DPP1 inhibitors with cyclic or linear linkers and uses thereof

Abstract

Provided herein are compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, or deuterated forms thereof, wherein R0, L, and R1 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) or pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, and methods of using a compound of formula (I) or pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, e.g., in the treatment of a disease that is treatable by administration of a DPP1 inhibitor. (I)

Description

DPP1 INHIBITORS WITH CYCLIC OR LINEAR LINKERS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to European Patent Application No.24383145.0, filed on October 18, 2024, the content of which is hereby incorporated by reference in its entirety for all purposes. 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 some aspects, the present disclosure provides a compound of formula (I)(I) or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein: R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2, or 5-12 membered polycyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkenylene, C2-12alkynylene, monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; R1is 5-12 membered carbocyclyl optionally substituted with 1-3 R4, 6-18 membered aryl optionally substituted with 1-3 R4, 5-12 membered monocyclic heterocyclyl containing 1- 3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 R4, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4, 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4, or a 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; and each R4is independently H, SF5, oxo, halogen, -CN, -OH, -NO2, NH2, -COOH, C1-6alkyl, C1-6alkoxy, C3-6cycloalkyloxy, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C2-6alkenyl, C2-5alkynyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COC1-6alkyl, -COOC1-6alkyl, -CONH2, -CONHC1-6alkyl, -CONHC3-6cycloalkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, -NHCOC3-5cycloalkyl, -P(O)(C1-6alkyl), -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, -S(O)NH2, -S(O)NHC1-6alkyl, -S(O)N(C1-6alkyl)2, -S(O)2NH2, -OSO2-C1-6alkyl, C1-6alkylene-O-C1-6alkyl, C3-8 -cycloalkenyloxy, aryl, heteroaryl, or 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the R4is optionally further substituted with 1-3 groups selected from C1-6alkyl, C1-6haloalkyl, C1-6-alkylene-OH, C1-6alkylene-O-C1-6alkyl, -CONH2, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, C1-6alkoxy, -OH, -COOH, halogen, or a 5-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, and wherein the 5-7-membered heterocycle is optionally substituted with 1-2 groups selected from oxo, halogen, -CN, C1-6alkyl, and C1-6haloalkyl.

[0009] In embodiments, the present disclosure provides a compound having a structure of formula (II)or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein: R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1- 6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2;each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

[0010] In embodiments, the present disclosure provides compounds of Table A or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof.

[0011] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof), and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0012] In another aspect, the present disclosure provides a method of treatment. The method of treatment, in embodiments, comprises, administering to a subject in need thereof, a composition comprising an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof).

[0013] The method of treatment, in embodiments, is a method of treating an obstructive disease of the airway, e.g., cystic fibrosis (CF), asthma or bronchiectasis (e.g., non-CF bronchiectasis). In embodiments, the present disclosure provides a method for treating an obstructive diseaseof 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) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof).

[0014] In embodiments, the method of treatment is a method for treating chronic rhinosinusitis (CRS). 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) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof).

[0015] In embodiments, the method of treatment is a method for treating hidradenitis suppurativa (HS). 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) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof).

[0016] In embodiments, the method of treatment is a method for treating cancer. 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) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof).

[0017] In some embodiments, the method of treatment is a method of treating lupus nephritis. 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) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof).

[0018] In some embodiments, the method of treatment is a method of treating rheumatoid arthritis. 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) or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof).

[0019] In some embodiments, the method of treatment is a method of treating inflammatory bowel disease (IBD). 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)or (II), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof). DETAILED DESCRIPTION

[0020] 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.

[0021] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0022] 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.

[0023] 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.

[0024] “Cyano” refers to the -CN radical.

[0025] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0026] “Oxo” refers to the =O substituent.

[0027] “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 upto 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.

[0028] “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.

[0029] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one, two, 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.

[0030] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one, two, 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 one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0031] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one, two, 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-C5alkynyl. A C2-C5alkynyl 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.

[0032] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one, two, 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 ofattachment 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.

[0033] “Alkoxy” refers to a radical of the formula -ORa where Ra is 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.

[0034] “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.

[0035] “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.

[0036] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rcwhere Rbis an alkylene group as defined above and Rc is 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.

[0037] “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.

[0038] “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. The term “cycloalkylene” as used herein means divalent counterpart of a cycloalkyl group.

[0039] Exemplary monocyclic cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and cyclooctylene.

[0040] “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. The term “cycloalkenylene” as used herein means divalent counterpart of a cycloalkenyl group.

[0041] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple 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. The term “cycloalkynylene” as used herein means divalent counterpart of a cycloalkynyl group.

[0042] “Cycloalkylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.

[0043] “Polycyclic” refers to ring systems comprising 2 or more rings, for example 2, 3, or 4 rings. Polycyclic rings may be fused, spiro, or bridged ring systems.

[0044] “Polycyclic cycloalkylene” refers to a divalent non-aromatic polycyclic fully saturated hydrocarbon ring consisting solely of carbon and hydrogen atoms, having from four to twenty carbon atoms, e.g., having from four to ten carbon atoms, and which is attached to the rest of the molecule (e.g., as shown in Formula I) by two single bonds. The polycyclic cycloalkylene can include fused, spiro, or bridged ring systems. Polycyclic cycloalkylene can include, forexample, bicyclo[2.2.2]octanylene, cubanylene, bicyclo(1.1.1)pentylene, adamantylene, norbornylene, decalinylene, 7,7-dimethyl-bicyclo[2.2.1]heptanylene, and the like. Unless otherwise stated specifically in the specification, a cycloalkylene group can be optionally substituted.

[0045] “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.

[0046] “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.

[0047] “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.

[0048] “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 radicalis a diradical. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0049] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Rewhere Rbis an alkylene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkyl group can be optionally substituted.

[0050] “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.

[0051] “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). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0052] “Heteroarylene” refers to a divalent 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring comprising at least one heteroatom selectedfrom nitrogen, oxygen and sulfur. For purposes of this disclosure, the heteroarylene radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, or bridged 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, azepinylene, acridinylene, benzimidazolylene, benzothiazolylene, benzindolylene, benzodioxolylene, benzofuranylene, benzooxazolylene, benzothiazolylene, benzothiadiazolylene, benzo[b][1,4]dioxepinylene, 1,4-benzodioxanylene, benzonaphthofuranylene, benzoxazolylene, benzodioxolylene, benzodioxinylene, benzopyranylene, benzopyranonylene, benzofuranylene, benzofuranonylene, benzothienylene (divalent benzothiophene radical), benzotriazolylene, benzo[4,6]imidazo[1,2-a]pyridinylene, carbazolylene, cinnolinylene, dibenzofuranylene, dibenzothiophene, furanylene, furanonylene, isothiazolylene, imidazolylene, indazolylene, indolylene, indazolylene, isoindolylene, indolinylene, isoindolinylene, isoquinolylene, indolizinylene, isoxazolylene, naphthyridinylene, oxadiazolylene, 2-oxoazepinylene, oxazolylene, oxiranylene, 1- oxidopyridinylene, 1-oxidopyrimidinylene, 1-oxidopyrazinylene, 1-oxidopyridazinylene, 1-phenyl-1H-pyrrolylene, phenazinylene, phenothiazinylene, phenoxazinylene, phthalazinylene, pteridinylene, purinylene, pyrrolylene, pyrazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, quinazolinylene, quinoxalinylene, quinolinylene, quinuclidinylene, isoquinolinylene, tetrahydroquinolinylene, thiazolylene, thiadiazolylene, triazolylene, tetrazolylene, triazinylene, and thiophene (e.g., thienylene). Unless stated otherwise specifically in the specification, a heteroarylene group can be optionally substituted.

[0053] “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.

[0054] “Heteroarylalkyl” refers to a radical of the formula -Rb-Rf where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.

[0055] “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.

[0056] 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.

[0057] “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.

[0058] As used herein, the symbol “ ” or “ ” (hereinafter can be referred to as “a pointof 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,XY“ ” or “XY ” 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.

[0059] 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.

[0060] 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.

[0061] The present disclosure is intended to include all solid forms of a given compound or formula disclosed herein in any embodiments. For example, Compound 1 of formula (I) includes anhydrous Compound 1, monohydrate of Compound 1, and any other hydrate forms or mixtures thereof.

[0062] The compounds of the disclosure, or their pharmaceutically acceptable salts or hydrates can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric 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 ofgeometric 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.

[0063] 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.

[0064] 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. The term “treating” in one embodiment, includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (i.e., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); (3) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms).

[0065] 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 affect such treatment.

[0066] 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.

[0067] 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.Compounds

[0068] In one aspect of the present disclosure, a DPP1 inhibitor is provided, and the DPP1 inhibitor is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof.

[0069] In embodiments, the present disclosure provides a compound of formula (I)or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein: R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2, or 5-12 membered polycyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkenylene, C2-12alkynylene, monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; R1is 5-12 membered carbocyclyl optionally substituted with 1-3 R4, 6-18 membered aryl optionally substituted with 1-3 R4, 5-12 membered monocyclic heterocyclyl containing 1- 3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 R4, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4, 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4, or a 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl;each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; and each R4is independently H, SF5, oxo, halogen, -CN, -OH, -NO2, NH2, -COOH, C1-6alkyl, C1-6alkoxy, C3-6cycloalkyloxy, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C2-6alkenyl, C2-5alkynyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COC1-6alkyl, -COOC1-6alkyl, -CONH2, -CONHC1-6alkyl, -CONHC3-6cycloalkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, -NHCOC3-5cycloalkyl, -P(O)(C1-6alkyl), -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, -S(O)NH2, -S(O)NHC1-6alkyl, -S(O)N(C1-6alkyl)2, -S(O)2NH2, -OSO2-C1-6alkyl, C1-6alkylene-O-C1-6alkyl, C3-8 -cycloalkenyloxy, aryl, heteroaryl, or 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the R4is optionally further substituted with 1-3 groups selected from C1-6alkyl, C1-6haloalkyl, C1-6-alkylene-OH, C1-6alkylene-O-C1-6alkyl, -CONH2, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, C1-6alkoxy, -OH, -COOH, halogen, or a 5-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, and wherein the 5-7-membered heterocycle is optionally substituted with 1-2 groups selected from oxo, halogen, -CN, C1-6alkyl, and C1-6haloalkyl.

[0070] In embodiments of formula (I) when R0is a 7-8 membered monocyclic heterocyclyl containing N and O, each R2in the compound of formula (I) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, - CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0071] In embodiments when R0is a 7-8 membered monocyclic heterocyclyl containing N and O, each R2in the compound of formula (I) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl-OH, -CONH2, - S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0072] In embodiments of formula (I) when R0is a 7-8 membered monocyclic heterocyclyl containing N and O, one R2is not -OCH3and the other R2is not -CH3.

[0073] In embodiments of formula (I) when R0is a 7-8 membered monocyclic heterocyclyl containing N and O, each R2in the compound of formula (I) is H.

[0074] In embodiments, the compound of formula (I) is not a compound in Table B (provided further below).

[0075] In embodiments, the present disclosure provides a compound having a structure of formula (II)(II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein: R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6 alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

[0076] In embodiments, the compound of formula (II) is not a compound in Table B (provided further below).

[0077] In embodiments, the present disclosure provides a compound having a structure of formula (III)or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein: R0is,and wherein: X1and X2are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1and X2are not CR12R13; X3 is O, S, NH, or N(C1-6alkyl);each R2is H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R12is H, halogen, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R13is H, halogen, or C1-C6alkyl; RAis H, C1-6alkyl, (C1-6alkylene)-carbocyclyl, or (C1-6alkylene)-heteroaryl; and RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; or RAand RBare taken together to form a heterocyclyl; and m is 0, 1, 2 or 3; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclegroups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6 cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

[0078] In embodiments, each R2in the compound of formula (III) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl- OH, -CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0079] In embodiments, each R2in the compound of formula (III) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl-OH, - CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0080] In embodiments of formula (III), when m is 2 or 3, one R2is not -OCH3and the other R2is not -CH3.In embodiments, when m is 2 or 3, each R2in the compound of formula (III) is H.

[0081] In embodiments, the compound of formula (III) is not a compound in Table B (provided further below).

[0082] In embodiments, the present disclosure provides a compound having a structure of formula (IV)or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein:each n1, n2, and n3 is independently an integer from 0-3, and the total sum of n1, n2, and n3 is ≤ 4, X1 and X2 are independently O, S, NR6, or CR12R13, wherein at least one of the X1and X2is not CR12R13; each R6, R12, and R13is independently H, halo, or C1-C6alkyl; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6 cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

[0083] In embodiments, the present disclosure provides a compound having a structure of formula (V)or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein: R0is 5-12-membered polycyclic heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1- 6 alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclegroups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6 cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

[0084] In embodiments, the present disclosure provides a compound having a structure of formula (VI) or (VII), (VI) (VII) or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein:wherein: each R2is H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1- 6alkoxy; X4is NR6, O, CR7, CR14R15, S, S(O), or S(O)2; Q is CH or N; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2- 6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH;each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH,-NH2, NHC1-6alkyl, N(C1-6alkyl)2, COOH, COC1-6alkyl, COOC1-6alkyl, CONHC1-6alkyl, CON(C1-6alkyl)2, NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O; L is C1-12alkylene, C2-12alkenylene, C2-12alkynylene, monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; and each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6 alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH.

[0085] In embodiments, each R2in the compound of formula (VI) or (VII) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0086] In embodiments, each R2in the compound of formula (VI) or (VII) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl-OH, - CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0087] In embodiments of formula (VI) or (VII), one R2is not -OCH3 and the other R2is not -CH3.

[0088] In embodiments, each R2in the compound of formula (VI) or (VII) is H.

[0089] In embodiments, the compound of formula (VI) or (VII) is not a compound in Table B (provided further below).

[0090] In embodiments, the present disclosure provides a compound having a structure of formula (VIII) or (IX)(VIII) (IX) or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein:each R2is H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; each X4is independently NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl; wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2,-COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; andR14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH,-NH2, and -COOH; alternatively, R14and R15form =O; L is C1-12alkylene, C2-12alkenylene, C2-12alkynylene, monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; and each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6 alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH.

[0091] In embodiments, each R2in the compound of formula (VIII) or (IX) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0092] In embodiments, each R2in the compound of formula (VIII) or (IX) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl-OH, - CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0093] In embodiments of formula (VIII) or (IX), one R2is not -OCH3 and the other R2is not -CH3.

[0094] In embodiments, each R2in the compound of formula (VIII) or (IX) is H.

[0095] In embodiments, the compound of formula (VI) or (VII) is not a compound in Table B (provided further below).

[0096] In embodiments, the present disclosure provides a compound having a structure of formula (X) or (XI)or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein:each R2is H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6 cycloalkoxy, -CN, -OH,-NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH,-NH2, and -COOH; alternatively, R14and R15form =O; W, X4, and Y2 are each independently CH or N, provided that a maximum of one of W, X4and Y2can be N; D-E is N(H)-C(=O), N(C1-6alkyl)-C(=O), CH2CH2, C(=O)-O, or CH2-O; R11is H, C1-6alkyl, alkylene-O-alkyl, or heterocyclyl; and i and j are each independently 1, 2, or 3; provided that the sum of i+j is 2, 3 or 4; X5and X6are each independently selected from single bond, -C(R14R15)-O-, - C(R14R15)-C(R14R15)-, -OC(R14R15)-, -C(R14R15)-, -O-, and -NR6-; R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6 cycloalkoxy, -CN, -OH,-NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and Ring D is selected from aryl and a 5-8 membered heteroaryl containing 1-3 heteroatoms, wherein aryl and the 5-8 membered heteroaryl containing 1-3 heteroatoms each independently optionally substituted with 1-3 R4, provided that when ring D is aryl, X5and X6are not both -C(R14R15)-C(R14R15)- or -C(R14R15)-; L is C1-12alkylene, C2-12alkenylene, C2-12alkynylene, monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; and each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, - C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independentlyoptionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH.

[0097] In embodiments, each R2in the compound of formula (X) or (XI) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl- OH, -CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0098] In embodiments, each R2in the compound of formula (X) or (XI) is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl-OH, - CONH2, -S(=O)NH2, -S(O)2NH2, or halogenated C1-6alkoxy.

[0099] In embodiments of formula (X) or (XI), one R2is not -OCH3and the other R2is not - CH3.

[0100] In embodiments, each R2in the compound of formula (X) or (XI) is H.

[0101] In embodiments, the compound of formula (X) or (XI) is not a compound in Table B (provided further below).

[0102] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2, or 5-12 membered polycyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R2. In embodiments, each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)- heteroaryl.

[0103] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2. In embodiments, each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, - CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)- carbocyclyl, or -(C1-6alkylene)-heteroaryl.

[0104] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)- heteroaryl.

[0105] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is independently H, -OH, halogen, -NH2, -COOH, C1-6alkyl, C1-6alkyl-OH, -C1-6alkoxy, or halogenated C1-6alkoxy.

[0106] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is independently H, -OH, halogen, -NH2, -COOH, unsubstituted C1-6alkyl, C1-6alkyl-OH, unsubstituted -C1-6alkoxy, or halogenated C1-6alkoxy.

[0107] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is independently H, methoxy, or -OH.

[0108] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII) (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is methoxy.

[0109] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII) (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is OH.

[0110] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII) (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is H.

[0111] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is 5-12 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2. In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is, and wherein: X1and X2are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1 and X2 are not CR12R13; X3 is O, S, NH, or N(C1-6alkyl); each R2is H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R12is H, halogen, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R13is H, halogen, or C1-C6alkyl; RAis H, C1-6alkyl, (C1-6alkylene)-carbocyclyl, or (C1-6alkylene)-heteroaryl; and RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; or RAand RBare taken together to form a heterocyclyl; and m is 0, 1, 2 or 3.

[0112] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R13is independently H, F, Cl, Br, I or C1-C6alkyl. In embodiments, R13is independently H, F, or C1-C6alkyl. In embodiments, R13is H.

[0113] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R12is H, OH, halogen, NH2, COOH, unsubstituted C1-4alkyl, C1-4alkyl-OH, unsubstituted C1-4alkoxy or halogenated C1-4alkoxy. In embodiments, R12is hydrogen.

[0114] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, X1and X2are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1 and X2 are not CR12R13. In embodiments, at least X1 is O, S, NH, N(C1-6alkyl).

[0115] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, X1and X2are independently O, S, or NH, N(C1-6alkyl). In embodiments, X1and X2 are independently O or NH.

[0116] In embodiments of the compound of formula (I), (II), (III), (VI), or (VII), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, X3is O, S, NH, or N(C1-6alkyl). In embodiments, X3is O, S, NH. In embodiments, X3is O.

[0117] In one embodiment of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is:.

[0118] In a further embodiment, RAis H, C1-6alkyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; and RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; or RAand RBare taken together to form a heterocyclyl.

[0119] In one embodiment of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is:. In a further embodiment, RAis H or C1-6alkyl. In embodiments, RAis H. In embodiments, RAis C1-6alkyl. In embodiments, RAis -CH3.

[0120] In one embodiment of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is:. In a further embodiment, RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl. In a further embodiment, RBis C1-6alkyl, C1-6alkylene-aryl or -C1-6alkylene-5-6 membered heteroaryl. In embodiments, RBis C1-6alkyl.

[0121] In one embodiment of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuteratedform thereof, R0is:further embodiment, RAand RBare taken together to form a heterocyclyl.

[0122] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated

[0123] In one embodiment of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,integer of 1-5, or 2-4. In embodiments, m is 2 or 3. In embodiments, m is 2.

[0124] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuteratedform thereof,.

[0125] In one embodiment of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuteratedform thereof, R0is. In a further embodiment, X1is O, X2is NH, and R2is C1-6alkoxy.

[0126] In embodiments,.

[0127] In embodiments,.

[0128] In embodiments,.

[0129] In embodiments, R0is.

[0130] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated.

[0132] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,embodiments, R0is.

[0133] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated.

[0134] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated.

[0135] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated.

[0136] In embodiments of the compound of formula (I), (II), (III), (VI), or (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,.

[0137] In embodiments,embodiments,.

[0138] In embodiments,embodiments,..

[0140] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,.

[0141] In embodiments of the compound of formula (I), (II), (IV), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,, wherein each n1, n2, and n3 is independently an integer from 0-3, and the total sum of n1, n2, and n3 is ≤ 4, X1 and X2 are independently O, S, NR6, or CR12R13, wherein at least one of the X1 and X2 is not CR12R13; each R6, R12, and R13is independently H, halo, or C1-C6alkyl. In embodiments of the compound of formula (I), (II), (IV), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a, wherein R2is H, F, -OH, -CH3, -OCH3, -OCHF2, -OCF3, -OCH2CH3, or -CH2OCH3.

[0142] In embodiments of the compound of formula (I), (II), (IV), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated

[0143] In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is 5-12-membered polycyclic heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R2. In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is 5-12-membered polycyclic heterocycle which is (i) 5-12 membered spiro heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R2, (ii) 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R2, or (iii) 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the bridge heterocycle is optionally substituted with 1-3 R2.

[0144] In one embodiment of the compound of formula (I), (II), (V), (VI), or (VII), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is a 5-12 membered spiro heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R2.

[0145] In a further embodiment, the 5-12-membered spiro heterocycle (i.e., R0) is, and wherein: m1 and m2 are each independently 0, 1, or 2, provided that both m1 and m2 are not 0, or both m1 and m2 are not 2; and p is 1 or 2.

[0146] In embodiments, the 5-12-membered spiro heterocycle

[0147] In one embodiment of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is a 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the fused heterocycle is optionally substituted with 1-3 R2.

[0148] In a further embodiment, the 5-12 membered fused heterocycle (i.e., R0) is, and wherein: m4 is 0 or 1; m5 is 1 or 2; X2is O, S, NH, N(C1-6alkyl), or CR12R13; each R12is independently H, halogen, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1- 6alkyl)2, -COOH, C1-6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; and each R13is independently H, F, Cl, Br, I, or C1-C6alkyl.

[0149] In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,

[0150] In one embodiment of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,,wherein: X2 is O, S, NH, N(C1-6alkyl), or CR12R13; R12is H, halogen, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R13is H, halogen, or C1-C6alkyl; and each m and m’ is independently an integer from 0-3, and the total sum of m and m’ is ≤ 3.

[0151] In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,, and wherein: X2is O, S, NH, N(C1-6alkyl), or CR12R13; R12is H, halogen, or C1-6alkyl; R13is H, halogen, or C1-C6alkyl; and each m and m’ is independently an integer from 0-3, and the total sum of mc and mc’ 2wherein X is NH, O, or S. In embodiments,.

[0153] In embodiments of the compound of formula (I) or (II), or a pharmaceuticallyacceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is or.

[0154] In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,, and wherein: X2 is O, S, NH, N(C1-6alkyl), or CR12R13; R12is H, halogen, or C1-6alkyl; and R13is H, halogen, or C1-6alkyl.

[0155] In embodiments,.

[0156] In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is a 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the bridged heterocycle is optionally substituted with 1-3 R2.

[0157] In embodiments, the 7-12 membered bridged heterocycle (i.e., R0) iseach of which is optionally substituted with 1-4 R2, and wherein: A is a bond, -O-, -O-CH2-, -CH2-O-CH2-, -CH2OCH2CH2-, -CH2-, -CH2CH2-, or - CH2NH-; B is N or CH; m4is 0 or 1; p1is 0, 1, or 2; andq1is 1, 2, or 3.

[0158] In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R0is,

[0159] In embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,,

[0160] In embodiments of the compound of formula (I), (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,.

[0161] In embodiments of the compound of formula (II),or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, whereinR0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6 alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH;alternatively, R14and R15form =O.

[0162] In embodiments of the compound of formula (II), (III), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, each R2is independently -C1-6alkoxy or -C1-6alkyl. In a further embodiment, R2is - C1-6alkoxy.

[0163] In embodiments of the compound of formula (II), (III), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, O HN R0is optionally substituted with 1-3 C1-6alkoxy. In a further embodiment, the C1- 6alkoxy is -OCH3, -OCH2CH3, -OCD3, -OCF3, or -OCHF2.

[0164] In embodiments of the compound of formula (II), (III), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, O HN R0is . L

[0165] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is alkylene, alkenylene, alkynylene, monocyclic heteroarylene, or monocyclic cycloalkylene.

[0166] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is monocyclic heteroarylene, C1-24alkylene, C2-24alkenylene, C2-24 alkynylene, or monocyclic C3-12 cycloalkylene. In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is monocyclic heteroarylene, C1-12alkylene, C2-12alkenylene, C2-12alkynylene, or monocyclic C3-9cycloalkylene. In embodiments, the monocyclic heteroarylene is not a thiophenylene. In a further embodiment, L is optionally substituted with 1-6 R3, 2-5 R3, 3-4 R3, or 1-2 R3. In embodiments, each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1- 6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH.

[0167] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is a monocyclic heteroarylene. In embodiments, the monocyclic heteroarylene is a 5-membered, 6-membered, 7-membered, 8 membered, or 9-membered heteroarylene optionally substituted with 1-6 R3, 2-5 R3, 3-4 R3, or 1-2 R3. In a further embodiment, the monocyclic heteroarylene is a 5-membered heteroarylene optionally substituted with 1-3 R3or a 6-membered heteroarylene optionally substituted with 1-3 R3. In a further embodiment, the monocyclic heteroarylene is a 5-membered heteroarylene optionally substituted with 1-3 R3.

[0168] In embodiments, the monocyclic heteroarylene contains 1-3 heteroatoms selected from N, S, or O. In embodiments, the monocyclic heteroarylene contains 1 or 2 heteroatoms selected from N, S, or O. In a further embodiment, the monocyclic heteroarylene contains 1 or 2 heteroatoms selected from N, or O. In embodiments, the monocyclic heteroarylene is not a thiophenylene.

[0169] In embodiments, the monocyclic heteroarylene is a 5-membered heteroarylene that contains 1 or 2 heteroatoms selected from N, S, or O. In embodiments, the monocyclic ,. In embodiments, the monocyclic heteroarylene is not substituted.

[0170] In embodiments, the monocyclic heteroarylene is, , ,, each of which is optionally substituted with one R3. In embodiments, the monocyclic heteroarylene is not substituted.

[0171] In embodiments, each R3, if present, is independently a halogen (e.g., F, Cl, Br, or I). In embodiments, the halogen is F, Cl, or Br. In embodiments, the halogen is F. In embodiments, each R3, if present, is independently -F, -Cl, or -Br. In embodiments, each R3, if present, is -F.

[0172] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or adeuterated form thereof, the monocyclic heteroarylene (i.e., L),.

[0173] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is a linear or branched hydrocarbon linker. In embodiments, L is a saturated hydrocarbon linker. In embodiments, L is an unsaturated hydrocarbon linker.

[0174] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is an optionally substituted C1-24alkylene, an optionally substituted C2-22alkylene, an optionally substituted C3-20alkylene, an optionally substituted C4-18alkylene, an optionally substituted C5-16 alkylene, an optionally substituted C6-14 alkylene, an optionally substituted C7-12alkylene, an optionally substituted C8-11alkylene, or an optionally substituted C9-10alkylene. In embodiments, L is an optionally substituted C1-12alkylene. In embodiments, L is an optionally substituted C2-8alkylene. In embodiments, L is an optionally substituted C1- 6 alkylene, an optionally substituted C2-5alkylene, or an optionally substituted C3-4 alkylene. In a further embodiment, L is optionally substituted with 1-6 R3, 2-5 R3, 3-4 R3or 1-2 R3. In embodiments, L is not substituted. The carbon counts described herein refer to the number of carbon atoms of the alkylene chain of L which excludes the carbon atoms of optionally present substituents.

[0175] In embodiments, L is an unsubstituted alkylene. In a further embodiment, L is a linear alkylene. In embodiments, L is a linear C1-24 alkylene, a linear C2-22 alkylene, a linear C3-20alkylene, a linear C4-18alkylene, a linear C5-16alkylene, a linear C6-14alkylene, a linear C7-12alkylene, a linear C8-11alkylene, or a linear C9-10alkylene. For example, L is -CH2-, - CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9- , and -(CH2)10-. In embodiments, L is a branched alkylene, such as -(CH2)2CH(CH3)-(CH2)-, - CH2CH(CH3)-(CH2)2-, -CH(CH3)-(CH2)3-, and -CH2CH(CH3)-(CH2)-.

[0176] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In embodiments, L is -CH2CH2-. In embodiments, L is -CH2CH2CH2-. In embodiments, L is -CH2CH2CH2CH2-.

[0177] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is an optionally substituted C2-24alkenylene, an optionally substituted C3-22alkenylene, an optionally substituted C4-20alkenylene, an optionally substituted C5-18alkenylene, an optionally substituted C6-16alkenylene, an optionally substituted C7-14alkenylene, an optionally substituted C8-12alkenylene, or an optionally substituted C9-10alkenylene. In a further embodiment, L is an optionally substituted C2-12alkenylene. In embodiments, L is an optionally substituted C2-8alkenylene. In embodiments, L is an optionally substituted C2-6alkenylene, an optionally substituted C2-5alkenylene, or an optionally substituted C3-4 alkenylene. In a further embodiment, L is optionally substituted with 1-6 R3, 2-5 R3, 3-4 R3or 1-2 R3. In embodiments, L is not substituted. The carbon counts described herein refer to the number of carbon atoms of the alkenylene chain of L which excludes the carbon atoms of optionally present substituents. L can be an alkenylene having a degree of unsaturation of 1-6, 2-5, or 3-4. In embodiments, L is an alkenylene having a degree of unsaturation of 1 or 2. Each double bond of L may have substituents arranged in cis or trans conformation.

[0178] In embodiments, L is an unsubstituted alkenylene. In a further embodiment, L is a linear alkenylene, such as a linear C2-12alkenylene, a linear C3-10alkenylene, a linear C4-9 alkenylene, a linear C5-8alkenylene, or a linear C6-7alkenylene. For example, L is -C=C-, -C=C-C=C-, -CH2-CH=CH-CH2-, -CH2-CH=CH-(CH2)2-, -CH2-CH=CH-(CH2)3-, - (CH2)2-CH=CH-(CH2)2-, -CH=CH-(CH2)3-, and -(CH2)3-CH=CH-(CH2)3-. In embodiments, L is a branched alkenylene, such as -CH2-C(CH3)=CH-CH2-, and -CH2-CH=C(CH3)-CH(CH3)-. In embodiments, L is a substituted alkenylene, for example an alkenylene substituted with one or more halogens (e.g., -CH2-CCl=CCl-CH2-, -CH2-CBr=CBr-CH2-, and -CCl=CCl-CCl=CCl- ).

[0179] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is -C=C- or -C=C-C=C-.

[0180] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), or (VII), (VIII), (IX), (X), (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is an optionally substituted C2-24alkynylene, an optionally substituted C3-22alkynylene, an optionally substituted C4-20alkynylene, an optionally substituted C5-18alkynylene, an optionally substituted C6-16alkynylene, an optionally substituted C7-14alkynylene, an optionally substituted C8-12alkynylene, or an optionally substituted C9-10alkynylene. In a further embodiment, L is an optionally substituted C2-12 alkynylene. In embodiments, L is an optionally substituted C2-8alkynylene. In embodiments, L is an optionally substituted C2-6alkynylene, an optionally substituted C2-5alkynylene, or an optionally substituted C3-4alkynylene. In embodiments, L is optionally substituted with 1-6 R3, 2-5 R3, 3-4 R3or 1-2 R3. In embodiments, L is not substituted. The carbon counts described herein refer to the number of carbon atoms of the alkynylene chain of L which excludes the carbon atoms of optionally present substituents. L may be an alkynylene having 1 or more triple bonds. In embodiments, L is an alkynylene having 1-6 triple bonds, 2-5 triple bonds, or 3-4 triple bonds. In embodiments, L is an alkynylene having 1 triple bond. In embodiments, L is an alkynylene having 2 triple bonds.

[0181] In embodiments, L is an unsubstituted alkynylene. In embodiments, L is a linear alkynylene, such as a linear C2-12alkynylene, a linear C3-10alkynylene, a linear C4-9alkynylene, a linear C5-8alkynylene, or a linear C6-7alkynylene. For example, L is -C≡C-, -C≡C-C≡C-, - CH2-C≡C≡CH2-, -CH2-C≡C-(CH2)2-, -CH2-C≡C-(CH2)3-, -(CH2)2-C≡C-(CH2)2-, -(CH2)2- C≡C-(CH2)3-, and -(CH2)3-C≡C-(CH2)3-.

[0182] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is -C≡C- or -C≡C-C≡C-. In embodiments, L is -C≡C-. In embodiments, L is -C≡C-C≡C-.

[0183] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is an optionally substituted cycloalkylene. In a further embodiment, L is an optionally substituted monocyclic cycloalkylene. In embodiments, L is an optionally substituted monocyclic C3-12cycloalkylene, an optionally substituted monocyclic C4-10 cycloalkylene, an optionally substituted monocyclic C5-9cycloalkylene, an optionally substituted monocyclic C6-8cycloalkylene, or an optionally substituted monocyclic C7cycloalkylene. In embodiments, L is an optionally substituted monocyclic C3-9cycloalkylene. In embodiments, L is an optionally substituted monocyclic C5-7cycloalkylene.In embodiments, L is an optionally substituted monocyclic C6cycloalkylene. In a further embodiment, L is optionally substituted with 1-6 R3, 2-5 R3, 3-4 R3or 1-2 R3. In embodiments, L is not substituted. The carbon counts described herein refer to the number of carbon atoms of the alkylene chain of L which excludes the carbon atoms of optionally present substituents.

[0184] In embodiments, L is an unsubstituted monocyclic cycloalkylene. For example, L is ,

[0185] In embodiments of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, L is. In embodiments, L is. In embodiments, L is. R1

[0186] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is (i) 5-12 membered carbocyclyl optionally substituted with 1-3 R4; (ii) 6-18 membered aryl optionally substituted with 1-3 R4; (iii) 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 R4; (iv) 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4; (v) 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4; or (vi) 7-20 membered tricyclic heteroaryl containing 1- 3 heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4. In embodiments, R1is 5-12 membered carbocyclyl optionally substituted with 1- 3 R4. In embodiments, R1is 6-18 membered aryl optionally substituted with 1-3 R4. In embodiments, R1is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S or O, wherein the monocyclic heterocyclyl is optionally substituted with 1- 3 R4. In embodiments, R1is 5-12 membered monocyclic heteroaryl containing 1-3 heteroatomsselected from N, S or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4. In embodiments, R1is 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4. In embodiments, R1is 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4. In embodiments, each R4is independently H, SF5, oxo, halogen, -CN, -OH, -NO2, NH2, -COOH, C1-6alkyl, C1-6alkoxy, C3-6cycloalkyloxy, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C2-6alkenyl, C2-5alkynyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COC1-6alkyl, -COOC1-6alkyl, -CONH2, -CONHC1-6alkyl, -CONHC3-6cycloalkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, -NHCOC3-5cycloalkyl, -P(O)(C1-6alkyl), -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, -S(O)NH2, -S(O)NHC1-6alkyl, -S(O)N(C1-6alkyl)2, -S(O)2NH2, -OSO2-C1-6alkyl, C1-6alkylene-O-C1-6alkyl, C3-8-cycloalkenyloxy, aryl, heteroaryl, or 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the R4is optionally further substituted with 1-3 groups selected from C1-6alkyl, C1-6haloalkyl, C1-6-alkylene-OH, C1-6alkylene-O-C1-6alkyl, -CONH2, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, C1-6alkoxy, -OH, -COOH, halogen, or a 5-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, and wherein the 5-7-membered heterocycle is optionally substituted with 1-2 groups selected from oxo, halogen, -CN, C1-6alkyl, and C1-6haloalkyl.

[0187] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is 5-12 membered carbocyclyl optionally substituted with 1-3 R4, 6-18 membered aryl optionally substituted with 1-3 R4, 5- 12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 R4, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4, 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4, or a 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4. In embodiments, R1is 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4. In embodiments, R1is 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4. In embodiments, each R4is independently H, SF5, oxo, halogen, -CN, -OH, -NO2,NH2, -COOH, C1-6alkyl, C1-6alkoxy, C3-6cycloalkyloxy, C2-6alkenyloxy, C2-6alkynyloxy, C3-6 cycloalkyl, C2-6alkenyl, C2-5alkynyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COC1-6alkyl, -COOC1-6alkyl, -CONH2, -CONHC1-6alkyl, -CONHC3-6cycloalkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, -NHCOC3-5cycloalkyl, -P(O)(C1-6alkyl), -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, -S(O)NH2, -S(O)NHC1-6alkyl, -S(O)N(C1-6alkyl)2, -S(O)2NH2, -OSO2-C1-6alkyl, C1-6alkylene-O-C1-6alkyl, C3-8- cycloalkenyloxy, aryl, heteroaryl, or 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the R4is optionally further substituted with 1-3 groups selected from C1-6alkyl, C1-6haloalkyl, C1-6-alkylene-OH, C1-6alkylene-O-C1-6alkyl, -CONH2, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, C1-6alkoxy, -OH, -COOH, halogen, or a 5-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, and wherein the 5-7- membered heterocycle is optionally substituted with 1-2 groups selected from oxo, halogen, -CN, C1-6alkyl, and C1-6haloalkyl.

[0188] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R4is selected from R6, R7, R11, R14or R15, wherein: each R6and R11is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2and COOH; each R7is independently selected from H, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl,C2-6alkynyl, C3-6cycloalkyl, cyano, hydroxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, COOH, COC1-6alkyl, COOC1-6alkyl, CONHC1-6alkyl, CON(C1-6alkyl)2, NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups within R7are optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2and COOH; R14and R15are each independently selected from H, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3- 7 membered heterocyclyl and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2and - COOH;alternatively, R14and R15form =O.

[0189] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 5-12 membered carbocyclyl optionally substituted with 1-3 R4groups. In embodiments, R1is, each of which is optionally substituted with 1-3 R4.

[0190] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 6-18 membered aryl optionally substituted with 1-3 R4.

[0191] In embodiments,, wherein L is attached to R1by replacing any hydrogen atom of R1, and wherein each R1is optionally substituted with 1-3 R4.

[0192] In embodiments,.

[0193] In embodiments,.

[0195] In embodiments,.

[0196] In embodiments,.

[0197] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 5-12 membered monocyclicheterocyclyl containing heteroatoms selected from N, S, or O, wherein the monocyclicheterocyclyl is optionally substituted with 1-3 R4. In embodiments,, wherein each R1is optionally substituted with 1-3 R4.

[0198] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 5-12 membered monocyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4. In embodiments, R1is, , , , or N , each of which is optionally substituted with 1-3 R4. In embodiments, each R4is independently H, halogen, C1-C6alkyl, -OSO2C1-6alkyl, or -CN. In embodiments, R1is.

[0199] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 7-14 membered bicyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4. In embodiments, R4is R6or R7, wherein: each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2- 6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl, and cycloalkyl within R6are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl,C2-6alkynyl, C3-6cycloalkyl, -CN, -OH,-NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclegroups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH.

[0200] In embodiments,, each of which is optionally substituted with 1-3 R4. In embodiments, R1is.

[0201] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is, and wherein: each Y is independently O, S, CHR6or NR6; and each R6is independently C1-6alkyl optionally substituted by 1, 2, or 3 F, or by -OH, -O- C1-6alkyl, -N(C1-6alkyl)2, cycloalkyl, or heterocyclyl.

[0202] In embodiments, R1is. In a further embodiment, R0is

[0203] In embodiments of the compound of formula (I), (VI) or (VII), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,wherein: X4is NR6, O, CR7, CR14R15, S, S(O), or S(O)2; Q is CH or N; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH,-NH2, NHC1-6alkyl, N(C1-6alkyl)2, COOH, COC1-6alkyl, COOC1-6alkyl, CONHC1-6alkyl, CON(C1-6alkyl)2, NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

[0204] In embodiments,.

[0205] In embodiments,.

[0206] In embodiments of the compound of formula (I), (VIII), or (IX), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,,wherein: each X4is independently NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl; wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2,-COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH,-NH2, and -COOH; alternatively, R14and R15form =O.R7X4N

[0207] In embodiments, R1is R6. In a further embodiment, each X4is independently O, S, NR6, or CR14R15. In a further embodiment, R6is C1-6alkyl optionally substituted by 1, 2 or 3 F, or by -OH, -O- C1-6alkyl, -N(C1-6alkyl)2, cycloalkyl, or heterocyclyl. In embodiments, R6is C1-6alkyl, wherein the C1-6alkyl is optionally substituted by 1, 2 or 3 F, OH, OC1-6alkyl, N(C1-6alkyl)2, cycloalkyl, or heterocyclyl. In embodiments, R6is C1-6alkyl optionally substituted by cycloalkyl and the cycloalkyl is cyclopropyl.

[0208] In embodiments, R6is C1-6alkyl optionally substituted by heterocyclyl and the heterocyclyl is tetrahydropyran. In embodiments, R6is C1-6alkyl wherein said C1-6alkyl is optionally substituted by 1, 2 or 3 F.

[0209] In embodiments, R6is methyl or ethyl.

[0210] In embodiments, R6is -CH3.

[0211] In embodiments, R7is H, halo, or C1-6alkyl.

[0212] In embodiments, R7is H, F, Cl or CH3.

[0213] In embodiments, R7is H.

[0214] In embodiments, R14and R15are independently H, halogen, or C1-6alkyl.

[0215] In embodiments, R7is H, halo or C1-6alkyl, and R14and R15are independently H, halo or C1-6alkyl.

[0216] In embodiments, each X4is independently NH, O, S, CHF, or CHF2.

[0217] In embodiments, X4is O. ,,

[0220] In embodiments, R1is . In a further embodiment, R0is . In a , -

[0221] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1isoptionally substituted with 1-4 R6or R7group, wherein ring C is a 7-8 membered heterocycle comprising 1-3 heteroatoms selected from O, S, or N.

[0222] In embodiments,each of which is optionally substituted with 1-4 R6or R7groups. In embodiments, R1is, each of which is optionally substituted with 1-4 R4groups..

[0224] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 7-20 membered tricyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4. In embodiments, R4is R6, R7, R11, R14, or R15.

[0225] In embodiments of the compound of formula (I), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 7-20 memberedspiro tricyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the spiro tricyclic heteroaryl is optionally substituted with 1-5 R4.

[0226] In embodiments of the compound of formula (I), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1iseach R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH,-NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH,-NH2, and -COOH; alternatively, R14and R15form =O.

[0227] In embodiments of the compound of formula (I), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is, and whereinW, X4, and Y2 are each independently CH or N, provided that a maximum of one of W, X4 and Y2 can be N; D-E is N(H)-C(=O), N(C1-6alkyl)-C(=O), CH2CH2, C(=O)-O, or CH2-O; R11is H, C1-6alkyl, alkylene-O-alkyl, or heterocyclyl; and i and j are each independently 1, 2, or 3; provided that the sum of i+j is 2, 3 or 4.

[0228] In a further embodiment, W, X4and Y2are each independently selected from CH and N, provided that that a maximum of one of W, X4and Y2can be N.

[0229] In a further embodiment, D-E is selected from N(H)-C(O), N(C1-3-alkyl)-C(O), CH2CH2, C(O)-O and CH2-O. In embodiments, D-E is N(H)-C(O), N(CH3)-C(O), CH2CH2, C(O)-O or CH2-O. In embodiments, D-E is CH2-O.

[0230] In a further embodiment, R11is H, alkylene-O-alkyl, or heterocyclyl. In embodiments, R11is H, CH3OCH2CH2, or heterocyclyl. In embodiments, R11is H, alkylene-O-alkyl, or oxetanyl, tetrahydrofuranyl, 4-tetrahydropyranyl or 3-tetrahydropyranyl. In embodiments, R11is H, C1-3-alkyl, CH3OCH2CH2, oxetanyl, tetrahydrofuranyl, 4-tetrahydropyranyl or 3- tetrahydropyranyl. In embodiments, R11is H, CH3- or oxetanyl.

[0231] In a further embodiment, i and j are each independently 1, 2 or 3; provided that the sum of i+j is 2, 3 or 4.

[0232] In embodiments, R11is H, CH3 or oxetanyl; W is CH or N; X4 is CH or N; Y2 is CH; provided that a maximum of one of W, X and Y can be N; D-E is selected from N(CH3)-C(O), CH2CH2, C(O)-O and CH2-O; i is 1 or 2 and j is 1 or 2 provided that the sum of i+j is 2, 3 or 4.

[0233] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt,

[0234] In embodiments of the compound of formula (I), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is a 7-20 membered fused tricyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4.

[0235] In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof,optionally substituted with 1-5 R4, and wherein: X5and X6are each independently selected from single bond, -C(R14R15)-O-, - C(R14R15)-C(R14R15)-, -OC(R14R15)-, -C(R14R15)-, -O-, and -NR6-; R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6 cycloalkoxy, -CN, -OH,-NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkylis optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and Ring D is selected from aryl and a 5-8 membered heteroaryl containing 1-3 heteroatoms, wherein aryl and the 5-8 membered heteroaryl containing 1-3 heteroatoms each independently optionally substituted with 1-3 R4, provided that when ring D is aryl, X5and X6are not both -C(R14R15)-C(R14R15)- or -C(R14R15)-.

[0236] In embodiments of the compound of formula (I), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is,wherein: R14and R15are each independently selected from H, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3- 7 membered heterocyclyl and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2and - COOH; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2and COOH; andRing D is selected from aryl and 5-8 membered heteroaryl containing 1-3 heteroatoms, wherein aryl and said 5-8 membered heteroaryl containing 1-3 heteroatoms each independently optionally substituted with 1-3 Rg. N

[0237] In a further embodiment, Ring Dor , each of which is optionally substituted with 1-3 R4.

[0238] In embodiments of the compound of formula (I), (X), or (XI), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is.

[0239] In embodiments of the compound of formula (I), (II) or (VII), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is.In a further embodiment, R0 is. In a further embodiment, L is,, ,.

[0240] In embodiments of the compound of formula (II),or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, wherein R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, - C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

[0241] In embodiments,embodiments,.

[0242] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is. In a further embodiment, (i) X4is O; (ii) R6is C1-6alkyl optionally substituted by 1, 2 or 3 F, or by -OH, -O- C1-6alkyl, -N(C1-6alkyl)2, cycloalkyl, or heterocyclyl, C1-6alkylene-NH2optionally substituted by C1-6alkylene-O-C1-6alkyl, NH(C1-6alkyl), or N(C1-6alkyl)2, C1-6alkylene-NH(C1-6alkyl) optionally substituted by C1-6alkylene-O-C1-6alkyl, NH(C1-6alkyl), or N(C1-6alkyl)2, or C1-6alkylene-N(C1-6alkyl)2optionally substituted by C1-6alkylene-O-C1-6alkyl, NH(C1-6alkyl), or N(C1-6alkyl)2; and (iii) each R7is H.

[0243] In embodiments, R6is methyl.

[0244] In embodiments of the compound of formula (II), or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof, R1is. In a furtherembodiment, R0 is. In a further embodiment, L,,.

[0245] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0246] In embodiments, provided herein is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a deuterated form thereof.

[0247] In embodiments, provided herein is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0248] In embodiments, provided herein is a pharmaceutically acceptable salt of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI). Further embodiments of the disclosure relate to a deuterated compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or a pharmaceutically acceptable salt thereof. Additional embodiments of the disclosure relate to a hydrate form of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII).

[0249] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a deuterated form thereof, racemic form thereof, or stereoisomer thereof.

[0250] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof.

[0251] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof.

[0252] In embodiments, provided herein is a compound in Table A, or a hydrate thereof.

[0253] In embodiments, provided herein is a compound set forth in Table A.

[0254] In embodiments, provided herein is a pharmaceutically acceptable salt of a compound in Table A.

[0255] In embodiments, provided herein is a hydrate form of a compound in Table A.

[0256] Table A. Various compounds of the present disclosure

[0257] In embodiments, the compound provided herein is not a compound in Table B, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a deuterated form thereof, racemic form thereof, or stereoisomer thereof.

[0258] Table B.Compositions

[0259] The compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A or pharmaceutically acceptable salts thereof, hydrates thereof, or deuteratedversions 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), 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.

[0260] Depending on the mode of administration, the pharmaceutical composition can comprise from 0.05 to 99 %w (per cent by weight), from 0.05 to 80 %w, from 0.10 to 70 %w, or from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

[0261] In embodiments, the present disclosure provides pharmaceutical composition(s) comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A or a pharmaceutically acceptable salt thereof, as hereinbefore defined in association with pharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s).

[0262] The disclosure further provides a process for the preparation of a pharmaceutical composition of the disclosure which comprises mixing a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A or a pharmaceutically acceptable salt thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s).

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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. Therapeutic Use

[0267] In embodiments, the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A or a pharmaceutically acceptable salt of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A. In embodiments, the composition is administered to the patient for an administration period.

[0268] 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; 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.

[0269] 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, neutrophilic, 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 other fungal 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.

[0270] 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 compoundsof formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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

[0271] 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof.

[0272] In one CF treatment method, a composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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.

[0273] 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%.

[0274] In one embodiment of a method provided herein, a composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or(XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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).

[0275] 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).

[0276] 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), , or Table A, or a pharmaceutically acceptable salt, a hydrate, 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.

[0277] In one embodiment, the bronchiectasis is non-CF bronchiectasis.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof.

[0282] 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).

[0283] 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 andsinuses; (n) rhinorrhea; or (o) any combinations thereof. In some embodiments, obstruction of the middle meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0284] 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.

[0285] 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. In some 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.

[0286] 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.

[0287] 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, physochological 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.

[0288] 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.

[0289] 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 of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), , or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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 thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, the fibroid cancer is leiomyosarcoma.

[0294] 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.

[0295] 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.

[0296] 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, thelymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma. In some embodiments, the lymphoma is Kaposi’s Sarcoma.

[0297] 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.

[0298] 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 lymphocytic leukemia (CLL), multiple myeloma (MM), or myelodysplastic syndrome (MDS). In some embodiments, the liquid tumor is acute myeloid leukemia (AML). In some embodiments, the liquid tumor is acute lymphoblastic leukemia. In some embodiments, the liquid tumor is acute 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).

[0299] 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 isretinoblastoma. In some embodiments, the pediatric cancer is osteosarcoma. In some embodiments, the pediatric cancer is Ewing sarcoma.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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 nociceptive hypersensitivity. 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.

[0305] 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof.

[0306] In embodiments of the present disclosure, a method for treating arthritis 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In embodiments, arthritis is osteoarthritis. In embodiments, arthritis is rheumatoid arthritis.

[0307] Osteoarthritis (OA) is typically not autoimmune in origin and is typically a gradual, degenerative joint disease due to age-related chronic use or injury of the joints leading tocartilage breakdown, bone changes and local non-resolving synovial inflammation. In embodiments, the present disclosure provides a method for treating osteoarthritis (OA) 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof). In embodiments, the treating of osteoarthritis (OA) comprises improving weight loss and / or inflamed paw volume of the patient during the administration period, as compared to the weight loss and / or inflamed paw volume of the patient prior reducing weight loss and / or inflamed paw volume of the patient during the administration period, as compared to the weight loss and / or inflamed paw volume of the patient prior to the administration period.

[0308] 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 invention, in one embodiment, provides a method for treating RA using reversible inhibitors of DPP1 of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0309] 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 invention, 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof.

[0310] 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.

[0311] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating heart failure. In some embodiments, heart failure is heart failure with reduced ejection fraction. In some embodiments, heart failure is heart failure with preserved ejection fraction.

[0312] In yet another embodiment of the disclosure, a method for treating ischemia / reperfusion (IR) injury is provided, comprising administering to a patient in need of treatment, a compound or composition of the present disclosure to the patient in need of treatment. The IR injury, in one embodiment, is due to Heart transplantation (HTX). As such, in one embodiment, the patient is a heart transplant recipient. In a further embodiment, the patient is administered a compound or composition of the present disclosure during heart transplantation or subsequent to heart transplantation. In one embodiment of this method, the patient is administered one of the compounds set forth in Tables A-C. In yet even a further embodiment, the compound is present in an oral composition and is administered once daily to the patient in need of treatment.

[0313] Treating the IR injury in one embodiment, comprises improving left-ventricular (LV) graft function. Graft function can be measured, in one embodiment, by measuring LV systolic function, e.g., by measuring left-ventricular systolic pressure (LVSP), developed pressure, maximal slope of systolic pressure increment (dP / dtmax), and / or rate pressure product (mmHg*bpm).

[0314] In one embodiment, treating IR injury comprises increasing the patient’s LVSP (mmHg) during or subsequent to the administration period, as compared to the patient’s LVSP (mmHg) prior to the administration period. In one embodiment, treating IR injury comprises increasing the patient’s developed pressure (mmHg) during or subsequent to the administration period, as compared to the patient’s developed pressure (mmHg) prior to the administration period. In yet another embodiment, treating IR injury in a patient in need of treatment comprises increasing the maximal slope of systolic pressure increment (dP / dtmax) for the patient during or subsequent to the administration period, as compared to the maximal slope of systolic pressure increment (dP / dtmax) for the patient prior to the administration period. In even yet another embodiment, treating IR injury in a patient in need of treatment comprises increasing the patient’s rate pressure product during or subsequent to the administration period, as compared to the patient’s rate pressure product prior to the administration period.

[0315] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating liver injury. The method comprises administering to thesubject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In embodiments, the liver injury is acute liver injury. In embodiments, the liver injury is drug-induced acute liver injury. In one embodiment, the liver injury is acetaminophen (APAP)-induced acute liver injury. In one embodiment, the liver injury is caused by acetaminophen overdose. In embodiment, the liver injury is caused by nonsteroidal anti- inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac, and naproxen. In one embodiment, the treatment of ALI is a prophylactic treatment

[0316] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating sepsis. The method comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In one embodiment, sepsis is a consequence of the patient’s response to overwhelming bacterial infection. In one embodiment, the treatment of sepsis prevents organ dysfunction and death of the patient.

[0317] 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.

[0318] 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 leastabout 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.

[0319] 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 180 days. 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.

[0320] 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.

[0321] 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.

[0322] 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, thecomposition comprising an effective amount of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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.

[0323] Administration, in one embodiment, is via the oral route. In a further embodiment, the composition is administered once daily.

[0324] The dosage administered will vary with the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, a stereoisomer, or a deuterated form thereof employed, the mode of administration, and the treatment outcome desired. For example, in one embodiment, the daily dosage of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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).

[0325] The compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or Table A, or a pharmaceutically acceptable salt, a hydrate, 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.EXAMPLES

[0326] 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.

[0327] 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. Example 1: Synthesis of (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3- thiazol-2-yl]ethyl}-1,4-oxazepane-2-carboxamide (Compound 1)

[0328] Step 1. Synthesis of 5-bromo-2-(bromomethyl)-1,3-thiazole

[0329] To a stirred solution of 5-bromo-2-methyl-1,3-thiazole (2 g, 11.23 mmol, 1.0 equiv) in CCl4(30 mL) were added BPO (0.06 g, 0.22 mmol, 0.02 equiv) and NBS (2.2 g, 12.35 mmol, 1.1 equiv). The resulting mixture was stirred for 3 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2(3 x 50 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 (20:1) to afford 5-bromo-2-(bromomethyl)-1,3-thiazole (2 g, 69.3%) as a yellow oil. LCMS (ES) [M+1]+m / z:256.

[0330] Step 2. Synthesis of 3-(5-bromo-1,3-thiazol-2-yl)-2- [(diphenylmethylidene)amino]propanenitrile

[0331] To a stirred solution of 5-bromo-2-(bromomethyl)-1,3-thiazole (1 g, 3.89 mmol, 1.0 equiv) and 2-[(diphenylmethylidene)amino]acetonitrile (0.86 g, 3.89 mmol, 1.0 equiv) in DCM (15 mL) and H2O (1.5 mL) were added NaOH (0.31 g, 7.78 mmol, 2.0 equiv) and benzyltrimethylazanium chloride (0.07 g, 0.38 mmol, 0.1 equiv). The resulting mixture was stirred for 3 h at 40°C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH2Cl2(3 x 30 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 residue was purified by silica gel column chromatography, eluted with PE / THF (9:1) to afford 3-(5-bromo-1,3-thiazol-2-yl)-2- [(diphenylmethylidene)amino]propanenitrile (1.1 g, 71.3%) as a yellow solid. LCMS (ES) [M+1]+m / z: 396.

[0332] Step 3. Synthesis of 2-[(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-2-yl]propanenitrile

[0333] To a stirred solution of 3-(5-bromo-1,3-thiazol-2-yl)-2- [(diphenylmethylidene)amino]propanenitrile (500 mg, 1.26 mmol, 1.0 equiv) and 3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (416 mg, 1.51 mmol, 1.2 equiv) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3(348 mg, 2.52 mmol, 2.0 equiv) and Pd(dppf)Cl2(92 mg, 0.12 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford 2-[(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-2- yl]propanenitrile (450 mg, 76.7%) as a yellow solid. LCMS (ES) [M+1]+m / z: 465.

[0334] Step 4. Synthesis of 2-amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol- 2-yl]propanenitrile

[0335] To a stirred solution of 2-[(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-2-yl]propanenitrile (450 mg, 0.96 mmol, 1.0 equiv) in THF (22 mL) and H2O (2 mL) were added HCl (1M) (1 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The aqueous layer was basified to pH 12 with NaOH (1M) (aq.). The resulting mixture was extracted with CH2Cl2(3 x 50 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- amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-2-yl]propanenitrile (220 mg, 75.6%) was used in the next step directly without further purification. LCMS (ES) [M+1]+m / z: 301.

[0336] Step 5. Synthesis of tert-butyl (2S)-2-({1-cyano-2-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

[0337] To a stirred solution of 2-amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3- thiazol-2-yl]propanenitrile (200 mg, 0.66 mmol, 1.0 equiv) and (2S)-4-(tert-butoxycarbonyl)- 1,4-oxazepane-2-carboxylic acid (196 mg, 0.79 mmol, 1.2 equiv) in DCM (3 mL) were added DIEA (258 mg, 1.99 mmol, 3.0 equiv) and HATU (303 mg, 0.79 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere. The residuewas purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford tert- butyl (2S)-2-({1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-2- yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (300 mg, 85.3%) as a white solid. LCMS (ES) [M+1]+m / z: 528.

[0338] Step 6. Synthesis of (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3- thiazol-2-yl]ethyl}-1,4-oxazepane-2-carboxamide

[0339] To a stirred solution of tert-butyl (2S)-2-({1-cyano-2-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (200 mg, 0.37 mmol, 1.0 equiv) in ACN (6 mL) was added TsOH (195 mg, 1.13 mmol, 3.00 equiv). The resulting mixture was stirred for 4 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 (10MMOL / L NH4HCO3) and ACN (30% PhaseB up to 40% in 7 min); Detector, UV. This resulted in (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-2-yl]ethyl}-1,4-oxazepane-2-carboxamide (17 mg, 10.8%) as an off-white solid. LCMS (ES) [M+1]+m / z: 428.1H NMR (300 MHz, DMSO-d6) δ 8.78 (dd, J = 8.5, 3.2 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.43–7.35 (m, 2H), 5.23 (p, J = 7.9 Hz, 1H), 4.10–3.85 (m, 2H), 3.82–3.51 (m, 3H), 3.39 (s, 3H), 3.14 (td, J = 14.3, 3.8 Hz, 1H), 2.88–2.59 (m, 3H), 1.84–1.68 (m, 2H). Example 2: (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-5- yl]ethyl}-1,4-oxazepane-2-carboxamide (Compound 2)

[0340] Step 1. Synthesis of 2-bromo-5-(bromomethyl)-1,3-thiazole

[0341] To a stirred solution of 2-bromo-5-methyl-1,3-thiazole (2 g, 11.233 mmol, 1.0 equiv) in CCl4 (30 mL) were added BPO (0.06 g, 0.225 mmol, 0.02 equiv) and NBS (2.20 g, 12.356 mmol, 1.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2(3 x 50 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 residue was purified by silica gel column chromatography, eluted with PE / THF (20:1) to afford 2-bromo-5-(bromomethyl)-1,3-thiazole (2 g, 69.3%) as a yellow solid. LCMS (ES) [M+H]+m / z:256.

[0342] Step 2. Synthesis of 3-(2-bromo-1,3-thiazol-5-yl)-2- [(diphenylmethylidene)amino]propanenitrile

[0343] To a stirred solution of 2-bromo-5-(bromomethyl)-1,3-thiazole (1 g, 3.892 mmol, 1 equiv) and 2-[(diphenylmethylidene)amino]acetonitrile (0.86 g, 3.892 mmol, 1.0 equiv) in DCM (10 mL) and H2O (1 mL) were added NaOH (0.31 g, 7.784 mmol, 2.0 equiv) and benzyltrimethylazanium chloride (0.07 g, 0.389 mmol, 0.1 equiv). The resulting mixture was stirred for 3 h at 40°C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH2Cl2(3 x 30 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 residue was purified by silica gel column chromatography, eluted with PE / THF (8:1) to afford 3-(2-bromo-1,3-thiazol-5-yl)-2- [(diphenylmethylidene)amino]propanenitrile (1.1 g, 71.3%) as a yellow oil. LCMS (ES) [M+1]+m / z: 396.

[0344] Step 3. Synthesis of 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-5-yl]propanenitrile

[0345] To a stirred solution of 3-(2-bromo-1,3-thiazol-5-yl)-2- [(diphenylmethylidene)amino]propanenitrile (600 mg, 1.514 mmol, 1.0 equiv) and 3-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (499 mg, 1.817 mmol, 1.2 equiv) in dioxane (6 mL) and H2O (0.6 mL) were added K2CO3(418 mg, 3.028 mmol, 2.0 equiv) and Pd(dppf)Cl2(110 mg, 0.151 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford 2- [(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-5- yl]propanenitrile (500 mg, 71.0%) as a yellow solid. LCMS (ES) [M+1]+m / z: 465.

[0346] Step 4. Synthesis of 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol- 5-yl]propanenitrile

[0347] To a stirred solution of 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-5-yl]propanenitrile (500 mg, 1.076 mmol, 1 equiv) in THF (25 mL) and H2O (2.5 mL) were added HCl(1M) (1.2 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL). The aqueous layer was basified to pH 12 with NaOH(1M) (aq.). The resulting mixture was extracted with CH2Cl2(3 x 30 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- amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-5-yl]propanenitrile (250mg) was used in the next step directly without further purification. LCMS (ES) [M+1]+m / z: 301.

[0348] Step 5. Synthesis of tert-butyl (2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-5-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

[0349] To a stirred solution of 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3- thiazol-5-yl]propanenitrile (200 mg, 0.666 mmol, 1.0 equiv) and (2S)-4-(tert-butoxycarbonyl)- 1,4-oxazepane-2-carboxylic acid (196 mg, 0.799 mmol, 1.2 equiv) in DCM (3 mL) were added DIEA (258 mg, 1.998 mmol, 3.0 equiv) and HATU (303 mg, 0.799 mmol, 1.2 equiv). The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford tert-butyl (2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-5- yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (300 mg, 85.3%) as a white solid. LCMS (ES) [M+1]+m / z: 528.

[0350] Step 6. Synthesis of (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3- thiazol-5-yl]ethyl}-1,4-oxazepane-2-carboxamide

[0351] To a stirred solution of tert-butyl (2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1,3-thiazol-5-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, 0.190 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (97 mg, 0.570 mmol, 3.0 equiv). The resulting mixture was stirred for 4 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 (10MMOL / L NH4HCO3) and ACN (30% PhaseB up to 40% in 7 min); Detector, UV. This resulted in (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1,3-thiazol-5-yl]ethyl}-1,4-oxazepane-2-carboxamide (40 mg, 49.3%) as a white solid. LCMS (ES) [M+ H]+m / z: 428.1H NMR (300 MHz, DMSO-d6) δ 8.73 (dd, J = 8.5, 3.5 Hz, 1H), 7.79–7.71 (m, 2H), 7.66 (dt, J = 8.3, 2.3 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 5.12–4.94 (m, 1H), 4.08–3.83 (m, 2H), 3.74 (ddt, J = 12.3, 8.2, 4.4 Hz, 1H), 3.52 (dq, J = 10.2, 5.9, 5.0 Hz, 2H), 3.41 (s, 3H), 3.20 – 3.03 (m, 1H), 2.88-2.49 (m, 3H), 1.91– 1.65(m, 2H). Example 3: Synthesis of (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1- benzothiophen-2-yl]ethyl}-1,4-oxazepane-2-carboxamide (Compound 3)

[0353] A solution of methyl 5-bromofuran-2-carboxylate (5.0 g, 24.38 mmol, 1.0 equiv) and NaBH4 (1.9 g, 48.77 mmol, 2.0 equiv) in MeOH (25 mL) THF (50 mL) was stirred for 16 h at 0℃. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (3x30 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 (5:1) to afford (5-bromofuran-2- yl)methanol (4.0 g, 92.6%) as a yellow green solid. LCMS (ES, m / z): [M-18+H]+:159.1H NMR (400 MHz, DMSO-d6) δ 6.47 (d, J = 3.3 Hz, 1H), 6.34 (d, J = 3.4 Hz, 1H), 5.30 (t, J = 5.8 Hz, 1H), 4.37 (d, J = 5.8 Hz, 2H.

[0354] Step 2. Synthesis of 5-bromo-2-(bromomethyl)-1-benzothiophene

[0355] A solution of (5-bromo-1-benzothiophen-2-yl)methanol (2.0 g, 8.22 mmol, 1.0 equiv), NBS (1.8 g, 9.87 mmol, 1.2 equiv) and PPh3 (2.6 g, 9.87 mmol, 1.2 equiv) in DCM (40 mL) was stirred for 2 h at room temperature. The residue was purified by silica gel columnchromatography, eluted with PE / EA (20:1) to afford 5-bromo-2-(bromomethyl)-1- benzothiophene (2.2 g, 87.3%) as a yellow green solid.

[0356] Step 3. Synthesis of 3-(5-bromofuran-2-yl)-2- [(diphenylmethylidene)amino]propanenitrile

[0357] A solution of 2-bromo-5-(bromomethyl)furan (1.9 g, 7.92 mmol, 1.0 equiv) in DCM (10 mL) was added 2-[(diphenylmethylidene)amino]acetonitrile (1.7 g, 7.92 mmol, 1.0 equiv), benzyltrimethylazanium chloride (0.2 g, 0.79 mmol, 0.1 equiv), NaOH (0.6 g, 15.84 mmol, 2.0 equiv) in H2O (5 mL) was stirred for 3 h at 40℃.The resulting mixture was extracted with CH2Cl2(3 x 100mL). The combined organic layers were washed with brine (3x30 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 (5:1) to afford 3-(5-bromofuran-2-yl)-2- [(diphenylmethylidene)amino]propanenitrile (1.9 g, 63.2%) as a white solid. LCMS (ES, m / z): [M+H]+:379.

[0358] Step 4. Synthesis of 2-[(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)furan-2-yl]propanenitrile

[0359] A solution of 3-(5-bromofuran-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (1.0 g, 2.63 mmol, 1.0 equiv), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3- benzoxazol-2-one (0.9 g, 3.16 mmol, 1.2 equiv), K2CO3(0.7 g, 5.27 mmol, 2.0 equiv) and Pd(dppf)Cl2(0.2 g, 0.26 mmol, 0.1 equiv) in 1,4-dioxane (10 mL) H2O (1mL) was stirred for 2 h at 90℃ under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford 2- [(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)furan-2- yl]propanenitrile (1.0 g, 84.7%) as a yellow oil. LCMS (ES, m / z): [M+H]+:448.

[0360] Step 5. Synthesis of 2-amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)furan-2- yl]propanenitrile

[0361] Into a 100 mL round-bottom flask were added 2-[(diphenylmethylidene)amino]-3-[5- (3-methyl-2-oxo-1,3-benzoxazol-5-yl)furan-2-yl]propanenitrile (400 mg, 0.89 mmol, 1.0 equiv), THF (25 mL), H2O (2.5 mL) and HCl (1 mL)(1M) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The residue was basified to pH 10 with NaOH. The resulting mixture was extracted with EtOAc (3 x50 mL). The combined organic layers were washed with brine (3x30 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 THF to afford 2-amino-3-[5-(3-methyl-2- oxo-1,3-benzoxazol-5-yl)furan-2-yl]propanenitrile (120 mg, 47.3%) as a yellow solid. LCMS (ES, m / z): [M+H]+:284.

[0362] Step 6. Synthesis of tert-butyl (2S)-2-({1-cyano-2-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)furan-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylateSS

[0363] A solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (60 mg, 0.24 mmol, 1.0 equiv) in DCM (5 mL) was treated with 2-amino-3-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)furan-2-yl]propanenitrile (76 mg, 0.27 mmol, 1.1 equiv), DIEA (95 mg, 0.73mmol, 3.0 equiv) followed by the addition of HATU (112 mg, 0.29 mmol, 1.2 equiv) in portions at 0℃. The resulting mixture was stirred for additional 2 h at 0℃. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford tert-butyl (2S)-2-({1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)furan-2-yl]ethyl}carbamoyl)- 1,4-oxazepane-4-carboxylate (120 mg, 96.08%) as a white solid. LCMS (ES, m / z): [M+H]+:511.

[0364] Step 7. Synthesis of (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1- benzothiophen-2-yl]ethyl}-1,4-oxazepane-2-carboxamideBoc

[0365] Into a 8 mL vial were added tert-butyl (2S)-2-({1-cyano-2-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, 0.17 mmol, 1.0 equiv), TsOH (89 mg, 0.51 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 3h at room temperature. The residue 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-{1-cyano-2-[5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepane-2-carboxamide (21.9 mg, 26.50%) as a white solid. LCMS (ES, m / z): [M+H]+:411.2.1H NMR (400 MHz, DMSO-d6) δ 8.65 (dd, J = 8.5, 5.2 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.88 (t, J = 2.7 Hz, 1H), 6.42 (d, J = 3.4 Hz, 1H), 5.11 (dq, J = 15.7, 7.9 Hz, 1H), 4.07 – 3.83 (m, 2H), 3.73 (ddt, J = 12.0, 8.0, 4.1 Hz, 1H), 3.40 – 3.31 (m, 3H), 3.31 – 3.23 (m, 2H), 3.13 (ddd, J = 20.4, 14.2, 3.7 Hz, 1H), 2.80 (dd, J = 12.7, 6.3 Hz, 1H), 2.76 – 2.55 (m, 2H), 1.81– 1.64 (m, 2H). Example 4: Synthesis of (2S)-N-(1-cyano-2-(5-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 4)

[0366] Step 1. Synthesis of tert-butyl 2-formyl-1H-pyrrole-1-carboxylate

[0367] To a mixture of pyrrole-2-carboxaldehyde (10 g, 105.15 mmol, 1.0 equiv), TEA (10.6 g, 105.15 mmol, 1.0 equiv), DMAP (642 mg, 5.26 mmol, 0.05 equiv) in DCM (200 mL), Boc2O (25 g, 115.67 mmol, 1.1 equiv) was added at 0°C. After addition, the reaction was stirred at room temperature for 1 h. Concentrated to remove the solvent, the residue was purified by silica gel column with ethyl acetate / petroleum ether (5%). tert-butyl 2-formyl-1H-pyrrole-1- carboxylate (20 g, 97%) was obtained as white solid. LCMS (ES, m / z): [M+H]+: 196.1H NMR (400 MHz, Chloroform-d) δ 10.35 (s, 1H), 7.46 (dd, J = 3.1, 1.7 Hz, 1H), 7.21 (dd, J = 3.7, 1.7 Hz, 1H), 6.31 (t, J = 3.5 Hz, 1H), 1.67 (s, 9H).

[0368] Step 2. Synthesis of tert-butyl 2-(hydroxymethyl)-1H-pyrrole-1-carboxylate

[0369] To a solution of tert-butyl 2-formyl-1H-pyrrole-1-carboxylate (20 g, 102.45 mmol, 1.0 equiv) in MeOH (240 mL), NaBH4(1.94 g, 51.22 mmol, 0.5 equiv) was added at 0°C. The mixture was stirred for 1 h at the room temperature. The reaction was quenched with water (300 mL), extracted with dichloromethane (2 L x 1, 1 L x 1). The combined organic phase was dried over anhydrous sodium sulfate. Filtered and the filtrate was concentrated to remove the solvent, this result in tert-butyl 2-(hydroxymethyl)-1H-pyrrole-1-carboxylate (20 g, 98%) as colorless oil and used to the next step without further purification. LCMS (ES, m / z): [M+H]+: 198.1H NMR (300 MHz, DMSO-d6) δ 7.19 (dd, J = 3.3, 1.9 Hz, 1H), 6.19 (ddt, J = 3.1, 2.0, 1.1 Hz, 1H), 6.14 (t, J = 3.3 Hz, 1H), 4.94 (t, J = 5.8 Hz, 1H), 4.60 (dd, J = 5.8, 1.1 Hz, 2H), 1.55 (s, 9H).

[0370] Step 3. Synthesis of tert-butyl 2-(chloromethyl)-1H-pyrrole-1-carboxylate

[0371] To a mixture of tert-butyl 2-(hydroxymethyl)-1H-pyrrole-1-carboxylate (20 g, 101.40 mmol, 1.0 equiv), DIEA (26.2 g, 202.80 mmol, 2.0 equiv) in DCM (300 mL), MsCl (14.0 g, 121.68 mmol, 1.2 equiv) was added dropwise. After addition, the reaction was stirred for 2 h at room temperature. The reaction was quenched with water (300 mL), extracted with dichloromethane (200 mL x 1), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This result in tert-butyl 2-(chloromethyl)-1H- pyrrole-1-carboxylate (20 g, 91.5%) as colorless oil and used to the next step without further purification (no LCMS signal). 1H NMR (300 MHz, DMSO-d6) δ 7.34 (dd, J = 3.3, 1.8 Hz, 1H), 6.45 (dd, J = 3.3, 1.8 Hz, 1H), 6.19 (t, J = 3.3 Hz, 1H), 4.96 (s, 2H), 1.59 (s, 9H).

[0372] Step 4. Synthesis of tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-1H- pyrrole-1-carboxylatert, 5

[0373] To a solution of tert-butyl 2-(chloromethyl)-1H-pyrrole-1-carboxylate (20 g, 92.73 mmol, 1.0 equiv) and 2-[(diphenylmethylidene)amino]acetonitrile (20.4 g, 92.73 mmol, 1.0 equiv) in DCM (400 mL), benzyl trimethyl ammonium chloride (1.72 g, 9.27 mmol, 0.1 equiv) was added room temperature. This was followed by the addition of NaOH (7.4 g, 185.46 mmol, 2.0 equiv) in H2O (40 mL) at room temperature. The mixture was stirred for 15 h. The reaction was diluted with water (300 mL), extracted with dichloromethane (300 mL x 1), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column with ethyl acetate / petroleum ether (5%). This result in tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-1H-pyrrole-1-carboxylate (11 g, 21%) as yellow oil and used to the next step without further purification. LCMS (ES, m / z): [M+H]+: 400.

[0374] Step 5. Synthesis of tert-butyl 2-bromo-5-(2-cyano-2- ((diphenylmethylene)amino)ethyl)-1H-pyrrole-1-carboxylate

[0375] To a solution of tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-1H- pyrrole-1-carboxylate (2.4 g, 6.01 mmol, 1.0 equiv) in THF (50 mL), NBS (1.28 g, 7.21 mmol, 1.2 equiv) was added at -78°C and stirred for 1 h. The reaction was warmed to room temperature and stirred for additional 2 h. The reaction was quenched with water (80 mL), extracted with ethyl acetate (60 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This result in tert-butyl 2-bromo-5-(2-cyano-2-((diphenylmethylene)amino)ethyl)-1H-pyrrole- 1-carboxylate (2.6 g, 90.5%) as light brown oil and used to the next step without further purification. LCMS (ES, m / z): [M+H]+: 478.

[0376] Step 6. Synthesis of tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-5-(3- methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrole-1-carboxylate

[0377] To a 100 mL round bottom flask, was added tert-butyl 2-bromo-5-(2-cyano-2- ((diphenylmethylene)amino)ethyl)-1H-pyrrole-1-carboxylate (2.6 g, 5.44 mmol, 1.0 equiv), 3- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (0.75 g, 2.72 mmol, 0.5 equiv), Na2CO3(1.15 g, 10.87 mmol, 2.0 equiv), dioxane (50 mL), H2O (5 mL) in sequence. After insert nitrogen gas, Pd(PPh3)4 (0.44 g, 0.38 mmol, 0.07 equiv) was added. The mixture was heated to 90°C and stirred for 10 h. The reaction was cooled to room temperature, concentrated to remove the solvent, the residue was purified by silica gel column with ethyl acetate / petroleum ether (30%). The fraction of the target was concentrated, 850 mg (purity: 81%) product was obtained and further purified by HPLC with conditions: C18-120 g, acetonitrile / water (0.05% FA contained), Gradient, 30%~80% within 15 min, detector 254 nm.This result in tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-5-(3-methyl-2-oxo- 2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrole-1-carboxylate (560 mg, 19%) as light yellow solid. LCMS (ES, m / z): [M+H]+: 547.

[0378] Step 7. Synthesis of tert-butyl 2-(2-amino-2-cyanoethyl)-5-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-1H-pyrrole-1-carboxylate

[0379] To a solution of tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-5-(3- methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrole-1-carboxylate (460 mg, 0.84 mmol, 1.0 equiv) in THF (25 mL), HCl (1.2 mL, 1 N in water) was added at room temperature. The reaction was stirred for 2 h, before diluted with water (30 mL), extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, the residue was purified by silica gel column with ethyl acetate / petroleum ether (10% to 100%). This result in tert-butyl 2-(2-amino-2-cyanoethyl)-5- (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrole-1-carboxylate (290 mg, 90%) as light yellow solid. LCMS (ES, m / z): [M+H]+: 383.

[0380] Step 8. Synthesis of tert-butyl (2S)-2-((2-(1-(tert-butoxycarbonyl)-5-(3-methyl-2-oxo- 2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4- carboxylate

[0381] To a solution of tert-butyl 2-(2-amino-2-cyanoethyl)-5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)pyrrole-1-carboxylate (280 mg, 0.73 mmol, 1.0 equiv) and (2S)-4-(tert- butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (180 mg, 0.73 mmol, 1.0 equiv) in DCM (6 mL) was added DIEA (190 mg, 1.46 mmol, 2.0 equiv), HATU (334 mg, 0.88 mmol, 1.2 equiv) in sequence. The mixture was stirred for 2 h, concentrated to remove the solvent, the residuewas purified by Prep-HPLC with conditions: MeCN / water (0.05% NH4OH), 20% to 100% within 13 min. This result in tert-butyl (2S)-2-((2-(1-(tert-butoxycarbonyl)-5-(3-methyl-2-oxo- 2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4- carboxylate (290 mg, 65%) as off-white solid. LCMS (ES, m / z): [M+H]+: 610.

[0382] Step 9. Synthesis of (2S)-N-(1-cyano-2-(5-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0383] To a stirred solution of tert-butyl (2S)-2-((2-(1-(tert-butoxycarbonyl)-5-(3-methyl-2- oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)-1-cyanoethyl)carbamoyl)-1,4- oxazepane-4-carboxylate (200 mg, 0.33 mmol, 1.0 equiv) in ACN (4 mL) was added TsOH (847 mg, 4.92 mmol, 15 equiv). The resulting mixture was stirred for 40 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-(1-cyano-2-(5- (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)ethyl)-1,4-oxazepane-2- carboxamide (35 mg, 26%) as a white solid. LCMS (ES, m / z): [M+H]+: 451.3.1H NMR (400 MHz, DMSO-d6) δ 11.13 (brs, 1H), 8.59 (dd, J = 8.2, 6.0 Hz, 1H), 7.43 (s, 1H), 7.37 – 7.27 (m, 2H), 6.47 – 6.41 (m, 1H), 6.00 – 5.97 (m, 1H), 5.09 – 5.00 (m, 1H), 4.05 – 3.97 (m, 1H), 3.95 – 3.84 (m, 1H), 3.77 – 3.69 (m, 1H), 3.37 (s, 3H), 3.28 – 3.11 (m, 2H), 3.14 – 3.05 (m, 1H), 2.88 – 2.58 (m, 3H), 1.82 – 1.69 (m, 2H). Example 5: Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3- benzoxazol-5-yl) pyrrol-3-yl] ethyl] carbamoyl}-1,4-oxazepane-4-carboxylate (Compound 5)

[0384] Step 1. Synthesis of tert-butyl 3-formylpyrrole-1-carboxylate Boc2O DIEA

[0385] A solution of 1H-pyrrole-3-carbaldehyde (6 g, 63.091 mmol, 1 equiv), Boc2O (16.52 g, 75.709 mmol, 1.2 equiv) and DIEA (16.31 g, 126.182 mmol, 2 equiv) in DCM (60 mL) was stirred for 2 h at 0 °C. The resulting mixture was extracted with CH2Cl2(3 x 100mL). The combined organic layers were washed with brine (2x50 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 (5:1) to afford tert-butyl 3- formylpyrrole-1-carboxylate (10 g, 81.19%) as a light yellow oil.

[0386] Step 2. Synthesis of tert-butyl 3-(hydroxymethyl) pyrrole-1-carboxylate N BHBoc Boc

[0387] To a stirred solution of tert-butyl 3-formylpyrrole-1-carboxylate (10 g, 51.225 mmol, 1 equiv) in MeOH (100 mL) was added NaBH4 (1.94 g, 51.225 mmol, 1 equiv) in portions at 0°C. The resulting mixture was stirred for 3 h at 0°C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2(2 x 200 mL). The combined organic layers were washed with brine (1x200 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 (3:1) to afford tert-butyl 3- (hydroxymethyl)pyrrole-1-carboxylate (9 g, 89.08%) as a light yellow oil.

[0388] Step 3. Synthesis of tert-butyl 3-(chloromethyl) pyrrole-1-carboxylateBoc Boc

[0389] To a stirred solution of tert-butyl 3-(hydroxymethyl) pyrrole-1-carboxylate (9 g, 45.631 mmol, 1 equiv) and TEA (13.85 g, 136.893 mmol, 3 equiv) in DCM (100 mL) was added MsCl (5.75 g, 50.194 mmol, 1.1 equiv) dropwise at 0°C.The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2(3 x 100 mL). The combined organic layers were washedwith water (2x50 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 3-(chloromethyl)pyrrole-1- carboxylate (8.5 g, 86.37%) as an off-white oil. LCMS (ES) [M+1]+m / z:217.

[0390] Step 4. Synthesis of tert-butyl 3-{2-cyano-2-[(diphenylmethylidene)amino] ethyl} pyrrole-1-carboxylate

[0391] To a stirred solution of tert-butyl 3-(chloromethyl) pyrrole-1-carboxylate (8 g, 37.092 mmol, 1 equiv) and 2-[(diphenylmethylidene)amino] acetonitrile (8.99 g, 40.801 mmol, 1.1 equiv) in DCM (10 mL) and H2O (1 mL) was added NaOH (4.45 g, 111.276 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for 16 h at 50°C.The resulting mixture was diluted with water (10mL). The resulting mixture was extracted with CH2Cl2(3 x20 mL). The combined organic layers were washed with water (2x10 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 3-{2-cyano-2-[(diphenylmethylidene)amino]ethyl}pyrrole-1-carboxylate (4 g, 26.99%) as a light yellow oil. LCMS (ES) [M+1]+m / z:400.

[0392] Step 5. Synthesis of 2-[(diphenylmethylidene)amino]-3-(1H-pyrrol-3-yl) propanenitrile

[0393] A solution of tert-butyl 3-{2-cyano-2-[(diphenylmethylidene)amino] ethyl} pyrrole-1- carboxylate (4 g, 10.013 mmol, 1 equiv) and DBU (3.05 g, 20.026 mmol, 2 equiv) in EtOH (40 mL) was stirred for 16 h at 80°C.The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-[(diphenylmethylidene)amino]-3-(1H- pyrrol-3-yl)propanenitrile (2.5 g, 83.40%) as a light yellow oil. LCMS (ES) [M+1]+m / z:300.

[0394] Step 6. Synthesis of 2-[(diphenylmethylidene)amino]-3-[1-(3-methyl-2-oxo-1,3- benzoxazol-5-yl) pyrrol-3-yl] propanenitrile

[0395] A solution of 2-[(diphenylmethylidene)amino]-3-(1H-pyrrol-3-yl) propanenitrile (2.5 g, 8.351 mmol, 1 equiv), Cs2CO3(5.44 g, 16.702 mmol, 2 equiv) and CuI (0.95 g, 5.011 mmol, 0.6 equiv) in Toluene (25 mL) was stirred for 12 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-[(diphenylmethylidene)amino]- 3-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl) pyrrol-3-yl] propane nitrile (1.7 g, 45.59%) as a yellow oil. LCMS (ES) [M+1]+m / z:447.

[0396] Step 7. Synthesis of 2-amino-3-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl) pyrrol-3-yl] propanenitrile

[0397] To a stirred solution of 2-[(diphenylmethylidene)amino]-3-[1-(3-methyl-2-oxo-1,3- benzoxazol-5-yl) pyrrol-3-yl] propanenitrile (1.7 g, 3.807 mmol, 1 equiv) in THF (17 mL) was added HCl(1M) (4.25 mL) dropwise at 0°C.The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-amino-3-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrol-3-yl]propanenitrile (650 mg, 60.48%) as a light yellow oil. LCMS (ES) [M+1]+m / z:283.

[0398] Step 8. Synthesis of tert-butyl (2S)-2-({1-cyano-2-[1-(3-methyl-2-oxo-1,3- benzoxazol-5-yl) pyrrol-3-yl] ethyl} carbamoyl)-1,4-oxazepane-4-carboxylate

[0399] To a stirred mixture of 2-amino-3-[1-(3-methyl-2H-1,3-benzoxazol-5-yl) pyrrol-3-yl] propanenitrile (60 mg, 0.224 mmol, 1 equiv), (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2- carboxylic acid (54 mg, 0.224 mmol, 1 equiv) and DIEA (86 mg, 0.672 mmol, 3 equiv) in DCM (1.5 mL) was added HATU (102 mg, 0.269 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for 2 h at 0oC. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:1) to afford tert-butyl (2S)-2-({1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl) pyrrol- 3-yl] ethyl} carbamoyl)-1,4-oxazepane-4-carboxylate (90 mg, 78.99%) as a white solid. LCMS (ES) [M+1]+m / z:510.

[0400] Step 9. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3- benzoxazol-5-yl) pyrrol-3-yl] ethyl] carbamoyl}-1,4-oxazepane-4-carboxylate

[0401] To a stirred mixture of tert-butyl (2S)-2-({1-cyano-2-[1-(3-methyl-2-oxo-1,3- benzoxazol-5-yl) pyrrol-3-yl] ethyl} carbamoyl)-1,4-oxazepane-4-carboxylate (90 mg, 0.177 mmol, 1 equiv) in ACN (1 mL) was added TsOH (106 mg, 0.619 mmol, 3.5 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl (2S)-2-{[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl) pyrrol-3-yl] ethyl] carbamoyl}-1,4-oxazepane-4-carboxylate (15 mg, 16.67%) as a white solid. LCMS (ES) [M+1]+m / z:410.1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 2.2 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.31 (tt, J = 4.5, 2.1 Hz, 2H), 7.26 (dt, J = 8.6, 2.5 Hz, 1H), 6.24 (dd, J = 2.8, 1.7 Hz, 1H), 4.88 (dq, J = 16.2, 7.9 Hz, 1H), 4.01 (ddd, J = 20.6, 7.9, 3.7 Hz, 1H), 3.89 (tdd, J = 12.1, 6.0, 4.5 Hz, 1H), 3.73 (ddt, J = 12.1, 8.1, 4.0 Hz, 1H), 3.39 (s, 3H), 3.20 – 3.01 (m, 2H), 3.00 – 2.90 (m, 1H), 2.86 – 2.57 (m, 3H), 2.36 (s, 1H), 1.82 – 1.66 (m, 2H). Example 6: Synthesis of (S)-N-((S)-1-cyano-4-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)but-3-yn-1-yl)-1,4-oxazepane-2-carboxamide (Compound 11)

[0402] Step 1. Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-methyl-2-oxo- 1,3-benzoxazol-5-yl)pent-4-ynoateDMF, rt, 12 h

[0403] To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]pent-4-ynoate (2 g, 8.80 mmol, 1.0 equiv), 5-bromo-3-methyl-1,3-benzoxazol-2-one (2.41 g, 10.56 mmol, 1.2 equiv) in DMF (25 mL), were added TEA (4.46 g, 44.09 mmol, 5.0 equiv) and Pd(PPh3)4 (1.02 g, 0.88 mmol, 0.1 equiv), CuI (0.34 g, 1.76 mmol, 0.2 equiv) under nitrogen atmosphere. The mixture was stirred for 12 h at room temperature. The reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with PE / THF (3:1) to afford methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-methyl-2-oxo- 1,3-benzoxazol-5-yl)pent-4-ynoate (2.1 g, 63.7%) as grey solid. LCMS (ES, m / z): [M+H]+: 375.

[0404] Step 2. Synthesis of tert-butyl N-[(1S)-1-carbamoyl-4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)but-3-yn-1-yl]carbamate

[0405] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)pent-4-ynoate (2 g, 5.34 mmol, 1.0 equiv) in Ammonia (7.0 M Solution in methanol) (50 mL) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The reaction was diluted by water (20 mL), extracted with EtOAc (30 mL x 2), washed with brine (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 / EA (2:1) to afford tert-butyl N-[(1S)-1-carbamoyl-4-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)but-3-yn-1-yl]carbamate (1.2 g, 62.5%) as grey solid. LCMS (ES, m / z): [M+H]+: 360.

[0406] Step 3. Synthesis of tert-butyl N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)but-3-yn-1-yl]carbamate

[0407] A solution of tert-butyl N-[(1S)-1-carbamoyl-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)but-3-yn-1-yl]carbamate (1.1 g, 3.06 mmol, 1.0 equiv) in DCM (15 mL) was treated with TEA (1.24 g, 12.24 mmol, 4.0 equiv). This was followed by the addition of TFAA (1.29 g, 6.12 mmol, 2.0 equiv) dropwise at 0°C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by water 10 mL at 5°C, extracted with DCM (10 mL), washed with brine (10 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 (1:1) to afford tert-butyl N-[(1S)-1-cyano-4-(3-methyl- 2-oxo-1,3-benzoxazol-5-yl)but-3-yn-1-yl]carbamate (750 mg, 71.8%) as white solid. LCMS (ES, m / z): [M+H]+: 342.

[0408] Step 4. Synthesis of (2S)-2-amino-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pent-4- ynenitrile

[0409] Into a 25 mL round-bottom flask were added tert-butyl N-[(1S)-1-cyano-4-(3-methyl- 2-oxo-1,3-benzoxazol-5-yl)but-3-yn-1-yl]carbamate (700 mg, 2.05 mmol, 1.0 equiv), TsOH (1059 mg, 6.15 mmol, 3.0 equiv) and ACN (10 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with EA (20 ml), basified to pH = 8~9 with saturation NaHCO3. The aqueous layer was extracted with EA (20 ml x 3). The combined organic layer was washed with brine (30 mL x 2), dried over anhydrous Na2SO4. This resulted in (2S)-2-amino-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pent-4- ynenitrile (430 mg, 86.9%) as white foam solid. LCMS (ES, m / z): [M+H]+: 242.

[0410] Step 5. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)but-3-yn-1-yl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0411] To a solution of (2S)-2-amino-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pent-4- ynenitrile (60 mg, 0.25 mmol, 1.0 equiv) in DCM (3 mL) was treated with (2S)-4-(tert- butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (67 mg, 0.27 mmol, 1.1 equiv), DIEA (64 mg, 0.50 mmol, 2.0 equiv). This was followed by the addition of HATU (113 mg, 0.30 mmol, 1.2 equiv) in portions at 0oC. The resulting mixture was stirred for 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 (2S)-2-{[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol- 5-yl)but-3-yn-1-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (93 mg, 79.8%) as white solid. LCMS (ES, m / z): [M+H]+: 469.

[0412] Step 6. Synthesis of tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-5-(3- methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrole-1-carboxylate

[0413] Into a 25 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-4-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)but-3-yn-1-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (93 mg, 0.20 mmol, 1.0 equiv), TsOH (102 mg, 0.60 mmol, 3.0 equiv) and ACN (2 mL) 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 (2S)-N-[(1S)-1-cyano-4-(3-methyl- 2-oxo-1,3-benzoxazol-5-yl)but-3-yn-1-yl]-1,4-oxazepane-2-carboxamide (35 mg, 47.8%) as white solid. LCMS (ES, m / z): [M+H]+: 369.0.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.6 Hz, 1H), 7.37 – 7.28 (m, 2H), 7.20 – 7.16 (m, 1H), 5.03 (q, J = 7.8 Hz, 1H), 4.07 (dd, J = 8.0, 3.6 Hz, 1H), 3.97 – 3.89 (m, 1H), 3.80 – 3.72 (m, 1H), 3.34 (s, 3H), 3.17 – 2.94 (m, 3H), 2.85 – 2.59 (m, 3H), 1.82 – 1.71 (m, 2H). Example 7: Synthesis of (2S)-N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexa-3,5-diyn-1-yl]-1,4-oxazepane-2-carboxamide (Compound 12)

[0414] Step 1. Synthesis of 3-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzoxazol-2-one, , C, 3 hS

[0415] To a stirred solution of 5-bromo-3-methyl-1,3-benzoxazol-2-one (2 g, 8.77 mmol, 1.0 equiv) and trimethylsilylacetylene (2.58 g, 26.31 mmol, 3.0 equiv) in TEA (20 mL) and THF(5 mL) were added CuI (80 mg, 0.44 mmol, 0.05 equiv) and Pd(PPh3)2Cl2(0.62 g, 0.88 mmol, 0.1 equiv). The resulting mixture was stirred for 3 h at 80°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL) extracted with EtOAc (2 x 50 mL). The combined organic layer was 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 (1:1) to afford 3-methyl-5-[2-(trimethylsilyl)ethynyl]- 1,3-benzoxazol-2-one (1.5 g, 69.71%) as light brown solid. LCMS (ES) [M+H]+m / z: 246.

[0416] Step 2. Synthesis of 5-(2-bromoethynyl)-3-methyl-1,3-benzoxazol-2-one

[0417] To a stirred solution of 3-methyl-5-[2-(trimethylsilyl)ethynyl]-1,3-benzoxazol-2-one (1.3 g, 5.30 mmol, 1.0 equiv) in ACN (20 mL) were added H2O (0.19 g, 10.60 mmol, 2.0 equiv) and AgF (0.67 g, 5.30 mmol, 1.0 equiv). The resulting mixture was stirred for 10 min at room temperature under dark atmosphere. To the above mixture was added NBS (0.19 g, 1.06 mmol, 0.2 equiv) in portions at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was 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 (2:1) to afford 5-(2-bromoethynyl)-3- methyl-1,3-benzoxazol-2-one (1.1 g, 82.4%) as a light brown solid. LCMS (ES) [M+H]+m / z: 252.

[0418] Step 3. Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-7-(3-methyl-2-oxo- 1,3-benzoxazol-5-yl)hepta-4,6-diynoateS S

[0419] To a stirred solution of 5-(2-bromoethynyl)-3-methyl-1,3-benzoxazol-2-one (1.1 g, 4.36 mmol, 1.0 equiv) and methyl (2S)-2-[(tert-butoxycarbonyl)amino]pent-4-ynoate (1.49 g,6.54 mmol, 1.5 equiv) in DMF (15 mL) were added TEA (2.21 g, 21.82 mmol, 5.0 equiv), CuI (0.17 g, 0.87 mmol, 0.2 equiv) and Pd(PPh3)4 (0.50 g, 0.44 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (20 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 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 methyl (2S)-2-[(tert- butoxycarbonyl)amino]-7-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)hepta-4,6-diynoate (1 g, 57.5%) as colorless oil. LCMS (ES) [M+H]+m / z: 399.

[0420] Step 4. Synthesis of tert-butyl N-[(1S)-1-carbamoyl-6-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)hexa-3,5-diyn-1-yl]carbamate

[0421] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-7-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)hepta-4,6-diynoate (1.0 g, 2.51 mmol, 1.0 equiv) in NH3(g) (7 M MeOH) (10 mL) was stirred for 3 h at room temperature. The resulting mixture 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-[(1S)-1-carbamoyl-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexa-3,5-diyn-1-yl]carbamate (500 mg, 52%) as a light brown oil. LCMS (ES) [M+H]+m / z: 384.

[0422] Step 5. Synthesis of tert-butyl N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexa-3,5-diyn-1-yl]carbamateS

[0423] To a stirred solution of tert-butyl N-[(1S)-1-carbamoyl-6-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)hexa-3,5-diyn-1-yl]carbamate (500 mg, 1.30 mmol, 1.0 equiv) and TEA (527 mg, 5.22 mmol, 4.0 equiv) in DCM (6 mL) was added TFAA (547 mg, 2.61 mmol, 2.0 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 5 h at room temperature under nitrogen atmosphere. extracted with CH2Cl2(3 x 20 mL). The combined organic layer was 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 (1:1) to afford tert-butyl N-[(1S)-1-cyano-6-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)hexa-3,5-diyn-1-yl]carbamate (250 mg, 52.5%) as a light brown solid. LCMS (ES) [M+H]+m / z: 366.

[0424] Step 6. Synthesis of (2S)-2-amino-7-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)hepta-4,6- diynenitrile

[0425] To a stirred solution of tert-butyl N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol- 5-yl)hexa-3,5-diyn-1-yl]carbamate (250 mg, 0.68 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (353 mg, 2.05 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The reaction was poured into NaHCO3(aq) (20 mL), extracted with EtOAc (3 x 100 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 (2S)-2-amino-7-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)hepta-4,6-diynenitrile (120 mg) was used in the next step directly without further purification. LCMS (ES) [M+H]+m / z: 266.

[0426] Step 7. Synthesis of (2S)-2-{[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexa-3,5-diyn-1-yl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0427] To a stirred solution of (2S)-2-amino-7-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)hepta- 4,6-diynenitrile (103 mg, 0.39 mmol, 1.2 equiv) and (2S)-4-(tert-butoxycarbonyl)-1,4- oxazepane-2-carboxylic acid (80 mg, 0.32 mmol, 1.0 equiv) in DCM (2 mL) were added DIEA (126 mg, 0.98 mmol, 3.0 equiv) and HATU (148 mg, 0.39 mmol, 1.2 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature. Concentrated under reduced pressure to remove the solvent. The residue was purified by silicagel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (2S)-2-{[(1S)-1- cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)hexa-3,5-diyn-1-yl]carbamoyl}-1,4- oxazepane-4-carboxylate (110 mg, 68.5%) as a light yellow solid. LCMS (ES) [M+H]+m / z: 493.

[0428] Step 8. Synthesis of (2S)-N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexa-3,5-diyn-1-yl]-1,4-oxazepane-2-carboxamide

[0429] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)hexa-3,5-diyn-1-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (110 mg, 0.23 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (115 mg, 0.67 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- 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-6-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)hexa-3,5-diyn-1-yl]-1,4-oxazepane-2-carboxamide (30 mg, 34%) as a white solid. LCMS (ES) [M+H]+m / z: 393.11H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.40 – 7.33 (m, 2H), 5.04 (q, J = 7.8 Hz, 1H), 4.07 (dd, J = 8.1, 3.6 Hz, 1H), 3.97 – 3.89 (m, 1H), 3.81 – 3.72 (m, 1H), 3.31 (s, 3H), 3.19 (dd, J = 14.1, 3.8 Hz, 1H), 3.14 – 2.99 (m, 2H), 2.90 – 2.61 (m, 3H), 1.86 – 1.69 (m, 2H). Example 8: Synthesis of (2S)-N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)butyl]-1,4-oxazepane-2-carboxamide (Compound 13)

[0430] Step 1. Synthesis of tert-butyl N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)but-3-yn-1-yl]carbamate

[0431] To a stirred solution of tert-butyl N-[(1S)-1-cyanobut-3-yn-1-yl]carbamate (1 g, 5.15 mmol, 1.0 equiv) and 5-bromo-3-methyl-1,3-benzoxazol-2-one (1.29 g, 5.66 mmol, 1.10 equiv) in DMF (20 mL) were added CuI (0.20 g, 1.03 mmol, 0.2 equiv) and Et3N (2.60 g, 25.74 mmol, 5.0 equiv) and Pd(PPh3)2Cl2(0.36 g, 0.515 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at 60°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL), extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (2 x 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 (4:1) to afford tert-butyl N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)but-3-yn-1-yl]carbamate (1.4 g, 79.6%yield, 95%purity) as a light brown solid. LCMS (ES) [M+1]+m / z: 342.

[0432] Step 2. Synthesis of tert-butyl N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5-

[0433] To a solution of tert-butyl N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)but-3-yn-1-yl]carbamate (700 mg, 2.05 mmol, 1.0 equiv) in MeOH (14 mL) and EA (7 mL) was added Pd / C (200 mg) and Palladium hydroxide, Pd 20% on carbon powder, nominally 50% water (200 mg) in a pressure tank. The mixture was hydrogenated at room temperature under 5 atm of hydrogen pressure for 48 h, filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The crude product tert-butyl N-[(1S)-1-cyano-4-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)butyl]carbamate (400 mg) was used in the next step directly without further purification. LCMS (ES) [M+1]+m / z: 346.

[0434] Step 3. Synthesis of (2S)-2-amino-5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentanenitrile

[0435] To a stirred solution of tert-butyl N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol- 5-yl)butyl]carbamate (400 mg, 1.16 mmol, 1.0 equiv) in ACN (8 mL) was added TsOH (598 mg, 3.47 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The mixture was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with CH2Cl2(3 x 20 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 (2S)-2-amino-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pentanenitrile (200 mg) was used in the next step directly without further purification. LCMS (ES) [M+1]+m / z: 246.

[0436] Step 4. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)butyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0437] To a stirred solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (80 mg, 0.33 mmol, 1.0 equiv) and (2S)-2-amino-5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentanenitrile (136 mg, 0.55 mmol, 1.7 equiv) in DCM (2 mL) were added DIEA (126 mg, 0.98 mmol, 3.0 equiv) and HATU (148 mg, 0.39 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred at 0°C for 2 h. Concentrated under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)butyl]carbamoyl}-1,4-oxazepane-4-carboxylate (110 mg, 71%yield) as a white solid. LCMS (ES) [M+1]+m / z: 473.

[0438] Step 5. Synthesis of (2S)-N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)butyl]-1,4-oxazepane-2-carboxamide

[0439] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)butyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 0.21 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (109 mg, 0.64 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19*150 mm, 5um; mobile phase, Water (0.1% NH3H2O) and ACN (10% Phase B up to 80% in 20 min), Detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)butyl]-1,4-oxazepane-2-carboxamide (25 mg, 31.7%yield) as a white solid. LCMS (ES) [M+1]+m / z: 373.4.1H NMR (300 MHz, DMSO-d6) δ 8.58 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 6.94 (dd, J = 8.2, 1.8 Hz, 1H), 4.80 (q, J = 7.9 Hz, 1H), 4.02 (dd, J = 7.9, 3.6 Hz, 1H), 3.94 – 3.86 (m, 1H), 3.77 – 3.69 (m, 1H), 3.33 (s, 3H), 3.15 (dd, J = 14.2, 3.6 Hz, 1H), 2.88 – 2.57 (m, 5H), 1.95 – 1.56 (m, 6H). Example 9: Synthesis of (2S)-N-[(1S)-1-cyano-5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentyl]-1,4-oxazepane-2-carboxamide (Compound 14)

[0440] Step 1. Synthesis of methyl 5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pent-4-ynoate

[0441] To a stirred solution of 5-bromo-3-methyl-1,3-benzoxazol-2-one (4.2 g, 18.42 mmol, 1.0 equiv) and methyl pent-4-ynoate (4.13 g, 36.83 mmol, 2.0 equiv) in THF (20 mL) and TEA (20 mL) were added Pd(PPh3)4(2.13 g, 1.84 mmol, 0.1 equiv) and CuI (0.70 g, 3.68 mmol, 0.2 equiv). The resulting mixture was stirred at 60°C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)pent-4-ynoate (4.0 g, 84%yield) as a light yellow solid. LCMS (ES) [M+H]+m / z: 260.

[0442] Step 2. Synthesis of methyl 5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pentanoate

[0443] To a stirred solution of methyl 5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pent-4-ynoate (4.0 g, 15.43 mmol, 1.0 equiv) in THF (60 mL) were added Pd / C (0.5 g) and Palladium hydroxide on carbon powder (0.5 g) in portions at room temperature. The resulting mixture was stirred at room temperature for 48 h under hydrogen atmosphere (~2 atm). The resulting mixture was filtered, the filter cake was washed with THF (60 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)pentanoate (3.8 g, 93%yield) as a light yellow solid. LCMS (ES) [M+H]+m / z: 264.

[0444] Step 3. Synthesis of 5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pentanal

[0445] To a stirred solution of methyl 5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pentanoate (1.5 g, 5.70 mmol, 1.0 equiv) in DCM (30 mL) was added Diisobutylaluminum hydride (1.0 M in DCM) (11.39 mL, 11.39 mmol, 2.0 equiv) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 3 h under nitrogen atmosphere. The reaction wasquenched by the addition of sat. NH4Cl (aq.) (20 mL) at -78°C. The resulting mixture was filtered, the filter cake was washed with DCM (30 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with CH2Cl2(3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 5-(3-methyl-2-oxo- 1,3-benzoxazol-5-yl)pentanal (800 mg) was used in the next step directly without further purification. LCMS (ES) [M+H]+m / z: 234.

[0446] Step 4. Synthesis of (S)-2-methyl-N-[5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentylidene]propane-2-sulfinamide

[0447] To a stirred solution of 5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pentanal (800 mg, 3.43 mmol, 1.0 equiv) and (S)-2-methylpropane-2-sulfinamide (623 mg, 5.15 mmol, 1.5 equiv) in DCM (15 mL) was added CuSO4(2189 mg, 13.72 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 40 h. The resulting mixture was diluted with water (30 mL), extracted with CH2Cl2(3 x 20 mL). The combined organic layer was 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 (1:1) to afford (S)-2-methyl-N-[5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentylidene]propane-2-sulfinamide (550 mg, 47%yield) as a light yellow solid. LCMS (ES) [M+H]+m / z: 337.

[0448] Step 5. Synthesis of (S)-N-[(1S)-1-cyano-5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentyl]-2-methylpropane-2-sulfinamide

[0449] To a stirred solution of (S)-2-methyl-N-[5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentylidene]propane-2-sulfinamide (450 mg, 1.34 mmol, 1.0 equiv) and trimethylsilyl cyanide (159 mg, 1.60 mmol, 1.2 equiv) in tetrahydrofuran (6 mL) was added CsF (243 mg,1.60 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 3 h. Filtered and the filtrate was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (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 / EA (1:1) to afford (S)-N-[(1S)-1-cyano-5- (3-methyl-2-oxo-1,3-benzoxazol-5-yl)pentyl]-2-methylpropane-2-sulfinamide (350 mg, 72%yield) as a light yellow oil. LCMS (ES) [M+H]+m / z: 364.

[0450] Step 6. Synthesis of (2S)-2-amino-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexanenitrile

[0451] To a stirred solution of (S)-N-[(1S)-1-cyano-5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentyl]-2-methylpropane-2-sulfinamide (350 mg, 0.96 mmol, 1.0 equiv) in DCM (2 mL) was added HCl (g) in 1,4-dioxane (4.0 M) (2 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with H2O (10 mL). The mixture was basified to pH 7 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 30 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 residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford (2S)-2-amino-6-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)hexanenitrile (200 mg, 80%yield) as a colorless oil. LCMS (ES) [M+H]+m / z: 260.

[0452] Step 7. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)pentyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0453] To a stirred solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (110 mg, 0.45 mmol, 1.0 equiv) and (2S)-2-amino-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexanenitrile (116 mg, 0.45 mmol, 1.0 equiv) in DCM (2 mL) were added DIEA (173 mg, 1.34 mmol, 3.0 equiv) and HATU (204 mg, 0.54 mmol, 1.2 equiv) in portions at 0°C . The resulting mixture was stirred at 0°C for 1 h. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-5-(3- methyl-2-oxo-1,3-benzoxazol-5-yl)pentyl]carbamoyl}-1,4-oxazepane-4-carboxylate (150 mg, 69%yield) as a colorless oil. LCMS (ES) [M+H]+m / z: 487.

[0454] Step 8. Synthesis of (2S)-N-[(1S)-1-cyano-5-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)pentyl]-1,4-oxazepane-2-carboxamide

[0455] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-5-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)pentyl]carbamoyl}-1,4-oxazepane-4-carboxylate (130 mg, 0.27 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (138 mg, 0.80 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The mixture 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-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pentyl]-1,4- oxazepane-2-carboxamide (40 mg, 39%yield) as off-white solid. LCMS (ES) [M+H]+m / z: 387.2.1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 6.94 (dd, J = 8.1, 1.7 Hz, 1H), 4.74 (q, J = 8.0 Hz, 1H), 4.05 – 3.90 (m, 1H), 3.93 – 3.80 (m, 1H), 3.78 – 3.64 (m, 1H), 3.34 (s, 3H), 3.13 (dd, J = 14.2, 3.6 Hz, 1H), 2.86 – 2.56 (m, 5H), 1.94 – 1.67 (m, 4H), 1.65 – 1.51 (m, 2H), 1.36 – 1.30 (m, 2H). Example 10: Synthesis of (2S)-N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexyl]-1,4-oxazepane-2-carboxamide (Compound 15)

[0456] Step 1. Synthesis of tert-butyl N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexyl]carbamate

[0457] To a stirred solution of tert-butyl N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol- 5-yl)hexa-3,5-diyn-1-yl]carbamate (600 mg, 1.64 mmol, 1.0 equiv) in EA (5 mL) and MeOH (5 mL) was added Pd / C (200 mg). The resulting mixture was stirred at room temperature for 48 h under hydrogen atmosphere (20 atm). The resulting mixture was filtered, the filter cake was washed with EA (20 mL). The filtrate was concentrated under reduced pressure. This resulted in tert-butyl N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexyl]carbamate (450 mg, 73%yield) as a light yellow solid. LCMS (ES) [M+H]+m / z: 374.

[0458] Step 2. Synthesis of (2S)-2-amino-7-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)heptanenitrile

[0459] To a stirred solution of tert-butyl N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol- 5-yl)hexyl]carbamate (450 mg, 1.20 mmol, 1.0 equiv) in ACN (6 mL) was added TsOH (622 mg, 3.62 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The mixture was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (4 x 20 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 residue was purified by silica gel column chromatography, eluted with PE / THF (1:2) to afford (2S)-2-amino-7-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)heptanenitrile (250 mg, 76%yield) as a light yellow solid. LCMS (ES) [M+H]+m / z: 274.

[0460] Step 3. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)hexyl]carbamoyl}-1,4-oxazepane-4-carboxylateBoc

[0461] To a stirred solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (90 mg, 0.37 mmol, 1.0 equiv) and (2S)-2-amino-7-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)heptanenitrile (110 mg, 0.40 mmol, 1.1 equiv) in DCM (2 mL) were added DIEA (142 mg, 1.10 mmol, 3.0 equiv) and HATU (167 mg, 0.44 mmol, 1.2 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1 h. Concentrated to remove the solvent, the residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexyl]carbamoyl}-1,4-oxazepane-4-carboxylate (130 mg, 71%yield) as a light yellow solid. LCMS (ES) [M+H]+m / z: 501.

[0462] Step 4. Synthesis of (2S)-N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)hexyl]-1,4-oxazepane-2-carboxamide

[0463] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)hexyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.24 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (123 mg, 0.72 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The mixture 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 15 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)hexyl]-1,4- oxazepane-2-carboxamide (30 mg, 31%yield) as a colorless oil. LCMS (ES) [M+H]+m / z: 401.2.1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H),7.09 (s, 1H), 6.92 (dd, J = 8.1, 1.7 Hz, 1H), 4.70 (q, J = 7.9 Hz, 1H), 3.99 (dd, J = 7.9, 3.6 Hz, 1H), 3.95 – 3.81 (m, 1H), 3.78 – 3.64 (m, 1H), 3.31 (s, 3H), 3.12 (dd, J = 14.2, 3.6 Hz, 1H), 2.86 – 2.72 (m, 1H), 2.73 – 2.53 (m, 4H), 1.88 – 1.66 (m, 4H), 1.64 – 1.48 (m, 2H), 1.38 – 1.22 (m, 4H). Example 11: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]ethyl]-1,4-oxazepane-2-carboxamide (Compound 16)

[0464] Step 1. Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4- hydroxycyclohexyl)propanoate

[0465] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4- hydroxyphenyl)propanoate (7 g, 23.702 mmol, 1 equiv) and Rh.Al2O3(1.4 g, 13.605 mmol, 0.57 equiv) in MeOH (100 mL) was stirred for 16 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x50 mL). The filtrate was concentrated under reduced pressure. This resulted in methyl (2S)-2- [(tert-butoxycarbonyl)amino]-3-(4-hydroxycyclohexyl)propanoate (5.5 g, 76.99%) as a white oil. The crude product mixture was used in the next step directly without further purification. LCMS (ES) [M+H]+m / z: 302.

[0466] Step 2. Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4- oxocyclohexyl)propanoate

[0467] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4- hydroxycyclohexyl)propanoate (5.5 g, 18.249 mmol, 1.0 equiv) and DMP (11.61 g, 27.373 mmol, 1.5 equiv) in DCM (60 mL) was stirred for 2 h at room temperature. The resulting mixture was washed with 60 mL of Na2SO3(aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4- oxocyclohexyl)propanoate (5 g, 91.52%) as a white oil. LCMS (ES) [M+H]+m / z:300.

[0468] Step 3. Synthesis of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4- (trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]propanoate

[0469] To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4- oxocyclohexyl)propanoate (5.5 g, 18.372 mmol, 1 equiv) in THF (50 mL) was added LiHMDS (45.93 mL, 45.930 mmol, 2.5 equiv) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78°C under nitrogen atmosphere. To the above mixture was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (8.53 g, 23.884 mmol, 1.3 equiv) in THF (50 mL) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were 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. This resulted in methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-1- yl]propanoate (6.4 g, 56.52%) as a light yellow oil. LCMS (ES) [M+H]+m / z:432.

[0470] Step 4. Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(3-methyl-2- oxo-1,3-benzoxazol-5-yl)cyclohex-3-en-1-yl]propanoateXphos Pd G2

[0471] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4- (trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]propanoate (6 g, 13.908 mmol, 1.0 equiv) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (1.91 g, 6.954 mmol, 0.5 equiv),Na2CO3(2.95 g, 27.816 mmol, 2.0 equiv) XPhos Pd G2 (1.18 g, 1.391 mmol, 0.1 equiv) in 1,4-dioxane (60 mL),H2O (6 mL) was stirred for 3h at 80°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl (2S)-2-[(tert- butoxycarbonyl)amino]-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)cyclohex-3-en-1- yl]propanoate (1 g, 16.70%) as a yellow oil. LCMS (ES) [M+H]+m / z:431.

[0472] Step 5. Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(3-methyl-2- oxo-1,3-benzoxazol-5-yl)cyclohexyl]propanoate

[0473] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)cyclohex-3-en-1-yl]propanoate (1 g, 2.323 mmol, 1 equiv) and Pd / C (0.2 g, 1.879 mmol, 0.81 equiv) in MeOH (10 mL) was stirred for 3h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x20 mL). The filtrate was concentrated under reduced pressure. This resulted in methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]propanoate (1 g, crude) as a light yellow oil. The crude product mixture was used in the next step directly without further purification. LCMS (ES) [M+H]+m / z:433.

[0474] Step 6. Synthesis of tert-butyl N-[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)cyclohexyl]ethyl]carbamate

[0475] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)cyclohexyl]propanoate (1.0 g, 2.312 mmol, 1 equiv) in NH4OH (25 mL) was stirred for 3 days at 40°C .The resulting mixture was concentrated under reduced pressure. This resulted in tert-butyl N-[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]ethyl]carbamate (1 g, crude) as a light yellow oil. The crude product mixture was used in the next step directly without further purification. LCMS (ES) [M+H]+m / z:418.

[0476] Step 7. Synthesis of tert-butyl N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol- 5-yl)cyclohexyl]ethyl]carbamate

[0477] To a stirred solution of tert-butyl N-[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)cyclohexyl]ethyl]carbamate (1.0 g, 2.395 mmol, 1.0 equiv) and TEA (0.97 g, 9.580 mmol, 4.0 equiv) in DCM (10 mL) was added TFAA (1.01 g, 4.790 mmol, 2.0 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 1h at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x30 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; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]ethyl]carbamate (200 mg, 20.90%) as a white solid. LCMS (ES) [M+H]+m / z:400.

[0478] Step 8. Synthesis of (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]propanenitrile

[0479] To a stirred solution of tert-butyl N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)cyclohexyl]ethyl]carbamate (200 mg, 0.501 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (258 mg, 1.503 mmol, 3.0 equiv) . The resulting mixture was stirred for 3 h at room temperature. The mixture was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2S)-2-amino-3-[4-(3-methyl-2-oxo- 1,3-benzoxazol-5-yl)cyclohexyl]propanenitrile (140 mg, 93.41%) was used in the next step directly without further purification. LCMS (ES) [M+H]+m / z:300.

[0480] Step 9. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)cyclohexyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylateS

[0481] To a stirred solution of (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]propanenitrile (130 mg, 0.434 mmol, 1.0 equiv) and (2S)-4-(tert- butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (106 mg, 0.434 mmol, 1.0 equiv) in DCM (2 mL) were added DIEA (168 mg, 1.302 mmol, 3.0 equiv) and HATU (198 mg, 0.521 mmol, 1.2 equiv) in portions at 0°C . The resulting mixture was stirred for 2 h at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano- 2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)cyclohexyl]ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (150 mg, 65.59%) as a white solid. LCMS (ES) [M+H]+m / z:527.

[0482] Step 10. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]ethyl]-1,4-oxazepane-2-carboxamide

[0483] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3- benzoxazol-5-yl)cyclohexyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (150 mg, 0.285 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (147.14 mg, 0.855 mmol, 3.0 equiv) . The resulting mixture was stirred for 2 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 15 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5- yl)cyclohexyl]ethyl]-1,4-oxazepane-2-carboxamide (40 mg, 32.93%) as a white solid. LCMS (ES) [M+H]+m / z:427.1H NMR (300 MHz, DMSO-d6) δ 8.59 (dd, J = 8.5, 4.1 Hz, 1H), 7.25 – 7.13 (m, 2H), 7.06 – 6.92 (m, 1H), 4.92 – 4.71 (m, 1H), 4.09 – 3.86 (m, 2H), 3.82 – 3.68 (m, 1H), 3.33 (s, 3H), 3.16 (dt, J = 14.2, 3.4 Hz, 1H), 2.91 – 2.52 (m, 4H), 2.11 – 1.90 (m, 1H), 1.88 – 1.69 (m, 6H), 1.63 – 1.39 (m, 5H), 1.16 – 1.02 (m, 1H). Example 12: DPP1 IC50 assay

[0484] Human DPP1 enzyme IC50assay

[0485] 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 was interpolated based on its activity relative to a standard curve of activated human recombinant DPP1 enzyme. IC50 values for each compound were calculated via the XLFit (IDBS Version 5.3.1.3) Add-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. Results are provided in Table 1 below.

[0486] DPP1 Cell IC50assay

[0487] 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. Results are provided in Table 1 below.

[0488] Table 1. DPP1 IC50 values[1][1]N / A means the IC50 data for this entry is not available.[2]The symbols correspond to ranges of IC50 according to the table below.

[0489] 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.

[0490] 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: R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2, or 5-12 membered polycyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkenylene, C2-12alkynylene, monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; R1is 5-12 membered carbocyclyl optionally substituted with 1-3 R4, 6-18 membered aryl optionally substituted with 1-3 R4, 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 R4, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4, 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4, or a 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle;wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; and each R4is independently H, SF5, oxo, halogen, -CN, -OH, -NO2, NH2, -COOH, C1-6alkyl, C1-6alkoxy, C3-6cycloalkyloxy, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C2-6alkenyl, C2-5alkynyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COC1-6alkyl, -COOC1-6alkyl, -CONH2, -CONHC1-6alkyl, -CONHC3-6cycloalkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, -NHCOC3-5cycloalkyl, -P(O)(C1-6alkyl), -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, -S(O)NH2, -S(O)NHC1-6alkyl, -S(O)N(C1-6alkyl)2, -S(O)2NH2, -OSO2-C1-6alkyl, C1-6alkylene-O-C1-6alkyl, C3-8 -cycloalkenyloxy, aryl, heteroaryl, or 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the R4is optionally further substituted with 1-3 groups selected from C1-6alkyl, C1-6haloalkyl, C1-6-alkylene-OH, C1-6alkylene-O-C1-6alkyl, -CONH2, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, C1-6alkoxy, -OH, -COOH, halogen, or a 5-7-membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, and wherein the 5-7-membered heterocycle is optionally substituted with 1-2 groups selected from oxo, halogen, -CN, C1-6alkyl, and C1-6haloalkyl wherein the compound of formula (I) is not a compound in Table B.

2. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is 5-12 membered monocyclic heterocycle containing 1- 3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is, and wherein:X1 and X2 are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1 and X2 are not CR12R13; X3is O, S, NH, or N(C1-6alkyl); each R2is H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1- 6 alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R12is H, halogen, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R13is H, halogen, or C1-C6alkyl; RAis H, C1-6alkyl, (C1-6alkylene)-carbocyclyl, or (C1-6alkylene)-heteroaryl; and RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; or RAand RBare taken together to form a heterocyclyl; and m is 0, 1, 2 or 3.

4. The compound of claim 3, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein, and wherein: X1and X2are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1and X2are not CR12R13;each R2is independently H, halogen, oxo, -CN, -OH, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, COOH, C1-6alkyl, C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R12is H, halogen, or C1-6alkyl; and R13is H, halogen, or C1-C6alkyl.

6. The compound of claim 3, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: X1 and X2 are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1and X2are not CR12R13; X3is O, S, NH, or N(C1-6alkyl); RAis H, C1-6alkyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; and RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; or RAand RBare taken together to form a heterocyclyl; R12is H, halogen, or C1-6alkyl; and R13is H, halogen, or C1-C6alkyl.

7. The compound of claim 5, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, whereinwherein X1is O, X2is NH, and R2is C1-6alkoxy.

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, a stereoisomer, or a X1(CH2)n2(CH2)n1 X2(C 0 H2)n3deuterated form thereof, wherein R is , and wherein: each n1, n2, and n3 is independently an integer from 0-3, and the total sum of n1, n2, and n3 is 4, X1and X2are independently O, S, NR6, or CR12R13, wherein at least one of the X1and X2 is not CR12R13; each R6, R12, and R13is independently H, halo, or C1-C6alkyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, a10. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, a11. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is 5-12-membered polycyclic heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R2.

12. The compound of claim 1 or 11, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is 5-12 membered spiro heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R2, 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R2, or 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the bridge heterocycle is optionally substituted with 1-3 R2.

13. The compound of any one of claims 1, 11, and 12, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is a 5-12 membered spiro heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R2.

14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: m1 and m2 are each independently 0, 1, or 2, provided that both m1 and m2 are not 0, or both m1 and m2 are not 2; and p is 1 or 2.

15. The compound of any one of claims 12-14, wherein16. The compound of any one of claims 1, 11, and 12, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is a 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the fused heterocycle is optionally substituted with 1-3 R2.

17. The compound of claim 16, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: m4 is 0 or 1; m5 is 1 or 2; X2is O, S, NH, N(C1-6alkyl), or CR12R13; each R12is independently H, halogen, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; and each R13is independently H, F, Cl, Br, I, or C1-C6alkyl.

18. The compound of claim 16, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: X2is O, S, NH, N(C1-6alkyl), or CR12R13; R12is H, halogen, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, C1-6alkyl, - CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, or halogenated C1-6alkoxy; R13is H, halogen, or C1-C6alkyl; and each m and m’ is independently an integer from 0-3, and the total sum of m and m’ is ≤ 3.

19. The compound of claim 17, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein20. The compound of claim 12 or 16, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: X2 is O, S, NH, N(C1-6alkyl), or CR12R13; R12is H, halogen, or C1-6alkyl; R13is H, halogen, or C1-C6alkyl; and each m and m’ is independently an integer from 0-3, and the total sum of mc and mc’ is 21. The compound of claim 20, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein X2is NH, O, or S.

22. The compound of claim 21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein.

23. The compound of claim 20, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is.

24. The compound of claim 18, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: X2 is O, S, NH, N(C1-6alkyl), or CR12R13; R12is H, halogen, or C1-6alkyl; and R13is H, halogen, or C1-6alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is.

26. The compound of claim 11 or 12, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is a 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the bridged heterocycle is optionally substituted with 1-3 R2.

27. The compound of claim 26, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0isB A, each of which is optionally substituted with 1-4 R2, and wherein:A is a bond, -O-, -O-CH2-, -CH2-O-CH2-, -CH2OCH2CH2-, -CH2-, -CH2CH2-, or - CH2NH-; B is N or CH; m4is 0 or 1; p1is 0, 1, or 2; and q1is 1, 2, or 3.

28. The compound of claim 26 or 27, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein, ,29. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein,30. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered carbocyclyl optionally substituted with 1-3 R4.

31. The compound of claim 30, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is, each of which is optionally substituted with 1-3 R4.

32. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 6-18 membered aryl optionally substituted with 1-3 R4.

33. The compound of claim 32, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein, wherein L is attached to R1by replacing any hydrogen atom of R1, and wherein each R1is optionally substituted with 1-3 R4.

34. The compound of claim 32, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is.

35. The compound of claim 34, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is.

36. The compound of claim 34 or 35, or a pharmaceutically acceptable salt, a stereoisomer,or a deuterated form thereof, wherein,37. The compound of claim 34, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein.

38. The compound of claim 37, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is.

39. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered monocyclic heterocyclyl containing heteroatoms selected from N, S, or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 R4.

40. The compound of claim 39, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein, wherein each R1is optionally substituted with 1-3 R4.

41. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5-12 membered monocyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 R4.

42. The compound of claim 41, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is, each of which is optionally substituted with 1-3 R4.

43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R4is independently H, halogen, C1-C6alkyl, - OSO2C1-6alkyl, or -CN.

44. The compound of claim 42 or 43, or a pharmaceutically acceptable salt, a stereoisomer, ora deuterated form thereof, wherein R1is, ,,45. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 7-14 membered bicyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 R4.

46. The compound of claim 1 or 45, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4is R6or R7, wherein: each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl, and cycloalkyl within R6are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6 alkenyl,C2-6alkynyl, C3-6cycloalkyl, -CN, -OH,-NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH.

47. The compound of claim 45, or a pharmaceutically acceptable salt, a stereoisomer, or a,each of which is optionally substituted with 1-3 R4.

48. The compound of claim 45 or 46, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: each Y is independently O, S, CHR6or NR6; and each R6is independently C1-6alkyl optionally substituted by 1, 2, or 3 F, or by -OH, -O- C1-6alkyl, -N(C1-6alkyl)2, cycloalkyl, or heterocyclyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is.

50. The compound of claim 45 or 46, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein: X4is NR6, O, CR7, CR14R15, S, S(O), or S(O)2; Q is CH or N; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH;each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2- 6 alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH,-NH2, NHC1-6alkyl, N(C1-6alkyl)2, COOH, COC1-6alkyl, COOC1-6alkyl, CONHC1-6alkyl, CON(C1-6alkyl)2, NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O.

51. The compound of claim 45 or 46, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein, and wherein: each X4is independently NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl; wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2,-COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2- 6 alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatomsselected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH,-NH2, and -COOH; alternatively, R14and R15form =O.

52. The compound of claim 50 or 51, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: each X4is independently O, S, NR6, or CR14R15; R6is C1-6alkyl optionally substituted by 1, 2 or 3 F, or by -OH, -O-C1-6alkyl, -N(C1-6alkyl)2, cycloalkyl, or heterocyclyl; R7is H, halo, or C1-6alkyl; and R14and R15are independently H, halogen, or C1-6alkyl.

53. The compound of claim 51 or 52, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each X4is independently NH, O, S, CHF, or CHF2.

54. The compound of any one of claims 51-53, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is.

55. The compound of any one of claims 51-53, or a pharmaceutically acceptable salt, astereoisomer, or a deuterated form thereof, wherein R1is .

56. The compound of any one of claims 45-53 , or a pharmaceutically acceptable salt, a57. The compound of claim 45 or 46, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1isoptionally substituted with 1-4 R6or R7group, wherein ring C is a 7-8 membered heterocycle comprising 1-3 heteroatoms selected from O, S, or N.

58. The compound of claim 57, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, whereineach of which is optionally substituted with 1-4 R6or R7groups.

59. The compound of claim 57 or 58, or a pharmaceutically acceptable salt, a stereoisomer,or a deuterated form thereof, wherein.

60. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 7-20 membered tricyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4, wherein R4is R6, R7, R11, R14, or R15.

61. The compound of claim 1 or 60, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 7-20 membered spiro tricyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the spiro tricyclic heteroaryl is optionally substituted with 1-5 R4.

62. The compound of claim 60 or 61, or a pharmaceutically acceptable salt, a stereoisomer, or ,, a w e e :each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH,-NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH,-NH2, and -COOH; alternatively, R14and R15form =O.

63. The compound of claim 61-62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinwherein W, X4, and Y2are each independently CH or N, provided that a maximum of one of W, X4 and Y2 can be N; D-E is N(H)-C(=O), N(C1-6alkyl)-C(=O), CH2CH2, C(=O)-O, or CH2-O; R11is H, C1-6alkyl, alkylene-O-alkyl, or heterocyclyl; and i and j are each independently 1, 2, or 3; provided that the sum of i+j is 2, 3 or 4.

64. The compound of any one of claims 60-63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein,.

65. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 7-20 membered fused tricyclic heteroaryl containing heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 R4.

66. The compound of claim 1 or 65, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinoptionally substituted with 1-5 R4, and wherein: X5and X6are each independently selected from single bond, -C(R14R15)-O-, -C(R14R15)- C(R14R15)-, -OC(R14R15)-, -C(R14R15)-, -O-, and -NR6-; R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH,-NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH;Ring D is selected from aryl and a 5-8 membered heteroaryl containing 1-3 heteroatoms, wherein aryl and the 5-8 membered heteroaryl containing 1-3 heteroatoms each independently optionally substituted with 1-3 R4, provided that when ring D is aryl, X5and X6are not both -C(R14R15)-C(R14R15)- or -C(R14R15)-.

67. The compound of claim 66, or a pharmaceutically acceptable salt, a stereoisomer, or aeach of which is optionally substituted with 1-5 R4.

68. The compound of claim 66 or 67, or a pharmaceutically acceptable salt, a stereoisomer, or Na deuterated form thereof, wherein Ring D is ,, or , each of which is optionally substituted with 1-3 R4.

69. The compound of any one of claims 66-68, or a pharmaceutically acceptable salt, a,O70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a monocyclic heteroarylene.

71. The compound of claim 70, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the monocyclic heteroarylene is a 5-membered heteroarylene optionally substituted with 1-3 R3or a 6-membered heteroarylene optionally substituted with 1-3 R3.

72. The compound of claim 70 or 71, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the monocyclic heteroarylene contains 1-3 heteroatoms selected from N, S, or O.

73. The compound of any one of claims 70-72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the monocyclic heteroarylene is74. The compound of any one of claims 70-73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the monocyclic heteroarylene iseach of which is optionally substituted with one R3.

75. The compound of claim 73 or 74, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R3is independently a halogen.

76. The compound of claim 75, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the halogen is -F.

77. The compound of any one of claims 70-76, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the monocyclic heteroarylene is78. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C1-12alkylene or a C2-12alkynylene, each of which is optionally substituted with 1-6 R3.

79. The compound of claim 78, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C1-12alkylene.

80. The compound of claim 78 or 79, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C2-8alkylene.

81. The compound of any one of claims 78-80, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

82. The compound of claim 78, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C2-12alkynylene.

83. The compound of claim 78 or 82, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C2-8alkynylene.

84. The compound of any one of claims 78, 82, and 83, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is -C≡C- or -C≡C-C≡C-.

85. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a monocyclic C3-9cycloalkylene optionally substituted with 1-6 R3.

86. The compound of claim 85, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a monocyclic C5-7cycloalkylene.

87. The compound of claim 85 or 86, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is.

88. The compound of any one of claims 70-87, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R0is.

89. The compound of any one of claims 70-88, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is.

90. The compound of claim 1, having a structure of formula (II)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R0is 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R2; L is C1-12alkylene, C2-12alkynylene, 5-membered monocyclic heteroarylene, or monocyclic C3-9cycloalkylene, provided that the monocyclic heteroarylene is not a thiophenylene, wherein L is optionally substituted with 1-6 R3; each R2is independently H, halogen, oxo, -CN, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -COOH, -C1-6alkyl, -C1-6alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -C1-6alkoxy, halogenated C1-6alkoxy, -(C1-6alkylene)-carbocyclyl, or -(C1-6alkylene)-heteroaryl; each R3is independently halogen, -C1-6alkyl, -C1-6alkoxy, -S-C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-6cycloalkyl, -CN, -OH, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CON1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, or heterocycle; wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH2, and -COOH; X4is NR6, O, CR14R15, S, S(O), or S(O)2; each R6is independently selected from H, C1-6alkyl, -COC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NH2, C1-6alkylene-NH(C1-6alkyl), C1-6alkylene-N(C1-6alkyl)2, -(C1-6alkylene)-heterocyclyl, wherein the R6is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)2, -COOH, and C1-6alkylene-O-C1-6alkyl; each R7is independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CN, -OH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -COOH, -COC1-6alkyl, -COOC1-6alkyl, -CONHC1-6alkyl, -CON(C1-6alkyl)2, -NHCOC1-6alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups within R7are optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; and R14and R15are each independently selected from H, deuterium, halogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, -CN, -OH, -NH2, -COOH, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, -SO2-3-7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1- 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from deuterium, halogen, -CN, -OH, -NH2, and -COOH; alternatively, R14and R15form =O, wherein the compound of formula (II) is not a compound in Table B.

91. The compound of claim 90, wherein each R2is independently -C1-6alkoxy or -C1-6alkyl.

92. The compound of claim 90 or 91, wherein R2is -C1-6alkoxy. O HN 93. The compound of any one of claims 90-92, wherein R0is optionally substituted with 1-3 C1-6alkoxy.

94. The compound of claim 93, wherein the C1-6alkoxy is -OCH3, -OCH2CH3, -OCD3, - OCF3, or -OCHF2. O HN 95. The compound of any one of claims 90-94, wherein R0is .

96. The compound of any one of claims 90-95, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: X4is O; R6is C1-6alkyl optionally substituted by 1, 2 or 3 F, or by -OH, -O-C1-6alkyl, -N(C1-6alkyl)2, cycloalkyl, or heterocyclyl, C1-6alkylene-NH2optionally substituted by C1-6alkylene-O-C1-6alkyl, NH(C1-6alkyl), or N(C1-6alkyl)2, C1-6alkylene-NH(C1-6alkyl) optionally substituted by C1-6alkylene-O-C1-6alkyl, NH(C1-6alkyl), or N(C1-6alkyl)2, or C1-6alkylene-N(C1-6alkyl)2optionally substituted by C1-6alkylene-O-C1-6alkyl, NH(C1-6alkyl), or N(C1-6alkyl)2; and each R7is H.

97. The compound of claim 96, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R6is methyl.

98. The compound of any one of claims 90-97, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a 5-membered monocyclic heteroarylene.

99. The compound of claim 98, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the 5-membered heteroarylene is optionally substituted with 1 or 2 R3.

100. The compound of claim 98 or 99, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the 5-membered monocyclic heteroarylene contains 1-3 heteroatoms selected from N, S, or O.

101. The compound of claim 99 or 100, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the 5-membered monocyclic heteroarylene is,, each of which is optionally substituted with 1 or 2 R3.

102. The compound of any one of claims 99-101, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the 5-membered monocyclic heteroarylene iseach of which is optionally substituted with one R3.

103. The compound of claim 101 or 102, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R3is independently a halogen.

104. The compound of claim 103, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the halogen is -F.

105. The compound of any one of claims 99-104, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the 5-membered monocyclic heteroarylene is106. The compound of any one of claims 90-97, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C1-12alkylene or a C2-12alkynylene, each of which is optionally substituted with 1-6 R3.

107. The compound of claim 106, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C1-12alkylene.

108. The compound of claim 106 or 107, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C2-8alkylene.

109. The compound of any one of claims 106-108, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

110. The compound of claim 106, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C2-12alkynylene.

111. The compound of claim 106 or 110, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a C2-8alkynylene.

112. The compound of any one of claims 106, 110, and 111, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is -C≡C- or -C≡C-C≡C-.

113. The compound of any one of claims 90-97, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a monocyclic C3-9cycloalkylene optionally substituted with 1-6 R3.

114. The compound of claim 113, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a monocyclic C5-7 cycloalkylene.

115. The compound of claim 113 or 114, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is.

116. The compound of any one of claims 1, 70, and 98, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound ispharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

117. The compound of any one of claims 1, 70, 98, and 116, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound ispharmaceutically acceptable salt or deuterated form thereof.

118. The compound of any one of claims 1, 78, and 106, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound is, ,119. The compound of any one of claims 1, 78, 106, and 118, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound isdeuterated form thereof.

120. The compound of any one of claims 1, 85, and 113, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound ispharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

121. The compound of any one of claims 1, 85, 113, and 120, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound is122. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

123. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

124. The method of claim 123, 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 rhinitis including 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).

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

126. The method of claim 124, wherein the obstructive disease of the airway is acute respiratory distress syndrome (ARDS).

127. The method of claim 124, wherein the obstructive disease of the airway is bronchitis.

128. The method of claim 124, wherein the obstructive disease of the airway is lung fibrosis.

129. The method of claim 124, wherein the obstructive disease of the airway is emphysema.

130. The method of claim 124, wherein the obstructive disease of the airway is cystic fibrosis (CF).

131. The method of claim 124, wherein the obstructive disease of the airway is bronchiectasis.

132. The method of claim 124, wherein the obstructive disease of the airway is sarcoidosis.

133. The method of claim 124, wherein the obstructive disease of the airway is alpha-1 antitrypsin (A1AT) deficiency.

134. The method of claim 124, wherein the obstructive disease of the airway is farmer’s lung.

135. The method of claim 124, wherein the obstructive disease of the airway is hypersensitivity pneumonitis.

136. The method of claim 124, wherein the obstructive disease of the airway is a complication of lung transplantation.

137. The method of claim 124, wherein the obstructive disease of the airway is a vasculitic or thrombotic disorder of the lung vasulature.

138. The method of claim 124, wherein the obstructive disease of the airway is pulmonary hypertension.

139. The method of claim 124, wherein the obstructive disease of the airway is iatrogenic cough.

140. The method of claim 124, wherein the obstructive disease of the airway is acute rhinitis.

141. The method of claim 124, wherein the obstructive disease of the airway is chronic rhinitis.

142. The method of claim 124, wherein the obstructive disease of the airway is rhinitis medicamentosa or vasomotor rhinitis.

143. The method of claim 124, wherein the obstructive disease of the airway is nasal polyposis.

144. The method of claim 124, wherein the obstructive disease of the airway is COPD.

145. The method of claim 125, wherein the asthma is bronchial, allergic, intrinsic, extrinsic, neutrophilic, exercise-induced, or drug-induced asthma.

146. The method of claim 127, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

147. The method of claim 128, wherein the lung fibrosis is idiopathic pulmonary fibrosis, cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, or fibrosis complicating anti-neoplastic therapy or chronic infection.

148. The method of claim 131, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

149. The method of claim 131, wherein the bronchiectasis is associated with cystic fibrosis.

150. The method of claim 138, wherein the pulmonary hypertension is pulmonary arterial hypertension.

151. The method of claim 138, wherein the pulmonary hypertension is pulmonary hypertension due to left heart disease.

152. The method of claim 138, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

153. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

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

155. The method of claim 154, 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.

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

157. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

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

159. The method of claim 157, wherein the bronchiectasis is associated with cystic fibrosis.

160. The method of any one of claims 157-159, wherein the treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

161. The method of claim 160, wherein improving lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 second (FEV1), increasing the patient’sforced 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.

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

163. The method of any one of claims 157-162, wherein the treating comprises decreasing the rate of pulmonary exacerbation, as compared to the rate of pulmonary exacerbation of the patient prior to treatment.

164. The method of any one of claims 157-163, wherein the treating comprises increasing the time to first pulmonary exacerbation, as compared to an untreated patient.

165. The method of claim 163 or 164, 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; and (6) hemoptysis.

166. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

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

168. The method of claim 166, wherein the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

169. The method of any one of claims 166-168, wherein the chronic rhinosinusitis is refractory chronic rhinosinusitis.

170. The method of any one of claims 166-169, wherein treating comprises reducing, diminishing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS.

171. The method of claim 170, 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.

172. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

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

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

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

176. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

177. The method of claim 176, wherein the cancer is a metastatic cancer.

178. The method of claim 177, wherein the metastatic cancer is breast to lung metastatic cancer.

179. The method of claim 177, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver.

180. The method of claim 177, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

181. The method of claim 177, 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.

182. The method of claim 177, 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.

183. The method of claim 177, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or the kidney.

184. The method of claim 177, wherein the metastatic cancer comprises metastasis of lymphoma to the kidney, ovary, liver, bladder, or the spleen.

185. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

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

187. The method of claim 186, wherein the arthritis is rheumatoid arthritis or osteoarthritis.

188. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

189. The method of claim 188, wherein the inflammatory bowel disease (IBD) is Crohn’s disease.

190. The method of claim 188, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

191. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

192. The method of claim 191, wherein the ANCA associated vasculitis is granulomatosis with polyangiitis (GPA).

193. The method of claim 191, wherein the ANCA associated vasculitis is microscopic polyangiitis (MPA).

194. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122, 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.

195. 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 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

196. The method of claim 195, wherein the heart failure is heart failure with reduced ejection fraction.

197. The method of claim 195, wherein the heart failure is heart failure with preserved ejection fraction.

198. A method for treating ischemia / reperfusion (IR) injury in a patient in need thereof comprising, administering to the patient, an effective amount of a compound of any one of claims 1-121, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 122.

199. The method of claim 198, wherein the patient is a heart transplant recipient.

200. The method of claim 198 or 199, wherein the IR injury is due to heart transplantation.

201. The method of any one of claims 198-200, wherein the treating comprises improving left-ventricular (LV) graft function of the patient.

202. The method of claim 201, wherein improving left-ventricular (LV) graft function comprises improving LV systolic function of the patient.

203. The method of claim 202, wherein improving left-ventricular (LV) systolic function of the patient comprises improving LV systolic pressure (LVSP), developed pressure, maximal slope of systolic pressure increment (dP / dtmax), the rate pressure product (mmHg*bpm) of the patient, or a combination thereof.

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

205. The method of claim 204, wherein the liver injury is acute liver injury.

206. The method of claim 204, wherein the liver injury is drug-induced acute liver injury.

207. The method of any one of claims 123-206, wherein the effective amount of the compound or composition is administered once daily during an administration period.

208. The method of any one of claims 123-207, wherein the effective amount of the compound or composition is administered orally.

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