Dipeptidyl peptidase 1 inhibitors and uses thereof

Abstract

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

Description

DIPEPTIDYL PEPTIDASE 1 INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 626,401, filed on January 29, 2024, the disclosure of which is incorporated by reference herein in its entirety.BACKGROUND

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

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

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

[0005] Neutrophils play a critical role in host defense against invading pathogens. Neutrophils are produced in the bone marrow and are fully mature when released into the circulation to take up their role as the first line of cellular defense. Pro-inflammatory mediators and chemotactic attractants activate neutrophils and draw them to the site of infection, where they act to engulf bacteria by phagocytosis, assaulting them with an arsenal of anti-bacterial compounds that useboth 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 a1- 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):

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

[0010] R1is a 4- to 10-membered heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;

[0011] R2is

[0012] X is -NR9-, -O-, -CRnR12-, -C(O)-, -S-, -S(O) - or -S(O)2-;

[0013] Q is CH or N;

[0014] L is a carbocyclene, arylene, heterocyclene, or heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3;

[0015] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tetracyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tetracyclic ring is optionally substituted with 1, 2, 3, or 4 R4;

[0016] each R4is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0017] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0018] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0019] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0020] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0021] R9is H, -C1-C6alkyl, or R10;

[0022] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8, -(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n;

[0023] R11and R12are each independently selected from H, deuterium, halogen, or -C1-C6alkyl;

[0024] each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, Y groups are connected by a peptide bond (-C(O)NH-);

[0025] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0026] p is 0, 1, 2, or 3.

[0027] In embodiments, the present disclosure provides a compound of formula (I-A):

[0028] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0029] X is -NR9-, -O-, -CRnR12-, -C(O)-, -S-, -S(O) - or -S(O)2-;

[0030] Q is CH or N;

[0031] R1is a 4-10 membered monocyclic or bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;

[0032] R2is

[0033] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tetracyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tetracyclic ring is optionally substituted with 1, 2, 3, or 4 R4;

[0034] each R4is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0035] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0036] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0037] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0038] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0039] R9is H, -C1-C6alkyl, or R10;

[0040] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), - (C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8, -(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n;

[0041] each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, adjacent Y forms a peptide bond (-C(O)NH-) or a modified peptide bond (-C(O)CH2-);

[0042] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0043] p is 0, 1, 2, or 3; and

[0044] r is O, 1, 2, 3, or 4.

[0045] In embodiments, the present disclosure provides a compound of formula (I-B):

[0046] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0047] R1is a 4-10 membered monocyclic or bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;

[0048] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl;

[0049] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0050] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0051] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0052] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), - (C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8, -(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n;

[0053] each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, adjacent Y forms a peptide bond (-C(O)NH-) or a modified peptide bond (- C(O)CH2-);

[0054] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0055] p is 0, 1, 2, or 3; and

[0056] r is O, 1, 2, 3, or 4.

[0057] In embodiments, the present disclosure provides a compound of formula (I-C):

[0058] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0059] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl;

[0060] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0061] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0062] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0063] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), - (C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8,-(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, or -(C1- C6alkylene)-heteroaryl;

[0064] r is 0, 1, 2, 3, or 4; and

[0065] t is O, 1, 2, 3, or 4.

[0066] In embodiments, the present disclosure provides compounds of Table A or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0067] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I- C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof), and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0068] In embodiments, the present disclosure provides a method for treating an obstructive disease of the airway in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0069] In embodiments, the present disclosure provides a method for treating cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0070] In embodiments, the present disclosure provides a method for treating chronic rhinosinusitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0071] In embodiments, the present disclosure provides a method for treating hidradenitis suppurativa in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I- C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0072] In embodiments, the present disclosure provides a method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0073] In embodiments, the present disclosure provides a method for treating lupus nephritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0074] 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), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0075] In embodiments, the present disclosure provides a method for treating inflammatory bowel disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I- C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0076] 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), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0077] In embodiments, the present disclosure provides a method for treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof), wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, sweet’s syndrome, dermatomyositis / polymyositis, neutrophilic dermatoses, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or a ventilator-induced lung injury.

[0078] In embodiments, the present disclosure provides a method for treating heart failure in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof).

[0079] In embodiments, the present disclosure provides a method for treating ischemia / reperfusion (IR) injury in a patient in need thereof, comprising administering to thepatient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof) or a pharmaceutical composition comprising the compound disclosed herein.

[0080] 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-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof) or a pharmaceutical composition comprising the compound disclosed herein.DETAILED DESCRIPTION

[0081] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0082] Definitions

[0083] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0084] 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.

[0085] 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 theendpoints of the range.

[0086] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0087] “Cyano” refers to the -CN radical.

[0088] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0089] “ Oxo” refers to the =O substituent.

[0090] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5alkyl. A C1-C5alkyl includes C5alkyls, C4alkyls, C3alkyls, C2alkyls and C1alkyl (i.e., methyl). A C1-C6alkyl includes all moieties described above for C1-C5alkyls but also includes C6alkyls. A C1-C10alkyl includes all moieties described above for C1-C5alkyls and C1-C6alkyls, but also includes C7, C8, C9and C10alkyls. Similarly, a C1-C12alkyl includes all the foregoing moieties, but also includes C11and C12alkyls. Non-limiting examples of C1-C12alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0091] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C1-C12alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0092] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6alkenyland an alkenyl comprising up to 5 carbon atoms is a C2-C5alkenyl. A C2-C5alkenyl includes C5alkenyls, C4alkenyls, C3alkenyls, and C2alkenyls. A C2-C6alkenyl includes all moieties described above for C2-C5alkenyls but also includes C6alkenyls. A C2-C10alkenyl includes all moieties described above for C2-C5alkenyls and C2-C6alkenyls, but also includes C7, C8, C9and C10alkenyls. Similarly, a C2-C12alkenyl includes all the foregoing moieties, but also includes C11and C12alkenyls. Non-limiting examples of C2-C12alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methy1-1-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1 -pentenyl, 2-pentenyl, 3 -pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3 -hexenyl, 4- hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2- undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5- dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11- dodecenyl. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted.

[0093] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0094] “ Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5alkynyl. A C2-C5alkynyl includes C5alkynyls, C4alkynyls, C3alkynyls, and C2alkynyls. A C2-C6alkynyl includes all moieties described above for C2-C5alkynyls but also includes C6alkynyls. A C2-C10alkynyl includesall moieties described above for C2-C5alkynyls and C2-C6alkynyls, but also includes C7, C8, C9and C10alkynyls. Similarly, a C2-C12alkynyl includes all the foregoing moieties, but also includes C11and C12alkynyls. Non-limiting examples of C2-C12alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.

[0095] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0096] “Alkoxy” refers to a radical of the formula -ORawhere 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.

[0097] “Alkylamino” refers to a radical of the formula -NHRaor -NRaRawhere each Rais, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0098] “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.

[0099] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rcwhere Rbis an alkylene group as defined above and Rcis one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.

[0100] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, whereinthe 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.

[0101] “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, norbomyl, decalinyl, 7,7-dimethy1-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0102] “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.

[0103] “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.

[0104] “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.

[0105] “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.

[0106] “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.

[0107] “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-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.

[0108] “Heterocyclyl” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, saturated or partially unsaturated ring radical which consists of two to twelve carbon ring atoms and from one to six heteroatoms as ring atoms selected from nitrogen, oxygen or sulfur, at least one non-aromatic, saturated or partially unsaturated ring containing at least one heteroatom as a ring atom. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally 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.

[0109] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Rewhere Rbis an alkylene group as defined above and Reis a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkyl group can be optionally substituted.

[0110] “N-heterocyclyl” refers to a heterocyclyl radical as defined above containing at leastone 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.

[0111] “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), benzotri azolyl, 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 -pheny1- 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.

[0112] “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.

[0113] “Heteroaryl alkyl” 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.

[0114] “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 statedotherwise specifically in the specification, a thioalkyl group can be optionally substituted.

[0115] 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.

[0116] “ Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further includes any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroaryl alkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0117] As used herein, the symbol(hereinafter can be referred to as “a pointof attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference.

[0118] 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.

[0119] 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.

[0120] 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 Eand Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0121] 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.

[0122] 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 display clinical 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).

[0123] 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.

[0124] 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.

[0125] 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.

[0126] Compounds

[0127] In one aspect of the present disclosure, a DPP1 inhibitor is provided, and the DPP1 inhibitor is a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceuticallyacceptable salt, a stereoisomer, or a deuterated form thereof.

[0128] In embodiments, the present disclosure provides a compound of formula (I):

[0129] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0130] R1is a 4- to 10-membered heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;

[0131] R2is

[0132] X is -NR9-, -O-, -CRnR12-, -C(O)-, -S-, -S(O) - or -S(O)2-;

[0133] Q is CH or N;

[0134] L is a carbocyclene, arylene, heterocyclene, or heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3;

[0135] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tetracyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tetracyclic ring is optionally substituted with 1, 2, 3, or 4 R4;

[0136] each R4is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1-C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0137] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OCi-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0138] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0139] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0140] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0141] R9is H, -C1-C6alkyl, or R10;

[0142] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), - (C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8, -(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n;

[0143] R11and R12are each independently selected from H, deuterium, halogen, or -C1-C6alkyl;

[0144] each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, Y groups are connected by a peptide bond (-C(O)NH-);

[0145] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0146] p is 0, 1, 2, or 3.

[0147] In one embodiment of the compound of formula (I), R1is a monocyclic or a bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5.

[0148] In one embodiment of the compound of formula (I), R1is a 4- to 10-membered polycyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle is substituted with 1, 2, 3, or 4 R5.

[0149]

[0150] In one embodiment of the compound of formula (I), L is a monocyclic carbocyclene, monocyclic arylene, monocyclic heterocyclene, or monocyclic heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3. In one embodiment, L is phenylene or 5- or 6- membered heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3. In some embodiments, L is phenylene or thiophene, each of which is optionally substituted with 1 or 2

[0151] In one embodiment of the compound of formula (I), L is a polycyclic carbocyclene, polycyclic arylene, polycyclic heterocyclene, or polycyclic heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3. In some embodiments, L isoptionally substituted with 1, 2, 3, or 4 R3.

[0152] In one embodiment of the compound of formula (I), L is, optionally substituted with 1, 2, 3, or 4 R3, wherein ring B is a heteroaryl ring and * indicates the bond toR2. In some embodiments,each of which is optionally substituted with 1, 2, 3, or 4 R3, wherein * indicates the bond to R2.

[0153] In one embodiment of the compound of formula (I), L is, optionally substituted with 1, 2, 3, or 4 R3, wherein ring B is a heteroaryl ring and * indicates the bond toR2. In some embodiments,each of which is optionally substituted with 1, 2, 3, or 4 R3, wherein * indicates the bond to R2.

[0154] In one embodiment of the compound of formula (I), L is

[0155] In one embodiment of the compound of formula (I), L is a fused bicyclic heteroaryl. In some embodiments, L isIn some embodiments, L is

[0156] In one embodiment of the compound of formula (I), L is a monocyclic heteroaryl. In some embodiments, L iseach of which is optionally substituted with 1, 2, 3, or 4 R3. In some embodiments, L is. In someembodiments, L is. In some embodiments, L iswherein * indicates the bond to R2.

[0157] In one embodiment of the compound of formula (I), L is phenyl optionally substituted with 1, 2, 3, or 4 R3. In some embodiments, L is phenyl optionally substituted with 1 or 2 R3. In some embodiments, L is phenyl optionally substituted with 1 R3.

[0158] In one embodiment of the compound of formula (I), L is. In one embodiment of the compound of formula (I), L is, wherein * indicates the bond to R2.

[0159] In embodiments, the present disclosure provides a compound of formula (I-A):

[0160] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0161] X is -NR9-, -O-, -CRnR12-, -C(O)-, -S-, -S(O) - or -S(O)2-;

[0162] Q is CH or N;

[0163] R1is a 4-10 membered monocyclic or bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;

[0164] R2is

[0165] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tetracyclic ringoptionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tetracyclic ring is optionally substituted with 1, 2, 3, or 4 R4;

[0166] each R4is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- Cio haloalkyl, -C1-Cio haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0167] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0168] each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- Cio haloalkyl, -C1-Cio haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;

[0169] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0170] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0171] R9is H, -C1-C6alkyl, or R10;

[0172] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), - (C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8, -(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n;

[0173] each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, adjacent Y forms a peptide bond (-C(O)NH-) or a modified peptide bond (- C(O)CH2-);

[0174] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0175] p is 0, 1, 2, or 3; and

[0176] r is O, 1, 2, 3, or 4.

[0177] In one embodiment of the compound of formula (I) or (I-A), R2is

[0178] In embodiments, the present disclosure provides a compound of formula (I-B):

[0179] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0180] R1is a 4-10 membered monocyclic or bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;

[0181] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6 alkyl, SOC1-6alkyl, or SO2C1-6alkyl;

[0182] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0183] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0184] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0185] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), - (C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8, -(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n;

[0186] each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, adjacent Y forms a peptide bond (-C(O)NH-) or a modified peptide bond (- C(O)CH2-);

[0187] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0188] p is 0, 1, 2, or 3; and

[0189] r is O, 1, 2, 3, or 4.

[0190] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is a 4-8 membered monocyclic heterocycle ring optionally substituted with 1 or 2 R5. In one embodiment, R1is a 4-8 membered monocyclic heterocycle containing 0, 1, or 2 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle is substituted with 1 or 2 R5.

[0191] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is a 4- to 10- membered spiro heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the spiro heterocycle is optionally substituted with 1, 2, 3, or 4 R5.

[0192] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is a 4- to 10- membered fused heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the fused heterocycle is optionally substituted with 1, 2, 3, or 4 R5.

[0193] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is a 6-10 membered bridged heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, O, wherein the bridged heterocycle is optionally substituted with 1, 2, 3, or 4 R5.

[0194] In one embodiment of the compound of formula (I), (I-A), or (I-B),

[0195] R1is, each of which is optionally substituted with 1, 2, 3, or 4 R5;

[0196] X1is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;

[0197] X2is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)- or -CRnR12-;

[0198] g is 0, 1, 2, or 3; and

[0199] k is O, 1, or 2.

[0200] In one embodiment of the compound of formula (I), (I-A), or (I-B),

[0201] R1is, each of which is optionally substituted with 1, 2, 3, or 4 R5;

[0202] X1is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CRnR12-;

[0203] X2is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;

[0204] g is 0, 1, 2, or 3; and

[0205] k is O, 1, or 2.

[0206] In one embodiment of the compound of formula (I), (I-A), or (I-B),

[0207] R1is, which is optionally substituted with 1, 2, 3, or 4 R5;

[0208] X1is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, - N(heterocycle)-, or -CRnR12-;

[0209] X2is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;

[0210] g is 0, 1, 2, or 3;

[0211] k is 0, 1, or 2.

[0212] In one embodiment of the compound of formula (I), (I-A), or (I-B),

[0213] R1is, which is optionally substituted with 1, 2, 3, or 4 R5;

[0214] X1is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, or -CRnR12-;

[0215] X2is -O-, -S-, -NH-, -N(C1-C6alkyl)-, or -N(C1-C6haloalkyl)-;

[0216] g is 0, 1, 2, or 3;

[0217] k is 0, 1, or 2.

[0218] In one embodiment of the compound of formula (I), (I-A), or (I-B),

[0219] R1is, which is optionally substituted with 1, 2, 3, or 4 R5;

[0220] X1is -O-, -NH-, or -CRnR12-;

[0221] X2is -O-, or -NH-;

[0222] g is 0, 1, 2, or 3;

[0223] k is O, 1, or 2.

[0224] In one embodiment of the compound of formula (I), (I-A), or (I-B),

[0225] R1is each of which isoptionally substituted with 1, 2, 3, or 4 R5;

[0226] X1is -O-, -S-, or -NH-; and

[0227] X2is -O-, -S-, -NH-, or -CH2-.

[0228] In one embodiment of the compound of formula (I), (I-A), or (I-B),optionally substituted with 1, 2, 3, or 4 R5;

[0230] X1is -O-, -S-, or -NH-; and

[0231] X2is -O-, -S-, -NH-, or -CH2-.

[0232] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is, each of which is optionally substituted with 1, 2, 3, or 4 R5. In one embodiment, R1isor, each of which is optionally substituted with 1, 2, 3, or 4 R5. In one embodiment, R1is, optionally substituted with 1, 2, 3, or 4 R5. In some embodiments, each R5is halogen, -NH2, -OH, -C1-C6alkyl, or -OC1-C6alkyl. In some embodiments, each R5is -OH, - C1-C6alkyl, or -OC1-C6alkyl. In some embodiments, each R5is -OH, -C1-C3alkyl, or -OC1- C3alkyl. In some embodiments, each R5is -OH, methyl, or methoxy.

[0233] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is, each of which is optionally substituted with 1, 2, 3, or 4 R5.

[0234] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is

[0235] In one embodiment of the compound of formula (I), (I-A), or (I-B), wherein:

[0236] R1is, wherein R1is optionally further substituted with 1, or 2 R5;

[0237] X2and X3are independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, - N(C(O)(C1-C6alkyl))-, -N(heterocycle)-, or -CRnR12-;

[0238] X4is O, S, NH, or N(C1-C6alkyl);

[0239] R11and R12are each independently H, halogen, or -C1-C6alkyl;

[0240] RAis H, -C1-C6alkyl, -C1-C6alkylene-carbocyclyl, or -C1-C6alkylene-heteroaryl; and

[0241] RBis -C1-C6alkyl, -C2-C6alkenyl, -C1-C6alkylene-carbocyclyl, or -C1-C6alkyleneheteroaryl; or

[0242] RAand RBare taken together to form a heterocyclyl.

[0243] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is an 8-10 membered bicyclic fused heterocycle ring optionally substituted with 1, 2, 3, or 4 R5.

[0244] In one embodiment of the compound of formula (I), (I-A), or (I-B), wherein:

[0245] R1is, wherein R1is optionally substituted with 1, 2, 3, or 4 R5;

[0246] gl is 0, 1, 2, or 3;

[0247] g3 is 1, 2, 3, or 4;

[0248] X2is each independently -O-, -S-, -NH-, -N(C1-C6alkyl)-, or -CRnR12-;

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

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

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

[0252] R1is wherein R1is optionally substituted with 1, 2, 3, or4 R5;

[0253] X2is -O-, -S-, -NH-, -NR5-, or -CRnR12-;

[0254] R11is H, halogen, cyano, hydroxyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -COOH,-C1-C6alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6alkyl or halogenated -OC1-C6alkyl;

[0255] R12is H, F, Cl, Br, I or Ci-C6alkyl; and

[0256] each gl and g2 is independently 0, 1, 2, or 3, and the total sum of gl and g2 is less than or equal to 3.

[0257] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is a 5,5-, 5,6-, 6,5-, 6,6-, or 5,7-fused heterocycle, each of which is optionally substituted with 1, 2, 3, or 4 R5. In one embodiment, R1is a 5,6-fused heterocycle, 6,5-fused heterocycle, or 6,6-fused heterocycle, each of which is optionally substituted with 1, 2, 3, or 4 R5. In some embodiments,R1is , each of whichis optionally substituted with 1, 2, 3, or 4 R5. In some embodiments, R1optionally substituted with 1, 2, 3, or 4 R5. In some embodiments, R1isoptionally substituted with 1, 2, 3, or 4 R5. In some embodiments, R1iseach of which is optionally substituted with 1, 2, 3, or 4 R5. In some embodiments, R1isor, each of which is optionally substituted with 1, 2, 3, or 4 R5.

[0258] In one embodiment of the compound of formula (I), R1is, each of which is optionally substituted with 1, 2,3, or 4 R5.

[0259] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1each of which is optionally substituted with 1, 2, 3, or 4 R5.

[0260] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is, each of which is optionally substituted with 1, 2, 3, or 4R5.

[0261] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is fromeach of which is optionally substituted with 1, 2, 3, or 4 R5.

[0262] In one embodiment of the compound of formula (I), (I-A), or (I-B), wherein:

[0263] R1is, wherein R1is optionally substituted with 1, 2, 3, or 4 R5;

[0264] g1 and g2 are each independently 0, 1, or 2, provided that both g1 and g2 are not 0, or both g1 and g2 are not 2; and

[0265] g3 is 1 or 2.

[0266] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1iswhereinR1is optionally substituted with 1, 2, 3, or 4 R5.

[0267] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is. In oneembodiment of the compound of formula (I), (I-A), or (I-B), R1is. In one embodiment of the compound of formula (I), (I-A), or (I-B), R i1is

[0268] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is

[0269] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is

[0270] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is

[0271] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is

[0272] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1isoptionally substituted with 1, 2, 3, or 4 R5. In some embodiments, R1is, optionally substituted with 1, 2, or 3 R5. In one embodiment, R1isoptionally substituted with lor2 R5.

[0273] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is In one embodiment. , R1is

[0274] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is, each of which is optionally further substituted with 1 or 2 R5.

[0275] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1is or; and R5is -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), or heterocycle. In some embodiments, R5is CH3, -CF3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2. In some embodiments, R5is -C(O)CH3,

[0276] In one embodiment of the compound of formula (I), (I-A), or (I-B), R1isIn some embodiments, R1isand R10is -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)- O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1- C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1- C6alkyl)-O-(C1-C6alkyl), or -(C1-C6alkylene)-NR7-(C1-C6alkylene)-NR7R8. In some embodiments, R1is

[0277] In one embodiment of the compound of formula (I-B):each of which is optionally substituted with 1, 2, 3, or 4 R5;

[0279] R3is halogen, -C1-C3alkyl, or -CN;

[0280] R5is halogen, -NH2, -OH, -C1-C6alkyl, or -OC1-C6alkyl;

[0281] R10is -(C1-C4alkyl)-NHCH3, -(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C4alkyl)-OH, -(C1-C3alkylene)-O-(C1-C4alkyl)-COOH, -(C1- C3alkyl ene)-O-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C4alkyl)-NH2, - (C1-C3alkyl ene)-O-(C1-C4alkyl)-NHCH3, -(C1-C3alkylene)-NH-(C1-C4alkyl)-OH, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NH2, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NHCH3, -(C1-C3alkylene)-NH-(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C3alkylene)-C(O)NH-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C4alkyl), -(C1- C3alkyl ene)-O-(C1-C3alkylene)-C(O)NH-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)- C(O)NH-(C1-C3alkylene)-O-(C1-C3alkylene)-NH-aryl, or -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C3alkylene)-NH-aryl; and

[0282] r is O or 1.

[0283] In one embodiment of the compound of formula (I-B):

[0284] each of which is optionally substituted with 1, 2, or 3 R5;

[0285] R3is halogen, -C1-C3alkyl, or -CN;

[0286] R5is halogen, -NH2, -OH, -C1-C6alkyl, or -OC1-C6alkyl;

[0287] R10is -CH2CH2N(CH3)2, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2COOH,CH2CH2OCH2CONH2, -CH2CH2OCH2CONHCH3, -CH2CH2OCH2CON(CH3)2,CH2CH2OCH2CH2COOH, -CH2CH2OCH2CH2CONH2, -CH2CH2OCH2CH2CONHCH3, -CH2CH2OCH2CH2CON(CH3)2, -CH2CH2OCH2CH2CONHCH2CH3,CH2CH2OCH2CH2CON(CH2CH3)2, -CH2CH2OCH2CH2CONHCH2CH2OCH3,CH2CH2OCH2CH2CON(CH3)CH2CH2OCH3, -CH2CH2OCH2CH2CONHCH2CH2OCH2CH3, -CH2CH2OCH2CH2CON(CH3)CH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH3,CH2CH2OCH2CH2NH2, -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2N(CH3)2, -CH2CH2OCH2C(O)NHCH3, -CH2CH2NHCH2CH2OH, -CH2CH2NHCH2CH2NH2,CH2CH2NHCH2CH2NHCH3, -CH2CH2NHCH2CH2N(CH3)2, -CH2CH2NHCH2CH2OCH3, -CH2CH2N(CH3)CH2CH2OCH3,or; and

[0288] r is O or 1.

[0289] In one embodiment of the compound of formula (I-B):

[0291] R3is halogen, -C1-C3alkyl, or -CN;

[0292] R10is -CH2CH2N(CH3)2, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2COOH,CH2CH2OCH2CONH2, CH2CH2OCH2CONHCH3, -CH2CH2OCH2CON(CH3)2,CH2CH2OCH2CH2COOH, -CH2CH2OCH2CH2CONH2, -CH2CH2OCH2CH2CONHCH3, -CH2CH2OCH2CH2CON(CH3)2, -CH2CH2OCH2CH2CONHCH2CH3,CH2CH2OCH2CH2CON(CH2CH3)2, -CH2CH2OCH2CH2CONHCH2CH2OCH3,CH2CH2OCH2CH2CON(CH3)CH2CH2OCH3, -CH2CH2OCH2CH2CONHCH2CH2OCH2CH3, -CH2CH2OCH2CH2CON(CH3)CH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH3, CH2CH2OCH2CH2NH2, -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2N(CH3)2, -CH2CH2OCH2C(O)NHCH3, -CH2CH2NHCH2CH2OH, -CH2CH2NHCH2CH2NH2, CH2CH2NHCH2CH2NHCH3, -CH2CH2NHCH2CH2N(CH3)2, -CH2CH2NHCH2CH2OCH3, -

[0293] r is 0 or 1.

[0294] In one embodiment of the compound of formula (I-B):

[0296] R3is halogen;

[0297] R10is

[0298] r is 0 or 1.

[0299] In embodiments, the present disclosure provides a compound of formula (I-C):

[0300] or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:

[0301] each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6 alkyl, SOC1-6alkyl, or SO2C1-6alkyl;

[0302] each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle;

[0303] each R7is independently H, -C1-C6alkyl, or heterocyclyl;

[0304] each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;

[0305] R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), - (C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkyl ene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7R8, -(C1-C6alkyl ene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, or -(C1- C6alkylene)-heteroaryl;

[0306] r is 0, 1, 2, 3, or 4; and

[0307] t is O, 1, 2, 3, or 4.

[0308] In one embodiment of the compound of formula (I), (I-A), or (I-B), when R1isoptionally substituted with R5, R5is not -OCH3at the 6-position of the oxazepane ring.

[0309] In one embodiment of the compound of formula (I), (I-A), or (I-B), when R1issubstituted with at least one R5and at least one R5is -OCH3at the 6-position of the oxazepane ring, then R10is not -C1-C6alkyl, -C1-C6alky1-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-O-(C1-C6alkyl)-OH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkyl ene)-O-(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -C1-C10haloalkyl, -C1-C10haloalky1-OH, -C1-C6alky1-NR7R8, or -(C1-C6alkylene)-heterocycle, wherein each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl.

[0310] In one embodiment of the compound of formula (I), (I-A), or (I-B), when R1issubstituted with 1 R5and R5is -OCH3at the 6-position of the oxazepane ring, then R10is not -CH2CH2N(CH3)2, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, - CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, or

[0311] In one embodiment of the compound of formula (I-C), R5is not -OCH3at the 6-position of the oxazepane ring.

[0312] In one embodiment of the compound of formula (I-C), when t is at least 1 and at least one R5is -OCH3at the 6-position of the oxazepane ring, then R10is not -C1-C6alkyl, -C1-C6alky1-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1- C6alkyl)-OH, -C1-C10haloalkyl, -C1-C10haloalky1-OH, -C1-C6alky1-NR7’R8’, or -(C1-C6alkylene)-heterocycle, wherein each R7and R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl.

[0313] In one embodiment of the compound of formula (I-C), when t is 1 and R5is -OCH3at the 6-position of the oxazepane ring, then R10is not -CH2CH2N(CH3)2, -CH2CH2OCH2CH3, - CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH,CH2CH2OCH2CH2OCH3, or

[0314] In one embodiment of the compound of formula (I- A), (I-B), or (I-C), r is 0 or 1.

[0315] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R3is each independently halogen, -C1-C3alkyl, or -CN. In some embodiments, R3is halogen. In one embodiment, R3is F.

[0316] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R10is -(C1- C4alkyl)-NHCH3, -(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C4alkyl)-OH, -(C1-C3alkylene)-O-(C1-C4alkyl)-COOH, -(C1-C3alkylene)- O-(C1-C3alkyl ene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C4alkyl)-NH2, -(C1-C3alkylene)-O-(C1-C4alkyl)-NHCH3, -(C1-C3alkylene)-NH-(C1-C4alkyl)-OH, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NH2, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NHCH3, -(C1-C3alkylene)-NH-(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C3alkylene)-C(O)NH-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C4alkyl), -(C1- C3alkyl ene)-O-(C1-C3alkylene)-C(O)NH-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)- C(O)NH-(C1-C3alkylene)-O-(C1-C3alkylene)-NH-aryl, or -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C3alkylene)-NH-aryl. In some embodiments, R10is -CH2CH2N(CH3)2, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2COOH, CH2CH2OCH2CONH2, -CH2CH2OCH2CONHCH3, -CH2CH2OCH2CON(CH3)2,CH2CH2OCH2CH2COOH, -CH2CH2OCH2CH2CONH2, -CH2CH2OCH2CH2CONHCH3, -CH2CH2OCH2CH2CON(CH3)2, -CH2CH2OCH2CH2CONHCH2CH3,CH2CH2OCH2CH2CON(CH2CH3)2, -CH2CH2OCH2CH2CONHCH2CH2OCH3,CH2CH2OCH2CH2CON(CH3)CH2CH2OCH3, -CH2CH2OCH2CH2CONHCH2CH2OCH2CH3, -CH2CH2OCH2CH2CON(CH3)CH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH3,CH2CH2OCH2CH2NH2, -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2N(CH3)2, -CH2CH2OCH2C(O)NHCH3, -CH2CH2NHCH2CH2OH, -CH2CH2NHCH2CH2NH2,CH2CH2NHCH2CH2NHCH3, -CH2CH2NHCH2CH2N(CH3)2, -CH2CH2NHCH2CH2OCH3, -

[0317] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R10is -(C1- C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7R8, - (C1-C6alkyl ene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)- NR7C(O)-(C1-C6alkyl ene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7- (C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1-C6alkylene)- NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O-(C1-C6alkyl), or -(C1-C6alkylene)-NR7- (C1-C6alkyl ene)-NR7R8.

[0318] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R10is - CH2CH2N(CH3)2, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2NHCH2CH2OCH3, or -CH2CH2N(CH3)CH2CH2OCH3.

[0319] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R10is

[0320] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R10is

[0321] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R5is halogen, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, - CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, - S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, - SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)- heteroaryl, or heterocycle. In one embodiment, R5is halogen, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, -C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, or -S(=NH)(O)(C1-C6alkyl).

[0322] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R5is halogen, -CN, -OH, -OCH3, or -SCH3. In one embodiment, R5is -SCH3, -OCH3, -OCH2CH3, -OCD3, - OCF3, or -OCHF2. In one embodiment, R5is -CH3, -CF3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, or -C(O)CH3. In one embodiment, R is -C(O)CH3,. In one embodiment,R5is -OC1-C6alkyl.

[0323] In one embodiment of the compound of formula (I), (I-A), (I-B), or (I-C), R5is -CH3, - OCH3, -OH, or -NH2.

[0324] In one embodiment of the compound of formula (I-C):

[0325] R3is halogen, -C1-C3alkyl, or -CN;

[0326] R5is halogen, -NH2, -OH, -C1-C6alkyl, or -OC1-C6alkyl;

[0327] R10is -(C1-C4alkyl)-NHCH3, -(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C4alkyl)-OH, -(C1-C3alkylene)-O-(C1-C4alkyl)-COOH, -(C1- C3alkyl ene)-O-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C4alkyl)-NH2, - (C1-C3alkyl ene)-O-(C1-C4alkyl)-NHCH3, -(C1-C3alkylene)-NH-(C1-C4alkyl)-OH, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NH2, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NHCH3, -(C1-C3alkylene)-NH-(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C3alkylene)-C(O)NH-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C4alkyl), -(C1- C3alkyl ene)-O-(C1-C3alkylene)-C(O)NH-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)- C(O)NH-(C1-C3alkylene)-O-(C1-C3alkylene)-NH-aryl, or -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C3alkylene)-NH-aryl;

[0328] r is 0 or 1; and

[0329] t is O, 1, or 2.

[0330] In one embodiment of the compound of formula (I-C):

[0331] R3is halogen, -C1-C3alkyl, or -CN;

[0332] R5is halogen, -NH2, -OH, -C1-C6alkyl, or -OC1-C6alkyl;

[0333] R10is -CH2CH2N(CH3)2, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, - CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2COOH, CH2CH2OCH2CONH2, -CH2CH2OCH2CONHCH3, -CH2CH2OCH2CON(CH3)2, CH2CH2OCH2CH2COOH, -CH2CH2OCH2CH2CONH2, -CH2CH2OCH2CH2CONHCH3, - CH2CH2OCH2CH2CON(CH3)2, -CH2CH2OCH2CH2CONHCH2CH3,CH2CH2OCH2CH2CON(CH2CH3)2, -CH2CH2OCH2CH2CONHCH2CH2OCH3, CH2CH2OCH2CH2CON(CH3)CH2CH2OCH3, -CH2CH2OCH2CH2CONHCH2CH2OCH2CH3, - CH2CH2OCH2CH2CON(CH3)CH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH3, CH2CH2OCH2CH2NH2, -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2N(CH3)2, - CH2CH2OCH2C(O)NHCH3, -CH2CH2NHCH2CH2OH, -CH2CH2NHCH2CH2NH2, CH2CH2NHCH2CH2NHCH3, -CH2CH2NHCH2CH2N(CH3)2, -CH2CH2NHCH2CH2OCH3, -CH2CH2N(CH3)CH2CH2OCH3,

[0334] r is 0 or 1; and

[0335] t is O, 1, or 2.

[0336] In one embodiment of the compound of formula (I-C):

[0337] R3is halogen;

[0338] R10is; and

[0339] r is 0 or 1; and

[0340] t is O, 1, or 2.

[0341] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0342] In embodiments, provided herein is a compound of formula (I), (I-A), (I-B), or (I-C), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0343] In embodiments, provided herein is a pharmaceutically acceptable salt of a compound of formula (I), (I-A), (I-B), or (I-C). Further embodiments of the disclosure relate to a deuterated compound of formula (I), (I-A), (I-B), or (I-C), or a pharmaceutically acceptable salt thereof.

[0344] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, racemic form thereof, or stereoisomer thereof.

[0345] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof.

[0346] In embodiments, provided herein is a compound in Table A, or a pharmaceutically acceptable salt thereof.

[0347] In one embodiment, provided herein is a compound set forth in Table A.

[0348] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound in Table A.455159*Represented stereochemistry is assumed.

[0349] In one embodiment, provided herein is a compound selected from, or a pharmaceutically acceptable salt, astereoisomer, or deuterated form thereof.

[0350] Compositions

[0351] The compounds of formula (I), (I-A), (I-B), or (I-C), or Table A or pharmaceutically acceptable salts thereof, or deuterated versions of the foregoing, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (I-A), (I-B), or (I-C), or Table A compound / salt (active ingredient) is in association with pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0352] 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.

[0353] In embodiments, the present disclosure provides pharmaceutical composition(s)comprising a compound of formula (I), (I-A), (I-B), or (I-C), or Table A or a pharmaceutically acceptable salt thereof, as hereinbefore defined in association with pharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s). The disclosure further provides a process for the preparation of a pharmaceutical composition of the disclosure which comprises mixing a compound of formula (I), (I-A), (I-B), or (I-C), or Table A or a pharmaceutically acceptable salt thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s).

[0354] 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.

[0355] For oral administration the compound of the disclosure may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, com starch or amylopectin; cellulose derivative; binder, for example, gelatin or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and / or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s). Alternatively, the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talcum and titanium dioxide.

[0356] 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.

[0357] 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 / orcarboxymethylcellulose as a thickening agent. Furthermore, other excipients known to those skilled in art may be used when making formulations for oral use.

[0358] Therapeutic Use

[0359] In embodiments, the compounds of formula (I), (I- A), (I-B), or (I-C), or Table A and their pharmaceutically acceptable salts, are DPP1 inhibitors, and thus may be used in any disease area where DPP1 plays a role. As such, in one aspect of the disclosure, a method of treatment is provided. The method of treatment, in one embodiment, comprises, administering to a subject in need thereof, a composition comprising an effective amount of a compound of formula (I), (I- A), (I-B), or (I-C), or Table A or a pharmaceutically acceptable salt of (I), (I- A), (I-B), or (I-C), or Table A. In embodiments, the composition is administered to the patient for an administration period.

[0360] 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.

[0361] 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).

[0362] 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.

[0363] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating pulmonary hypertension. In some embodiments, pulmonary hypertension is pulmonary arterial hypertension. In some embodiments, pulmonary hypertension is pulmonary hypertension due to left heart disease. In some embodiments, pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

[0364] 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), (I-A), (I-B), or (I-C), (I-D), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, administered via the methods provided herein have beneficial effects via inhibiting the activation of NSPs and decreasing inflammation, which in turn leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (e.g., forced expiratory volume in 1second [FEV1]) in CF patients.

[0365] In one embodiment, a method is provided for treating CF comprising administering to a CF patient in need of treatment, a composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0366] In one CF treatment method, a composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, is administered to a CF patient in need of treatment for an administration period. The method comprises improving the lung function of the patient during the administration period, as compared to the lung function of the patient prior to the administration period. The improvement in lung function in one embodiment, is measured by spirometry.

[0367] 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 to the respective value prior to the administration period. Increasing, in one embodiment, is by about 5%, by about 10%, by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45% or by about 50% of the respective value. Increasing, in one embodiment, is by at least about 5%, by at least about 10%, by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45% or by at least about 50%. In yet another embodiment, the increasing is by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30% or by about 5% to about 20%. In even another embodiment, increasing is by about 10% to about 50%, by about 15% to about 50%, by about 20% to about 50%, or by about 25% to about 50%.

[0368] In one embodiment of a method provided herein, a composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, is administered to a bronchiectasis patient in need of treatment for an administration period. Bronchiectasis is considered a pathological endpoint that results from many disease processes and is a persistent or progressive condition characterized by dilated thick- walled bronchi. The symptoms vary from intermittent episodes of expectoration and infection localized to the region of the lung that is affected to persistent daily expectoration often of large volumes of purulent sputum.Bronchiectasis may be associated with other non-specific respiratory symptoms. The underlying pathological process of bronchiectasis, without wishing to be bound by theory, has been reported as damage to the airways which results from an event or series of events where inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V. 65(Suppl 1), incorporated by reference herein in its entirety for all purposes).

[0369] 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).

[0370] 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), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, administered via the methods provided herein have beneficial effects via decreasing inflammation and mucus hypersecretion, which in some embodiments, leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (cough, sputum production, and forced expiratory volume in 1 second [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.

[0371] In one embodiment, the bronchiectasis is non-CF bronchiectasis.

[0372] 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.

[0373] 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’sdecision to prescribe an antibiotic(s) to the patient exhibiting the symptoms.

[0374] 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.

[0375] In another aspect, a method for treating chronic rhinosinusitis (CRS) in a subject in need thereof is provided. The method comprises in one embodiment, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0376] The chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP), or chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic rhinosinusitis is refractory chronic rhinosinusitis. In some embodiments, the refractory chronic rhinosinusitis is refractory chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the refractory chronic rhinosinusitis is refractory chronic rhinosinusitis with nasal polyps (CRSwNP).

[0377] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) post-nasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (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.

[0378] In some embodiments, the administration of the pharmaceutical composition reduces, diminishes the severity of, delays the onset of, or eliminates one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are: (a) nasal congestion; (b) nasal obstruction; (c) nasal discharge; (d) post-nasal drip; (e) facial pressure; (f) facial pain; (g) facial fullness; (h) reduced smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (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.

[0379] 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.

[0380] In some embodiments, the methods comprise decreasing the Sino-Nasal Outcome Test- 22 (SNOT-22) score of the subject during the administration period or subsequent to the administration period, compared to the SNOT-22 score of the subject prior to the administration period. As used herein, “SNOT-22” is a patient-reported measure of outcome developed for use in CRS with or without nasal polyps and contains 22 individual questions. The questions cover a broad range of health and health-related quality of life problems including physical problems, functional limitations and emotional consequences. The theoretical range of the SNOT-22 score is 0-110, with lower scores implying a better health- related quality of life. Further details of SNOT-22 are provided in Hopkins, et al., Clin. Otolaryngol. 2009, 34, 447-454, and Kennedy, et al., Ann Allergy Asthma Immunol. 2013 October; 111(4): 246-251, the contents of which are incorporated herein by reference in its entirety.

[0381] 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 wel1-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.

[0382] 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.

[0383] 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-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0384] 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.

[0385] The disclosure provides methods of treating cancer in a subject in need thereof, comprising, administering to the subject, a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. The disclosure provides methods of treating cancer-induced pain in a subject having cancer, comprising, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. In some embodiments, the cancer-induced pain is cancer-induced bone pain. The disclosure also provides methods of treating cancer-induced bone pain in a subject having cancer, comprising, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein.

[0386] 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.

[0387] 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 islymphoma. 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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] In some embodiments, the cancer is liquid tumor. In some embodiments, the liquid tumor is acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphocyticleukemia, 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).

[0393] 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.

[0394] 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, themetastatic cancer comprises metastasis of lymphoma to the kidney, the ovary, the liver, the bladder, and / or the spleen.

[0395] 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.

[0396] 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.

[0397] 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.

[0398] 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 neuropathicpain. 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.

[0399] In yet another embodiment of the present disclosure, a method for treating lupus nephritis (LN) in a subject in need thereof is provided. The method comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I- A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0400] 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), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In embodiments, arthritis is osteoarthritis. In embodiments, arthritis is rheumatoid arthritis.

[0401] 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), (LB), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof). In embodiments, the treating of osteoarthritis (OA) comprises improving weight loss and / or inflamed paw volume of the patient during the administration period, as compared to the weight loss and / or inflamed paw volume of the patient prior reducing weight loss and / or inflamed paw volume of the patient during the administration period, as compared to the weight loss and / or inflamed paw volume of the patient prior to the administration period.

[0402] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, together with an effect on the underlying bone and cartilage. Currently, the cause of RA is unknown and no satisfactory cure for RA is available. While a number of therapeutic agents have been developed and utilized to alleviate pain and inflammation associated with the disease, such as disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory agents (NSAIDs), they often produce intolerable side effects. To addresses this and other needs, the present disclosure, in one embodiment, provides a method for treating RA using reversible inhibitors of DPP1 of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In one embodiment, a method of for treating RA in a subject in need thereof is provided, and comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), or (I- C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0403] Inflammatory bowel disease (IBD) is a group of inflammatory conditions that affect the colon and small intestine. The most common IBDs are Crohn’s disease and ulcerative colitis. The present disclosure, in one embodiment, addresses the need for novel IBD therapies. Specifically, in one embodiment, a method for treating an inflammatory bowel disease (IBD) in a subject in need thereof is provided. The method comprises administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0404] 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.

[0405] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating heart failure. In some embodiments, heart failure is heart failure with reduced ejection fraction. In some embodiments, heart failure is heart failure with preserved ejection fraction.

[0406] 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-C. In yet even a further embodiment, the compound is present in an oral composition and is administered once daily to the patient in need of treatment.

[0407] 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).

[0408] 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.

[0409] 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), (I- A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In embodiments, the liver injury is acute liver injury. In embodiments, the liver injury is drug-induced acute liver injury. In one embodiment, the liver injury is acetaminophen (APAP)-induced acute liver injury. In one embodiment, the liver injury is caused by acetaminophen overdose. In embodiment, the liver injury is caused by nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac, and naproxen. In one embodiment, the treatment of ALI is a prophylactic treatment

[0410] 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), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof. In one embodiment, sepsis is a consequence of the patient’ s response to overwhelming bacterial infection. In one embodiment, the treatment of sepsis prevents organ dysfunction and death of the patient.

[0411] The length of the administration period in any given case may depend on the nature andseverity of the condition being treated and / or prevented and be determined by the physician. In one embodiment, the administration period starts at about the time of condition / disease diagnosis and continues for the lifetime of the patient.

[0412] 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.

[0413] 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 12months to about 36 months, or from about 12 months to about 24 months.

[0414] 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.

[0415] 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.

[0416] In embodiments, an effective amount of the compound of formula (I), (I-A), (I-B), or (I-C), or Table A, 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), (I- A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated is administered orally

[0417] 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), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered once a day or twice a day during the administration period. In yet another embodiment, the composition comprising an effective amount of the compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered once per week, every other day, every third day, twice per week, three times per week, four times per week, or five times per week during the administration period.

[0418] Administration, in one embodiment, is via the oral route. In a further embodiment, the composition is administered once daily.

[0419] The dosage administered will vary with the compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof employed, the mode of administration, and the treatment outcome desired. Forexample, in one embodiment, the daily dosage of the compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (pg / kg) to 100 micrograms per kilogram body weight (pg / kg). Alternatively, in one embodiment, if the compound of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is administered orally, then the daily dosage of the compound of the disclosure may be in the range from 0.01 micrograms per kilogram body weight (pg / kg) to 100 milligrams per kilogram body weight (mg / kg).

[0420] The compounds of formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (I-A), (I-B), or (I-C), or Table A, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof is in association with pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0421] EXAMPLES

[0422] 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.

[0423] 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.

[0424] Example 1: Synthesis of Compound 1

[0425] Step 1.

[0426] To a solution of Compound a (2 g, 5.13 mmol) in DCM (60 mL) was added methoxycarbony1-(triethylammonio)sulfony1-azanide (2.69 g, 11.28 mmol) at 0°C. The mixture was stirred at 20°C for 16 hours. LC-MS showed starting material was consumed and 97.1% of desired product was detected. The reaction mixture was poured into water (50 mL) and extracted with di chloromethane (3 x 40 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was stirred in petroleum ether (15 mL) at 20°C for 0.5 hour to form a slurry, filtered, the filtered cake was dried by high vacuum to give Compound b (1.6 g, 83.87% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.78 (br d, J=7.88 Hz, 1 H), 7.68 (d, J=8.13 Hz, 2 H), 7.12 (d, J=8.13 Hz, 2 H), 4.58 - 4.69 (m, 1 H), 2.93 - 3.06 (m, 2 H), 1.35 (s, 9 H).

[0427] Step 2.

[0428] A solution of Compound b (1.55 g, 4.16 mmol) in HCOOH (15.5 mL) was stirred at 50°C for 15 mins. LC-MS showed starting material was consumed and 86.4% of desired product was detected. The reaction mixture was concentrated in vacuum under 20°C to give Compound c (1.2 g, 90.58% yield, FA) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.64 - 7.73 (m, 2 H), 7.11 (d, J=8.25 Hz, 2 H), 3.95 (s, 1 H), 3.92 (d, J=7.13 Hz, 1 H), 2.80 - 2.92 (m, 2 H).

[0429] Step 3.

[0430] To a solution of 4-(tert-butoxycarbonylamino)tetrahydropyran-4-carboxylic acid (1.19 g, 4.85 mmol) and DIEA (3.13 g, 24.26 mmol, 4.23 mL) in DMF (11 mL) was added EDCI (1.16 g, 6.06 mmol) and HOBt (819.41 mg, 6.06 mmol) at 0°C. The mixture was stirred for 1hour at 0°C. A solution of Compound c (1.1 g, 4.04 mmol) in DMF (11 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 20°C for 12 hours. LC-MS showed starting material was consumed and 20.7% of desired product was detected. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (3 x 40 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether and ethyl acetate from 0% to 35% to give Compound d (1.52 g, 75.29% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.38 (br d, J=5.25 Hz, 1 H), 7.65 (d, J=8.13 Hz, 2 H), 7.08 (d, J=8.13 Hz, 1 H), 6.93 - 7.05 (m, 1 H), 5.00 (br d, J=5.75 Hz, 1 H), 3.41 - 3.64 (m, 3 H), 2.96 - 3.15 (m, 2 H), 1.89 (br d, J=1.25 Hz, 1 H), 1.50 - 1.76 (m, 3 H), 1.37 (br s, 9 H).

[0431] Step 4.

[0432] To a solution of Compound 2 (1.55 g, 4.90 mmol) in DMF (31 mL) was added Compound e (1.36 g, 6.37 mmol) and K2CO3 (2.03 g, 14.70 mmol) at 20°C. The mixture was stirred for 3 hours at 80°C. LC-MS showed 0.02% of starting material was remained and 19.9% of desired product was detected. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 40 mL). The organic layer was washed with brine (30 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether and ethyl acetate from 0% to 15% to give Compound f (1.55 g, 88.33% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.54 (s, 1 H), 7.28 - 7.31 (m, 2 H), 3.95 - 3.98 (m, 2 H), 3.88 - 3.95 (m, 2 H), 3.67 (t, J=5.19 Hz, 2 H), 3.61 (t, J=6.00 Hz, 2 H), 2.43 (t, J=6.07 Hz, 2 H), 1.10 (t, J=7.07 Hz, 3 H).

[0433] Step 5.

[0434] To a solution of Compound f (1.5 g, 4.19 mmol) and BPD (1.38 g, 5.44 mmol) in dioxane (30mL) was added KO Ac (821.98 mg, 8.38 mmol) and Pd(dppf)Cl2.CH2Cl2(341.99 mg, 418.78 μmol) at 20°C under N2. The mixture was stirred for 5 hours at 80°C. LC-MS showed starting material was consumed and 42.3% of desired product was detected. The reaction mixture was filtered through a pad of celite, the filter cake was washed with ethyl acetate (3 x 30mL) and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether and ethyl acetate from 0% to 20% to give Compound g (1.65 g, 97.22% yield) as a yellow oil.1H NMR (400 MHz, METHANOL-d4) δ = 7.51 (s, 1 H), 7.45 (dd, J=8.00, 0.88 Hz, 1 H), 7.32 (d, J=7.88 Hz, 1 H), 3.97 - 4.03 (m, 2 H), 3.87 (q, J=7.05 Hz, 2 H), 3.68 (t, J=5.00 Hz, 2 H), 3.61 (t, J=6.13 Hz, 2 H) 2.44 (t, J=6.13 Hz, 2H), 1.30 (s, 11 H), 1.16 (s, 3 H), 1.02 - 1.10 (m, 1 H), 1.00 - 1.14 (m, 8 H).

[0435] Step 6.

[0436] To a solution of Compound g (500 mg, 1.23 mmol) in THF (5 mL) was added a solution of LiOH.H2O (113.91 mg, 2.71 mmol) in H2O (5 mL) at 20°C. The mixture was stirred for 6 hours at 20°C. LC-MS showed 17.3% of desired product was detected. The reaction mixture was diluted with water (20 mL) and adjusted to pH=3 with HC1 (IN), then extracted with dichloromethane (4 x 20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give Compound h (0.3 g, 64.46% yield) as a brown foam.1H NMR (400 MHz, METHANOL-d4) δ = 7.51 (s, 1 H), 7.45 (dd, J=8.00, 0.88 Hz, 1 H), 7.32 (d, J=7.88 Hz, 1 H), 3.97 - 4.03 (m, 2 H), 3.87 (q, J=7.05 Hz, 2 H), 3.68 (t, J=5.00 Hz, 2 H), 3.61 (t, J=6.13 Hz, 2 H), 2.44 (t, J=6.13 Hz, 2H), 1.30 (s, 11 H), 1.16 (s, 3 H), 1.02 - 1.10 (m, 1 H), 1.00 - 1.14 (m, 8 H).

[0437] Step 7.

[0438] To a solution of Compound h (290 mg, 768.83 μmol) and Compound d (383.91 mg, 768.83 μmol) in THF (5.8 mL) and H2O (1.45 mL) was added K3PO4(326.40 mg, 1.54 mmol) and ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (30.06 mg, 46.13 μmol) at 20°C under N2. The reaction mixture was stirred for 1 hour at 80°C. LCMS showed 39.5% of the desired product was detected. The reaction mixture was diluted with water (30 mL) and adjusted to pH = 5 with HC1 (IN), then extracted with ethyl acetate (4 x 40 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether and ethyl acetate from 0% to 66% to give Compound i (300 mg, 62.67% yield) as a yellow solid.

[0439] 1H NMR (400 MHz, METHANOL-d4) δ = 12.13 (br s, 1 H), 8.41 - 8.49 (m, 1 H), 7.57 - 7.65 (m, 3 H), 7.33 - 7.41 (m, 4 H), 6.98 - 7.06 (m, 1 H), 5.01 - 5.11 (m, 1 H), 4.02 - 4.07 (m, 2 H), 3.73 (br t, J=5.25 Hz, 2 H), 3.62 (br t, J=6.32 Hz, 2 H), 3.34 - 3.59 (m, 4 H), 3.03 - 3.21 (m, 2 H), 2.38 (br t, J=6.25 Hz, 2 H), 1.82 - 1.96 (m, 1H), 1.57 - 1.78 (m, 3 H), 1.37 (br s, 9 H).

[0440] Step 8.

[0441] To a solution of Compound C2(63.80 mg, 216.81 μmol, 5.70 μL) and DIEA (149.44 mg, 1.16 mmol, 201.41 μL) in DMF (1.8 mL) was added EDCI (41.56 mg, 216.81 μmol) and HOBt (29.30 mg, 216.81 μmol) at 0°C. The mixture was stirred for 1 hour at 0°C. A solution of Compound i (90 mg, 144.54 μmol) in DMF (0.45 mL) was added to the mixture at 0°C. The mixture was stirred at 20°C for 12 hours. LC-MS showed starting material was consumed and 58.3% of desired product was detected. The reaction mixture was diluted with water (15mL) and extracted with ethyl acetate (3 x 15mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product.The crude product was purified by prep-TLC (ethyl acetate / methanol=25 / l) to give Compound j (75 mg, 66.11% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ = 8.40 - 8.56 (m, 1 H), 8.31 (s, 1 H), 7.76 - 7.86 (m, 1 H), 7.62 (br d, J=7.88 Hz, 1 H), 7.57 (s, 1 H), 7.35 - 7.39 (m, 4 H), 7.04 (t, J=7.75 Hz, 3 H), 6.56 (d, J=8.25 Hz, 2 H), 6.48 - 6.53 (m, 1 H), 5.00 -5.11 (m, 1 H), 4.02 (br t, J=4.94 Hz, 2 H), 3.70 (br t, J=5.25 Hz, 2 H), 3.61 (t, J=6.69 Hz, 2 H),3.46 - 3.52 (m, 4 H), 3.08 - 3.16 (m, 6 H), 2.26 (t, J=6.50 Hz, 2 H), 1.87 - 1.97 (m, 1 H), 1.60- 1.76 (m, 3 H), 1.37 (br s, 9 H).

[0442] Step 9.

[0443] A solution of Compound j (65 mg, 82.81 μmol) in HCOOH (0.65 mL) was stirred at 50°C for 0.25 hour. LC-MS showed starting material was consumed and 81.5% of desired product was detected. The reaction mixture was concentrated in vacuum under 20°C to give the crude product. The crude product was purified by prep-HPLC and lyophilized to give Compound 1 (25.4 mg, 96.6% purity) as a white solid. Column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 mins.1H NMR (400 MHz, METHANOL-d4) δ = 7.68 - 7.86 (m, 3 H), 7.11 (t, J=7.82 Hz, 2 H), 6.64 (br d, J=7.88 Hz, 2 H), 6.56 - 6.63 (m, 1 H), 3.60 (t, J=5.38 Hz, 4 H), 3.22 (t, J=5.63 Hz, 2 H), 2.96 - 3.08 (m, 2 H).

[0444] Example 2: Synthesis of Compound 2

[0445] Step 1.

[0446] To a solution of 2-ethoxyethanamine (17.18 mg, 192.72 μmol) and DIEA (132.84 mg, 1.03 mmol, 179.03 μL) in DMF (1.6 mL) was added EDCI (36.94 mg, 192.72 μmol) and HOBt (26.04 mg, 192.72 μmol) at 0°C. The mixture was stirred for 1 hour at 0°C. A solution ofCompound i from Example 1 (80 mg, 128.48 μmol) in DMF (0.4 mL) was added to the mixture at 0°C. The mixture was stirred at 20°C for 12 hours. LC-MS showed starting material was consumed and 16.1% desired product was detected. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by prep-TLC (ethyl acetate / methanol =25: 1) to give Compound k (76 mg, 85.26% yield) as a white solid.

[0447] Step 2.

[0448] A solution of Compound k (65 mg, 93.69 μmol) in HCOOH (0.65 mL) was stirred at 50°C for 0.25 hours. LC-MS showed starting material was consumed and 65.7% of desired product was detected. The reaction mixture was concentrated in vacuum under 20°C to give the crude product. The crude product was purified by prep-HPLC and lyophilized to give Compound 2 formic acid (FA) salt (20.5 mg, 99.0% purity) as a white solid. Column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 8 mins.1H NMR (400 MHz, METHANOL-d4) δ = 8.37 (br d, J=8.50 Hz, 1 H), 8.02 (s, 1 H), 7.54 (d, J=8.25 Hz, 2 H), 7.37 (d, J=8.25 Hz, 2 H), 7.27 - 7.33 (m, 2 H), 7.27 - 7.27 (m, 2 H), 7.23 - 7.27 (m, 1 H), 6.30 (br s, 1 H), 5.09 - 5.19 (m, 1 H), 4.08 (t, J=5.07 Hz, 2 H), 3.78 - 3.92 (m, 4 H), 3.73 (t, J=5.88 Hz, 2 H), 3.60 - 3.70 (m, 2 H), 3.45 (q, J=7.00 Hz, 2 H), 3.35 - 3.41 (m, 2 H), 3.26 (q, J=5.29 Hz, 2 H), 3.17 (d, J=6.75 Hz, 2 H), 2.41 (t, J=5.88 Hz, 2 H), 2.26 - 2.35 (m, 1 H), 2.16 - 2.24 (m, 1 H), 1.29 - 1.43 (m, 2 H), 1.16 (t, J=7.00 Hz, 3 H).

[0449] Example 3: Synthesis of Compound 3

[0450] Step 1.

[0451] To a solution of ethanamine (17.68 mg, 216.81 μmol, 25.66 μL) and DIEA (149.44 mg, 1.16 mmol, 201.41 μL) in DMF (1.8 mL) was added EDCI (41.56 mg, 216.81 μmol) and HOBt (29.30 mg, 216.81 μmol) at 0°C. The mixture was stirred for 1 hour at 0°C. A solution of Compound i from Example 1 (90 mg, 144.54 μmol) in DMF (0.45 mL) was added to the mixture at 0°C. The mixture was stirred at 20°C for 12 hours. LC-MS showed starting material was consumed and 20.2% of desired product was detected. The reaction mixture was diluted with water (15mL) and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by prep-TLC (ethyl acetate / methanol= 25 / 1) to give Compound m (90 mg, 95.83% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ = 8.40 - 8.55 (m, 1 H), 7.68 (br t, J=4.88 Hz, 1 H), 7.55 - 7.65 (m, 3 H), 7.32 - 7.42 (m, 4 H), 7.03 (br s, 1 H), 4.98 - 5.12 (m, 1 H), 4.03 (br t, J=5.19 Hz, 2 H), 3.71 (t, J=5.32 Hz, 2 H), 3.61 (t, J=6.50 Hz, 2 H), 3.35 - 3.59 (m, 4 H), 3.05 - 3.21 (m, 2 H), 2.90 - 2.99 (m, 2 H), 2.22 (t, J=6.44 Hz, 2 H), 1.83 - 1.98 (m, 1 H), 1.56 - 1.81 (m, 3 H), 1.38 (br s, 9 H), 0.90 (t, J=7.25 Hz, 3 H).

[0452] Step 2.

[0453] A solution of Compound 12 (90 mg, 138.52 μmol) in HCOOH (0.9 mL) was stirred at 50°C for 0.25 hours. LC-MS showed starting material was consumed and 40.9% of desired product was detected. The reaction mixture was concentrated in vacuum under 20°C to give the crude product. The crude product was purified by prep-HPLC and lyophilized to give Compound 3 formic acid (FA) salt (30.6 mg, 98.9% purity) as a white solid. Column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (FA)-ACN]; B%: 10%-45%, 8 mins.1H NMR (400 MHz, METHANOL-d4) δ = 8.17 (s, 1 H), 7.67 (br d, J=6.00 Hz, 1 H), 7.64 (d, J=8.13 Hz, 2 H), 7.58 (s, 1 H), 7.35 - 7.43 (m, 4 H), 5.00 (t, J=7.75 Hz, 1 H), 4.03 (br t, J=5.19 Hz, 2 H), 3.71 (br t, J=5.25 Hz, 2 H), 3.56 - 3.65 (m, 5 H), 3.45 - 3.50 (m, 1 H), 3.19 (br dd, J=7.44, 4.94 Hz, 2 H), 2.90 - 2.98 (m, 2 H), 2.22 (t, J=6.44 Hz, 2 H), 1.90 (ddd, J=13.41 , 10.41, 5.07 Hz, 1 H), 1.76 (ddd, J=13.48, 10.79, 4.63 Hz, 1 H), 1.10 - 1.26 (m, 2 H), 0.90 (t,J=7.25 Hz, 3 H).

[0454] Example 4: Synthesis of Compound 4

[0455] Step 1.

[0456] To a mixture of Compound n (259 mg, 905.21 μmol), BPD (229.87 mg, 905.21 μmol) and potassium acetate (266.52 mg, 2.72 mmol) in dioxane (5.2 mL) was added Pd(dppf)Cl2(66.23 mg, 90.52 μmol) under N2, and then the mixture was stirred at 100°C for 16 hours under N2atmosphere. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient at 25mL / min) to give Compound o (128 mg, 42.44% yield) as a yellow solid.1HNMR (400MHz, DMSO-d6) δ = ppm 1.03 (t, J=7.02 Hz, 3 H), 1.30 (s, 12 H), 3.42 (q, J=7.02 Hz, 2 H), 3.65 (t, J=5.15 Hz, 2 H), 4.02 (t, J=5.15 Hz, 2 H), 7.33 (d, J=7.89 Hz, 1 H), 7.46 (dd, J=8.00, 0.99 Hz, 1 H), 7.56 (s, 1 H).

[0457] Step 2.

[0458] To a solution of Compound o (150 mg, 300.40 μmol) and Compound d from Example 1 (100.09 mg, 300.40 μmol) in tetrahydrofuran (1.2 mL) was added a solution of K3PO4(127.53 mg, 600.79 μmol) in H2O (0.3 mL) at 20°C, then Pd(dtbpf)Cl2(11.75 mg, 18.02 μmol) was added to the mixture under N2. The mixture was stirred at 80°C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water (20 mL) at 20°C, and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over by Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient at35 mL / min) to give Compound p (130 mg, 74.79% yield) as an orange solid.1H NMR (400MHz, DMSO-d6) δ = ppm 1.34 (br s, 3 H), 3.30 (s, 6 H), 3.41 (d, J=7.02 Hz, 1 H), 3.66 (t, J=5.26 Hz, 1 H), 4.00 - 4.03 (m, 1 H), 7.59 (br d, J=4.60 Hz, 1 H), 7.60 - 7.64 (m, 1 H).

[0459] Step 3.

[0460] A solution of Compound p (130 mg, 224.66 μmol) in HCOOH (2 mL) was stirred at 50°C for 15 minutes. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum under 20°C to give the crude product. The crude product was purified by prep-HPLC and lyophilized to give Compound 4 (41.9 mg, 99.8% purity) as a white solid. Column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (FA)-CH3CN]; B%: 20%-55%, 8 mins.1H NMR (400MHz, DMSO-d6) δ = ppm 1.02 (t, J=7.02 Hz, 3 H), 1.09 - 1.25 (m, 2 H), 1.75 (ddd, J=13.32, 10.91, 4.71 Hz, 1 H), 1.89 (ddd, J=13.48, 10.41, 5.04 Hz, 1 H), 3.19 (dd, J=7.89, 4.38 Hz, 2 H), 3.41 - 3.50 (m, 4 H), 3.54 - 3.66 (m, 3 H), 3.70 (t, J=5.26 Hz, 2 H), 4.05 (t, J=5.37 Hz, 2 H), 5.01 (t, J=7.78 Hz, 1 H), 7.40 (s, 4 H), 7.60 - 7.67 (m, 3 H), 8.15 (s, 1 H).

[0461] Example 5: Synthesis of (2S)-N-[(lS)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide (Compound 5)

[0462] Step 1. Synthesis of tert-butyl (S)-(1-cyano-2-(4-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)carbamate

[0463] Into a 50 mL round bottom flask, tert-butyl N-[(lS)-1-cyano-2-(4- iodophenyl)ethyl]carbamate (1.5 g, 4.03 mmol, 1.0 equiv), 3-(2-propoxyethyl)-5-(4,4,5,5- tetramethy1-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazo1-2-one (1.6 g, 4.836 mmol, 1.2 equiv)K2CO3( 1.1 g, 8.06 mmol, 2.0 equiv), 1,4-dioxane (15 mL), H2O (1.5 mL) and Pd(dppf)Cl2(0.3 g, 0.40 mmol, 0.1 equiv) were added in sequence at room temperature. The resulting mixture was stirred for additional 2 h at 80°C under nitrogen atmosphere. The reaction was cooled to room temperature, concentrated to remove the solvent, the residue was purified by silica gel column chromatography, eluted with PE / THF (4: 1) to afford tert-butyl N-[(1S)-1-cyano-2- {4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamate (1.8 g, 95%) as a yellow oil. LCMS (ES, m / z) [M+H]+: 466.

[0464] Step 2. Synthesis of (2S)-2-amino-3-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5- yl]phenyl}propanenitrile

[0465] Into a 250 mL round-bottom flask were added tert-butyl N-[(lS)-1-cyano-2-{4-[2-oxo- 3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamate (1.8 g, 3.86 mmol, 1.0 equiv), TsOH (2.0 g, 11.59 mmol, 3.0 equiv) and ACN (54 mL) at room temperature. The resulting mixture was stirred for additional 2 h. The mixture was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layer was washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (2S)-2-amino- 3-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}propanenitrile (1.4 g, 99%) as a yellow oil. LCMS (ES, m / zy [M+H]+: 366.

[0466] Step 3. Synthesis of (2S)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl } ethyl] carbamoyl } - 1 ,4-oxazepane-4-carboxylate

[0467] To a stirred solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (60 mg, 0.25 mmol, 1.0 equiv), (2S)-2-amino-3-{4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}propanenitrile (107 mg, 0.29 mmol, 1.2 equiv), DIEA (94 mg, 7.35 mmol, 3.0 equiv) in DCM (5 mL) was added HATU (111 mg, 0.29 mmol, 1.2 equiv) inportions at 0°C. The resulting mixture was stirred for additional 2 h at room temperature. Concentrated to remove the solvent, the residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4- [2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (75 mg, 52%) as a white solid. LCMS (ES, m / z): [M+H]+: 579.

[0468] Step 4. Synthesis of (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide

[0469] Into a 8 mL vial were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2- propoxy ethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (75 mg, 0.12 mmol, 1.0 equiv), TsOH (65 mg, 0.38 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18-80 g, mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 80% gradient in 10 min; detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in Compound 5 (20.6 mg, 33%) as a white solid. LCMS (ES, m / z): [M+H]+: 493.2. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J= 8.5 Hz, 1H), 7.65 - 7.62 (m, 3H), 7.43 - 7.35 (m, 4H), 5.03 (q, J= 8.2 Hz, 1H), 4.06 (t, J= 5.2 Hz, 2H), 4.00 (dd, J= 7.9, 3.7 Hz, 1H), 3.90 - 3.80 (m, 1H), 3.77 - 3.69 (m, 3H), 3.35 (t, J= 6.3 Hz, 2H), 3.21 (dd, J= 7.9, 3.3 Hz, 2H), 3.04 (dd, J= 14.3, 3.7 Hz, 1H), 2.82 - 2.75 (m, 1H), 2.68 - 2.54 (m, 2H), 1.85 - 1.62 (m, 2H), 1.48 - 1.24 (m, 2H), 0.74 (t, J= 7.4 Hz, 3H).

[0470] Example 6: Synthesis of (S)-N-((S)-1-cyano-2-(5-(2-oxo-3-(2-propoxyethyl)-2,3 dihydrobenzo[d]oxazo1-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 6)

[0471] Step 1. Synthesis of (2S)-3-(5-bromothiophen-2-yl)-2-[(tert- butoxy carbonyl)amino]propanoic acid

[0472] To a stirred solution of (2S)-2-amino-3-(5-bromothiophen-2-yl)propanoic acid (10 g, 39.98 mmol, 1.0 equiv) and TEA (12.1 g, 119.94 mmol, 3.0 equiv) in DCM (120 mL) was added Boc2O (13.1 g, 59.97 mmol, 1.5 equiv). The resulting mixture was stirred for 3 h at room temperature. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10: 1) to afford (2S)-3-(5- bromothiophen-2-yl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (13 g, 93%) as a light yellow oil. LCMS (ES) [M+1]+m / z: 350.

[0473] Step 2. Synthesis of tert-butyl N-[(lS)-2-(5-bromothiophen-2-yl)-1- carb amoy 1 ethyl ] carb am ate

[0474] To a stirred solution of (2S)-3-(5-bromothiophen-2-yl)-2-[(tert- butoxycarbonyl)amino]propanoic acid (13.0 g, 37.12 mmol, 1.0 equiv) and NH4Cl (4.0 g, 74.23 mmol, 2.0 equiv) and DIEA (14.4 g, 111.35 mmol, 3.0 equiv) in DMF (150 mL) was added HATU (17.0 g, 44.54 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with Water (500 mL). The precipitated solid was collected by filtration and washed with H2O (50 mL). The resulting solid was dried under infrared light for 4 h. This resulted in tert-butyl N-[(1S)-2-(5-bromothiophen-2-yl)-1- carbamoylethyl]carbamate (11 g, 85%) as a white solid. LCMS (ES) [M+1]+m / z: 349.

[0475] Step 3. Synthesis of tert-butyl N-[(1S)-2-(5-bromothiophen-2-yl)-1- cyanoethyl]carbamate

[0476] To a stirred solution of tert-butyl N-[(1S)-2-(5-bromothiophen-2-yl)-1- carbamoylethyl]carbamate (11 g, 31.49 mmol, 1.0 equiv) and TEA (12.8 g, 125.98 mmol, 4.0 equiv) in DCM (120 mL) was added TFAA (13.23 g, 62.99 mmol, 2.0 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water (200 mL), extracted with CH2CI2(3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE / EA=10 / l (50 mL). This resulted in tert-butyl N-[(lS)-2-(5-bromothiophen-2-yl)-1-cyanoethyl]carbamate (8 g, 76%) as a white solid. LCMS (ES) [M+1]+m / z: 331.

[0477] Step 4. Synthesis of tert-butyl N-[(1S)-1-cyano-2-{5-[2-oxo-3-(2-propoxyethyl)-2,3- benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamate

[0478] To a 50 mL round bottom flask, tert-butyl N-[(lS)-2-(5-bromothiophen-2-yl)-1- cyanoethyl]carbamate (1.5 g, 4.52 mmol, 1.0 equiv), 3-(2-propoxyethyl)-5-(4,4,5,5- tetramethy1-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazo1-2-one (1.9 g, 5.43 mmol, 1.2 equiv),Dioxane (20 mL), H2O (2 mL), K2CO3(1.25 g, 9.05 mmol, 2.0 equiv) and Pd(dppf)Cl2(0.33 g, 0.45 mmol, 0.1 equiv) were added in sequence. The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The reaction was cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford tert-butyl N-[(1S)-1-cyano-2-{5-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamate (1.5 g, 70%) as a light yellow solid. LCMS (ES) [M+1]+m / z: 472.

[0479] Step 5. Synthesis of (2S)-2-amino-3-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5- yl]thiophen-2-yl}propanenitrile

[0480] To a stirred solution of tert-butyl N-[(1S)-1-cyano-2-{5-[2-oxo-3-(2-propoxyethyl)- 1,3-benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamate (1.5 g, 3.18 mmol, 1.0 equiv) in ACN (15 mL) was added TsOH (1.64 g, 9.54 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The mixture was basified to pH 8 with saturated NaHCCL (aq.), extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford (2S)-2-amino-3-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]thiophen-2-yl}propanenitrile (900 mg, 76%) as a light yellow solid. LCMS (ES) [M+1]+m / z: 372.

[0481] Step 6. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[5-(3-methy1-2-oxo-1,3- benzoxazo1-5-yl)thiophen-2-yl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0482] To a stirred solution of (2S)-2-amino-3-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1- 5-yl]thiophen-2-yl}propanenitrile (109 mg, 0.29 mmol, 1.2 equiv) and (2S)-4-(tert- butoxy carbonyl)-1,4-oxazepane-2-carboxylic acid (60 mg, 0.24 mmol, 1.0 equiv) in DCM (2 mL) were added DIEA (94 mg, 0.73 mmol, 3.0 equiv). To the above mixture was added HATU (111 mg, 0.29 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for additional 1 h at 0°C. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl (2S)-2-{[(1S)-1- cyano-2-[5-(3-methy1-2-oxo-1,3-benzoxazo1-5-yl)thiophen-2-yl]ethyl]carbamoyl}-1,4- oxazepane-4 -carb oxy late (100 mg, 77.6%) as off-white solid. LCMS (ES) [M+1]+m / z: 527.

[0483] Step 7. Synthesis of (S)-N-((S)-1-cyano-2-(5-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0484] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{5-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (90 mg, 0.15 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (77 mg, 0.45 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by Prep-HPLC with the following conditions: XB ridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, Water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min); Detector, UV, 220 nm. The fraction of the target was freezing dried to afford Compound 6 (30 mg, 40%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J= 8.6 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.39 - 7.30 (m, 3H), 7.01 (d, J = 3.6 Hz, 1H), 5.04 - 4.97 (m, 1H), 4.07 - 4.00 (m, 3H), 3.93 - 3.87 (m, 1H), 3.78 - 3.72 (m, 1H), 3.70 (t, J = 5.2 Hz, 2H), 3.47-3.33 (m, 4H), 3.11 (dd, J= 14.3, 3.7 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.70 -2.58 (m, 2H), 1.80 - 1.71 (m, 2H), 1.47 - 1.38 (m, 2H), 0.75 (t, J= 7.4 Hz, 3H). LCMS (ES) [M+1]+m / z: 499.

[0485] Example 7: Synthesis of (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-oxo-3-(2- propoxy ethyl)-2,3-dihydrobenzo [d] oxazo1-5-yl)phenyl)ethyl)- 1 ,4-oxazepane-2- carboxamide (Compound 7)

[0486] Step 1. Synthesis of 5-bromo-3-(2-propoxyethyl)benzo[d]oxazo1-2(3H)-one

[0487] A solution of 5-bromobenzo[d]oxazo1-2(3H)-one (12.0 g, 56.07 mmol, 1.0 equiv) in DCM (30 mL) was treated with ethylene glycol monopropyl ether (8.8 g, 84.10 mmol, 1.5 equiv), PPh3(22.1 g, 84.10 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. This was followed by the addition of DIAD (17.0 g, 84.10 mmol, 1.5 equiv) dropwise at 0°C. After addition, the mixture was stirred for 2 h. Concentrated to remove the solvent, the residue was purified by silica gel column chromatography, eluted with PE / THF (10:1) to afford 5- bromo-3-(2-propoxyethyl)benzo[d]oxazo1-2(3H)-one (14.5 g, 86%) as a brown solid. LCMS (ES, m / z). [M+H]+: 300.

[0488] Step 2. Synthesis of 3-(2-propoxyethyl)-5-(4,4,5,5-tetramethy1-l,3,2-dioxaborolan-2- yl)benzo[d]oxazo1-2(3H)-one

[0489] To a mixture of 5-bromo-3-(2-propoxyethyl)benzo[d]oxazo1-2(3H)-one (14.0 g, 46.64 mmol, 1.0 equiv), bis(pinacolato)diboron (14.2 g, 55.97 mmol, 1.2 equiv), KOAc (9.2 g, 93.28 mmol, 2.0 equiv) in dioxane (210 mL), Pd(OAc)2(1.1 g, 4.66 mmol, 0.1 equiv), and XPhos (4.5 g, 9.32 mmol, 0.2 equiv) was added ub sequence. The reaction was heated to 90°C and stirred for 2 h under nitrogen atmosphere. After cooled to room temperature, concentrated to remove the solvent, the residue was purified by silica gel column chromatography, eluted withPE / THF (10:1) to afford 3-(2-propoxyethyl)-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2- yl)benzo[d]oxazo1-2(3H)-one (16 g, 98%) as a black solid. LCMS (ES, m / z) [M+H]+: 348.

[0490] Step 3. Synthesis of tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-oxo-3-(2-propoxyethyl)- 2,3-dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)carbamate

[0491] To a stirred solution of tert-butyl N-[(1S)-2-(4-bromo-2-fluorophenyl)-1- cyanoethyl]carbamate (3.5 g, 10.20 mmol, 1.0 equiv) and 3-(2 -propoxy ethyl)-5-(4,4,5,5- tetramethy1-1,3,2-dioxaborolan-2-yl)benzo[d]oxazo1-2(3H)-one (4.2 g, 12.24 mmol, 1.2 equiv) in dioxane (50 mL) and H2O (5 mL) were added K2CO3(2.8 g, 20.40 mmol, 2.0 equiv) and Pd(dppf)Cl2(0.75 g, 1.02 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The reaction was cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (4: 1) to afford tert-butyl N-[(1S)-1-cyano-2-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)- 1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamate (4.2 g, 85%) as a light yellow oil. LCMS (ES, m / z). [M+H]+: 484.

[0492] Step 4. Synthesis of (S)-2-amino-3-(2-fluoro-4-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)propanenitrile

[0493] To a stirred solution of tert-butyl N-[(1S)-1-cyano-2-{2-fluoro-4-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamate (4.2 g, 8.69 mmol, 1.0 equiv) in ACN (120 mL) was added TsOH (4.5 g, 26.06 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h. The reaction solution was basified to pH 8 with saturated NaHCO3(aq.), extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography, eluted with PE / THF(1 : 1) to afford (2S)-2-amino-3-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5- yl]phenyl}propanenitrile (3 g, 90%) as a light yellow oil. LCMS (ES, m / z) : [M+H]+: 384.

[0494] Step 5. Synthesis of tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-oxo-3-(2- propoxyethyl)-2,3-dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4- carboxylate

[0495] To a stirred solution of (2S)-2-amino-3-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}propanenitrile (1.89 g, 4.93 mmol, 1.1 equiv) and (2S)-4-(tert- butoxy carbonyl)-1,4-oxazepane-2-carboxylic acid (1.1 g, 4.49 mmol, 1.0 equiv) in DCM (30 mL) were added DIEA (1.74 g, 13.46 mmol, 3.0 equiv) and HATU (2.05 g, 5.382 mmol, 1.2 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0°C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL), extracted with CH2Cl2(30 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (2.4 g, 87%) as off-white solid. LCMS (ES, m / z): [M+H]+: 611.

[0496] Step 6. Synthesis of (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0497] To a stirred solution of tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-oxo-3-(2- propoxyethyl)-2,3-dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4- carboxylate (2.3 g, 3.77 mmol, 1.0 equiv) in ACN (50 mL) was added TsOH (1.95 g, 11.30 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h. The residue was basified to pH 8with saturated NaHCO3(aq.), extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19*150 mm 5 um, mobile phase, Water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min), Detector, UV 254 nm. This resulted in Compound 7 (1.4 g, 72.8%) as a white solid. LCMS (ES, m / z): [M+H]+: 511.2.1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.60 - 7.38 (m, 5H), 5.06 (q, J= 8.2 Hz, 1H), 4.07 (t, J= 5.3 Hz, 2H), 4.01 (dd, J= 8.0, 3.6 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.79 - 3.68 (m, 3H), 3.37 - 3.31 (m, 3H), 3.20 (dd, J= 13.8, 8.5 Hz, 1H), 3.06 (dd, J = 14.2, 3.7 Hz, 1H), 2.81 - 2.75 (m, 1H), 2.67 - 2.54 (m, 2H), 2.20 (br, 1H), 1.78 - 1.70 (m, 2H), 1.48 - 1.33 (m, 2H), 0.75 (t, J= 7.2 Hz, 3H).

[0498] Example 8: Synthesis of (S)-N-(1-cyano-2-(4-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo [d] oxazo1-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (Compound 8 TEA salt)

[0499] Step 1. Synthesis of tert-butyl 3-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}azetidine-1-carboxylate

[0500] To a stirred solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50 mg, 0.24 mmol, 1.0 equiv), (2S)-2-amino-3-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5- yl]phenyl}propanenitrile (109 mg, 0.29 mmol, 1.2 equiv) and DIEA (96 mg, 0.74 mmol, 3.0 equiv) in DCM (5 mL) was added HATU (113 mg, 0.29 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for additional 2 h at room temperature. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with PE / THF (1 :1) to afford tert-butyl 3-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}azetidine-1-carboxylate (80 mg, 58.7%) as white solid. LCMS (ES, m / z): [M+H]+: 549.

[0501] Step 2. Synthesis of (S)-N-(1-cyano-2-(4-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

[0502] Into a 25 mL round-bottom flask were added tert-butyl 3-{[(1S)-1-cyano-2-{4-[2-oxo- 3 -(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}azetidine-1-carboxylate (80 mg, 0.14 mmol, 1.0 equiv) and TsOH (75 mg, 0.43 mmol, 3.0 equiv) at room temperature. The reaction was stirred for 2 h at the room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18-120 g, mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min, detector, UV 254 nm. This resulted in Compound 82,2,2-trifluoroacetate (16.4 mg, 25%) as white solid. LCMS (ES, m / z). [M-TFA+H]+: 449.3.1H NMR (400 MHz, DMSO-d6) δ 9.06 - 9.03 (m, 1H), 8.70 (brs, 2H), 7.70 - 7.62 (m, 3H), 7.46 - 7.37 (m, 4H), 5.05 (q, J= 7.6 Hz, 1H), 4.08 - 3.99 (m, 5H), 3.83 (t, J = 16.9 Hz, 1H), 3.72 (t, J = 5.3 Hz, 2H), 3.62 - 3.50 (m, 1H), 3.36 (t, J = 6.5 Hz, 2H), 3.20 -3.08 (m, 2H), 1.46 - 1.37 (m, 2H), 0.75 (t, J= 7.4 Hz, 3H).

[0503] Example 9: Synthesis of (S)-N-(1-cyano-2-(5-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo [d] oxazo1-5-yl)thiophen-2-yl)ethyl)azetidine-3-carboxamide 2,2,2- trifluoroacetate (Compound 9 TEA salt)

[0504] Step 1. Synthesis of tert-butyl 3-{[(1S)-1-cyano-2-{5-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamoyl}azetidine-1-carboxylate

[0505] To a stirred solution of (2S)-2-amino-3-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1- 5-yl]thiophen-2-yl}propanenitrile (111 mg, 0.29 mmol, 1.0 equiv) and 1-(tert- butoxycarbonyl)azetidine-3-carboxylic acid (60 mg, 0.29 mmol, 1.0 equiv) in DCM (2 mL) was added DIEA (116 mg, 0.89 mmol, 3.0 equiv). To the above mixture was added HATU (136 mg, 0.35 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford tert-butyl 3-{[(1S)-1-cyano-2-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamoyl}azetidine-1-carboxylate (100 mg, 60.4%) as off-white solid. LCMS (ES, m / z): [M+H]+: 555.

[0506] Step 2. Synthesis of (S)-N-(1-cyano-2-(5-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)thiophen-2-yl)ethyl)azetidine-3-carboxamide 2,2,2- trifluoroacetate

[0507] Into a 25 mL round-bottom flask were added tert-butyl 3-{[(1S)-1-cyano-2-{5-[2-oxo- 3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamoyl}azetidine-1- carboxylate (100 mg, 0.18 mmol, 1.0 equiv) and TsOH (93 mg, 0.54 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18-120 g, mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 9 2,2,2-trifluoroacetate (26.9 mg, 26%) as white solid. LCMS (ES, m / z): [M-TFA+H]+: 455.2.1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.6 Hz, 1H), 8.70 (brs, 2H), 7.58 (s, 1H), 7.37 (dd, J= 9.7, 3.1 Hz, 3H), 7.04 (d, J= 3.6 Hz, 1H), 5.04 (q, J= 7.4 Hz, 1H), 4.13 - 3.97 (m, 5H), 3.94 - 3.89 (m, 1H), 3.70 (t, J = 5.2 Hz, 2H), 3.63 - 3.55 (m, 1H), 3.42 - 3.33 (m, 4H), 1.47 - 1.38 (m, 2H), 0.75 (t, .7= 7.4 Hz, 3H).

[0508] Example 10: Synthesis of (S)-N-(1-cyano-2-(2-fluoro-4-(2-oxo-3-(2-propoxyethyl)- 2,3-dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2- trifluoroacetate (Compound 10 TEA salt)Step 1. Synthesis of tert-butyl 3-{[(1S)-1-cyano-2-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}azetidine-1-carboxylate

[0509] To a stirred mixture of (2S)-2-amino-3-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}propanenitrile (114 mg, 0.30 mmol, 1.2 equiv) and 1-(tert- butoxycarbonyl)azetidine-3-carboxylic acid (50 mg, 0.25 mmol, 1.0 equiv), DIEA (96 mg, 0.74 mmol, 3.0 equiv) in DCM (3 mL) was added HATU (113 mg, 0.30 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred for 2 h at 0°C. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl 3-{ [(1S)-1-cyano-2-{2-fluoro- 4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}azetidine-1- carboxylate (100 mg, 71%) as light yellow oil. LCMS (ES, m z): [M+H]+: 567.

[0510] Step 2. Synthesis of (S)-N-(1-cyano-2-(2-fluoro-4-(2-oxo-3-(2-propoxyethyl)-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

[0511] Into a 50 mL round-bottom flask were added tert-butyl 3-{[(1S)-1-cyano-2-{2-fluoro- 4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}azetidine-1- carboxylate (100 mg, 0.21 mmol, 1.0 equiv), ACN (3 mL) and TsOH.H2O (91 mg, 0.53 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was purified by Prep-HPLC with the following conditions: Column, Atlantis Prep T3 OBD Column, 19*150 mm, 5 um, mobile phase, Water (0.05% TFA) and ACN (25% Phase B up to 50% in 10 min) to afford Compound 102,2,2-trifluoroacetate (24.7 mg, 24%) as white solid. LCMS (ES, m / z): [M-TFA+H]+: 467.1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J= 7.7 Hz, 1H), 8.73 (brs, 2H), 7.71 (d, J= 1.8 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.54 - 7.45 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 5.09 (q, J = 7.6 Hz, 1H), 4.13 - 3.95 (m, 5H), 3.92 - 3.83 (m, 1H), 3.72 (t, J = 5.3 Hz, 2H), 3.61 - 3.52 (m, 1H), 3.37 (d, J = 6.5 Hz, 2H), 3.25 - 3.13 (m, 2H), 1.46 - 1.37 (m, 2H), 0.75 (t, J= 7.4 Hz, 3H).

[0512] Example 11: Synthesis of (2S,3aS,6aR)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2- carboxamide (Compound 11)

[0513] Step 1. Synthesis of tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole- 1 -carboxylate

[0514] A solution of (2S,3aS,6aR)-1-(tert-butoxycarbonyl)-hexahydrofuro[3,4-b]pyrrole-2- carboxylic acid (60 mg, 0.23 mmol, 1.0 equiv) in DCM (5 mL) was treated with (2S)-2-amino- 3-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}propanenitrile (102 mg, 0.28 mmol, 1.2 equiv), DIEA (90 mg, 0.69 mmol, 3.0 equiv) followed by the addition of HATU (106 mg, 0.28 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for additional 2 h at 0°C. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole- 1-carboxylate (80 mg, 56.7%) as a white solid. LCMS (ES, m / z): [M+H]+: 605.

[0515] Step 2. Synthesis of (2S,3aS,6aR)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)- 1,3-benzoxazo1-5-yl]phenyl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

[0516] Into a 50mL round-bottom flask were added tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano- 2-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}- hexahydrofuro[3,4-b]pyrrole-1-carboxylate (80 mg, 0.132 mmol, 1 equiv, TsOH (68 mg, 0.39 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 11 (15.4 mg, 23.07%) as a white solid. LCMS (ES, m / z). [M+H]+: 505.3.1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.4 Hz, 1H), 7.67 - 7.60 (m, 3H), 7.44 - 7.37 (m, 4H), 5.02 (q, J = 7.8 Hz, 1H), 4.06 (t, J = 5.3 Hz, 2H), 3.86 - 3.78 (m, 1H), 3.71 (t, J = 5.3 Hz, 2H), 3.68 - 3.56 (m, 2H), 3.51 - 3.40 (m, 2H), 3.35 (t, J = 6.4 Hz, 3H),3.20 (t, J = 10.3 Hz, 3H), 2.77 - 2.63 (m, 1H),2.1O (dt, J = 12.4, 8.1 Hz, 1H), 1.49 - 1.35 (m, 3H), 0.74 (t, J = 7.4 Hz, 3H).

[0517] Example 12: Synthesis of (2S,3aS,6aR)-N-((S)-1-cyano-2-(5-(2-oxo-3-(2- propoxyethyl)-2,3-dihydrobenzo[d]oxazo1-5-yl)thiophen-2-yl)ethyl)hexahydro-1H- furo[3,4-b]pyrrole-2-carboxamide (Compound 12)

[0518] Step 1. Synthesis of tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{5-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamoyl}-hexahydrofuro[3,4- b]pyrrole-1-carboxylate

[0519] A solution of (2S,3aS,6aR)-1-(tert-butoxycarbonyl)-hexahydrofuro[3,4-b]pyrrole-2- carboxylic acid (60 mg, 0.23 mmol, 1.0 equiv) in DCM (5 mL) was treated with (2S)-2-amino- 3-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]thiophen-2-yl}propanenitrile (104 mg, 0.28 mmol, 1.2 equiv) and DIEA (90 mg, 0.69 mmol, 3.0 equiv). This was followed by the addition of HATU (106 mg, 0.28 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for 2 h at 0°C. Concentrated under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography, eluted with PE / THF(1 : 1) to afford tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5- yl]thiophen-2-yl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylate (100 mg, 70.2%) as white solid. LCMS (ES, m / z): [M+H]+: 611.

[0520] Step 2. Synthesis of (2S,3aS,6aR)-N-((S)-1-cyano-2-(5-(2-oxo-3-(2-propoxyethyl)- 2,3-dihydrobenzo[d]oxazo1-5-yl)thiophen-2-yl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2- carboxamide

[0521] Into a 25 mL round-bottom flask were added tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{5-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]thiophen-2-yl}ethyl]carbamoyl}- hexahydrofuro[3,4-b]pyrrole-1-carboxylate (100 mg, 0.16 mmol, 1.0 equiv), TsOH (85 mg,0.49 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18- 120 g, mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 12 (38.4 mg, 45%) as white solid. LCMS (ES, m / z):. [M+H]+: 511.2.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J= 8.5 Hz, 1H), 7.58 (s, 1H), 7.40 - 7.31 (m, 3H), 7.02 (d, J = 3.6 Hz, 1H), 5.01 (q, J = 7.7 Hz, 1H), 4.04 (t, J = 5.2 Hz, 2H), 3.87 - 3.81 (m, 1H), 3.75 - 3.58 (m, 4H), 3.51 - 3.45 (m, 2H), 3.44 - 3.32 (m, 5H), 2.76 - 2.68 (m, 1H), 2.17 - 2.08 (m, 1H), 1.58 - 1.52 (m, 1H), 1.47 - 1.38 (m, 2H), 0.75 (t, J= 7.4 Hz, 3H).

[0522] Example 13: Synthesis of (2S,3aS,6aR)-N-[(1S)-1-cyano-2-{2-fluoro-4-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2- carboxamide (Compound 13)

[0523] Step 1. Synthesis of tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{2-fluoro-4-[2-oxo-3- (2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-hexahydrofuro[3,4- b]pyrrole-1-carboxylate

[0524] To a stirred mixture of (2S)-2-amino-3-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)-1,3- benzoxazo1-5-yl]phenyl}propanenitrile (107 mg, 0.28 mmol, 1.2 equiv) and (2S,3aS,6aR)-1- (tert-butoxycarbonyl)-hexahydrofuro[3,4-b]pyrrole-2-carboxylic acid (60 mg, 0.23 mmol, 1.00 equiv), DIEA (90 mg, 0.70 mmol, 3 equiv) in DCM (3 mL) was added HATU (106 mg, 0.28 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred for 2 h at 0°C. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5- yl]phenyl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylate (100 mg, 68.86%) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 623.

[0525] Step 2. Synthesis of (2S,3aS,6aR)-N-[(1S)-1-cyano-2-{2-fluoro-4-[2-oxo-3-(2- propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2- carboxamide

[0526] Into a 50 mL round-bottom flask were added tert-butyl (2S,3aS,6aR)-2-{[(1S)-1-cyano- 2-{2-fluoro-4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}- hexahydrofuro[3,4-b]pyrrole-1-carboxylate (100 mg, 0.16 mmol, 1 equiv) , ACN (3 mL) and TsOH.H2O (91 mg, 0.48 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, Atlantis Prep T3 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3H2O) and ACN (25% Phase B up to 50% in 10 min) to afford Compound 13 (18.3 mg, 21.81%) as a white solid. LCMS (ES, m / z): [M+H]+: 523.1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J= 8.4 Hz, 1H), 7.70 (d, J= 1.8 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.50 - 7.44 (m, 2H), 7.42 (d, J= 8.4 Hz, 1H), 5.05 (q, J= 8.0 Hz, 1H), 4.07 (t, J= 5.3 Hz, 2H), 3.83 (t, J= 7.2 Hz, 1H), 3.72 (t, J= 5.3 Hz, 2H), 3.66 (dd, J= 9.0, 2.0 Hz, 1H), 3.61 (t, J= 7.5 Hz, 1H), 3.51 - 3.40 (m, 2H), 3.39 - 3.33 (m, 3H), 3.29 - 3.17 (m, 2H), 2.77 - 2.63 (m, 1H), 2.15 - 2.03 (m, 1H), 1.55 - 1.33 (m, 3H), 0.74 (t, J= 7.4 Hz, 3H).

[0527] Example 14: Synthesis of (2S)-N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3- benzoxazo1-5-yl]phenyl}-1-cyanoethyl]-1,4-oxazepane-2-carboxamide (Compound 14)

[0528] Step 1. Synthesis of 5-bromo-3-(2-butoxyethyl)-1,3-benzoxazo1-2-one

[0529] To a stirred solution of 2-benzoxazolinone, 5-bromo- (3.0 g, 14.01 mmol, 1.0 equiv), butoxyethanol (2.5 g, 21.02 mmol, 1.5 equiv) and PPh3(5.5 g, 21.02 mmol, 1.5 equiv) in DCM (100 mL) was added DIAD (4.3 g, 21.02 mmol, 1.5 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for additional 16 h at room temperature. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford 5-bromo-3-(2-butoxyethyl)-1,3-benzoxazo1-2-one (4.0 g, 90.8%) as a yellow oil. LCMS (ES, m / z)'. [M+H]+: 314.

[0530] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3- benzoxazo1-5-yl]phenyl}-1-cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0531] A solution of 5-bromo-3-(2-butoxyethyl)-1,3-benzoxazo1-2-one (0.8 g, 2.40 mmol, 1.2 equiv) tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (1.0 g, 2.00 mmol, 1.0 equiv), K2CO3(0.6 g, 4.00 mmol, 2.0 equiv) and Pd(dppf)Cl2(0.2 g, 0.20 mmol, 0.1 equiv) in 1,4- dioxane (10 mL) and H2O (1 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}- 1-cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (1.0 g, 82.3%) as a yellow solid. LCMS (ES, m / z): [M+H]+: 607.

[0532] Step 3. Synthesis of (2S)-N-[(lS)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazo1-5- yl]phenyl}-1-cyanoethyl]-1,4-oxazepane-2-carboxamide

[0533] Into a 100mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2- butoxyethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}-1-cyanoethyl]carbamoyl}-1,4-oxazepane- 4-carboxylate (1.0 g, 1.64 mmol, 1.0 equiv) in ACN (30 mL) and TsOH (0.6 g, 4.94 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O),10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 14 (357.3 mg, 42.79%) as a white solid. LCMS (ES, m / z): [M+H]+: 507.3.1H NMR (400 MHz, DMSO- d6) 5 8.60 (d, J = 8.6 Hz, 1H), 7.67 - 7.59 (m, 3H), 7.39 (d, J = 7.1 Hz, 4H), 5.03 (q, J = 8.2 Hz, 1H), 4.06 (t, J = 5.2 Hz, 2H), 4.01 (dd, J = 8.1, 3.5 Hz, 1H), 3.85 (dt, J = 10.8, 5.1 Hz, 1H), 3.78 - 3.67 (m, 3H), 3.39 (t, J = 6.4 Hz, 2H), 3.28 - 3.13 (m, 2H), 3.05 (dd, J = 13.9, 3.7 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.60 (dd, J = 21.6, 7.6 Hz, 2H), 1.81 - 1.62 (m, 2H), 1.44 - 1.32 (m, 2H), 1.21- 1.15 (m, 2H), 0.74 (t, J = 7.3 Hz, 3H).

[0534] Example 15: Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(2- hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2- carboxamide (Compound 15)

[0535] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(2- hydroxy ethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0536] A solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-1,3,2- dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (130 mg, 0.26 mmol, 1.0 equiv), 5-bromo-3-[2-(2-hydroxyethoxy)ethyl]-1,3-benzoxazo1-2-one (86 mg, 0.28 mmol, 1.1 equiv), K2CO3(72 mg, 0.52 mmol, 2.0 equiv) and Pd(dppf)Cl2(19 mg, 0.02 mmol, 0.1 equiv) in 1,4-di oxane (5 mL), H2O (0.5 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4- {3 -[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4- oxazepane-4-carboxylate (120 mg, 77.5%) as a yellow oil. LCMS (ES, m / z): [M+H]+: 595.

[0537] Step 2. Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo- 1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide

[0538] Into a 8 mL vial were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(2- hydroxy ethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane- 4-carboxylate (80 mg, 0.13 mmol, 1.0 equiv) in ACN (3 mL) and TsOH (69 mg, 0.40 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 15 (21.0 mg, 31.56%) as a white solid. LCMS (ES, m / z): [M+H]+: 495.1.1H NMR (400 MHz, DMSO- d6) δ 8.61 (d, J = 8.5 Hz, 1H), 7.69 - 7.61 (m, 3H), 7.39 (d, J = 9.0 Hz, 4H), 5.03 (q, J = 8.2 Hz, 1H), 4.57 (brs, 1H), 4.06 (t, J = 5.4 Hz, 2H), 4.00 (dd, J = 7.9, 3.6 Hz, 1H), 3.90 - 3.80 (m, 1H), 3.75 (dt, J = 18.7, 6.7 Hz, 3H), 3.50 - 3.40 (m, 4H), 3.28 - 3.13 (m, 2H), 3.04 (dd, J = 14.2, 3.8 Hz, 1H), 2.77 (dt, J = 11.8, 5.4 Hz, 1H), 2.66 - 2.51 (m, 2H), 1.78 - 1.67 (m, 2H).

[0539] Example 16: Synthesis of (S)-N-((S)-1-cyano-2-(4-(3-(2-(2-methoxyethoxy)ethyl)- 2-oxo-2,3-dihydrobenzo[d]oxazo1-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 16)

[0540] Step 1. Synthesis of 5-bromo-3-[2-(2-methoxyethoxy)ethyl]-1,3-benzoxazo1-2-one

[0541] To a stirred mixture of 5-bromobenzo[d]oxazo1-2(3H)-one (250 mg, 1.17 mmol, 1.0 equiv) and diglycol methyl ether (210 mg, 1.75 mmol, 1.5 equiv), PPh3(460 mg, 1.75 mmol, 1.5 equiv) in DCM (10 mL) was added DIAD (354 mg, 1.75 mmol, 1.5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford5-bromo-3-[2-(2-methoxyethoxy)ethyl]-1,3-benzoxazo1-2-one (300 mg, 81%) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 316.

[0542] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(2- methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0543] To a 40 mL vial, 5-bromo-3-[2-(2-methoxyethoxy)ethyl]-1,3-benzoxazo1-2-one (80 mg, 0.25 mmol, 1.0 equiv) and tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (126 mg,0.25 mmol, 1 equiv), dioxane (5 mL), H2O (0.5 mL), K2CO3(70 mg, 0.51 mmol, 2 equiv) and Pd(dppf)Cl2·CH2Cl2(20 mg, 0.03 mmol, 0.1 equiv) were added in sequence. The mixture was heated to 80°C and stirred for 2 h under nitrogen atmosphere. The reaction was cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl (2S)-2-{[(1S)-1- cyano-2-(4-{3-[2-(2 -methoxy ethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5- yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (80 mg, 52%) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 609.

[0544] Step 3. Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(2-methoxyethoxy)ethyl]-2- oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide

[0545] Into a 50 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(2 -methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4- oxazepane-4 -carb oxy late (80 mg, 0.13 mmol, 1 equiv), ACN (3 mL) and TsOHH2O (75 mg, 0.39 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions: Column, Atlantis Prep T3 OBD Column, 19*150 mm, 5 um; mobile phase, Water (0.05% NH3.H2O) and ACN (25% up to 50% in 10 min) to afford Compound 16 (16.4 mg, 24.54%) as a white solid. LCMS (ES, m / z): [M+H]+: 509.1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.5 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.41 - 7.38 (m, 4H), 5.03 (q, J= 8.1 Hz, 1H), 4.06 (t, J= 5.3 Hz, 2H), 4.01 (dd, J= 8.0, 3.7 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.79 - 3.68 (m, 3H), 3.55 - 3.52 (m, 2H), 3.37 - 3.34 (m, 2H), 3.24 - 3.18 (m, 2H), 3.11 (s, 3H), 3.05 (dd, J= 14.2, 3.7 Hz, 1H), 2.81 - 2.75 (m, 1H), 2.67 - 2.55 (m, 2H), 1.79 - 1.65 (m, 2H).

[0546] Example 17: Synthesis of (2S)-N-[(1S)-2-(4-{3-[2-(2-aminoethoxy)ethyl]-2-oxo- 1,3-benzoxazo1-5-yl}phenyl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide (Compound 17)

[0547] Step 1. Synthesis of tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy] ethyl } carbamate

[0548] A solution of 2-benzoxazolinone, 5-bromo- (500 mg, 2.34 mmol, 1 equiv) in DCM (15 mL) was treated with tert-butyl N-[2-(2 -hydroxy ethoxy )ethyl] carbamate (575 mg, 2.80 mmol, 1.2 equiv), PPh3(735 mg, 2.80 mmol, 1.2 equiv) at room temperature under nitrogen atmosphere followed by the addition of DIAD (567 mg, 2.80 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred for additional 3 h at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (5: 1) to afford tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethoxy]ethyl}carbamate (500 mg, 53.34%) as a yellow oil. LCMS (ES, m / z): [M+H]+: 401.

[0549] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-{2-[(tert- butoxycarbonyl)amino]ethoxy}ethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}-1- cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0550] To a solution of tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy]ethyl}carbamate (80 mg, 0.200 mmol, 1 equiv) and tert-butyl (2S)-2-{ [(1S)-1 - cyano-2-[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4 -carb oxy late (100 mg, 0.20 mmol, 1.00 equiv) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3(55 mg, 0.40 mmol, 2 equiv) and Pd(dppf)Cl2CH2Cl2(16 mg, 0.02 mmol, 0.1 equiv) . After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl (2S)-2-{[(1S)-2-{4- [3-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}-1- cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 73.42%) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 694.

[0551] Step 3. Synthesis of (2S)-N-[(1S)-2-(4-{3-[2-(2-aminoethoxy)ethyl]-2-oxo-1,3- benzoxazo1-5-yl}phenyl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide

[0552] Into a 50 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-2-(4-{3-[2-(2- aminoethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)-1-cyanoethyl]carbamoyl}-1,4- oxazepane-4 -carb oxy late (100 mg, 0.17 mmol, 1 equiv), ACN (3 mL) and TsOH (87 mg, 0.50 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, Atlantis Prep T3 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and ACN (25% PhaseB up to 50% in 10 min) to afford Compound 17 (21.9 mg, 26.34%) as a white solid. LCMS (ES, m / z): [M+H]+: 494.1H NMR (400 MHz,DMSO-d6) δ 8.61 (d, J = 8.5 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.43 - 7.36 (m, 4H), 5.03 (q, J = 8.1 Hz, 1H), 4.10 - 3.96 (m, 3H), 3.91 - 3.79 (m, 1H), 3.79 - 3.71 (m, 3H), 3.59 - 3.31 (m, 3H), 3.28 - 3.13 (m, 2H), 3.08 - 2.99 (m, 2H), 2.81 - 2.54 (m, 3H), 1.81 - 1.67 (m, 2H). HTEM- NMR (300 MHz, DMSO-d6, 353K) 5 8.37 (d, J = 8.3 Hz, 1H), 7.68 - 7.55 (m, 3H), 7.44 - 7.32 (m, 4H), 5.02 (q, J = 7.9 Hz, 1H), 4.07 (t, J = 5.4 Hz, 2H), 4.01 (dd, J = 7.9, 3.7 Hz, 1H), 3.90 (dt, J = 10.8, 5.1 Hz, 1H), 3.83 - 3.66 (m, 3H), 3.41 (t, J = 5.7 Hz, 2H), 3.23 (dd, J = 7.8, 3.6 Hz, 2H), 3.15 - 3.03 (m, 1H), 2.88 - 2.77 (m, 1H), 2.72 - 2.57 (m, 4H), 1.82 - 1.70 (m, 2H).

[0553] Example 18: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[2-(methylamino)ethoxy]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4-oxazepane-2- carboxamide (Compound 18)

[0554] Step 1. Synthesis of tert-butyl N-(2-{2-[(tert- butyldimethylsilyl)oxy]ethoxy}ethyl)carbamate

[0555] To a stirred solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (5 g, 24.36 mmol, 1.0 equiv) and imidazole (3.32 g, 48.72 mmol, 2.0 equiv) in DCM (100 mL) was added TBSC1 (4.41 g, 29.23 mmol, 1.2 equiv) in portions at 0°C under nitrogen gas atmosphere. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (100 mL), extracted with CH2CI2(3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (20: 1) to afford tert-butyl N-(2-{2-[(tert- butyldimethylsilyl)oxy]ethoxy}ethyl)carbamate (7.2 g, 92.5%) as white solid. LCMS (ES) [M+1]+m / z:320.

[0556] Step 2. Synthesis of tert-butyl N-(2-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}ethyl)-N- methylcarbamate

[0557] To a stirred solution of tert-butyl N-(2-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}ethyl)carbamate (2 g, 6.26 mmol, 1.0 equiv) in DMF (30 mL) were added NaH (60% in mineral oil) (375 mg, 9.39 mmol, 1.5 equiv) in portions at 0°C under nitrogen gas atmosphere. The resulting mixture was stirred for 30 min at the same temperature. To the above mixture was added Mel (1.33 g, 9.39 mmol, 1.5 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 3 h at room temperature. The reaction was quenched by the addition of ice-water (30 mL), extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (20: 1) to afford tert-butyl N-(2-{2-[(tert- butyldimethylsilyl)oxy]ethoxy}ethyl)-N-methylcarbamate (1.6 g, 76.6%) as colorless oil. LCMS (ES) [M+1]+m / z: 334.

[0558] Step 3. Synthesis of tert-butyl (2-(2-hydroxyethoxy)ethyl)(methyl)carbamate

[0559] To a stirred solution of tert-butyl N-(2-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}ethyl)- N-methylcarbamate (1 g, 3.00 mmol, 1.0 equiv) in THF (15 mL) was added TEA.3HF (2.42 g, 14.99 mmol, 5.0 equiv). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL), extracted with CH2Q2 (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl N-[2-(2- hydroxyethoxy)ethyl]-N-methylcarbamate (600 mg, 91.2%) as colorless oil. LCMS (ES) [M+1]+m / z: 220.

[0560] Step 4. Synthesis of tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy] ethyl } -N-m ethylcarbamate

[0561] To a stirred solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methylcarbamate (368 mg, 1.68 mmol, 1.2 equiv) and 5-bromobenzo[d]oxazo1-2(3H)-one (300 mg, 1.40 mmol, 1.0 equiv) in DCM (5 mL) were added PPI13 (551 mg, 2.10 mmol, 1.5 equiv) and DIAD (425mg, 2.10 mmol, 1.5 equiv) in sequence at 0°C under nitrogen gas atmosphere. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (6:1) to afford tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy]ethyl}-N-methylcarbamate (450 mg, 77.3%) as red solid. LCMS (ES) [M+1]+m / z: 415.

[0562] Step 5. Synthesis of tert-butyl (2S)-2-{[(lS)-2-{4-[3-(2-{2-[(tert- butoxycarbonyl)(methyl)amino]ethoxy}ethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}-1- cy anoethyl] carbamoyl } -1,4-oxazepane-4-carboxylate

[0563] To a stirred solution of tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy]ethyl}-N-methylcarbamate (300 mg, 0.72 mmol, 1.0 equiv) and tert-butyl (2S)-2- {[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-l,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}- 1,4-oxazepane-4-carboxylate (360 mg, 0.72 mmol, 1.0 equiv) in dioxane (3 mL) and H2O (0.3 mL) were added K2CO3 (199 mg, 1.44 mmol, 2.0 equiv) and Pd(dppf)Cl2(52 mg, 0.07 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen gas atmosphere. The reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-{2-[(tert- butoxycarbonyl)(methyl)amino]ethoxy}ethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}-1- cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (300 mg, 58.6%) as yellow solid. LCMS (ES) [M+1]+m / z: 708.

[0564] Step 6. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[2-(methylamino)ethoxy]ethyl}- 2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide

[0565] To a stirred solution of tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-{2-[(tertbutoxy carbonyl)(methyl)amino]ethoxy}ethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}-1- cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 0.14 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (97 mg, 0.56 mmol, 4.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, Water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min), Detector, UV 254 nm. This resulted in Compound 18 (20 mg, 27.8%) as white solid. LCMS (ES) [M+1]+m / z: 508.1H NMR (300 MHz, DMSO-d6) δ 8.82 - 8.48 (m, 1H), 7.62 - 7.59 (m, 3H), 7.40 - 7.35 (m, 4H), 5.03 (q, J = 8.2 Hz, 1H), 4.08 - 3.99 (m, 3H), 3.87 - 3.71 (m, 4H), 3.48 - 3.45 (m, 2H), 3.26 - 3.14 (m, 3H), 3.09 - 2.97 (m, 1H), 2.77 -2.54 (m, 3H), 2.49 - 2.46 (m, 3 H), 2.18 - 2.10 (m, 2H), 1.78 - 1.69 (m, 2H).

[0566] Example 19: Synthesis of (2S)-N-[(1S)-2-(4-{3-[2-(2-aminoethoxy)ethyl]-2-oxo- 1,3-benzoxazo1-5-yl}phenyl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide (Compound 19)

[0567] Step 1. Synthesis of tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy] ethyl } carbamate

[0568] Into a 50 mL round-bottom flask were added tert-butyl N-{2-[2-(5-bromo-2-oxo-1,3- benzoxazo1-3-yl)ethoxy]ethyl} carbamate (500 mg, 1.25 mmol, 1 equiv), DCM (5 mL) and TFA (1 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. This resulted in 3-[2-(2- aminoethoxy)ethyl]-5-bromo-1,3-benzoxazo1-2-one; trifluoroacetic acid (500 mg, 96.65%) asa light yellow oil. LCMS (ES, m / z):. [M+H]+: 301.

[0569] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-{2-[(tert- butoxycarbonyl)amino]ethoxy}ethyl)-2-oxo-1,3-benzoxazo1-5-yl]phenyl}-1- cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0570] To a stirred mixture of 3-[2-(2-aminoethoxy)ethyl]-5-bromo-1,3-benzoxazo1-2-one (500 mg, 1.66 mmol, 1 equiv) in THF (10 mL) was added HCHO (1.64 mL, 16.60 mmol, 10 equiv, 37%) dropwise at room temperature. The resulting mixture was stirred for 30 min at room temperature. To the above mixture was added NaBH(OAc)3(704 mg, 3.32 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 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 / THF (1 : 1) to afford 5-bromo-3-{2-[2-(dimethylamino)ethoxy]ethyl}-1,3-benzoxazo1-2-one (350 mg, 64.03%) as a light yellow solid. LCMS (ES, m / z):. [M+H]+: 329.

[0571] Step 3. Synthesis of (2S)-N-[(lS)-2-(4-{3-[2-(2-aminoethoxy)ethyl]-2-oxo-1,3- benzoxazo1-5-yl}phenyl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide

[0572] To a solution of 5-bromo-3-{2-[2-(dimethylamino)ethoxy]ethyl}-1,3-benzoxazo1-2- one (86 mg, 0.26 mmol, 1 equiv) and tert-butyl (2S)-2-{[(lS)-1-cyano-2-[4-(4,4,5,5- tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate(130 mg, 0.26 mmol, 1.00 equiv) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3 (72 mg, 0.52 mmol, 2 equiv) and Pd(dppf)Cl2CH2Cl2(21 mg, 0.03 mmol, 0.1 equiv) . After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[2- (dimethylamino)ethoxy]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4 -carb oxy late (120 mg, 74.15%) as a light yellow oil. LCMS (ES, m / z):. [M+H]+: 622.

[0573] Step 4. Synthesis of (2S)-N-[(lS)-2-(4-{3-[2-(2-aminoethoxy)ethyl]-2-oxo-1,3- benzoxazo1-5-yl}phenyl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide

[0574] Into a 50 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3- {2-[2-(dimethylamino)ethoxy]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}- 1,4-oxazepane-4-carboxylate (100 mg, 0.16 mmol, 1 equiv) , ACN (3 mL) and TsOH. H2O (92 mg, 0.48 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, Atlantis Prep T3 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and ACN (25% PhaseB up to 50% in 10 min) to afford Compound 19 (16.2 mg, 19.31%) as a white solid. LCMS (ES, m / z): [M+H]+: 522.1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.5 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.43 - 7.36 (m, 4H), 5.03 (q, J = 8.2 Hz, 1H), 4.06 (t, J = 5.3 Hz, 2H), 4.00 (dd, J = 8.0, 3.6 Hz, 1H), 3.85 (dt, J = 11.0, 5.3 Hz, 1H), 3.78 - 3.68 (m, 3H), 3.48 (t, J = 5.8 Hz, 2H), 3.26 - 3.13 (m, 2H), 3.04 (dd, J = 14.2, 3.7 Hz, 1H), 2.77 (dt, J = 12.0, 5.5 Hz, 1H), 2.66 - 2.52 (m, 2H), 2.30 (t, J = 5.8 Hz, 2H), 2.02 (s, 6H), 1.80 - 1.65 (m, 2H).

[0575] Example 20: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[(2- hydroxyethyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4-oxazepane-2- carboxamide (Compound 20)

[0576] Step 1. Synthesis of tert-butyl N-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethyl]-N-{2-[(tert-butyldimethylsilyl)oxy]ethyl(carbamate

[0577] To a stirred solution of 5-bromobenzo[d]oxazo1-2(3H)-one (2 g, 9.35 mmol, 1.0 equiv) and tert-butyl N,N-bis(2-hydroxyethyl)carbamate (2.30 g, 11.21 mmol, 1.2 equiv) in THF (30 mL) were added PPU (3.68 g, 14.02 mmol, 1.5 equiv) and DIAD (2.83 g, 14.02 mmol, 1.5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 60°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL). To the above mixture was added TEA (1.89 g, 18.69 mmol, 2.0 equiv) and DMAP (0.11 g, 0.94 mmol, 0.1 equiv) and TBSC1 (2.11 g, 14.02 mmol, 1.5 equiv). The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (12: 1) to afford tert-butyl N-[2-(5-bromo-2-oxo-1,3- benzoxazo1-3-yl)ethyl]-N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}carbamate (1 g, 21%) as off- white solid. LCMS (ES) [M+H]+m / z: 515. (Use TBS as PG was easy to purify).

[0578] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(2,2,3,3,10,10- hexamethy1-8-oxo-4,9-dioxa-7-aza-3-silaundecan-7-yl)ethyl]-2-oxo-1,3-benzoxazo1-5- yl }phenyl)ethyl]carbamoyl } -1 ,4-oxazepane-4-carboxylate

[0579] To a stirred solution of tert-butyl N-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethyl]-N- { 2- [(tert-butyl dimethyl silyl)oxy] ethyl (carbamate (200 mg, 0.39 mmol, 1.0 equiv) and tert- butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-l,3,2-dioxaborolan-2- yl)phenyl]ethyl]carbamoyl(-1,4-oxazepane-4-carboxylate (232 mg, 0.47 mmol, 1.2 equiv) indioxane (3 mL) and H2O (0.3 mL) were added K2CO3 (107 mg, 0.78 mmol, 2.0 equiv) and Pd(dppf)Cl2(28 mg, 0.04 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl (2S)-2-{[(1S)-1- cyano-2-(4-{3-[2-(2,2,3,3,10,10-hexamethy1-8-oxo-4,9-dioxa-7-aza-3-silaundecan-7- yl)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (180 mg, 57.4%) as light yellow oil. LCMS (ES) [M+H]+m / z: 808.

[0580] Step 3. Synthesis of tert-butyl (2S)-2-{[(1S)-2-[4-(3-{2-[(tert-butoxycarbonyl)(2- hydroxyethyl)amino]ethyl }-2-oxo- 1 ,3-benzoxazo1-5-yl)phenyl]-1-cyanoethyl]carbamoyl }-1 ,4-oxazepane-4-carboxylate

[0581] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(2,2,3,3,10,10- hexamethy1-8-oxo-4,9-dioxa-7-aza-3-silaundecan-7-yl)ethyl]-2-oxo-1,3-benzoxazo1-5- yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (180 mg, 0.23 mmol, 1.0 equiv) in THF (5 mL) was added TBAF (116 mg, 0.45 mmol, 2.0 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-2-[4-(3- {2-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]-1-cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 65%) as white solid. LCMS (ES) [M+1]+m / z: 694.

[0582] Step 4. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[(2-hydroxyethyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide

[0583] To a stirred solution of tert-butyl (2S)-2-{[(lS)-2-[4-(3-{2-[(tert-butoxycarbonyl)(2- hydroxyethyl)amino]ethyl }-2-oxo- 1 ,3-benzoxazo1-5-yl)phenyl]- 1 -cyanoethyl]carbamoyl }- l,4-oxazepane-4-carboxylate (200 mg, 0.29 mmol, 1.0 equiv) in ACN (6 mL) was added TsOH (148 mg, 0.86 mmol, 3.0 equiv). The resulting mixture was stirred for 16 h at room temperature. The reaction solution was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, Water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min); Detector, UV 254 nm. This resulted in Compound 20 (60 mg, 42%) as white solid. LCMS (ES) [M+H]+m / z: 494.1H NMR (300 MHz, DMSO-d6) δ 8.86 - 8.57 (m, 1H), 7.69 - 7.50 (m, 3H), 7.40 - 7.36 (m, 4H), 5.03 (q, J= 8.1 Hz, 1H), 4.02 - 3.92 (m, 3H), 3.89 - 3.66 (m, 2H), 3.40 (t, J= 5.7 Hz, 2H), 3.27 - 3.14 (m, 2H), 3.03 (dd, J= 14.3, 3.7 Hz, 1H), 2.90 (t, J= 6.2 Hz, 2H), 2.81 - 2.72 (m, 1H), 2.70 - 2.51 (m, 4H), 1.77 - 1.67 (m, 2H).

[0584] Example 21: Synthesis of ((2S)-N-[(lS)-2-[4-(3-{2-[(2-aminoethyl)amino]ethyl}-2- oxo-1, 3-benzoxazo1-5-yl)phenyl]-1-cyanoethyl]-1,4-oxazepane-2-carboxamide(Compound 21)

[0585] Step 1. Synthesis of tert-butyl N-{2-[(tert-butoxycarbonyl)[2-(5-{4-[(2S)-2-cyano-2-[(2S)- 1 ,4-oxazepan-2-ylformamido]ethyl]phenyl } -2-oxo- 1 ,3 -benzoxazo1-3 - yl)ethyl]amino]ethyl}carbamate

[0586] A solution of tert-butyl N-(2-aminoethyl)-N-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethyl]carbamate (120 mg, 0.300 mmol, 1 equiv) , tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4- (4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (149 mg, 0.30 mmol, 1.0 equiv), K2CO3(83 mg, 0.60 mmol, 2.0 equiv) and Pd(dppf)Cl2(22 mg, 0.03 mmol, 0.1 equiv) in 1,4-dioxane (5 mL) H2O (0.5 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl N-{2-[(tert- butoxycarbonyl)[2-(5-{4-[(2S)-2-cyano-2-[(2S)-1,4-oxazepan-2-ylformamido]ethyl]phenyl}- 2-oxo-1,3-benzoxazo1-3-yl)ethyl]amino]ethyl}carbamate (70 mg, 33.7%) as a white oil. LCMS (ES, m / z): [M+H]+: 793.

[0587] Step 2. Synthesis of (2S)-N-[1 S)-2-[4-(3-{2-[(2-aminoethyl)amino]ethyl}-2-oxo-1,3- benzoxazo1-5-yl)phenyl]-1-cyanoethyl]-1,4-oxazepane-2-carboxamide

[0588] Into a 50mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-2-[4-(3-{2-[(tert- butoxycarbonyl)({2-[(tert-butoxycarbonyl)amino]ethyl })amino]ethyl } -2-oxo- 1,3- benzoxazo1-5-yl)phenyl]-1-cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (70 mg, 0.08 mmol, 1.0 equiv), TsOH (46 mg, 0.26 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 21 (20 mg, 45.99%) as a white solid. LCMS (ES, m / z): [M+H]+: 493.3. *H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.5 Hz, 1H), 7.68 - 7.61 (m, 3H), 7.41 - 7.39 (m, 3H), 5.03 (q, J = 8.1 Hz, 1H), 4.00 -3.65 (m, 5H), 3.28 - 3.13 (m, 2H), 3.03 (dd, J = 14.4, 3.7 Hz, 1H), 2.88 (t, J = 6.2 Hz, 2H), 2.78 - 2.59 (m, 1H), 2.58 -2.50 (m, 6H), 1.76 - 1.69 (m, 2H).

[0589] Example 22: Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[(3S)-morpholin-3- ylmethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide (Compound 22A) and (2S)-N-[(1S)-1-cyano-2-(4-{3-[(3R)-morpholin-3-ylmethyl]- 2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide (Compound 22B)

[0590] Step 1. Synthesis of tert-butyl (3S)-3-[(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)methyl]morpholine-4-carboxylate

[0591] A solution of 2-benzoxazolinone, 5-bromo- (1 g, 4.68 mmol, 1 equiv) in THF (30 mL) was treated with tert-butyl (3S)-3-(hydroxymethyl)morpholine-4-carboxylate (1.22 g, 5.61 mmol, 1.2 equiv), PPI13 (1.47 g, 5.61 mmol, 1.2 equiv) at room temperature under nitrogen atmosphere followed by the addition of DIAD (1.13 g, 5.61 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred for additional 3 h at room temperature. The residue was purified by silica gel column chromatography, eluted with PE / THF (5: 1) to afford tert-butyl (3S)-3- [(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)methyl]morpholine-4-carboxylate (400 mg, 20.71%) as a light brown oil. LCMS (ES, m / zy. [M+H]+: 413.

[0592] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-2-[4-(3-{[(3S)-4-(tert- butoxycarbonyl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]-1- cy anoethyl] carbamoyl } - 1 ,4-oxazepane-4-carboxylate

[0593] A solution of tert-butyl (3S)-3-[(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)methyl]morpholine-4-carboxylate (100 mg, 0.24 mmol, 1 equiv), tert-butyl (2S)-2-{[(lS)- 1-cyano-2-[4-(4,4,5,5-tetramethy1-l,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4 -carboxylate (133 mg, 0.27 mmol, 1.1 equiv), K2CO3(67 mg, 0.484 mmol, 2 equiv) and Pd(dppf)Cl2CH2Cl2(20 mg, 0.02 mmol, 0.1 equiv) in dioxane (5 mL) ,H2O (0.5 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford tert-butyl (2S)-2-{ [(1 S)-2-[4-(3-{[(3S)-4-(tert-butoxycarbonyl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]-1-cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 70.26%) as a white solid. LCMS (ES, m / z):. [M+H]+: 706.

[0594] Step 3. Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[(3S)-morpholin-3-ylmethyl]-2- oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide

[0595] Into a 50 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-2-[4-(3-{[(3S)-4- (tert-butoxycarbonyl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]-1 - cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.17 mmol, 1 equiv), TsOH. H2O (97 mg, 0.51 mmol, 3 equiv) and ACN (4 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2S)-N-[(1S)-1-cyano-2-(4-{3-[(3S)-morpholin-3-ylmethyl]-2-oxo- 1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide (Compound 22A) (16.6 mg, 19.31%) as a white solid. LCMS (ES, m / zy. [M+H]+: 506.1H NMR (400 MHz, DMSO- d6) δ 8.60 (d, J= 8.5 Hz, 1H), 7.69-7.61 (m, 3H), 7.42 - 7.38 (m, 4H), 5.03 (q, J= 8.2 Hz, 1H), 4.00 (dd, J= 7.9, 3.7 Hz, 1H), 3.90-3.68 (m, 5H), 3.64-3.56 (m, 1H), 3.43-3.34 (m, 1H), 3.29-3.09 (m, 4H), 3.04 (dd, J= 14.3, 3.8 Hz, 1H), 2.77 (t, J= 9.8 Hz, 2H), 2.68-2.51 (m, 4H), 1.72 (s, 2H).

[0596] (2S)-N-[(1S)-1-cyano-2-(4-{3-[(3R)-morpholin-3-ylmethyl]-2-oxo-1,3-benzoxazo1-5- yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide (Compound 22B) was synthesized according to the synthesis of Compound 22A. LCMS (ES, m / zy. [M+H]+: 506.1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.5 Hz, 1H), 7.69 - 7.61 (m, 3H), 7.42 - 7.38 (m, 4H), 5.03 (q, J = 8.2 Hz, 1H), 4.00 (dd, J = 7.9, 3.7 Hz, 1H), 3.90 - 3.67 (m, 5H), 3.60 (dt, J = 10.9, 3.1 Hz, 1H), 3.38 (td, J = 11.1, 10.5, 2.6 Hz, 1H), 3.28 - 3.09 (m, 4H), 3.04 (dd, J = 14.3, 3.7 Hz, 1H), 2.83 - 2.72 (m, 2H), 2.71 - 2.51 (m, 3H), 1.85 - 1.63 (m, 2H).

[0597] Example 23: Synthesis of (S)-N-((S)-1-cyano-2-(4-(3-(2-morpholinoethyl)-2-oxo-2,3-dihydrobenzo[d]oxazo1-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide(Compound 23)

[0598] Step 1. Synthesis of 5-bromo-3-[2-(morpholin-4-yl)ethyl]-1,3-benzoxazo1-2-one

[0599] To a stirred solution of 6-bromobenzo[d]oxazo1-2(3H)-one (300 mg, 1.40 mmol, 1.0 equiv) and 4-morpholineethanol (275 mg, 2.10 mmol, 1.5 equiv) in DCM (5 mL) was addedPPh3(551 mg, 2.10 mmol, 1.5 equiv) under nitrogen atmosphere. To the above mixture was added DIAD (425 mg, 2.10 mmol, 1.5 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted withPE / THF (1 : 1) to afford 5-bromo-3-[2-(morpholin-4-yl)ethyl]-1,3-benzoxazo1-2-one (300 mg, 65%) as off-white oil. LCMS (ES) [M+1]+m / z: 327.

[0600] Step 2. Synthesis of tert-butyl (2S)-2-{[(1 S)-1-cyano-2-(4-{3-[2-(morpholin-4- yl)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate

[0601] To a stirred solution of 5-bromo-3-[2-(morpholin-4-yl)ethyl]-1,3-benzoxazo1-2-one (80 mg, 0.25 mmol, 1.0 equiv) and tert-butyl (2S)-2-{[(lS)-1-cyano-2-[4-(4,4,5,5-tetramethy1- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (122 mg, 0.25 mmol, 1.0 equiv) in dioxane (2 mL) and H2O (0.2 mL) were added K2CO3(67 mg, 0.49 mmol, 2.0 equiv) and Pd(dppf)Cl2(17 mg, 0.02 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert -butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 66%) as off-white oil. LCMS (ES) [M+1]+m / z: 620.

[0602] Step 3. Synthesis of (S)-N-((S)-1-cyano-2-(4-(3-(2-morpholinoethyl)-2-oxo-2,3- dihydrobenzo[d]oxazo1-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0603] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(morpholin-4- yl)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (100 mg, 0.16 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (83 mg, 0.48 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19*150 mm, 5um; mobile phase, Water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min), Detector, UV 220 nm. The fraction of the target was freezing dried to afford Compound 23 (30 mg, 35%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 8.5 Hz, 1H), 7.69 - 7.61 (m, 3H), 7.40 - 7.39 (m, 4H), 5.03 (q, J= 8.2 Hz, 1H), 4.05 - 3.96 (m, 3H), 3.93 - 3.80 (m, 1H), 3.76 - 3.70 m, 1H), 3.49 (t, J= 4.6 Hz, 4H), 3.28 - 3.13 (m, 2H), 3.04 (dd, J= 14.3, 3.8 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.67 (t, J= 6.2 Hz, 2H), 2.65 - 2.58 (m, 1H), 2.57 - 2.53 (m, 1H), 2.45 (t, J= 4.6 Hz, 4H), 2.30 (br, 1H), 1.78 - 1.69 (m, 2H). LCMS (ES) [M+1]+m / z: 520.

[0604] Example 24: Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]- 2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide (Compound 25)

[0605] Step 1. Synthesis of 5-bromo-3-[2-(dimethylamino)ethyl]-1,3-benzoxazo1-2-one

[0606] To a stirred solution of 2-benzoxazolinone, 5-bromo- (500 mg, 2.336 mmol, 1.0 equiv) and dimethylaminoethanol (416 mg, 4.672 mmol, 2.0 equiv) in THF (6 mL) was added PPh3(919 mg, 3.504 mmol, 1.5 equiv) under nitrogen atmosphere. To the above mixture was added DIAD (708 mg, 3.504 mmol, 1.5 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford 5-bromo-3-[2-(dimethylamino)ethyl]-1,3-benzoxazo1-2-one (480 mg, 72.05%) as a colorless oil. LCMS (ES) [M+1]+m / z:285

[0607] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2- (dimethylamino)ethyl]-2-oxo- 1 ,3-benzoxazo1-5-yl }phenyl)ethyl]carbamoyl }- 1 ,4-oxazepane-4-carboxylate

[0608] To a stirred solution of 5-bromo-3-[2-(dimethylamino)ethyl]-1,3-benzoxazo1-2-one (80 mg, 0.281 mmol, 1.0 equiv) and tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (140 mg, 0.281 mmol, 1.0 equiv) in dioxane (2 mL) and H2O (0.2 mL) were added K2CO3(77 mg, 0.562 mmol, 2.0 equiv) and Pd(dppf)Cl2(20 mg, 0.028 mmol, 0.1 equiv) . The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2- (dimethylamino)ethyl]-2-oxo- 1 ,3-benzoxazo1-5-yl }phenyl)ethyl]carbamoyl }- 1 ,4-oxazepane- 4-carboxylate (105 mg, 64.78%) as an off-white oil. LCMS (ES) [M+1]+m / z:578.

[0609] Step 3. Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo- 1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide

[0610] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo- 1 ,3-benzoxazo1-5-yl }phenyl)ethyl]carbamoyl }- 1 ,4-oxazepane- 4-carboxylate (100 mg, 0.173 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (89 mg, 0.519 mmol, 3.0 equiv) . The resulting mixture was stirred for 3 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column, XBridge Prep C18OBD Column, 19*150mm 5um; mobile phase, Water (10MMOL / L NH4HCO3) and ACN (30% PhaseB up to 40% in 7 min; Detector, UV, 220 nm) to afford Compound 25 (30 mg, 36.29%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.5 Hz, 1H), 7.69 - 7.58 (m, 3H), 7.39 (d, J= 6.2 Hz, 4H), 5.03 (q, J= 8.1 Hz, 1H), 4.04 - 3.95 (m, 3H), 3.90 - 3.80 (m, 1H), 3.78 - 3.65 (m, 1H), 3.21 (t, J = 7.3 Hz, 2H), 3.04 (dd, J = 14.2, 3.8 Hz, 1H), 2.77 (dt, J= 12.1, 5.6 Hz, 1H), 2.66 - 2.51 (m, 4H), 2.19 (s, 6H), 1.79 - 1.69 (m, 2H). LCMS (ES) [M+1]+m / z:478.

[0611] Example 25: Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(4-methylpiperazin-1- yl)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide (Compound 26)

[0612] Step 1. Synthesis of 5-bromo-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-benzoxazo1-2- one

[0613] To a stirred solution of 2-benzoxazolinone, 5-bromo- (500 mg, 2.34 mmol, 1.0 equiv) and 2-(4-methylpiperazin-1-yl)ethanol (673 mg, 4.67 mmol, 2.0 equiv) in DCM (8 mL) was added PPh3(919 mg, 3.50 mmol, 1.5 equiv) under nitrogen gas atmosphere. To the above mixture was added DIAD (708 mg, 3.50 mmol, 1.5 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture wasconcentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18-120 g, mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-bromo-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-benzoxazo1-2-one (600 mg, 75.5%) as a light brown oil. LCMS (ES) [M+1]+m / z:340.

[0614] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(4-methylpiperazin- 1 -yl)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)ethyl]carbamoyl } - 1 ,4-oxazepane-4- carboxylate

[0615] To a stirred solution of 5-bromo-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-benzoxazo1- 2-one (80 mg, 0.24 mmol, 1.0 equiv) and tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5- tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (117 mg, 0.24 mmol, 1.0 equiv) in dioxane (2.0 mL) and H2O (0.2 mL) were added K2CO3(65 mg, 0.47 mmol, 2.0 equiv) and Pd(dppf)Cl2(17 mg, 0.024 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen gas atmosphere. The reaction was cooled to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 :2) to afford tertbutyl (2 S)-2- { [( 1 S)- 1 -cyano-2-(4- { 3 - [2-(4-methylpiperazin- 1 -yl)ethyl]-2-oxo- 1,3- benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 67%) as off-white oil. LCMS (ES) [M+1]+m / z: 633.

[0616] Step 3. Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(4-methylpiperazin-1-yl)ethyl]- 2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide

[0617] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(4- methylpiperazin-1-yl)ethyl]-2-oxo-1,3-benzoxazo1-5-yl }phenyl)ethyl]carbamoyl }- 1 ,4- oxazepane-4 -carb oxy late (90 mg, 0.14 mmol, 1.0 equiv) in ACN (2.0 mL) was added TsOH (73 mg, 0.43 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature.The reaction solution was purified by Prep-HPLC with the following conditions Column, XB ridge Prep C18 OBD Column, 19*150 mm, 5 um, mobile phase, Water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min), Detector, UV 220 nm. The fraction of the target was freezing dried to afford Compound 26 (35 mg, 46%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J= 8.5 Hz, 1H), 7.69 - 7.61 (m, 3H), 7.41 - 7.39 (m, 4H), 5.03 (q, J= 8.2 Hz, 1H), 4.03 - 3.95 (m, 3H), 3.88 - 3.82 (m, 1H), 3.76 - 3.70 (m, 1H), 3.22 - 3.13 (m, 2H), 3.04 (dd, J = 14.3, 3.8 Hz, 1H), 2.80 - 2.74 (m, 1H), 2.65 (t, J= 6.3 Hz, 2H), 2.62 - 2.52 (m, 2H), 2.49 - 2.39 (m, 4H), 2.27 - 2.16 (m, 4H), 2.10 (s, 3H), 1.79 - 1.68 (m, 2H). LCMS (ES) [M+1]+m / z: 533.4.

[0618] Example 26: Synthesis of 3-[2-(5-{4-[(2S)-2-cyano-2-[(2S)-1,4-oxazepan-2- ylformamido]ethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)ethoxy]propanoic acid(Compound 30)

[0619] Step 1. Synthesis of tert-butyl 3-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy]propanoate

[0620] A solution of 2-benzoxazolinone, 5-bromo- (1 g, 4.67 mmol, 1 equiv) in DCM (30 mL) was treated with tert-butyl 3 -(2 -hydroxy ethoxy )propanoate (1.07 g, 5.61 mmol, 1.2 equiv),PPI13 (1.47 g, 5.61 mmol, 1.2 equiv) at room temperature under nitrogen atmosphere followed by the addition ofDIAD (1.13 g, 5.61 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred for additional 3 h at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (5: 1) to afford tert -butyl 3-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethoxy]propanoate (1.6 g, 88.66%) as a light brown oil. LCMS (ES, m / z): [M+H]+: 386.

[0621] Step 2. Synthesis of 3-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethoxy]propanoic acid

[0622] To a stirred solution of tert-butyl 3-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)ethoxy]propanoate (1.8 g, 4.660mmol, 1 equiv) in DCM (15 mL) was added TFA (5 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-[2-(5-bromo-2-oxo-1,3- benzoxazo1-3-yl)ethoxy]propanoic acid (1.4 g, 91.00%) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 330.

[0623] Step 3. Synthesis of 3-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan- 2-yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)ethoxy]propanoic acid

[0624] To a solution of 3-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethoxy]propanoic acid (180 mg, 0.545 mmol, 1 equiv) and tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (272.30 mg,0.545 mmol, 1 equiv) in dioxane (10 mL) and H2O (1 mL) were added K2CO3 (150.71 mg, 1.090 mmol, 2 equiv) and Pd(dppf)Cl2CH2Cl2(44.42 mg, 0.055 mmol, 0.1 equiv) . After stirring for 2 h at 80 °C under a nitrogen atmosphere, the mixture was acidified to pH 3 with HC1 (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-[2-(5-{4-[(2S)-2-{[(2S)-4- (tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3- benzoxazo1-3-yl)ethoxy]propanoic acid (400 mg, 82.47%) as a black oil. LCMS (ES, m / z): [M+H]+: 623.

[0625] Step 4. Synthesis of 3-[2-(5-{4-[(2S)-2-cyano-2-[(2S)-1,4-oxazepan-2- ylformamido]ethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)ethoxy]propanoic acid

[0626] Into a 50 mL round-bottom flask were added 3-[2-(5-{4-[(2S)-2-{ [(2S)-4-(tert- butoxy carbonyl)- 1 ,4-oxazepan-2-yl]formamido} -2-cyanoethyl]phenyl } -2-oxo- 1,3- benzoxazo1-3-yl)ethoxy]propanoic acid (200 mg, 0.23 mmol, 1 equiv, 70%), TsOH. H2O (128 mg, 0.68 mmol, 3 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 30 (21.3 mg, 18.13%) as a white solid. LCMS (ES, m / z):. [M+H]+: 523.3.1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J= 8.7 Hz, 1H), 7.65 (d, J= 7.8 Hz, 2H), 7.58 (s, 1H), 7.42 - 7.34 (m, 4H), 5.05 (q, J = 8.4 Hz, 1H), 4.04 (t, J = 5.2 Hz, 3H), 3.92 - 3.83 (m, 1H), 3.73 (t, J= 5.4 Hz, 3H), 3.63 (t, J= 6.3 Hz, 2H), 3.21 (d, J= 7.7 Hz, 2H), 3.02 (d, J= 12.5 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.69 - 2.60 (m, 2H), 2.56 - 2.54 (m, 1H), 2.37 - 2.29 (m, 2H), 1.86 - 2.65 (m, 2H).

[0627] Example 27: Synthesis of (2S)-N-[(lS)-2-(4-{3-[2-(2-carbamoylethoxy)ethyl]-2- oxo-1, 3-benzoxazo1-5-yl}phenyl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide(Compound 31)

[0628] Step 1. Synthesis of tert-butyl (2S)-2-{[(lS)-2-(4-{3-[2-(2-carbamoylethoxy)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)- 1 -cyanoethyl] carbamoyl } - 1 ,4-oxazepane-4-carboxylate

[0629] To a stirred mixture of 3-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4- oxazepan-2-yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3- yl)ethoxy]propanoic acid (100 mg, 0.16 mmol, 1.0 equiv), NH4CI (43 mg, 0.80 mmol, 5.0 equiv) and DIEA (62 mg, 0.48 mmol, 3.0 equiv) in DCM (5 mL) was added HATU (73 mg, 0.19 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for additional 3 h at room temperature. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-2-(4-{3-[2-(2-carbamoylethoxy)ethyl]- 2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)- 1 -cyanoethyl] carbamoyl } - 1 ,4-oxazepane-4-carboxylate (100 mg, crude) as a yellow solid. LCMS (ES, m / z): [M+H]+: 622.

[0630] Step 2. Synthesis of (2S)-N-[(1S)-2-(4-{3-[2-(2-carbamoylethoxy)ethyl]-2-oxo-1,3- benzoxazo1-5-yl}phenyl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide

[0631] Into a 50mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-2-(4-{3-[2-(2- carbamoylethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)-1-cyanoethyl]carbamoyl}-1,4- oxazepane-4 -carboxylate (100 mg, 0.16 mmol, 1.0 equiv) in ACN (3 mL) and TsOH (83 mg, 0.48 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 31 (17.2 mg, 20.50%) as a white solid. LCMS (ES, m / z): [M+H]+: 522.4.1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.5 Hz, 1H), 7.69 - 7.59 (m, 3H), 7.45 - 7.36 (m, 4H), 7.23 (br, 1H), 6.75 (br, 1H), 5.03 (q, J = 8.3 Hz, 1H), 4.08 - 3.96 (m, 3H), 3.90 - 3.80 (m, 1H), 3.75 -3.69 (m, 3H), 3.62 (t, J = 6.6 Hz, 2H), 3.19 (dt, J = 13.6, 7.5 Hz, 2H), 3.03 (dd, J = 14.3, 3.7 Hz, 1H), 2.76 (dt, J = 11.7, 5.4 Hz, 1H), 2.66 - 2.51 (m, 2H), 2.24 (t, J = 6.6 Hz, 2H), 1.81- 1.64(m, 2H).

[0632] Example 28: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[2-(methylcarbamoyl)ethoxy] ethyl}-2-oxo- 1 ,3-benzoxazo1-5-yl)phenyl] ethyl] -1 ,4- oxazepane-2-carboxamide (Compound 32)

[0633] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[2-(methylcarbamoyl)ethoxy]ethyl }-2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]carbamoyl } -1 ,4- oxazep ane-4 -carb oxy 1 ate

[0634] To a stirred mixture of 3-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4- oxazepan-2-yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3- yl)ethoxy]propanoic acid (100 mg, 0.16 mmol, 1.0 equiv), methylamine (15 mg, 0.48 mmol, 3.0 equiv) and DIEA (62 mg, 0.48 mmol, 3.0 equiv) in DCM (5 mL) was added HATU (73 mg, 0.19 mmol, 1.2 equiv) in portions at 0°C. The resulting mixture was stirred for additional 3h at 0°C. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[2- (methylcarbamoyl)ethoxy]ethyl }-2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]carbamoyl } -1 ,4- oxazepane-4-carboxylate (100 mg, 78.3%) as a yellow oil. LCMS (ES, m / z): [M+H]+: 636.

[0635] Step 2. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[2- (methylcarbamoyl)ethoxy]ethyl }-2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]- 1 ,4-oxazepane-2- carb oxami de

[0636] Into a 50mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3- {2-[2-(methylcarbamoyl)ethoxy]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}- 1,4-oxazepane-4-carboxylate (100 mg, 0.15 mmol, 1.0 equiv) in ACN (3 mL) and TsOH (81 mg, 0.47 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred foradditional 3 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 32 (17.2 mg, 20.42%) as a white solid. LCMS (ES, m / z):. [M+H]+: 536.2.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.5 Hz, 1H), 7.71 - 7.59 (m, 4H), 7.39 - 7.31 (m, 4H), 5.03 (q, J = 8.1 Hz, 1H), 4.02 (dt, J = 16.3, 4.6 Hz, 3H), 3.93 - 3.68 (m, 4H) , 3.62 (t, J = 6.5 Hz, 2H), 3.26 -3.12 (m, 2H), 3.04 (dd, J = 14.3, 3.8 Hz, 1H), 2.77 (dt, J = 11.8, 5.4 Hz, 1H), 2.66 - 2.51 (m, 2H), 2.44 (d, J = 4.6 Hz, 3H), 2.23 (t, J = 6.4 Hz, 2H), 1.82 - 1.64 (m, 2H).

[0637] Example 29: Synthesis of (S)-N-((S)-2-(4-(3-((1H-pyrro1-1-yl)methyl)-2-oxo-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (Compound 33)

[0638] Step 1. Synthesis of (1H-pyrro1-1-yl)methanol

[0639] To a stirred solution of tert-butyl pyrrole- 1 -carboxylate (3 g, 17.94 mmol, 1.0 equiv) in THF (150 mL) was added LAH (2 M in THF) (44.8 mL, 89.70 mmol, 5.0 equiv) dropwise at 0°C under nitrogen atmosphere. After addition, the mixture was heated to 50°C and stirred for 0.5 h. The reaction was cooled to room temperature, quenched with Na2SO4.10H2O at room temperature. The resulting mixture was filtered, the filter cake was washed with THF (3 x 30 mL). The filtrate was concentrated under reduced pressure. This resulted in pyrro1-1- ylmethanol (1.5 g, 86%) as light-yellow oil and used to the next step directly without further purification.1H NMR (300 MHz, DMSO-d6) δ 6.82 (t, J = 2.1 Hz, 2H), 6.36 (t, J = 7.4 Hz, 1H), 6.01 (t, J= 2.1 Hz, 2H), 5.17 (d, J = 7.3 Hz, 2H).

[0640] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(pyrro1-1- ylmethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0641] To a stirred solution of pyrro1- 1-ylmethanol (340 mg, 3.50 mmol, 1.5 equiv) and 5- bromobenzo[d]oxazo1-2(3H)-one (500 mg, 2.34 mmol, 1.0 equiv), PPh3(919 mg, 3.50 mmol,1.5 equiv) in DCM (15 mL) was added DIAD (709 mg, 3.50 mmol, 1.5 equiv) dropwise at 0°C under nitrogen gas atmosphere. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 5 -bromo-3 -(pyrro1- 1- ylmethyl)-1,3-benzoxazo1-2-one (400 mg, 58%) as a light-yellow oil. LCMS (ES, m / z): [M+H]+: 293.

[0642] Step 3. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(pyrro1-1- ylmethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylateBoc

[0643] To a solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-1,3,2- dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 0.20 mmol, 1.0 equiv), 5-bromo-3-(pyrro1-1-ylmethyl)-1,3-benzoxazo1-2-one (70 mg, 0.24 mmol, 1.2 equiv) in 1,4-dioxane (5 mL) and H2O (0.5 mL), K2CO3(55 mg, 0.40 mmol, 2.0 equiv) and Pd(dppf)Cl2(35 mg, 0.04 mmol, 0.1 equiv) were added in sequence. The mixture was stirred for 2 h at 80°C under nitrogen gas atmosphere. The reaction was cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4- [2-oxo-3 -(pyrro1- 1 -ylmethyl)- 1 ,3 -benzoxazo1-5-yl]phenyl } ethyl] carbamoyl } - 1 ,4-oxazepane- 4-carboxylate (75 mg, 64%) as white solid. LCMS (ES, m / z): [M+H]+: 586.

[0644] Step 4. Synthesis of (S)-N-((S)-2-(4-(3-((1H-pyrro1-1-yl)methyl)-2-oxo-2,3- dihydrobenzo[d]oxazo1-5-yl)phenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide

[0645] Into a 25 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4-[2- oxo-3-(pyrro1-1-ylmethyl)-1,3-benzoxazo1-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (75 mg, 0.12 mmol, 1.0 equiv), TsOH (66 mg, 0.38 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica ge1-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 33 (20.5 mg, 33%) as white solid. LCMS (ES, m / z): [M+H]+: 486.2.1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J= 8.5 Hz, 1H), 7.89 (s, 1H), 7.66 (d, J= 7.9 Hz, 2H), 7.47 - 7.41 (m, 4H), 7.08 (t, J = 2.1 Hz, 2H), 6.06 (s, 4H), 5.04 (q, J= 8.2 Hz, 1H), 4.01 (dd, J= 8.0, 3.7 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.76 - 3.70 (m, 1H), 3.26 - 3.14 (m, 2H), 3.05 (dd, J = 14.5, 3.7 Hz, 1H), 2.80 - 2.74(m, 1H), 2.66 - 2.55 (m, 2H), 1.79 - 1.68 (m, 2H).

[0646] Example 30: Synthesis of (2S)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2- methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2- carboxamide (Compound 34)

[0647] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2- methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

[0648] To a solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethy1- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (120 mg, 0.23 mmol, 1.0 equiv) and 5-bromo-3-[2-(2-methoxyethoxy)ethyl]-1,3-benzoxazo1-2-one (88 mg, 0.28 mmol, 1.2 equiv) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3(64 mg, 0.46 mmol, 2.0 equiv) and Pd(dppf)Cl2(17 mg, 0.02 mmol, 0.1 equiv). After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF(3: 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]- 2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (100 mg, 69%) as a yellow oil. LCMS (ES, m / z): [M+H]+: 627.

[0649] Step 2. Synthesis of (2S)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2- methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2- carboxamide

[0650] Into a 25 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2- fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5- yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 0.16 mmol, 1.0 equiv), TsOH (82 mg, 0.48 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction solution was purified by reversed- phase flash chromatography with the following conditions: C18-120 g column, mobile phase, MeCN in Water (0.05% NH3.H2O), 10% to 60% gradient in 10 min; detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in Compound 34 (13.6 mg, 16%) as a white solid. LCMS (ES, m / z): [M+H]+: 527.3.1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.5 Hz, 1H), 7.70 (d, J= 1.9 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.50 - 7.38 (m, 3H), 5.06 (q, J = 8.1 Hz, 1H), 4.06 (t, J= 5.3 Hz, 2H), 4.01 (dd, J = 7.9, 3.7 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.78 - 3.71 (m, 3H), 3.54 (dd, J= 5.8, 3.6 Hz, 2H), 3.39 - 3.32 (m, 2H), 3.31 - 3.27 (m, 1H), 3.23 - 3.17 (m, 1H), 3.12 (s, 3H), 3.06 (dd, J= 14.3, 3.7 Hz, 1H), 2.83 - 2.75 (m, 1H), 2.68 - 2.53 (m, 2H), 1.79 - 1.68 (m, 2H).

[0651] Example 31: Synthesis of (2S)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4- yl)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide (Compound 35)

[0652] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin- 4-yl)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl } - 1 ,4-oxazepane-4- carboxylate

[0653] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5- tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.23 mmol, 1.0 equiv) and 5-bromo-3-[2-(morpholin-4-yl)ethyl]-1,3-benzoxazo1-2- one (83 mg, 0.26 mmol, 1.1 equiv) in dioxane (2 mL) and H2O (0.2 mL) were added K2CO3(64 mg, 0.46 mmol, 2.0 equiv) and Pd(dppf)Cl2(16 mg, 0.02 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, concentrated to remove the solvent. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2- { [( 1S)-1-cyano-2-(2-fluoro-4- { 3 - [2-(morpholin-4-yl)ethyl] -2-oxo- 1, 3 -benzoxazo1-5 - yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 67.6%) as yellow oil. LCMS (ES) [M+H]+m / z: 638.

[0654] Step 2. Synthesis of (2S)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4- yl)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)ethyl]- 1 ,4-oxazepane-2-carboxamide

[0655] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2- (morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane- 4-carboxylate (100 mg, 0.16 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (81 mg, 0.47 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by Prep-HPLC with the following conditions: Column, XB ridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, Water (10 mmol / L NH4HCO3) and ACN (30% Phase B up to 40% in 7 min); Detector, UV 254 nm. This resulted in Compound 35 (30mg, 35.5%) as white solid. LCMS (ES) [M+1]+m / z: 538.1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 8.5 Hz, 1H), 7.71 (d, J= 1.8 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.52 - 7.37 (m, 3H), 5.06 (q, J= 8.2 Hz, 1H), 4.04 - 3.98 (m, 3H), 3.94 - 3.80 (m, 1H), 3.78 - 3.69 (m, 1H), 3.49 (t, J= 4.6 Hz, 4H), 3.29 - 3.16 (m, 2H), 3.06 (dd, J= 14.3, 3.7 Hz, 1H), 2.84 - 2.56 (m, 5H), 2.45 (t, J= 4.6 Hz, 4H), 1.82 - 1.66 (m, 2H).

[0656] Example 32: Synthesis of (2S)-N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3- benzoxazo1-5-yl]-2-fluorophenyl}-1-cyanoethyl]-1,4-oxazepane-2-carboxamide (Compound 37)

[0657] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3- benzoxazo1-5-yl]-2-fluorophenyl } - 1 -cyanoethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate

[0658] To a solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethy1- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (120 mg, 0.23 mmol, 1.0 equiv) and 5-bromo-3-(2-butoxyethyl)-1,3-benzoxazo1-2-one (87 mg, 0.28 mmol, 1.2 equiv) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3 (64 mg, 0.46 mmol, 2.0 equiv) and Pd(dppf)Cl2(17 mg, 0.02 mmol, 0.1 equiv). After stirring for 2 h at 80°C under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (3 : 1) to afford tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazo1-5-yl]-2- fluorophenyl}-1-cyanoethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 69%) as a yellow oil. LCMS (ES, m / z): [M+H]+: 625.

[0659] Step 2. Synthesis of (2S)-N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazo1-5- yl]-2-fluorophenyl } - 1 -cyanoethyl]- 1 ,4-oxazepane-2-carboxamide

[0660] Into a 25 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-2-{4-[3-(2- butoxyethyl)-2-oxo-1,3-benzoxazo1-5-yl]-2-fluorophenyl}-1-cyanoethyl]carbamoyl}-1,4- oxazepane-4 -carboxylate (100 mg, 0.16 mmol, 1.0 equiv), TsOH (83 mg, 0.48 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Cl 8- 120 g column, mobile phase, MeCN in Water (0.05% NH3.H2O), 10% to 60% gradient in 10 min; detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in Compound 37 (16.2 mg, 19%) as a white solid. LCMS (ES, m / z): [M+H]+: 525.3.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J= 8.6 Hz, 1H), 7.69 (d, J= 1.7 Hz, 1H), 7.61 - 7.37 (m, 5H), 5.06 (q, J= 8.1 Hz, 1H), 4.08 - 4.00 (m, 3H), 3.92 - 3.81 (m, 1H), 3.79 - 3.67 (m, 3H), 3.39 (t, J= 12.7 Hz, 2H), 3.28 - 3.15 (m, 2H), 3.07 (dd, J= 14.2, 3.6 Hz, 1H), 2.85 - 2.76 (m, 1H), 2.70 - 2.56 (m, 2H), 1.79 - 1.64 (m, 2H), 1.42 - 1.33 (m, 2H), 1.25 - 1.13 (m, 2H), 0.74 (t, J= 7.3 Hz, 3H).

[0661] Example 33: Synthesis of (2S)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2- hydroxyethoxy)ethyl] -2-oxo-1,3-benzoxazo1-5-yl} phenyl)ethyl]- 1 ,4-oxazepane-2- carboxamide (Compound 38)

[0662] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2-fhroro-4-{3-[2-(2- hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane- 4-carboxylate

[0663] To a solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[2-fhroro-4-(4,4,5,5-tetramethy1-1 ,3 ,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl } - 1 ,4-oxazepane-4-carboxylate (164 mg, 0.32 mmol, 1.2 equiv) and 5-bromo-3-[2-(2-hydroxyethoxy)ethyl]-1,3-benzoxazo1-2-one (80 mg, 0.26 mmol, 1.0 equiv) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3(73 mg, 0.53 mmol, 2.0 equiv) and Pd(dppf)Cl2(19 mg, 0.03 mmol, 0.1 equiv). After stirring for 2 h at 80°C under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (3: 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]- 2-oxo- 1 ,3 -benzoxazo1-5-yl }phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 61.6%) as yellow oil. LCMS (ES, m / z): [M+H]+: 613.

[0664] Step 2. Synthesis of (2S)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2- hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}phenyl)ethyl]-1,4-oxazepane-2- carb oxami de

[0665] Into a 25 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-(2- fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazo1-5- yl}phenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 0.16 mmol, 1.0 equiv), TsOH (84 mg, 0.49 mmol, 3.0 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The reaction solution was purified by reversed-phase flash chromatography with the following conditions: Cl 8-120 g column, mobile phase, MeCN in Water (0.05% NH3.H2O), 10% to 60% gradient in 10 min; detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in Compound 38 (20 mg, 24%) as white solid. LCMS (ES, m / z): [M+H]+: 513.2.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.6 Hz, 1H), 7.71 (d, J= 1.9 Hz, 1H), 7.63 - 7.51 (m, 2H), 7.51 - 7.43 (m, 2H), 7.44 - 7.40 (m, 1H), 5.06 (q, J= 8.3 Hz, 1H), 4.58 (brs, 1H), 4.07 (t, J= 5.3 Hz, 2H), 4.01 (dd, J= 8.0, 3.6 Hz, 1H), 3.90 - 3.84 (m, 1H), 3.81 - 3.68 (m, 3H), 3.47 - 3.44 (m, 4H), 3.29 (d, J = 7.4 Hz, 2H), 3.23 - 3.17 (m, 1H), 3.05 (dd, J= 14.2, 3.7 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.67 - 2.54 (m, 2H), 1.79 - 1.73 (m, 2H).

[0666] Example 34: Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazo1-5-yl}-2-fluorophenyl)ethyl]-1,4-oxazepane-2-carboxamide(Compound 39)

[0667] Step 1. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl } -2-fluorophenyl)ethyl]carbamoyl } -1 ,4- oxazepane-4-carboxylate

[0668] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5- tetramethy1-l,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.23 mmol, 1.0 equiv) and 5-bromo-3-[2-(dimethylamino)ethyl]-1,3-benzoxazo1-2- one (72 mg, 0.26 mmol, 1.1 equiv) in dioxane (2 mL) and H2O (0.2 mL) were added K2CO3(64 mg, 0.46 mmol, 2.0 equiv) and Pd(dppf)Cl2(16 mg, 0.02 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3- benzoxazo1-5-yl}-2-fluorophenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 72.3%) as yellow oil. LCMS (ES) [M+1]+m / z: 596.

[0669] Step 2. Synthesis of (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo- l,3-benzoxazo1-5-yl}-2-fluorophenyl)ethyl]-1,4-oxazepane-2-carboxamide

[0670] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo- 1 ,3 -benzoxazo1-5-yl } -2-fluorophenyl)ethyl]carbamoyl } - 1 ,4- oxazepane-4-carboxylate (100 mg, 0.17 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (86 mg, 0.50 mmol, 3.0 equiv). The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by Prep-HPLC with the following conditions Column,XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, Water (10 mmol / L NH4HCO3) and ACN (10% Phase B up to 80% in 20 min); Detector, UV 254 nm. This resulted in Compound 39 (30 mg, 36%) as white solid. LCMS (ES) [M+1]+m / z: 496.1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J= 8.5 Hz, 1H), 7.70 (d, J= 1.7 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.49 - 7.39 (m, 3H), 5.06 (q, J= 8.2 Hz, 1H), 4.03 - 3.97 (m, 3H), 3.91 - 3.83 (m, 1H), 3.78 - 3.69 (m, 1H), 3.29 - 3.15 (m, 2H), 3.06 (dd, J= 14.3, 3.7 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.67 - 2.56 (m, 4H), 2.19 (s, 6H), 1.80 - 1.65 (m, 2H).

[0671] Example 35: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[(2- methoxyethyl)(methyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4- oxazepane-2-carboxamide (Compound 42)

[0672] Step 1. Synthesis of methyl 2-[(2-methoxyethyl)(methyl)amino]acetate

[0673] Into a 250 mL round-bottom flask were added methyl 2-(methylamino)acetate hydrochloride (5.00 g, 35.82 mmol, 1.00 equiv), CH3CN (70.00 mL), 2-bromoethyl methyl ether (9.96 g, 71.64 mmol, 2.00 equiv), K2CO3(14.85 g, 107.47 mmol, 3.00 equiv)and Nal (0.54 g, 3.58 mmol, 0.10 equiv). The resulting mixture was stirred for 2 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with acetone (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (43%) to afford methyl 2-[(2 -methoxy ethyl)(methyl)amino] acetate (1.20 g, 20.78%) as light yellow oil. LCMS (ES, m / z): [M+H]+: 162.

[0674] Step 2. Synthesis of 2-[(2-methoxyethyl)(methyl)amino]ethanol

[0675] Into a 100 mL 3-necked round-bottom flask were added methyl 2-[(2- methoxyethyl)(methyl)amino]acetate (1.15 g, 7.13 mmol, 1.00 equiv) and THF (20.00 mL). To the above mixture was added LiAlH4 (7.13 mL, 14.27 mmol, 2.00 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional 1 h at 0 °C. The reaction was quenched by theaddition of Na2SO4H2O at 0 °C. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (18%) to afford 2-[(2- methoxyethyl)(methyl)amino]ethanol (680.00 mg, 71.57%) as light yellow oil. LCMS (ES, m / z): [M+H]+: 134.

[0676] Step 3. Synthesis of 5-bromo-3-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-1,3- benzoxazo1-2-one

[0677] Into a 40 mL vial were added 2-[(2-methoxyethyl)(methyl)amino]ethanol (642.25 mg, 4.822 mmol, 1.20 equiv), DCM (20.00 mL), 5-bromobenzo[d]oxazo1-2(3H)-one (860.00 mg, 4.018 mmol, 1.00 equiv) and PPh3(1580.97 mg, 6.027 mmol, 1.50 equiv). To the above mixture was added DIAD (1218.83 mg, 6.027 mmol, 1.50 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional 1 h at 0 °C. The reaction was quenched with Water / Ice. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (21%) to afford 5-bromo-3-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-1,3- benzoxazo1-2-one (700.00 mg, 52.92%) as an orange oil. LCMS (ES, m / z):. [M+H]+: 329.

[0678] Step 4. Synthesis of methyl tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[(2- methoxyethyl)(methyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}- 1 ,4-oxazepane-4-carboxylate

[0679] Into a 20 mL vial were added 5-bromo-3-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-1.3-benzoxazo1-2-one (170.00 mg, 0.52 mmol, 1.00 equiv), tert-butyl (2S)-2-{[(1S)-1-cyano- 2-[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (309.49 mg, 0.62 mmol, 1.20 equiv), dioxane (6.00 mL), H2O (0.60 mL), Na2CO3(109.47 mg, 1.03 mmol, 2.00 equiv) and Pd(dppf)Cl2(37.79 mg, 0.05 mmol, 0.10 equiv). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (48%) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[(2- methoxyethyl)(methyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}-1.4-oxazepane-4-carboxylate (200.00 mg, 70.60%) as a yellow oil. LCMS (ES, m / z): [M+H]+: 622.

[0680] Step 5. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[(2- methoxyethyl)(methyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4- oxazepane-2 -carboxamide

[0681] Into a 10 mL vial were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[(2- methoxyethyl)(methyl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (1.00 equiv), ACN (4.00 mL) and TsOH·H2O (146.85 mg, 0.77 mmol, 3.00 equiv). The resulting mixture was stirred for 2 h at room temperature. The reaction solution was purified by Prep-HPLC with the following conditions XB ridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, Water (0.05%NH3·H20) and ACN (35% Phase B up to 55% in 8.8 min); Detector, UV 254 nm. This resulted in Compound 42 (78.30 mg, 58.33%) as yellow solid. LCMS (ES, m / z): [M+H]+: 522.1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J= 8.5 Hz, 1H), 7.70-7.58 (m, 3H), 7.44-7.35 (m, 4H), 5.03 (q, J= 8.1 Hz, 1H), 4.05- 3.92 (m, 3H), 3.85 (dt, J = 10.7, 5.3 Hz, 1H), 3.72 (ddd, J= 12.2, 7.4, 4.3 Hz, 1H), 3.29-3.14 (m, 4H), 3.05 (s, 3H), 3.01 (d, J= 3.7 Hz, 1H), 2.86-2.69 (m, 3H), 2.65-2.51 (m, 4H), 2.26 (s, 3H), 1.79-1.66 (m, 2H).

[0682] Example 36: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[(2-methoxyethyl)(oxetan-3-yl)amino] ethyl}-2-oxo- 1 ,3-benzoxazo1-5-yl)phenyl] ethyl] - 1 ,4- oxazepane-2-carboxamide (Compound 43)

[0683] Step 1. Synthesis of N-(2-methoxyethyl)oxetan-3 -amine

[0684] To a stirred solution of 3-oxetanone (3 g, 41.63 mmol, 1.0 equiv) and 2-methoxyethan- 1-amine (9.38 g, 124.89 mmol, 3.0 equiv) in MeOH (60 mL) was added HOAc (2.50 g, 41.63 mmol, 1.0 equiv) dropwise at room temperature. The resulting mixture was stirred for 30 min at room temperature. To the above mixture was added NaBH3CN (2.88 g, 45.79 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with NaHCO3(aq) (50 mL), extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in N-(2-methoxyethyl)oxetan-3-amine (4 g, 44%) as a light yellow oil and used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+: 132.

[0685] Step 2. Synthesis of ethyl N-(2-methoxyethyl)-N-(oxetan-3-yl)glycinate

[0686] To a stirred solution of N-(2-methoxyethyl)oxetan-3 -amine (4 g, 30.49 mmol, 1.0 equiv) and ethyl bromoacetate (5.1 g, 30.49 mmol, 1.0 equiv) in ACN (100 mL) was added K2CO3 (6.3 g, 45.74 mmol, 1.5 equiv) and KI (5.06 g, 30.49 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for 16 h at 80°C. The reaction was cooled to room temperature, the resulting mixture was filtered, the filter cake was washed with ACN (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2: 1) to afford ethyl 2-[(2- methoxyethyl)(oxetan-3-yl)amino]acetate (2.5 g, 37.7%) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 218.

[0687] Step 3. Synthesis of 2-((2 -methoxyethyl)(oxetan-3-yl)amino)ethan-1-ol

[0688] To a stirred solution of ethyl 2-[(2-methoxyethyl)(oxetan-3-yl)amino]acetate (2.5 g, 11.51 mmol, 1.0 equiv) in THF (40 mL) was added LAH (2 M in THF) (11.5 mL, 23.01 mmol, 2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0°C under nitrogen atmosphere. The reaction was quenched with Na2SO4. IOH2O at 0°C. The resulting mixture was filtered, the filter cake was washed with THF (3 x 30 mL). The filtrate was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-[(2-methoxyethyl)(oxetan-3-yl)amino]ethanol (1.3 g, 64.5%) as light yellow oil. LCMS (ES, m / z): [M+H]+: 218.

[0689] Step 4. Synthesis of 5-bromo-3-(2-((2-methoxyethyl)(oxetan-3- yl)amino)ethyl)benzo[d]oxazo1-2(3H)-one

[0690] To a stirred solution of 2-[(2-methoxyethyl)(oxetan-3-yl)amino]ethanol (737 mg, 4.21 mmol, 1.5 equiv) and 5-bromobenzo[d]oxazo1-2(3H)-one (600 mg, 2.80 mmol, 1.0 equiv)and PPI13 (1103 mg, 4.21 mmol, 1.5 equiv) in DCM (15 mL) was added DIAD (850 mg, 4.21 mmol, 1.5 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford 5-bromo-3-{2-[(2-methoxyethyl)(oxetan-3-yl)amino]ethyl}-1,3-benzoxazo1-2- one (800 mg, 76.9%) as yellow oil. LCMS (ES, m / z): [M+H]+: 371.

[0691] Step 5. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[(2- methoxyethyl)(oxetan-3-yl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl }- 1 ,4-oxazepane-4-carboxylate

[0692] To a mixture of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-l,3,2- dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.24 mmol, 1.0 equiv), 5-bromo-3-{2-[(2-methoxyethyl)(oxetan-3-yl)amino]ethyl}-1,3- benzoxazo1-2-one (134 mg, 0.36 mmol, 1.5 equiv), Na2SO4(51 mg, 0.48 mmol, 2.0 equiv) in 1,4-dioxane (5 mL) and H2O (0.5 mL). This was followed by the addition of Pd(dppf)Cl2(18 mg, 0.02 mmol, 0.1 equiv) under nitrogen atmosphere. The mixture was cooled to room temperature, concentrated to remove the solvent. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 :2) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4- (3-{2-[(2-methoxyethyl)(oxetan-3-yl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 62.7%) as yellow oil. LCMS (ES, m / z): [M+H]+: 664.

[0693] Step 6. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[(2-methoxyethyl)(oxetan-3- yl)amino]ethyl } -2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]- 1 ,4-oxazepane-2-carboxamide

[0694] Into a 25 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3- {2-[(2 -methoxy ethyl)(oxetan-3-yl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 0.15 mmol, 1.0 equiv), ACN (3 mL) and TsOH. H2O (86 mg, 0.45 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica ge1-120 g; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 43 (19.4 mg, 23%) as white solid. LCMS (ES, m / z): [M+H]+: 564.4.1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J= 8.5 Hz, 1H), 7.66 - 7.63 (m,3H), 7.41 - 7.39 (m, 4H), 5.03 (q, J= 8.2 Hz, 1H), 4.43 (t, J= 6.7 Hz, 2H), 4.24 (t, J= 6.3 Hz, 2H), 4.03 - 3.92 (m, 4H), 3.90 - 3.80 (m, 1H), 3.76 - 3.70 (m, 1H), 3.28 (t, J = 5.6 Hz, 2H), 3.25 - 3.14 (m, 2H), 3.12 (s, 3H), 3.03 (dd, J= 14.3, 3.8 Hz, 1H), 2.89 (t, J= 6.2 Hz, 2H), 2.79 - 2.73 (m, 3H), 2.65 - 2.52 (m, 2H), 1.78 - 1.66 (m, 2H).

[0695] Example 37: Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{[(3S)-4- methylmorpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4-carboxylate (Compound 44A) and tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3- {[(3R)-4-methylmorpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (Compound 44B)

[0696] Step 1. Synthesis of 5-bromo-3-[(3S)-morpholin-3-ylmethyl]-1,3-benzoxazo1-2-one

[0697] Into a 50mL round-bottom flask were added tert-butyl (3S)-3-[(5-bromo-2-oxo-1,3- benzoxazo1-3-yl)methyl]morpholine-4-carboxylate (400 mg, 0.96 mmol, 1 equiv) and HC1 (gas)in 1,4-dioxane (2 mL) at room temperature. The resulting mixture was stirred for additional 3h at room temperature. The mixture wasbasified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-bromo-3-[(3S)-morpholin- 3-ylmethyl]-1,3-benzoxazo1-2-one (700 mg, 108.68%) as a white oil. LCMS (ES, m / z): [M+H]+: 313.

[0698] Step 2. Synthesis of 5-bromo-3-{[(3S)-4-methylmorpholin-3-yl]methyl}-1,3- benzoxazo1-2-one

[0699] A solution of 5-bromo-3-[(3S)-morpholin-3-ylmethyl]-1,3-benzoxazo1-2-one (200 mg, 0.63 mmol, 1.0 equiv) in THF (5 mL) was treated with HCHO (504 mg, 6.39 mmol, 10 equiv, 38%) , HOAc (0.1 mL) for Ih at room temperature followed by the addition of NaBH(OAc) 3 (270 mg, 1.27 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture wasstirred for additional Ih at room temperature. The resulting mixture was extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-bromo-3-{[(3S)-4-methylmorpholin-3-yl]methyl}-1,3-benzoxazo1-2-one (200 mg, 95.71%) as a white oil. LCMS (ES, m / z): [M+H]+: 327.

[0700] Step 3. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{[(3S)-4- methylmorpholin-3 -yl]methyl } -2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]carbamoyl } -1 ,4- oxazep ane-4 -carb oxy 1 ate

[0701] A solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-l,3,2- dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.240 mmol, 1.0 equiv), 5-bromo-3-{[(3S)-4-methylmorpholin-3-yl]methyl}-1,3-benzoxazo1-2-one (94 mg, 0.28 mmol, 1.2 equiv), K2CO3(66 mg, 0.48 mmol, 2.0 equiv) and Pd(dppf)Cl2(17 mg, 0.02 mmol, 0.1 equiv) in 1,4-di oxane (5 mL) H2O (0.5 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4- (3-{[(3S)-4-methylmorpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 80.59%) as a light yellow oil. LCMS (ES, m / z): [M+H]+: 620.

[0702] Step 4. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{[(3S)-4- methylmorpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4-carboxylate

[0703] Into a 50 mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{[(3S)-4-methyhnorpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.19 mmol, 1 equiv), TsOH.H2O (110 mg, 0.58 mmol, 3 equiv) and ACN (3 mL) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. 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), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 44A (22 mg, 18.33%) as a white solid. LCMS (ES, m / z): [M+H]+: 520.1H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.51 (s, 1H), 7.43 - 7.34 (m, 4H), 5.02 (q, J = 8.2 Hz, 1H), 4.12 (dd, J = 14.6, 4.3 Hz, 1H), 3.98 (dd, J = 7.8, 3.7 Hz, 1H), 3.88 - 3.58 (m, 5H), 3.56 - 3.42 (m, 1H), 3.27 - 3.10 (m, 2H), 3.01 (dd, J = 14.3, 3.8 Hz, 1H), 2.81 - 2.68 (m, 2H), 2.64 - 2.49 (m, 3H), 2.38 (s, 3H), 2.29 - 2.16 (m, 1H), 1.74 - 1.64 (m, 2H).

[0704] Compound 44B was synthesized according to the synthesis for Compound 44A. LCMS (ES, m / z): [M+H]+: 520. 1H NMR (300 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO- d6) δ 8.62 (d, J = 8.5 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.57 - 7.50 (m, 1H), 7.44 - 7.37 (m, 4H), 5.04 (td, J = 8.7, 7.2 Hz, 1H), 4.14 (dd, J = 14.7, 4.4 Hz, 1H), 4.00 (dd, J = 7.9, 3.7 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.78 - 3.68 (m, 1H), 3.72 - 3.61 (m, 2H), 3.52 (ddd, J = 11.3, 9.0, 2.6 Hz, 1H), 3.37 - 3.28 (m, 1H), 3.28 - 3.14 (m, 2H), 3.03 (dd, J = 14.3, 3.8 Hz, 1H), 2.81 - 2.70 (m, 2H), 2.66 - 2.52 (m, 3H), 2.40 (s, 3H), 2.25 (ddd, J = 12.2, 9.0, 3.3 Hz, 1H), 1.78 - 1.66 (m, 2H).

[0705] Example 38: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{[(3S)-4-(oxetan-3- yl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4-oxazepane-2- carboxamide (Compound 45A) and (2S)-N-[(1S)-1-cyano-2-[4-(3-{[(3R)-4-(oxetan-3- yl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4-oxazepane-2- carboxamide (Compound 45B)

[0706] Step 1. Synthesis of 5-bromo-3-{[(3R)-4-(oxetan-3-yl)morpholin-3-yl]methyl}-1,3- benzoxazo1-2-one

[0707] A solution of 5-bromo-3-[(3R)-morpholin-3-ylmethyl]-1,3-benzoxazo1-2-one (130 mg,0.41 mmol, 1.0 equiv) in THF (3 mL) was treated with 3-oxetanone (89 mg, 1.24 mmol, 3.0 equiv), HO Ac (0.1 mL) for 1 h at room temperature followed by the addition of NaBH(OAc)3(176 mg, 0.83 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-bromo-3-{[(3R)-4-(oxetan-3-yl)morpholin-3-yl]methyl}-1,3- benzoxazo1-2-one (170 mg, crude) as a white solid. LCMS (ES, m / z): [M+H]+: 369.

[0708] Step 2. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{[(3R)-4-(oxetan-3- yl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]carbamoyl}-1,4- oxazepane-4 -carboxylate

[0709] A solution of 5-bromo-3-{[(3R)-4-(oxetan-3-yl)morpholin-3-yl]methyl}-1,3- benzoxazo1-2-one (106.46 mg, 0.288 mmol, 1.2 equiv), tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4- (4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (120 mg, 0.24 mmol, 1.0 equiv), Na2CO3(51 mg, 0.48 mmol, 2.0 equiv) and Pd(dppf)Cl2(18 mg, 0.02 mmol, 0.1 equiv) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1- cyano-2-[4-(3-{[(3R)-4-(oxetan-3-yl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (130 mg, 81.7%) as a white oil. LCMS (ES, m / z): [M+H]+: 662.

[0710] Step 3. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{[(3R)-4-(oxetan-3-yl)morpholin- 3 -yl]methyl } -2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]- 1 ,4-oxazepane-2-carboxamide

[0711] Into a 50mL round-bottom flask were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3- {[(3R)-4-(oxetan-3-yl)morpholin-3-yl]methyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (100 mg, 0.15 mmol, 1.0 equiv) in ACN (3 mL) and TsOH (78 mg, 0.45 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 45B (17.3 mg, 20.38%) as a white solid. LCMS (ES, m / z): [M+H]+: 562.3.1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.6 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.50 (d, J = 1.4 Hz, 1H), 7.47 - 7.37 (m, 4H), 5.03 (td, J = 8.6, 7.2 Hz, 1H), 4.49 - 4.39 (m, 3H), 4.26 (t, J = 6.0 Hz, 1H), 4.11 (q, J = 6.6 Hz, 1H), 4.09 - 3.93 (m, 3H), 3.85 (ddd, J = 12.4, 6.1, 4.4 Hz, 1H), 3.73 (ddd, J = 11.9, 7.7, 4.0 Hz, 2H), 3.62 - 3.49 (m, 3H), 3.28 - 3.14 (m, 2H), 3.08 - 2.99 (m, 2H), 2.92 (td, J = 12.9, 11.4, 3.4 Hz, 1H), 2.82 - 2.71 (m, 1H), 2.66 - 2.51 (m, 2H), 2.43 - 2.35 (m, 1H), 1.79 - 1.69 (m, 2H).

[0712] Compound 45A was synthesized according to the synthesis for Compound 45B. LCMS (ES, m / z): [M+H]+: 562.3.1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.7 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.50 (d, J = 5.2 Hz, 1H), 7.47 - 7.37 (m, 4H), 5.09 - 4.99 (m, 1H), 4.43 (dd, J = 8.6, 6.4 Hz, 3H), 4.25 (t, J = 6.0 Hz, 1H), 4.11 (q, J = 6.6 Hz, 1H), 4.09 - 3.93 (m, 3H), 3.92 - 3.79 (m, 1H), 3.78 - 3.67 (m, 2H), 3.62 - 3.50 (m, 4H), 3.28 - 3.14 (m, 2H), 3.07 - 2.98 (m, 2H), 2.92 (ddd, J = 13.1, 10.2, 3.4 Hz, 1H), 2.76 (ddd, J = 13.1, 6.5, 4.8 Hz, 1H), 2.65 - 2.52 (m, 2H), 2.38 (dt, J = 12.5, 2.8 Hz, 1H), 1.80 - 1.66 (m, 2H).

[0713] Example 39: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[methyl(oxetan-3- yl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide (Compound 46)

[0714] Step 1. Synthesis of tert-butyl N-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethyl]-N- methylcarbamate

[0715] Into a 250 mL 3-necked round-bottom flask were added 2-benzoxazolinone, 5-bromo- (2.00 g, 9.34 mmol, 1.00 equiv), tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (2.46 g, 14.01 mmol, 1.50 equiv), DCM (60.00 mL) andPPh3(4.90 g, 18.69 mmol, 2.00 equiv) at room temperature. To the above mixture was added DIAD (3.78 g, 18.69 mmol, 2.00 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (10: 1) to afford tert-butyl N-[2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)ethyl]-N-methylcarbamate (1.3 g, 37.47%) as brown solid. LCMS (ES) [M+1]+m / z: 371.

[0716] Step 2. Synthesis of 5-bromo-3-[2-(methylamino)ethyl]-1,3-benzoxazo1-2-one

[0717] Into a 50 mL round-bottom flask were added tert-butyl N-[2-(5-bromo-2-oxo-1,3- benzoxazo1-3-yl)ethyl]-N-methylcarbamate (310.00 mg, 0.83 mmol, 1.00 equiv) and HCl(gas)in 1,4-dioxane (91.34 mg, 2.50 mmol, 3.00 equiv), DCM (10.00 mL) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The mixture was neutralized to pH 7 with saturated NaHCO3(aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 30% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in 5-bromo-3-[2-(methylamino)ethyl]-1,3-benzoxazo1-2-one (220 mg, 97.17%) as Brown yellow oil. LCMS (ES) [M+1]+m / z: 271.

[0718] Step 3. Synthesis of 5-bromo-3-{2-[methyl(oxetan-3-yl)amino]ethyl}-1,3-benzoxazo1- 2-one

[0719] Into a 40 mL vial were added 5-bromo-3-[2-(methylamino)ethyl]-1,3-benzoxazo1-2- one (290.00 mg, 1.07 mmol, 1.00 equiv), 3-oxetanone (231.25 mg, 3.21 mmol, 3.00 equiv), HOAc (0.05 mL) and THF (5.00 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. To the above mixture was added NaBH(AcO)3(453.41 mg, 2.14 mmol, 2.00 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with Water / Ice at 0 °C. The aqueous layer was extracted with EtOAc (3x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5: 1) to afford 5-bromo-3-{2-[methyl(oxetan-3-yl)amino]ethyl}-1,3-benzoxazo1-2-one (230 mg, 42.72%) as off-white solid. LCMS (ES) [M+1]+m / z: 327.

[0720] Step 4. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[methyl(oxetan-3- yl)amino]ethyl } -2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]carbamoyl } - 1 ,4-oxazepane-4- carboxylate

[0721] Into a 40 mL vial were added 5-bromo-3-{2-[methyl(oxetan-3-yl)amino]ethyl}-1,3- benzoxazo1-2-one (85.17 mg, 0.26 mmol, 1.30 equiv), tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4- (4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4- carboxylate (100.00 mg, 0.20 mmol, 1.00 equiv), K2CO3(55.35 mg, 0.40 mmol, 2.00 equiv), Pd(dppf)Cl2(14.65 mg, 0.02 mmol, 0.10 equiv), dioxane (5.00 mL) and H2O (0.50 mL) at room temperature. The resulting mixture was stirred for additional 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1 : 1) to afford tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2-[methyl(oxetan-3-yl)amino]ethyl}-2-oxo-1,3-benzoxazo1-5- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (130 mg, 89.05%) as colorless oil.LCMS (ES) [M+1]+m / z: 620.

[0722] Step 5. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-{2-[methyl(oxetan-3- yl)amino]ethyl } -2-oxo- 1 ,3 -benzoxazo1-5-yl)phenyl]ethyl]- 1 ,4-oxazepane-2-carboxamide

[0723] Into a 20 mL vial were added tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-{2- [methyl(oxetan-3 -yl)amino]ethyl } -2-oxo- 1 ,3 -benzoxazo1-5 -yl)phenyl]ethyl]carbamoyl } - 1 ,4- oxazepane-4 -carboxylate (120.00 mg, 0.19 mmol, 1.00 equiv), ACN (5.00 mL) and TsOH (100.03 mg, 0.58 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 46 (31.1 mg, 30.91%) as white solid.1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J = 8.6 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.45 - 7.35 (m, 4H), 5.03 (q, J = 8.2 Hz, 1H), 4.44 (t, J = 6.5 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 4.05 - 3.95 (m, 3H), 3.85 (dt, J = 10.7, 4.8 Hz, 1H),3.72 (ddd, J = 12.1, 7.4, 4.3 Hz, 1H), 3.56 (p, J = 6.4 Hz, 1H), 3.21 (dd, J = 7.9, 3.8 Hz, 2H), 3.03 (dd, J = 14.2, 3.8 Hz, 1H), 2.78 - 2.70 (m, 1H), 2.58 (q, J = 8.0,7.1 Hz, 4H), 2.18 (s, 3H),1.72 (d, J = 5.9 Hz, 2H). LCMS (ES) [M+1]+m / z: 520.

[0724] Example 40: Synthesis of (2S)-2-[(2S)-3-carboxy-2-[(2S)-3-carboxy-2-[(2S)-3- carboxy-2-[(2S)-3-carboxy-2-[(2S)-3-carboxy-2-[2-(5-{4-[(2S)-2-cyano-2-[(2S)-1,4- oxazepan-2-ylformamido]ethyl]phenyl}-2-oxo-1,3-benzoxazo1-3- yl )acetam ido ] propanam ido ] propanamido ] propanamido] propanamido] propanamido] bu tanedioic acid 2,2,2-trifluoroacetic acid salt (Compound 47 TEA salt)

[0725] Step 1. Synthesis of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2- aminobutanedioate resin

[0726] To a stirred mixture of 1-chloro-2-(chlorodiphenylmethyl)benzene resin (6 g, 19.15 mmol, 7.57 equiv) in DCM (30 mL) was added DIEA (0.98 g, 7.58 mmol, 3.0 equiv) and (2S)- 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid (1 g, 2.52 mmol, 1.0 equiv) at room temperature. The precipitated solid was collected by filtration and washed with DCM (3 x 15 mL). To the above mixture was added DCM / MeOH / DIEA=36:6:2 (10 mL) at room temperature. The resulting mixture was stirred for additional 15 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 10 mL). To the above mixture was added DMF (10 mL), piperidine (0.5 mL) at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). The crude product was used in the next step directly without further purification, 1 -(2- chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2-aminobutanedioate resin (1.1 g, 96.7%) as a brown solid. LCMS (ES, m / z): [M-resin+H]+: 174.

[0727] Step 2. Synthesis of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2-[(2S)- 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- y 1 oxy )butanami do]butanedi oate resin

[0728] To a stirred mixture of (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4- (prop-2-en-1-yloxy)butanoic acid (2.90 g, 7.33 mmol, 3.0 equiv), DIEA (0.95 g, 7.33 mmol, 3.0 equiv), HATU (2.79 g, 7.33 mmol, 3.0 equiv) in DMF (20 mL) was added 1-(2- chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2-aminobutanedioate resin (1.1 g, 2.44 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15mL). The crude product was used in the next step directly without further purification, 1 -(2- chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2-[(2S)-2-{[(9H-fluoren-9- ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate resin(2 g, 98.9%) as a brown solid. LCMS (ES, m / z): [M-resin+H]+: 551.

[0729] Step 3. Synthesis of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2-[(2S)- 2- [(2 S)-2- { [(9H-fluoren-9-ylmethoxy)carbonyl] amino } -4-oxo-4-(prop-2-en- 1 - yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate resin

[0730] To a stirred mixture of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2- [(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- yloxy)butanamido]butanedioate resin (2 g, 2.42 mmol, 1.0 equiv) was added DMF (20 mL), piperidine (1 mL) at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). To the above mixture was added (2S)-2-{[(9H-fluoren-9- ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid (2.87 g, 7.25 mmol, 3.0 equiv), DIEA (0.94 g, 7.25 mmol, 3.0 equiv), HATU (2.76 g, 7.25 mmol, 3.0 equiv) in DMF (20 mL). The resulting mixture was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). The crude product was used in the next step directly without further purification. This resulted in 1-(2- chlorophenyl)diphenylmethyl 4-prop-2-en- 1 -yl (2 S)-2- [(2 S)-2- [(2 S)-2- { [(9H-fluoren-9- ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en- 1-yloxy)butanamido]butanedioate resin (2 g, 84.2%) as a brown solid. LCMS (ES, m z)'. [M- resin+H]+: 706.

[0731] Step 4. Synthesis of tert-butyl 2-(5-bromo-2-oxo-1,3-benzoxazo1-3-yl)acetate

[0732] To a stirred solution of 5-bromobenzo[d]oxazo1-2(3H)-one (6 g, 28.03 mmol, 1.0 equiv) and tert-butyl 2-hydroxyacetate (4.44 g, 33.64 mmol, 1.2 equiv), PPh3(8.82 g, 33.64 mmol, 1.2 equiv) in DCM (120 mL) was added DIAD (6.80 g, 33.64 mmol, 1.2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica ge1-120 g; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 15 min; detector, UV 254 nm. This resulted in tert-butyl 2-(5-bromo-2-oxo-1,3-benzoxazo1-3- yl)acetate (6 g, 65%) as a yellow solid. LCMS (ES, m / z): [M+H]+: 328.

[0733] Step 5. Synthesis of (5-bromo-2-oxo-1,3-benzoxazo1-3-yl)acetic acid

[0734] Into a 250 mL round-bottom flask were added tert-butyl 2-(5-bromo-2-oxo-1,3- benzoxazo1-3-yl)acetate (6 g, 18.28 mmol, 1.0 equiv) and DCM (60 mL), TFA (20 mL) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in (5-bromo-2-oxo- l,3-benzoxazo1-3-yl)acetic acid (5 g, crude) as a yellow solid. LCMS (ES, m / z): [M+H]+: 272.

[0735] Step 6. Synthesis of (5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2- yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetic acid

[0736] To a mixture of (5-bromo-2-oxo-1,3-benzoxazo1-3-yl)acetic acid (850 mg, 3.12 mmol, 1.0 equiv), tert-butyl (2S)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethy1-l,3,2-dioxaborolan-2- yl)phenyl]ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (1.87 g, 3.74 mmol, 1.2 equiv), K2CO3(863 mg, 6.24 mmol, 2.0 equiv) in 1,4-dioxane (10 mL), H2O (1 mL), was addedPd(dppf)Cl2CH2Cl2(254 mg, 0.31 mmol, 0.1 equiv) under nitrogen gas. The mixture was stirred for 3 h at 80°C under nitrogen atmosphere. The reaction was cooled to room temperature, acidified to pH 4 with saturated citric acid (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica ge1-120 g; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (5-{4-[(2S)-2-{[(2S)- 4-(tert-butoxycarbonyl)- 1 ,4-oxazepan-2-yl ]formamido } -2-cyanoethyl]phenyl } -2-oxo- 1,3- benzoxazo1-3-yl)acetic acid (850 mg, 48.2%) as a yellow solid. LCMS (ES, m / z): [M+H]+: 565.

[0737] Step 7. Synthesis of (2S)-2-[(2S)-2-[(2S)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert- butoxy carbonyl)- 1 ,4-oxazepan-2-yl]formamido} -2-cyanoethyl]phenyl } -2-oxo- 1,3- benzoxazo1-3 -yl)acetamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en- 1 - yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid

[0738] To a stirred mixture of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2- [(2S)-2-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate resin (696 mg, 0.70 mmol, 2.0 equiv) was added DMF (10 mL), piperidine (0.5 mL) at room temperature. The resulting mixture was stirred for 20 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). To the above mixture was added (5- {4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2- cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetic acid (200 mg, 0.35 mmol, 1.00 equiv), DIEA (137 mg, 1.06 mmol, 3.0 equiv), HATU (404 mg, 1.06 mmol, 3.0 equiv) in DMF (10 mL). The resulting mixture was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with DCM (3 x 15 mL). To the above mixture was addedTFA (0.5 mL) in DCM (10 mL) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica ge1-120 g; mobile phase, MeCN in Water (0.1% TFA), 10% to 30% gradient in 15 min; detector, UV 254 nm. This resulted in (2S)-2- [(2S)-2-[(2S)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2- yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop- 2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanoic acid (180 mg, 49%) as a white solid. LCMS (ES, m / z): [M+H]+: 1030.

[0739] Step 8. Synthesis of (2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[2-(5-{4-[(2S)-2- {[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2-cyanoethyl]phenyl}-2-oxo- 1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2- en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanoic acid

[0740] To a stirred mixture of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2- [(2S)-2-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate resin (515 mg, 0.52 mmol, 3.0 equiv) was added DMF (10 mL), piperidine (0.5 mL) at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). To the above mixture was added (2S)-2-[(2S)-2-[(2S)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2- yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop- 2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanoic acid (180 mg, 0.17 mmol, 1.0 equiv), DIEA (67 mg, 0.52 mmol, 3.0 equiv), HATU (199 mg, 0.52 mmol, 3.0 equiv) in DMF (10 mL). The resulting mixture was stirred for2 h at room temperature. The precipitated solid was collected by filtration and washed with DCM (3 x 15 mL). To the above mixture was added TFA (0.5 mL) in DCM (10 mL) at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica ge1-120 g; mobile phase, MeCN in Water (0.1% TFA), 10% to 30% gradient in 15 min; detector, UV 254 nm. This resulted in (2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)- 2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2- cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid (100 mg, 38.3%) as white solid. LCMS (ES, m / z): [M+H]+: 1496.

[0741] Step 9. Synthesis of (2S)-2-[(2S)-3-carboxy-2-[(2S)-3-carboxy-2-[(2S)-3-carboxy-2- [(2S)-3-carboxy-2-[(2S)-3-carboxy-2-[2-(5-{4-[(2S)-2-cyano-2-[(2S)-1,4-oxazepan-2- ylformamido]ethyl]phenyl} -2-oxo- 1 , 3 -benzoxazo1-3 - yl)acetamido]propanamido]propanamido]propanamido]propanamido]propanamido]butanedio ic acid trifluoroacetic acid salt

[0742] To a stirred solution of (2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2-cyanoethyl]phenyl}-2- oxo-1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4- (prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2- en- 1 -yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid (100 mg, 0.06 mmol, 1.0 equiv) and morpholine (11 mg, 0.13 mmol, 2.0 equiv) in THF (5 mL) was added Pd(PPh3)4(7.73 mg, 0.007 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. To the above mixture was added ACN (5 mL) and TFA (1 mL) at room temperature. The resulting mixture was stirred for additional 5 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica ge1- 120 g; mobile phase, MeCN in Water (0.1% TFA), 0% to 30% gradient in 15 min; detector, UV 254 nm. This resulted in Compound 47 trifluoroacetic acid salt (10 mg, 11.8%) as an off- white solid. LCMS (ES, m / z): [M+H]+: 1155.1H NMR (400 MHz, Methanol-d4) δ 7.75 - 7.61 (m, 2H), 7.50 - 7.32 (m, 5H), 5.20 - 5.11 (m, 1H), 4.00 - 3.83 (m, 7H), 3.81 - 3.59 (m, 2H), 3.27 - 3.23 (m, 1H), 3.07 - 2.99 (m, 1H), 2.88 - 2.80 (m, 1H), 2.63 - 2.59 (m, 1H), 2.48 - 2.32 (m, 3H), 2.32 - 2.22 (m, 1H), 2.22 - 1.78 (m, 12H), 2.18-2.02 (m, 2H).

[0743] Example 41: Synthesis of (2-(5-(4-((S)-2-cyano-2-((S)-1,4-oxazepane-2- carboxamido)ethyl)phenyl)-2-oxobenzo[d]oxazo1-3(2H)-yl)acetyl)-D-asparty1-D- asparty1-D-asparty1-D-asparty1-D-asparty1-D-aspartic acid-2, 2, 2-trifluoroacetic acid salt (Compound 48 TEA Salt)

[0744] Step 1. Synthesis of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2- aminobutanedioate resin

[0745] To a stirred mixture of 1-chloro-2-(chlorodiphenylmethyl)benzene resin (6 g, 19.16 mmol, 7.5 equiv) in DCM (30 mL) was added DIEA (0.98 g, 7.58 mmol, 3.0 equiv) and (2R)- 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid (1 g, 2.53 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with DCM (3 x 15 mL). To the above mixture was added DCM / MeOH / DIEA=36 / 6 / 2 mL at room temperature. The resulting mixture was stirred for additional 15 min at room temperature. The precipitatedsolid was collected by filtration and washed with DMF (3 x 10 mL). To the above mixture was added DMF (10 mL), piperidine (0.5 mL) at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). The crude product was used in the next step directly without further purification, 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2-aminobutanedioate resin (1.1 g, 96 %) as a brown solid. LCMS (ES, m / z): [M-resin+H]+: 174.

[0746] Step 2. Synthesis of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2-[(2R)- 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- yloxy )butanamido]butanedioate resin

[0747] To a stirred mixture of (2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4- (prop-2-en-1-yloxy)butanoic acid (2.90 g, 7.33 mmol, 3.0 equiv), DIEA (0.95 g, 7.33 mmol, 3.0 equiv), HATU (2.79 g, 7.33 mmol, 3.0 equiv) in DMF (20 mL) was added 1-(2- chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2S)-2-aminobutanedioate resin (1.1 g, 2.44 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). The crude product was used in the next step directly without further purification, 1 -(2- chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2-[(2R)-2-{[(9H-fluoren-9- ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate resin (1.9 g, 94%) as a brown solid. LCMS (ES, m / z): [M-resin+H]+: 551.

[0748] Step 3. Synthesis of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2-[(2R)- 2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate resin

[0749] To a stirred mixture of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2- [(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- yloxy)butanamido]butanedioate resin (1.9 g, 2.29 mmol, 1 equiv) was added DMF (20 mL), piperidine (1 mL) at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). To the above mixture was added (2R)-2-{[(9H-fluoren-9- ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid (2.87 g, 7.25 mmol, 3.0 equiv), DIEA (0.94 g, 7.25 mmol, 3.0 equiv), HATU (2.76 g, 7.25 mmol, 3.0 equiv) in DMF (20 mL). The resulting mixture was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). The crude product was used in the next step directly without further purification, 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2-[(2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4- oxo-4-(prop-2-en- 1 -yloxy)butanamido]-4-oxo-4-(prop-2-en- 1 - yloxy)butanamido]butanedioate resin (2.1 g, 93%) as a brown solid. LCMS (ES, m / z): [M- resin+H]+: 706.

[0750] Step 4. Synthesis of (2R)-2-[(2R)-2-[(2R)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert- butoxy carbonyl)- 1 ,4-oxazepan-2-yl]formamido} -2-cyanoethyl]phenyl } -2-oxo- 1,3- benzoxazo1-3 -yl)acetamido]-4-oxo-4-(prop-2-en- 1 -yloxy)butanamido]-4-oxo-4-(prop-2-en- 1 - yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid

[0751] To a stirred mixture of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2- [(2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate (1218 mg, 1.24 mmol, 2.0 equiv) was added DMF (10 mL), piperidine (0.5 mL) at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The precipitated solid was collected by filtration and washed with DMF (3 x 15 mL). To the above mixture was added (5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2- cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetic acid (350 mg, 0.62 mmol, 1.0 equiv), DIEA (240 mg, 1.86 mmol, 3.0 equiv), HATU (707 mg, 1.86 mmol, 3.0 equiv) in DMF (10 mL). The resulting mixture was stirred for 2 h at room temperature. The precipitated solid was collected by filtration and washed with DCM (3 x 15 mL). To the above mixture was added DCM (10 mL) at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18-120 g silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 30% gradient in 15 min; detector, UV 254 nm. This resulted in (2R)-2-[(2R)-2- [(2R)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2- cyanoethyl]phenyl } -2-oxo- 1 ,3 -benzoxazo1-3 -yl)acetamido]-4-oxo-4-(prop-2-en- 1 - yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanoic acid (240 mg, 37.6%) as a white solid. LCMS (ES, m / z): [M+H]+: 1030.

[0752] Step 5. Synthesis of (2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-[2-(5-{4-[(2S)-2- {[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2-cyanoethyl]phenyl}-2-oxo- 1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2- en- 1 -yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanoic acid

[0753] To a stirred mixture of 1-(2-chlorophenyl)diphenylmethyl 4-prop-2-en-1-yl (2R)-2- [(2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl] amino } -4-oxo-4-(prop-2-en- 1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]butanedioate resin (686 mg, 0.69 mmol, 3.0 equiv) in DMF (10 mL), piperidine (0.5 mL) at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The precipitated solids were collected by filtration and washed with DMF (3 x 15 mL). To the above mixture was added (2R)-2-[(2R)-2-[(2R)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2- yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop- 2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanoic acid (240 mg, 0.23 mmol, 1.0 equiv), DIEA (90 mg, 0.69 mmol, 3.0 equiv), HATU (265 mg, 0.69 mmol, 3.0 equiv) in DMF (10 mL). The resulting mixture was stirred for 2 h at room temperature. The precipitated solids were collected by filtration and washed with DCM (20 mL) (3 x 15 mL). To the above mixture was added DCM / TFA(20v / lv, 10.5 mL) at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 30% gradient in 15 min; detector, UV 254 nm. This resulted in (2R)-2-[(2R)-2-[(2R)-2-[(2R)-2- [(2R)-2-[(2R)-2-[2-(5-{4-[(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2- yl]formamido}-2-cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanoic acid (120 mg, 34.44%) as a white solid. LCMS (ES, m / z): [M+H]+: 1496.

[0754] Step 6. Synthesis of (2R)-2-[(2R)-3-carboxy-2-[(2R)-3-carboxy-2-[(2R)-3-carboxy-2- [(2R)-3-carboxy-2-[(2R)-3-carboxy-2-[2-(5-{4-[(2S)-2-cyano-2-[(2S)-1,4-oxazepan-2- ylformamido] ethyl ]phenyl } -2-oxo- 1 , 3 -benzoxazo1-3 - yl)acetamido]propanamido]propanamido]propanamido]propanamido]propanamido]butanedio ic acid; trifluoroacetic acid -2,2,2-trifluoroacetic acid salt

[0755] To a stirred solution of (2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-[(2R)-2-[2-(5-{4- [(2S)-2-{[(2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-yl]formamido}-2- cyanoethyl]phenyl}-2-oxo-1,3-benzoxazo1-3-yl)acetamido]-4-oxo-4-(prop-2-en-1- yloxy)butanamido]-4-oxo-4-(prop-2-en-1-yloxy)butanamido]-4-oxo...

Claims

CLAIMSWhat is claimed is:

1. A compound of formula (I):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R1is a 4- to 10-membered heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;X is -NR9-, -O-, -CRnR12-, -C(O)-, -S-, -S(O) - or -S(O)2-;Q is CH or N;L is a carbocyclene, arylene, heterocyclene, or heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3; each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6 alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tetracyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tetracyclic ring is optionally substituted with 1, 2, 3, or 4 R4; each R4is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle; each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle; each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle; each R7is independently H, -C1-C6alkyl, or heterocyclyl; each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;R9is H, -C1-C6alkyl, or R10;R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1- C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)- NR7R8, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O- (C1-C6alkyl), -(C1-C6alkylene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n;R11and R12are each independently selected from H, deuterium, halogen, or -C1-C6alkyl; each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, Y groups are connected by a peptide bond (-C(O)NH-); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a monocyclic or a bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a monocyclic carbocyclene, monocyclic arylene, monocyclic heterocyclene, or monocyclic heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is phenylene or 5- or 6-membered heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is phenylene or thiophene, each of which is optionally substituted with 1 or 2 R3.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is a polycyclic carbocyclene, polycyclic arylene, polycyclic heterocyclene, or polycyclic heteroarylene, each of which is optionally substituted with 1, 2, 3, or 4 R3.

7. The compound of any one of claims 1, 2, and 6, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L iseach of which is optionally substituted with 1, 2, 3, or 4 R3.

8. The compound of any one of claims 1, 2, and 6, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L isoptionally substituted with 1, 2, 3, or 4 R3, wherein ring B is a heteroaryl ring and * indicates the bond to R2.

9. The compound of any one of claims 1, 2, and 8, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L iseach of which is optionally substituted with 1, 2, 3, or 4 R3, wherein * indicates the bond to R2.

10. The compound of any one of claims 1, 2, and 8, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is, optionally substituted with 1, 2, 3, or 4 R3, wherein ring B is a heteroaryl ring and * indicates the bond to R2.

11. The compound of any one of claims 1, 2, and 8, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L is, each optionally substituted with 1, 2, 3, or 4 R , wherein * indicates the bond to R2.

12. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the formula (I- A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R1is a 4-10 membered monocyclic or bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5;X is -NR9-, -O-, -CRnR12-, -C(O)-, -S-, -S(O) - or -S(O)2-;Q is CH or N; each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6 alkyl, SOC1-6alkyl, or SO2C1-6alkyl; or R3together with one of R6can form a tetracyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tetracyclic ring is optionally substituted with 1, 2, 3, or 4 R4; each R4is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle;each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle; each R6is independently halogen, -OH, oxo, -CN, -C1-C6alkyl, -C1-C6alky1-OH, -C1- C10haloalkyl, -C1-C10haloalky1-OH, -NR7R8, -C1-C6alky1-NR7R8, -S(C1-C6alkyl), -SO(C1- C6alkyl), -SO2(C1-C6alkyl), -SO2N(C1-C6alkyl), -SO2NR7R8, -(C1-C6alkylene)-carbocycle, -(C1-C6alkylene)-heterocycle, carbocycle, or heterocycle; each R7is independently H, -C1-C6alkyl, or heterocyclyl; each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;R9is H, -C1-C6alkyl, or R10;R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1- C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)- NR7R8, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O- (C1-C6alkyl), -(C1-C6alkylene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n; each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, adjacent Y forms a peptide bond (-C(O)NH-) or a modified peptide bond (- C(O)CH2-); n is 1, 2, 3, 4, 5, 6, 7, or 8; p is 0, 1, 2, or 3; and r is 0, 1, 2, 3, or 4.

13. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:R1is a 4-10 membered monocyclic or bicyclic heterocycle ring optionally substituted with 1, 2, 3, or 4 R5; each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6alkyl, SOC1-6alkyl, or SO2C1-6alkyl; each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle; each R7is independently H, -C1-C6alkyl, or heterocyclyl; each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)- O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1- C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)- NR7R8, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O- (C1-C6alkyl), -(C1-C6alkylene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, -(C1-C6alkylene)-heteroaryl, (Y)nor -(CH2C(O))(Y)n; each Y is independently an amino acid or an amino acid residue, wherein when n is greater than 2, adjacent Y forms a peptide bond (-C(O)NH-) or a modified peptide bond (- C(O)CH2-); n is 1, 2, 3, 4, 5, 6, 7, or 8; p is 0, 1, 2, or 3; andr is 0, 1, 2, 3, or 4.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 4-8 membered monocyclic heterocycle ring optionally substituted with 1 or 2 R5.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:each of which is optionally substituted with 1, 2, 3, or 4 R5;X1is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, or -N(heterocycle)-;X2is -O-, -S-, -NH-, -N(C1-C6alkyl)-, -N(C1-C6haloalkyl)-, -N(C(O)(C1-C6alkyl))-, -N(heterocycle)- or -CRnR12-; g is 0, 1, 2, or 3; and k is 0, 1, or 2.

16. The compound of claim 15, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:optionally substituted with 1, 2, 3, or 4 R5;X1is -O-, -S-, or -NH-; and X2is -O-, -S-, -NH-, or -CH2-.

17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1iseach of which is optionally substituted with 1, 2, 3, or 4 R5.

18. The compound of any one of claims 15-17, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, whereineach of which is optionally substituted with 1, 2, 3, or 4 R5.

19. The compound of any one of claims 15-18, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein20. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is an 8-10 membered bicyclic fused heterocycle ring optionally substituted with 1, 2, 3, or 4 R5.

21. The compound of claim 20, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is a 5,5-, 5,6-, 6,5-, 6,6-, or 5,7-fused heterocycle, optionally substituted with 1 or 2 R5.

22. The compound of claim 20 or 21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein, each of which is optionally substituted with 1, 2,3, or 4 R5.

23. The compound of any one of claims 20-22, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R1is24. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has the formula (I-C):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: each R3is independently halogen, -OH, -CN, -C1-C6alkyl, -C1-C6haloalkyl, SC1-6 alkyl, SOC1-6alkyl, or SO2C1-6alkyl; each R5is independently halogen, oxo, -CN, -OH, -C1-C6alkyl, -C1-C6haloalkyl, - C(O)(C1-C6alkyl), -C1-C6alky1-OH, -COOH, -CONH2, -OC1-C6alkyl, -OC1-C6haloalkyl, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, -S(C1-C6alkyl), -SO(C1-C6alkyl), -SO2(C1- C6alkyl), -SO2N(C1-C6alkyl), -SONR7R8, -SO2NR7R8, -S(=NH)(O)(C1-C6alkyl), -(C1-C6alkylene)-carbocyclyl,-(C1-C6alkylene)-heteroaryl, or heterocycle; each R7is independently H, -C1-C6alkyl, or heterocyclyl; each R8is independently H or -C1-C6alkyl; or R7and R8together with the nitrogen atom to which they are attached form a heterocyclyl;R10is -(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkyl)-OH, -(C1- C6alkylene)-O-(C1-C6alkyl)-COOH, -(C1-C6alkylene)-O-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)- C(O)NR7R8, -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkyl), -(C1-C6alkylene)-O-(C1-C6alkylene)-C(O)NR7-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)-O-(C1- C6alkylene)-NR7C(O)-(C1-C6alkylene)-O-(C1-C6alkylene)-NR7-aryl, -(C1-C6alkylene)- NR7R8, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-OH, -(C1-C6alkylene)-NR7-(C1-C6alkyl)-O- (C1-C6alkyl), -(C1-C6alkylene)-NR7-(C1-C6alkylene)-NR7R8, -(C1-C6alkylene)-heterocycle, or -(C1-C6alkylene)-heteroaryl; r is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4.

25. The compound of any one of claims 12-24, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein r is 0 or 1.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is halogen.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R10is -(C1-C4alkyl)-NHCH3, -(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C4alkyl)-OH, - (C1-C3alkyl ene)-O-(C1-C4alkyl)-COOH, -(C1-C3alkylene)-O-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkyl ene)-O-(C1-C4alkyl)-NH2, -(C1-C3alkylene)-O-(C1-C4alkyl)-NHCH3, - (C1-C3alkyl ene)-NH-(C1-C4alkyl)-OH, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NH2, -(C1-C3alkylene)-NH-(C1-C4alkyl)-NHCH3, -(C1-C3alkylene)-NH-(C1-C4alkyl)-N(CH3)2, -(C1-C3alkylene)-O-(C1-C3alkylene)-C(O)NH-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkylene)- O-(C1-C3alkylene)-NHC(O)-(C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-C(O)NH- (C1-C4alkyl), -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C4alkyl), -(C1-C3alkyl ene)-O-(C1-C3alkylene)-C(O)NH-(C1-C3alkylene)-O-(C1-C3alkylene)- NH-aryl, or -(C1-C3alkylene)-O-(C1-C3alkylene)-NHC(O)-(C1-C3alkylene)-O-(C1-C3alkylene)-NH-aryl .

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R10is -CH2CH2N(CH3)2, - CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, - CH2CH2OCH2CH2OH, -CH2CH2OCH2COOH, -CH2CH2OCH2CONH2, - CH2CH2OCH2CONHCH3, -CH2CH2OCH2CON(CH3)2, -CH2CH2OCH2CH2COOH, - CH2CH2OCH2CH2CONH2, -CH2CH2OCH2CH2CONHCH3, -CH2CH2OCH2CH2CON(CH3)2, -CH2CH2OCH2CH2CONHCH2CH3, -CH2CH2OCH2CH2CON(CH2CH3)2, -CH2CH2OCH2CH2CONHCH2CH2OCH3, -CH2CH2OCH2CH2CON(CH3)CH2CH2OCH3, -CH2CH2OCH2CH2CONHCH2CH2OCH2CH3, -CH2CH2OCH2CH2CON(CH3)CH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH3, -CH2CH2OCH2CH2NH2, -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2N(CH3)2, -CH2CH2OCH2C(O)NHCH3, -CH2CH2NHCH2CH2OH, -CH2CH2NHCH2CH2NH2, -CH2CH2NHCH2CH2NHCH3, -CH2CH2NHCH2CH2N(CH3)2, -CH2CH2NHCH2CH2OCH3, -CH2CH2N(CH3)CH2CH2OCH3,29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R10is30. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R10is31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is -CH3, -OCH3, -OH, or -NH2.

32. The compound of claim 24, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R5is not -OCH3at the 6-position of the oxazepane ring.

33. The compound of claim 24, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein when t is 1 and R5is -OCH3at the 6-position of the oxazepane ring, then R10is not -CH2CH2N(CH3)2, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, or34. The compound of claim 1, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound isstereoisomer, or deuterated form thereof.

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

36. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-35, or a pharmaceutically acceptable salt or deuterated form thereof and a pharmaceutically acceptable adjuvant, diluent or carrier.

37. 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 1-35, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

38. The method of claim 37, wherein the obstructive disease of the airway is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (Al AT) 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).

39. The method of claim 38, wherein the obstructive disease of the airway is asthma.

40. The method of claim 38, wherein the obstructive disease of the airway is acute respiratory distress syndrome (ARDS).

41. The method of claim 38, wherein the obstructive disease of the airway is bronchitis.

42. The method of claim 38, wherein the obstructive disease of the airway is pulmonary fibrosis.

43. The method of claim 38, wherein the obstructive disease of the airway is emphysema.

44. The method of claim 38, wherein the obstructive disease of the airway is cystic fibrosis (CF).

45. The method of claim 38, wherein the obstructive disease of the airway is bronchiectasis.

46. The method of claim 38, wherein the obstructive disease of the airway is sarcoidosis.

47. The method of claim 38, wherein the obstructive disease of the airway is alpha- 1 antitrypsin (Al AT) deficiency.

48. The method of claim 38, wherein the obstructive disease of the airway is farmer’s lung.

49. The method of claim 38, wherein the obstructive disease of the airway is hypersensitivity pneumonitis.

50. The method of claim 38, wherein the obstructive disease of the airway is a complication of lung transplantation.

51. The method of claim 38, wherein the obstructive disease of the airway is a vasculitic or thrombotic disorder of the lung vasculature.

52. The method of claim 38, wherein the obstructive disease of the airway is pulmonary hypertension.

53. The method of claim 38, wherein the obstructive disease of the airway is iatrogenic cough.

54. The method of claim 38, wherein the obstructive disease of the airway is acute rhinitis.

55. The method of claim 38, wherein the obstructive disease of the airway is chronic rhinitis.

56. The method of claim 38, wherein the obstructive disease of the airway is rhinitis medicamentosa or vasomotor rhinitis.

57. The method of claim 38, wherein the obstructive disease of the airway is nasal polyposis.

58. The method of claim 38, wherein the obstructive disease of the airway is COPD.

59. The method of claim 39, wherein the asthma is bronchial, allergic, intrinsic, extrinsic, neutrophilic, exercise-induced or drug-induced asthma.

60. The method of claim 59, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

61. The method of claim 42, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, or fibrosis complicating anti-neoplastic therapy or chronic infection.

62. The method of claim 45, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

63. The method of claim 45, wherein the bronchiectasis is associated with cystic fibrosis.

64. The method of claim 52, wherein the pulmonary hypertension is pulmonary arterial hypertension.

65. The method of claim 52, wherein the pulmonary hypertension is pulmonary hypertension due to left heart disease.

66. The method of claim 52, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

67. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

68. The method of claim 67, wherein the treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

69. The method of claim 68, 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 treatment.

70. The method of claim 68 or 69, wherein the lung function is measured by spirometry.

71. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

72. The method of claim 71, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

73. The method of claim 71, wherein the bronchiectasis is associated with cystic fibrosis.

74. The method of any one of claims 71-73, wherein treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

75. The method of claim 74, 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.

76. The method of claim 74 or 75, wherein the lung function is measured by spirometry.

77. The method of any one of claims 71-76, wherein treating comprises decreasing the rate of pulmonary exacerbation, as compared to the rate of pulmonary exacerbation of the patient prior to treatment.

78. The method of any one of claims 71-77, wherein treating comprises increasing the time to first pulmonary exacerbation, as compared to an untreated patient.

79. The method of claim 77 or 78, 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.

80. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

81. The method of claim 80, wherein the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

82. The method of claim 80, wherein the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

83. The method of any one of claims 80-82, wherein the chronic rhinosinusitis is refractory chronic rhinosinusitis.

84. The method of any one of claims 80-83, wherein treating comprises reducing, diminishing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS.

85. The method of claim 84, 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.

86. A method for treating hidradenitis suppurativa (HS) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

87. The method of claim 86, wherein the hidradenitis suppurativa (HS) is Hurley stage I.

88. The method of claim 86, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

89. The method of claim 86, wherein the hidradenitis suppurativa (HS) is Hurley stageIII.

90. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

91. The method of claim 90, wherein the cancer is a metastatic cancer.

92. The method of claim 91, wherein the metastatic cancer is breast to lung metastatic cancer.

93. The method of claim 91, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver.

94. The method of claim 91, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

95. The method of claim 91, 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.

96. The method of claim 91, 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.

97. The method of claim 91, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or the kidney.

98. The method of claim 91, wherein the metastatic cancer comprises metastasis of lymphoma to the kidney, ovary, liver, bladder, or the spleen.

99. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

100. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

101. The method of claim 100, wherein the arthritis is rheumatoid arthritis.

102. The method of claim 100, wherein the arthritis is osteoarthritis.

103. A method for treating inflammatory bowel disease (IBD) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

104. The method of claim 103, wherein the inflammatory bowel disease (IBD) is Crohn’s disease.

105. The method of claim 103, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

106. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

107. The method of claim 106, wherein the ANCA associated disease is granulomatosis with polyangiitis (GPA).

108. The method of claim 106, wherein the ANCA associated disease is microscopic polyangiitis (MPA).

109. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36, 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.

110. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

111. The method of claim 110, wherein the heart failure is heart failure with reduced ejection fraction.

112. The method of claim 110, wherein the heart failure is heart failure with preserved ejection fraction.

113. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

114. The method of claim 113, wherein the patient is a heart transplant recipient.

115. The method of claim 113 or 114, wherein the IR injury is due to heart transplantation.

116. The method of any one of claims 113-115, wherein the treating comprises improving left-ventricular (LV) graft function of the patient.

117. The method of claim 116, wherein improving left-ventricular (LV) graft function comprises improving LV systolic function of the patient.

118. The method of claim 117, 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.

119. 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 1-35 or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, or the composition of claim 36.

120. The method of claim 119, wherein the lung injury is acute liver injury.

121. The method of claim 119, wherein the lung injury is drug-induced acute liver injury.

122. The method of any one of claims 37-121, wherein the effective amount of the compound or composition is administered once daily during an administration period.

123. The method of any one of claims 37-121, wherein the effective amount of the compound or composition is administered orally.

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