in DCM (80 mL) was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction was quenched with water (80 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was concentrated to remove the solvent, yielding methyl 2-{[(1R)-1-phenylethyl]imino}acetate (10 g, 78.5%) as a colorless oil, which could be used in the next step without further purification. LCMS (ES, m / z): [M+H] + : 192.

[0657] Step 2. Synthesis of methyl (1S,3R,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

[0658]

[0659] Under a nitrogen atmosphere at -78°C, TFA (3.58 g, 31.38 mmol, 1.0 equivalent) and BF3 were added dropwise to a solution of methyl 2-{[(1R)-1-phenylethyl]imino}acetate (6 g, 31.37 mmol, 1.0 equivalent) and cyclopentadiene (2.49 g, 37.65 mmol, 1.2 equivalent) in DCM (60 mL). . Et₂O (4.68 g, 32.95 mmol, 1.05 equivalents). After addition, the mixture was slowly heated to room temperature and stirred for 1 h. The reaction was quenched with water (20 mL), the pH was adjusted to 9-10 with 20% Na₂CO₃ aqueous solution, and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (3 x 60 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give methyl (1S,3R,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (2.6 g, 32%) as a yellow oil. LCMS (ES, m / z): [M+H] + : 258.

[0660] Step 3. Synthesis of (1R,3R,4S)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl-3-methyl ester

[0661]

[0662] Under a nitrogen atmosphere, Pd(OH)₂ / C (20% wt, 60 mg) was added to a solution of (1S,3R,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-5-en-3-carboxylic acid methyl ester (300 mg, 1.17 mmol, 1.0 equivalent) and Boc₂O (305 mg, 1.40 mmol, 1.2 equivalent) in MeOH (5 mL). The mixture was hydrogenated at room temperature and stirred under a hydrogen atmosphere for 16 h. The mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure to give (1R,3R,4S)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl-3-methyl ester (230 mg, 77%) as a light-colored oil, which could be used in the next step without further purification. LCMS (ES, m / z): [M+H] + : 256.

[0663] Step 4. Synthesis of (1R,3R,4S)-3-{[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0664]

[0665] At 0 °C, LiOH (594 mg, 1.91 mmol, 2.0 equivalent) was added to a solution of (1R,3R,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (230 mg, 0.95 mmol, 1.0 equivalent) in THF (2 mL) and H₂O (0.5 mL). The mixture was stirred for 15 min, then warmed to room temperature and stirred for 16 h. The mixture was acidified to pH 3–4 with HCl (1 N). The reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic phases were washed with 10% NaCl aqueous solution (3 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded a white, foamy solid of (1R,3R,4S)-3-{[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (210 mg, 41%). LCMS (ES, m / z): [M+H + : 242.

[0666] Step 5. Synthesis of (1R,3S,4S)-3-{[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0667]

[0668] At 0 °C, a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (210 mg, 0.87 mmol, 1.0 equivalence) in DCM (4 mL) was treated with (2S)-2-amino-3-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionitrile (298 mg, 0.96 mmol, 1.1 equivalence), DIEA (225 mg, 1.74 mmol, 2.0 equivalence), followed by fractional addition of HATU (397 mg, 1.04 mmol, 1.2 equivalence). oThe resulting mixture was stirred at C for another 3 hours. The mixture was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography, eluting with PE / THF (1:1), to give (1R,3S,4S)-3-{[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (250 mg, 53.7%) as a white solid. LCMS (ES, m / z): [M+H] + : 535.

[0669] Step 6. Synthesis of (1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0670]

[0671] At room temperature, add (1R,3S,4S)-3-{[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (250 mg, 0.47 mmol, 1.0 equivalent) and TsOH to a 25 mL round-bottom flask. . H2O (267 mg, 1.40 mmol, 3.0 equivalent) and ACN (5 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with EA (20 mL). The mixture was alkalized to pH 8-9 with saturated NaHCO3. The aqueous layer was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. This gave (1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide (200 mg, 98%) as a white, foamy solid. LCMS (ES, m / z): [M+H] + : 435.

[0672] Step 7. Synthesis of (1R,3S,4S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-2-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0673]

[0674] A solution of (1R,3R,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide (100 mg, 0.23 mmol, 1.0 equivalent) and formaldehyde (0.15 g, 0.35 mmol, 1.5 equivalent, 30% in water) in THF (2 mL) was treated with sodium bis(acetoxy)borylacetic acid (0.15 g, 0.69 mmol, 3.0 equivalent). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN aqueous solution (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (1R,3S,4S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-2-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide (50 mg, 48%) as a white solid. LCMS (ES, m / z): [M+H] + : 449.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.5 Hz, 1H), 7.65 (d, J =1.9 Hz, 1H), 7.63 – 7.52 (m, 2H), 7.51 – 7.37 (m, 3H), 5.03 (q, J = 8.2 Hz,1H), 3.41 (s, 3H), 3.31 – 3.27 (m, 2H), 3.21 – 3.14 (m, 1H), 2.28 (s, 1H), 2.20 (s, 3H), 2.19 – 2.17 (m, 1H), 1.85 – 1.78 (m, 1H), 1.61 – 1.48 (m, 1H),1.32 – 1.21 (m, 3H), 1.05 (d, J = 9.5 Hz, 1H).

[0675] Example 16: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-ethyl-1,4-oxazetane-2-carboxamide (compound 18)

[0676] Step 1. Synthesis of (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazolidine-4-carboxylic acid tert-butyl ester

[0677]

[0678] DIEA (179 mg, 1.39 mmol, 3.0 equivalent) and HATU (211 mg, 0.55 mmol, 1.2 equivalent) were added in portions to a stirred mixture of (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionitrile (149 mg, 0.51 mmol, 1.1 equivalent) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazolidine-2-carboxylic acid (120 mg, 0.46 mmol, 1.0 equivalent) in DCM (3 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure at room temperature. The residue was purified by silica gel column chromatography, eluting with 10% to 70% ethyl acetate / petroleum ether. This yields (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazolidine-4-carboxylic acid tert-butyl ester (200 mg, 80.84%) as a white solid. LCMS (ES, m / z): [M+H] + : 535.

[0679] Step 2. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidine-2-carboxamide

[0680]

[0681] At room temperature, TsOH was added in portions to a stirred solution of (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazolidine-4-carboxylic acid tert-butyl ester (200 mg, 0.37 mmol, 1.0 equivalent) in ACN (4 mL). .H₂O (193 mg, 1.12 mmol, 3.0 equivalents). The resulting mixture was stirred at room temperature for 2 h. The mixture was alkalized to pH 8 with saturated NaHCO₃ (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product could be used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :435.

[0682] Step 3. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-methyl-1,4-oxazolidine-2-carboxamide

[0683]

[0684] Under a nitrogen atmosphere and at room temperature, HCHO (230 mg, 2.30 mmol, 10.0 equivalent, 30% in water) and HOAc (0.05 mL) were added dropwise to a stirred solution of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazolidine-2-carboxamide (100 mg, 0.23 mmol, 1.0 equivalent) in MeOH (2 mL). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 0.5 h. NaBH(OAc)3 (146 mg, 0.69 mmol, 3.0 equivalent) was added in portions to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 70% gradient over 10 min; detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-methyl-1,4-oxazolidine-2-carboxamide (20 mg, 19%) as a white solid. LCMS (ES, m / z): [M+H] + : 449.1. 1H NMR (400 MHz, DMSO-d6) δ8.65 (d, J = 8.6 Hz, 1H), 7.70 – 7.62 (m, 2H), 7.57 (t, J = 1.2 Hz, 1H), 7.45– 7.35 (m, 4H), 5.06 – 4.99 (m, 1H), 3.99 (dd, J = 9.3, 2.6 Hz, 1H), 3.98 –3.90 (m, 1H), 3.76 – 3.70 (m, 1H), 3.41 (s, 3H), 3.28 – 3.13 (m, 2H), 2.73 –2.52 (m, 3H), 2.35 – 2.22 (m, 4H), 1.76 – 1.72 (m, 1H), 1.62 – 1.52 (m, 3H).

[0685] Example 17: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-(methylthio)-1,4-oxazetane-2-carboxamide (compound 20)

[0686] Step 1. Synthesis of (2S)-6-oxo-1,4-oxazacycloheptan-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester

[0687]

[0688] K₂CO₃ (1.17 g, 8.486 mmol, 2.0 equivalent) was added to a stirred solution of (2S)-4-(tert-butoxycarbonyl)-6-oxo-1,4-oxazetane-2-carboxylic acid (1.1 g, 4.243 mmol, 1.0 equivalent) and BnBr (1.09 g, 6.365 mmol, 1.5 equivalent) in DMF (15 mL). The resulting mixture was stirred at 80 °C for 3 hours. The mixture was then cooled to room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give a colorless oil, (2S)-6-oxo-1,4-oxazetane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester (1.1 g, 74.20%). LCMS (ES) [M+H-56] + m / z:294.

[0689] Step 2. Synthesis of (2S)-6-hydroxy-1,4-oxazacycloheptane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester

[0690]

[0691] NaBH4 (95 mg, 2.518 mmol, 0.8 equivalent) was added in portions to a stirred solution of (2S)-6-oxo-1,4-oxazetane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester (1.1 g, 3.148 mmol, 1.0 equivalent) in THF (20 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. The reaction was quenched at 0 °C by adding water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give a colorless oil, (2S)-6-hydroxy-1,4-oxazacycloheptane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester (800 mg, 72.31%). LCMS (ES) [M+H] + m / z:352.

[0692] Step 3. Synthesis of (2S)-6-(methanesulfonyloxy)-1,4-oxazacycloheptane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester

[0693]

[0694] DMAP (20 mg, 0.171 mmol, 0.1 equivalent) was added to a stirred solution of (2S)-6-hydroxy-1,4-oxazacycloheptane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester (600 mg, 1.707 mmol, 1.0 equivalent) and pyridine (405 mg, 5.121 mmol, 3.0 equivalent) in DCM (10 mL). A solution of methanesulfonic anhydride (446 mg, 2.561 mmol, 1.5 equivalent) in DCM (2 mL) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The resulting mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2S)-6-(methanesulfonyloxy)-1,4-oxazacycloheptane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester (600 mg) can be used directly in the next step without further purification. LCMS (ES) [M+H]+ m / z:430.

[0695] Step 4. Synthesis of 4-(tert-butoxycarbonyl)-6-(methylthio)-1,4-oxazacycloheptane-2-carboxylic acid

[0696]

[0697] At 0 °C, sodium (methylthio) (244 mg, 3.492 mmol, 3.0 equivalent) was added in portions to a stirred solution of (2S)-6-(methanesulfonyloxy)-1,4-oxazacycloheptane-2,4-dicarboxylic acid 2-benzyl-4-tert-butyl ester (500 mg, 1.164 mmol, 1.0 equivalent) in DMF (10 mL). The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was extracted with EtOAc (3 x 20 mL). The aqueous layer was acidified to pH 6 with citric acid. The resulting mixture was extracted with CH2Cl2 (4 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 4-(tert-butoxycarbonyl)-6-(methylthio)-1,4-oxazacycloheptan-2-carboxylic acid (200 mg, 58.96%), a pale yellow oil. LCMS (ES) [M+H] + m / z:292.

[0698] Step 5.2 Synthesis of {[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0699]

[0700] Under a nitrogen atmosphere, at 0 °C, DIEA (132 mg, 1.023 mmol, 3.0 equivalent) and T3P (216 mg, 0.682 mmol, 2.0 equivalent) were added dropwise to a stirred solution of 4-(tert-butoxycarbonyl)-6-(methylthio)-1,4-oxazacycloheptane-2-carboxylic acid (148 mg, 0.512 mmol, 1.5 equivalent) and (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionitrile (100 mg, 0.341 mmol, 1.0 equivalent) in DMF (2 mL). The resulting mixture was stirred at 0 °C for 3 h. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give tert-butyl 2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-(methylthio)-1,4-oxazolidinyl heptane-4-carboxylate (120 mg, 62.12%), a pale yellow solid. LCMS (ES) [M+H] + m / z:567.

[0701] Step 6. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-(methylthio)-1,4-oxazetane-2-carboxamide

[0702]

[0703] TsOH (109 mg, 0.636 mmol, 3.0 equivalent) was added to a stirred solution of 2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 0.212 mmol, 1.0 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 3 h. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yields (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methylthio-1,4-oxazheptan-2-carboxamide (30 mg, 30.36%), which is a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.64(t, J = 7.7 Hz, 1H), 7.71 – 7.61 (m, 2H), 7.58 (d, J = 4.9 Hz, 1H), 7.47 –7.35 (m, 4H), 5.12 – 4.91 (m, 1H), 4.13 – 3.90 (m, 2H), 3.86 – 3.53 (m, 1H), 3.41 (s, 3H), 3.30 – 3.08 (m, 3H), 3.13 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.50 (m, 1H), 2.50 – 2.29 (m, 1H), 2.08 (t, J = 4.1 Hz, 3H). LCMS (ES)[M+H] + m / z:467.

[0704] Example 18: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-ethyl-1,4-oxazolylheptane-2-carboxamide (compound 21) and (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-ethyl-1,4-oxazolylheptane-2-carboxamide (compound 22)

[0705] Step 1. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazetane-4-carboxylate

[0706]

[0707] At room temperature, tert-butyl (2S)-2-[(benzyloxy)methyl]-6-oxo-1,4-oxazetane-4-carboxylate (1 equivalent, 1.6 g, 4.77 mmol) in EtOH (23.85 mL) was added with NaBH4 (2 equivalents, 0.36 g, 9.54 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated NH4Cl (30 mL) solution and then diluted with EtOAc (100 mL) and water (70 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (2S)-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazetane-4-carboxylate (1.66 g, 100%, crude) as a colorless oil. The crude product was used as is in the next step. LC / MS: room temperature = 1.49 min, 100%, [M- t Bu+H] + = 282.1.

[0708] Step 2. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methanesulfonyloxy)-1,4-oxazetane-4-carboxylate

[0709]

[0710] At 0 °C, tert-butyl methanesulfonyl chloride (1.2 equivalent, 1.059 g, 0.72 mL, 9.25 mmol) was added to a solution of (2S)-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazacycloheptane-4-carboxylic acid (1 equivalent, 2.6 g, 7.706 mmol) and Et3N (2 equivalent, 1.56 g, 2.14 mL, 15.41 mmol) in DCM (38.53 mL). The reaction mixture was stirred at room temperature for 2 h. RM was diluted with DCM (200 mL) and water (200 mL). The aqueous layer was extracted with DCM (2 x 200 mL), and the combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give (2S)-2-[(benzyloxy)methyl]-6-(methanesulfonyloxy)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (3.4 g, 100%, crude) as a yellow oil. The crude product was used as is in the next step. LC / MS: room temperature = 1.61 min, 89.39%, [M⁻¹] t Bu+H] + = 360.1.

[0711] Step 3. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methylthio)-1,4-oxazetane-4-carboxylate

[0712]

[0713] At room temperature, NaSMe (3 equivalents, 1.57 g, 22.38 mmol) was added to a solution of (2S)-2-[(benzyloxy)methyl]-6-(methanesulfonyloxy)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1 equivalent, 3.1 g, 7.46 mmol) in DMF (37.304 mL). The reaction mixture was stirred at 60 °C for 4 h. The RM was diluted with EtOAc (200 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL), and the combined organic layers were washed with brine (3 x 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude substance (2.72 g) as a yellow oil. The crude product was purified by silica gel rapid chromatography (50 µm, 80 g, cyclohexane / EtOAc, 100:0 to 75:25, 35 min) to give (2S)-2-[(benzyloxy)methyl]-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (2.08 g, 76%) as a colorless oil. LC / MS: room temperature = 1.61 min, 62.68%, [M- t Bu+H]+ = 312.1.

[0714] Step 4. Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-6-(methylthio)-1,4-oxazetane-4-carboxylate

[0715]

[0716] Step a: At -78°C, a solution of 1 M BCl3 in DCM (5 equivalents, 6.80 mL, 6.80 mmol) was added to a solution of (2S)-2-[(benzyloxy)methyl]-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1 equivalent, 500 mg, 1.36 mmol) in DCM (7 mL). The reaction mixture was stirred at -78°C for 6 h. The reaction mixture was quenched with MeOH (10 mL) and then concentrated under reduced pressure to give a crude product (291 mg) as a colorless gel. The crude product was used as is in the next step (Step b).

[0717] Step b: A solution of Boc2O (1 equivalent, 285 mg, 1.33 mmol) was added to a solution of crude material (1 equivalent, 285 mg, 1.33 mmol) and Et3N (3 equivalent, 0.56 mL, 4.00 mmol) in DCM (3 mL) and MeOH (3 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness under reduced pressure to give crude material (205 mg) as a pale yellow oil. The crude product was purified by silica gel rapid chromatography (50 µm, 12 g Interchim, dry loading (silica), mobile phase gradient: cyclohexane / EtOAc from 100 / 0 to 50 / 50, 50 min) to give tert-butyl (2S)-2-(hydroxymethyl)-6-(methylthio)-1,4-oxazetane-4-carboxylate (71.6 mg, 19%, in two steps) as a colorless oil. LCMS: Poor UV activity, room temperature = 1.29 min, 85%, [M- t Bu+H] + = 222.1.

[0718] Step 5. Synthesis of (2S)-4-[(tert-butoxy)carbonyl]-6-(methylthio)-1,4-oxazacycloheptane-2-carboxylic acid and (2S)-4-[(tert-butoxy)carbonyl]-6-methylsulfinyl-1,4-oxazacycloheptane-2-carboxylic acid

[0719]

[0720] At room temperature, 2,2,6,6-tetramethylpiperidinoxy (0.2 equivalents, 5.63 mg, 0.036 mmol) and diacetate iodobenzene (2.5 equivalents, 145.15 mg, 0.45 mmol) were added to a solution of (2S)-2-(hydroxymethyl)-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1 equivalent, 50 mg, 0.18 mmol) in H₂O (0.45 mL) and DCM (0.45 mL). The reaction mixture was stirred at room temperature for 1 h. DCM (25 mL) and a solution of 1 M HCl in H₂O (25 mL) were added. The two phases were separated, and the aqueous layer was washed with DCM (2 x 25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give a mixture (41 mg, 76%) of (2S)-4-[(tert-butoxy)carbonyl]-6-(methylthio)-1,4-oxazacycloheptane-2-carboxylic acid and (2S)-4-[(tert-butoxy)carbonyl]-6-methylsulfinyl-1,4-oxazacycloheptane-2-carboxylic acid as a white solid. The crude product was used as is in the next coupling step. LCMS: Non-UV active compound, (2S)-4-[(tert-butoxy)carbonyl]-6-(methylthio)-1,4-oxazacycloheptane-2-carboxylic acid: room temperature = 1.37 min, ND, [M- t Bu+H] + =236.1, and (2S)-4-[(tert-butoxy)carbonyl]-6-methylsulfinyl-1,4-oxazacycloheptane-2-carboxylic acid: room temperature = 1.20 min, ND, [M- t Bu+H] + = 252.1.

[0721] Step 6. Synthesis of (2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester and (2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylsulfinyl)-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0722]

[0723] DIPEA (2.5 equivalents) and TBTU (1.5 equivalents) were added to a solution of (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propionitrile (1 equivalent, 37.7 mg, 0.11 mmol) in anhydrous DMF (7.14 mL / mmol amine) and a mixture of (2S)-4-[(tert-butoxy)carbonyl]-6-(methylthio)-1,4-oxazacycloheptane-2-carboxylic acid and (2S)-4-[(tert-butoxy)carbonyl]-6-methylsulfinyl-1,4-oxazacycloheptane-2-carboxylic acid (1.05 equivalents, 35.0 mg, 0.12 mmol) under an argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL), and the combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel rapid chromatography (50 µm, 12 g, cyclohexane / EtOAc from 10:0 to 0:10 over 85 min, then DCM / MeOH from 100:0 to 90:10 over 25 min), a light orange solid (2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylsulfinyl)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (12 mg, 19%) and (2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylsulfinyl)-1,4-oxazolidinyl heptane-4-carboxylate (15 mg, 23%). LC / MS: (2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylthio)-1,4-oxazolidinyl heptane-4-carboxylate: room temperature = 1.66 min, 84%, [M- t Bu+H] + = 511.2, and (2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylsulfinyl)-1,4-oxazetane-4-carboxylate: room temperature = 1.42 min, 100, [M- t Bu+H] + = 527.2.

[0724] Step 7. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-(methylthio)-1,4-oxazetane-2-carboxamide

[0725]

[0726] Add formic acid (7.6 mL / mmol), also preheated at 50°C, to a preheated vial (50°C) containing tert-butyl (1 equivalent, 12.0 mg, 0.021 mmol) cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1 equivalent, 12.0 mg, 0.021 mmol). Stir the reaction mixture at 50°C for 15 minutes. Cool the reaction mixture to room temperature and add dropwise to a cooled (0°C) mixture of stirred saturated NaHCO3 aqueous solution (40 mL) and DCM (40 mL). Separate the layers and extract the aqueous layer with DCM (2 x 40 mL). Dry the combined organic layers with Na2SO4, filter, and concentrate under reduced pressure. After purification by silica gel rapid chromatography (15 µm, 4 g, DCM / MeOH (from 100:0 to 95:5 within 35 min), a mixture of diastereomers of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-(methylthio)-1,4-oxazetane-2-carboxamide (4.30 mg, 44%) was obtained as a white solid. The diastereomer ratio was determined to be 55:45 by LC / MS. LC / MS: room temperature = 4.83 min, 53.60%, [M+H] + = 467.43 & room temperature = 4.88 min, 43.92%, [M+H] + = 467.38. 1H NMR (400 MHz, DMSO) δ 8.64 (d, J = 8.5 Hz, 1H), 7.69– 7.62 (m, 2H), 7.59 – 7.54 (m, 1H), 7.45 – 7.35 (m, 4H), 5.09 – 4.97 (m,1H), 4.07 – 3.95 (m, 2H), 3.75 – 3.56 (m, 1H), 3.40 (s, 3H), 3.27 – 3.07 (m,3H), 3.07 – 2.94 (m, 1H), 2.91 – 2.82 (m, 1H), 2.65 – 2.57 (m, 1H), 2.44 –2.33 (m, 1H), 2.15 – 2.05 (m, 3H), one missing proton (NH).

[0727] Step 8. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methanesulfinyl-1,4-oxazetane-2-carboxamide

[0728]

[0729] Starting with (2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methylsulfinyl)-1,4-oxazolidinyl heptane-4-carboxylate (1 equivalent, 15.0 mg, 0.026 mmol) and using the procedure of step 7 above, after purification by silica gel rapid chromatography (15 µm, 4 g, DCM / MeOH (from 100:0 to 92:8 within 40 minutes), a white solid (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl)phenyl]ethyl]-6-methylsulfinyl)-1,4-oxazolidinyl heptane-2-carboxamide (6.20 mg) was obtained. mg, 50%). (Through) 1 The diastereomer ratio was determined to be 28:32:20:20 by 1H NMR. LC / MS: room temperature = 4.53 min, 97.12%, [M+H] + = 483.37. 1H NMR (400 MHz, DMSO) δ 8.79 – 8.52(m, 1H), 7.73 – 7.63 (m, 2H), 7.60 – 7.55 (m, 1H), 7.45 – 7.35 (m, 4H), 5.08– 4.94 (m, 1H), 4.21 – 3.92 (m, 2H), 3.40 (s, 3H), 3.25 – 2.75 (m, 6H), 2.62 – 2.54 (m, 3H), 2.45 – 2.35 (m, 2H), one missing proton (NH).

[0730] Example 19: Synthesis of compound 23A (a mixture of two diastereomers) and compound 23B (a mixture of two diastereomers)

[0731] Step 1. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-methylsulfinyl-1,4-oxazetane-4-carboxylate

[0732]

[0733] At 0 °C, m-CPBA (0.9 equivalents, 274.41 mg, 0.49 mL, 1.22 mmol) was added to a solution of (2S)-2-[(benzyloxy)methyl]-6-(methylthio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1 equivalent, 500 mg, 1.36 mmol) in DCM (6.604 mL). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with 10% K2CO3 aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness to give a crude product (506 mg) as a yellow oil. The crude product was purified by rapid SiO2 chromatography (50 µm, 40 g, DCM / MeOH 100:0 to 94:06 over 35 minutes) to obtain a colorless oily substance, (2S)-2-[(benzyloxy)methyl]-6-methylsulfinyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (344 mg, 66%). LC / MS: room temperature = 1.44 min, 100%, [M- t Bu+H] + = 328.1.

[0734] Step 2. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ6-thio)-1,4-oxazacycloheptan-4-carboxylate

[0735]

[0736] At room temperature, tert-butyl carbamate (2 equivalents, 476.53 mg, 4.068 mmol), magnesium oxide (4 equivalents, 327.9 mg, 0.092 mL, 8.14 mmol), iodobenzene diacetate (1.5 equivalents, 982.67 mg, 3.051 mmol), and rhodium acetate (0.05 equivalents, 44.95 mg, 0.102 mmol) were added to a solution of (2S)-2-[(benzyloxy)methyl]-6-methanesulfinyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1 equivalent, 780 mg, 2.034 mmol) in DCM (10 mL). The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to obtain a crude substance (1.77 g) that was a yellow oil. The crude product was purified by rapid SiO₂ chromatography (50 µm, 80 g, cyclohexane / EtOAc 100:0 to 50:50 over 50 minutes) to obtain a colorless oil, (2S)-2-[(benzyloxy)methyl]-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ6-thio)-1,4-oxazetane-4-carboxylic acid tert-butyl ester (763 mg, 75%). LC / MS: room temperature = 1.44 min, 100%, [M-Boc+H₂] + = 399.2.

[0737] Step 3. (2S)-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ 6 Synthesis of tert-butyl thio(2-thio)-2-(hydroxymethyl)-1,4-oxazine-heptane-4-carboxylate

[0738]

[0739] At room temperature, 10% Pd / C (0.1 equivalents) was added to an argon-purged solution of (2S)-2-[(benzyloxy)methyl]-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ6-thio)-1,4-oxazacycloheptan-4-carboxylate (1 equivalent, 760 mg, 1.76 mmol) in EtOH (4.78 mL / mmol protected alcohol). The resulting mixture was purged with argon (x3) and then with H2 (3x). The reaction mixture was stirred for 18 h at room temperature and atmospheric pressure of H2. The reaction mixture was purged with argon, filtered on a diatomaceous earth mat, and washed with EtOH (3x5 mL). The filtrate was concentrated under reduced pressure to give a colorless oil of (2S)-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ6-thio) 6 tert-butyl 2-(hydroxymethyl)-1,4-oxazetane-4-carboxylate (533 mg, 77%). LC / MS: UV-free, room temperature = 1.33 min, ND, [M-Boc+H] + = 309.1.

[0740] Step 4. (2S)-4-[(tert-butoxy)carbonyl]-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ 6 Synthesis of (-thio)-1,4-oxazacycloheptan-2-carboxylic acid

[0741]

[0742] At 0°C, (2S)-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ 6 tert-butyl 2-(tert-butoxy)-2-(hydroxymethyl)-1,4-oxazetane-4-carboxylate (1 equivalent, 350 mg, 0.86 mmol) was added to a solution of acetone (8.57 mL) with Jones' reagent (2.5 equivalent, 1.071 mL, 2.14 mmol). The solution was stirred at room temperature for 1 h, then isopropanol (10 mL) was added at room temperature, and RM was stirred at room temperature for 30 min. DCM (50 mL) and 1 M HCl (50 mL) were added. The two phases were separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a colorless gel of (2S)-4-[(tert-butoxy)carbonyl]-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ 6 (-Thio)-1,4-oxazetane-2-carboxylic acid (294 mg, 81%). LC / MS: UV-free, room temperature = 1.41 min, ND, [MH]- = 421.4.

[0743] Step 5. (2S)-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ 6 Synthesis of tert-butyl 1-(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazolidinyl-4-carboxylate

[0744]

[0745] At room temperature and under an argon atmosphere, a solution of (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propionitrile (1 equivalent, 216 mg, 0.65 mmol) in anhydrous DMF (7.14 mL / mmol amine) and (2S)-4-[(tert-butoxy)carbonyl]-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ 6 (-thio)-1,4-oxazacycloheptan-2-carboxylic acid (1.05 equivalence, 290 mg, 0.69 mmol) was supplemented with DIPEA (2.5 equivalence) and TBTU (1.5 equivalence). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL), and the combined organic layers were washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel rapid chromatography (50 µm, 24 g, cyclohexane / EtOAc, 100:0 to 25:75 over 45 min), a white solid (2S)-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ) was obtained. 6 (-Thio)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazolidinyl heptane-4-carboxylic acid tert-butyl ester (305 mg, 67%). LC / MS: room temperature = 2.61 min, 73%, [M-Boc+H] + = 598.3.

[0746] Step 6. Synthesis of Compound 23A and Compound 23B

[0747]

[0748] To contain (2S)-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ 6 (-thio)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazolidinyl heptane-4-carboxylate tert-butyl ester (1 equivalent, 100 mg, 0.14 mmol) was added to a preheated vial (50 °C) containing formic acid (7.6 mL / mmol), also preheated at 50 °C. The reaction mixture was stirred at 50 °C for 15 min. The reaction mixture was cooled to room temperature and added dropwise to a cooled (0 °C) mixture of a stirred saturated aqueous solution of NaHCO3 (40 mL) and DCM (40 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. After purification by silica gel rapid chromatography (4 g, DCM / MeOH (from 100:0 to 91:09 within 50 minutes)), a mixture of compounds 25 and 26 as white solids and a mixture of compounds 23 and 24 (9.5 mg, 13%) and (12.5 mg, 18%) were obtained. The two pairs of diastereomers and stereochemistry have been arbitrarily designated.

[0749] A mixture of two diastereomers (compound 23A – arbitrarily designated (2S,6R*)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-[(R)*-imino(methyl)oxo-λ) 6 [-thio]-1,4-oxazetane-2-carboxamide and (2S,6S*)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-[(S)*-imino(methyl)oxo-λ 6 [-Thio]-1,4-oxazetane-2-carboxamide. LC / MS: room temperature = 4.54 and 4.56 min, 39.79 and 56.49%, [M+H] + = 498.34. 1H NMR (400 MHz, DMSO) δ 8.77 – 8.69 (m, 1H), 7.70 –7.61 (m, 2H), 7.61 – 7.55 (m, 1H), 7.46 – 7.36 (m, 4H), 5.08 – 4.97 (m, 1H), 4.23 (dd, J = 13.0, 5.2 Hz, 1H), 4.13 – 3.98 (m, 2H), 3.71 – 3.59 (m, 1H), 3.40 (s, 3H), 3.37 – 3.33 (m, 1H), 3.26 – 3.09 (m, 3H), 2.96 (dd, J = 14.3,5.3 Hz, 1H), 2.92 – 2.81 (m, 3H), 2.46 – 2.37 (m, 2H).

[0750] A mixture of two diastereomers (compound 23B – arbitrarily designated (2S,6R*)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-[(S)*-imino(methyl)oxo-λ) 6 [-thio]-1,4-oxazetane-2-carboxamide and (2S,6S*)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-[(R)*-imino(methyl)oxo-λ 6 [-Thio]-1,4-oxazetane-2-carboxamide. LC / MS: room temperature = 4.53 and 4.56 min, 46.10 and 50.12%, [M+H] + = 498.41. 1H NMR (400 MHz, DMSO) δ 8.82 – 8.71 (m, 1H), 7.76 –7.67 (m, 2H), 7.65 – 7.59 (m, 1H), 7.53 – 7.38 (m, 4H), 5.14 – 5.03 (m, 1H),4.54 – 4.42 (m, 1H), 4.16 (dt, J = 13.6, 4.7 Hz, 1H), 4.00 (td, J = 9.2, 3.6Hz, 1H), 3.70 – 3.62 (m, 1H), 3.46 (s, 3H), 3.44 – 3.41 (m, 1H), 3.31 – 3.10(m, 3H), 3.01 – 2.94 (m, 3H), 2.94 – 2.77 (m, 1H), 2.70 – 2.61 (m, 1H), 2.39 – 2.25 (m, 1H).

[0751] Example 20: Synthesis of (2S)-N-{1-cyano-2-[2,8-difluoro-9-(oxetane-3-yl)-6H-benzo[c]chromen-3-yl]ethyl}-4-methyl-1,4-oxazetane-2-carboxamide (compound 25)

[0752]

[0753] To a stirred solution of (2S)-N-{1-cyano-2-[2,8-difluoro-9-(oxetane-3-yl)-6H-benzo[c]chromen-3-yl]ethyl}-1,4-oxazetane-2-carboxamide (100 mg, 0.213 mmol, 1.0 equivalent) and HCHO (63 mg, 2.130 mmol, 10.0 equivalent) in MeOH (2 mL), HOAc (1 mg, 0.021 mmol, 0.1 equivalent) and NaBH(OAc)3 (135 mg, 0.639 mmol, 3.0 equivalent) were added. The resulting mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19*150mm 5µm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded (2S)-N-{1-cyano-2-[2,8-difluoro-9-(oxetane-3-yl)-6H-benzo[c]chromen-3-yl]ethyl}-4-methyl-1,4-oxazetane-2-carboxamide (30 mg, 29.1%) as a white solid. LCMS (ES, m / z): [M+H] + : 484.2. 1 HNMR (300 MHz, DMSO-d6) δ 8.72 (dd, J = 8.5, 3.5 Hz, 1H), 8.02 – 7.89 (m, 2H), 7.18 (d, J = 10.3 Hz, 1H), 6.98 (dd, J = 6.6, 3.2 Hz, 1H), 5.10 (d, J = 2.1Hz, 2H), 5.06 – 4.79 (m, 5H), 4.53 (p, J = 7.9 Hz, 1H), 4.11 (ddd, J = 15.0,8.1, 2.9 Hz, 1H), 3.89 – 3.69 (m, 2H), 3.27 – 3.11(m, 2H), 3.05 – 2.74 (m,1H), 2.67 –2.54 (m, 1H), 2.48 – 2.30 (m, 2H), 2.29 –2.15 (m, 3H), 1.88 – 1.73(m, 2H).

[0754] Example 21. Human DPP1 enzyme IC 50 Measurement

[0755] Recombinant human DPP1 enzyme (R&D Systems, Minneapolis, .M.) was first proteolytically processed to its mature form using recombinant human cathepsin L (R&D Systems) in a buffer consisting of 20 mM citrate, 150 mM NaCl, 1 mM EDTA, and 10 mM DTT at pH 4.5. The test sample was applied to activate the human DPP1 enzyme in an assay buffer (25 mM MES, 50 mM NaCl, and 5 mM DTT at pH 6.0) in a total reaction volume of 125 µL. First, 25 µL of the compound in the assay buffer and 5% DMSO were added to 50 µL of activated human DPP1 enzyme at a concentration of 1 ng / µL, and the mixture was pre-incubated at 37 °C for 10 min. Then, 50 µL of 1000 µM H-Gly-Arg-AMC substrate (Bahen; San Torrance, CA) was added to obtain a final substrate concentration of 400 µM and a final DMSO concentration of 1%. Substrate lysis was measured at 37 °C for 90 min, and fluorescence at 350 / 450 nm was measured every 5 min. The DPP1 concentration was interpolated based on its activity relative to a standard curve of activated human recombinant DPP1 enzyme. IC50 values ​​for each compound were calculated via the XLFit (IDBS version 5.3.1.3) add-in to Microsoft Excel, using a four-parameter fitted equation y = {A + [(BA)] / [1 + ((C / x)^D)]}, displayed in XLFit as equation number 205 (4-parameter logistic model or Sigmund dose-response model). Default constraints were applied to each parameter. IC50 is defined as the concentration of a compound that inhibits enzyme activity by 50% compared to the no-compound control.

[0756] The results are provided in Table 1 below. In Table 1, *** indicates the average IC. 50 ≤ 5 nM, ** indicates average IC 50 Within the range of 5-15 nM, and * indicates the average IC. 50 Within the range of ≥ 15 nM, where the annotations are based solely on the mean without taking into account the standard deviation.

[0757] Table 1. Human DPP1 enzyme IC50 50 value

[0758]

[0759] Example 22. DPP1 cell IC 50 Measurement

[0760] HL-60 cells (ATCC; Manassas, VA) were maintained in RPMI-1640 culture medium supplemented with 20% heat-inactivated FBS and 1X antibiotic antifungal agent (Stopfan, Marlborough, MA). The medium was changed every three to four days, and cells were not allowed to exceed 1 x 10⁻⁶ cells / day. 6 Cells / mL. Prior to assay, cells were collected by centrifugation at 500 rcf for 3 min, resuspended in PBS, and counted. Cells were diluted to 5 x 10⁻⁶ cells / mL in PBS. 5 The concentration of live cells / mL was measured and transferred to black 96-well plates, 60 µL per well. The test sample was diluted in PBS with 0.5% DMSO, and 20 µL was added to each well. The compound was pre-incubated with cells for 60 min at 37°C with gentle shaking at 100 rpm in a cell culture incubator maintained at 5% CO2. Then, 20 µL of 500 µM H-Gly-Phe-AFC substrate (MP Biomedical; Soren, Ohio) was added to each well. The plate was returned to the incubator and shaken at 100 rpm for 30 min, after which fluorescence was measured at excitation / emission at 400 / 505 nm. The inhibition rate was calculated from RFU values ​​compared to control wells that received only PBS with 0.5% DMSO. IC50 values ​​for each compound were calculated using the XLFit (IDBS version 5.3.1.3) add-in to Microsoft Excel, using a four-parameter fitted equation y = (A + ((BA) / (1 + ((C / x)^D)))), displayed in XLFit as equation number 205 (4-parameter logistic model or Sigmund dose-response model). IC50 is defined as the concentration of a compound that inhibits 50% of enzyme activity compared to the no-compound control.

[0761] The results of the measurements are provided in Table 2 below. In Table 2, *** indicates the average IC50. 50 ≤ 1 nM, ** indicates average IC 50 Within the range of 1-1.5 nM, and * indicates the average IC. 50 Within the range of ≥ 1.5 nM, where the annotation is based solely on the mean without taking into account the standard deviation.

[0762] Table 2. IC50 in DPP1 cells 50 value

[0763]

[0764] Example 23: IC50 assay of mouse DPP1 enzyme

[0765] The test sample was applied to active mouse DPP1 enzyme (R&D Systems, Minneapolis, MN) in assay buffer (50 mM MES, 50 mM NaCl, 5 mM DTT, pH 5.5), with a total reaction volume of 125 μL. First, 25 μL of the compound from the assay buffer and 5% DMSO were added to 50 µL of active mouse DPP1 enzyme at a concentration of 62.5 pg / µL, and the mixture was pre-incubated at 37°C for 10 min. Then, 50 µL of 1000 µM H-Gly-Arg-AMC substrate (Bahen, San Torrance, CA) was added to obtain a final substrate concentration of 400 µM and a final DMSO concentration of 1%. Substrate lysis was measured at 37°C for 90 min, and fluorescence at 350 / 450 nm was measured every 5 min. DPP1 concentrations were interpolated based on their activity relative to a standard curve of recombinant active mouse DPP1 enzyme. IC50 of each compound 50 The values ​​were calculated via the XLFit (IDBS version 5.3.1.3) add-in to Microsoft Excel, using a four-parameter fitted equation y = (A+((BA) / (1+((C / x)^D)))), displayed in XLFit as equation number 205 (4-parameter logical model or Sigmund dose-response model). Default constraints were applied for each parameter. IC 50 Defined as the concentration of a compound that inhibits enzyme activity by 50% compared to a control without the compound.

[0766] The results are provided in Table 3 below. In Table 3, *** indicates the average IC. 50 ≤ 5 nM, ** indicates average IC 50 Within the range of 5-20 nM, and * indicates the average IC. 50 Within the range of ≥ 20 nM, where the annotations are based solely on the mean without taking into account the standard deviation.

[0767] Table 3. Mouse DPP1 enzyme IC50 50 value

[0768]

[0769] The publications discussed herein are provided only for the purpose of disclosing them prior to the filing date of this application. Nothing herein should be construed as an admission that the invention is not entitled to any prior disclosure by means of prior inventions.

[0770] While the invention has been described in conjunction with specific embodiments presented herein, it should be understood that the invention is capable of further modifications, and this application is intended to cover any variations, uses, or modifications of the invention that generally follow the principles of the invention and include such deviations from the disclosure as are known or conventional practices in the field to which this invention pertains, and may be applied to the essential features set forth above and within the scope of the appended claims.

Claims

1. A compound of formula (I): (I)， Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring; R 1 Is it through 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 Substituted heterocycles; R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace; R 3 It is H, halogen, -OH, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, SC 1-6 Alkyl, SOC 1-6 Alkyl or SO2C 1-6 Alkyl; or R 3 Can be used with R 6 Together, they form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally connected by 1, 2, 3, or 4 R atoms. 10 replace; Each R 4 Independently, it is a halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -SC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -CN; Each R 5 Independently, it is C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S (=NH)(O)(C1-C6 alkyl) or heterocyclic rings; R 6 Each of the following can be independently H, halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic; Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups; R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 10 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic; and m is 0, 1, 2, or 3; in: (i) R 1 The heterocycle contains at least one R selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle. 5 Substituted nitrogen atom; (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or (iii) Combinations of (i) and (ii).

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-12 membered monocyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-12 membered polycyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , or ; X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -, where X 2 and X 3 At least one of them is -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; in: (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace; or (iii) Combinations of (i) and (ii); R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl; k is 0 or 1; and g 0, 1, 2 or 3.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace; X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -, where X 2 and X 3 At least one of them is -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl; k is 0 or 1; and g 0, 1, 2 or 3.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , or ; X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -, where X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl; k is 0 or 1; and g 0, 1, 2 or 3.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace; X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -, where X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl; k is 0 or 1; and g 0, 1, 2 or 3.

8. The compound according to any one of claims 4 to 7, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes ,in: (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or (iii) Combinations of (i) and (ii); k is 0 or 1; and g is 2 or 3.

9. The compound according to any one of claims 4 to 6, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes ,in: (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; (ii) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; or (iii) Combinations of (i) and (ii).

10. The compound according to claim 4 or 5, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes And R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl).

11. The compound according to claim 4 or 5, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes And R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl).

12. The compound according to any one of claims 4, 5, and 8 to 11, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace.

13. The compound according to any one of claims 4, 5, and 8 to 12, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 The carbon atom of the heterocycle is selected from an R atom of -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -S (=NH)(O)(C1-C6 alkyl). 5 replace.

14. The compound according to any one of claims 4, 5, and 8 to 13, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 The carbon atom of the heterocyclic ring is selected from an R atom of -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. 5 replace.

15. The compound according to claim 4 or 6, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes , , , , , or ;R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1.

16. The compound according to claim 4 or 6, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes or ;R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1.

17. The compound according to claim 15 or 16, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -CH3, -CF3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2.

18. The compound according to claim 15 or 16, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -C(O)CH3, or .

19. The compound according to any one of claims 15 to 18, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It is an -OC1-C6 alkyl group.

20. The compound according to any one of claims 15 to 19, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein k is 0.

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes , , , , , , , , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 replace.

22. The compound of claim 21 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 Further through 1 R 9 replace.

23. The compound of claim 21 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 Further through 2 R 9 replace.

24. The compound of claim 21 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 Further through 3 R 9 replace.

25. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes , , , , , , , , , , or And R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 replace.

26. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 Further through 1, 2 or 3 R 9 replace.

27. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 Further through 1 R 9 replace.

28. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 Further through 2 R 9 replace.

29. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R1 is further comprising 3 R... 9 replace.

30. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes ;and R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl).

31. The compound of claim 30 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

32. The compound according to claim 30 or 31, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -NHCH3 or -N(CH3)2.

33. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes ; X 2 and X 3 Independently, it is -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -; in: (i) X 2 and X 3 At least one of them is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; or (ii-a) R 1 The carbon atoms of the heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace; (ii-b) -X 4 -R A R is selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl) or -S(=NH)(O)(C1-C6 alkyl). 5 ; (iii) Any combination of (i), (ii-a), and (ii-b); and Where R 1 Optionally further via 1, 2, or 3 R 9 replace; X 4 It is O, S, NH or N (C1-C6 alkyl); R 11 and R 12 Each is independently H, halogen, or -C1-C6 alkyl; R A It is H, -C1-C6 alkyl, -C1-C6 alkylene-carbocycloyl or -C1-C6 alkylene-heteroaryl; and R B It is -C1-C6 alkyl, -C2-C6 alkenyl, -C1-C6 alkylene-carbocycloyl, or -C1-C6 alkylene-heteroaryl; or R A and R B Together they form a heterocyclic group.

34. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-12 membered spiroheterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

35. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

36. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 6-12-membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

37. The compound according to any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 replace; g1 is 0, 1, 2, or 3; g3 is 1, 2, 3, or 4; X 2 Each of these can be independently -O-, -S-, -NH-, -N(C1-C6 alkyl)-, N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -; R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic; R 11 Selected from H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, or halo-OC1-C6 alkyl; and R 12 It is independently H, F, Cl, Br, I or -C1-C6 alkyl.

38. The compound according to any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 replace; g1 is 0, 1, 2, or 3; g3 is 1, 2, 3, or 4; X 2 Each of these can be independently -O-, -S-, -NH-, -N(C1-C6 alkyl)-, N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))-, -N(heterocyclic)-, or -CR 11 R 12 -;and R 11 It is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, or halo-OC1-C6 alkyl; and R 12 It is H, F, Cl, Br, I or -C1-C6 alkyl; in: (i) X 2 At least one of them is -N(C1-C6 alkyl)-, N(C1-C6 haloalkyl)-, -N(C(O)(C1-C6 alkyl))- or -N(heterocyclic)-; or (ii) R 1 The carbon atoms of the fused heterocycle are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 replace.

39. The compound according to any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , or , where R 1 Optionally further via 1, 2, or 3 R 9 replace; X 2 It is -O-, -S-, -NH-, -NR 5 -or-CR 11 R 12 -; R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic; R 11 It is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl or halo-OC1-C6 alkyl; R 12 It is H, F, Cl, Br, I or C1-C6 alkyl; and Each g1 and g2 is independently 0, 1, 2 or 3, and the sum of g1 and g2 is less than or equal to 3.

40. The compound according to any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 Each is independently a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic.

41. The compound according to any one of claims 37, 39 and 40, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is aryl or heteroaryl.

43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is a monocyclic or bicyclic ring.

44. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a single ring, double ring, or triple ring, where R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace.

45. The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a monocyclic carbocyclic, monocyclic aryl, monocyclic heterocyclic, or monocyclic heteroaryl, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace.

46. ​​The compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It can be chosen to pass through 1, 2, 3 or 4 Rs. 6 Substituted phenyl groups.

47. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is phenyl.

48. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IA): (I-A), Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: R 3 It's H.

49. The compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 6 Yes - CN.

50. The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein m is 0.

51. The compound according to any one of claims 48 to 50, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

52. The compound according to any one of claims 48 to 50, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes , , , , , , , , , , , , , , , , , , , , , , or ,in: R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 replace.

53. The compound according to any one of claims 48 to 50, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes ; R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 or -S(=NH)(O)(C1-C6 alkyl); and R 1 Optionally further via 1, 2, or 3 R 9 replace.

54. The compound of claim 53 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

55. The compound according to claim 53 or 54, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -NHCH3 or -N(CH3)2.

56. The compound according to any one of claims 48 to 50, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , , , , or , R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 5 It is a -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1.

57. The compound of claim 56 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

58. The compound according to claim 56 or 57, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It is an -OC1-C6 alkyl group.

59. The compound according to claim 56 or 57, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein k is 0.

60. The compound according to any one of claims 48 to 50, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 Or -S(=NH)(O)(C1-C6 alkyl).

61. The compound of claim 60 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl) or -S(=NH)(O)(C1-C6 alkyl).

62. The compound according to claim 60 or 61, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -SCH3, -S(O)CH3 or -S(=O)(=NH)CH3.

63. The compound according to any one of claims 48 to 50, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

64. The compound according to any one of claims 48 to 50 and 63, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 7-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

65. The compound according to any one of claims 48 to 50, 63 and 64, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein R 1 It is a 5,6-fused heterocycle, a 6,5-fused heterocycle, or a 6,6-fused heterocycle, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

66. The compound according to any one of claims 48 to 50 and 63 to 65, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , , , , , , , , , , , or , where R 1 Choose any route via 1, 2, or 3 Rs 9 Replace; and R 5 It is -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic.

67. The compound according to any one of claims 48 to 50 and 63 to 66, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , where R 1 Choose any route via 1, 2, or 3 Rs 9 Replace; and R 5 It is a C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic.

68. The compound according to claim 66 or 67, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 Is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(O)CH3.

69. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a bicyclic carbocyclic ring, a bicyclic aryl ring, a bicyclic heterocyclic ring, or a bicyclic heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace.

70. The compound of claim 69 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a fused ring or a spiro ring.

71. The compound according to any one of claims 1 to 43, 69 and 70, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 2 yes , , or ; Each X 1a Independently is -NR 6a -、-O-、-CR 13 R 14 -、-C(O)-、-S-、-S(O)- or -S(O)2-; Each R 6a Independently, it is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic; R 13 and R 14 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl; and p is 0, 1, 2 or 3.

72. The compound of claim 71 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 yes ; , or And p is 0 or 1.

73. The compound according to any one of claims 1 to 43, 69 and 70, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein R 2 yes , , or .

74. The compound according to any one of claims 71 to 73, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IB): (I-B); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form; wherein: R 3 It is H; R 6a It is H, C 1-6 Alkyl, C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic; and p is 0.

75. The compound according to claims 69 to 74 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein m is 0 or 1.

76. The compound according to any one of claims 69 to 75, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein at least one R 4 It is halogen.

77. The compound according to any one of claims 71, 72, and 74 to 76, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 6a It is a C1-C6 alkyl group.

78. The compound of claim 77 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 6a It is -CH3.

79. The compound according to any one of claims 78, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

80. The compound according to any one of claims 74 to 79, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 yes , , , , , , , , , , , , , , , , , , , , , , or , where R 1 The carbon atoms of the monocyclic heterocyclic ring are selected from -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -SH, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), and -SO2NR. 7 R 8 or -S(=NH)(O)(C1-C6 alkyl) one of the R 5 Replace; and R 1 Optionally further via 1, 2, or 3 R 9 replace.

81. The compound according to any one of claims 74 to 79, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , , , , , or ; R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1.

82. The compound according to any one of claims 74 to 79, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes or ; R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1.

83. The compound of claim 82 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -CH3, -CF3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2.

84. The compound of claim 82 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -C(O)CH3, or .

85. The compound according to any one of claims 82 to 84, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It is an -OC1-C6 alkyl group.

86. The compound according to any one of claims 82 to 84, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein k is 0.

87. The compound according to any one of claims 74 to 79, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes ; R 5 It is -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), o-SO2NR 7 R 8 or -S(=NH)(O)(C1-C6 alkyl); and R 1 Optionally further via 1, 2, or 3 R 9 replace.

88. The compound of claim 87 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl) or -S(=NH)(O)(C1-C6 alkyl).

89. The compound according to claim 87 or 88, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -SCH3, -S(O)CH3 or -S(=O)(=NH)CH3.

90. The compound according to any one of claims 74 to 79, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-12 membered spiroheterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

91. The compound according to any one of claims 74 to 79, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

92. The compound according to any one of claims 74 to 79, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 1 It is a 6-12-membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, and O, wherein R 1 Heterocyclic rings via 1 or 2 R 5 Replace and optionally further via 1, 2 or 3 R 9 replace.

93. The compound according to any one of claims 74 to 79 and 90, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 , , , , , , , , , , , or , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic.

94. The compound according to any one of claims 74 to 79 and 92, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes , where R 1 Optionally further via 1, 2, or 3 R 9 Replace; and R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl) or heterocyclic.

95. The compound of claim 94 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -CH3, -CF3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2.

96. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is phenyl and R 3 With R 6 One of them, together with ring A, forms a tricycle, wherein the tricycle optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O, and the tricycle optionally passes through 1, 2, 3, or 4 R atoms. 10 replace.

97. The compound according to claims 1 to 43 or 96, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IC): (I-C); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: Ring B is a 5- to 8-membered ring that optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O; p is 0, 1, 2, or 3; and q can be 0, 1, 2 or 3.

98. The compound according to claim 97, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: Tricyclic rings containing ring B are , or ; X 1a Yes -NR 6a -、-O-、-CR 13 R 14 -、-C(O)-、-S-、-S(O)- or -S(O)2-; and R 13 and R 14 Each is independently selected from H, deuterium, halogen, or C. 1-6 alkyl.

99. The compound of claim 97 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein X 1a It is -NH-, -NCH3-, -O-, or -CH2-.

100. The compound according to any one of claims 97 to 99, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the tricyclic ring containing ring B is , , , , , , , or Where m is 0 or 1 and p is 0, 1 or 2.

101. The compound according to any one of claims 97 to 100, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 4 It is independently a halogen, -C1-C3 alkyl, or -CN.

102. The compound according to any one of claims 97 to 101, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 6 Independently, it is a halogen, -OH, -CN, -C1-C3 alkyl, -C1-C3 haloalkyl, -S (C1-C3 alkyl), -SO (C1-C3 alkyl), -SO2 (C1-C3 alkyl), -SO2N (C1-C3 alkyl), -SO2NR 7 R 8 Or 4-6 membered heterocyclic rings.

103. The compound according to any one of claims 97 to 101, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 6 Independently, it is a halogen, -OH, -CN, -SO2CH3, , , or .

104. The compound according to any one of claims 97 to 103, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 1 yes or ; R 9 It includes halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR 7 R 8 -S(=NH)(O)(C1-C6 alkyl), -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocyclic; and k is 0 or 1.

105. The compound of claim 104 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 5 It is -CH3, -CF3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2.

106. The compound according to claim 104 or 405, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It is an -OC1-C6 alkyl group.

107. The compound according to any one of claims 104 to 106, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein k is 0.

108. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (ID): (I-D); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: Ring A is a monocyclic or bicyclic heteroaryl ring; R 3 It is H; and R 6 It is H, C 1-6 Alkyl, C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 Or -(C1-C6 alkylene)-heterocyclic.

109. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IE): (IE); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: R 2 It is a tricyclic carbocyclic ring, a tricyclic aryl ring, a tricyclic heterocyclic ring, or a tricyclic heteroaryl ring, wherein each R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replace; and R 3 It's H.

110. The compound according to any one of claims 1 to 109, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein at least one R 5 Is -SCH3, -S(O)CH3, -S(=O)(=NH)CH3, -OCH3, -OCH2CH3, -OCD3, -OCF3 or -OCHF2.

111. The compound according to any one of claims 1 to 110, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein at least one R 5 It is -SCH3, -S(O)CH3 or -S(=O)(=NH)CH3.

112. The compound according to any one of claims 1 to 109, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein at least one R 5 It is -CH3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(O)CH3, or .

113. The compound according to claim 1 or 48, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , or Or its pharmaceutically acceptable salt or deuterated form.

114. The compound according to claim 1 or 48, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , Or its pharmaceutically acceptable salt or deuterated form.

115. The compound according to claim 1 or 74, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

116. The compound according to claim 1 or 74, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

117. The compound according to claim 1 or 74, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , or Or its pharmaceutically acceptable salt or deuterated form.

118. The compound according to claim 1 or 74, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

119. The compound according to claim 1 or 97, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is Or its pharmaceutically acceptable salt or deuterated form.

120. The compound according to claim 1 or 97, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is Or its pharmaceutically acceptable salt or deuterated form.

121. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

122. A method for treating an airway obstructive disease in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

123. The method of claim 122, wherein the airway obstructive disease is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonia, pulmonary fibrosis, lung transplant complications, vasculitis and thrombotic conditions of the pulmonary vasculature, pulmonary hypertension; antitussive activity, including treatment of chronic cough associated with airway inflammatory and secretory conditions; iatrogenic cough; acute and chronic rhinitis, including drug-induced rhinitis and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including neurogenic rhinitis (hay fever), nasal polyposis; acute viral infections, including the common cold and infections caused by respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

124. The method of claim 123, wherein the airway obstructive disease is asthma.

125. The method of claim 123, wherein the airway obstructive disease is acute respiratory distress syndrome (ARDS).

126. The method of claim 123, wherein the airway obstructive disease is bronchitis.

127. The method of claim 123, wherein the airway obstructive disease is pulmonary fibrosis.

128. The method of claim 123, wherein the airway obstructive disease is emphysema.

129. The method of claim 123, wherein the airway obstructive disease is cystic fibrosis (CF).

130. The method of claim 123, wherein the airway obstructive disease is bronchiectasis.

131. The method of claim 123, wherein the airway obstructive disease is sarcoidosis.

132. The method of claim 123, wherein the airway obstructive disease is α-1 antitrypsin (A1AT) deficiency.

133. The method of claim 123, wherein the airway obstructive disease is farmer's lung.

134. The method of claim 123, wherein the airway obstructive disease is hypersensitivity pneumonia.

135. The method of claim 123, wherein the airway obstructive disease is a lung transplant complication.

136. The method of claim 123, wherein the airway obstructive disease is a vasculitis or thrombotic condition of the pulmonary vasculature.

137. The method of claim 123, wherein the airway obstructive disease is pulmonary hypertension.

138. The method of claim 123, wherein the airway obstructive disease is iatrogenic cough.

139. The method of claim 123, wherein the airway obstructive disease is acute rhinitis.

140. The method of claim 123, wherein the airway obstructive disease is chronic rhinitis.

141. The method of claim 123, wherein the airway obstructive disease is drug-induced rhinitis or vasomotor rhinitis.

142. The method of claim 123, wherein the airway obstructive disease is nasal polyposis.

143. The method of claim 123, wherein the airway obstructive disease is COPD.

144. The method of claim 124, wherein the asthma is bronchial asthma, allergic asthma, endogenous asthma, extrinsic asthma, exercise-induced asthma, or drug-induced asthma.

145. The method of claim 144, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

146. The method of claim 127, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, cryptogenic fibrotic alveolitis, idiopathic interstitial pneumonia, or fibrosis resulting from antitumor therapy or chronic infection.

147. The method of claim 130, wherein the bronchiectasis is noncystic fibrotic bronchiectasis (NCFBE).

148. The method of claim 130, wherein the bronchiectasis is associated with cystic fibrosis.

149. The method of claim 137, wherein the pulmonary hypertension is pulmonary arterial hypertension.

150. The method of claim 137, wherein the pulmonary hypertension is pulmonary hypertension caused by left ventricular disease.

151. The method of claim 137, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

152. A method for treating cystic fibrosis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

153. The method of claim 152, wherein the treatment comprises improving the lung function of the patient compared to the lung function of the patient prior to treatment.

154. The method of claim 153, wherein improving the patient's lung function comprises, compared to corresponding values ​​of the patient before treatment, increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow rate (FEF) between 25% and 75% of FVC. (25-75%) ).

155. The method according to claim 153 or 154, wherein the lung function is measured by spirometry.

156. A method for treating bronchiectasis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

157. The method of claim 156, wherein the bronchodilator is noncystic fibrotic bronchiectasis (NCFBE).

158. The method of claim 156, wherein the bronchiectasis is associated with cystic fibrosis.

159. The method according to any one of claims 156 to 158, wherein the treatment comprises improving the lung function of the patient compared with the lung function of the patient prior to treatment.

160. The method of claim 159, wherein improving the patient's lung function comprises, compared to corresponding values ​​of the patient before treatment, increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow rate (FEF) between 25% and 75% of FVC. (25-75%) ).

161. The method of claim 159 or 160, wherein the lung function is measured by spirometry.

162. The method according to any one of claims 156 to 161, wherein the treatment comprises reducing the rate of lung deterioration compared to the rate of lung deterioration of the patient prior to treatment.

163. The method according to any one of claims 156 to 162, wherein the treatment includes increasing the time before the first lung deterioration compared to an untreated patient.

164. The method according to claim 162 or 163, wherein the lung deterioration is characterized by the patient exhibiting three or more of the following symptoms for at least 48 hours: (1) increased cough; (2) increased sputum volume or altered sputum consistency; (3) increased purulent sputum; (4) worsening dyspnea and / or decreased exercise tolerance; (5) fatigue and / or lethargy; (6) hemoptysis.

165. A method for treating chronic sinusitis (CRS) in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

166. The method of claim 165, wherein the chronic sinusitis is chronic sinusitis without nasal polyps (CRSsNP).

167. The method of claim 165, wherein the chronic sinusitis is chronic sinusitis with nasal polyps (CRSwNP).

168. The method according to any one of claims 165 to 167, wherein the chronic sinusitis is refractory chronic sinusitis.

169. The method according to any one of claims 165 to 168, wherein the treatment comprises alleviating one or more symptoms of CRS, reducing the severity of the one or more symptoms, delaying the onset of the one or more symptoms, or eliminating the one or more symptoms.

170. The method of claim 169, wherein one or more symptoms of CRS are nasal congestion; nasal obstruction; nasal discharge; postnasal drip; facial pressure; facial pain; facial fullness; decreased sense of smell; depression; mucosal edema; mucopurulent discharge; middle nasal meatus obstruction; changes in the mucosa of the ostiomeatal complex and sinuses; or nasal discharge.

171. A method for treating hidradenitis suppurativa (HS) in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

172. The method of claim 171, wherein the suppurative hidradenitis (HS) is Hurley stage I.

173. The method of claim 171, wherein the suppurative hidradenitis (HS) is Hurley stage I.

174. The method of claim 171, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

175. A method for treating cancer in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

176. The method of claim 175, wherein the cancer is a metastatic cancer.

177. The method of claim 176, wherein the metastatic cancer is a breast-to-lung metastatic cancer.

178. The method of claim 176, wherein the metastatic cancer includes breast cancer metastasized to the brain, bone, pancreas, lymph nodes, or liver.

179. The method of claim 176, wherein the metastatic cancer includes bone cancer metastasized to the lungs.

180. The method of claim 176, wherein the metastatic cancer includes colorectal cancer metastasized to the peritoneum, pancreas, stomach, lung, liver, kidney, or spleen.

181. The method of claim 176, wherein the metastatic cancer includes gastric cancer metastasized to the mesentery, spleen, pancreas, lung, liver, adrenal gland, or ovary.

182. The method of claim 176, wherein the metastatic cancer includes liver cancer metastasized to the intestine, spleen, pancreas, stomach, lung, or kidney.

183. The method of claim 176, wherein the metastatic cancer includes lymphoma metastasized to the kidney, ovary, liver, bladder, or spleen.

184. A method for treating lupus nephritis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

185. A method for treating rheumatoid arthritis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

186. A method for treating inflammatory bowel disease (IBD) in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

187. The method of claim 186, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

188. The method of claim 186, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

189. A method for treating antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

190. The method of claim 189, wherein the ANCA-related disease is granulomatous disease with polyangiitis (GPA).

191. The method of claim 189, wherein the ANCA-related disease is microscopic polyangiitis (MPA).

192. A method for treating a disease in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpassu), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, obstructive bronchiolitis, atopic dermatitis, pyoderma gangrenosa, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatitis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

193. A method for treating heart failure in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 120 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 121.

194. The method of claim 193, wherein the heart failure is heart failure with reduced ejection fraction.

195. The method of claim 193, wherein the heart failure is heart failure with preserved ejection fraction.

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