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, R1, R2, R3, R4, and m are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) or pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of formula (I) or pharmaceutically acceptable salt or deuterated form thereof, e.g., in the treatment of a disease that is treatable by administration of a DPP1 inhibitor.

Description

DIPEPTIDYL PEPTIDASE 1 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 538,521, filed on September 15, 2023, the disclosure of which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine protease belonging to the papain family having a molecular weight of 200 kDa. DPP1 was first discovered by Gutman and Fruton in 1948 (J Biol Chem, 174, 851-858); however, the cDNA of the human enzyme was first described in 1995 (Paris et al. 1995, FEBS Lett, 369, 326-330). DPP1 is the only member of the papain family that is functional as a tetramer, consisting of four identical subunits. Each subunit is composed of an N-terminal fragment, a heavy chain and a light chain (Dolenc et al.1995, J Biol Chem, 270, 21626-21631).

[0003] DPP1 is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen. DPP1 catalyzes the removal of dipeptides from the N-terminal end of polypeptide substrates with broad specificity. Recent data suggest that besides being an important enzyme in lysosomal protein degradation, DPP1 also functions as a key enzyme in the activation of granule serine proteases in cytotoxic T-lymphocytes and natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G, neutrophil elastase and proteinase-3).

[0004] Mast cells are found in many tissues but are present in greater numbers along the epithelial linings of the 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 tryptase, and the MC-type, which expresses both tryptase and chymase. In humans, the T-type mast cells are located primarily in alveolar tissue and intestinal mucosa while the TC-type cells predominate in skin and conjunctiva. Tryptase and chymase appear to be important mediators of allergic diseases, being involved in processes of inflammation, bronchoconstriction and mucus secretion.

[0005] Neutrophils play a critical role in host defense against invading pathogens. Neutrophils are produced in the bone marrow and are fully mature when released into the circulation to take up their role as the first line of cellular defense. Pro-inflammatory mediators and chemotactic attractants activate neutrophils and draw them to the site of infection, where they act to engulfbacteria by phagocytosis, assaulting them with an arsenal of anti-bacterial compounds that use both oxidative and non-oxidative methods of attack. The powerful serine protease, neutrophil elastase, is one of those anti-bacterial compounds that are clearly involved in destroying bacteria. Neutrophil elastase is released into the phagolysome surrounding the microorganism, which it proceeds to destroy. Neutrophil elastase is able to attack the outer membrane protein, OmpA, in gram-negative bacteria, helping to directly kill the pathogen by degrading its membrane, as well as enabling other anti-bacterial compounds to gain access to the pathogen. In addition, neutrophil elastase may help process other antibacterial compounds, converting them from inactive pro-peptides into their active states, such as for cathelicidin.

[0006] Yet neutrophil elastase can also cause problems for its host. It is one of the most destructive enzymes in the body, with the capability of degrading extracellular matrix proteins (including collagens, proteoglycan, fibronectin, platelet receptors, complement receptor, thrombomodulin, lung surfactant and cadherins) and key plasma proteins (including coagulation and complement factors, immunoglobulin, several proteases and protease inhibitors). Under physiological conditions, endogenous protease inhibitors, such as α1- antitrypsin, tightly regulate the activity of neutrophil elastase. However, at inflammatory sites, neutrophil elastase is able to 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. It can even impair host defense against infection by degrading phagocyte surface receptors and opsonins. Its negative role is illustrated by its involvement in the tissue destruction and inflammation that characterize numerous diseases, including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemic-reperfusion injury and rheumatoid arthritis.

[0007] As such, there is a need in the art to provide novel DPP1 inhibitors in order to treat the aforementioned diseases, and others associated with DPP1 and neutrophil elastase. SUMMARY

[0008] In embodiments, the present disclosure provides a compound of formula (I):

[0009] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0010] ring A is a carbocycle, aryl, heterocycle, or heteroaryl ring;

[0011] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0012] R2is a carbocycle, aryl, heterocycle, or heteroaryl ring, wherein R2is optionally substituted with 1, 2, 3, or 4 R6;

[0013] R3is H, halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally substituted with 1, 2, 3, or 4 R10;

[0014] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0015] each R5is independently C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0016] R6is each independently H, halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-O- (C1-C6alkyl)-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, - (C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0017] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0018] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6 alkylene)-heteroaryl;

[0019] R10is each independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle; and

[0020] m is 0, 1, 2, or 3; wherein:

[0021] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0022] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0023] (iii) a combination of (i) and (ii).

[0024] In embodiments, the present disclosure provides a compound of formula (I-A):

[0025] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0026] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0027] R3is H;

[0028] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0029] each R5is independently C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), heterocycle;

[0030] R6is halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0031] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0032] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0033] m is 0, 1, 2, or 3; wherein:

[0034] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0035] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0036] (iii) a combination of (i) and (ii).

[0037] In embodiments, the present disclosure provides a compound of formula (I-B):

[0038] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0039] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0040] R3is H;

[0041] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0042] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0043] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0044] R6ais H, C1-6alkyl, C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle;

[0045] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0046] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;

[0047] m is 0, 1, 2, or 3; and

[0048] p is 0; wherein:

[0049] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle;

[0050] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0051] (iii) a combination of (i) and (ii).

[0052] In embodiments, the present disclosure provides a compound of formula (I-C):

[0053] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0054] ring B is 5-8 membered ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O;

[0055] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0056] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0057] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), heterocycle;

[0058] each R6and R10is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0059] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0060] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6 alkylene)-heteroaryl; and

[0061] m is 0, 1, 2, or 3;

[0062] p is 0, 1, 2, or 3; and

[0063] q is 0, 1, 2, or 3; wherein:

[0064] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0065] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0066] (iii) a combination of (i) and (ii).

[0067] In embodiments, the present disclosure provides a compound of formula (I-D):

[0068] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0069] ring A is a carbocycle, aryl, heterocycle, or heteroaryl ring;

[0070] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0071] R3is H;

[0072] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0073] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0074] each R6is independently H, C1-6alkyl, C1-C6alkyl-OH, -C1-C10haloalkyl, -C1- C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle;

[0075] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0076] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0077] m is 0, 1, 2, or 3; wherein:

[0078] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0079] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0080] (iii) a combination of (i) and (ii).

[0081] In embodiments, the present disclosure provides a compound of formula (I-E):

[0082] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0083] ring A is a carbocycle, aryl, heterocycle, or heteroaryl ring;

[0084] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0085] R2is a carbocycle, aryl, heterocycle, or heteroaryl ring, wherein R2is optionally substituted with 1, 2, 3, or 4 R6;

[0086] R3is H;

[0087] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0088] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0089] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6 alkylene)-heterocycle, carbocycle, or heterocycle;

[0090] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0091] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0092] m is 0, 1, 2, or 3; wherein:

[0093] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0094] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0095] (iii) a combination of (i) and (ii).

[0096] In embodiments, the present disclosure provides compounds of Table A or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0097] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof), and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0098] In embodiments, the present disclosure provides a method for treating an obstructive disease of the airway in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0099] In embodiments, the present disclosure provides a method for treating cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0100] In embodiments, the present disclosure provides a method for treating chronic rhinosinusitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0101] In embodiments, the present disclosure provides a method for treating hidradenitis suppurativa in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0102] In embodiments, the present disclosure provides a method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0103] In embodiments, the present disclosure provides a method for treating lupus nephritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0104] In embodiments, the present disclosure provides a method for treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0105] In embodiments, the present disclosure provides a method for treating inflammatory bowel disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0106] In embodiments, the present disclosure provides a method for treating an anti- neutrophil cytoplasmic antibody associated vasculitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0107] In embodiments, the present disclosure provides a method for treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof), wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, sweet’s syndrome, dermatomyositis / polymyositis, neutrophilic dermatoses, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or a ventilator-induced lung injury.

[0108] In embodiments, the present disclosure provides a method for treating heart failure in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof). DETAILED DESCRIPTION

[0109] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0110] Definitions

[0111] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0112] Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0113] The term “about” when immediately preceding a numerical value means a range encompassing said numerical value plus or minus an acceptable amount of variation in the art (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an 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(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0114] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0115] “Cyano” refers to the -CN radical.

[0116] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0117] “Oxo” refers to the =O substituent.

[0118] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5alkyl. A C1-C5alkyl includes C5alkyls, C4alkyls, C3alkyls, C2alkyls and C1alkyl (i.e., methyl). A C1-C6alkyl includes all moieties described above for C1-C5alkyls but also includes C6alkyls. A C1-C10alkyl includes all moieties described above for C1-C5alkyls and C1-C6alkyls, but also includes C7, C8, C9and C10alkyls. Similarly, a C1-C12alkyl includes all the foregoing moieties, but also includes C11and C12alkyls. Non-limiting examples of C1-C12alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0119] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C1-C12alkylene include methylene, ethylene, propylene, n-butylene, ethenylene,propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0120] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5alkenyl. A C2-C5alkenyl includes C5alkenyls, C4alkenyls, C3alkenyls, and C2alkenyls. A C2-C6alkenyl includes all moieties described above for C2-C5alkenyls but also includes C6alkenyls. A C2-C10alkenyl includes all moieties described above for C2-C5alkenyls and C2-C6alkenyls, but also includes C7, C8, C9and C10alkenyls. Similarly, a C2-C12alkenyl includes all the foregoing moieties, but also includes C11and C12alkenyls. Non-limiting examples of C2-C12alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 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, 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 stated otherwise specifically in the specification, an alkenyl group can be optionally substituted.

[0121] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through onecarbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0122] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5alkynyls, C4alkynyls, C3alkynyls, and C2alkynyls. A C2-C6alkynyl includes all moieties described above for C2-C5alkynyls but also includes C6alkynyls. A C2-C10alkynyl includes all moieties described above for C2-C5alkynyls and C2-C6alkynyls, but also includes C7, C8, C9and C10alkynyls. Similarly, a C2-C12alkynyl includes all the foregoing moieties, but also includes C11and C12alkynyls. Non-limiting examples of C2-C12alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.

[0123] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0124] “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0125] “Alkylamino” refers to a radical of the formula -NHRaor -NRaRawhere each Rais, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0126] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of this disclosure, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged,or spiro ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In embodiments where “L” is aryl, the aryl radical is a diradical. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted.

[0127] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rcwhere Rbis an alkylene group as defined above and Rcis one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.

[0128] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0129] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0130] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0131] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbontriple bonds, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0132] “Cycloalkylalkyl” refers to a radical of the formula -Rb-Rdwhere Rbis an alkylene, alkenylene, or alkynylene group as defined above and Rdis a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.

[0133] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0134] “Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[0135] “Haloalkynyl” refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.

[0136] “Heterocyclyl” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, saturated or partially unsaturated ring radical which consists of two to twelve carbon ring atoms and from one to six heteroatoms as ring atoms selected from nitrogen, oxygen or sulfur, at least one non-aromatic, saturated or partially unsaturated ring containing at least one heteroatom as a ring atom. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In embodiments where “L” is heterocyclyl, the heterocyclyl radical is a diradical. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0137] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Rewhere Rbis an alkylene group as defined above and Reis a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkyl group can be optionally substituted.

[0138] “N-heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted.

[0139] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising one to thirteen carbon ring atoms, one to six heteroatoms as ring atoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring containing at least one heteroatom as a ring atom. For purposes of this disclosure, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e. thienyl). In embodiments where “L” is heteroaryl, the heteroaryl radical is adiradical. Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0140] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.

[0141] “Heteroarylalkyl” refers to a radical of the formula -Rb-Rfwhere Rbis an alkylene chain as defined above and Rfis a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.

[0142] “Thioalkyl” refers to a radical of the formula -SRawhere Rais an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.

[0143] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N- oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups.

[0144] “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further includes any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0145] As used herein, the symbol “ ” or “ ” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, “” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference.

[0146] In this specification, unless stated otherwise, the term “pharmaceutically acceptable” is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0147] The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, 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 may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0148] The compounds of the disclosure, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0149] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0150] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

[0151] An “effective amount” means the amount compound or pharmaceutical formulation, that when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment.

[0152] The term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof. A “therapeutically effective amount”, in some embodiments, is a dose or amount of a compound or pharmaceutical formulation that is sufficient to result in prophylaxis after administration to a patient in need thereof.

[0153] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, such as a mammal. The mammal may be, for example, a mouse, a rat, a rabbit, a cat, a dog, a pig, a sheep, a horse, a non-human primate (e.g., cynomolgus monkey, chimpanzee), or a human.

[0154] Compounds

[0155] In one aspect of the present disclosure, a DPP1 inhibitor is provided, and the DPP1 inhibitor is a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0156] In embodiments, the present disclosure provides a compound of formula (I):

[0157] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0158] ring A is a carbocycle, aryl, heterocycle, or heteroaryl ring;

[0159] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0160] R2is a carbocycle, aryl, heterocycle, or heteroaryl ring, wherein R2is optionally substituted with 1, 2, 3, or 4 R6;

[0161] R3is H, halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally substituted with 1, 2, 3, or 4 R10;

[0162] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0163] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0164] R6is each independently H, halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-O- (C1-C6alkyl)-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, - (C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0165] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0166] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;

[0167] R10is each independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6 alkylene)-heterocycle, carbocycle, or heterocycle; and

[0168] m is 0, 1, 2, or 3; wherein:

[0169] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0170] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0171] (iii) a combination of (i) and (ii).

[0172] In one embodiment of the compound of formula (I), R1is a 5-12 membered monocyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0173] In one embodiment of the compound of formula (I), R1is a 5-12-membered polycyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0174] In one embodiment of the compound of formula (I), wherein:

[0176] X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one ofX2and X3is -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or - N(heterocycle)-; wherein:

[0177] (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;

[0178] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0179] (iii) a combination of (i) and (ii);

[0180] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;

[0181] R11and R12are each independently H, halogen, or -C1-C6alkyl;

[0182] k is 0 or 1; and

[0183] g 0, 1, 2, or 3.

[0184] In one embodiment of the compound of formula (I), wherein:, and a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl);

[0186] X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one of X2and X3is -NH- or -N(C1-C6alkyl)-;

[0187] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;

[0188] R11and R12are each independently H, halogen, or -C1-C6 alkyl;

[0189] k is 0 or 1; and

[0190] g 0, 1, 2, or 3.

[0191] In one embodiment of the compound of formula (I), wherein:

[0193] X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one of X2and X3is -N(C1-C6alkyl)-, N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or - N(heterocycle)-;

[0194] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;

[0195] R11and R12are each independently H, halogen, or -C1-C6alkyl;

[0196] k is 0 or 1; and

[0197] g 0, 1, 2, or 3.

[0198] In one embodiment of the compound of formula (I), wherein:, and a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl);

[0200] X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or - N(heterocycle)-;

[0201] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;

[0202] R11and R12are each independently H, halogen, or -C1-C6alkyl;

[0203] k is 0 or 1; and

[0204] g 0, 1, 2, or 3.

[0205] In one embodiment of the compound of formula (I), wherein:wherein:

[0207] (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;

[0208] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0209] (iii) a combination of (i) and (ii);

[0210] k is 0 or 1; and

[0211] g is 2 or 3.

[0212] In one embodiment of the compound of formula (I), wherein Rwherein:

[0213] (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; or

[0214] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

[0215] In one embodiment of the compound of formula (I), whereinR5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl). In one embodiment, R1alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

[0216] In one embodiment of the compound of formula (I), a carbon atom of the R1heterocycle ring is substituted with one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), or -SO2NR7R8. In one embodiment, a carbon atom of the R1heterocycle ring is substituted with one R5selected from -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl). In one embodiment, a carbon atom of the R1heterocycle ring is substituted one R5selected from - SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. In one embodiment, a carbon atom of the R1heterocycle ring is substituted one R5selected from -SCH3.

[0217] In one embodiment of the compound of formulais -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; and k is 0 or 1. In one embodiment, R5is CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2. In one embodiment, R5is -C(O)CH3,. In one embodiment, R9is -OC1-C6alkyl. In one embodiment, k is 0.

[0218] In one embodiment of the compound of formulaalkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; and k is 0 or 1. In one embodiment, R5is CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2.In one embodiment, R5is -C(O)CH3,. In one embodiment, R9is -OC1-C6alkyl. In one embodiment, k is 0., , , , , , ，carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9. In one embodiment, R1is further substituted with 1, 2, or 3 R9. In one embodiment, wherein R1is further substituted with 1 R9. In one embodiment, R1is further substituted with 2 R9. In one embodiment, R1is further substituted with 3 R9.

[0220] In one embodiment of the compound of formula (I), R1is, , ,,and a carbon atom of the R1heterocycle ring is substituted one R5selected from - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9. In one embodiment, R1is further substituted with 1, 2, or 3 R9. In one embodiment, R1is further substituted with 1 R9. In one embodiment, R1is further substituted with 2 R9. In one embodiment, R1is further substituted with 3 R9.

[0221] In one embodiment of the compound of formulaalkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1- C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl). In one embodiment, R5is -NH(C1-C6alkyl) or -N(C1-C6alkyl)2. In one embodiment, R5is -NHCH3or -N(CH3)2.

[0222] In one embodiment of the compound of formula (I), wherein: X2X4RAX3

[0223] R1is RB, wherein R1is optionally further substituted with 1, 2, or 3 R9;

[0224] X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-;

[0225] X4is O, S, NH, or N(C1-C6alkyl);

[0226] R11and R12are each independently H, halogen, or -C1-C6alkyl;

[0227] RAis H, -C1-C6alkyl, -C1-C6alkylene-carbocyclyl, or -C1-C6alkylene- heteroaryl; and

[0228] RBis -C1-C6alkyl, -C2-C6alkenyl, -C1-C6alkylene-carbocyclyl, or -C1-C6alkylene-heteroaryl; or

[0229] RAand RBare taken together to form a heterocyclyl; wherein:

[0230] (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;

[0231] (ii-a) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl);

[0232] (ii-b) -X4-RAis R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, - S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl); or

[0233] (iii) any combination of (i), (ii-a), and (ii-b).

[0234] In one embodiment of the compound of formula (I), R1is a 5-12 membered spiro heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the spiro heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0235] In one embodiment of the compound of formula (I), R1is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the fused heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0236] In one embodiment of the compound of formula (I), R1is a 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the bridged heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0237] In one embodiment of the compound of formula (I), wherein:

[0238] wh1erein R is optionally further substituted with 1, 2, or 3 R9;

[0239] R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0240] g1 and g2 are each independently 0, 1, or 2, provided that both g1 and g2 are not 0, or both g1 and g2 are not 2; and

[0241] g3 is 1 or 2.is optionally further substituted with 1, 2, or 3 R9; and R5is -C1-C6 alkyl, -C1-C6 haloalkyl, - C(O)(C1-C6alkyl), or heterocycle.

[0243] In one embodiment of the compound of formula (I), wherein:

[0244] 1wherein R is optionally further substituted with 1, 2, or 3 R9;

[0245] g1 is 0, 1, 2, or 3;

[0246] g3 is 1, 2, 3, or 4;

[0247] X2is each independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, or -CR11R12-;

[0248] R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0249] R11is selected from H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), - N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl or halogenated -OC1-C6alkyl; and

[0250] R12is independently H, F, Cl, Br, I or -C1-C6alkyl.

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

[0252] wherein R1is optionally further substituted with 1, 2, or 3 R9;

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

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

[0255] X2is each independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)- , -N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-;

[0256] R11is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl or halogenated - OC1-C6alkyl; and

[0257] R12is H, F, Cl, Br, I or -C1-C6alkyl; wherein

[0258] (i) at least one of X2is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;

[0259] (ii) a carbon atom of the R1fused heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0260] (iii) a combination of (i) and (ii).

[0261] In one embodiment of the compound of formula (I), wherein:is optionally further substituted with 1, 2, or 3 R9;

[0263] X2is -O-, -S-, -NH-, -NR5-, or -CR11R12-;

[0264] R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0265] R11is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl or halogenated - OC1-C6 alkyl;

[0266] R12is H, F, Cl, Br, I or C1-C6alkyl; and

[0267] each g1 and g2 is independently 0, 1, 2, or 3, and the total sum of g1 and g2 is less than or equal to 3.further substituted with 1, 2, or 3 R9; and R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.optionally further substituted with 1, 2, or 3 R9; and R5is each independently -C1-C6alkyl, - C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.further substituted with 1, 2, or 3 R9; and R5is each independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.

[0271] In one embodiment of the compound of formula (I), R1is selected from,optionally further substituted with 1, 2, or 3 R9; and R5is each independently -C1-C6alkyl, - C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.

[0272] In one embodiment of the compound of formula (I), each R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

[0273] In one embodiment of the compound of formula (I), ring A is aryl or heteroaryl. In one embodiment, ring A is phenyl.

[0274] In one embodiment of the compound of formula (I), ring A is a monocyclic or a bicyclic ring.

[0275] In one embodiment of the compound of formula (I), R2is a monocyclic, bicyclic, or tricyclic ring, wherein R2is optionally substituted with 1, 2, 3, or 4 R6. In one embodiment, R2is a monocyclic carbocycle, monocyclic aryl, monocyclic heterocycle, or monocyclic heteroaryl, wherein R2is optionally substituted with 1, 2, 3, or 4 R6. In one embodiment, R2is phenyl, optionally substituted with 1, 2, 3, or 4 R6.

[0276] In one embodiment of the compound of formula (I), R2is a bicyclic carbocycle, bicyclic aryl, bicyclic heterocycle, or bicyclic heteroaryl, wherein R2is optionally substituted with 1, 2, 3, or 4 R6. In some embodiments, R2is a fused ring or a spiral ring.

[0277] In one embodiment of the compound of formula (I), wherein:

[0279] each X1ais independently -NR6a-, -O-, -CR13R14-, -C(O)-, -S-, -S(O) - or -S(O)2-;

[0280] each R6ais independently H, -C1-C6alkyl, -C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle;

[0281] R13and R14are each independently selected from H, deuterium, halogen, or - C1-C6alkyl; and

[0282] p is 0, 1, 2, or 3.

[0283] In one embodiment of the compound of formula (I), R2is

[0284] In one embodiment of the compound of formula (I), R2is phenyl and R3together with one of R6forms a tricyclic ring with ring A, wherein the tricyclic ring optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O, and the tricyclic ring is optionally substituted with 1, 2, 3, or 4 R10.

[0285] In embodiments, the present disclosure provides a compound of formula (I-A):

[0286] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0287] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0288] R3is H;

[0289] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0290] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0291] R6is halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0292] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0293] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0294] m is 0, 1, 2, or 3; wherein:

[0295] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0296] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0297] (iii) a combination of (i) and (ii).

[0298] In one embodiment of the compound of formula (I) or formula (I-A), R6is -CN.

[0299] In one embodiment of the compound of formula (I) or formula (I-A), m is 0.

[0300] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9. In some embodiments, a 6 membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N, S, O, wherein the monocyclic heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0301] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl). In some embodiments, R1is a 6 membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

[0302] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein, a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C3alkyl) or -N(C1-C3alkyl)2. In one embodiment of the compound of formula (I) or formula (I-A), R1is a 6 membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C3alkyl) or -N(C1- C3alkyl)2.

[0303] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), - SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

[0304] In one embodiment of the compound of formula (I) or formula (I-A), R1iswherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

[0305] In one embodiment of the compound of formula (I) or formula (I-A), wherein: O

[0306] R1isR5;

[0307] R5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and

[0308] R1is optionally further substituted with 1, 2, or 3 R9.

[0309] In one embodiment of the compound of formula (I) or formula (I-A), R5is -NH(C1-C6alkyl) or -N(C1-C6alkyl)2. In some embodiments, R5is -NHCH3or -N(CH3)2.

[0310] In one embodiment of the compound of formula (I) or formula (I-A), wherein:

[0311]

[0312] R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0313] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6 alkyl, -S(C1-C6 alkyl), -SO(C1-C6 alkyl), -SO2(C1-C6 alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0314] k is 0 or 1.

[0315] In one embodiment of the compound of formula (I) or formula (I-A), R5is -CH3, CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

[0316] In one embodiment of the compound of formula (I) or formula (I-A), R9is -OC1-C6alkyl.

[0317] In one embodiment of the compound of formula (I) or formula (I-A), k is 0.

[0318] In one embodiment of the compound of formula (I) or formula (I-A), wherein: R1is H, wherein R1is optionally further substituted with 1, 2, or 3 R9; and R5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl). In some embodiments, R5is - S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or - S(=NH)(O)(C1-C6alkyl). In some embodiments, R5is -S(C1-C6alkyl), -SO(C1-C6alkyl), or - S(=NH)(O)(C1-C6alkyl). In some embodiments, R5is -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3.In some embodiments, R5is -SCH3.

[0319] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5-12 membered spiro heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1spiro heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0320] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1fused heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0321] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1bridge heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0322] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 7-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the fused heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0323] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5,5-fused heterocycle, 5,6-fused heterocycle, 6,5-fused heterocycle, or 6,6-fused heterocycle, wherein R1is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0324] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5,5-fused heterocycle, 5,6-fused heterocycle, 6,5-fused heterocycle, or 6,6-fused heterocycle, wherein a carbon atom of the R1fused heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

[0325] In one embodiment of the compound of formula (I) or formula (I-A), R1is a 5,5-fused heterocycle, 5,6-fused heterocycle, 6,5-fused heterocycle, or 6,6-fused heterocycle, wherein the R1fused heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In one embodiment, R1is a 5,5-fused heterocycle, 5,6-fused heterocycle, 6,5-fused heterocycle, or 6,6- fused heterocycle, wherein the R1fused heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C3 alkyl, -C1-C3 haloalkyl, -C(O)(C1-C3 alkyl), or 4- 5 membered heterocycle with one ring heteroatom selected from O, S, or N.

[0326] In one embodiment of the compound of formula (I) or formula (I-A), R1isand R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In one embodiment, R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

[0327] In one embodiment of the compound of formula (I) or formula (, wherein R1is optionally further substituted with 1, 2, or 3 R9; and R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In one embodiment, R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

[0328] In one embodiment of the compound of formula (I) or formula (I-A), R1is, wherein R1is optionally further substituted with 1, 2, or 3 R9; and R5is each independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In one embodiment, R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

[0329] In one embodiment of the compound of formula (I) or formula (I-A), R1iswherein R1is optionally further substituted with 1, 2, or 3 R9; and R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In one embodiment, R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

[0330] In embodiments, the present disclosure provides a compound of formula (I-B):

[0331] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0332] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0333] R3is H;

[0334] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0335] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0336] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0337] R6ais H, C1-6alkyl, C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle;

[0338] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0339] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;

[0340] m is 0, 1, 2, or 3; and

[0341] p is 0; wherein:

[0342] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0343] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0344] (iii) a combination of (i) and (ii).

[0345] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), m is 0 or 1.

[0346] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), at least one R4is a halogen.

[0347] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), m is 1 and R4is a halogen. In one embodiment, m is 1 and R4is F.

[0348] In one embodiment of the compound of formula (I-B), R6ais C1-C6 alkyl, - CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -one embodiment, R6ais -CH3.

[0349] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1monocyclic heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0350] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6 alkyl), and the R1monocyclic heterocycle is optionally further substituted with 1, 2, or 3 R9. In one embodiment, R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl). In one embodiment, R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is optionally further substituted one R5selected from -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. In one embodiment, R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein a carbon atom of the R1monocyclic heterocycle ring is optionally further substituted one R5selected from -SCH3.

[0351] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1monocyclic heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle, and the R1monocyclic heterocycle is optionally further substituted with 1, 2, or 3 R9. In one embodiment, R1is a 5-8 membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N, S, O, wherein the R1monocyclic heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3 alkyl), or 4-5 membered heterocycle with one ring heteroatom selected from O, S, or N, and the R1monocyclic heterocycle is optionally further substituted with 1 R9. In one embodiment, R1is a 5-8 membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N, S, O, wherein the R1monocyclic heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3alkyl), or 4-5 membered heterocycle with one ring heteroatom selected from O, S, or N, andthe R1monocyclic heterocycle is optionally further substituted with 1 R9selected from -OH or -OCH3.

[0352] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1, , , , , , , ,, , wherein a carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), - SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9. In one embodiment, R5is - SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl). In one embodiment, R5is -SH, -SCH3, -S(O)CH3, or -S(=NH)(O)CH3.

[0353] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1

[0354] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1R5and 1 or 2 R9; R5is -SH, -SCH3, -S(O)CH3, or -S(=NH)(O)CH3; and R9is halogen or -C1- C3 alkyl.

[0355] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), wherein:

[0357] R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0358] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0359] k is 0 or 1.

[0360] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), wherein:

[0361]

[0362] R5is C1-C3alkyl;

[0363] R9is halogen, hydroxyl, -OC1-C6alkyl, or halogenated -OC1-C6alkyl; and

[0364] k is 0 or 1.

[0365] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1one embodiment, R9is halogen, hydroxyl, -OC1-C6alkyl, or halogenated -OC1-C6alkyl. In one embodiment,one embodiment,one embodiment,.

[0366] embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1isone embodiment, R1isembodiment, R9is halogen, hydroxyl, -OC1-C6alkyl, or halogenated -OC1-C6alkyl. In one

[0367] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), wherein: ,

[0369] R5is C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0370] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0371] k is 0 or 1.

[0372] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), wherein: ,

[0374] R5is C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3alkyl), or 4-5 membered heterocycle with one heteroatom selected from O, S, or N;

[0375] R9is halogen, hydroxyl, -OC1-C6alkyl, or halogenated -OC1-C6alkyl; and

[0376] k is 0 or 1.

[0377] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), wherein:

[0379] R5is C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3alkyl), or 4-5 membered heterocycle with one heteroatom selected from O, S, or N;

[0380] R9is halogen, hydroxyl, -OC1-C6alkyl, or halogenated -OC1-C6alkyl; and

[0381] k is 0 or 1.

[0382] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2. In some embodiments, R5is -CH3.

[0383] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R5

[0384] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R9is -OC1-C6alkyl. In some embodiments, R9is hydroxyl. In some embodiments, R9is halogen.

[0385] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), k is 0.

[0386] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), wherein:

[0387] wherein R1is further optionally further substituted with1, 2, or 3 R9; and

[0388] R5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), or -SO2NR7R8.

[0389] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R5is -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl). In one embodiment, R5is -S(C1-C3alkyl), -SO(C1-C3alkyl), or -S(=NH)(O)(C1-C3alkyl). In one embodiment, R5is -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. In one embodiment, R5is -SCH3.

[0390] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R5is -SO(C1-C6alkyl). In one embodiment, R5is -S(O)CH3.

[0391] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R5is -S(=NH)(O)(C1-C6alkyl). In one embodiment, R5is -S(=NH)(O)CH3.

[0392] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1

[0394] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 5-12 membered spiro heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1spiro heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0395] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1fused heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0396] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1fused heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle, and the R1fused heterocycle is optionally further substituted with 1, 2, or 3 R9. In one embodiment, R1is a 5,5-, 5,6-, or 6,5-fused heterocycle containing 1 or 2 heteroatoms selected from N, S, O, wherein the R1fused heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3alkyl), or 4-5 memberedheterocycle with one ring heteroatom selected from O, S, or N, and the R1fused heterocycle is optionally further substituted with 1 or 2 R9.

[0397] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1bridged heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0398] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is a 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1bridged heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle, and the R1bridged heterocycle is optionally further substituted with 1, 2, or 3 R9. In one embodiment, R1is a 7-10 membered bridged heterocycle containing 1 or 2 heteroatoms selected from N, S, O, wherein the R1bridged heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3alkyl), or 4-5 membered heterocycle with one ring heteroatom selected from O, S, or N, and the R1bridged heterocycle is optionally further substituted with 1 or 2 R9.

[0399] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In one embodiment, R1is.

[0400] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O,wherein the R1bridged heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

[0401] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In some embodiments, R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

[0402] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-B), R1is, wherein R1is optionally further substituted with 1, 2, or 3 R9; and R5is -C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In some embodiments, R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3. In one embodiment,.

[0403] In embodiments, the present disclosure provides a compound of formula (I-C):

[0404] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0405] ring B is 5-8 membered ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O;

[0406] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0407] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0408] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6 alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6 alkyl), or heterocycle;

[0409] each R6and R10is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1- C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0410] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0411] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0412] m is 0, 1, 2, or 3;

[0413] p is 0, 1, 2, or 3; and

[0414] q is 0, 1, 2, or 3; wherein:

[0415] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0416] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6 alkyl); or

[0417] (iii) a combination of (i) and (ii).

[0418] In one embodiment of the compound of formula (I-C), the tricyclic ring containing ringR13and R14are each independently selected from H, deuterium, halogen, or C1-6alkyl; q is 0, 1, or 2. In one embodiment, X1ais -NH-, -NCH3-, -O-, or -CH2-.

[0419] In one embodiment of the compound of formula (I-C), the tricyclic ring containing ringor 1 and p is 0, 1, or 2.

[0420] In one embodiment of the compound of formula (I-C), each R4is independently halogen, -C1-C3alkyl, or -CN. In one embodiment, R4is halogen and p is 1.

[0421] In one embodiment of the compound of formula (I), formula (I-A), or formula (I-C), each R6is independently halogen, -OH, -CN -C1-C3alkyl, -C1-C3haloalkyl, -S(C1-C3alkyl), - SO(C1-C3alkyl), -SO2(C1-C3alkyl), -SO2N(C1-C3alkyl), -SO2NR7R8, or 4-6 membered heterocycle. In one embodiment, each R6is independently halogen, -OH, -CN, -SO2CH3,

[0422] In some embodiments of the compound of formula (I-C), the tricyclic ring containingis 4-6 membered heterocycle. In some embodiments, R4is halogen; and at least one R6is 4-5 membered heterocycle with one ring heteroatom selected from O, S, or N. In some embodiments, R4is halogen; and at least one R6is 4-5 membered heterocycle with one ring heteroatom selected from O. In some embodiments, R4is halogen; and at least one R6is 46O . In some embodiments, R is F; and at least one R is , or. bodiments, m is 1, R4is F, p is 2, one R6is, and the other R6is halogen.

[0423] some embodiments of the compound of formula (I-C), the tricyclic ring containing ring

[0424] In embodiments, the present disclosure provides a compound of formula (I-D):

[0425] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0426] ring A is a carbocycle, aryl, heterocycle, or heteroaryl ring;

[0427] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0428] R3is H;

[0429] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0430] each R5is independently -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0431] each R6is independently H, C1-6alkyl, C1-C6alkyl-OH, -C1-C10haloalkyl, -C1- C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle;

[0432] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0433] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0434] m is 0, 1, 2, or 3; wherein:

[0435] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0436] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0437] (iii) a combination of (i) and (ii).

[0438] In one embodiment of the compound of formula (I) or formula (I-D), ring A is a 5- membered heteroaryl, 6-membered heteroaryl, 5,6-fused heteroaryl, 6,5-fused heteroaryl, or 6,6-fused heteroaryl. In one embodiment, ring A contains one or two heteroatoms selected from N, S, or O.

[0439] In one embodiment of the compound of formula (I) or formula (I-D), ring A is

[0440] In one embodiment of the compound of formula (I) or formula (I-D), ring A is

[0441] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), or formula (I-D), each R4is independently halogen, -C1-C3alkyl, or -CN. In some embodiments, m is 0 or 1.

[0442] In one embodiment of the compound of formula (I-D), R6is C1-C6alkyl, - CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -one embodiment, R6is C1-C3alkyl.

[0443] In embodiments, the present disclosure provides a compound of formula (I-E):

[0444] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0445] ring A is a carbocycle, aryl, heterocycle, or heteroaryl ring;

[0446] R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9;

[0447] R2is a carbocycle, aryl, heterocycle, or heteroaryl ring, wherein R2is optionally substituted with 1, 2, 3, or 4 R6;

[0448] R3is H;

[0449] each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, - SOC1-6alkyl, -SO2C1-6alkyl, or -CN;

[0450] each R5is independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle;

[0451] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl- OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0452] each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0453] R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; and

[0454] m is 0, 1, 2, or 3; wherein:

[0455] (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle;

[0456] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or

[0457] (iii) a combination of (i) and (ii).

[0458] In one embodiment of the compound of formula (I) or formula (I-E), wherein:

[0459] wherein R2is optionally substituted with 1, 2, 3, or 4 R6;

[0460] -D-E- is -N(R6a)-C(O)-, -CH2CH2-, -C(O)-O- or -CH2-O-;

[0461] W, Y and Z are each independently CH or N, provided that a maximum of two of W, Y and Z can be N;

[0462] X1ais -NR6b-, -O-, -CR13R14-, -C(O)-, -S-, -S(O) - or -S(O)2-;

[0463] R6ais H or C1-C6alkyl;

[0464] R6bis H, C1-C6alkyl, C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, heterocycle, or -(C1-C6alkylene)-heterocycle;

[0465] R13and R14are each independently selected from H, deuterium, halogen, or C1- C6alkyl;

[0466] s is 1, 2, or 3; and

[0467] t is 1, 2, or 3;

[0468] provided that the sum of s and t is 2, 3, or 4.

[0469] In one embodiment of the compound of formula (I) or formula (I-E),

[0470] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), ,, , , , , wherein R2is optionally substitu6 6ated with 1 or 2 R ; and R is H or C1- C6alkyl.

[0471] In one embodiment of the compound of formula (I-E), W and Z are both CH or W is CH and Z is N.

[0472] In one embodiment of the compound of formula (I-E), X1ais -NR6b-.

[0473] In one embodiment of the compound of formula (I-E), R6bis H, C1-6alkyl, or 4-6 membered heterocycle. In some embodiments, R6bis H, methyl.

[0474] In one embodiment of the compound of formula (I-E), 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.

[0475] In one embodiment of the compound of formula (I) or formula (I-E), R2is

[0476] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), wherein:

[0477] wherein:

[0478] (i) at least one of X2and X3is -N(C1-C6alkyl)-;

[0479] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and

[0480] (iii) a combination of (i) and (ii); and

[0481] g is 2 or 3.

[0482] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), wherein:

[0483] (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; or

[0484] (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

[0485] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B),formula (I-C), formula (I-D), or formulaalkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1- C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl). In some embodiments, R1isalkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

[0486] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), a carbon atom of the R1heterocycle ring is substituted with one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -S(C1-C6alkyl), - SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl). In one embodiment, a carbon atom of the R1heterocycle ring is substituted with one R5selected from -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl). In one embodiment, a carbon atom of the R1heterocycle ring is substituted one R5selected from -SCH3,-S(O)CH3, or -S(=O)(=NH)CH3. In one embodiment, a carbon atom of the R1heterocycle ring is substituted one R5selected from -SCH3.

[0487] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formulaand k is 0 or 1. In some embodiments, R5is -CH3, -CH3, -CF3, -CH2CH3, - CH2CH2CH3, - CH(CH3)2, or -C(O)CH3. In some embodiments, R9is -OC1-C6alkyl. In some embodiments, k is 0.

[0488] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formulaand a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1- C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9. In some embodiments, R1is further substituted with 1 R9. In some embodiments, R1is further substituted with 2 R9. In some embodiments, R1is further substituted with 3 R9.

[0489] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), a carbon atom of the R1heterocycle ring is substituted with at least one R5selected from -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl). In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), a carbon atom of the R1heterocycle ring is substituted with at least one R5selected from -S(C1-C3alkyl), -SO(C1- C3alkyl), -SO2(C1-C3alkyl), or -S(=NH)(O)(C1-C3alkyl). In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), a carbon atom of the R1heterocycle ring is substituted with at least one R5selected from -S(C1- C3alkyl), -SO(C1-C3alkyl), or -S(=NH)(O)(C1-C3alkyl). In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), a carbon atom of the R1heterocycle ring is substituted with at least one R5selected from SCH3, -S(O)CH3, or -S(=O)(=NH)CH3.

[0490] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), a carbon atom of the R1heterocycle ring is substituted with at least one R5selected from -SCH3, -OCH3, -OCH2CH3, -OCD3, -OCF3, or - OCHF2. In some embodiments, R5is -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3. In some embodiments, R5is -SCH3

[0491] In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with at least one R5selected from C1-C6alkyl, C1-C6haloalkyl, - C(O)(C1-C6alkyl), or heterocycle. In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with at least one R5selected from -C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3alkyl), or 4-6 membered heterocycle. In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with at least one R5selected from -C1-C3alkyl, -C1-C3haloalkyl, -C(O)(C1-C3alkyl), or 4-5 membered heterocycle with one ring heteroatom selected from O, S, or N. In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with at least one R5selected from -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3. In one embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with at least one R5selected from 4-5 membered heterocycle with one ring heteroatom selected from O. In one embodiment of the compound of formula (I), formula (I- A), formula (I-B), formula (I-C), formula (I-D), or formula (I-E), R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with at least one R5selected from.

[0492] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0493] In embodiments, provided herein is a compound of formula (I), (I-A), (I-B), (I-C), (I- D), or (I-E) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0494] In embodiments, provided herein is a pharmaceutically acceptable salt of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E). Further embodiments of the disclosure relate to a deuterated compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or a pharmaceutically acceptable salt thereof.

[0495] In embodiments of the compounds of formula (I) or (I-A), the compound is Compound 1, 2, or 3, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0496] In embodiments of the compounds of formula (I) or (I-B), the compound is Compound 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0497] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, racemic form thereof, or stereoisomer thereof.

[0498] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof.

[0499] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof.

[0500] In one embodiment, provided herein is a compound set forth in Table A.

[0501] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound in Table A.

[0502] The diastereomer designations of the compounds in Table A may be assumed unless indicated otherwise herein.

[0503] Table A. Various compounds of the invention

[0504] Compositions

[0505] The compounds of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A or pharmaceutically acceptable salts thereof, or deuterated versions of the foregoing, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A compound / salt (active ingredient) is in association with pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed.2002.

[0506] Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

[0507] In embodiments, the present disclosure provides pharmaceutical composition(s) comprising a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A or a pharmaceutically acceptable salt thereof, as hereinbefore defined in association withpharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s). The disclosure further provides a process for the preparation of a pharmaceutical composition of the disclosure which comprises mixing a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A or a pharmaceutically acceptable salt thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s).

[0508] The pharmaceutical compositions may be administered topically (e.g., to the skin or to the lung and / or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g., by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.

[0509] For oral administration the compound of the disclosure may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, com starch or amylopectin; cellulose derivative; binder, for example, gelatin or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and / or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s). Alternatively, the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talcum and titanium dioxide.

[0510] For the preparation of soft gelatin capsules, the compound of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using pharmaceutical excipients like the abovementioned excipients for tablets. Additionally, liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatin capsules.

[0511] Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example may contain the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and / or carboxymethylcellulose as a thickening agent. Furthermore, other excipients known to those skilled in art may be used when making formulations for oral use.

[0512] Therapeutic Use

[0513] In embodiments, the compounds of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A and their pharmaceutically acceptable salts, are DPP1 inhibitors, and thus may be used in any disease area where DPP1 plays a role. As such, in one aspect of the disclosure, a method of treatment is provided. The method of treatment, in one embodiment, comprises, administering to a subject in need thereof, a composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A or a pharmaceutically acceptable salt of (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A. In embodiments, the composition is administered to the patient for an administration period.

[0514] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating a obstructive disease of the airway; chronic rhinosinusitis (CRS); hidradenitis suppurativa (HS); cancer (e.g., cancer metastasis); granulomatosis with polyangiitis (GPA); microscopic polyangiitis (MPA); giant cell arteritis; polyarteritis nodosa; anti-GBM disease (Goodpasture’s); 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 ulcers; Duchenne muscular dystrophy; bronchiolitis obliterans; long covid) – prophylaxis of ILD; atopic dermatitis; pyoderma gangrenosum; sweet’s syndrome; dermatomyositis / polymyositis; neutrophilic dermatoses; uveitis; Behcet’s disease; thrombosis; bronchopulmonary dysplasia; amyotrophic lateral sclerosis; sickle cell anemia; psoriasis; ventilator-induced lung injury.

[0515] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating an obstructive disease of the airway. The obstructive disease of the airway, in one embodiment, is asthma (e.g., bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced and dust-induced asthma, both intermittent and persistent and of all severities) airway hyper-responsiveness, chronic obstructive pulmonary disease (COPD), bronchitis (e.g., infectious bronchitis, eosinophilic bronchitis), emphysema, cystic fibrosis (CF), bronchiectasis (e.g., non-CF bronchiectasis (NCFBE) and bronchiectasis associated with CF), cystic fibrosis; sarcoidosis; alpha-1 antitrypsin (A1AT) deficiency, farmer’s lung and related diseases, hypersensitivity pneumonitis, interstitial lung disease, lung fibrosis (including idiopathic pulmonary fibrosis, cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti- neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and otherfungal infections), complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension (e.g., pulmonary arterial hypertension), antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever), nasal polyposis; acute viral infection including the common cold, and infection due to a respiratory virus (e.g., respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus), acute lung injury, acute respiratory distress syndrome (ARDS), as well as exacerbations of each of the foregoing respiratory tract disease states.

[0516] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating pulmonary hypertension. In some embodiment, pulmonary hypertension is pulmonary arterial hypertension. In some embodiments, pulmonary hypertension is pulmonary hypertension due to left heart disease. In some embodiments, pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

[0517] Cystic fibrosis (CF) is caused by abnormalities in the CF transmembrane conductance regulator protein, causing chronic lung infections (particularly with Pseudomonas aeruginosa) and excessive inflammation, and leading to bronchiectasis, declining lung function, respiratory insufficiency and quality of life. The inflammatory process is dominated by neutrophils that produce NE, as well as other destructive NSPs including CatG and PR3, that directly act upon extracellular matrix proteins and play a role in the host response to inflammation and infection (Dittrich et al., Eur Respir J. 2018;51(3)). The methods provided herein employ reversible inhibitors of DPP1. Without wishing to be bound by theory, it is thought that the compounds of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, administered via the methods provided herein have beneficial effects via inhibiting the activation of NSPs and decreasing inflammation, which in turn leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (e.g., forced expiratory volume in 1 second [FEV1]) in CF patients.

[0518] In one embodiment, a method is provided for treating CF comprising administering to a CF patient in need of treatment, a composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0519] In one CF treatment method, a composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, is administered to a CF patient in need of treatment for an administration period. The method comprises improving the lung function of the patient during the administration period, as compared to the lung function of the patient prior to the administration period. The improvement in lung function in one embodiment, is measured by spirometry.

[0520] Improving the lung function of the patient, in one embodiment, comprises increasing the patient’s forced expiratory volume in 1 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 between 25% and 75% of FVC (FEF(25-75%)), as compared to the respective value prior to the administration period. Increasing, in one embodiment, is by about 5%, by about 10%, by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45% or by about 50% of the respective value. Increasing, in one embodiment, is by at least about 5%, by at least about 10%, by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45% or by at least about 50%. In yet another embodiment, the increasing is by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30% or by about 5% to about 20%. In even another embodiment, increasing is by about 10% to about 50%, by about 15% to about 50%, by about 20% to about 50%, or by about 25% to about 50%.

[0521] In one embodiment of a method provided herein, a composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, is administered to a bronchiectasis patient in need of treatment for an administration period. Bronchiectasis is considered a pathological endpoint that results from many disease processes and is a persistent or progressive condition characterized by dilated thick-walled bronchi. The symptoms vary from intermittent episodes of expectoration and infection localized to the region of the lung that is affected to persistent daily expectoration often of large volumes of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. The underlying pathological process of bronchiectasis, without wishing to be bound by theory, has been reported as damage to the airways which results from an event or series of events where inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V.65(Suppl 1), incorporated by reference herein in its entirety for all purposes).

[0522] Bronchiectasis is considered a pathological endpoint that results from many disease processes and is a persistent or progressive condition characterized by dilated thick-walled bronchi. The symptoms vary from intermittent episodes of expectoration and infection localized to the region of the lung that is affected to persistent daily expectoration often of large volumes of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. The underlying pathological process of bronchiectasis, without wishing to be bound by theory, has been reported as damage to the airways which results from an event or series of events where inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V. 65(Suppl 1), incorporated by reference herein in its entirety for all purposes).

[0523] The methods provided herein employ reversible inhibitors of DPP1. Without wishing to be bound by theory, it is thought that the compounds of formula (I), (I-A), (I-B), (I-C), (I- D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, administered via the methods provided herein have beneficial effects via decreasing inflammation and mucus hypersecretion, which in some embodiments, leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (cough, sputum production, and forced expiratory volume in 1 second [FEV1]) in bronchiectasis patients. Without wishing to be bound by theory, it is thought that the methods provided herein modify bronchiectasis progression by reducing the accelerated rate of lung function decline or lung tissue destruction.

[0524] In one embodiment, the bronchiectasis is non-CF bronchiectasis.

[0525] In one embodiment, the method for treating bronchiectasis comprises improving lung function of the patient during the administration period, as compared to the lung function of the patient prior to the administration period.

[0526] A pulmonary exacerbation, in one embodiment, is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis. In a further embodiment, the three or more symptoms result in a physician’s decision to prescribe an antibiotic(s) to the patient exhibiting the symptoms.

[0527] In one embodiment of a method for treating bronchiectasis, the method comprises decreasing the rate of pulmonary exacerbation in the subject, compared to the rate of pulmonary exacerbation experienced by the subject prior to the administration period of the composition,or compared to a control subject with bronchiectasis that is not subject to the method of treatment. In a further embodiment, the bronchiectasis is non-CF bronchiectasis.

[0528] In another aspect, a method for treating chronic rhinosinusitis (CRS) in a subject in need thereof is provided. The method comprises in one embodiment, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0529] The chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP), or chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic rhinosinusitis is refractory chronic rhinosinusitis. In some embodiments, the refractory chronic rhinosinusitis is refractory chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the refractory chronic rhinosinusitis is refractory chronic rhinosinusitis with nasal polyps (CRSwNP).

[0530] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) post-nasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (l) obstruction of the middle meatus; (m) mucosal changes within the ostiomeatal complex and sinuses; (n) rhinorrhea; or (o) any combinations thereof. In some embodiments, obstruction of the middle meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0531] In some embodiments, the administration of the pharmaceutical composition reduces, diminishes the severity of, delays the onset of, or eliminates one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) post-nasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (l) obstruction of the middle meatus; (m) mucosal changes within the ostiomeatal complex and sinuses; (n) rhinorrhea; (o) or any combinations thereof. In some embodiments, the administration of the pharmaceutical composition enhances sinus drainage.

[0532] In some embodiments, the methods comprise reducing a composite severity score of one or more symptoms of CRS. As used herein, the “composite severity score” is a quantitative measure of all the symptoms of CRS exhibited by the subject. In some embodiments, the composite severity score is a sum total of all the daily symptoms exhibited by the subject. Insome embodiments, the composite severity score is reduced during or subsequent to the administration period, as compared to the composite severity score measured prior to the administration period. In some embodiments, the one or more symptoms of CRS exhibited by the subject may be any symptoms described herein or known in the art to be associated with CRS. In some embodiments, the one or more symptoms of CRS are: nasal congestion, reduced smell, rhinorrhea, or any combination thereof. In some embodiments, the rhinorrhea is anterior rhinorrhea. In some embodiments, the rhinorrhea is posterior rhinorrhea.

[0533] In some embodiments, the methods comprise decreasing the Sino-Nasal Outcome Test- 22 (SNOT-22) score of the subject during the administration period or subsequent to the administration period, compared to the SNOT-22 score of the subject prior to the administration period. As used herein, “SNOT-22” is a patient-reported measure of outcome developed for use in CRS with or without nasal polyps and contains 22 individual questions. The questions cover a broad range of health and health-related quality of life problems including physical problems, functional limitations and emotional consequences. The theoretical range of the SNOT-22 score is 0-110, with lower scores implying a better health- related quality of life. Further details of SNOT-22 are provided in Hopkins, et al., Clin. Otolaryngol. 2009, 34, 447–454, and Kennedy, et al., Ann Allergy Asthma Immunol. 2013 October; 111(4): 246–251, the contents of which are incorporated herein by reference in its entirety.

[0534] Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory disorder. The symptoms include skin lesions that are often associated hair follicles, and may be painful, inflamed and / or swollen. In some cases, when the skin lesions heal, they can recur, and may lead to tunnels under the skin and progressive scarring. Since HS is a chronic condition, it can persist for many years and also, worsen over time, with serious effects on quality of life, psychological and emotional well-being. In fact, HS patients have increased rates of anxiety and depression with a risk of suicide two and a half times that of the general population.

[0535] HS patients are categorized according to disease severity, termed Hurley staging, as mild (Stage I), moderate (Stage II), or severe (Stage III). Although more than 200,000 cases of HS are diagnosed in the U.S. per year, this disease can be difficult to diagnose and requires specialized care. HS may be mistaken for an infection, an ingrown hair or other conditions. Moreover, current treatment options are limited and lack efficacy.

[0536] In one aspect, a method of treating HS in a subject in need thereof is provided. The method comprises in one embodiment, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound offormula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0537] The HS in one embodiment, is Hurley Stage I HS, Hurley Stage II HS or Hurley Stage III HS. In some embodiments, the HS is Hurley Stage I HS. In some embodiments, the HS is Hurley Stage II HS. In some embodiments, the HS is Hurley Stage III HS.

[0538] The disclosure provides methods of treating cancer in a subject in need thereof, comprising, administering to the subject, a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. The disclosure provides methods of treating cancer-induced pain in a subject having cancer, comprising, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. In some embodiments, the cancer-induced pain is cancer-induced bone pain. The disclosure also provides methods of treating cancer-induced bone pain in a subject having cancer, comprising, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein.

[0539] In some embodiments, the cancer comprises a primary solid tumor. In some embodiments, the 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, fibroid cancer, lymphoma, virus-induced cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, melanoma, or bone cancer.

[0540] 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 fibroid cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is 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 thymus cancer. In some embodiments, the cancer is thyroidcancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, the fibroid cancer is leiomyosarcoma.

[0541] In some embodiments, the breast cancer comprises ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, the breast cancer comprises ductal carcinoma. In some embodiments, the breast cancer comprises lobular carcinoma. In some embodiments, the breast cancer comprises medullary carcinoma. In some embodiments, the breast cancer comprises colloid carcinoma. In some embodiments, the breast cancer comprises tubular carcinoma. In some embodiments, the breast cancer comprises inflammatory breast cancer.

[0542] In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer does not respond to hormonal therapy or therapeutics that target the HER2 protein receptors.

[0543] 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.

[0544] In some embodiments, the brain cancer is astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. In some embodiments, the brain cancer is astrocytoma. In some embodiments, the brain cancer is anaplastic astrocytoma. In some embodiments, the brain cancer is glioblastoma multiforme. In some embodiments, the brain cancer is oligodendroglioma. In some embodiments, the brain cancer is ependymoma. In some embodiments, the brain cancer is meningioma. In some embodiments, the brain cancer is schwannoma. In some embodiments, the brain cancer is medulloblastoma.

[0545] In some embodiments, the cancer is liquid tumor. In some embodiments, the liquid tumor is acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, a myeloproliferative disorder, Natural Killer cell leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocyticleukemia (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 lymphocytic 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 a myeloproliferative disorder. In some embodiments, the liquid tumor is Natural Killer cell leukemia. In some embodiments, the liquid tumor is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the liquid tumor is chronic myelogenous 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).

[0546] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer is neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing 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 sarcoma.

[0547] In some embodiments, the cancer is metastatic cancer. In some embodiments, the subject is at a risk for developing metastatic cancer. In some embodiments, the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, and / or liver. In some embodiments, the metastatic cancer comprises metastasis of bone cancer to the lung. In some embodiments, the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, and / or the spleen. In some embodiments, the metastatic cancer comprises metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, and / or the ovary. In some embodiments, the metastatic cancer comprises metastasis of leukemia to the lymph nodes, the lung, the liver, the hind limb, the brain, the kidney, and / or the spleen. In some embodiments, the metastatic cancer comprises metastasis of liver cancer to the intestine, the spleen, the pancreas, the stomach, the lung, and / or the kidney. In some embodiments, the metastatic cancer comprises metastasis of lymphoma to the kidney, the ovary, the liver, the bladder, and / or the spleen.

[0548] In some embodiments, the metastatic cancer comprises metastasis of hematopoietic cancer to the intestine, the lung, the liver, the spleen, the kidney, and / or the stomach. In some embodiments, the metastatic cancer comprises metastasis of melanoma to lymph nodes and / or the lung. In some embodiments, the metastatic cancer comprises metastasis of pancreatic cancer to the mesentery, the ovary, the kidney, the spleen, the lymph nodes, the stomach, and / or the liver. In some embodiments, the metastatic cancer comprises metastasis of prostate cancer to the lung, the pancreas, the kidney, the spleen, the intestine, the liver, the bone, and / or the lymph nodes. In some embodiments, the metastatic cancer comprises metastasis of ovarian cancer to the diaphragm, the liver, the intestine, the stomach, the lung, the pancreas, the spleen, the kidney, the lymph nodes, and / or the uterus. In some embodiments, the metastatic cancer comprises metastasis of myeloma to the bone.

[0549] In some embodiments, the metastatic cancer comprises metastasis of lung cancer to the bone, the brain, the lymph nodes, the liver, the ovary, and / or the intestine. In some embodiments, the metastatic cancer comprises metastasis of kidney cancer to the liver, the lung, the pancreas, the stomach, the brain, and / or the spleen. In some embodiments, the metastatic cancer comprises metastasis of bladder cancer to the bone, the liver and / or the lung. In some embodiments, the metastatic cancer comprises metastasis of thyroid cancer to the bone, the liver and / or the lung.

[0550] In some embodiments, the methods disclosed herein comprise treating cancer-induced bone pain (CIBP) in a subject having metastasis of a cancer to the bone. In some embodiments, the subject has metastasis of prostate cancer, breast cancer, lung cancer, or myeloma to the bone. In some embodiments, the subject is identified as having metastasis to the bone by the use of any one of the following methods: plain film 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 is not yet feeling cancer-induced bone pain. In some embodiments, the subject is suffering from cancer-induced bone pain, which is indicative of metastasis of a previously treated or untreated primary tumor to the bone. In some embodiments, the cancer has metastasized to vertebrae, pelvis, long bones, or ribs.

[0551] In some embodiments, administration of the composition diminishes the severity of, delays the onset of, or eliminates a symptom of cancer. In some embodiments, the symptom of cancer is cancer-induced bone pain (CIBP). In some embodiments, the CIBP is neuropathic pain. In some embodiments, the CIBP is inflammatory pain. In some embodiments, the CIBP is spontaneous pain. In some embodiments, the symptom of cancer is nociceptivehypersensitivity. In some embodiments, the symptom of cancer is allodynia. In some embodiments, the allodynia is tactile allodynia. In some embodiments, the tactile allodynia is static mechanical allodynia. In some embodiments, the tactile allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastasis to the bone.

[0552] In yet another embodiment of the present disclosure, a method for treating lupus nephritis (LN) in a subject in need thereof is provided. The method comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0553] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, together with an effect on the underlying bone and cartilage. Currently, the cause of RA is unknown and no satisfactory cure for RA is available. While a number of therapeutic agents have been developed and utilized to alleviate pain and inflammation associated with the disease, such as disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti- inflammatory agents (NSAIDs), they often produce intolerable side effects. To addresses this and other needs, the present disclosure, in one embodiment, provides a method for treating RA using reversible inhibitors of DPP1 of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In one embodiment, a method of for treating RA in a subject in need thereof is provided, and comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0554] Inflammatory bowel disease (IBD) is a group of inflammatory conditions that affect the colon and small intestine. The most common IBDs are Crohn’s disease and ulcerative colitis. The present disclosure, in one embodiment, addresses the need for novel IBD therapies. Specifically, in one embodiment, a method for treating an inflammatory bowel disease (IBD) in a subject in need thereof is provided. The method comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0555] In a further embodiment, the IBD is Crohn’s disease or ulcerative colitis. In even a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0556] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating heart failure. In some embodiment, heart failure is heart failure with reduced ejection fraction. In some embodiments, heart failure is heart failure with preserved ejection fraction.

[0557] The length of the administration period in any given case may depend on the nature and severity of the condition being treated and / or prevented and be determined by the physician. In one embodiment, the administration period starts at about the time of condition / disease diagnosis and continues for the lifetime of the patient.

[0558] In some embodiments, the administration 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 administered for a period of about 24 weeks. In some embodiments, the compounds or compositions disclosed herein may be administered for a period of about 52 weeks. In yet another embodiment, the administration 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.

[0559] In some embodiments, the administration period for 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, at least about 5 years. The administration period for the methods provided herein, in another embodiment, is from about 30 days to about 180days. In another embodiment, the administration 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.

[0560] In one embodiment, the administration period is from about 1 year to about 30 years. For example, the administration period, in one embodiment, is from about 1 year to about 25 years, 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 year to about 10 years, from about 2 years to about 8 years, from about 2 year to about 5 years, from about 2 years to about 4 years, or from about 2 years to about 3 years.

[0561] In one embodiment of the method, the subject is administered the composition once daily during the administration period. In another embodiment, the patient is administered the composition twice daily, or every other day, or once a week during the administration period. In another embodiment, administration is every other day, every third day, 3 times per week or 4 times per week during the administration period.

[0562] 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 every day, e.g., prior to breakfast. In another embodiment, the composition comprising an effective amount of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered once a day or twice a day during the administration period. In yet another embodiment, the composition comprising an effective amount of formula (I), (I-A), (I-B), (I- C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered once per week, every other day, every third day, twice per week, three times per week, four times per week, or five times per week during the administration period.

[0563] Administration, in one embodiment, is via the oral route. In a further embodiment, the composition is administered once daily.

[0564] The dosage administered will vary with the compound of formula (I), (I-A), (I-B), (I- C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof employed, the mode of administration, and the treatment outcomedesired. For example, in one embodiment, the daily dosage of the compound of formula (I), (I- A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg / kg) to 100 micrograms per kilogram body weight (μg / kg). Alternatively, in one embodiment, if the compound of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered orally, then the daily dosage of the compound of the disclosure may be in the range from 0.01 micrograms per kilogram body weight (μg / kg) to 100 milligrams per kilogram body weight (mg / kg).

[0565] The compounds of formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is in association with pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed.2002.

[0566] EXAMPLES

[0567] The present disclosure is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the disclosure in any way.

[0568] In embodiments, compounds of the present disclosure can be synthesized using the following methods. General reaction conditions are given, and reaction products can be purified by generally known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.

[0569] 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)

[0570] Step 1. Synthesis of methyl 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4- carboxylate

[0571] A solution of 4-[(tert-butoxycarbonyl)amino]oxane-4-carboxylic acid (1.0 g, 4.07 mmol, 1.0 equiv) in DMF (10 mL) was treated with NaH (0.5 g, 12.23 mmol, 3.0 equiv, 60% in mineral oil) under nitrogen atmosphere. The mixture was stirred for 30 min at 0oC followed by the addition of MeI (1.7 g, 12.25 mmol, 3.0 equiv) dropwise at 0oC. The resulting mixture was stirred for additional 5 h at room temperature. The resulting mixture was quenched with water (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in methyl 4-[(tert- butoxycarbonyl)(methyl)amino]oxane-4-carboxylate (1 g, crude) as colorless oil. LCMS (ES, m / z): [M+H]+: 274.

[0572] Step 2. Synthesis of 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid O O

[0573] A solution of methyl 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylate (1.0 g, 3.65 mmol, 1.0 equiv) in MeOH (9 mL) and NaOH (0.4 g, 11.00 mmol, 3.0 equiv) in H2O (3 mL) was stirred for 36 h at 60oC. The mixture was cooled to 0oC, acidified to PH = 3 with HCl (1 M). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-[(tert- butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid (520 mg, 54.8%) as colorless oil. LCMS (ES, m / z): [M+H]+: 260.

[0574] Step 3. Synthesis of tert-butyl N-(4-{[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4- yl}ethyl]carbamoyl}oxan-4-yl)-N-methylcarbamate

[0575] A solution of 4-[(tert-butoxycarbonyl)(methyl)amino]oxane-4-carboxylic acid (520 mg, 2.00 mmol, 1.2 equiv) in DMF (2 mL) was treated with HOAT (341 mg, 2.50 mmol, 1.5 equiv), HATU (953 mg, 2.50 mmol, 1.5 equiv) for 30 min at 0oC under nitrogen atmosphere. This was followed by the addition of 4'-[(2S)-2-amino-2-cyanoethyl]-[1,1'-biphenyl]-4- carbonitrile (413 mg, 1.67 mmol, 1.0 equiv), DIEA (648 mg, 5.01 mmol, 3.0 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 36 h at room temperature. The reaction was quenched with water (10 mL), extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl N-(4- {[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}oxan-4-yl)-N- methylcarbamate (120 mg, 14.7%) as yellow oil. LCMS (ES, m / z): [M+H]+: 489.

[0576] Step 4. Synthesis of (S)-N-(1-cyano-2-(4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)-4- (methylamino)tetrahydro-2H-pyran-4-carboxamide

[0577] Into a 25 mL round-bottom flask were added tert-butyl N-(4-{[(1S)-1-cyano-2-{4'- cyano-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}oxan-4-yl)-N-methylcarbamate (120 mg, 0.24 mmol, 1.0 equiv) in ACN (3 mL) and TsOH.H2O (140 mg, 0.73 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50%gradient in 10 min; detector, UV 254 nm. This resulted in (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 white solid. LCMS (ES, m / z): [M+H]+: 389.2.1H 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 = 8.6 Hz, 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).

[0578] Example 2: Synthesis of N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]- 4-(dimethylamino)oxane-4-carboxamide (Compound 2)

[0579] 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 equiv), HCHO (366 mg, 4.63 mmol, 10.0 equiv, 38% in H2O), NaBH(OAc)3(196 mg, 0.92 mmol, 2.0 equiv) and HOAc (0.1 mL) in THF (3 mL) was stirred for 1 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel- 120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4- yl}ethyl]-4-(dimethylamino)oxane-4-carboxamide (20.5 mg, 11%) as white solid. LCMS (ES, m / z): [M+H]+: 403.1.1H NMR (400 MHz, DMSO-d6) δ 8.45 (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).

[0580] Example 3: Synthesis of (2S,3aS,6aS)-N-[(1S)-1-cyano-2-{4'-cyano-[1,1'- biphenyl]-4-yl}ethyl]-1-methyl-hexahydro-2H-cyclopenta[b]pyrrole-2-carboxamide (Compound 3)

[0581] To a stirred solution of (2S,3aS,6aS)-N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4- yl}ethyl]-octahydrocyclopenta[b]pyrrole-2-carboxamide (100 mg, 0.26 mmol, 1.0 equiv) in MeOH (3 mL) were added HCHO (260 mg, 2.60 mmol, 10.0 equiv, 30% in water) and HOAc (0.05 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature under nitrogen atmosphere. To the above mixture was added NaBH(OAc)3(275 mg, 1.30 mmol, 5.0 equiv) in portions at 0°C. The resulting mixture was stirred for additional 3 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel- 120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in (2S,3aS,6aS)-N-[(1S)-1-cyano-2-{4'-cyano-[1,1'- biphenyl]-4-yl}ethyl]-1-methyl-hexahydro-2H-cyclopenta[b]pyrrole-2-carboxamide (20 mg, 19%) as off-white solid. LCMS (ES, m / z): [M+H]+: 399.4.1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.97 – 7.82 (m, 4H), 7.68 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 5.10 (q, J = 8.0 Hz, 1H), 3.26 (d, J = 8.0 Hz, 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).

[0582] 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-cyclopenta[b]pyrrole-2- carboxamide (Compound 4)

[0583] 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]-octahydrocyclopenta[b]pyrrole-2-carboxamide (100 mg, 0.22 mmol, 1.0 equiv) in MeOH (2 mL) were added HCHO (223 mg, 2.23 mmol, 10.0 equiv, 30% in H2O) and HOAc (0.05 mL) dropwise at room temperature under nitrogen atmosphere.The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. To the above mixture was added NaBH(OAc)3(142 mg, 0.67 mmol, 3.0 equiv) in portions at 0°C. The resulting mixture was stirred for additional 3 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (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- cyclopenta[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).

[0584] 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)

[0585] Step 1. Synthesis of tert-butyl (3R)-3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1-carboxylate and tert-butyl (3S)-3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}- 3-hydroxypyrrolidine-1-carboxylate

[0586] A solution of (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]propanenitrile (130 mg, 0.44 mmol, 1.0 equiv) in DCM (5 mL) was treated with 1- (tert-butoxycarbonyl)-3-hydroxypyrrolidine-3-carboxylic acid (102 mg, 0.44 mmol, 1.0 equiv), DIEA (172 mg, 1.32 mmol, 3.0 equiv) at room temperature. This was followed by the addition of HATU (202 mg, 0.53 mmol, 1.2 equiv) dropwise at 0oC. The resulting mixture was stirred for 2 h at room temperature. Concentrated to remove the solvent, the residue waspurified by silica gel column chromatography, eluted with PE / THF (1:1) to afford tert-butyl (3R)-3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}- 3-hydroxypyrrolidine-1-carboxylate (90 mg 20%) and tert-butyl (3S)-3-{[(1S)-1-cyano-2-[4- (3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1- carboxylate(90 mg 20% ) as white solid. LCMS (ES, m / z): [M+H]+: 507.

[0587] 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

[0588] Into a 25 mL round-bottom flask were added tert-butyl (3R)-3-{[(1S)-1-cyano-2-[4-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1- carboxylate (90 mg, 0.17 mmol, 1.0 equiv), ACN (3 mL) and TsOH.H2O (101 mg, 0.53 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (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 white solid. LCMS (ES, m / z): [M+H]+: 406.

[0589] 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

[0590] 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 equiv) in THF (3 mL) was treated with HCHO (136 mg, 1.72 mmol, 10 equiv, 38% in water) and HOAc (0.1 mL). The mixture was stirred for 1 h at room temperature. This was followed by the addition of NaBH(OAc)3(73 mg, 0.34 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The residue was purified byreversed-phase flash chromatography with the following conditions: column, C18 silica gel- 120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (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 white solid. LCMS (ES, m / z): [M+H]+: 421.5.1H 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).

[0591] 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)

[0592] 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-carboxamideAssumed Assumed

[0593] Into a 50 mL round-bottom flask were added tert-butyl (3S)-3-{[(1S)-1-cyano-2-[4-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-3-hydroxypyrrolidine-1- carboxylate (90 mg, 0.17 mmol, 1.0 equiv) in ACN (3 mL) and TsOH.H2O (101 mg, 0.53 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (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 white solid. LCMS (ES, m / z): [M+H]+: 406.

[0594] 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-carboxamideAssumed Assumed

[0595] 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 equiv) in THF (3 mL) was treated with HCHO (136 mg, 1.72 mmol, 10 equiv, 38% in water) and HOAc (0.1 mL). The reaction was stirred for 1 h at room temperature, this was followed by the addition of NaBH(OAc)3(73 mg, 0.34 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel- 120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (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 white solid. LCMS (ES, m / z): [M+H]+: 421.5.1H 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).

[0596] 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-oxazepane-2-carboxamide (Compound 7)

[0597] 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-oxazepane-2-carboxamide (100 mg, 0.238 mmol, 1.0 equiv) and HCHO (71 mg, 2.380 mmol, 10.0 equiv) in MeOH (2 mL) were added HOAc (1 mg, 0.024 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added NaBH(OAc)3(151 mg, 0.714 mmol, 3.0 equiv) in portions at 0°C. The resulting mixture was stirred for additional 1 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column, XBridge Prep C18 OBD Column,19*150mm 5um; mobile phase, Water (0.1% NH3H2O) and ACN (10% PhaseB up to 80% in 20 min); Detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo- 1,3-benzoxazol-5-yl)phenyl]ethyl]-4-methyl-1,4-oxazepane-2-carboxamide (50 mg, 48.3%) as a white solid. LCMS (ES) [M+1]+m / z:435.1H NMR (300 MHz, DMSO-d6) δ 8.66 (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).

[0598] 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-oxazepane-2-carboxamide (Compound 8)

[0599] Into a 8 mL vial were added (2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide (60.00 mg, 0.14 mmol, 1.00 equiv), THF (3.00 mL), HCHO (136.96 mg, 1.37 mmol, 10.00 equiv, 30%) and AcOH (0.08 mg, 0.001 mmol, 0.01 equiv). The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added NaBH(OAc)3(87.01 mg, 0.41 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: C18-120 g column, mobile phase, MeCN in Water (0.1% NH3.H2O), 20% to 50% gradient in 8 min; detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in (2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-4-methyl-1,4-oxazepane-2-carboxamide (35.40 mg, 57.17%) as light yellow solid. LCMS (ES, m / z): [M+H]+: 453.1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 1.8 Hz, 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).

[0600] 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-oxazepane-2-carboxamide (Compound 9)

[0601] Step 1. Synthesis of tert-butyl (2S,6R)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazepane-4-carboxylate

[0602] To a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazepane-2- carboxylic acid (90 mg, 0.327 mmol, 1.0 equiv) and (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]propanenitrile (105 mg, 0.360 mmol, 1.1 equiv) in DCM (1 mL) were added DIEA (126 mg, 0.981 mmol, 3.0 equiv) and HATU (149 mg, 0.392 mmol, 1.2 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (2S,6R)-2-{[(1S)-1-cyano-2- [4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4- oxazepane-4-carboxylate (170 mg, 94.4%) as a white solid. LCMS (ES) [M+H]+m / z:551.

[0603] 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-oxazepane-2-carboxamide

[0604] To a stirred solution of tert-butyl (2S,6R)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazepane-4-carboxylate (160 mg, 0.291 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (150 mg, 0.873 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column, XBridge Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3H2O) and ACN (10% PhaseB up to 80% in 20 min); Detector, UV 254 nm. This resulted in (2S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazepane-2-carboxamide (90 mg, 68.7%) as a white solid. LCMS (ES) [M+H]+m / z: 451.

[0605] 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-oxazepane-2-carboxamide

[0606] 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-oxazepane-2-carboxamide (90 mg, 0.200 mmol, 1.0 equiv) and HCHO (59 mg, 2.000 mmol, 10.0 equiv) in MeOH (2 mL) were added HOAc (1 mg, 0.020 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added NaBH(OAc)3(127 mg, 0.600 mmol, 3.0 equiv) in portions at 0°C. The resulting mixture was stirred for additional 1 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column, XBridge Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3H2O) and ACN (10% PhaseB up to 80% in 20 min); Detector, UV 254 nm. This resulted in (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-oxazepane-2-carboxamide (30 mg, 32.3%) as a white solid. LCMS (ES) [M+1]+m / z: 465.1H NMR (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).

[0607] 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-oxazepane-2-carboxamide (Compound 11)

[0608] A mixture of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide (110 mg, 0.26 mmol, 1.0 equiv), CH3CH2I (45 mg, 0.28 mmol, 1.1 equiv) and K2CO3(72 mg, 0.52 mmol, 2.0 equiv) in ACN (3 mL) was stirred for 16 h at room temperature. Filtered and the filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-4-ethyl-1,4-oxazepane-2-carboxamide (24.4 mg, 20.8%) as white solid. LCMS (ES, m / z): [M+H]+: 449.2.1H NMR (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).

[0609] 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-oxazepane-2-carboxamide (Compound 12)

[0610] A solution of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide (100 mg, 0.23 mmol, 1.0 equiv) in THF (3 mL) was treated with acetone (41 mg, 0.71 mmol, 3.0 equiv) and HOAc (0.1 mL). The mixture was stirred for 1 h at room temperature. This was followed by the addition of NaBH(OAc)3(100 mg, 0.47 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-4-isopropyl-1,4-oxazepane-2-carboxamide (20.0 mg, 18%) as white solid. LCMS (ES, m / z): [M+H]+: 463.2.1H NMR (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).

[0611] 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-oxazepane-2-carboxamide (Compound 13)

[0612] 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-oxazepane-2-carboxamide (100 mg, 0.24 mmol, 1.0 equiv) and K2CO3(99 mg, 0.71 mmol, 3.0 equiv) in ACN (3 mL) was added iodopropane (49 mg, 0.29 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for 3 h at 60°C. Filtered and the filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano- 2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-4-propyl-1,4-oxazepane-2- carboxamide (20 mg, 18%) as a white solid.LCMS (ES, m / z): [M+H]+: 463.3.1H 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= 7.3 Hz, 3H).

[0613] Example 13: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]-4-(oxetan-3-yl)-1,4-oxazepane-2-carboxamide (Compound 14)

[0614] A solution of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide (100 mg, 0.23 mmol, 1.0 equiv) in THF (3 mL) was treated with 3-oxetanone (51 mg, 0.71 mmol, 3.0 equiv) and HOAc (0.1 mL). The mixture was stirred for 1 h at room temperature, this was followed by the addition of NaBH(OAc)3(100 mg, 0.47 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-4-(oxetan-3-yl)-1,4-oxazepane-2-carboxamide (17.3 mg, 15.3%) as 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).

[0615] 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-oxazepane-2-carboxamide (Compound 16)

[0616] 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-oxazepane-2-carboxamide (110 mg, 0.26 mmol, 1.0 equiv) and TEA (79 mg, 0.78 mmol, 3.0 equiv) in DCM (3 mL) was added acetyl chloride (25 mg, 0.31 mmol, 1.2 equiv) dropwise at 0oC. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched with water (20 mL), extracted with CH2Cl2(3 x 10 mL). The combinedorganic layer was washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel- 120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-4-acetyl-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo- 1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide (17.3 mg, 14%) as white solid. LCMS (ES, m / z): [M+H]+: 463.2.1H NMR (400 MHz, 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).

[0617] 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)

[0618] Step 1. Synthesis of methyl 2-{[(1R)-1-phenylethyl]imino}acetate

[0619] A solution of methyl 2-hydroxy-2-methoxyacetate (8 g, 66.61 mmol, 1.0 equiv) and D- α-methylbenzylamine (8.07 g, 66.61 mmol, 1.0 equiv) in DCM (80 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (80 mL), extracted with dichloromethane (100 ml x 3). The combined organic phase was dried over anhydrous sodium sulfate. Filtered and the filtrate was concentrated to remove the solvent, this result in methyl 2-{[(1R)-1-phenylethyl]imino}acetate (10 g, 78.5%) as colorless oil and used to the next step without further purification. LCMS (ES, m / z): [M+H]+: 192.

[0620] Step 2. Synthesis of methyl (1S,3R,4R)-2-[(1R)-1-phenylethyl]-2- azabicyclo[2.2.1]hept-5-ene-3-carboxylate

[0621] To a solution of methyl 2-{[(1R)-1-phenylethyl]imino}acetate (6 g, 31.37 mmol, 1.0 equiv) and cyclopentadiene (2.49 g, 37.65 mmol, 1.2 equiv) in DCM (60 mL) was added TFA (3.58 g, 31.38 mmol, 1.0 equiv) and BF3.Et2O (4.68 g, 32.95 mmol, 1.05 equiv) dropwise under nitrogen atmosphere at -78oC. After addition, the mixture was slowly warmed to rt, and stirred for 1 h. The reaction was quenched with water (20 mL), basified pH to 9~10 with 20% Na2CO3aqueous solution, extracted with DCM (3 x 60 mL). The combined organic layer was washed with brine (3 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl (1S,3R,4R)-2-[(1R)-1- phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (2.6 g, 32%) as yellow oil. LCMS (ES, m / z): [M+H]+: 258.

[0622] Step 3. Synthesis of 2-tert-butyl 3-methyl (1R,3R,4S)-2-azabicyclo[2.2.1]heptane-2,3- dicarboxylate

[0623] To a solution of methyl (1S,3R,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5- ene-3-carboxylate (300 mg, 1.17 mmol, 1.0 equiv) and Boc2O (305 mg, 1.40 mmol, 1.2 equiv) in MeOH (5 mL) was added Pd(OH)2 / C (20% Wt, 60 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature and stirred for 16 h under hydrogen atmosphere. Filtered through a Celite pad and the filtrate was concentrated under reduced pressure, to afford 2-tert-butyl 3-methyl (1R,3R,4S)-2-azabicyclo[2.2.1]heptane-2,3- dicarboxylate (230 mg, 77%) as Light colored oil which was used to the next step without further purification. LCMS (ES, m / z): [M+H]+: 256.

[0624] Step 4. Synthesis of tert-butyl (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- carboxylate O LiOH, THF / H2O (SOH o)0 C~rt, 16 h NBoc

[0625] 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 equiv) in THF (2 mL) and H2O (0.5 mL) was addedLiOH (594 mg, 1.91 mmol, 2.0 equiv) at 0oC. The mixture was stirred for 15 min, followed to warm to rt and stirred for 16 h. The mixture was acidified to pH 3~4 with HCl (1 N). The reaction mixture was quenched by water (20 mL) and extracted with EA (3 x 20 mL). The combined organic phase was washed with 10% NaCl aqueous solution (3 x 20 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl (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-carboxylate (210 mg, 41%) as White foam solid. LCMS (ES, m / z): [M+H]+: 242.

[0626] Step 5. Synthesis of tert-butyl (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- carboxylate

[0627] To 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 equiv) in DCM (4 mL) was treated with (2S)-2-amino- 3-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propanenitrile (298 mg, 0.96 mmol, 1.1 equiv), DIEA (225 mg, 1.74 mmol, 2.0 equiv) followed by the addition of HATU (397 mg, 1.04 mmol, 1.2 equiv) in portions at 0oC. The resulting mixture was stirred for additional 3 h at 0oC. Concentrated to remove the solvent, the residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford tert-butyl (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-carboxylate (250 mg, 53.7%) as white solid. LCMS (ES, m / z): [M+H]+: 535.

[0628] 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

[0629] Into a 25 mL round-bottom flask were added tert-butyl (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-carboxylate (250 mg, 0.47 mmol, 1.0 equiv), TsOH.H2O (267 mg, 1.40 mmol, 3.0 equiv) and ACN (5 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with EA (20 ml). The mixture was basified PH to 8~9 with saturation NaHCO3.The aqueous layer was extracted with EA (3 x 20 ml). The combined organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. This resulted in (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 white foam solid. LCMS (ES, m / z): [M+H]+: 435.

[0630] 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

[0631] 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 equiv) and formaldehyde (0.15 g, 0.35 mmol, 1.5 equiv, 30% in water) in THF (2 mL) was treated with sodium bis(acetyloxy)boranuidyl acetate (0.15 g, 0.69 mmol, 3.0 equiv). The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (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 white solid. LCMS (ES, m / z): [M+H]+: 449.1.1H 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).

[0632] 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-oxazepane-2-carboxamide (Compound 18)

[0633] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazocane-4-carboxylate

[0634] To a stirred mixture of (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]propanenitrile (149 mg, 0.51 mmol, 1.1 equiv) and (2S)-4-(tert-butoxycarbonyl)- 1,4-oxazocane-2-carboxylic acid (120 mg, 0.46 mmol, 1.0 equiv) in DCM (3 mL) were added DIEA (179 mg, 1.39 mmol, 3.0 equiv) and HATU (211 mg, 0.55 mmol, 1.2 equiv) in portions at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 0oC under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure at room temperature. The residue was purified by silica gel column eluted with ethyl acetate / petroleum ether from 10% to 70%. This resulted in tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2- oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazocane-4-carboxylate (200 mg, 80.84%) as white solid. LCMS (ES, m / z): [M+H]+: 535.

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

[0636] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazocane-4-carboxylate (200 mg, 0.37 mmol, 1.0 equiv) in ACN (4 mL) was added TsOH.H2O (193 mg, 1.12 mmol, 3.0 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The mixture was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The crude product was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+: 435.

[0637] 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-oxazocane-2-carboxamide

[0638] 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-oxazocane-2-carboxamide (100 mg, 0.23 mmol, 1.0 equiv) in MeOH (2 mL) were added HCHO (230 mg, 2.30 mmol, 10.0 equiv, 30% in water) and HOAc (0.05 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature under nitrogen atmosphere. To the above mixture was added NaBH(OAc)3(146 mg, 0.69 mmol, 3.0 equiv) in portions at 0°C. The resulting mixture was stirred for additional 3 h at room temperature. The reaction solution was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-4-methyl-1,4-oxazocane-2-carboxamide (20 mg, 19%) as white solid. LCMS (ES, m / z): [M+H]+: 449.1.1H NMR (400 MHz, DMSO-d6) δ 8.65 (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).

[0639] Example 17: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]-6-(methylsulfanyl)-1,4-oxazepane-2-carboxamide (Compound 20)

[0640] Step 1. Synthesis of 2-benzyl 4-tert-butyl (2S)-6-oxo-1,4-oxazepane-2,4-dicarboxylate O O

[0641] To a stirred solution of (2S)-4-(tert-butoxycarbonyl)-6-oxo-1,4-oxazepane-2- carboxylic acid (1.1 g, 4.243 mmol, 1.0 equiv) and BnBr (1.09 g, 6.365 mmol, 1.5 equiv) in DMF (15 mL) was added K2CO3(1.17 g, 8.486 mmol, 2.0 equiv). The resulting mixture was stirred for 3 h at 80°C. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2-benzyl 4-tert-butyl (2S)-6-oxo-1,4- oxazepane-2,4-dicarboxylate (1.1 g, 74.20%) as a colorless oil. LCMS (ES) [M+H-56]+m / z:294.

[0642] Step 2. Synthesis of 2-benzyl 4-tert-butyl (2S)-6-hydroxy-1,4-oxazepane-2,4- dicarboxylateBoc Boc

[0643] To a stirred solution of 2-benzyl 4-tert-butyl (2S)-6-oxo-1,4-oxazepane-2,4- dicarboxylate (1.1 g, 3.148 mmol, 1.0 equiv) in THF (20 mL) was added NaBH4(95 mg, 2.518 mmol, 0.8 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0°C under nitrogen atmosphere. The reaction was quenched by the addition of Water (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-benzyl 4-tert-butyl (2S)-6-hydroxy-1,4-oxazepane-2,4-dicarboxylate (800 mg, 72.31%) as a colorless oil. LCMS (ES) [M+H]+m / z:352.

[0644] Step 3. Synthesis of 2-benzyl 4-tert-butyl (2S)-6-(methanesulfonyloxy)-1,4- oxazepane-2,4-dicarboxylateBoc Boc

[0645] To a stirred solution of 2-benzyl 4-tert-butyl (2S)-6-hydroxy-1,4-oxazepane-2,4- dicarboxylate (600 mg, 1.707 mmol, 1.0 equiv) and Pyridine (405 mg, 5.121 mmol, 3.0 equiv)in DCM (10 mL) was added DMAP (20 mg, 0.171 mmol, 0.1 equiv) . To the above mixture was added methanesulfonic anhydride (446 mg, 2.561 mmol, 1.5 equiv) in DCM (2 mL) dropwise at 0°C. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 2-benzyl 4-tert-butyl (2S)-6- (methanesulfonyloxy)-1,4-oxazepane-2,4-dicarboxylate (600 mg) was used in the next step directly without further purification. LCMS (ES) [M+H]+m / z:430.

[0646] Step 4. Synthesis of 4-(tert-butoxycarbonyl)-6-(methylsulfanyl)-1,4-oxazepane-2- carboxylic acid

[0647] To a stirred solution of 2-benzyl 4-tert-butyl (2S)-6-(methanesulfonyloxy)-1,4- oxazepane-2,4-dicarboxylate (500 mg, 1.164 mmol, 1.0 equiv) in DMF (10 mL) was added (methylsulfanyl)sodium (244 mg, 3.492 mmol, 3.0 equiv) in portions at 0°C. The resulting mixture was stirred for 5 h at room temperature. 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 dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-(tert-butoxycarbonyl)-6-(methylsulfanyl)-1,4-oxazepane-2-carboxylic acid (200 mg, 58.96%) as a light yellow oil. LCMS (ES) [M+H]+m / z:292.

[0648] Step 5. Synthesis of tert-butyl 2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-(methylsulfanyl)-1,4-oxazepane-4-carboxylateBoc

[0649] To a stirred solutionof 4-(tert-butoxycarbonyl)-6-(methylsulfanyl)-1,4-oxazepane-2- carboxylic acid (148 mg, 0.512 mmol, 1.5 equiv) and (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]propanenitrile (100 mg, 0.341 mmol, 1.0 equiv) in DMF (2 mL) wasadded DIEA (132 mg, 1.023 mmol, 3.0 equiv) and T3P (216 mg, 0.682 mmol, 2.0 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl 2-{[(1S)-1-cyano-2-[4-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-(methylsulfanyl)-1,4- oxazepane-4-carboxylate (120 mg, 62.12%) as a light yellow solid. LCMS (ES) [M+H]+m / z:567.

[0650] Step 6. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-6-(methylsulfanyl)-1,4-oxazepane-2-carboxamide

[0651] To a stirred solution of tert-butyl 2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-(methylsulfanyl)-1,4-oxazepane-4-carboxylate (120 mg, 0.212 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (109 mg, 0.636 mmol, 3.0 equiv) . The resulting mixture was stirred for 3 h at room temperature. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)phenyl]ethyl]-6-(methylsulfanyl)-1,4-oxazepane-2-carboxamide (30 mg, 30.36%) as a white solid.1H 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.

[0652] 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-oxazepane-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-oxazepane-2-carboxamide (Compound 22)

[0653] Step 1. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazepane- 4-carboxylate NaBH4

[0654] To a solution of tert-butyl (S)-2-((benzyloxy)methyl)-6-oxo-1,4-oxazepane-4- carboxylate (1 eq., 1.6 g, 4.77 mmol) in EtOH (23.85 mL) was added NaBH4(2 eq., 0.36 g, 9.54 mmol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was quenched with sat. aq. solution of NH4Cl (30 mL), 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 afford tert-butyl (2S)-2-[(benzyloxy)methyl]-6-hydroxy-1,4- oxazepane-4-carboxylate as a colorless oil (1.66 g, 100%, crude). The crude was used as such in the next step. LC / MS: Rt = 1.49 min, 100%, [M-tBu+H]+= 282.1.

[0655] Step 2. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methanesulfonyloxy)- 1,4-oxazepane-4-carboxylate

[0656] To a solution of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazepane-4- carboxylate (1 eq., 2.6 g, 7.706 mmol) and Et3N (2 eq., 1.56 g, 2.14 mL, 15.41 mmol) in DCM (38.53 mL) was added mesyl chloride (1.2 eq., 1.059 g, 0.72 mL, 9.25 mmol) at 0 °C. The reaction mixture was stirred for 2 h at RT. The 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 layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methanesulfonyloxy)- 1,4-oxazepane-4-carboxylate as a yellow oil (3.4 g, 100%, crude). The crude was used as such in the next step. LC / MS: Rt = 1.61 min, 89.39%, [M-tBu+H]+= 360.1.

[0657] Step 3. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methylsulfanyl)-1,4- oxazepane-4-carboxylate

[0658] To a solution of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methanesulfonyloxy)-1,4- oxazepane-4-carboxylate (1 eq., 3.1 g, 7.46 mmol) in DMF (37.304 mL) was added NaSMe (3 eq., 1.57 g, 22.38 mmol) at RT. 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 afford crude material (2.72 g) as a yellow oil. The crude was purified by flash chromatography over silica gel (50 µm, 80 g, cyclohexane / EtOAc from 100:0 to 75:25 over 35 min) to afford tert-butyl (2S)-2- [(benzyloxy)methyl]-6-(methylsulfanyl)-1,4-oxazepane-4-carboxylate as a colorless oil (2.08 g, 76%). LC / MS: Rt = 1.61 min, 62.68%, [M-tBu+H]+= 312.1.

[0659] Step 4. Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-6-(methylsulfanyl)-1,4- oxazepane-4-carboxylate

[0660] Step a: To a solution of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methylsulfanyl)-1,4- oxazepane-4-carboxylate (1 eq., 500 mg, 1.36 mmol) in DCM (7 mL) at -78 °C was added BCl31M in DCM (5 eq., 6.80 mL, 6.80 mmol). The reaction mixture was stirred at -78 °C for 6 h. The RM was quenched with MeOH (10 mL), then concentrated under reduced pressure to afford crude material (291 mg) as a colorless gum. The crude was used as such in the next step (Step b).

[0661] Step b: To a solution of crude material (1 eq., 285 mg, 1.33 mmol) and Et3N (3 eq., 0.56 mL, 4.00 mmol) in DCM (3 mL) and MeOH (3 mL), was added a solution of Boc2O (1 eq., 291 mg, 1.33 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated to dryness under reduced pressure to afford crude material (205 mg) as a yellowish oil. The crude was purified by flash chromatography over silica gel (50 µm, 12 g Interchim, dry loading (silica), mobile phase gradient: cyclohexane / EtOAc from 100 / 0 to 50 / 50 over 50 min) to afford tert-butyl (2S)-2-(hydroxymethyl)-6-(methylsulfanyl)-1,4-oxazepane- 4-carboxylate as a colorless oil (71.6 mg, 19% over two steps). LCMS: Poorly UV active, Rt = 1.29 min, 85%, [M-tBu+H]+= 222.1.

[0662] Step 5. Synthesis of (2S)-4-[(tert-butoxy)carbonyl]-6-(methylsulfanyl)-1,4-oxazepane- 2-carboxylic acid and (2S)-4-[(tert-butoxy)carbonyl]-6-methanesulfinyl-1,4-oxazepane-2- carboxylic acid

[0663] To a solution of tert-butyl (2S)-2-(hydroxymethyl)-6-(methylsulfanyl)-1,4-oxazepane- 4-carboxylate (1 eq., 50 mg, 0.18 mmol) in H2O (0.45 mL) and DCM (0.45 mL) was added 2,2,6,6-tetramethylpiperidinooxy (0.2 eq., 5.63 mg, 0.036 mmol) and iodobenzene diacetate (2.5 eq., 145.15 mg, 0.45 mmol) at RT. The reaction mixture was stirred at RT for 1 h. DCM (25 mL) and HCl 1M 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 afford a mixture of (2S)-4-[(tert-butoxy)carbonyl]-6-(methylsulfanyl)-1,4-oxazepane-2-carboxylic acid and (2S)-4-[(tert-butoxy)carbonyl]-6-methanesulfinyl-1,4-oxazepane-2-carboxylic acid (41 mg, 76%) as a white solid. The crude was used as such in the next coupling step. LCMS: Not UV active compounds, (2S)-4-[(tert-butoxy)carbonyl]-6-(methylsulfanyl)-1,4-oxazepane-2- carboxylic acid: Rt = 1.37 min, ND, [M-tBu+H]+= 236.1 and (2S)-4-[(tert-butoxy)carbonyl]- 6-methanesulfinyl-1,4-oxazepane-2-carboxylic acid: Rt = 1.20 min, ND, [M-tBu+H]+= 252.1.

[0664] Step 6. Synthesis of tert-butyl (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-oxazepane-4- carboxylate and tert-butyl (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-oxazepane-4- carboxylate

[0665] To a solution of (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)propanenitrile (1 eq., 37.7 mg, 0.11 mmol) in anhydrous DMF (7.14 mL / mmol of amine) and mixture of (2S)-4-[(tert-butoxy)carbonyl]-6-(methylsulfanyl)-1,4-oxazepane-2-carboxylic acid and (2S)-4-[(tert-butoxy)carbonyl]-6-methanesulfinyl-1,4-oxazepane-2- carboxylic acid (1.05 eq., 35.0 mg, 0.12 mmol) were added DIPEA (2.5 eq.) and TBTU (1.5 eq.) at room temperature under argon atmosphere. 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. tert-butyl (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-oxazepane-4- carboxylate (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-oxazepane-4- carboxylate (15 mg, 23%) were obtained as light orange solids after purification by flash chromatography over silica gel (50 µm, 12 g, cyclohexane / EtOAc from 10:0 to 0:10 over 85 min, then DCM / MeOH 100:0 to 90:10 over 25 min)). LC / MS: tert-butyl (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-oxazepane-4-carboxylate: Rt = 1.66 min, 84%, [M-tBu+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-oxazepane-4-carboxylate: Rt = 1.42 min, 100, [M-tBu+H]+= 527.2.

[0666] 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-(methylsulfanyl)-1,4-oxazepane-2-carboxamide

[0667] To a preheated vial (50 °C) containing tert-butyl (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- oxazepane-4-carboxylate (1 eq., 12.0 mg, 0.021 mmol) was added 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 back to room temperature and added dropwise into a cooled (0 °C) mixture of stirred aqueous solution of saturated 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. (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6- (methylsulfanyl)-1,4-oxazepane-2-carboxamide was obtained as a mixture of diastereomers as a white solid (4.30 mg, 44%) after purification by flash chromatography over silica gel (15 µm, 4 g, DCM / MeOH (from 100:0 to 95:5 over 35 min). A diastereomeric ratio of 55:45 was determined by LC / MS. LC / MS: Rt = 4.83 min, 53.60%, [M+H]+= 467.43 & Rt = 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).

[0668] 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-oxazepane-2-carboxamide

[0669] Starting from (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-oxazepane-4-carboxylate (1 eq., 15.0 mg, 0.026 mmol) and using the procedure of Step 7 above, (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- oxazepane-2-carboxamide was obtained as a white solid (6.20 mg, 50%) after purification by flash chromatography over silica gel (15 µm, 4 g, DCM / MeOH (from 100:0 to 92:8 over 40 min). A diastereomeric ratio of 28:32:20:20 was determined by1H NMR. LC / MS: Rt = 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).

[0670] Example 19: Synthesis of a Compound 23A (a Mixture of 2 Diastereomers) and Compound 23B (a Mixture of 2 Diastereomers)

[0671] Step 1. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-methanesulfinyl-1,4- oxazepane-4-carboxylate

[0672] To a solution of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-(methylsulfanyl)-1,4- oxazepane-4-carboxylate (1 eq., 500 mg, 1.36 mmol) in DCM (6.604 mL) was added m-CPBA (0.9 eq., 274.41 mg, 0.49 mL, 1.22 mmol) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The reaction mixture was diluted with sat. aq. NaHCO3(50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with a 10% K2CO3aqueous solution, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure affording crude (506 mg) as a yellow oil. ) The crude was purified by flash chromatography over SiO2(50 µm, 40 g, DCM / MeOH 100:0 to 94:06 over 35 min) to afford tert-butyl (2S)-2- [(benzyloxy)methyl]-6-methanesulfinyl-1,4-oxazepane-4-carboxylate as a colorless oil (344 mg, 66%). LC / MS: Rt = 1.44 min, 100%, [M-tBu+H]+= 328.1.

[0673] Step 2. Synthesis of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)- 1,4-oxazepane-4-carboxylateBoc Boc

[0674] To a solution of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-methanesulfinyl-1,4- oxazepane-4-carboxylate (1 eq., 780 mg, 2.034 mmol) in DCM (10 mL) was added tert-butyl carbamate (2 eq., 476.53 mg, 4.068 mmol), magnesium oxide (4 eq., 327.9 mg, 0.092 mL, 8.14 mmol), iodobenzene diacetate (1.5 eq., 982.67 mg, 3.051 mmol), and rhodium acetate (0.05 eq., 44.95 mg, 0.102 mmol) at RT. 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 afford crude material (1.77 g) as a yellow oil. The crude was purified by flash chromatography over SiO2(50 µm, 80 g, cyclohexane / EtOAc 100:0 to 50:50 over 50 min) to afford tert-butyl (2S)-2- [(benzyloxy)methyl]-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)- 1,4- oxazepane-4-carboxylate as a colorless oil (763 mg, 75%). LC / MS: Rt = 1.44 min, 100%, [M- Boc+H]+= 399.2.

[0675] Step 3. Synthesis of tert-butyl (2S)-6-({[(tert-butoxy)carbonyl]imino}(methyl)oxo-λ6- sulfanyl)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate

[0676] To an argon-purged solution of tert-butyl (2S)-2-[(benzyloxy)methyl]-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)- 1,4-oxazepane-4-carboxylate (1 eq., 760 mg, 1.76 mmol) in EtOH (4.78 mL / mmol of protected alcohol) was added 10% Pd / C (0.1 eq.) at room temperature. The resulting mixture was purged with argon (x3) and then with H2(3x). The reaction mixture was stirred under an atmospheric pressure of H2at room temperature for 18 h. The reaction mixture was purged with argon, filtered on a pad of celite and rinsed with EtOH (3x5 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl (2S)- 6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)-2-(hydroxymethyl)-1,4- oxazepane-4-carboxylate as a colorless oil (533 mg, 77%). LC / MS: Not UV active, Rt = 1.33 min, ND, [M-Boc+H]+= 309.1.

[0677] Step 4. Synthesis of (2S)-4-[(tert-butoxy)carbonyl]-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)- 1,4-oxazepane-2-carboxylic acid

[0678] To a solution of tert-butyl (2S)-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6- sulfanyl)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1 eq., 350 mg, 0.86 mmol) in acetone (8.57 mL) was added Jones reagent (2.5 eq., 1.071 mL, 2.14 mmol) at 0 °C. The solution was stirred at RT for 1 h, then isopropanol (10 mL) was added at RT and the RM was stirred at RT 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 afford (2S)-4-[(tert-butoxy)carbonyl]-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)- 1,4-oxazepane-2-carboxylic acid as a colorless gum (294 mg, 81%). LC / MS: Not UV active, Rt = 1.41 min, ND, [M-H]-= 421.4.

[0679] Step 5. Synthesis of tert-butyl (2S)-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6- sulfanyl)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4-carboxylate

[0680] To a solution of (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)propanenitrile (1 eq., 216 mg, 0.65 mmol) in anhydrous DMF (7.14 mL / mmol of amine) and (2S)-4-[(tert-butoxy)carbonyl]-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6- sulfanyl)- 1,4-oxazepane-2-carboxylic acid (1.05 eq., 290 mg, 0.69 mmol) were added DIPEA (2.5 eq.) and TBTU (1.5 eq.) at room temperature under argon atmosphere. 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. tert-butyl (2S)-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo- 2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4-carboxylate was obtained as a white solid (305 mg, 67%) after purification by flash chromatography over silica gel (50 µm, 24 g, cyclohexane / EtOAc from 100:0 to 25:75 over 45 min). LC / MS: Rt = 2.61 min, 73%, [M-Boc+H]+= 598.3.

[0681] Step 6. Synthesis of Compound 23A and Compound 23B

[0682] To a preheated vial (50 °C) containing tert-butyl (2S)-6-({[(tert- butoxy)carbonyl]imino}(methyl)oxo-λ6-sulfanyl)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo- 2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4-carboxylate (1 eq., 100 mg, 0.14 mmol) was added 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 back to room temperature and added dropwise into a cooled (0 °C) mixture of stirred aqueous solution of saturated 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. A mixture of Compounds 25 and 26 and a mixture of Compounds 23 and 24 were obtained as white solids (9.5 mg, 13%) and (12.5 mg, 18%) after purification by flash chromatography over silica gel (4 g, DCM / MeOH (from 100:0 to 91:09 over 50 min)). The two pairs of diastereomers as well as the stereochemistry have been arbitrarily assigned.

[0683] Mixture of Two diastereomers (Compound 23A – arbitrarily assigned (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-λ6-sulfanyl]-1,4-oxazepane-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-λ6-sulfanyl]-1,4-oxazepane-2-carboxamide). LC / MS: Rt = 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).

[0684] Mixture of Two diastereomers (Compounds 23B – arbitrarily assigned (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-λ6-sulfanyl]-1,4-oxazepane-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-λ6-sulfanyl]-1,4-oxazepane-2- carboxamide). LC / MS: Rt = 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, 3.6 Hz, 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).

[0685] Example 20: Synthesis of (2S)-N-{1-cyano-2-[2,8-difluoro-9-(oxetan-3-yl)-6H- benzo[c]chromen-3-yl]ethyl}-4-methyl-1,4-oxazepane-2-carboxamide (Compound 25)

[0686] To a stirred solution of (2S)-N-{1-cyano-2-[2,8-difluoro-9-(oxetan-3-yl)-6H- benzo[c]chromen-3-yl]ethyl}-1,4-oxazepane-2-carboxamide (100 mg, 0.213 mmol, 1.0 equiv) and HCHO (63 mg, 2.130 mmol, 10.0 equiv) in MeOH (2 mL) were added HOAc (1 mg, 0.021 mmol, 0.1 equiv) and NaBH(OAc)3(135 mg, 0.639 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column, XBridge Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3H2O) and ACN (10% PhaseB up to 80% in 20 min); Detector, UV 254 nm. This resulted in (2S)-N-{1-cyano-2-[2,8-difluoro-9-(oxetan-3-yl)-6H- benzo[c]chromen-3-yl]ethyl}-4-methyl-1,4-oxazepane-2-carboxamide (30 mg, 29.1%) as a white solid. LCMS (ES, m / z): [M+H]+: 484.2.1H NMR (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 = 2.1 Hz, 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).

[0687] Example 21. Human DPP1 enzyme IC50assay

[0688] Recombinant human DPP1 enzyme (R&D Systems; Minneapolis, MN) was first proteolytically processed into its mature form using recombinant human cathepsin L (R&D Systems) in a buffer consisting of 20 mM citric acid pH 4.5, 150 mM NaCl, 1 mM EDTA and 10 mM DTT. Test articles were applied to activated human DPP1 enzyme in Assay Buffer (25 mM MES pH 6.0, 50 mM NaCl, 5 mM DTT) in a total reaction volume of 125 µL.25 µL of compound in Assay Buffer plus 5% DMSO was first added to 50 µL of activated human DPP1 enzyme at a concentration of 1 ng / µL and allowed to pre-incubate for 10 minutes at 37 ℃ after which 50 µL of 1000 µM H-Gly-Arg-AMC substrate (Bachem; St. Torrance, CA) was added, giving final substrate concentration of 400 µM and a final DMSO concentration of 1%. Substrate cleavage was measured for 90 minutes at 37 ℃, with fluorescence at Excitation / Emission 350 / 450 nm measured every 5 minutes. DPP1 concentration wasinterpolated 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-On to Microsoft Excel using the four parameter fit equation y = {A+[(B- A)] / [1+((C / x)^D)]}, which appears as equation number 205 (4 Parameter Logistic Model or Sigmoidal Dose-Response Model) in XLFit. Default constraints were used for each Parameter. IC50 was defined as the compound concentration at which 50% of enzyme activity was inhibited when compared to the no-compound control.

[0689] Results are provided in Table 1 below. In Table 1, *** represent average IC50≤ 5 nM, ** represents average IC50 in the range of 5-15 nM, and * represents average IC50 in the range of ≥ 15 nM, where the designations were made solely based on the average value without taking into account of the standard deviations.

[0690] Table 1. Human DPP1 enzyme IC50values

[0691] Example 22. DPP1 Cell IC50 assay

[0692] HL-60 cells (ATCC; Manassas, VA) were maintained in RPMI-1640 supplemented with 20% heat-inactivated FBS and 1X Antibiotic Antimycotic (Cytiva; Marlborough, MA). Media was changed every three to four days and cells were not allowed to exceed 1x106cells per mL. Prior to assay, cells were collected by centrifugation at 500 rcf for 3 minutes, resuspended in PBS and counted. Cells were diluted in PBS to a concentration of 5x105live cells per mL and transferred to black 96-well plates for assay, 60 µL per well. Test articles were diluted in PBS plus 0.5% DMSO, and 20 µL was added to each assay well. Compound was allowed to pre-incubate with cells with gentle shaking at 100 rpm for 60 minutes at 37 ℃ in a cell culture incubator maintained at 5% CO2, after which 20 µL of 500 µM H-Gly-Phe- AFC substrate (MP Biomedicals; Solon, OH) was added to each well. Plates were returned to the incubator with shaking at 100 rpm for 30 minutes, after which fluorescence was measured at Excitation / Emission 400 / 505 nm. % Inhibition was calculated from RFU values compared to control cell wells that received only PBS plus 0.5% DMSO. IC50 values for each compound were calculated via the XLFit (IDBS Version 5.3.1.3) Add-On to Microsoft Excel using the four parameter fit equation y = (A+((B-A) / (1+((C / x)^D)))), which appears as equation number 205 (4 Parameter Logistic Model or Sigmoidal Dose-Response Model) in XLFit. IC50 was defined as the compound concentration at which 50% of enzyme activity was inhibited when compared to the no-compound control.

[0693] The result of the assay is provided in Table 2, below. In Table 2, *** represent average IC50≤ 1 nM, ** represents average IC50in the range of 1-1.5 nM, and * represents average IC50in the range of ≥ 1.5 nM, where the designations were made solely based on the average value without taking into account of the standard deviations.

[0694] Table 2. DPP1 Cell IC50values

[0695] Example 23: Mouse DPP1 enzyme IC50 assay

[0696] Test articles were applied to active mouse DPP1 enzyme (R&D Systems; Minneapolis, MN) in Assay Buffer (50 mM MES pH 5.5, 50 mM NaCl, 5 mM DTT) in a total reaction volume of 125 µL.25 µL of compound in Assay Buffer plus 5% DMSO was first added to 50 µL of active mouse DPP1 enzyme at a concentration of 62.5 pg / µL and allowed to pre-incubate for 10 minutes at 37 ℃ after which 50 µL of 1000 µM H-Gly-Arg-AMC substrate (Bachem; St. Torrance, CA) was added, giving final substrate concentration of 400 µM and a final DMSO concentration of 1%. Substrate cleavage was measured for 90 minutes at 37 ℃, with fluorescence at Excitation / Emission 350 / 450 nm measured every 5 minutes. DPP1concentration was interpolated based on its activity relative to a standard curve of recombinant active mouse DPP1 enzyme. IC50values for each compound were calculated via the XLFit (IDBS Version 5.3.1.3) Add-On to Microsoft Excel using the four parameter fit equation y = (A+((B-A) / (1+((C / x)^D)))), which appears as equation number 205 (4 Parameter Logistic Model or Sigmoidal Dose-Response Model) in XLFit. Default constraints were used for each Parameter. IC50was defined as the compound concentration at which 50% of enzyme activity was inhibited when compared to the no-compound control.

[0697] Results are provided in Table 3 below. In Table 3, *** represent average IC50≤ 5 nM, ** represents average IC50 in the range of 5-20 nM, and * represents average IC50 in the range of ≥ 20 nM, where the designations were made solely based on the average value without taking into account of the standard deviations.

[0698] Table 3. Mouse DPP1 enzyme IC50values

[0699] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0700] While the invention has been described in connection with proposed specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: ring A is a carbocycle, aryl, heterocycle, or heteroaryl ring; R1is a heterocycle ring substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9; R2is a carbocycle, aryl, heterocycle, or heteroaryl ring, wherein R2is optionally substituted with 1, 2, 3, or 4 R6; R3is H, halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally substituted with 1, 2, 3, or 4 R10; each R4is independently halogen, -C1-C6alkyl, -C1-C6haloalkyl, -SC1-6alkyl, -SOC1-6alkyl, -SO2C1-6alkyl, or -CN; each R5is independently C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), or heterocycle; R6is each independently H, halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl-OH, - (C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1-C6alkylene)- O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl)- OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)- carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle; each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl; R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R10is each independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alkyl-OH, - C1-C10haloalkyl, -C1-C10haloalkyl-OH, -NR7R8, -C1-C6alkyl-NR7R8, -S(C1-C6alkyl), - SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)- carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle; and m is 0, 1, 2, or 3; wherein: (i) the R1heterocycle ring contains at least 1 nitrogen heteroatom substituted with one R5selected from C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or (iii) a combination of (i) and (ii).

2. The compound of claim 1 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered monocyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

3. The compound of claim 1 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12-membered polycyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one of X2and X3is - NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;wherein: (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or (iii) a combination of (i) and (ii); R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R11and R12are each independently H, halogen, or -C1-C6alkyl; k is 0 or 1; and g 0, 1, 2, or 3.

5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:and a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one of X2and X3is - NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl;R11and R12are each independently H, halogen, or -C1-C6alkyl; k is 0 or 1; and g 0, 1, 2, or 3.

6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one of X2and X3is - N(C1-C6alkyl))-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R11and R12are each independently H, halogen, or -C1-C6alkyl; k is 0 or 1; and g 0, 1, 2, or 3.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:and a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-, wherein at least one of X2and X3is - N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R11and R12are each independently H, halogen, or -C1-C6alkyl; k is 0 or 1; and g 0, 1, 2, or 3.

8. The compound of any one of claims 4-7 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:wherein: (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or (iii) a combination of (i) and (ii); k is 0 or 1; and g is 2 or 3.

9. The compound of any one of claims 4-6 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R, wherein: (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; (ii) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); or (iii) a combination of (i) and (ii).

10. The compound of claim 4 or 5, or a pharmaceutically acceptable salt, a stereoisomer,or a deuterated form thereof, whereinalkyl), - N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

11. The compound of claim 4 or 5, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinalkyl), - N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

12. The compound of any one of claims 4, 5, and 8-11, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein a carbon atom of the R1heterocycle ring is substituted with one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or - S(=NH)(O)(C1-C6alkyl).

13. The compound of any one of claims 4, 5, and 8-12 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein a carbon atom of the R1heterocycle ring is substituted with one R5selected from -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl).

14. The compound of any one of claims 4, 5, and 8-13 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein a carbon atom of the R1heterocycle ring is substituted one R5selected from -SCH3, -S(O)CH3, or -S(=O)(=NH)CH3.

15. The compound of claim 4 or 6 or a pharmaceutically acceptable salt, a stereoisomer,alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; and k is 0 or 1.

16. The compound of claim 4 or 6 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinC6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; and k is 0 or 1.

17. The compound of claim 15 or 16 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2.

18. The compound of claim 15 or 16 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -C(O)CH3,19. The compound of any one of claims 15-18 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R9is -OC1-C6alkyl.

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

21. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer,carbon atom of the R1heterocycle ring is5substituted one R selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6 alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6 alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

22. The compound of claim 21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is further substituted with 1 R9.

23. The compound of claim 21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is further substituted with 2 R9.

24. The compound of claim 21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is further substituted with 3 R9.

25. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinand a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

26. The compound of claim 25, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is further substituted with 1, 2, or 3 R9.

27. The compound of claim 25, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is further substituted with 1 R9.

28. The compound of claim 25, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is further substituted with 2 R9.

29. The compound of claim 25, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is further substituted with 3 R9.

30. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6 alkyl), -SO2N(C1-C6 alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6 alkyl).

31. The compound of claim 30 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -NH(C1-C6alkyl) or -N(C1-C6alkyl)2.

32. The compound of claim 30 or 31 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -NHCH3or -N(CH3)2.

33. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:X2and X3are independently -O-, -S-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-or -CR11R12-; wherein: (i) at least one of X2and X3is -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; or(ii-a) a carbon atom of the R1heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); (ii-b) -X4-RAis R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, - S(C1-C6alkyl), -SO(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl); (iii) any combination of (i), (ii-a), and (ii-b); and wherein R1is optionally further substituted with 1, 2, or 3 R9; X4is O, S, NH, or N(C1-C6alkyl); R11and R12are each independently H, halogen, or -C1-C6 alkyl; RAis H, -C1-C6alkyl, -C1-C6alkylene-carbocyclyl, or -C1-C6alkylene-heteroaryl; and RBis -C1-C6alkyl, -C2-C6alkenyl, -C1-C6alkylene-carbocyclyl, or -C1-C6alkylene- heteroaryl; or RAand RBare taken together to form a heterocyclyl.

34. The compound of claim 1 or 3 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered spiro heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

35. The compound of claim 1 or 3 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

36. The compound of claim 1 or 3 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

37. The compound of any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:wherein R1is optionally further substituted with 1, 2, or 3 R9; g1 is 0, 1, 2, or 3; g3 is 1, 2, 3, or 4; X2is each independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-; R5is C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; R11is selected from H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH, -C1-C6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl or halogenated -OC1-C6alkyl; and R12is independently H, F, Cl, Br, I or -C1-C6alkyl.

38. The compound of any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:wherein R1is optionally further substituted with 1, 2, or 3 R9; g1 is 0, 1, 2, or 3; g3 is 1, 2, 3, or 4; X2is each independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CR11R12-; and R11is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl or halogenated -OC1- C6alkyl; and R12is H, F, Cl, Br, I or -C1-C6alkyl; wherein: (i) at least one of X2is -N(C1-C6alkyl)-, N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-; or (ii) a carbon atom of the R1fused heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

39. The compound of any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:optionally further substituted with 1, 2, or 3 R9; X2is -O-, -S-, -NH-, -NR5-, or -CR11R12-; R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; R11is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl or halogenated -OC1- C6alkyl; R12is H, F, Cl, Br, I or C1-C6alkyl; and each g1 and g2 is independently 0, 1, 2, or 3, and the total sum of g1 and g2 is less than or equal to 3.

40. The compound of any one of claims 1, 3, and 35, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:, , wherein R1is op9tionally further substituted with 1, 2, or 3 R ; and R5is each independently -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.

41. The compound of any one of claims 37, 39, and 40 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

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

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

44. The compound of any one of claims 1-43 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is a monocyclic, bicyclic, or tricyclic ring, wherein R2is optionally substituted with 1, 2, 3, or 4 R6.

45. The compound of any one of claims 1-44 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is a monocyclic carbocycle, monocyclic aryl, monocyclic heterocycle, or monocyclic heteroaryl, wherein R2is optionally substituted with 1, 2, 3, or 4 R6.

46. The compound of any one of claims 1-45 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is phenyl, optionally substituted with 1, 2, 3, or 4 R6.

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

48. The compound of any one of claims 1-41 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the structure of formula (I-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: R3is H.

49. The compound of any one of claims 1-48 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R6is -CN.

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

51. The compound of any one of claims 48-50 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

52. The compound of any one of claims 48-50 or a pharmaceutically acceptable salt, aa carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

53. The compound of any one of claims 48-50 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

54. The compound of claim 53 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -NH(C1-C6alkyl) or -N(C1-C6alkyl)2.

55. The compound of claim 53 or 54, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -NHCH3or -N(CH3)2.

56. The compound of any one of claims 48-50 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R5is -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)(C1-C6 alkyl), or heterocycle; and k is 0 or 1.

57. The compound of claim 56 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or - C(O)CH3.

58. The compound of claim 56 or 57 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R9is -OC1-C6alkyl.

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

60. The compound of any one of claims 48-50 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:, wherein R1is optionally further substituted with 1, 2, or 3 R9;and R5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), - SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

61. The compound of claim 60 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl).

62. The compound of claim 60 or 61, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -SCH3, -S(O)CH3, or - S(=O)(=NH)CH3.

63. The compound of any one of claims 48-50 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

64. The compound of any one of claims 48-50 and 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 7-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

65. The compound of any one of claims 48-50, 63, and 64, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5,6-fused heterocycle, 6,5-fused heterocycle, or 6,6-fused heterocycle, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

66. The compound of any one of claims 48-50, and 63-65, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.

67. The compound of any one of claims 48-50, and 63-66, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: wherein R1is optionally substituted with 1,92, or 3 R ; and R5is C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.

68. The compound of claim 66 or 67, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3.

69. The compound of any one of claims 1-43 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is a bicyclic carbocycle, bicyclic aryl,bicyclic heterocycle, or bicyclic heteroaryl, wherein R2is optionally substituted with 1, 2, 3, or 4 R6.

70. The compound of claim 69 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is a fused ring or a spiral ring.

71. The compound of any one of claims 1-43, 69 and 70, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each X1ais independently -NR6a-, -O-, -CR13R14-, -C(O)-, -S-, -S(O) - or -S(O)2-; each R6ais independently H, -C1-C6alkyl, -C1-C6alkyl-OH, -C1-C10haloalkyl, -C1- C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle; R13and R14are each 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, a stereoisomer, or a deuterated form thereof, wherein73. The compound of any one of claims 1-43, 69 and 70, or a pharmaceutically acceptablesalt, a stereoisomer, or a deuterated form thereof, wherein R2is,74. The compound of any one of claims 71-73 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the structure of formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof; wherein: R3is H; R6ais H, C1-6alkyl, C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle; and p is 0.

75. The compound of claim 69-74 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0 or 1.

76. The compound of any one of claims 69-75 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein at least one R4is a halogen.

77. The compound of any one of claims 71, 72, and 74-76, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R6ais C1-C6alkyl.

78. The compound of claim 77 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R6ais -CH3.

79. The compound of any one of claims 78 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-8 membered monocyclic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

80. The compound of any one of claims 74-79 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is, ,carbon atom of the R1monocyclic heterocycle ring is substituted one R5selected from - NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

81. The compound of any one of claims 74-79 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R5is C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; andk is 0 or 1.

82. The compound of any one of claims 74-79 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R5is C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; and k is 0 or 1.

83. The compound of claim 82 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2.

84. The compound of claim 82 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -C(O)CH3,.

85. The compound of any one of claims 82-84, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R9is -OC1-C6alkyl.

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

87. The compound of any one of claims 74-79 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R5is -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), o-SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl); and R1is optionally further substituted with 1, 2, or 3 R9.

88. The compound of claim 87 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), or -S(=NH)(O)(C1-C6alkyl).

89. The compound of claim 87 or 88, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -SCH3, -S(O)CH3, or - S(=O)(=NH)CH3.

90. The compound of any one of claims 74-79 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered spiro heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

91. The compound of any one of claims 74-79 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

92. The compound of any one of claims 74-79 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 6-12 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the R1heterocycle is substituted with 1 or 2 R5and optionally further substituted with 1, 2, or 3 R9.

93. The compound of any one of claims 74-79 and 90, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R5is C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.

94. The compound of any one of claims 74-79 and 92, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: R1is, wherein R1is optionally further substituted with 1, 2, or 3 R9; andR5is C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle.

95. The compound of claim 94, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2.

96. The compound of any one of claims 1-43 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is phenyl and R3together with one of R6forms a tricyclic ring with ring A, wherein the tricyclic ring optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O, and the tricyclic ring is optionally substituted with 1, 2, 3, or 4 R10.

97. The compound of claim 1-43 or 96, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the structure of formula (I-C):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: ring B is 5-8 membered ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.

98. The compound of claim 97 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: the tricyclic ring containing ring B isX1ais -NR6a-, -O-, -CR13R14-, -C(O)-, -S-, -S(O) - or -S(O)2-; and R13and R14are each independently selected from H, deuterium, halogen, or C1-6alkyl.

99. The compound of claim 97 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein X1ais -NH-, -NCH3-, -O-, or -CH2-.

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

101. The compound of any one of claims 97-100 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R4is independently halogen, -C1-C3 alkyl, or -CN.

102. The compound of any one of claims 97-101 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R6is independently halogen, -OH, - CN -C1-C3alkyl, -C1-C3haloalkyl, -S(C1-C3alkyl), -SO(C1-C3alkyl), -SO2(C1-C3alkyl), - SO2N(C1-C3alkyl), -SO2NR7R8, or 4-6 membered heterocycle.

103. The compound of any one of claims 97-101 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R6is independently halogen, -OH, -104. The compound of any one of claims 97-103 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R9is halogen, oxo, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - COOH, -C1-C6alkyl, -C1-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl, halogenated -OC1-C6alkyl, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), - SO2N(C1-C6alkyl), -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl, or –(C1-C6alkylene)-heteroaryl; R5is C1-C6alkyl, C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle; and k is 0 or 1.

105. The compound of claim 104 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2.

106. The compound of claim 104 or 405, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R9is -OC1-C6alkyl.

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

108. The compound of any one of claims 1-43 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the structure of formula (I-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: ring A is a monocyclic or bicyclic heteroaryl ring; R3is H; andR6is H, C1-6alkyl, C1-C6alkyl-OH, -C1-C10haloalkyl, -C1-C10haloalkyl-OH, -C1-C6alkyl-NR7R8, or -(C1-C6alkylene)-heterocycle.

109. The compound of claim any one of claims 1-43 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the structure of formula (I-E):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: R2is a tricyclic carbocycle, tricyclic aryl, tricyclic heterocycle, or tricyclic heteroaryl ring, wherein each R2is optionally substituted with 1, 2, 3, or 4 R6; and R3is H.

110. The compound of any one of claims 1-109 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein at least one R5is -SCH3, -S(O)CH3, - S(=O)(=NH)CH3, -OCH3, -OCH2CH3, -OCD3, -OCF3, or -OCHF2.

111. The compound of any one of claims 1-110 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein at least one R5is -SCH3, -S(O)CH3, or - S(=O)(=NH)CH3.

112. The compound of any one of claims 1-109 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein at least one R5is -CH3, -CF3, -CH2CH3, -113. The compound of claim 1 or 48, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound isdeuterated form thereof.

114. The compound of claim 1 or 48, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound isdeuterated form thereof.

115. The compound of claim 1 or 74, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound ispharmaceutically acceptable salt or deuterated form thereof.

116. The compound of claim 1 or 74, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound isO O N Opharmaceutically acceptable salt or deuterated form thereof.

117. The compound of claim 1 or 74, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound is, or a pharmaceutically acceptable salt or deuterated form thereof.

118. The compound of claim 1 or 74, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound is,119. The compound of claim 1 or 97, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound ispharmaceutically acceptable salt or deuterated form thereof.

120. The compound of claim 1 or 97, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound ispharmaceutically acceptable salt or deuterated form thereof.

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

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

123. The method of claim 122, wherein the obstructive disease of the airway 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 pneumonitis, lung fibrosis, complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension, antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitisincluding rhinitis nervosa (hay fever), nasal polyposis; acute viral infection including the common cold, and infection due to a respiratory virus, acute lung injury, or acute respiratory distress syndrome (ARDS).

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

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

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

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

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

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

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

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

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

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

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

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

136. The method of claim 123, wherein the obstructive disease of the airway is a vasculitic or thrombotic disorder of the lung vasculature.

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

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

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

140. The method of claim 123, wherein the obstructive disease of the airway is chronic rhinitis.

141. The method of claim 123, wherein the obstructive disease of the airway is rhinitis medicamentosa or vasomotor rhinitis.

142. The method of claim 123, wherein the obstructive disease of the airway is nasal polyposis.

143. The method of claim 123, wherein the obstructive disease of the airway is COPD.

144. The method of claim 124, wherein the asthma is bronchial, allergic, intrinsic, extrinsic, exercise-induced 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 lung fibrosis is idiopathic pulmonary fibrosis, cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, or fibrosis complicating anti-neoplastic therapy or chronic infection.

147. The method of claim 130, wherein the bronchiectasis is non-cystic fibrosis 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 due to left heart 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 thereof, comprising, administering to the patient an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 121.

153. The method of claim 152, wherein the treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

154. The method of claim 153, wherein improving lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 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 between 25% and 75% of FVC (FEF(25-75%)), as compared to the respective value for the patient prior treatment.

155. The method of claim 153 or 154, wherein the lung function is measured by spirometry.

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

157. The method of claim 156, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

158. The method of claim 156, wherein the bronchiectasis is associated with cystic fibrosis.

159. The method of any one of claims 156-158, wherein treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

160. The method of claim 159, wherein improving lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 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 between 25% and 75% of FVC (FEF(25-75%)), as compared to the respective value for the patient prior to treatment.

161. The method of claim 159 or 160, wherein the lung function is measured by spirometry.

162. The method of any one of claims 156-161, wherein treating comprises decreasing the rate of pulmonary exacerbation, as compared to the rate of pulmonary exacerbation of the patient prior to treatment.

163. The method of any one of claims 156-162, wherein treating comprises increasing the time to first pulmonary exacerbation, as compared to an untreated patient.

164. The method of claim 162 or 163, wherein the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis.

165. A method for treating chronic rhinosinusitis (CRS) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 121.

166. The method of claim 165, wherein the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

167. The method of claim 165, wherein the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

168. The method of any one of claims 165-167, wherein the chronic rhinosinusitis is refractory chronic rhinosinusitis.

169. The method of any one of claims 165-168, wherein treating comprises reducing, diminishing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS.

170. The method of claim 169, wherein the one or more symptoms of CRS is nasal congestion; nasal obstruction; nasal discharge; post-nasal drip; facial pressure; facial pain; facial fullness; reduced smell; depression; mucosal edema; mucopurulent discharge; obstruction of the middle meatus; mucosal changes within the ostiomeatal complex and sinuses; or rhinorrhea.

171. A method for treating hidradenitis suppurativa (HS) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 121.

172. The method of claim 171, wherein the hidradenitis suppurativa (HS) is Hurley stage I.

173. The method of claim 171, wherein the hidradenitis suppurativa (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 thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of 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 breast to lung metastatic cancer.

178. The method of claim 176, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver.

179. The method of claim 176, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

180. The method of claim 176, wherein the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, or the spleen.

181. The method of claim 176, wherein the metastatic cancer comprises metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, or the ovary.

182. The method of claim 176, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or the kidney.

183. The method of claim 176, wherein the metastatic cancer comprises metastasis of lymphoma to the kidney, ovary, liver, bladder, or the spleen.

184. A method for treating lupus nephritis in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 121.

185. A method for treating rheumatoid arthritis in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 121.

186. A method for treating inflammatory bowel disease (IBD) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of 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 an anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 121.

190. The method of claim 189, wherein the ANCA associated disease is granulomatosis with polyangItis (GPA).

191. The method of claim 189, wherein the ANCA associated disease is microscopic polyangItis (MPA).

192. A method for treating a disease in a patient in need thereof comprising, administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 121, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti- GBM disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, sweet’s syndrome, dermatomyositis / polymyositis, neutrophilic dermatoses, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or a ventilator-induced lung injury.

193. A method for treating a heart failure in a patient in need thereof, comprising administering to the patient, an effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of 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.