Dipeptidyl peptidase 1 inhibitors and uses thereof

Abstract

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

Description

DIPEPTIDYL PEPTIDASE 1 INHIBITORS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to International Patent Application No. PCT / CN2024 / 087534, filed on April 12, 2024, and International Patent Application No. PCT / CN2025 / 082555, filed on March 14, 2025, the contents of which are hereby incorporated by reference in their entireties 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 takeup 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 engulf bacteria 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 al- 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 has been reported in a number of diseases characterized by tissue destruction and inflammation.

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

[0008] In embodiments, the present disclosure provides a compound of formula (I):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; each R4is independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -COOH, -Ci-C6alkyl, -Ci-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OCi- C6alkyl, halogenated -OCi-C6alkyl, -S(Ci-C6alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), - SO2N(CI-C6alkyl), -SO2NR5R6, or -S(=NH)(O)(CI-C6alkyl);R4ais -OH or -OC1-C3 alkyl;R5and R6are each independently hydrogen, C1-6 alkyl, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), or R5and R6together with the nitrogen atom to which they are attached form a heterocyclyl; each R7is independently Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl; m is 0, 1, or 2; and each k is independently 0, 1, 2, 3, or 4.

[0009] In embodiments, the present disclosure provides a compound of formula (I-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

[0010] In embodiments of the compounds of formula (I-A), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (LAI)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0011] In embodiments of the compounds of formula (I), (I-A), or (LAI), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (LA2)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0012] In embodiments of the compounds of formula (I), (LA), or (LAI), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (LA3)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0013] In embodiments, the present disclosure provides a compound of formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

[0014] In embodiments of the compounds of formula (I) or (I-B), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-B 1)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0015] In embodiments of the compounds of formula (I), (I-B), or (I-Bl), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-B2)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0016] In embodiments of the compounds of formula (I), (I-B), or (I-Bl), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-B3)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0017] In embodiments, the present disclosure provides a compound of formula (I-C):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

[0018] In embodiments of the compounds of formula (I) or (I-C), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-Cl)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0019] In embodiments of the compounds of formula (I) or (I-C), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-C2)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0020] In embodiments, the present disclosure provides a compound of formula (II):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN;each R4and R4aare independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci- C6alkyl)2, -COOH, -Ci-C6alkyl, -Ci-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, - OC1-C6 alkyl, halogenated -OCi-C6alkyl, -S(Ci-C6alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), -SO2N(CI-C6alkyl), -SO2NR5R6, or -S(=NH)(O)(CI-C6alkyl);R5and R6are each independently hydrogen, C1-6 alkyl, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), or R5and R6together with the nitrogen atom to which they are attached form a heterocyclyl;R7is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl; p is 0 or 1; m is 0, 1, or 2; and each k is independently 0, 1, 2, 3, or 4.

[0021] In embodiments, the present disclosure provides a compound selected from Compounds A145-A156, or a pharmaceutically acceptable salt, a stereoisomer, a racemic form thereof, or a deuterated form thereof.

[0022] In embodiments, the present disclosure provides a compound selected from Compounds H1-H44, or a pharmaceutically acceptable salt, a stereoisomer, a racemic form thereof, or a deuterated form thereof.

[0023] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-Al), (I- A2), (I-A3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof), and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0024] In embodiments, the present disclosure provides a method for treating an obstructive disease of the airway in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (LA), (I- Al), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0025] In embodiments, the present disclosure provides a method for treating cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (LA), (LAI), (LA2), (LA3), (I- B), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0026] In embodiments, the present disclosure provides a method for treating chronic chinosinusitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-Al), (I-A2), (I-A3), (LB), (LB1), (LB2), (LB3), (I-C), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0027] 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), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0028] 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), (LA), (LAI), (LA2), (LA3), (I- B), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0029] 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), (LA), (LAI), (LA2), (LA3), (I- B), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0030] In embodiments, the present disclosure provides a method for treating 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), (LA), (LAI), (LA2), (LA3), (I- B), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0031] 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), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0032] In embodiments, the present disclosure provides a method for treating an antineutrophil cytoplasmic antibody associated vasculitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0033] In embodiments, the present disclosure provides a method for treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-Al), (I-A2), (I-A3), (I- B), (I-Bl), (I-B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof), wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, sweet’s syndrome, dermatomyositis / polymyositis, neutrophilic dermatoses, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or a ventilator-induced lung injury.

[0034] In embodiments, the present disclosure provides a method for treating heart failure in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-Al), (I-A2), (I-A3), (I- B), (I-Bl), (I-B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0035] In embodiments, the present disclosure provides 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 disclosed herein (e.g., a compound of formula (I), (I-A), (I-Al), (I-A2), (I-A3), (LB), (I-Bl), (I-B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof) or a pharmaceutical composition comprising the compound disclosed herein.

[0036] In embodiments, the present disclosure provides a method for treating liver injury in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-Al), (I-A2), (I-A3), (I- B), (I-Bl), (I-B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof) or a pharmaceutical composition comprising the compound disclosed herein.DETAILED DESCRIPTION

[0037] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in theirentireties 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.

[0038] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0039] 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.

[0040] 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.

[0041] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0042] “Cyano” refers to the -CN radical.

[0043] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0044] “ Oxo” refers to the =0 substituent.

[0045] “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-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes allmoieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl 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.

[0046] “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-C12 alkylene 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.

[0047] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, Cs, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l -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.

[0048] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene 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.

[0049] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.

[0050] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0051] “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.

[0052] “Alkylamino” refers to a radical of the formula -NHRa or -NRaRa where 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.

[0053] “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.

[0054] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rcis one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.

[0055] “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.

[0056] “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.

[0057] “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.

[0058] “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.

[0059] “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.

[0060] “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.

[0061] “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.

[0062] “Haloalkynyl” refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1 -fluor opropynyl, 1 -fluor obutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.

[0063] “Heterocyclyl” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, saturated or partially unsaturated ring radical which consists oftwo 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 quatemized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. In embodiments where “L” is heterocyclyl, the heterocyclyl radical is a diradical. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0064] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Re where Rb is an alkylene group as defined above and Reis a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkyl group can be optionally substituted.

[0065] “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.

[0066] “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, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[l,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- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e. thienyl). In embodiments where “L” is heteroaryl, the heteroaryl radical is a diradical. Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0067] “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.

[0068] “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.

[0069] “Thioalkyl” refers to a radical of the formula -SRa 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, a thioalkyl group can be optionally substituted.

[0070] 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.

[0071] “ 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, -SChRg, -OSO2Rg, -SChORg, =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 Rh are 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.

[0072] As used herein, the symbol “ -i I- ” or “ —I » ” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, XY-i—XY_|“ ■ ” or“ «” 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.

[0073] 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.

[0074] 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.

[0075] The compounds of the disclosure, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (5)- 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 (5)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0076] 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.

[0077] The term “treating” as used herein with regard to a patient, refers to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and / or a prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. 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 displayclinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., 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 (for example, by causing regression, or reducing the severity of the state, disorder or condition or at least one of its clinical or subclinical symptoms).

[0078] An “effective amount” means the amount compound or pharmaceutical formulation, that when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment.

[0079] 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.

[0080] 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.

[0081] In one aspect of the present disclosure, a DPP1 inhibitor is provided, and the DPP1 inhibitor is a compound of formula (I), (I-A), (I-Al), (I-A2), (I-A3), (I-B), (I-Bl), (I-B2), (I- B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0082] In embodiments, the present disclosure provides a compound of formula (I):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; each R4is independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -COOH, -Ci-C6alkyl, -Ci-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OCi- C6alkyl, halogenated -OCi-C6alkyl, -S(Ci-C6alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), - SO2N(CI-C6alkyl), -SO2NR5R6, or -S(=NH)(O)(CI-C6alkyl);R4ais -OH or -OC1-C3 alkyl;R5and R6are each independently hydrogen, C1-6 alkyl, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), or R5and R6together with the nitrogen atom to which they are attached form a heterocyclyl; each R7is independently Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl; m is 0, 1, or 2; and each k is independently 0, 1, 2, 3, or 4.

[0083] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,alkyl, and k is 0, 1, 2, or 3. In embodiments, R4ais -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, or - OCH(CH3)2. In embodiments, R4ais -OH, -OCH3, or -OCH2CH3. In embodiments, R4ais -OH or -OCH3. In embodiments, R4ais -OCH3. In embodiments, k is 0, 1, or 2. In embodiments, k is 0. In embodiments, k is 1. In embodiments, each R4is independently halogen, -OH, -Ci-Ce alkyl, or -OCi-Ce alkyl. In embodiments, k is 0. In embodiments, k is 1.

[0084] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,R or S configuration. In embodiments,the carbon center marked by * has an R configuration. In embodiments,embodiments, R1is

[0085] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,OC1-C3 alkyl, and R4is halogen, -OH, -Ci-Ce alkyl, or -OCi-Ce alkyl. In embodiments, R1isembodiments, R4aand R4are different. In embodiments, R4aand R4are the same. In embodiments, R4ais -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In embodiments, R4ais -OH, -OCH3, or -OCH2CH3. In embodiments, R4ais - OH. In embodiments, R4is halogen, -OH, -C1-C3 alkyl, or -OC1-C3 alkyl. In embodiments, R4is -C1-C6 alkyl, -C2-C5 alkyl, or -C3-C4 alkyl. In embodiments, R4is -C1-C3 alkyl. Inalkyl. In embodiments, R4is methyl or ethyl. In embodiments, R4is methyl. In embodiments,

[0086] In embodiments, R4and R4ahave cis configuration. In embodiments, R1is, embodiments,embodiments, R4and R4ahave trans configuration. In embodiments,

[0087] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,In embodiments, each R4is independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -COOH, -Ci-Ce alkyl, -Ci-Ce alkyl-OH, -OCi-Ce alkyl, halogenated -OCi-Ce alkyl. In embodiments, each R4is independently halogen, -OH, -OCi-Ce alkyl, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2. In embodiments, each R4is independently halogen or -OCi-Ce alkyl. In embodiments, each R4is independently -F, -Cl, -Br, or -I. In embodiments, each R4is independently -OCi-Ce alkyl, -OC2-C5 alkyl, or -OC3-C4 alkyl. In embodiments, each R4is independently -F or -OCH3. In embodiments, k is 1 or 2. In embodiments, k is 1. Inan R configuration. In embodiments, R1is. In embodiments, R1is,

[0088] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,

[0089] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,and each R7is independently Ci-Ce alkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl. In embodiments, each R7is independently CH3, CH2CH3, CH2CH2CH3, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl. In embodiments, R7is CH3, CH2CH3, cyclopropyl, azetidinyl, or oxetanyl. In embodiments, R7is CH3 or oxetanyl. In embodiments, R7is CH3. In embodiments, R7is oxetanyl.

[0090] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,eachR7is independently CH3, CH2CH3, CH2CH2CH3, or cyclopropyl. In embodiments, each R7is independently CH3 or CH2CH3. In embodiments, R7is CH3.

[0091] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,CH2CH2CH3, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl. In embodiments, R7is CH3, CH2CH3, cyclopropyl, azetidinyl, or oxetanyl. In embodiments, R7is CH3. In embodiments, R7is oxetanyl.

[0092] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, R2is

[0093] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt,\ . In embodiments, R2isx\ . In embodiments, R2is \ .

[0094] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt,

[0095] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,

[0096] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,

[0097] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, R1is, and R2is

[0098] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 0.

[0099] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 1 or 2. In embodiments, m is 1. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-Ce alkyl), -SO2(Ci-Ce alkyl), or -CN. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, or -CN. In embodiments, each R3is independently halogen, e.g., -F, -Cl, -Br, or -I. In embodiments, one or more R3is -F. In embodiments, m is1 and R3is -F. In embodiments, the phenyl ringwherein * denotes the connectivity to R2. In embodiments, the phenyl ring with R3is, wherein * denotes the connectivity to R2.

[0100] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0101] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0102] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment,R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0103] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0104] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C2 alkyl. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0105] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0106] In one embodiment of a compound of formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0107] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0108] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0109] In one embodiment of a compound of formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, or a deuterated form thereof,further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0110] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3.In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0111] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0112] In one embodiment of a compound of formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0113] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0114] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3.In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0115] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0116] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCi-C3 alkyl. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0117] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0118] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3.In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. Ineven a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0119] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,alkylIn a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0120] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0121] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0122] In one embodiment of a compound of formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3.In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0123] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,alkylIn a further embodiment, R4aisOCH2CH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0124] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0125] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0126] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0127] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0128] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0129] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0130] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0131] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0132] In one embodiment of a compound of formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0133] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,1 1 ? alkyl and R2is 1 In a further embodiment, R4ais -OCH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0134] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0135] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0136] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,XOC1-C3 alkyl and R2is \ . In a further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0137] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,£ ;Nalkyl and R2is V In a further embodiment, R4ais -OCH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0138] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,alkyl and R2isIn a further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0139] In one embodiment of a compound of formula (I), or a pharmaceutically acceptablesalt, a stereoisomer, or a deuterated form thereof,alkyl and R2In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0140] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0141] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,XX? alkyl and R2is . In a further embodiment, R4ais -OCH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0142] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0143] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 0. In even a further embodiment, R7is methyl or ethyl. In yet even a further embodiment, R7is methyl.

[0144] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,£ X ;NOC1-C3 alkyl and R2is \ . In a further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 0.

[0145] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,y J^byb^Nalkyl and R2is \ . In a further embodiment, R4ais -OCH3. In a further embodiment, m is 0.

[0146] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,alkyl and R2a further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 0.

[0147] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,alkyl and R2is. In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 0.

[0148] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,X ?\ . In a further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0149] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH3. In a further embodiment, m is 1 andR3is halogen. In yet a further embodiment, R3is F.

[0150] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,J D\ . In a further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0151] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,JL J\ . In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0152] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is1 and R3is halogen. In yet a further embodiment, R3is F.

[0153] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH3. In a further embodiment, m is 1 andR3is halogen. In yet a further embodiment, R3is F.

[0154] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0155] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 1 and R3is halogen. In yet a further embodiment, R3is F.

[0156] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is

[0157] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH3. In a further embodiment, m is 0.

[0158] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 0.

[0159] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 0.

[0160] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OC1-C3 alkyl. In a further embodiment, m is

[0161] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH3. In a further embodiment, m is 0.

[0162] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH2CH3. In a further embodiment, m is 0.

[0163] In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,. In a further embodiment, R4ais -OCH2CH2CH3. In a further embodiment, m is 0.

[0164] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-A)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

[0165] In embodiments of the compounds of formula (I-A), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-Al)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0166] In embodiments of the compounds of formula (I), (I-A), or (I-Al), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-A2)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0167] In embodiments of the compounds of formula (I), (I-A), or (I-Al), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-A3)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0168] In embodiments of the compounds of formula (I-A), (I-Al), (I-A2), or (I-A3), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, R2is

[0169] In embodiments of the compounds of formula (I-A), (I-Al), (I-A2), or (I-A3), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 0. In a

[0170] In embodiments of the compounds of formula (I-A), (I-Al), (I-A2), or (I-A3), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 1 or 2. In embodiments, m is 1. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-Ce alkyl), -SO2(Ci-Ce alkyl), or -CN. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, or -CN. In embodiments, each R3is independently halogen, e.g., -F, -Cl, -Br, or -I. In embodiments, one or more R3is -F. Inembodiments, m is 1 and R3is -F. In embodiments, the phenyl ring with R3is, wherein * denotes the connectivity to R2. In embodiments, the phenyl ring withR3is , wherein * denotes the connectivity to R2.

[0171] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-B)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

[0172] In embodiments of the compounds of formula (I) or (I-B), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-Bl)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0173] In embodiments of the compounds of formula (I), (I-B), or (I-Bl), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-B2)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0174] In embodiments of the compounds of formula (I), (I-B), or (I-Bl), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-B3)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0175] In embodiments of the compounds of formula (I-B), (I-Bl), (I-B2), or (I-B3), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, R2is

[0176] In embodiments of the compounds of formula (I-B), (I-Bl), (I-B2), or (I-B3), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 0.

[0177] In embodiments of the compounds of formula (I-B), (I-Bl), (I-B2), or (I-B3), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 1 or 2. In embodiments, m is 1. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-Ce alkyl), -SO2(Ci-Ce alkyl), or -CN. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, or -CN. In embodiments, each R3is independently halogen, e.g., -F, -Cl, -Br, or -I. In embodiments, one or more R3is -F. Inembodiments, m is 1 and R3is -F. In embodiments, the phenyl ring with R3is, wherein * denotes the connectivity to R2. In embodiments, the phenyl ring withR3is , wherein * denotes the connectivity to R2.

[0178] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-C)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

[0179] In embodiments of the compounds of formula (I) or (I-C), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-Cl)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0180] In embodiments of the compounds of formula (I) or (I-C), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound has the structure of formula (I-C2)or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0181] In embodiments of the compounds of formula (I-C), (I-Cl), or (I-C2), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, R2is

[0182] In embodiments of the compounds of formula (I-C), (I-Cl), or (I-C2), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 0.

[0183] In embodiments of the compounds of formula (I-C), (I-Cl), or (I-C2), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 1 or 2. In embodiments, m is 1. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-Ce alkyl), -SO2(Ci-Ce alkyl), or -CN. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, or -CN. In embodiments, each R3is independently halogen, e.g., -F, -Cl, -Br, or -I. In embodiments, one or more R3is -F. Inembodiments, m is 1 and R3is -F. In embodiments, the phenyl ring with R3is or, wherein * denotes the connectivity to R2. In embodiments, the phenyl ring withR3is , wherein * denotes the connectivity to R2.

[0184] In embodiments, the present disclosure provides a compound of formula (II):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; each R4and R4aare independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci- C6alkyl)2, -COOH, -Ci-C6alkyl, -Ci-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, - OC1-C6 alkyl, halogenated -OCi-C6alkyl, -S(Ci-C6alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), -SO2N(CI-C6alkyl), -SO2NR5R6, or -S(=NH)(O)(CI-C6alkyl);R5and R6are each independently hydrogen, C1-6 alkyl, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), or R5and R6together with the nitrogen atom to which they are attached form a heterocyclyl;R7is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl; p is 0 or 1;m is 0, 1, or 2; and each k is independently 0, 1, 2, 3, or 4.

[0185] In embodiments of the compounds of formula (II), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,halogen, -CN, -OH, -NH2, -NH(CI-C6alkyl), -N(CI-C6alkyl)2, -COOH, -Ci-C6alkyl, -Ci-C6alkyl-OH, - CONH2, -SH, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halogenated -OCi-C6alkyl, -S(Ci-C6alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), -SO2N(CI-C6alkyl), -SO2NR5R6, or - S(=NH)(O)(Ci-Ce alkyl), and k is 0, 1, 2, or 3. In embodiments, R4ais halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, or -OC1-C4 alkyl. In embodiments, R4ais -OH or -OC1-C3 alkyl. In embodiments, R4ais -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In embodiments, R4ais -OH, -OCH3, or -OCH2CH3. In embodiments, R4ais -OH or -OCH3. In embodiments, R4ais -OCH3. In embodiments, k is 0, 1, or 2. In embodiments, k is 0. In embodiments, k is 1. In embodiments, each R4is independently halogen, -OH, -Ci-Ce alkyl, or -OC1-C6 alkyl.

[0186] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,OCH2CH2CH3, or -OCH(CH3)2. In embodiments, R4ais -OH, -OCH3, or -OCH2CH3. In embodiments, R4ais -OH or -OCH3. In embodiments, R4ais -OCH3. In embodiments, R1is

[0187] In embodiments of the compounds of formula (II), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,-OC1-C3 alkyl, and R4is halogen, -OH, -Ci-Ce alkyl, or -OCi-Ce alkyl. In embodiments, R1isembodiments,embodiments, R4aand R4are different. In embodiments,R4aand R4are the same. In embodiments, R4ais -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, or-OCH(CH3)2. In embodiments, R4ais -OH, -OCH3, or -OCH2CH3. In embodiments, R4ais - OH. In embodiments, R4is halogen, -OH, -C1-C3 alkyl, or -OC1-C3 alkyl. In embodiments, R4is -Ci-Ce alkyl, -C2-C5 alkyl, or -C3-C4 alkyl. In embodiments, R4is -C1-C3 alkyl. Inalkyl. In embodiments, R4is methyl or ethyl. In embodiments, R4is methyl. In embodiments,

[0188] In embodiments, R4and R4ahave cis configuration. In embodiments, R1isembodiments, R1is

[0189] In embodiments of the compounds of formula (II), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,or 4. In embodiments, each R4is independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl),-N(Ci-Ce alkyl)2, -COOH, -Ci-Ce alkyl, -Ci-Ce alkyl-OH, -OCi-Ce alkyl, halogenated -OCi- Ce alkyl. In embodiments, each R4is independently halogen, -OH, -OCi-Ce alkyl, -NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl)2. In embodiments, each R4is independently halogen or -OCi-Ce alkyl. In embodiments, each R4is independently -F, -Cl, -Br, or -I. In embodiments, each R4is independently -OCi-Ce alkyl, -OC2-C5 alkyl, or -OC3-C4 alkyl. In embodiments, each R4is independently -F or -OCH3. In embodiments, k is 1 or 2. In embodiments, k is 1. Inthe carbon center marked by * has an R or S configuration. In embodiments, R1is

[0191] In embodiments,embodiments,the carbon center marked by * has an R or S configuration. In embodiments, R1is, and the carbon center marked by * has an S configuration. In embodiments,, ents,the carbon center marked by * has an R or S configuration. In embodiments,and the carbon center marked by * has an R configuration. In embodiments, R1is,

[0193] In embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt,

[0194] In embodiments of the compounds of formula (II), or a pharmaceutically acceptableNH salt, a stereoisomer, or a deuterated form thereof, p is 0 and R1is ' . In embodiments,

[0195] In embodiments of the compounds of formula (II), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, R7is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl. In embodiments, R7is Ci-Ce alkyl, Ci-Ce haloalkyl, or 3- to 5- membered cycloalkyl. In embodiments, R7is Ci-Ce alkyl, C2-C5 alkyl, or C3-C4 alkyl. In embodiments, R7is CH3, CH2CH3, or CH2CH2CH3. In embodiments, R7is CH3 or CH2CH3. In embodiments, R7is CH3 and the compounds of formula (II) has the following structure:

[0196] In embodiments of the compounds of formula (II) or (II-A), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 0.

[0197] In embodiments of the compounds of formula (II) or (II-A), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, m is 1 or 2. In embodiments, m is 1. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Cealkyl), -SO(Ci-Ce alkyl), -SO2(Ci-Ce alkyl), or -CN. In embodiments, each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, or -CN. In embodiments, each R3is independently halogen, e.g., -F, -Cl, -Br, or -I. In embodiments, one or more R3is -F. In embodiments, m iswherein * denotes the connectivity tembodiments, the phenyl ring withwherein * denotes the connectivity

[0198] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0199] In embodiments, provided herein is a pharmaceutically acceptable salt of a compound of formula (I), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B. Further embodiments of the disclosure relate to a deuterated compound of formula (I), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (I- Cl), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt thereof.

[0200] In embodiments of the compound of formula (I), (LA), (LAI), (LA2), (LA3), (LB), (I- Bl), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the compound is not a compound disclosed in WO2024 / 148308.

[0201] In embodiments, provided herein is a compound of formula (I) selected from Compounds HLH44, or a pharmaceutically acceptable salt thereof, a deuterated form thereof, racemic form thereof, or stereoisomer thereof. In embodiments, the compound of formula (I) is selected from Compounds H5, H7, H12, H12-B, H29, or H31, or a pharmaceutically acceptable salt thereof, a deuterated form thereof, racemic form thereof, or stereoisomer thereof.

[0202] In embodiments, the compound provided herein is Compound H4, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0203] In embodiments, the compound provided herein is Compound H5, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0204] In embodiments, the compound provided herein is Compound H7, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0205] In embodiments, the compound provided herein is Compound Hl l, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0206] In embodiments, the compound provided herein is Compound H12, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0207] In embodiments, the compound provided herein is Compound H12-A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0208] In embodiments, the compound provided herein is Compound H12-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0209] In embodiments, the compound provided herein is Compound H21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0210] In embodiments, the compound provided herein is Compound H29, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0211] In embodiments, the compound provided herein is Compound H31, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0212] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, deuterated form thereof, racemic form thereof, or stereoisomer thereof.

[0213] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof.

[0214] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof.

[0215] In one embodiment, provided herein is a compound set forth in Table A.

[0216] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound in Table A.

[0217] In embodiments, provided herein is a compound of formula (II) or (II-A) selected from Compounds A145-A156, or a pharmaceutically acceptable salt thereof, a deuterated form thereof, racemic form thereof, or stereoisomer thereof.

[0218] In embodiments, provided herein is a compound in Table B, or a pharmaceutically acceptable salt thereof, deuterated form thereof, racemic form thereof, or stereoisomer thereof.

[0219] In embodiments, provided herein is a compound in Table B, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof.

[0220] In embodiments, provided herein is a compound in Table B, or a pharmaceutically acceptable salt thereof.

[0221] In one embodiment, provided herein is a compound set forth in Table B.

[0222] In embodiments, provided herein is a compound selected from Compounds A145- A156, or a pharmaceutically acceptable salt thereof, a deuterated form thereof, racemic form thereof, or stereoisomer thereof.

[0223] In embodiments, the compound provided herein is Compound A146, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0224] embodiments, the compound provided herein is Compound A147, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0225] In embodiments, the compound provided herein is Compound A148, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0226] In embodiments, the compound provided herein is Compound Al 52, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0227] In embodiments, the compound provided herein is Compound Al 56, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0228] In embodiments, the compound provided herein is not

[0229] In embodiments, the compound provided herein is notere n s not

[0230] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound in Table B.

[0231] The compounds of formula (I), (LA), (LAI), (LA2), (I- A3), (LB), (LB1), (LB2), (I- B3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or pharmaceutically acceptable saltsthereof, or deuterated versions of the foregoing, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of formula (I), (I-A), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or pharmaceutically acceptable salts thereof, or deuterated versions thereof (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, 2ndEd. 2002.

[0232] Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

[0233] In embodiments, the present disclosure provides pharmaceutical composition(s) comprising a compound of formula (I), (LA), (LAI), (LA2), (I- A3), (LB), (LB1), (LB2), (I- B3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt thereof, as hereinbefore defined in association with pharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s).

[0234] The disclosure further provides a process for the preparation of a pharmaceutical composition of the disclosure which comprises mixing a compound of (I), (LA), (LAI), (I- A2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s).

[0235] 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 (HF A) 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.

[0236] 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 / orlubricant, 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.

[0237] 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.

[0238] 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.

[0239] In embodiments, the compounds of formula (I), (LA), (I-Al), (I-A2), (LA3), (LB), (I- Bl), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, and their pharmaceutically acceptable salts or deuterated form thereof, 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), (LA), (LAI), (LA2), (I- A3), (LB), (LB1), (LB2), (I- B3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt thereof, a deuterated form thereof, a racemic form thereof, or a stereoisomer thereof. In embodiments, the composition is administered to the patient for an administration period.

[0240] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating a obstructive disease of the airway; chronic rhinosinusitis (CRS); hidradenitis suppurativa (HS); cancer (e.g., cancer metastasis); granulomatosis with polyangiitis (GPA); microscopic polyangiitis (MPA); giant cell arteritis; polyarteritis nodosa; anti-GBM disease (Goodpasture’s); rheumatoid arthritis; lupus nephritis; systemic lupus erythematosus; systemic scleroderma; inflammatory bowel disease (IBD) (e.g., ulcerative colitis; Crohn’s disease); diabetic nephropathy; diabetic neuropathy; diabetic retinopathy;diabetic ulcers; Duchenne muscular dystrophy; bronchiolitis obliterans; long covid) - prophylaxis of ILD; atopic dermatitis; pyoderma gangrenosum; sweet’s syndrome; dermatomyositis / polymyositis; neutrophilic dermatoses; uveitis; Behcet’s disease; thrombosis including deep vein thrombosis (DVT); bronchopulmonary dysplasia; amyotrophic lateral sclerosis; sickle cell anemia; psoriasis; ventilator-induced lung injury.

[0241] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating thrombosis. In embodiments, the thrombosis is deep vein thrombosis (DVT).

[0242] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating an obstructive disease of the airway. The obstructive disease of the airway, in one embodiment, is asthma (e.g., bronchial, allergic, intrinsic, extrinsic, exercise-induced, neutrophilic, drug-induced (including aspirin and NSAID-induced) asthma, dust-induced asthma, and both intermittent and persistent asthma and asthma 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, pulmonary fibrosis (also known as 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. In embodiments, asthma is neutrophilic asthma.

[0243] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating pulmonary hypertension. In some embodiment, pulmonary hypertension is pulmonary arterial hypertension. In some embodiments, pulmonaryhypertension is pulmonary hypertension due to left heart disease. In some embodiments, pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

[0244] 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 DPP 1. Without wishing to be bound by theory, it is thought that the compounds of formula (I), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, administered via the methods provided herein have beneficial effects via inhibiting the activation of NSPs and decreasing inflammation, which in turn leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (e.g., forced expiratory volume in 1 second [FEVi]) in CF patients.

[0245] 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), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0246] In one CF treatment method, a composition comprising an effective amount of a compound of (I), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (I- C2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, is administered to a CF patient in need of treatment for an administration period. The method comprises improving the lung function of the patient during the administration period, as compared to the lung function of the patient prior to the administration period. The improvement in lung function in one embodiment, is measured by spirometry.

[0247] Improving the lung function of the patient, in one embodiment, comprises increasing the patient’s forced expiratory volume in 1 second (FEVi), 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 tothe 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%.

[0248] In one embodiment of a method provided herein, a composition comprising an effective amount of a compound of formula (I), (I- A), (I-Al), (I-A2), (I- A3), (I-B), (I-Bl), (I-B2), (I- B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, is administered to a bronchiectasis patient in need of treatment for an administration period. Bronchiectasis is considered a pathological endpoint that results from many disease processes and is a persistent or progressive condition characterized by dilated thick-walled bronchi. The symptoms vary from intermittent episodes of expectoration and infection localized to the region of the lung that is affected to persistent daily expectoration often of large volumes of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. The underlying pathological process of bronchiectasis, without wishing to be bound by theory, has been reported as damage to the airways which results from an event or series of events where inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V. 65(Suppl 1), incorporated by reference herein in its entirety for all purposes).

[0249] 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).

[0250] The methods provided herein employ reversible inhibitors of DPP1. Without wishing to be bound by theory, it is thought that the compounds of formula (I), (I-A), (I-Al), (I-A2), (I-A3), (LB), (LB1), (LB2), (LB3), (I-C), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, administered via the methods provided herein have beneficial effects via decreasing inflammation and mucus hypersecretion, which in some embodiments, leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (cough, sputum production, and forced expiratory volume in 1 second [FEVi]) 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.

[0251] In one embodiment, the bronchiectasis is non-CF bronchiectasis.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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), (LA), (LAI), (LA2), (I- A3), (LB), (LB1), (LB2), (I- B3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0256] The chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP), or chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronicrhinosinusitis 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).

[0257] 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; I facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (1) obstruction of the middle meatus; (m) mucosal changes within the ostiomeatal complex and sinuses; (n) rhinorrhea; or (o) any combinations thereof. In some embodiments, obstruction of the middle meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0258] 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; I facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (1) 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.

[0259] 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.

[0260] 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 theadministration 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.

[0261] Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory disorder. The symptoms include skin lesions that are often associated hair follicles, and may be painful, inflamed and / or swollen. In some cases, when the skin lesions heal, they can recur, and may lead to tunnels under the skin and progressive scarring. Since HS is a chronic condition, it can persist for many years and also, worsen over time, with serious effects on quality of life, psychological and emotional well-being. In fact, HS patients have increased rates of anxiety and depression with a risk of suicide two and a half times that of the general population.

[0262] 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.

[0263] 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), (I-A), (I-Al), (I-A2), (I-A3), (I-B), (I-Bl), (I-B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0264] 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.

[0265] The disclosure provides methods of treating cancer in a subject in need thereof, comprising, administering to the subject, a pharmaceutical composition comprising aneffective 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] In some embodiments, the lymphoma is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, Natural Killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma or Kaposi’s Sarcoma. In some embodiments, the lymphoma is Hodgkin’s lymphoma. In some embodiments, the lymphoma is non-Hodgkin’s lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the lymphoma is B-cell immunoblastic lymphoma. In some embodiments, the lymphoma is Natural Killer cell lymphoma. In some embodiments, the lymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma. In some embodiments, the lymphoma is Kaposi’s Sarcoma.

[0271] 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.

[0272] 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).

[0273] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer is neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma. In some embodiments, the pediatric cancer is neuroblastoma. In some embodiments, the pediatric cancer is Wilms tumor. In some embodiments, the pediatric cancer is rhabdomyosarcoma. In some embodiments, the pediatric cancer is retinoblastoma. In some embodiments, the pediatric cancer is osteosarcoma. In some embodiments, the pediatric cancer is Ewing sarcoma.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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), (LA), (LAI), (LA2), (I- A3), (LB), (LB1), (LB2), (I-B3), (I-C), (I-C 1), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0280] 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), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (I- C 1 ), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In embodiments, arthritis is osteoarthritis. In embodiments, arthritis is rheumatoid arthritis.

[0281] 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 to cartilage 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), (LA), (LAI), (LA2), (LA3), (I- B), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, 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.

[0282] 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 antiinflammatory agents (NSAIDs), they often produce intolerable side effects. To addresses this and other needs, the present disclosure, in one embodiment, provides a method for treating RA using reversible inhibitors of DPP1 of formula (I), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In one embodiment, a method of for treating RA in a subject in need thereof is provided, and comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effectiveamount of a compound of formula (I), (I- A), (I-Al), (I-A2), (I- A3), (I-B), (I-Bl), (I-B2), (I- B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0283] Inflammatory bowel disease (IBD) is a group of inflammatory conditions that affect the colon and small intestine. The most common IBDs are Crohn’s disease and ulcerative colitis. The present disclosure, in one embodiment, addresses the need for novel IBD therapies. Specifically, in one embodiment, a method for treating an inflammatory bowel disease (IBD) in a subject in need thereof is provided. The method comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (LA), (LAI), (LA2), (LA3), (LB), (LB1), (LB2), (LB3), (I-C), (I- Cl), ( C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0284] 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.

[0285] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating heart failure. In some embodiment, heart failure is heart failure with reduced ejection fraction. In some embodiments, heart failure is heart failure with preserved ejection fraction.

[0286] In yet another embodiment of the disclosure, a method for treating ischemia / reperfusion (IR) injury is provide, 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-B. 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.

[0287] 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).

[0288] 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.

[0289] 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 the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (LA), (LAI), (LA2), (I- A3), (LB), (LB1), (LB2), (I- B3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, 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

[0290] 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 formula (I), (LA), (LAI), (LA2), (I- A3), (LB), (LB1), (LB2), (LB3), (LC), (I- Cl), (LC2), (II), or (ILA), or Tables A-B, 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.

[0291] 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. Inone embodiment, the administration period starts at about the time of condition / disease diagnosis and continues for the lifetime of the patient.

[0292] In some embodiments, the administration period is about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 36 months, about 4 years, about 5 years, about 10 years, about 15 years or about 20 years. In some embodiments, the compounds or compositions disclosed herein may be administered for a period of about 24 weeks. In some embodiments, the compounds or compositions disclosed herein may be administered for a period of about 52 weeks. In yet another embodiment, the administration period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years or at least about 20 years.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] In embodiments, an effective amount of the compound of formula (I), (LA), (LAI), (I- A2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof or the composition comprising an effective amount of the compound of formula (I), (LA), (LAI), (I- A2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated is administered orally

[0297] In one embodiment, the oral dosage form is administered once daily during the administration period. In a further embodiment, the oral dosage form is administered at approximately the same time every day, e.g., prior to breakfast. In another embodiment, the composition comprising an effective amount of the compound of formula (I), (LA), (LAI), (I- A2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered once a day or twice a day during the administration period. In yet another embodiment, the composition comprising an effective amount of the compound of formula (I), (LA), (LAI), (I- A2), (LA3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered once per week, every other day, every third day, twice per week, three times per week, four times per week, or five times per week during the administration period.

[0298] Administration, in one embodiment, is via the oral route. In a further embodiment, the composition is administered once daily.

[0299] The dosage administered will vary with the compound of formula ((I), (I-A), (I-Al), (I- A2), (I-A3), (LB), (LB1), (LB2), (LB3), (LC), (LC1), (LC2), (II), or (ILA), or Tables A-B, ora pharmaceutically acceptable salt, 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), (I- A), (I-Al), (I-A2), (I- A3), (I-B), (I-Bl), (I- B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (pg / kg) to 100 micrograms per kilogram body weight (pg / kg). Alternatively, in one embodiment, if the compound of formula (I), (I-A), (I- Al), (I-A2), (I-A3), (I-B), (I-Bl), (I-B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered orally, then the daily dosage of the compound of the disclosure may be in the range from 0.01 micrograms per kilogram body weight (pg / kg) to 100 milligrams per kilogram body weight (mg / kg).

[0300] The compounds of formula (I), (I-A), (I-Al), (I-A2), (I- A3), (I-B), (I-Bl), (I-B2), (I- B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (I-A), (I- Al), (I-A2), (I-A3), (I-B), (I-Bl), (I-B2), (I-B3), (I-C), (I-Cl), (I-C2), (II), or (II-A), or Tables A-B, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is in association with pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2ndEd. 2002.

[0301] EXAMPLES

[0302] 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.

[0303] 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.

[0304] Example 1: Synthesis of (2S,7R)-N-[(lS)-l-cyano-2-[2-fluoro-4-(l-methylindazol- 6-yl)phenyl]ethyl]-7-methoxy-l,4-oxazocane-2-carboxamide (Compound H7)

[0305] Step 1. Synthesis of tert-butyl (2S,7R)-2-{[(lS)-l-cyano-2-[2-fluoro-4-(l- methylindazol-6-yl)phenyl]ethyl]carbamoyl}-7-methoxy-l,4-oxazocane-4-carboxylate

[0306] Into a 100 mL round-bottom flask were added (2S)-2-amino-3-[2-fluoro-4-(l- methylindazol-6-yl)phenyl]propanenitrile (915.57 mg, 3.11 mmol, 1.50 equiv), DMF (10.00 mL), (2S,7R)-4-(tert-butoxycarbonyl)-7-methoxy-l,4-oxazocane-2-carboxylic acid (600.00 mg, 2.07 mmol, 1.00 equiv) and DIEA (804.09 mg, 6.22 mmol, 3.00 equiv) at room temperature. To the above mixture was added HATU (946.22 mg, 2.48 mmol, 1.20 equiv) in portions at 0°C. The resulting mixture was stirred at 0°C for additional Ih. The reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 : 1) to afford tert-butyl (2S,7R)-2-{[(lS)-l-cyano-2-[2- fluoro-4-(l-methylindazol-6-yl)phenyl]ethyl]carbamoyl}-7-methoxy-l,4-oxazocane-4- carboxylate (700 mg, 59.68% yield, 85% purity) as colorless oil. LCMS (ES) [M+H]+m / z: 566.

[0307] Step 2. Synthesis of (2S,7R)-N-[(lS)-l-cyano-2-[2-fhioro-4-(l-methylindazol-6-

[0308] Into a 40 mL vial were added tert-butyl (2S,7R)-2-{[(lS)-l-cyano-2-[2-fluoro-4-(l- methylindazol-6-yl)phenyl]ethyl]carbamoyl}-7-methoxy-l,4-oxazocane-4-carboxylate (650.00 mg, 1.14 mmol, 1.00 equiv) and MeCN (12.00 mL) at room temperature. To the above mixture was added TsOH (593.64 mg, 3.44 mmol, 3.00 equiv) in portions at 0°C. The resultingmixture was stirred at room temperature for additional 3h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 30% to 65% gradient in 11 min; detector, UV 254 nm. This resulted in Compound H7 (200 mg, 37.39% yield, 98.77% purity) as white solid. LCMS (ES) [M+H]+m / z: 466.3. *H NMR (300 MHz, DMSO-t / 6) 5 8.97 - 8.74 (m, 1H), 8.07 (d, J= 0.9 Hz, 1H), 8.00 (s, 1H), 7.83 (d, J= 8.5 Hz, 1H), 7.74 - 7.60 (m, 2H), 7.55 - 7.42 (m, 2H), 5.07 (q, J= 8.3 Hz, 1H), 4.11 (s, 4H), 3.98 - 3.87 (m, 1H), 3.70 - 3.53 (m, 1H), 3.30 (d, J = 23.7 Hz, 7H), 3.08 - 2.70 (m, 2H), 2.46 - 2.28 (m, 1H), 1.95 - 1.88 (m, 1H), 1.85 - 1.50 (m, 1H).

[0309] Example 2: Synthesis of Compounds of the Disclosure

[0310] Step 1. SynthesisAmine Intermediate-1O NRIntermediate-2

[0311] Step 1 : Starting Amine (25-30 mg, 1.00 equiv), CH3CN (2 mL) and N,O- bis(trimethylsilyl)acetamide (BSA) (1.20 equiv) were placed into a sealed 8-mL tube. The mixture was stirred for 4 h at 40°C. After cooled to room temperature. The reaction was used in the next step directly.

[0312] Examples of the starting Amine includes:

[0313] Step 2: Intermediate- 1 (25-30 mg, 1.00 equiv) in CH3CN, or the mixture of the preceding step were placed into a sealed 8-mL tube. Then DIEA (4.00 equiv), Acid-A (1.20 equiv), HATU (1.20 equiv) and CH3CN (2 mL) were added to the tube. The mixture was stirred for 1 h at room temperature. The reaction was quenched with MeOH (1 mL). The mixture was purified by Prep-HPLC to give Intermediate-2.

[0314] Examples of Acid-A includes:

[0315] Step 3: Intermediate-2 (15-25 mg, 1.00 equiv), BSA (1.20 equiv) in CH3CN (3 mL) was stirred at room temperature for 4 h. The reaction was quenched with MeOH (1 mL). The mixture was purified by the following methods (e.g., Prep-HPLC) to give the desired product.

[0316] Purification methods:

[0317] Method 1 : Prep-HPLC: Column: Welch Xtimate C18 30*150 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3), Mobile Phase B: ACN; Flow rate: 35 mL / min; Wavelength: 254 nm, 220 nm.

[0318] Method 2: Prep-HPLC: Column: Welch Xtimate C18 30*150 mm, 10 pm; Mobile phase A: 0.1% FA; Mobile phase B: ACN; Flow rate: 35 mL / min; Wavelength: 254 nm, 220 nm.

[0319] Method 3: HP-Flash: YM C18 50*150 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3), Mobile Phase B: ACN; Flow rate: 80 mL / min; Wavelength: 254 nm, 220 nm.

[0320] Compounds prepared according to this Example are listed in Table 1 below.

[0321] Example 3. Human DPP1 enzyme IC50 assay

[0322] 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 pL. 25 pL of compound in Assay Buffer plus 5% DMSO was first added to 50 pL of activated human DPP1enzyme at a concentration of 1 ng / pL and allowed to pre-incubate for 10 minutes at 37 °C after which 50 pL of 1000 pM H-Gly-Arg-AMC substrate (Bachem; St. Torrance, CA) was added, giving final substrate concentration of 400 pM and a final DMSO concentration of 1%. Substrate cleavage was measured for 90 minutes at 37 °C, 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)] / [l+((C / x)AD)]}, which appears as equation number 205 (4 Parameter Logistic Model or Sigmoidal Dose-Response Model) in XLFit. Default constraints were used for each Parameter. IC50 was defined as the compound concentration at which 50% of enzyme activity was inhibited when compared to the no-compound control.

[0323] Results are provided in Table 2 below. In Table 2, *** represent average ICso < 5 nM, ** represents average ICso in the range of 5-15 nM, and * represents average ICso in the range of > 15 nM, where the designations were made solely based on the average value without taking into account of the standard deviations.

[0324] Example 4. Human DPP1 Enzyme Single-Point Percent Inhibition Testing

[0325] A crude lysate of HL-60 cells (ATCC; Manassas, VA) was used as a source of human DPP1 enzyme in the assay. Lysate was prepared in 1% Triton X-100 in PBS at a concentration of 20,000 live cells per pL of lysis buffer and was centrifuged at 16,000 ref for 10 minutes at 4 °C, after which supernatant was collected and flash-frozen in liquid nitrogen. Test articleswere applied to 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 pL. 25 pL of compound diluted to 50 nM in Assay Buffer plus 5% DMSO was first added to 50 pL of HL-60 lysate diluted to contain a DPP1 enzyme concentration of roughly 1 ng / pL and allowed to pre-incubate for 10 minutes at 37 °C after which 50 pL of 1000 pM H-Gly-Arg-AMC substrate (Bachem; St. Torrance, CA) was added, giving final compound concentration of 10 nM, a final substrate concentration of 400 pM and a final DMSO concentration of 1%. Substrate cleavage was measured for 90 minutes at 37 °C, 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. Percent inhibition at 10 nM was calculated for each test article based on remaining DPP1 activity compared to enzyme activity in wells that received only vehicle control.

[0326] Results are provided in Table 3 below. In Table 3, *** represents percent inhibition of > 66.7%, ** represents percent inhibition in the range of 40-66.7%, and * represents percent inhibition of < 40%.

[0327] Example 5. DPP1 Cell ICso assay

[0328] HL-60 cells (ATCC; Manassas, VA) were maintained in RPMI-1640 supplemented with 20% heat-inactivated FBS and IX 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 ref for 3 minutes, resuspended in PBS and counted. Cells were diluted in PBS to a concentration of 5xl05live cells per mL and transferred to black 96-well plates for assay, 60 pL per well. Test articles were diluted in PBS plus 0.5% DMSO, and 20 pL 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 °C in a cell culture incubator maintained at 5% CO2, after which 20 pL of 500 pM 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) / (l+((C / x)AD)))), 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.

[0329] The result of the assay is provided in Table 4, below. In Table 4, *** represent average IC50 < 1 nM, ** represents average IC50 in the range of 1-2.5 nM, and * represents average IC50 in the range of > 2.5 nM, where the designations were made solely based on the average value without taking into account of the standard deviations.

[0330] Example 6. DPP1 Cell Single-Point Percent Inhibition Testing

[0331] HL-60 cells (ATCC; Manassas, VA) were maintained in RPMI- 1640 supplemented with 20% heat-inactivated FBS and IX 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 ref for 3 minutes, resuspended in RPMI (with no additional supplements) and counted. Cells were diluted in RPMI to a concentration of 5xl05live cells per mL and transferred to black 96-well plates for assay, 60 pL per well. Test articles were diluted to 25 nM in RPMI plus 0.5% DMSO, and 20 pL 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 °C in a cell culture incubator maintained at 5% CO2, after which 20 pL of 500 pM H-Gly-Phe-AFC cell-permeable substrate (MP Biomedicals; Solon, OH) in RPMI was added to each well, giving final compound concentration of 5 nM, a final substrate concentration of 100 pM and a final DMSO concentration of 0.1%. 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. Percent Inhibition was calculated from RFU values by first subtracting background values (wells in which RPMI was substituted for cells) from each well, and then subtracting background- subtracted RFU derived from wells that received a final concentration of 10 pM brensocatib. This value represents the non-specific substrate cleavage from the HL-60 cells, and the remaining RFU should theoretically be solely the contribution of DPP1 enzyme activity. The final percent inhibition value was calculated for each test article based on remaining RFU compared to RFU from wells that received only vehicle control.

[0332] Results are provided in Table 5 below. In Table 5, *** represents percent inhibition of > 93.9%, ** represents percent inhibition in the range of 76.5-93.9%, and * represents percent inhibition of < 76.5%.

[0333] 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.

[0334] 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

CLAIMSWhat is claimed is:

1. A compound of formulaor a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; each R4is independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -COOH, -Ci-C6alkyl, -Ci-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, -S(O)2NH2, - OC1-C6 alkyl, halogenated -OCi-C6alkyl, -S(Ci-C6alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), -SO2N(CI-C6alkyl), -SO2NR5R6, or -S(=NH)(O)(CI-C6alkyl);R4ais -OH or -OC1-C3 alkyl;R5and R6are each independently hydrogen, C1-6 alkyl, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), or R5and R6together with the nitrogen atom to which they are attached form a heterocyclyl; each R7is independently Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl; m is 0, 1, or 2; and each k is independently 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinOCH2CH3.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein k is 0.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein k is 1, and R4is halogen, -Ci-Ce alkyl, or -OCi-Ce alkyl.

10. The compound of any one of claims 1, 2, and 9, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinalkyl.

11. The compound of any one of claims 1-2 and 9-10, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein12. The compound of claim 10, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4and R4ahave cis configuration.

13. The compound of claim 10, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4and R4ahave trans configuration.

14. The compound of claim 11, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein15. The compound of claim 11, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein16. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a17. The compound of claim 1 or 16, or a pharmaceutically acceptable salt, a stereoisomer,18. The compound of any one of claims 1, 16, or 17, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4is halogen or -OC1-C3 alkyl.

19. The compound of any one of claims 1 and 16-18, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4is F or -OCH3.

20. The compound of any one of claims 1 and 16-19, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4is -OCH3.

21. The compound of any one of claims 1 and 16-19, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein22. The compound of any one of claims 1 and 16-21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein23. The compound of any one of claims 1, and 16-22, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein24. The compound of any one of claims 1 and 16-22, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein25. The compound of any one of claims 1 and 16-24, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is26. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is28. The compound of any one of claims 1, 2, and 27, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein29. The compound of claim 28, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein30. The compound of claim 28, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein31. The compound of claim 1 or 16, or a pharmaceutically acceptable salt, a stereoisomer,32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0.

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1.

34. The compound of any one of claims 1-31 and 33, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is halogen.

35. The compound of any one of claims 1-31 and 33-34, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is F.

36. The compound of claim 35, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3iswherein * denotes the connectivity to R2.

37. The compound of claim 35, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3is , wherein * denotes the connectivity to R2.

8. The compound of claim 1, wherein the compound is selected fromor a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

39. The compound of claim 1 or 38, wherein the compound is selected fromʼnllor a pharmaceutically acceptable salt or a deuterated form thereof.

40. The compound of claim 1, 38, or 39, wherein the compound is selected frompharmaceutically acceptable salt or a deuterated form thereof.

41. The compound of claim 1, having a structure of formula (I- A) :or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

42. The compound of claim 41, having a structure of formula (I-Al):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

43. The compound of claim 41, having a structure of formula (I-A2):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

44. The compound of claim 41, having a structure of formula (I-A3):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

45. The compound of any one of claims 41-44, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is46. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is47. The compound of any one of claims 41-46, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0.

48. The compound of any one of claims 41-46, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1, and R3is halogen.

49. The compound of any one of claims 41-46 and 48, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1 and R3is F.

50. The compound of claim 49, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3iswherein * denotes the connectivity to R2.

51. The compound of claim 49, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3is wherein * denotes the connectivity to R2.

52. The compound of claim 41, wherein the compound is selected fromstereoisomer, or a deuterated form thereof.

53. The compound of claim 41 or 52, wherein the compound is selected fromdeuterated form thereof.

54. The compound of claim 41, 52, or 53, wherein the compound isor a pharmaceutically acceptable salt or a deuterated form thereof.

55. The compound of claim 1, having a structure of formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

56. The compound of claim 55, having a structure of formula (I-Bl):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

57. The compound of claim 55, having a structure of formula (I-B2):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

58. The compound of claim 55, having a structure of formula (I-B3):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

59. The compound of any one of claims 55-58, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is60. The compound of any one of claims 55-59, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is61. The compound of any one of claims 55-60, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0.

62. The compound of any one of claims 55-60, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1, and R3is halogen.

63. The compound of any one of claims 55-60 and 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1 and R3is F.

64. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3iswherein * denotes the connectivity to R2.

65. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3is wherein * denotes the connectivity to R2.

66. The compound of claim 55, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound is selected fromor a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

67. The compound of claim 55 or 66, wherein the compound is selected fromor a pharmaceutically acceptable salt or a deuterated form thereof.

68. The compound of claim 67, wherein the compound isor a pharmaceutically acceptable salt, or a deuterated form thereof.

69. The compound of claim 1, having a structure of formula (I-C):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; and m is 0, 1, or 2.

70. The compound of claim 69, having a structure of formula (I-C 1):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

71. The compound of claim 69, having a structure of formula (I-C2):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

72. The compound of any one of claims 69-71, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is73. The compound of any one of claims 69-71, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R2is74. The compound of any one of claims 69-73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0.

75. The compound of any one of claims 69-73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1, and R3is halogen.

76. The compound of any one of claims 69-73 and 75, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1, and R3is F.

77. The compound of claim 76, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3is or wherein * denotes the connectivity to R2.

78. The compound of claim 76, or a pharmaceutically acceptable salt, a stereoisomer, or adeuterated form thereof, wherein the phenyl ring with R3is , wherein * denotes the connectivity to R2.

79. The compound of claim 69, wherein the compound is selected fromstereoisomer, or a deuterated form thereof.

80. The compound of claim 69 or 79, wherein the compound is selected fromor a pharmaceutically acceptable salt, or a deuterated form thereof.

81. The compound of claim 69, 79, or 80, wherein the compound isor a pharmaceutically acceptable salt, or a deuterated form thereof.

82. A compound of formula (II):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each R3is independently halogen, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -S(Ci-Ce alkyl), -SO(Ci-C6alkyl), -SO2(Ci-C6alkyl), or -CN; each R4and R4aare independently halogen, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), - N(CI-C6alkyl)2, -COOH, -Ci-C6alkyl, -Ci-C6alkyl-OH, -CONH2, -SH, -S(=O)NH2, - S(O)2NH2, -OC1-C6 alkyl, halogenated -OCi-C6alkyl, -S(Ci-C6alkyl), -SO(Ci-C6alkyl), - SO2(Ci-C6alkyl), -SO2N(CI-C6alkyl), -SO2NR5R6, or -S(=NH)(O)(CI-C6alkyl);R5and R6are each independently hydrogen, C1-6 alkyl, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), or R5and R6together with the nitrogen atom to which they are attached form a heterocyclyl;R7is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 5- membered cycloalkyl, or 3- to 5- membered heterocyclyl; p is 0 or 1; m is 0, 1, or 2; and each k is independently 0, 1, 2, 3, or 4.

83. The compound of claim 82, wherein R4ais -OH or -OC1-C3 alkyl.

84. The compound of claim 82 or 83, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinOCH3, or -OCH2CH3.

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

86. The compound of any one of claims 82-85, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein87. The compound of any one of claims 82-86, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein88. The compound of any one of claims 82-87, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein89. The compound of claim any one of claims 82-84, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein k is 1, and R4is halogen, -Ci-Ce alkyl, or -OCi-Ce alkyl.

90. The compound of any one of claims 82-84, and 89, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereinC3 alkyl.

91. The compound of any one of claims 82-84 and 89-90, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein92. The compound of claim 90, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4and R4ahave cis configuration.

93. The compound of claim 90, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4and R4ahave trans configuration.

94. The compound of claim 91, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein95. The compound of claim 91, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein96. The compound of claim 82, or a pharmaceutically acceptable salt, a stereoisomer, or a97. The compound of claim 82 or 96, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein98. The compound of any one of claims 82, 96, or 97, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4is halogen or -OC1-C3 alkyl.

99. The compound of any one of claims 82 and 96-98, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4is F or -OCH3.

100. The compound of any one of claims 82 and 96-99, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein101. The compound of any one of claims 82 and 96-100, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein102. The compound of any one of claims 82 and 96-101, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein103. The compound of claim 82, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is104. The compound of claim 102, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is105. The compound of any one of claims 82-104, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0.

106. The compound of any one of claims 82-104, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1.

107. The compound of any one of claims 82-104 and 106, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is halogen.

108. The compound of any one of claims 82-104 and 106-107, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is F.

109. The compound of claim 108, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the phenyl ringwherein * denotes the connectivity t110. The compound of claim 108, or a pharmaceutically acceptable salt, a stereoisomer, ordenotes the connectivity t111. The compound of any one of claims 82-110, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R7is CH3.

112. The compound of claim 82, wherein the compound is selected fromor a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

113. The compound of claim 82 or 112, wherein the compound is selected fromor a pharmaceutically acceptable salt, or a deuterated form thereof.

114. The compound of claim 82, 112, or 113, wherein the compound is selected fromor a pharmaceutically acceptable salt, or a deuterated form thereof.

115. A compound having the structure116. A compound having the structure117. A compound having the structure118. A compound having the structure119. A compound having the structure120. A compound having the structure121. A compound having the structure122. A compound having the structure123. A compound having the structure124. A compound having the structure125. A compound having the structure127. A compound having the structure129. A compound having the structurepharmaceutically acceptable salt thereof.

130. A compound having the structurepharmaceutically acceptable salt thereof.

131. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a132. The compound of claim 131, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein, R4ais -OC1-C3 alkyl.

133. The compound of claim 131 or 132, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1 and R3is halogen.

134. The compound of claim 133, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the halogen is F.

135. The compound of claim 131 or 132, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0.

136. The compound of any one of claims 131-135, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R7is methyl or ethyl.

137. The compound of claim 136, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R7is methyl.

138. The compound of any one of claims 131-137, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4ais -OCH3.

139. The compound of any one of claims 131-137, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4ais -OCH2CH3.

140. The compound of any one of claims 131-137, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4ais -OCH2CH2CH3.

141. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein142. The compound of claim 141, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4ais -OC1-C3 alkyl.

143. The compound of claim 141 or 142, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 1, and R3is halogen.

144. The compound of claim 143, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the halogen is F.

145. The compound of claim 141 or 142, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is 0.

146. The compound of any one of claims 141-145, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R7is methyl or ethyl.

147. The compound of claim 146, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R7is methyl.

148. The compound of any one of claims 141-147, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4ais -OCH3.

149. The compound of any one of claims 141-147, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4ais -OCH2CH3.

150. The compound of any one of claims 141-147, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R4ais -OCH2CH2CH3.

151. The compound of any one of claims 131-150, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein152. The compound of claim 151, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein153. The compound of claim 152, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R7is methyl or ethyl.

154. The compound of claim 153, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R7is methyl.

155. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-154, or a pharmaceutically acceptable salt or deuterated form thereof and a pharmaceutically acceptable adjuvant, diluent or carrier.

156. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

157. The method of claim 156, 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, pulmonary 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).

158. The method of claim 157, wherein the obstructive disease of the airway is asthma.

159. The method of claim 157, wherein the obstructive disease of the airway is acute respiratory distress syndrome (ARDS).

160. The method of claim 157, wherein the obstructive disease of the airway is bronchitis.

161. The method of claim 157, wherein the obstructive disease of the airway is pulmonary fibrosis.

162. The method of claim 157, wherein the obstructive disease of the airway is emphysema.

163. The method of claim 157, wherein the obstructive disease of the airway is cystic fibrosis (CF).

164. The method of claim 157, wherein the obstructive disease of the airway is bronchiectasis.

165. The method of claim 157, wherein the obstructive disease of the airway is sarcoidosis.

166. The method of claim 157, wherein the obstructive disease of the airway is alpha- 1 antitrypsin (Al AT) deficiency.

167. The method of claim 157, wherein the obstructive disease of the airway is farmer’s lung.

168. The method of claim 157, wherein the obstructive disease of the airway is hypersensitivity pneumonitis.

169. The method of claim 157, wherein the obstructive disease of the airway is a complication of lung transplantation.

170. The method of claim 157, wherein the obstructive disease of the airway is a vasculitic or thrombotic disorder of the lung vasculature.

171. The method of claim 157, wherein the obstructive disease of the airway is pulmonary hypertension.

172. The method of claim 157, wherein the obstructive disease of the airway is iatrogenic cough.

173. The method of claim 157, wherein the obstructive disease of the airway is acute rhinitis.

174. The method of claim 157, wherein the obstructive disease of the airway is chronic rhinitis.

175. The method of claim 157, wherein the obstructive disease of the airway is rhinitis medicamentosa or vasomotor rhinitis.

176. The method of claim 157, wherein the obstructive disease of the airway is nasal polyposis.

177. The method of claim 157, wherein the obstructive disease of the airway is COPD.

178. The method of claim 158, wherein the asthma is bronchial, allergic, intrinsic, extrinsic, neutrophilic, exercise-induced or drug-induced asthma.

179. The method of claim 178, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

180. The method of claim 161, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, or fibrosis complicating anti-neoplastic therapy or chronic infection.

181. The method of claim 164, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

182. The method of claim 164, wherein the bronchiectasis is associated with cystic fibrosis.

183. The method of claim 171, wherein the pulmonary hypertension is pulmonary arterial hypertension.

184. The method of claim 171, wherein the pulmonary hypertension is pulmonary hypertension due to left heart disease.

185. The method of claim 171, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

186. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

187. The method of claim 186, wherein the treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

188. The method of claim 187, wherein improving lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 second (FEVi), increasing the patient’s forced vital capacity (FVC), increasing the patient’s peak expiratory flow rate (PEFR), orincreasing 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.

189. The method of claim 187 or 188, wherein the lung function is measured by spirometry.

190. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

191. The method of claim 190, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

192. The method of claim 190, wherein the bronchiectasis is associated with cystic fibrosis.

193. The method of any one of claims 190-192, wherein treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

194. The method of claim 193, wherein improving lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 second (FEVi), increasing the patient’s forced vital capacity (FVC), increasing the patient’s peak expiratory flow rate (PEFR), or increasing the patient’s forced expiratory flow between 25% and 75% of FVC (FEF (25-75%)), as compared to the respective value for the patient prior to treatment.

195. The method of claim 193 or 194, wherein the lung function is measured by spirometry.

196. The method of any one of claims 190-195, wherein treating comprises decreasing the rate of pulmonary exacerbation, as compared to the rate of pulmonary exacerbation of the patient prior to treatment.

197. The method of any one of claims 190-196, wherein treating comprises increasing the time to first pulmonary exacerbation, as compared to an untreated patient.

198. The method of claim 196 or 197, wherein the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis.

199. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

200. The method of claim 199, wherein the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

201. The method of claim 199, wherein the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

202. The method of any one of claims 199-201, wherein the chronic rhinosinusitis is refractory chronic rhinosinusitis.

203. The method of any one of claims 199-202, wherein treating comprises reducing, diminishing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS.

204. The method of claim 203, 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.

205. A method for treating hi dradenitis suppurativa (HS) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

206. The method of claim 205, wherein the hidradenitis suppurativa (HS) is Hurley stage I.

207. The method of claim 205, wherein the hidradenitis suppurativa (HS) is Hurley stageII.

208. The method of claim 205, wherein the hidradenitis suppurativa (HS) is Hurley stageIII.

209. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

210. The method of claim 209, wherein the cancer is a metastatic cancer.

211. The method of claim 210, wherein the metastatic cancer is breast to lung metastatic cancer.

212. The method of claim 210, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver.

213. The method of claim 210, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

214. The method of claim 210, 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.

215. The method of claim 210, 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.

216. The method of claim 210, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or the kidney.

217. The method of claim 210, wherein the metastatic cancer comprises metastasis of lymphoma to the kidney, ovary, liver, bladder, or the spleen.

218. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

219. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

220. The method of claim 219, wherein the arthritis is rheumatoid arthritis.

221. The method of claim 219, wherein the arthritis is osteoarthritis.

222. 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 ofclaims 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

223. The method of claim 222, wherein the inflammatory bowel disease (IBD) is Crohn’s disease.

224. The method of claim 222, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

225. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

226. The method of claim 225, wherein the ANCA associated disease is granulomatosis with polyangiitis (GPA).

227. The method of claim 225, wherein the ANCA associated disease is microscopic poly angiitis (MPA).

228. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155, 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.

229. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

230. The method of claim 229, wherein the heart failure is heart failure with reduced ejection fraction.

231. The method of claim 229, wherein the heart failure is heart failure with preserved ejection fraction.

232. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

233. The method of claim 232, wherein the patient is a heart transplant recipient.

234. The method of claim 232 or 233, wherein the IR injury is due to heart transplantation.

235. The method of any one of claims 232-234, wherein the treating comprises improving left-ventricular (LV) graft function of the patient.

236. The method of claim 235, wherein improving left-ventricular (LV) graft function comprises improving LV systolic function of the patient.

237. The method of claim 236, 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.

238. 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 1-154 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 155.

239. The method of claim 238, wherein the lung injury is acute liver injury.

240. The method of claim 238, wherein the lung injury is drug-induced acute liver injury.

241. The method of any one of claims 156-240, wherein the effective amount of the compound or composition is administered once daily during an administration period.

242. The method of any one of claims 156-240, wherein the effective amount of the compound or composition is administered orally.

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