Use of Certain 1,4-Oxazepane-2-Carboxamides as DPP1 Inhibitors

Abstract

Provided herein are compositions comprising an effective amount of a DPP1 inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof, and their use in treating disorders mediated by dipeptidyl peptidase 1 (DPP1). In embodiments of the methods provided herein, the compositions are orally administered once daily. [Formula 1] JPEG2026507449000150.jpg19128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 445,955, filed February 15, 2023, and U.S. Provisional Application No. 63 / 599,868, filed November 16, 2023, the entire contents of which are incorporated herein by reference for all purposes. [Background technology]

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a lysosomal cysteine ​​protease capable of removing dipeptides from the amino terminus of protein substrates. The earliest discovery of DPP1 was by Gutman and Fruton in 1948 (J. Biol. Chem. 174, 851-858), followed by its earliest description of a human cDNA in 1995 (FEBS Lett. 369, 326-330). DPP1 is the only member of the papain-like protease family with a tetrameric effect, consisting of four identical subunits. Each subunit is composed of an N-terminal fragment, a heavy chain, and a light chain (J. Biol. Chem. 270, 21626-21631).

[0003] High levels of DPP1 are expressed by many tissues, including the lung, kidney, liver, and spleen (Biol. Chem. Hoppe Seyler 373:367-373, 1992). Thus, DPP1 plays a similar role in the activation of serine proteases in hematopoietic stem cells, and is also relatively highly expressed in neutrophils, cytotoxic lymphocytes, natural killer cells, alveolar macrophages, and mast cells. Recent data indicate that, apart from being a key enzyme in lysosomal protein degradation, DPP1 also plays a key role in the activation of cellular serine protease particles: cytotoxic T lymphocytes and natural killer cells (granzymes A and B; Proc. Nat. Acad. Sci. 96:8627-8632, 1999), mast cells (chymotrypsin and fibrinogenase; J. Biol. Chem. 276:18551-18556, 2001), and neutrophils (cathepsin G, elastinase, and protease hydrolase 3; J. Clin. Invest. 109:363-371, 2002). Activation of these proteases can lead to the degradation of multiple extracellular matrix components, resulting in tissue damage and chronic inflammation. DPP1 has come to be considered as a valid therapeutic target due to its important role in the activation of these proteases (J Clin Invest, 2002, 109, 363-271; J Immunol, 2004, 173, 7277-7281).

[0004] Considering this, cathepsin C inhibitors have potential for use in the treatment of various inflammatory diseases. Considering the effect of DPP1 on certain pro-inflammatory serine proteases, the clinical application of inhibiting its activity and thus inhibiting downstream serine protease activity may have promising prospects. Currently, there are many related patents reporting the synthesis of DPP1 inhibitors. For example, WO 2004 / 110988 relates to nitrile derivatives and their use as DPP1 inhibitors. WO 2009 / 074829 relates to peptidyl nitriles and their use as DPP1 inhibitors. WO 2010 / 128324 relates to α-aminonitriles and their use as DPP1 inhibitors. WO 2012 / 119941 relates to peptidyl nitriles and their use as DPP1 inhibitors. WO 2013 / 041497 relates to N-[-1-cyano-2-(phenyl)ethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide and its use as a DPP1 inhibitor. WO 2001 / 096285 and WO 2003 / 048123 relate to β-aminonitriles and their cysteine ​​protease inhibitory activity.

[0005] Because DPP1 is involved in many disease states, and because DPP1 inhibitors have not been approved by regulatory agencies, there remains a need for new DPP1 inhibitors. Summary of the Invention

[0006] In one aspect, the present invention provides a method of treating a disorder associated with altered DPP1 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for an administration period;

[0007] [ka] During the ceremony, G is a 5- to 12-membered carbocyclic ring, a 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, or O, or a ring represented by formula (I-1):

[0008] [ka] (I-1) is a fused ring L1 is bonded to G by replacing any hydrogen atom on ring G, and a bond, C 1~3 Alkylene, -NH-, -N(C 1~4 Alkyl)-, -O-, -S-, C 2~6 Ortho-alkenyl, C 2~6 ortho-alkynyl, -CO-, or -CONH-, wherein the alkylene, ortho-alkenyl, or ortho-alkynyl optionally contains 1 to 3 halogens, C 1~4 substituted with alkyl, cyano, hydroxyl, NH2, and -COOH groups; R1, R2, and R3 are independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH, or alternatively, R1 and R2 are C 3~6 Forming a cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the cycloalkyl or heterocycle is optionally ═O, halogen, cyano, hydroxyl, NH, COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; Y1 and Y2 are both independently selected from CR4 or N; Each R4 is independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1~4 Alkyl, N(C 1~4 Alkyl)2, COOH, COC 1~4 Alkyl, COOC 1~4 Alkyl, CONHC 1~4 Alkyl, CON(C 1~4 alkyl)2, NHCOC 1~4 alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in R4 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; X1, X2, X3, and X4 are each independently selected from a bond, NR5, O, CR6R7, S, S(O), and S(O)2, and at most one of X1, X2, X3, and X4 is a bond; Rc is H, ═O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, halogenated C 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6 Alkoxyalkyl or halogenated C 1~4 is an alkoxy, Each R5 is independently H, C 1~4 Alkyl, -COC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH, and COOH; R6 and R7 are each independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, cyano, hydroxyl, NH, COOH, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 groups optionally selected from deuterium, halogen, cyano, hydroxyl, NH, and —COOH; Alternatively, R6 and R7 form =O, or Alternatively, two R5 on adjacent ring atoms within X1, X2, X3, and X4, or two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms and the atoms bonded thereto, form a double bond, or Alternatively, R6 and R7 on the same carbon atom may be bonded to the carbon atom to which they are bonded. 3~12 Forms a carbocyclic ring or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, or O, and the carbocyclic ring or heterocyclic ring is not ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl, Z is CH or N; A,

[0009] [ka] A 6-atom heteroaryl or a 5- to 7-membered non-aromatic monocyclic heterocycle, wherein the heteroaryl and the non-aromatic monocyclic heterocycle contain 1 to 3 heteroatoms selected from N, S, or O, * " represents a terminal bond to an alkyl carbon, B is C 4~6 a carbocycle or a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 and cycloalkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, or cycloalkyl is optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH, and —COOH.

[0010] In one embodiment of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the compound is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0011] [ka] During the ceremony, R1, R2, R3, and G are defined above for formula (I); Rc is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, halogenated C 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6 Alkoxyalkyl or halogenated C 1~4 It is an alkoxy.

[0012] In one embodiment of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the compound is a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof:

[0013] [ka] During the ceremony, R1, R2, R3, Z, and G are defined above for formula (I); Rc is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, halogenated C 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6 Alkoxyalkyl or halogenated C 1~4 It is an alkoxy.

[0014] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0015] [ka] is selected from one of the following:

[0016] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0017] [ka] is selected from one of the following:

[0018] In another embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is

[0019] [ka] is.

[0020] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0021] [ka] is selected from one of the following:

[0022] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0023] [ka] is selected from one of the following:

[0024] In yet another embodiment, the compound or pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0025] [ka] is selected from one of the following:

[0026] In still yet another embodiment, the compound or pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0027] [ka] is selected from one of the following:

[0028] The compounds and methods provided herein can be used to treat any disease in which altered DPP1 activity is thought to play a role. For example, in one embodiment, the method of treatment is a method of treating an obstructive disease of the airways, such as cystic fibrosis (CF), asthma, or bronchiectasis (e.g., non-CF bronchiectasis).

[0029] In another embodiment, the method of treatment is a method for treating chronic rhinosinusitis (CRS). In some embodiments, the method of treatment is a method for treating hidradenitis suppurativa (HS). In some embodiments, the method of treatment is a method for treating cancer. In some embodiments, the method of treatment is a method for treating lupus nephritis. In some embodiments, the method of treatment is a method for treating rheumatoid arthritis. In some embodiments, the method of treatment is a method for treating inflammatory bowel disease (IBD). In some embodiments, the method of treatment is a method for treating Granulomatosis with polyangiitis (GPA).

[0030] In yet another embodiment, the method of treatment is for giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture's disease), systemic sclerosis, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatosis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury. [Brief explanation of the drawings]

[0031] [Figure 1] Graph of percent inhibition of human DPP1 as a function of INSM-201 concentration, with IC50 indicated by the dashed line. [Figure 2] Graph of percent inhibition of mouse DPP1 as a function of INSM-201 concentration, with IC50 indicated by the dashed line. [Figure 3] Graph of percent inhibition of DPP1 in HL-60 cells as a function of INSM-201 concentration, with IC50 indicated by the dashed line. [Figure 4] Graph of percent inhibition of human DPP1 as a function of INSM-202 concentration, with IC50 indicated by the dashed line. [Figure 5] Graph of percent inhibition of mouse DPP1 as a function of INSM-202 concentration, with IC50 indicated by the dashed line. [Figure 6] Graph of percent inhibition of DPP1 in HL-60 cells as a function of INSM-202 concentration, with IC50 indicated by the dashed line. [Figure 7] Graph of percent inhibition of human DPP1 as a function of INSM-202 concentration, with IC50 indicated by the dashed line. [Figure 8] Graph of percent inhibition of mouse DPP1 as a function of INSM-203 concentration, with IC50 indicated by the dashed line. [Figure 9] Graph of percent inhibition of DPP1 in HL-60 cells as a function of INSM-203 concentration, with IC50 indicated by the dashed line. DETAILED DESCRIPTION OF THE INVENTION

[0032] term Unless specifically stated in the present invention, the terms of the present invention have the following meanings.

[0033] Carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen associated with the groups and compounds referred to in the present invention includes all isotopes thereof, and carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen associated with the groups and compounds referred to in the present invention is more preferably replaced by one or more of their corresponding isotopes, whereby the isotopes of carbon are12 C. 13 C, and 14 C, isotopes of hydrogen include protium (H), deuterium (deuterium is also called deuterohydrogen), and tritium (T, also called heavy hydrogen), and isotopes of oxygen include 16 O. 17 O, and 18 O, and sulfur isotopes are 32 S, 33 S, 34 S, and 36 Contains S, and nitrogen isotopes are 14 N and 15 Contains N, and the isotopes of fluorine are 19 Contains F, and the chlorine isotopes are 35 Cl and 37 Contains Cl, and the isotopes of bromine are 79 Br and 81 Contains Br.

[0034] In this document, "halogen" refers to F, Cl, Br, I, or an isotope thereof.

[0035] "Halogenated" or "halogen substituted" refers to substitution with one or more of the above F, Cl, Br, or I, or isotopes thereof, where the upper limit of the number of halogen substituents is equal to the total number of substitutable hydrogens, and unless otherwise defined, the number of halogen substituents is any integer from 1 to the upper limit, and when the number of halogen substituents is more than 1, substitution with the same or different halogens is possible. Conventionally, this includes 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, and 1 halogen substitution.

[0036] "Deuterium" refers to an isotope of hydrogen (H).

[0037] "Deuterated" refers to hydrogen atoms on an alkyl group, a cycloalkyl group, an alkylene group, an aryl group, a heteroaryl group, an alkenyl group, or an alkynyl group being deuterized with at least one isotope, and the upper limit of deuteration is equal to the total number of substitutable hydrogen atoms in the group to be substituted. Unless otherwise defined, the number of deuterations is any integer from 1 to the upper limit, preferably 1 to 20 deuterium atom substitutions, more preferably 1 to 10 deuterium atom substitutions, even more preferably 1 to 6 deuterium atom substitutions, and even more preferably 1 to 3 deuterium atom substitutions.

[0038] "C x~y " group refers to a group containing x to y carbon atoms, e.g., "C 1~6 "Alkyl" refers to an alkyl containing 1 to 6 carbon atoms.

[0039] "Alkyl" refers to a monovalent straight- or branched-chain saturated aliphatic hydrocarbon group, and unless otherwise specified, is an alkyl having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched-chain isomers thereof.

[0040] "Alkylene" refers to divalent straight and branched chain alkyl. Embodiments of alkylene include, but are not limited to, methylene and ethylidene.

[0041] "Halogenated alkyl" refers to a situation in which one or more hydrogen atoms in an alkyl are replaced by one or more halogen atoms (i.e., fluorine, bromine, iodine, or isotopes thereof), and the upper limit of the number of halogen substituents is equal to the total number of substitutable hydrogen atoms in the alkyl. Unless otherwise specified, the number of halogen substituents is any integer from 1 to the upper limit. Conventionally, alkyl has 1 to 5 halogen substitutions, or 1 to 3 halogen substitutions, or 1 to 2 halogen substitutions, or 1 halogen substitution. When the number of halogen substituents is more than 1, substitutions with the same or different halogens can occur, and specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, and CF3.

[0042] "Alkoxy" or "alkyloxy" refers to -O-alkyl, e.g., -OC 1~8 Alkyl, -OC 1~6 Alkyl, -OC 1~4 Alkyl or -OC 1~2 Alkyl. Specific non-limiting embodiments include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexoxy, cyclopropoxy, and cyclobutoxy, and the alkoxy can be optionally substituted.

[0043] "Halogenated alkoxy" refers to an -O-halogenated alkyl. For example, -O-halogenated C 1~8 Alkyl, -O-halogenated C 1~6 Alkyl, -O-halogenated C 1~4 Alkyl or -O-halogenated C 1~2The upper limit of halogen substituents is equal to the total number of substitutable hydrogen atoms in the substituted group, and unless otherwise defined, the number of halogen substituents is any integer from 1 to the upper limit, preferably 1 to 5 halogen substituents, 1 to 3 halogen substituents, 1 to 2 halogen substituents, or 1 halogen substituent. When the number of halogen substituents is more than 1, substitution with the same or different halogen atoms is possible, and non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, and difluoroethoxy.

[0044] "Alkylamine" or "alkanamine" refers to an ammonia group substituted with one or two alkyl groups, also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkylamine. Non-limiting examples include dimethylamine, monomethylamine, diethylamine, and monoethylamine.

[0045] "Alkenyl" refers to a straight or branched chain hydroxyl containing at least one carbon-carbon double bond (C=C), which conventionally contains 2 to 18 carbon atoms, e.g., 2 to 8 carbon atoms, as well as 2 to 6 carbon atoms, and even 2 to 4 carbon atoms, examples of which include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, Examples of alkenyl include 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the alkenyl can be optionally further substituted with any substituent.

[0046] "Ortho-alkenyl" refers to a straight or branched chain divalent unsaturated hydroxyl containing at least one carbon-carbon double bond (C=C), and unless otherwise specified, an ortho-alkynyl contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, a non-limiting example of which is ortho-ethynyl, and an alkenyl group can be optionally substituted with substituents.

[0047] "Alkynyl" means an alkyl group having at least one carbon-carbon triple bond.

[0048] [ka] and is conventionally a straight or branched chain hydroxyl of 2 to 18 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, or even 2 to 4 carbon atoms, examples of which include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl, wherein the alkynyl may be optionally substituted.

[0049] "Ortho-alkenyl" refers to a straight- or branched-chain, divalent, unsaturated hydroxyl containing at least one carbon-carbon double bond (C=C) and conventionally containing 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms; a non-limiting example is ortho-ethynyl; alkenyl groups can be optionally substituted with substituents. "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydroxyl containing no heterocyclic ring atoms. Cycloalkyl can be monocyclic, bicyclic, or polycyclic; bicyclic or polycyclic rings can be fused, spirocyclic, bridged, or combinations thereof; bicyclic or polycyclic rings can be composed of one or more aromatic rings, although the entire ring system is not aromatic and the binding site can be on an aromatic or non-aromatic ring. Conventionally, cycloalkyls contain 3 to 20 carbon atoms, can contain 3 to 8 carbon atoms, or can even contain 3 to 6 carbon atoms; when single monocyclic cycloalkyls are involved, they contain 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms; when bicyclic or polycyclic cycloalkyls are involved, they contain 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms.

[0050] "Carbocycle" or "carbocyclic" refers to a substituted or unsubstituted carbocyclic group, and includes mono- or bi-bridged, bi-fused, bi-spirocyclic, and poly-membered rings having three or more rings, conventionally having 3 to 14 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 6 to 8 carbon atoms, or 3 to 6 carbon atoms. In non-limiting embodiments, mono-ring carbocycles include bi-bridged, bi-fused, bi-spirocyclic, and the like, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.

[0051] "Heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, containing 1 to 5 heteroatoms selected from N, O, or S, unless otherwise specified, preferably 1 to 4 heteroatoms, more preferably 1 to 3 heteroatoms, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spiro heterocycles, as well as heterocycles having three or more rings. Preferably, these are 3- to 15-membered heterocycles, more preferably 4- to 14-membered heterocycles, more preferably 4- to 10-membered or 5- to 12-membered heterocycles, and even more preferably 5- to 8-membered or 5- to 6-membered heterocycles. The heterocycle is preferably a saturated heterocycle such as a 5- to 12-membered saturated heterocycle, more preferably a 5- to 8-membered saturated heterocycle, a 7-membered saturated heterocycle, or a 5- to 6-membered saturated heterocycle. The N or S ring atom of the heterocyclyl can be oxidized to various oxidation states. The heterocyclyl can be bonded to a heteroatom or a carbon atom, and non-limiting examples include glycidyl, azacyclic propyl, oxyheterocyclic butyl, azacyclic butyl, 1,3-dioxypentyl, 1,4-dioxypentyl, 1,3-dioxane, piperazinyl, azacyclic heptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidyl, piperidinyl, morpholinyl, thio-morpholinyl, 1,3-dithianyl, dihydrofuryl, and the like. Examples of aryl include aryl, dihydropyranyl, dithiopentyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantane, and oxaspiro[3.3]heptane.

[0052] "Ortho-heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclyl group.

[0053] "Aryl" refers to aromatic groups, including 5- and 6-membered monocyclic aromatic groups containing zero to four N, S, or O atoms, as well as polycyclic systems with at least one aromatic ring. Conceptually, this includes aromatic carbocyclic and heteroaromatic rings such as phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyridine, and polycyclic aromatic groups (tricyclic or bicyclic) such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxybenzene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Aryl in a ring structure containing heteroatoms is also known as a "heteroaromatic ring," "heteroaryl," or "heteroaromatic ring."

[0054] "Spirocycle" refers to a polycyclic group in which there are shared carbon atoms (referred to as spiroatoms) between the rings, which may contain zero to one or more double or triple bonds, and which may contain zero to five heteroatoms selected from N, O, S, P, or Si. Conventionally, spirocycles are 6- to 14-membered, or 6- to 12-membered, or 6- to 10-membered rings. Conventionally, spirocycles are spiro[3.3] (representing a three-membered spiro tricycle), spiro[3.4], spiro[3.5], spiro[3.6], spiro[4.4], spiro[4.5], spiro[4.6], spiro[5.5], or spiro[5.6].

[0055] "Fused ring" refers to a polycyclic group in which two adjacent atoms and one chemical bond are shared by the ring, which may contain one or more double or triple bonds, and the fused ring may contain 0 to 5 heteroatoms of N, S, O, P, or Si and their oxidation states. Conventionally, the fused ring is a 5 to 30-membered ring, or a 5 to 14-membered ring, or a 5 to 12-membered ring, or a 5 to 10-membered ring. Conventionally, the fused ring is a 3,4-cyclo (referring to the 3- and 4-membered rings that form the fused ring; according to the IUPC nomenclature, it may consist of a fused ring having a 3-membered ring or a 4-membered ring as the base ring, which also applies below), a 3,5-cyclo, a 3,6-cyclo, a 4,4-cyclo, a 4,5-cyclo, a 4,6-cyclo, a 5,5-cyclo, a 5,6-cyclo, and a 6,6-cyclo. Non-limiting examples of fused rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, where the fused ring is optionally substituted with any substituent.

[0056] A "bridged ring" refers to two rings that share two non-adjacent ring atoms, which may contain one or more double or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, or Si, and their oxidation states. Conventionally, the bridged ring has 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10 ring atoms.

[0057] "Substitution" or "substituent" refers to any substitution occurring at any chemically possible position, unless otherwise specified, and the number of substituents satisfies the rules of chemical bonding. Examples of substituents include, but are not limited to, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Heteroalkyl, C 5~12 Aryl, 5-12 membered heteroaryl, hydroxyl, C 1~6 Alkoxy, C 5~12 Aryloxy, thiol, C 1~6 Alkylthio, cyano, halogen, C 1~6 Alkylthiocarbonyl, C 1~6Alkaneamine formyl, N-carbazochrome, nitrile, methylsilyl, ortho-sulfonyl, sulfonyl, sulfoxide, halogenated C 1~6 Alkyl, halogenated C1-6 alkoxy, azyl, phosphonic acid, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -HC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, and -SO2C 1~6 Alkyl and the like.

[0058] "Pharmaceutically acceptable salts" refers to compounds of the present invention that retain the bioavailability and characteristics of the free acids or free bases, the free acids being obtained by reaction with non-toxic inorganic or organic alkalis, or the free bases being obtained by reaction with non-toxic inorganic or organic acids.

[0059] "Stereoisomer" refers to isomers resulting from different modes of spatial orientation of molecular atoms, and includes cis-trans isomers, enantiomers, and conformational isomers.

[0060] "Solvate" refers to a stoichiometric or non-stoichiometric substance resulting from the intermolecular bonding of the compounds of the present invention or their salts due to non-covalent forces. When the solvent is water, these are hydrates.

[0061] "Eutectic" refers to a crystal formed due to the effects of hydrogen or non-covalent bonds formed due to bonding between an active pharmaceutical ingredient (API) and a co-crystal former (CCF), whereby the pure states of the API and CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic crystals are a type of multi-component crystal; therefore, they include binary eutectics formed between a neutral solid and a salt or solvate.

[0062] As used herein, the symbols

[0063] [ka] (which may hereafter be referred to as a "point bond") represents a bond that is a point of attachment between two chemical entities, one of which is shown as being attached to the point bond and the other of which is not shown as being attached to the point bond. For example,

[0064] [ka] indicates that a chemical entity "XY" is attached to another chemical entity via a point-of-attachment bond. Furthermore, specific points of attachment to chemical entities not shown can be identified by inference. For example, R L But H or

[0065] [ka] The compound CH3-R L is R L If is "XY", the bond point is R L is inferred to be the same bond shown attached to CH3.

[0066] The compounds of Formula (I), (Ia), and (Ib), and pharmaceutically acceptable salts thereof, are dipeptidyl peptidase 1 (DPP1 or cathepsin C) inhibitors and may therefore be used in any disease area in which DPP1 plays a role. Accordingly, in one aspect of the present invention, methods of treatment are provided. In one embodiment, the method of treatment comprises administering to a subject in need of treatment a composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, for an administration period. In one embodiment, the subject's symptoms or clinical outcome are improved during or after the administration period, compared to the respective symptoms or clinical outcome measured before the administration period.

[0067] As used herein, "prior to the administration period" refers to the period from about 28 days prior to the first administration of a pharmaceutical composition or compound of Formula (I) provided herein to immediately prior to the first administration of a pharmaceutical composition or compound of Formula (I). In one embodiment, "immediately prior to the administration period" is from about 24 hours to about 1 minute prior to the first administration of a pharmaceutical composition or compound of Formula (I) provided herein.

[0068] In one embodiment, prior to the administration period is about 28 days prior to or immediately prior to the administration period. In another embodiment, prior to the administration period is about 21 days prior to or immediately prior to the administration period. In another embodiment, prior to the administration period is about 14 days prior to or immediately prior to the administration period. In yet another embodiment, prior to the administration period is about 10 days prior to or immediately prior to the administration period. In yet another embodiment, prior to the administration period is about 7 days prior to or immediately prior to the administration period. In yet another embodiment, prior to the administration period is about 4 days prior to or immediately prior to the administration period.

[0069] In one embodiment, "before the administration period" refers to about 28 days to about 1 day before the administration period. In another embodiment, "before the administration period" refers to about 21 days to about 1 day before the administration period. In another embodiment, "before the administration period" refers to about 14 days to about 1 day before the administration period. In yet another embodiment, "before the administration period" refers to about 10 days to about 1 day before the administration period. In yet another embodiment, "before the administration period" refers to about 7 days to about 1 day before the administration period. In yet another embodiment, "before the administration period" refers to about 4 days to about 1 day before the administration period.

[0070] As used herein, the terms "treatment," "treating," and "ameliorating," and variations thereof, are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement or effect on one or more diseases, conditions, or symptoms under treatment. In one embodiment, the term "treating" includes: (1) preventing or delaying the onset of clinical symptoms of a state, disorder, or condition that develops in a patient who may be afflicted with or predisposed to the state, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder, or condition; (2) inhibiting the state, disorder, or condition (e.g., halting, reducing, or delaying the onset of, or in the case of maintenance treatment, the recurrence of, at least one clinical or subclinical symptom thereof); or (3) alleviating the condition (e.g., by causing a regression or reduction in the severity of the state, disorder, or condition, or at least one of its clinical or subclinical symptoms).

[0071] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent that is sufficient to achieve a certain outcome, e.g., to bring about a beneficial or desired result. The therapeutically effective amount may vary depending on one or more of the subject and disease state being treated, the subject's weight and age, the severity of the disease state, the mode of administration, etc.

[0072] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, such as a mammal. A mammal can be, for example, a mouse, rat, rabbit, cat, dog, pig, sheep, horse, non-human primate (e.g., cynomolgus monkey, chimpanzee), or human. Also encompassed are subject tissues, cells, or derivatives thereof obtained in vivo or cultured in vitro. A human subject can be an adult, teenager, child (2-14 years), infant (1-24 months), or newborn (up to 1 month). In some embodiments, an adult is about 65 years of age or older, or elderly, about 60 years of age or older.

[0073] In one aspect, the present invention provides a method of treating a disorder associated with altered DPP1 activity in a subject in need thereof, comprising administering to the subject a composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for an administration period;

[0074] [ka] During the ceremony, G is a 5- to 12-membered carbocyclic ring, a 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, or O, or a ring represented by the formula

[0075] [ka] is a fused ring of L1 is bonded to G by replacing any hydrogen atom on G, and the bond, C 1~3 Alkylene, -NH-, -N(C 1~4 Alkyl)-, -O-, -S-, C 2~6 Ortho-alkenyl, C 2~6 ortho-alkynyl, -CO-, or -CONH-, wherein the alkylene, ortho-alkenyl, or ortho-alkynyl optionally contains 1 to 3 halogens, C 1~4 substituted with alkyl, cyano, hydroxyl, NH2, and -COOH groups; R1, R2, and R3 are independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH, or alternatively, R1 and R2 are C 3~6 Forming a cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the cycloalkyl or heterocycle is optionally ═O, halogen, cyano, hydroxyl, NH, COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; Y1 and Y2 are each independently selected from CR4 or N; Each R4 is independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1~4 Alkyl, N(C 1~4 Alkyl)2, COOH, COC 1~4 Alkyl, COOC 1~4 Alkyl, CONHC 1~4 Alkyl, CON(C 1~4 alkyl)2, NHCOC 1~4alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in R4 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; X1, X2, X3, and X4 are each independently selected from a bond, NR5, O, CR6R7, S, S(O), and S(O)2, and at most one of X1, X2, X3, and X4 is a bond; Rc is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, halogenated C 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6 Alkoxyalkyl or halogenated C 1~4 is an alkoxy, Each R5 is independently H, C 1~4 Alkyl, -COC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH, and COOH; R6 and R7 are each independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, cyano, hydroxyl, NH, COOH, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 groups optionally selected from deuterium, halogen, cyano, hydroxyl, NH, and —COOH; Alternatively, R6 and R7 form =O, or Alternatively, two R5 on adjacent ring atoms within X1, X2, X3, and X4, or two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms and the atoms bonded thereto, form a double bond, or Alternatively, R6 and R7 on the same carbon atom may be bonded to the carbon atom to which they are bonded. 3~12 Forms a carbocyclic ring or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, or O, and the carbocyclic ring or heterocyclic ring is not ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl, Z is CH or N; A,

[0076] [ka] a 6-atom heteroaryl or a 5- to 7-membered non-aromatic monocyclic heterocycle, wherein the heteroaryl and non-aromatic monocyclic heterocycle contain 1 to 3 heteroatoms selected from N, S, or O; B is C 4~6 a carbocycle or a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 and cycloalkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, or cycloalkyl is optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH, and —COOH.

[0077] In one embodiment of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the compound is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0078] [ka] During the ceremony, R1, R2, R3, and G are defined above for formula (I); Rc is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, halogenated C 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6 Alkoxyalkyl or halogenated C 1~4 It is an alkoxy.

[0079] In one embodiment of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the compound is a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof:

[0080] [ka] During the ceremony, R1, R2, R3, Z, and G are defined above for formula (I); Rc is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, halogenated C 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6 Alkoxyalkyl or halogenated C 1~4 It is an alkoxy.

[0081] Those skilled in the art can prepare the compounds of formula (I) based on known organic synthesis techniques, and the starting materials are commercially available chemicals and / or compounds mentioned in chemical literature. "Commercially available chemicals" are those that can be obtained from actual commercial sources, such as Titan, Energy Chemical, Shanghai Demo, Chengdu Chron Chemicals, Accela ChemBio Co., Ltd., Nanjing PharmaBlock, WuXi AppTec, and J&K Scientific.

[0082] Reference publications and monographs in this field either describe in detail the synthesis of the reagents used in the preparation of the compounds described herein or provide articles describing such preparation methods for reference. These reference books and monographs include "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2 nd Ed., Academic Press, New York, 1983, HOHouse, “Modern Synthetic Reactions”, 2 nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972, TLGilchrist, “Heterocyclic Chemistry”, 2 nd Ed., John Wiley&Sons, New York, 1992, J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4 thEd.,Wiley-Interscience,New York,1992、Fuhrhop and Penzlin.「Organic Synthesis:Concepts,Methods,Starting Materials」,Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5、Hoffman,R.V.「Organic Chemistry,An Intermediate Text」(1996)Oxford University Press,ISBN 0-19-509618-5、Larock,R.C.「Comprehensive Organic Transformations:A Guide to Functional Group Preparations」2 nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4、March,J.「Advanced Organic Chemistry:Reactions,Mechanisms,and Structure」4 th Edition(1992)John Wiley&Sons,ISBN:0-471-60180-2、Otera,J.(editor)「Modern Carbonyl Chemistry」(2000)Wiley-VCH,ISBN:3-527-29871-1、Patai,S.Patai’s 1992 Guide to the Chemistry of Functional Groups」(1992)Interscience ISBN:0-471-93022-9、Solomons,T.W.G.「Organic Chemistry」7 th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0、Stowell,J.C.,「Intermediate Organic Chemistry」2 ndEdition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopaedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, Vol. 8, "Organic Reactions" (1942-2000) John Wiley & Sons, Vol. 55, and "Chemistry of Functional Groups" John Wiley & Sons, Vol. 73.

[0083] Specific similar reagents can be selectively identified by accessing the CAS indexes of known chemicals compiled by the American Chemical Society; these indexes are accessible in most public and university libraries and online. Known chemicals in the list that cannot be purchased commercially can alternatively be made to order by chemical synthesis laboratories, and many of the standard chemical suppliers (e.g., those listed above) offer custom synthesis services. A reference publication for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0084] In one embodiment of the compounds of Formula (I), (Ia), or (Ib) for use in the methods provided herein, G is

[0085] [ka] is.

[0086] In one embodiment of the compounds of Formula (I), (Ia), or (Ib), G is

[0087] [ka] is.

[0088] In one embodiment of the compounds of Formula (I), (Ia), or (Ib), G is

[0089] [ka] (I-12).

[0090] In a preferred embodiment, G is

[0091] [ka] In a further embodiment, Rc is halogen, C 1~2 Alkyl, or C 1~2 In a further embodiment, Rc is methoxy or ethoxy. In yet another embodiment, Rc is hydroxyl.

[0092] In one embodiment, G is a substituted cyclopentane, cyclohexane, cycloheptane, or benzene,

[0093] [ka] is.

[0094] In one embodiment, G is

[0095] [ka] (I-21).

[0096] In one embodiment of the methods of treatment provided herein, in the compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, G is

[0097] [ka] In a further embodiment, G is:

[0098] [ka] It is one of them.

[0099] In one embodiment, G is

[0100] [ka] In a further embodiment, Rc is halogen, C 1~2 Alkyl, or C 1~2 In a further embodiment, Rc is methoxy or ethoxy. In yet another embodiment, Rc is hydroxyl.

[0101] In another embodiment, G is

[0102] [ka] In further embodiments, R, R, and R are each H. In still further embodiments, R is hydroxyl, C 1~4 Alkyl, or C 1~4 It is an alkoxy.

[0103] In some embodiments of the methods of treatment provided herein, the G moiety of formula (I), (Ia), or (Ib) is selected from one or more R G In a further embodiment, each RG are independently deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CONHC 3~6 Cycloalkyl, -CON(C 1~4 alkyl)2, -NHCOC 1~4 Alkyl, -NHCOC 3~6 Cycloalkyl, -P(O)(C 1~4 alkyl)2, -S(O)C 1~4 Alkyl, -S(O)2C 1~4 Alkyl, -S(O)2C 3~6 Cycloalkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl), -S(O)NH, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O, G is preferably deuterium, C 1~4 Alkyl, halogenated C 1~4 Alkyl, Hydroxyl C 1~4 Alkyl, -CONH2, NH2, C 1~6 Optionally substituted with 1 to 3 groups selected from alkoxy, hydroxyl, -COOH, halogen, and a 5- to 7-membered ring containing 1 to 3 heteroatoms selected from N, S, or O, and preferably the 5- to 7-membered heterocycle is optionally substituted with 1 to 2 groups selected from ═O, halogen, cyano, C 1~4 Alkyl or halogenated C 1~4 Optionally substituted with alkyl.

[0104] In one embodiment, G is one or more R GIn a further embodiment, each R G are independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN, wherein the methyl, ethyl, and propyl are optionally substituted with 1 to 3 groups selected from F, Cl, Br, and I.

[0105] In a further embodiment, Rc is halogen, C 1~2 Alkyl, or C 1~2 In a further embodiment, Rc is methoxy or ethoxy. In yet another embodiment, Rc is hydroxyl.

[0106] In one embodiment, R, R, and R are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein the alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 It is optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH.

[0107] In a preferred embodiment, each of R, R, and R is H. In a further embodiment, when a compound of formula (Ib) is used, Z is CH. In yet a further embodiment, R is halogen, C 1~2 Alkyl, or C 1~2 In still yet further embodiments, G is

[0108] [ka] is.

[0109] In another embodiment, R and R together with the carbon atom to which they are attached form a C 3~6Form a cycloalkyl or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O, wherein the cycloalkyl or heterocycle is selected from halogen, cyano, hydroxyl, NH, COOH, and C 1~4 and optionally substituted with 1 to 3 groups selected from alkyl.

[0110] In yet another embodiment, R, R, and R are each independently selected from H, deuterium, halogen, C 1~4 Alkyl, or C 1~4 alkoxy, wherein the alkyl and alkoxy are selected from halogen, C 1~4 It is optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH.

[0111] In yet another embodiment, R and R together with the carbon atom to which they are attached are C 3~6 Forms a cycloalkyl, which is substituted with halogen, cyano, hydroxyl, NH2, COOH, and C 1~4 optionally substituted with 1 to 3 groups selected from alkyl; In certain particular embodiments, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy is optionally substituted with 1 to 3 groups selected from F, Cl, Br, cyano, hydroxyl, and NH2.

[0112] In one embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein, L is a bond. In a further embodiment, R is hydroxyl, C 1~4 Alkyl, or C 1~4 In still further embodiments, Rc is hydroxyl, methoxy, ethoxy, methyl, ethyl, or propyl.

[0113] In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in one of the methods provided herein, L is a bond and G is

[0114] [ka] and Y1 and Y2 are both independently selected from CR4 or N, X1 is N, X2 is C(O), and X3 is O.

[0115] In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in one of the methods provided herein, A is

[0116] [ka] wherein r is an integer from 1 to 3 and E is NH, S, or O. In a further embodiment, A is

[0117] [ka] is.

[0118] In one preferred embodiment, A is

[0119] [ka] is.

[0120] In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in one of the methods provided herein, A is

[0121] [ka] is.

[0122] In one embodiment, the compound for use in one of the methods provided herein has the following structure:

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka] is selected from one of the following:

[0127] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0128] [ka] is selected from one of the following:

[0129] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0130] [ka] is selected from one of the following:

[0131] In yet another embodiment, the compound or pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0132] [ka] is selected from one of the following:

[0133] In a preferred embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is

[0134] [ka] is.

[0135] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0136] [ka] is selected from one of the following:

[0137] In one embodiment, the compound or a pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0138] [ka] is selected from one of the following:

[0139] In still yet another embodiment, the compound or pharmaceutically acceptable salt thereof for use in one of the methods provided herein is selected from the group consisting of:

[0140] [ka] is selected from one of the following:

[0141] Although the compounds of formula (I), (Ia), (Ib), or pharmaceutically acceptable salts thereof may be used on their own, they are generally administered in the form of a pharmaceutical composition in which the compounds / salts of formula (I), (Ia), (Ib) (active ingredients) are associated with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 2nd Ed. 2002.

[0142] In one aspect, the disclosure provides a method of treating a disorder associated with altered DPP1 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for an administration period; The compound of formula (I)

[0143] [ka] and The method is provided wherein the disorder associated with altered DPP1 activity is selected from rheumatoid arthritis, ulcerative colitis, chronic obstructive pulmonary disease (COPD), asthma, lupus nephritis, granulomatosis with polyangiitis (GPA), chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps, hidradenitis suppurativa (HS), or neutrophilic asthma.

[0144] In one aspect, the disclosure provides a method of treating a disorder associated with altered DPP1 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for an administration period; The compound of formula (I)

[0145] [ka] and The method is provided wherein the disorder associated with altered DPP1 activity is selected from rheumatoid arthritis, ulcerative colitis, lupus nephritis, granulomatosis with polyangiitis (GPA), chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps, chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps, hidradenitis suppurativa (HS), or neutrophilic asthma.

[0146] In embodiments, the present disclosure provides

[0147] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0148] In embodiments, the present disclosure provides a structure

[0149] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0150] In embodiments, the present disclosure provides a structure

[0151] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0152] In embodiments, the present disclosure provides a structure

[0153] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0154] In embodiments, the present disclosure provides a structure

[0155] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0156] In embodiments, the present disclosure provides a structure

[0157] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0158] In embodiments, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (Ia), (Ib), or a pharmaceutically acceptable salt thereof, as defined above, in association with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0159] The present disclosure further provides a process for the preparation of a pharmaceutical composition of the present disclosure, comprising mixing a compound of formula (I), (Ia), (Ib) as defined above, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0160] Pharmaceutical compositions may be administered topically (e.g., to the skin, or lungs, and / or airways), for example, in the form of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols, and dry powder formulations, for example, in inhaler devices known as Turbuhaler®, or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules, or parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) in the form of a sterile solution, suspension, or emulsion for injection, or rectally in the form of a suppository.

[0161] For oral administration, the compound of the present invention can be mixed with adjuvants, diluents or carriers, such as lactose, saccharose, sorbitol, mannitol; starches, such as potato starch, corn starch or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; disintegrants, such as cellulose derivatives, and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets.If coated tablets are required, the core prepared as described above can be coated with a suitable polymer dissolved or dispersed in water or a readily volatile organic solvent.Alternatively, tablets can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide.

[0162] For the preparation of soft gelatin capsules, the compounds of the present disclosure can be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules can contain granules of the compounds using pharmaceutical excipients such as those mentioned above for tablets.In addition, liquid or semi-solid formulations of the compounds of the present disclosure can be filled into hard gelatin capsules.

[0163] Liquid preparations for oral administration may be in the form of syrup, solution or suspension.The solution may contain, for example, the compound of the present disclosure, and the remainder is a mixture of sugar, ethanol, water, glycerol and propylene glycol.Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin and / or carboxymethylcellulose as a thickener.In addition, when preparing preparations for oral administration, other excipients known to those skilled in the art may be used.

[0164] The administered dosage will vary depending on the compound of Formula (I), (Ia), or (Ib) used, the mode of administration, and the desired therapeutic outcome. For example, in one embodiment, the daily dosage of a compound of Formula (I), (Ia), or (Ib) when inhaled may range from 0.05 micrograms per kilogram of body weight (μg / kg) to 100 micrograms per kilogram of body weight (μg / kg). Alternatively, in one embodiment, when a composition comprising a compound of Formula (I), (Ia), or (Ib) is administered orally, the daily dosage of a compound of the present disclosure may range from 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0165] Although the compounds of formula (I), (Ia), (Ib), or pharmaceutically acceptable salts thereof may be used on their own, they are generally administered in the form of a pharmaceutical composition in which the compounds / salts of formula (I), (Ia), (Ib) (active ingredients) are associated with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 2nd Ed. 2002.

[0166] Depending on the mode of administration, the pharmaceutical composition preferably contains 0.05-99% w (weight percent), more preferably 0.05-80% w, even more preferably 0.10-70% w, and even more preferably 0.10-50% w of the active ingredient, all weight percentages being based on the total composition.

[0167] For example, in one embodiment, a compound of the invention is administered to a patient in a method for treating an obstructive airway disease. In one embodiment, the obstructive airway disease is selected from the group consisting of asthma (e.g., bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin- and NSAID-induced and dust-induced asthma, both intermittent and persistent, and all severities), airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis (e.g., infectious bronchitis, eosinophilic bronchitis), emphysema, cystic fibrosis (CF), bronchiectasis (e.g., non-CF bronchiectasis), and bronchitis (e.g., non-CF bronchiectasis). bronchiectasis (NCFBE) and CF-associated bronchiectasis), cystic fibrosis; sarcoidosis; alpha-1 antitrypsin (A1AT) deficiency; farmer's lung and related diseases; hypersensitivity pneumonitis; pulmonary fibrosis (including idiopathic pulmonary fibrosis, fibrosing alveolitis of unknown cause, idiopathic interstitial pneumonia, fibrosis associated with anti-tumor therapy, and chronic infections including tuberculosis, aspergillosis, and other fungal infections); complications of lung transplantation; vasculitic and thrombotic disorders of the pulmonary vasculature; pulmonary hypertension antitussive activity, including the treatment of hypertension (e.g., pulmonary arterial hypertension), chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis including rhinitis medication, and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including rhinitis neuropathica (hay fever), nasal polyposis; acute viral infections, including the common cold, and infections caused by respiratory viruses (e.g., respiratory syncytial virus, influenza, coronaviruses (including SARS), and adenoviruses), acute lung injury, acute respiratory distress syndrome (ARDS), and exacerbations of each of the aforementioned airway disease states.

[0168] In one embodiment, the methods of treatment provided herein are used to treat cystic fibrosis (CF). CF is caused by abnormalities in the CF transmembrane conductance regulator protein, leading to chronic lung infections (particularly those caused by Pseudomonas aeruginosa) and excessive inflammation, resulting in bronchiectasis, decreased lung function, respiratory failure, and a reduced quality of life. The inflammatory process is governed by neutrophils, which produce NE, as well as other destructive NSPs, including CatG and PR3, which act directly on extracellular matrix proteins and are involved in the host response to inflammation and infection (Dittrich et al., Eur Respir J. 2018;51(3)). The methods provided herein use a reversible inhibitor of DPP1. Without wishing to be bound by theory, it is believed that the compounds of Formula (I), (Ia), and (Ib) administered via the methods provided herein have beneficial effects through inhibiting activation of NSPs and reducing inflammation, which in turn leads to fewer pulmonary exacerbations, a reduced pulmonary exacerbation rate, and / or improved pulmonary function (e.g., forced expiratory volume in 1 second, [FEV1]) in CF patients.

[0169] In one embodiment, a method for treating CF in a subject in need thereof is provided, comprising administering to a CF patient in need thereof an effective amount of a composition comprising a compound of Formula (I), (Ia), or (Ib) or a pharmaceutically acceptable salt thereof. Routes of administration include oral administration. The administration schedule and duration can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, administration is once daily. In another embodiment, administration is twice daily. In another embodiment, administration is every other day, every third day, three times per week, or four times per week.

[0170] In one method of treating CF, a composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib) or a pharmaceutically acceptable salt thereof is administered to a CF patient in need of treatment for a dosing period. The method includes improving the patient's pulmonary function during the dosing period compared to the patient's pulmonary function prior to the dosing period. In a further embodiment, the compound is administered orally once daily. In one embodiment, the improvement in pulmonary function is measured by spirometry.

[0171] In one embodiment, improving the patient's pulmonary function includes increasing the patient's forced forced expiratory flow in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow between 25% and 75% of the patient's FVC (FEFR), compared to the respective values ​​before the administration period. (25~75%) ) is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the respective value. In one embodiment, the increase is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In yet another embodiment, the increase is from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, or from about 5% to about 20%. In yet another embodiment, the increase is from about 10% to about 50%, from about 15% to about 50%, from about 20% to about 50%, or from about 25% to about 50%.

[0172] In one embodiment of the methods provided herein, a composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib) or a pharmaceutically acceptable salt thereof is administered to a patient with bronchiectasis in need of treatment for an administration period. Bronchiectasis is considered a pathological endpoint resulting from many disease processes and is a persistent or progressive condition characterized by dilated, thick-walled bronchi. Symptoms range from intermittent episodes of sputum and infection localized to affected lung areas to persistent daily expectoration of often copious amounts of purulent sputum. Bronchiectasis may be associated with other nonspecific respiratory symptoms. Without wishing to be bound by theory, the pathological process underlying bronchiectasis has been reported as damage to the airways resulting from an event or series of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V.65(Suppl 1), incorporated herein by reference in its entirety for all purposes).

[0173] Bronchiectasis is considered a pathological endpoint resulting from many disease processes and is a persistent or progressive condition characterized by dilated, thick-walled bronchi. Symptoms range from intermittent episodes of sputum and infection localized to affected lung areas to persistent daily expectoration, often of large amounts of purulent sputum. Bronchiectasis may be associated with other nonspecific respiratory symptoms. Without wishing to be bound by theory, the underlying pathological process of bronchiectasis has been reported as damage to the airways resulting from an event or series of events in which inflammation is central to the process ("Guideline for non-CF Bronchiectasis," Thorax, July 2010, Vol. 65 (Suppl 1), incorporated herein by reference in its entirety for all purposes).

[0174] The methods provided herein use reversible inhibitors of DPP1. Without wishing to be bound by theory, it is believed that the compounds of Formula (I), (Ia), and (Ib) administered via the methods provided herein have beneficial effects through reducing inflammation and mucus hypersecretion, which in some embodiments results in fewer pulmonary exacerbations, a reduced exacerbation rate, and / or improved lung function (cough, sputum production, and forced forced expiratory volume in one second [FEV1]) in patients with bronchiectasis. Without wishing to be bound by theory, it is believed that the methods provided herein alter the progression of bronchiectasis by reducing the rate of decline in lung function or accelerated destruction of lung tissue.

[0175] In one embodiment, the bronchiectasis is non-CF bronchiectasis.

[0176] In one embodiment, the method for treating bronchiectasis comprises improving the patient's pulmonary function during the administration period compared to the patient's pulmonary function before the administration period.

[0177] In one embodiment, the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited by the patient for at least 48 hours: (1) increased cough, (2) increased sputum volume or change in sputum consistency, (3) increased sputum purulence, (4) increased shortness of breath and / or decreased exercise tolerance, (5) fatigue and / or malaise, and (6) hemoptysis. In a further embodiment, the three or more symptoms result in a physician's decision to prescribe an antibiotic to the symptomatic patient.

[0178] In one embodiment of the method for treating bronchiectasis, the method comprises reducing the pulmonary exacerbation rate in the subject compared to the pulmonary exacerbation rate experienced by the subject prior to the administration period of the composition, or compared to a control subject with bronchiectasis who is not subjected to the method of treatment. In a further embodiment, the bronchiectasis is non-CF bronchiectasis.

[0179] In another aspect, a method for treating chronic rhinosinusitis (CRS) in a subject in need thereof is provided. In one embodiment, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, for an administration period.

[0180] The chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP) or chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the chronic sinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic sinusitis is refractory chronic rhinosinusitis. In some embodiments, the refractory chronic sinusitis is refractory chronic sinusitis without nasal polyps (CRSsNP). In some embodiments, the refractory chronic sinusitis is refractory chronic sinusitis with nasal polyps (CRSwNP).

[0181] 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) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced odor, (i) depression, (j) mucosal edema, (k) mucopurulent secretions, (l) obstruction of the middle nasal meatus, (m) mucosal changes in the ostiomeatal complex and sinuses, (n) rhinorrhea, or (o) any combination thereof. In some embodiments, the obstruction of the middle nasal meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0182] In some embodiments, administration of the pharmaceutical composition reduces, decreases 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 runny nose, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced odor, (i) depression, (j) mucosal edema, (k) mucopurulent secretions, (l) obstruction of the middle nasal meatus, (m) mucosal changes within the middle meatus ostium and sinuses, (n) rhinorrhea, (o), or any combination thereof. In some embodiments, administration of the pharmaceutical composition enhances sinus drainage.

[0183] In some embodiments, the method includes reducing a composite severity score of one or more symptoms of CRS. As used herein, a "composite severity score" is a quantitative measure of all symptoms of CRS exhibited by a subject. In some embodiments, the composite severity score is the sum of all daily symptoms exhibited by the subject. In some embodiments, the composite severity score is reduced during or after the administration period compared to the composite severity score measured before the administration period. In some embodiments, the one or more symptoms of CRS exhibited by the subject can be any symptom 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 odor, rhinorrhea, or any combination thereof. In some embodiments, the rhinorrhea is anterior rhinorrhea. In some embodiments, the rhinorrhea is posterior rhinorrhea.

[0184] In some embodiments, the method comprises reducing the subject's Sino-Nasal Outcome Test-22 (SNOT-22) score during or after the administration period, compared to the subject's SNOT-22 score before the administration period. As used herein, "SNOT-22" is a patient-reported outcome measure developed for use in CRS with or without nasal polyps, and includes 22 individual questions. The questions cover a wide range of health and health-related quality of life issues, including physical problems, functional limitations, and emotional consequences. The theoretical range of SNOT-22 scores is 0 to 110, with lower scores indicating 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 entire contents of which are incorporated herein by reference.

[0185] Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory disorder. Symptoms include skin lesions, often associated with hair follicles, which may be accompanied by pain, inflammation, and / or swelling. If the skin lesions heal, they may recur, potentially resulting in subcutaneous tunnels and progressive scarring. Because HS is a chronic condition, it can persist for many years and worsen over time, significantly impacting quality of life and psychological and emotional well-being. Indeed, HS patients have increased rates of anxiety and depression, with a suicide risk 2.5 times higher than that of the general population.

[0186] Patients with HS are classified as mild (Stage I), moderate (Stage II), or severe (Stage III) depending on the severity of the disease, called the Hurley stage. Although more than 200,000 cases of HS are diagnosed annually in the United States, the disease can be difficult to diagnose and requires specialized care. HS can be mistaken for infection, ingrown hairs, or other conditions. Furthermore, current treatment options are limited and lack effectiveness.

[0187] In one aspect, a method of treating HS in a subject in need thereof is provided. In one embodiment, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, for an administration period. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0188] In one embodiment, the HS 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.

[0189] In some embodiments, the disorder mediated by dipeptidyl peptidase 1 (DPP1) is granulomatosis with polyangiitis (GPA).

[0190] The present disclosure provides a method 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 present disclosure provides a method of treating cancer-induced pain in a subject with cancer, comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein for an administration period. In some embodiments, the cancer-induced pain is cancer-induced bone pain. The present disclosure also provides a method of treating cancer-induced bone pain in a subject with cancer, comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein for an administration period.

[0191] In some embodiments, the cancer comprises a primary solid tumor, hi some embodiments, the cancer is selected from the group consisting of bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, renal cancer, gastric cancer, skin cancer, fibroid cancer, lymphoma, virally induced cancer, oropharyngeal cancer, testicular cancer, thymic cancer, thyroid cancer, melanoma, and bone cancer.

[0192] 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 renal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibroid cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is virally induced cancer. In some embodiments, the cancer is oropharyngeal cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is thymic carcinoma. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, the fibroid cancer is leiomyosarcoma.

[0193] In some embodiments, breast cancer comprises ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, breast cancer comprises ductal carcinoma. In some embodiments, breast cancer comprises lobular carcinoma. In some embodiments, breast cancer comprises medullary carcinoma. In some embodiments, breast cancer comprises colloid carcinoma. In some embodiments, breast cancer comprises tubular carcinoma. In some embodiments, breast cancer comprises inflammatory breast cancer.

[0194] In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer does not respond to hormone therapy or therapeutic agents that target the HER2 protein receptor.

[0195] 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's 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's lymphoma. In some embodiments, the lymphoma is Kaposi's sarcoma.

[0196] 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.

[0197] In some embodiments, the cancer is a liquid tumor. In some embodiments, the liquid tumor is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorders, natural killer cell leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and 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 myeloid leukemia (CML). In some embodiments, the liquid tumor is mastocytosis. In some embodiments, the liquid tumor is chronic lymphocytic leukemia (CLL). In some embodiments, the liquid tumor is multiple myeloma (MM). In some embodiments, the liquid tumor is myelodysplastic syndrome (MDS).

[0198] In some embodiments, the cancer is a childhood cancer. In some embodiments, the childhood cancer is neuroblastoma, Wilms' tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, or Ewing's sarcoma. In some embodiments, the childhood cancer is neuroblastoma. In some embodiments, the childhood cancer is Wilms' tumor. In some embodiments, the childhood cancer is rhabdomyosarcoma. In some embodiments, the childhood cancer is retinoblastoma. In some embodiments, the childhood cancer is osteosarcoma. In some embodiments, the childhood cancer is Ewing's sarcoma.

[0199] In some embodiments, the cancer is metastatic cancer. In some embodiments, the subject is at risk of developing metastatic cancer. In some embodiments, the metastatic cancer comprises breast cancer metastasis to the brain, bone, pancreas, lymph nodes, and / or liver. In some embodiments, the metastatic cancer comprises bone cancer metastasis to the lung. In some embodiments, the metastatic cancer comprises colorectal cancer metastasis to the peritoneum, pancreas, stomach, lung, liver, kidney, and / or spleen. In some embodiments, the metastatic cancer comprises gastric cancer metastasis to the mesentery, spleen, pancreas, lung, liver, adrenal glands, and / or ovaries. In some embodiments, the metastatic cancer comprises leukemia metastasis to the lymph nodes, lung, liver, hind limb, brain, kidney, and / or spleen. In some embodiments, the metastatic cancer comprises liver cancer metastasis to the intestine, spleen, pancreas, stomach, lung, and / or kidney. In some embodiments, the metastatic cancer comprises lymphoma metastasis to the kidney, ovary, liver, bladder, and / or spleen.

[0200] In some embodiments, the metastatic cancer comprises hematopoietic cancer metastasis to the intestine, lung, liver, spleen, kidney, and / or stomach. In some embodiments, the metastatic cancer comprises melanoma metastasis to the lymph nodes and / or lung. In some embodiments, the metastatic cancer comprises pancreatic cancer metastasis to the mesentery, ovary, kidney, spleen, lymph nodes, stomach, and / or liver. In some embodiments, the metastatic cancer comprises prostate cancer metastasis to the lung, pancreas, kidney, spleen, intestine, liver, bone, and / or lymph nodes. In some embodiments, the metastatic cancer comprises ovarian cancer metastasis to the diaphragm, liver, intestine, stomach, lung, pancreas, spleen, kidney, lymph nodes, and / or uterus. In some embodiments, the metastatic cancer comprises myeloma metastasis to the bone.

[0201] In some embodiments, the metastatic cancer comprises lung cancer metastasis to bone, brain, lymph nodes, liver, ovaries, and / or intestines. In some embodiments, the metastatic cancer comprises kidney cancer metastasis to liver, lung, pancreas, stomach, brain, and / or spleen. In some embodiments, the metastatic cancer comprises bladder cancer metastasis to bone, liver, and / or lung. In some embodiments, the metastatic cancer comprises thyroid cancer metastasis to bone, liver, and / or lung.

[0202] In some embodiments, the methods disclosed herein include treating cancer-induced bone pain (CIBP) in a subject with cancer metastasis to bone. In some embodiments, the subject has prostate cancer, breast cancer, lung cancer, or myeloma metastasis to bone. In some embodiments, the subject has been identified as having bone metastasis using 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 has not yet experienced cancer-induced bone pain. In some embodiments, the subject is suffering from cancer-induced bone pain indicative of metastasis of a previously treated or untreated primary tumor to bone. In some embodiments, the cancer has metastasized to the vertebrae, pelvis, long bones, or ribs.

[0203] In some embodiments, administration of the composition reduces the severity of the cancer, delays the onset of the cancer, or eliminates a symptom of the cancer. In some embodiments, the symptom of the cancer is cancer-induced bone pain (CIBP). In some embodiments, the CIBP is neuropathic pain. In some embodiments, the CIBP is inflammatory pain. In some embodiments, the CIBP is spontaneous pain. In some embodiments, the symptom of the cancer is nociceptive hypersensitivity. In some embodiments, the symptom of the 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 metastases to bone.

[0204] In yet another embodiment of the present invention, there is provided a method for treating lupus nephritis (LN) in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, for an administration period.

[0205] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, along with effects on the underlying bone and cartilage. Currently, the cause of RA is unknown, and no satisfactory treatment for RA is available. While several therapeutic agents have been developed and utilized to alleviate the pain and inflammation associated with the disease, such as disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs), they often result in intolerable side effects. To address this and other needs, the present invention, in one embodiment, provides a method for treating RA using a reversible inhibitor of DPP1 of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating RA in a subject in need thereof is provided, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, for an administration period. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0206] Inflammatory bowel disease (IBD) is a group of inflammatory conditions that affect the colon and small intestine. The most common IBDs are Crohn's disease and ulcerative colitis. The present invention, in one embodiment, addresses the need for new IBD therapies. Specifically, in one embodiment, a method is provided for treating inflammatory bowel disease (IBD) in a subject in need thereof. The method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, for an administration period.

[0207] In a further embodiment, the IBD is Crohn's disease or ulcerative colitis. In yet a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0208] In any case, the length of the administration period will depend on the nature and severity of the condition being treated and / or prevented and can be determined by a physician, hi one embodiment, the administration period begins around the time of diagnosis of the condition / disease and continues for the life of the patient.

[0209] 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.

[0210] In some embodiments, the administration period of the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, or at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. In another embodiment, the administration period of the methods provided herein is from about 30 days to about 180 days. In another embodiment, the administration period is from about 30 days to about 36 months, or from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months.

[0211] In one embodiment, the administration period is about 1 year to about 30 years. For example, in one embodiment, the administration period is about 1 year to about 25 years, 1 year to about 20 years, about 1 year to about 15 years, about 1 year to about 10 years, about 1 year to about 5 years, about 1 year to about 3 years, about 1 year to about 2 years, about 2 years to about 15 years, about 2 years to about 10 years, about 2 years to about 8 years, about 2 years to about 5 years, about 2 years to about 4 years, or about 2 years to about 3 years.

[0212] In one embodiment of the method, the subject is administered the composition once a day during the administration period.In another embodiment, the patient is administered the composition twice a day, every other day, or once a week during the administration period.In another embodiment, the administration is every other day, every third day, three times a week, or four times a week during the administration period.

[0213] In a preferred embodiment, the oral dosage form is administered once daily during the administration period. In a further embodiment, the oral dosage form is administered at approximately the same time each day, for example, before breakfast. In another embodiment, an effective amount of a composition comprising Formula (I), (Ia), or (Ib) is administered twice daily during the administration period. In yet another embodiment, an effective amount of a composition comprising Formula (I), (Ia), or (Ib) 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.

[0214] Administration is via the oral route in one embodiment, hi a further embodiment, the composition is administered once daily. [Example]

[0215] The present disclosure is further illustrated by reference to the following examples, however, it should be noted that the examples, like the above embodiments, are illustrative and should not be construed as limiting the scope of the invention in any way.

[0216] Glossary of abbreviations: Burgess's Reagent: (Methoxycarbonylsulfamoyl)triethylammonium Hydroxide Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl DMF: N,N-dimethylformamide HATU: 2-7-Aza-1h-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate DIPEA: N,N-diisopropylethylamine LDA: lithium diisopropylamide PE: Petroleum ether EA: Ethyl acetate THF: tetrahydrofuran MeOH: Methanol DCM: dichloromethane TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0217] Example 1 - Prospective synthesis of compounds of formula (I) and key intermediates In one embodiment, INT-1: tert-butyl (S)-(1-cyano-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate is used as a reactant to obtain one of the compounds described herein.

[0218] [ka]

[0219] Compound 1a (for the preparation method, see WO 2013 / 041497) is dissolved in 1,4-dioxane, and pinacolborane, triethylamine, and Pd(dppf)Cl2 are added. The mixture is then reacted under microwave conditions at 100°C for 1 hour. After the reaction is completed, the mixture is filtered and the filtrate is concentrated. The residue is separated and purified by silica gel column chromatography (eluent ratio PE:EA (v / v) = 1:0 to 10:1) to obtain a white solid, INT-1.

[0220] In one embodiment, INT-2: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate is used as a reactant to obtain one of the compounds described herein.

[0221] [ka]

[0222] Compound 2a (2.0 g, 5.8 mmol, preparation method see WO 2016 / 016242) is dissolved in glycol dimethyl ether, and then bis(pinacolato)diboron is added, followed by potassium acetate and Pd(dppf)Cl2. The temperature is raised to 90°C and the reaction is continued for 3 hours. After the reaction is completed, the mixture is filtered, and the filtrate is concentrated. The resulting residue is separated and purified by silica gel column chromatography.

[0223] In one embodiment, (S)—N—((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 1) is synthesized according to the following scheme:

[0224] [ka]

[0225] Compound 1A (for synthetic methods, see International Publication No. 2016 / 016242, the entire contents of which are incorporated herein by reference) is dissolved in 1,4-dioxane and water. Then, intermediate 2a, potassium carbonate, and Pd(dppf)Cl2DCM are added and reacted at 90 ° C. for 3 hours. The mixture is cooled to room temperature, and then a saturated aqueous solution of sodium chloride is added. Ethyl acetate is used for extraction, and the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is separated and purified by silica gel column chromatography to obtain compound 1B as a white solid.

[0226] Compound 1B is dissolved in formic acid and allowed to react overnight at room temperature. After concentrating to dryness, ethyl acetate is added, and saturated aqueous sodium bicarbonate is added dropwise to adjust the pH to about 8, and the organic layer is separated. Extraction is then performed using ethyl acetate, and the organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1C as a pale yellow solid.

[0227] Compound 1C is dissolved in DMF. DIPEA, HATU, and INT-3 (preparation method according to International Publication No. 2015 / 110826, the entire contents of which are incorporated by reference) are added, and then the mixture is reacted at room temperature overnight. Saturated aqueous solution of ammonium chloride is added dropwise, extraction reaction is carried out, saturated aqueous solution of sodium chloride is added, ethyl acetate is used for extraction, the organic phase is washed with saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1D as a light yellow solid, which is directly used in the next reaction step.

[0228] Compound 1D is dissolved in formic acid and reacted at 50°C for 10 minutes. The product is concentrated to dryness, and ethyl acetate is added. Then, a saturated aqueous solution of sodium bicarbonate is added to adjust the pH to about 8, and the organic layer is separated. Ethyl acetate is used for extraction, and the organic phases are combined, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue is separated and purified, for example, by silica gel column chromatography.

[0229] In one embodiment, N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 2) is synthesized as follows.

[0230] [ka]

[0231] Compound 2A was dissolved in DCM and then CBr4 was added. PPh3 was then slowly added and the mixture was allowed to react at room temperature for 1 hour. PE / EA (v / v = 5:1) was added to the reaction mixture, followed by stirring and suction filtration. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 30:1 to 20:1) to obtain compound 2B as a white solid.

[0232] (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine is dissolved in THF (20 mL), the atmosphere is replaced with nitrogen, and the temperature is reduced to -78 °C. n-Butyllithium is added and the reaction is allowed to proceed for 1 hour. A THF solution of 2B (1.67 g, 5.97 mmol) is then added, and the reaction is continued at -78 °C for 2 hours. The reaction is then quenched using saturated NH4Cl solution, followed by extraction with ethyl acetate (EA). The organic phases are combined, washed with household salt water, dried over anhydrous sodium sulfate, concentrated, and then passed through a silica gel column (EA / PA (v / v) = 0% to 6%) to obtain compound 2C, which has a colorless oily appearance.

[0233] Compound 2C is dissolved in acetonitrile, then 1M HCl is added, and the mixture is allowed to react overnight at room temperature. The system is centrifuged and dried, and a saturated aqueous solution of sodium bicarbonate is added to neutralize the system to a weak alkaline state, and EA is added to perform liquid separation and extraction. The organic phases are combined, washed with saturated household salt water, dried over anhydrous sodium sulfate, and concentrated. The residue is separated and purified by silica gel column chromatography to obtain compound 2D.

[0234] Compound 2D is dissolved in DCM, triethylamine and di-tert-butyl dicarbonate ester are added, and the mixture is reacted at room temperature for 3 hours. Then, water is added to the system, and liquid separation extraction is carried out. The organic phase is combined, and the organic phase is washed with saturated household salt water, dried with anhydrous sodium sulfate, and concentrated. The residue is separated and purified by silica gel column chromatography to obtain compound 2E, which has a colorless oily appearance.

[0235] Compound 2E (0.7 g, 1.87 mmol) was dissolved in methanol and water, NaOH was added, and the mixture was allowed to react at room temperature for 2 hours. Then, the methanol was centrifuged, and the pH was adjusted to a weak acidic level using dilute hydrochloric acid. EA was added to carry out liquid separation and extraction, and the organic phase was centrifuged and dried to obtain compound 2F.

[0236] Compound 2F, NH4Cl, and HATU are dissolved in DMF, DIPEA is added, and the mixture is allowed to react at room temperature overnight. Water and EA are added, and the liquid is separated and extracted. The organic phase is dried over anhydrous Na2SO4 and concentrated to obtain the crude product compound 2G.

[0237] Compound 2G is dissolved in DCM, Burgess reagent is added, and the mixture is allowed to react at room temperature overnight. The mixture is centrifuged and concentrated, and the crude product is subjected to silica gel column chromatography separation and purification to obtain compound 2H.

[0238] Compound 2H, compound 1B, Pd(dppf)Cl2·DCM, and potassium carbonate were dissolved in 1,4-dioxane. The system was protected under nitrogen and reacted at 90 °C for 3 hours. The mixture was concentrated and centrifuged, then dissolved in DCM and filtered through diatomaceous earth with suction. The filtrate was centrifuged to dryness, and the crude product was subjected to silica gel column chromatography to obtain compound 2I as a pale yellow solid.

[0239] Compound 2I is dissolved in formic acid, and the mixture is stirred overnight at room temperature.DCM is added to the system to dilute, and saturated sodium bicarbonate solution is used to adjust the acidity to a mild level.Then, DCM is separated from water using liquid separation, and the organic phase is dried, concentrated, and centrifuged to obtain crude product compound 2J.

[0240] Compound 2J and INT-3 are dissolved in DMF, and HATU and DIPEA are added. The mixture is allowed to react overnight at room temperature. Water and EA are added to the reaction mixture for liquid separation and extraction. The organic phase is dried and concentrated to obtain a pale yellow oily crude product. This is then treated with MeOH / DCM (v / v) = 0-10% to obtain compound 2K.

[0241] 2K (90 mg, 0.16 mmol) is dissolved in formic acid (5 ml) and reacted at room temperature for 4 hours. DCM is added to dilute the system, and saturated sodium bicarbonate solution is used to adjust the system to a weak alkalinity. Then, DCM and water are separated into a liquid phase, and the organic phase is dried, concentrated, and centrifuged to dryness. This gives a residue, which is then separated and purified by silica gel column chromatography to give compound 2.

[0242] In one embodiment, (S)—N—((S)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 3) is synthesized according to the following scheme:

[0243] [ka]

[0244] Compound 3 is prepared from compound 3A according to the above method for preparing compound 2.

[0245] In one embodiment, (S)—N—((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 4) is synthesized according to the following scheme:

[0246] [ka]

[0247] Compound 4A is dissolved in acetonitrile, potassium carbonate (23 g, 94.32 mmol) and methyl iodide (2.96 ml, 47.16 mmol) are added, and the mixture is heated to 70° C. and stirred overnight. The reaction mixture is concentrated, and then extracted with DCM and water. The organic phase is dried, concentrated, and subjected to column chromatography separation to give compound 4B as a brown solid.

[0248] Compound 4B, palladium acetate, potassium acetate, XPHOS, and bis(pinacolato)diboron were mixed and dissolved in 1,4-dioxane. The mixture was heated to 95°C under a protective nitrogen atmosphere and reacted for 3 hours. After the completion of the reaction was confirmed by LCMS, the reaction mixture was concentrated and separated by column chromatography to obtain compound 4C as a pale yellow solid.

[0249] N-[(1S)-2-(5-thiophen-2-yl)-1-cyanoethyl]carbamic acid tert-butyl ester, compound 4C, potassium carbonate, and Pd(dppf)Cl₂·DCM are mixed and dissolved in 1,4-dioxane and water, heated to 120°C by microwave irradiation, and reacted for 1 hour. After the reaction is complete (e.g., as detected by LCMS), the reaction mixture is concentrated and subjected to column chromatography separation to obtain compound 4D as a pale yellow solid.

[0250] Compound 4D is added to formic acid and stirred at room temperature for 3 hours. After the completion of the reaction is confirmed by LCMS, saturated sodium carbonate solution is added to the reaction mixture to adjust the pH to 10, and then extracted with DCM. The organic phase is dried and concentrated to give compound 4E.

[0251] Compound 4E (119 mg, 0.4 mmol), INT-3 (98 mg, 0.4 mmol), HATU (180 mg, 0.48 mmol), and DIEA (0.13 mL, 0.8 mmol) were dissolved in DMF and stirred overnight at room temperature. After the completion of the reaction was confirmed by LCMS, water and EA were added, extraction was performed, and the organic phase was dried, concentrated, and subjected to column chromatography separation. This gave compound 4F as a yellow solid 4F.

[0252] Compound 4F is dissolved in formic acid and reacted at room temperature for 3 hours. After the completion of the reaction is detected by LCMS, the reaction solution is poured into saturated sodium carbonate solution and the pH is adjusted to 10. EA extraction is performed, and the organic phase is dried and concentrated, followed by separation and purification by silica gel column chromatography to obtain compound 4.

[0253] In one embodiment, (S)—N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 5) is synthesized according to the following scheme:

[0254] [ka]

[0255] In one embodiment, (S)—N—((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 6) is synthesized according to the following synthetic route:

[0256] [ka]

[0257] Compound 5A is dissolved in methanol, triethylamine is added, and then di-tert-butyl dicarbonate ester is added. The mixture is reacted at room temperature for 2 hours. The mixture is then concentrated and adjusted to pH 6-7 with dilute hydrochloric acid (1N). Dichloromethane is used for extraction, followed by repeated concentration. After separation and purification by silica gel column chromatography, compound 5B is obtained as a yellow solid.

[0258] Compound 5B is dissolved in DMF, and ammonium chloride, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, and DIPEA are added to the reaction vessel. The mixture is allowed to react at room temperature overnight. Water is then added, and ethyl acetate (EA) is used for extraction. The mixture is then washed with water, dried using anhydrous sodium sulfate, and concentrated. Separation and purification are then carried out by silica gel column chromatography. This gives compound 5C as a pale yellow solid.

[0259] Compound 5C is dissolved in dichloromethane. Burgess reagent is added in an ice bath and the reaction is continued for 2 hours. Water is added, and ethyl acetate is used for extraction. After drying and concentration with anhydrous sodium sulfate, separation and purification are carried out by silica gel column chromatography to obtain compound 5D as a pale yellow solid.

[0260] Compound 5D is dissolved in dioxane, and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzo[d]oxazole-2(3H), potassium carbonate, and Pd(dppf)Cl2 are added, followed by water. The mixture is heated to 100 °C in a microwave oven and reacted for 12 hours. The mixture is then concentrated, separated, and purified by silica gel column chromatography to give compound 5E as a yellow solid.

[0261] Compound 5E is dissolved in formic acid and reacted at room temperature for 3 hours. The pH is adjusted to 7-8 using a saturated aqueous solution of sodium carbonate, and dichloromethane is used for extraction. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. Concentration, separation, and purification are carried out by silica gel column chromatography. This gives compound 5F as a yellow solid.

[0262] Compound 5F is dissolved in DMF. HATU, DIEA, and (S)-4-(t-butyloxycarbonyl)-1-4-oxepane-2-carboxylic acid are added in that order, and the mixture is allowed to react at room temperature for 12 hours. Water is added, and ethyl acetate is used for extraction. The organic phases are combined, washed with water, then washed with saturated household salt water, and then dried with anhydrous sodium sulfate. Concentration, separation, and purification are carried out by silica gel column chromatography, thereby obtaining compound 5G as a yellow solid.

[0263] Compound 5G is dissolved in formic acid and reacted at room temperature for 3 hours. Then, the pH is adjusted to 7-8 using a saturated aqueous solution of sodium carbonate, and dichloromethane is used for extraction. The organic phases are then combined, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. Compound 5 is obtained by concentrating, separating, and purifying using silica gel column chromatography.

[0264] In one embodiment, (S)—N—((S)-1-cyano-2-(4-(1,1-dioxide-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 7) is synthesized according to the following synthetic route:

[0265] [ka]

[0266] Compound 7A (see, for example, the preparation method according to European Patent No. 3342765, the entire contents of which are incorporated herein by reference), INT-2, and Pd(dppf)Cl·DCM potassium carbonate (0.33 g, 2.43 mmol) are dissolved in 1,4-dioxane. Water is added, and the atmosphere is replaced three times using nitrogen. The mixture is then reacted at 90° C. under nitrogen for 4 hours. The reaction mixture is concentrated to dryness, and dichloromethane is added to dissolve the mixture. After filtration and concentration, the residue is separated and purified by silica gel column chromatography to obtain compound 7B as a white solid.

[0267] Compound 7B is dissolved in acetonitrile and p-toluenesulfonic acid is added. The mixture is reacted at room temperature for 16 hours and then filtered. The filter cake is then rinsed once with acetonitrile and centrifuged to dry. This gives compound 7C as a white solid.

[0268] INT-3 is dissolved in dichloromethane, and then triethylamine and HATU are added. The mixture is stirred at room temperature for 1 hour. Compound 7C is then added and the mixture is left at room temperature overnight. After the reaction is complete, the mixture is concentrated to obtain crude product 7D.

[0269] The crude product 7D is dissolved in acetonitrile, p-toluenesulfonic acid is added, and the mixture is reacted at room temperature for 16 hours, concentrated to dryness, and ethyl acetate is added. A saturated aqueous solution of sodium bicarbonate is added dropwise to adjust the pH to about 8, and the organic layer is separated. Ethyl acetate is used for extraction, and after combining, the organic layer is dried using anhydrous sodium sulfate, filtered, and concentrated. The residue is separated and purified by silica gel column chromatography to obtain compound 7.

[0270] In one embodiment, (S)—N—((S)-1-cyano-2-(3-fluoro-4′-(pentafluoro-16-sulfanyl)-[1,1′-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 8) is synthesized according to the following synthetic route:

[0271] [ka]

[0272] INT-2 is dissolved in dioxane, and 4-bromophenylsulfur pentafluoride, potassium carbonate, and Pd(dppf)Cl2 are added. Water is then added, and the reaction is carried out at 100 °C under nitrogen for 4 hours. Concentration, separation, and purification are carried out by silica gel column chromatography. This gives compound 8A.

[0273] Compound 8A is dissolved in acetonitrile. Then, p-toluenesulfonic acid is added and the mixture is reacted at 30°C for 2 hours. Water (30 ml) is added and the pH is adjusted to 7-8 using a saturated aqueous solution of sodium carbonate. Dichloromethane is used for extraction. The product is then washed with saturated household salt water, dried, and concentrated with anhydrous sodium sulfate to obtain compound 8B.

[0274] Compound 8B is dissolved in DMF. Then, HATU, DIPEA, and INT-3 are added sequentially, and the mixture is allowed to react at room temperature for 12 hours. Then, water is added, and ethyl acetate is used for extraction. The organic phases are combined, and then the organic phase is washed with water. Then, saturated household salt water is used for washing, and anhydrous sodium sulfate is used for drying. Concentration, separation, and purification are carried out by silica gel column chromatography, thereby obtaining compound 8C.

[0275] Compound 8C is dissolved in acetonitrile, p-toluenesulfonic acid (220 mg, 1.26 mmol) is added, and the mixture is reacted at 30 °C for 3 hours. The pH is adjusted to 7-8 using a saturated aqueous solution of sodium carbonate, and dichloromethane is used for extraction. The organic phases are then combined and washed with a saturated aqueous solution of sodium chloride. The product is then dried over anhydrous sodium sulfate. Concentration, separation, and purification by silica gel column chromatography are carried out to obtain compound 8.

[0276] In one embodiment, (S)—N—((S)-1-cyano-2-(3-fluoro-3′-(pentafluoro-16-sulfanyl)-[1,1′-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 9) is synthesized according to the following synthetic route:

[0277] [ka]

[0278] INT-2 is dissolved in dioxane, and 3-bromophenylsulfur pentafluoride, potassium carbonate, and Pd(dppf)Cl2 are added. Water is then added, and the mixture is reacted at 100°C under nitrogen for 4 hours. Concentration, separation, and purification are carried out by silica gel column chromatography. This gives compound 9A.

[0279] Compound 9A is dissolved in acetonitrile, p-toluenesulfonic acid is added, and the mixture is allowed to react at 30°C for 2 hours. Water is then added and the pH is adjusted to 7-8 using a saturated aqueous solution of sodium carbonate. Dichloromethane is used for extraction, and saturated household salt water is used for washing. The mixture is then dried over anhydrous sodium sulfate, followed by a concentration step. Compound 9B is then obtained.

[0280] Compound 9B is dissolved in DMF, and then HATU, DIEA, and INT-3 are added sequentially. The mixture is allowed to react at room temperature for 12 hours. Water is then added, and ethyl acetate is used for extraction. The organic phases are combined, washed with water, and then washed again with saturated household salt water. The mixture is dried over sodium sulfate and concentrated, followed by separation and purification by silica gel column chromatography. This gives compound 9C.

[0281] Compound 9C is dissolved in acetonitrile, p-toluenesulfonic acid is added, and the mixture is reacted at 30°C for 3 hours. The pH is adjusted to 7-8 using a saturated aqueous solution of sodium carbonate, and dichloromethane is used for extraction. The organic phases are then combined, washed with an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Concentration, separation, and purification are carried out by silica gel column chromatography to obtain compound 9.

[0282] In one embodiment, (S)—N—((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 10) is synthesized according to the following synthetic route.

[0283] [ka]

[0284] Compound 4A, INT-2, Pd(dppf)Cl2, and potassium carbonate are added sequentially to 1,4-dioxane and water. The atmosphere in the system is replaced with nitrogen three times, and then the mixture is reacted at 100 °C for 2 hours. After the reaction is completed, it is cooled to room temperature and water is added. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined and a saturated aqueous solution of sodium chloride is used for washing. The mixture is then dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under vacuum. The residue is separated using silica gel column chromatography, thereby obtaining compound 10A as a brown solid.

[0285] Compound 10A is dissolved in formic acid, then reacted at 50°C for 10 minutes, and concentrated to dryness. Ethyl acetate is added to the mixture, and a saturated aqueous solution of sodium bicarbonate is added dropwise to adjust the pH to about 8. The organic layer is separated, and the organic phase is extracted with ethyl acetate. The organic phases are combined and dried over anhydrous sodium sulfate. Filtration and concentration are carried out to obtain compound 10B.

[0286] Compound 10B is dissolved in DMF, and INT-3, diisopropylethylamine, and HATU are added. The mixture is allowed to react at room temperature for 1 hour. A saturated aqueous solution of sodium chloride is added, and ethyl acetate is used for extraction. The organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and then filtered and concentrated. The residue is separated by silica gel column chromatography. This process gives compound 10C as a pale yellow solid.

[0287] Compound 10C is dissolved in formic acid and reacted at 50°C for 10 minutes. After vacuum concentration, ethyl acetate is added, and then the pH is adjusted to about 8 using a saturated aqueous solution of sodium bicarbonate. The organic layer is separated, and ethyl acetate is used for extraction. The organic phases are then combined, and anhydrous sodium sulfate is used for drying. After filtration and concentration, the residue is separated and purified by silica gel column chromatography to obtain compound 10.

[0288] In one embodiment, (S)—N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 11) is synthesized according to the following synthetic route.

[0289] [ka]

[0290] Compound 11A, INT-2, Pd(dppf)Cl2, and potassium carbonate were placed in a single-neck flask, followed by the addition of 1,4-dioxane and water. The atmosphere was replaced with nitrogen three times, and the reaction was then carried out at 95 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated. Separation and purification by silica gel column chromatography were then carried out to obtain the title compound 11B as a white solid.

[0291] Compound 11B is dissolved in formic acid and reacted at 35°C for 4 hours. The reaction mixture is adjusted to alkaline using saturated potassium carbonate solution, and ethyl acetate is used for extraction, followed by drying with anhydrous sodium sulfate, filtration, and concentration to obtain compound 11C as a pale yellow oil.

[0292] Compound 11C is dissolved in DMF, INT-3, HATU, and DIPEA are added, and then the mixture is allowed to react overnight at room temperature after the addition is complete. Water is added to the mixture, and then ethyl acetate is used for extraction. After drying with sodium sulfate, filtration and concentration are carried out, and the mixture is separated and purified by silica gel column chromatography to obtain compound 11D, which is a white solid.

[0293] Compound 11D is dissolved in formic acid and reacted at 35°C for 4 hours. The reaction system is adjusted to alkaline using saturated potassium carbonate, and ethyl acetate is used for extraction, followed by drying with anhydrous sodium sulfate. Then, the mixture is filtered and concentrated. Separation and purification are carried out by silica gel column chromatography to obtain compound 11.

[0294] In one embodiment, (S)—N—((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 12) is synthesized according to the following synthetic route.

[0295] [ka]

[0296] Compound 12A is dissolved in 30% ammonium hydroxide and reacted at 35° C. for 24 hours. After cooling to room temperature, ethyl acetate is used for extraction, and the organic phases are combined and dried over anhydrous sodium sulfate. After filtration and concentration, compound 12B is obtained as a yellow solid.

[0297] Compound 12B is dissolved in dichloromethane, Burgess reagent is added, and the mixture is allowed to react overnight at room temperature. After concentration, separation and purification are carried out by silica gel column chromatography to obtain the title compound 12C as a white solid.

[0298] Compound 12C, INT-2, Pd(dppf)Cl, and potassium carbonate were added to a single-neck flask, followed by the addition of 1,4-dioxane and water. After three nitrogen atmosphere changes, the mixture was reacted at 95°C for 4 hours. The mixture was then cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain the title compound 12D as a yellow solid.

[0299] Compound 12D is dissolved in formic acid and reacted at 35° C. for 4 hours. The reaction system is adjusted to alkaline using saturated potassium carbonate solution, and ethyl acetate is used for extraction, followed by drying with anhydrous sodium sulfate, filtration, and concentration to obtain the title compound 12E as a pale yellow oil.

[0300] Compound 12E is dissolved in DMF, INT-3, HATU, and DIPEA are added, and then the mixture is allowed to react overnight at room temperature after the addition is complete. Water is added to the mixture, and then ethyl acetate is used for extraction. After drying with sodium sulfate, filtration and concentration are carried out, and the mixture is separated and purified by silica gel column chromatography to obtain the title compound 12F as a yellow solid.

[0301] Compound 12F is dissolved in formic acid and reacted at 35° C. for 4 hours. The reaction mixture is adjusted to a slightly alkaline state using saturated potassium carbonate solution, and ethyl acetate is used for extraction and anhydrous sodium sulfate is used for drying. After filtration and concentration, the mixture is separated and purified by silica gel column chromatography to obtain the title compound 12.

[0302] In one embodiment, (S)—N—((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 13) is synthesized according to the following synthetic route.

[0303] [ka]

[0304] INT-2 is dissolved in 1,4-dioxane, and bis(pinacolato)diboron, potassium acetate, and Pd(dppf)Cl2·DCM are added. The mixture is then heated to 100 °C and reacted for 2 hours after adding a protective nitrogen atmosphere. After cooling to room temperature, the mixture is filtered and concentrated. The residue is separated and purified by silica gel column chromatography to obtain compound 13B as a colorless liquid.

[0305] Compound 13B was dissolved in 1,4-dioxane and water, and 2-benzothiazole, Pd(dppf)Cl2·DCM (0.17 g, 0.20 mmol), and potassium carbonate were added. After adding nitrogen, the mixture was reacted at 90°C for 2 hours. The reaction was carried out at room temperature overnight. After concentrating to dryness, saturated aqueous ammonium chloride solution was added, and ethyl acetate was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain compound 13C as a pale yellow liquid.

[0306] Compound 13C is dissolved in formic acid and then reacted at 30°C for 3 hours. A saturated aqueous solution of sodium bicarbonate is added dropwise to adjust the pH to about 8, and ethyl acetate is used for extraction. The organic phases are combined, then dried over anhydrous sodium sulfate, then filtered and concentrated. This gives compound 13D as a colorless liquid.

[0307] Compound 13D is dissolved in dichloromethane, INT-1, diisopropylethylamine, and HATU are added, and the mixture is allowed to react overnight at room temperature. A saturated aqueous solution of sodium chloride is added, and ethyl acetate is used for extraction. The organic phase is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The product is filtered and concentrated, and the residue is separated and purified by silica gel column chromatography to obtain compound 13E as a pale yellow solid.

[0308] Compound 13E is dissolved in formic acid and reacted at 35° C. for 4 hours. Concentrate to dryness, add ethyl acetate, add saturated aqueous sodium bicarbonate to adjust pH to about 8, separate the organic layer, use ethyl acetate for extraction, combine the organic layers, use anhydrous sodium sulfate for drying, filter and concentrate, and the residue is separated and purified by silica gel column chromatography to obtain compound 13.

[0309] In one embodiment, (S)—N-((S)-1-cyano-2-(3-fluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 14) is synthesized according to the following synthetic route:

[0310] [ka]

[0311] Compound 14A, INT-2, potassium carbonate, and Pd(dppf)Cl2 are dissolved in 1,4-dioxane and water, the atmosphere is replaced with nitrogen three times, the temperature is raised to 95 °C, and reflux is performed for 3 hours. Then, it is filtered and the filter cake is washed with ethyl acetate. The filtrate is dried over anhydrous sodium sulfate and concentrated, and the resulting residue is subjected to separation and purification by silica gel column chromatography to obtain compound 14B as a brown solid.

[0312] Compound 14B is dissolved in formic acid and stirred overnight at room temperature. Water and dichloromethane are added, and the pH is adjusted to alkaline using sodium bicarbonate. The organic phase is separated, and the aqueous phase is extracted with dichloromethane. The organic phases are combined, then dried over anhydrous sodium sulfate, and concentrated. The resulting residue is separated and purified by silica gel column chromatography. This gives compound 14C as a brown oil.

[0313] Compound 14C, INT-3, HATU, and DIPEA are dissolved in dichloromethane and stirred at room temperature for 4 hours. The reaction mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated and dried over anhydrous sodium sulfate. The mixture is then concentrated, and the resulting residue is purified by silica gel column chromatography to obtain compound 14D as a yellow solid.

[0314] Compound 14D and 2,6-lutidine are dissolved in dichloromethane and stirred in an ice bath. TBDMS triflate is added dropwise to the flask. After the addition, the flask is removed from the ice bath and stirred at room temperature for 2 hours. The reaction mixture is washed with saturated sodium bicarbonate solution and the organic phase is separated. Anhydrous sodium sulfate is used for drying and concentration is carried out. After concentration, the residue is obtained, which is subjected to separation and purification by silica gel column chromatography. This gives compound 14.

[0315] In one embodiment, (S)—N—((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 15) is synthesized according to the following synthetic route.

[0316] [ka]

[0317] Compound 15A, INT-2, Pd(dppf)Cl2, and potassium carbonate are dissolved in a mixture of dioxane and water, and then reacted at 90°C under nitrogen for 5 hours. The reaction mixture is cooled to room temperature, and water is added. Ethyl acetate is then used for extraction. The organic layers are combined, washed with saturated sodium bicarbonate and saturated household salt water, and dried with anhydrous sodium sulfate. The reaction mixture is concentrated, and the residue is then separated and purified by silica gel column chromatography to obtain compound 15B.

[0318] Compound 15B is dissolved in formic anhydride and reacted at 50°C for 20 minutes. The reaction mixture is cooled to room temperature and concentrated to remove most of the solvent. Saturated sodium bicarbonate solution is added to the residue. Ethyl acetate is used for extraction, the organic layers are combined, and anhydrous sodium sulfate is used for drying, and the residue is concentrated. After concentration, the residue is then subjected to silica gel column chromatography separation and purification, thereby obtaining compound 15C.

[0319] INT-3 is dissolved in DMF, and HATU and DIPEA are added under nitrogen protection and stirred. Compound 15C is added and reacted at room temperature for 1 hour. Water is added to the reaction mixture, and ethyl acetate is used for extraction. The organic layers are combined and dried over anhydrous sodium sulfate. Then, the mixture is concentrated. After concentration, the residue is subjected to silica gel column chromatography separation and purification to obtain compound 15D.

[0320] Compound 15D is dissolved in formic acid and reacted at 50°C for 30 minutes. Concentrate to dryness, add ethyl acetate, add saturated aqueous sodium bicarbonate to adjust pH to about 8, separate organic layer, use ethyl acetate for extraction, combine organic phases, use anhydrous sodium sulfate for drying, then filter and concentrate, and the residue is separated and purified by silica gel column chromatography to obtain compound 15.

[0321] In one embodiment, (S)—N—((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 16) is synthesized according to the following synthetic route.

[0322] [ka]

[0323] Compound 16A, INT-2, Pd(dppf)Cl2·DCM, and potassium carbonate are dissolved in 1,4-dioxane. Water is added, and the atmosphere is replaced with nitrogen three times. The mixture is then reacted at 90 °C under nitrogen for 4 hours. The reaction mixture is concentrated to dryness, and dichloromethane is added to dissolve the mixture, followed by filtration and concentration. The residue is then purified by silica gel column chromatography to give the title compound 16B as a white solid.

[0324] Compound 16B is dissolved in acetonitrile, and p-toluenesulfonic acid monohydrate is added, and they are reacted at room temperature for 16 hours, and then filtered. The filter cake is rinsed once with acetonitrile, and the filter cake is centrifuged and dried. This gives compound 16C.

[0325] Compound INT-3 is dissolved in dichloromethane, then triethylamine and HATU are added, and the mixture is stirred at room temperature for 1 hour, and then compound 16C is added and the mixture is left at room temperature overnight. After the reaction is completed, the mixture is concentrated to obtain crude product 16D.

[0326] Compound 16D is dissolved in acetonitrile and p-toluenesulfonic acid monohydrate is added. The mixture is reacted at room temperature for 16 hours, concentrated to dryness, and ethyl acetate is added. Then, a saturated aqueous solution of sodium bicarbonate is added dropwise to adjust the pH to about 8. The organic layer is separated, and ethyl acetate is used for extraction. The organic phases are combined and then dried using anhydrous sodium sulfate, followed by filtration and concentration. The resulting residue is purified to obtain the title compound 16.

[0327] In one embodiment, (S)—N-((S)-1-cyano-2-(4′-cyano-3′-cyclopropyl-3-fluoro-[1,1′-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 17) is synthesized according to the following synthetic route.

[0328] [ka]

[0329] Compound 17A, INT-2, Pd(dppf)Cl2·DCM, and potassium carbonate were dissolved in 1,4-dioxane, water was added, and the atmosphere was replaced with nitrogen three times. The mixture was reacted at 100 °C under nitrogen for 16 hours. The reaction mixture was concentrated to dryness and dissolved in dichloromethane. After filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain compound 17B as a white solid.

[0330] Compound 17B is dissolved in acetonitrile, p-toluenesulfonic acid monohydrate is added, and the mixture is allowed to react at room temperature for 16 hours. Upon completion, the reaction is filtered, and the filter cake is then rinsed once with acetonitrile. The filter cake is centrifuged to dryness, thereby obtaining compound 17C as a white solid.

[0331] INT-3 is dissolved in dichloromethane, and then triethylamine and HATU are added. The mixture is stirred at room temperature for 1 hour. Compound 17C is added and the mixture is left at room temperature overnight. After the reaction is complete, the mixture is concentrated and the product 17D is used directly in the next reaction step.

[0332] Product 17D is dissolved in acetonitrile, p-toluenesulfonic acid monohydrate is added, and the mixture is reacted at room temperature for 16 hours. The mixture is concentrated to dryness, ethyl acetate is added, and saturated aqueous sodium bicarbonate solution is added dropwise to adjust the pH to about 8. The organic layer is separated, and ethyl acetate is used for extraction. After combining, the organic layer is dried using anhydrous sodium sulfate, filtered, and concentrated. The residue is separated and purified by silica gel column chromatography. This gives the title compound 17.

[0333] In one embodiment, (S)—N—((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 30) is synthesized according to the following synthetic route.

[0334] [ka]

[0335] Compound 30A, INT-2, Pd(dppf)Cl2, and potassium carbonate are added sequentially to 1,4-dioxane and water. The atmosphere in the system is replaced with nitrogen three times. The mixture is then reacted at 100 °C for 2.5 hours. After the reaction is complete, it is cooled to room temperature and water is added. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined and washed with a saturated aqueous solution of sodium chloride. The mixture is dried over anhydrous sodium sulfate and filtered, and the filtrate is concentrated under vacuum. The residue is separated using silica gel column chromatography to obtain compound 30B.

[0336] Compound 30B is dissolved in formic acid, reacted at 50°C for 10 minutes, and concentrated to dryness. Ethyl acetate is then added, and saturated aqueous sodium bicarbonate is added dropwise to adjust the pH to about 8. The organic layer is separated and extracted with ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate, then filtered and concentrated to obtain compound 30C.

[0337] Compound 30C is dissolved in N,N-dimethylformamide, and INT-3, triethylamine, and HATU are added, and then the mixture is reacted at room temperature for 1 hour. Saturated aqueous sodium chloride solution is added, and ethyl acetate is used for extraction. The organic phase is washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by silica gel column chromatography to obtain compound 30D.

[0338] Compound 30D is dissolved in formic acid and reacted at 50° C. for 10 minutes. Vacuum concentration is carried out, ethyl acetate is added, and then saturated aqueous sodium bicarbonate solution is used to adjust the pH to about 8. The organic layer is separated, and dichloromethane is used for extraction. Then the organic layers are combined and dried with anhydrous sodium sulfate. After filtration and concentration, the residue is separated and purified by silica gel column chromatography to obtain compound 30.

[0339] In one embodiment, (S)—N—((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 31) is synthesized according to the following synthetic route.

[0340] [ka]

[0341] Compound 30A is dissolved in dry N,N-dimethylformamide and cooled to 0 ° C under nitrogen protection. Sodium hydride is added in batches. After the addition is complete, the mixture is allowed to react for 20 minutes, and methyl iodide is added dropwise to the system. After the addition of methyl iodide is complete, the reaction is allowed to proceed at room temperature for 30 minutes. Water is added to quench the reaction, and ethyl acetate is used for extraction. The organic phases are then combined, washed with saturated household brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under vacuum. The residue is subjected to silica gel column chromatography to obtain compound 31A.

[0342] Compound 31A, INT-2, Pd(dppf)Cl2, and potassium carbonate are added sequentially to 1,4-dioxane and water, and the atmosphere in the system is replaced with nitrogen three times. Then, they are reacted at 100 °C for 2 hours. After the reaction is completed, it is cooled to room temperature, water is added, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, and a saturated aqueous solution of sodium chloride is used for washing. Then, it is dried over anhydrous sodium sulfate and filtered, and the filtrate is concentrated under vacuum. The residue is separated using silica gel column chromatography to obtain compound 31B.

[0343] Compound 31B is dissolved in formic acid, then reacted at 50°C for 10 minutes, concentrated to dryness, and ethyl acetate is added. A saturated aqueous solution of sodium bicarbonate is added dropwise to adjust the pH to about 8, the organic layer is separated, the organic layer is extracted with ethyl acetate, and the organic layers are combined and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain compound 31C.

[0344] Compound 31C is dissolved in N,N-dimethylformamide, and INT-3, triethylamine, and HATU are added, and then the mixture is reacted at room temperature for 1 hour. Saturated aqueous sodium chloride solution is added, and ethyl acetate is used for extraction. The organic phase is washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by silica gel column chromatography to obtain compound 31D.

[0345] Compound 31D is dissolved in formic acid and reacted at 50°C for 10 minutes. Vacuum concentration is carried out, and ethyl acetate is added. Then, the pH is adjusted to about 8 using a saturated aqueous solution of sodium bicarbonate, the organic layer is separated, and dichloromethane is used for extraction. Then, the organic phases are combined and dried with anhydrous sodium sulfate. After filtration and concentration, the residue is separated and purified by silica gel column chromatography to obtain compound 31.

[0346] In one embodiment, (S)—N—((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)—N—((R)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 33 and Compound 34) are synthesized according to the following synthetic route:

[0347] [ka]

[0348] 5-Bromo-2-picoline (compound 33A) is dissolved in tetrachloromethane, and N-bromosuccinimide and azodiisobutyronitrile are added, followed by reaction at 90° C. for 2.5 hours. The product is cooled to room temperature, the reaction mixture is concentrated, and the residue is separated and purified to obtain compound 33B.

[0349] Compound 33B and N-(diphenylmethylene)aminoacetonitrile are dissolved in dichloromethane, and benzyltrimethylammonium chloride is added. Then, an aqueous solution of sodium hydroxide is added with vigorous stirring, and the reaction is carried out overnight at room temperature. Water is added, and dichloromethane is used for extraction. The organic layers are combined and dried over anhydrous sodium sulfate. After concentration, the residue is separated and purified, for example, by silica gel column chromatography.

[0350] Compound 33C, compound 1A, Pd(dppf)Cl2, and potassium carbonate are dissolved in a mixture of dioxane and water, and then reacted for 5 hours under nitrogen protection at 90°C. The product is cooled to room temperature, water is added, ethyl acetate is used for extraction, the organic layers are combined, saturated sodium bicarbonate and saturated household salt water are used for washing, and anhydrous sodium sulfate is used for drying. After concentration, the residue is separated and purified, for example, by silica gel column chromatography.

[0351] Compound 33D is then dissolved in tetrahydrofuran and water (5 ml), and 2.5 ml of 1 M HCl aqueous solution is added dropwise, and the reaction is then carried out at room temperature for 5 hours. Diethyl ether (15 ml x 3) is used to extract the reaction solution and discarded, and the pH of the aqueous layer is adjusted to about 12, and DCM is used for extraction. The organic layers are combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound 33E, which is used directly in the next step without further purification.

[0352] Compound 33E was dissolved in dichloromethane, and DIPEA, HATU, and intermediate INT-3 were added sequentially. The mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, water was poured into the reaction mixture, and layering occurred. The organic phase was washed sequentially with water and saturated household salt water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which appeared as a yellow oil. The crude product was purified to give 33F, a white solid.

[0353] Compound 33F is dissolved in dichloromethane, TMSOTf is added, and 2,6-lutedine is slowly added dropwise using an ice bath. The temperature is then raised to room temperature and the reaction is allowed to proceed for 1 hour. The reaction mixture is poured into a saturated aqueous solution of ammonium chloride, and dichloromethane is used for extraction. The organic phase is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the product is concentrated. Compound 33G is then obtained by purification, for example, by column chromatography and separation.

[0354] Supercritical fluid chromatography (SFC) chiral separation is performed on compound 33G to give compounds 33 and 34.

[0355] In one embodiment, N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (compound 43) is synthesized according to the following scheme.

[0356] [ka]

[0357] Compound 43A (prepared according to Eur. J. Org. Chem. 2007, 2107-2113 DOI: 10.1002 / ejoc.200700011) is dissolved in tetrahydrofuran at 0°C. Sodium hydride is then added and the mixture is stirred for 30 minutes. Methyl iodide is then added and the reaction is carried out at room temperature for 3-4 hours. Water is then added at 0°C, followed by extraction with ethyl acetate (EA), followed by washing with saturated household brine, followed by drying with anhydrous sodium sulfate, and then concentration to obtain 43B, a colorless oil.

[0358] Compound 43B is dissolved in methanol, magnesium turnings are added, and the mixture is sonicated at 50° C. for 2 hours, then allowed to react at room temperature for 16 hours. The product is then filtered and concentrated to give 43C as a white oil, which is used directly in the next step.

[0359] Compound 43C was dissolved in DCM, and triethylamine (0.087 g, 0.85 mmol) and TBSCl (0.37 g, 1.71 mmol) were added sequentially. The mixture was reacted at room temperature under nitrogen for 2 hours, then concentrated to dryness and purified by column chromatography (PE:EA = 10:1 to 4:1) to give colorless oily substance 43D (0.12 g, 47% yield).

[0360] Compound 43D is dissolved in methanol, Pd / C is added, the mixture is reacted under hydrogen atmosphere for 24 hours, filtered and concentrated to dryness, and then a colorless oily substance, Compound 43E, is obtained.

[0361] 43E is dissolved in acetone. Saturated sodium bicarbonate, sodium bromide, and TEMPO are then added. Trichloroisocyanuric acid is added at 0°C. The reaction is allowed to proceed for 16 hours. Dilute hydrochloric acid is added to adjust the pH to 5-6. Water is added, and dichloromethane is used for extraction. The mixture is washed with water and then with saturated sodium chloride. Anhydrous sodium sulfate is used for drying, and the mixture is then concentrated to obtain 43F, a yellow oil.

[0362] Compound 8B, compound 43F, HATU, and DIEA are mixed with DMF, dissolved, and stirred overnight. After the reaction is completed, water is added, and EA is used for extraction. The organic phase is then dried, concentrated, and subjected to column chromatography separation to obtain compound 43G.

[0363] Compound 43g was dissolved in acetonitrile, p-toluenesulfonic acid was added, and the mixture was heated to 40°C and reacted for 2 hours. After the reaction was completed, the reaction solution was concentrated, and a saturated aqueous solution of EA and sodium bicarbonate was added for extraction. The liquid was separated, and the organic phase was dried, concentrated, and separated by column chromatography to obtain the title compound 43.

[0364] Example 2 - Preparation of Certain Intermediates For Examples 2 to 5, 1H NMR and LC / MS analyses were carried out as follows unless otherwise indicated.

[0365] 1 H NMR analysis: 1H-NMR spectra were recorded on a Bruker Ultrashield (400 MHz). The multiplicities of the signals are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet.

[0366] All observed coupling constants J are reported in Hertz (Hz).

[0367] Exchangeable protons are not always observed.

[0368] LC / MS analysis: LC / MS method AN01_001_012: LC-MS data were generated using a Waters Acquity system: TUV detector, SQD2 MS detector, Sedere SEDEX 80 (light scattering detector). LC-MS method: Reversed phase HPLC analysis Column: Agilent Cortex C18 Solvent A: Water containing formic acid (0.1% V / V) Solvent B: Acetonitrile

[0369] [Table 1]

[0370] LC / MS method AN01_001_026: LC-MS data were generated using a Waters Acquity system: TUV detector, SQD2 MS detector, Sedere SEDEX 80 (light scattering detector). LC-MS method: Reversed phase HPLC analysis Column: Agilent: Poroshell Solvent A: Water containing formic acid (0.1% V / V) Solvent B: Acetonitrile

[0371] [Table 2]

[0372] UV detection: 220 nm Chiral SFC purity analysis conditions: Column details: Chiralpak OD-3 (4.6 x 100 mm) Column temperature: 35℃ Flow rate: 3.5mL / min Detector wavelength: 220 to 410 nm Injection volume: 2μL BPR: 1500 PSI Isocratic conditions: i-PrOH:CO2, 30:70 Synthetic scheme for the preparation of intermediate B1-2-4 & intermediate B1-2-6

[0373] [ka]

[0374] Experimental procedure tert-Butyl N-[(2S)-2,3-dihydroxypropyl]carbamate B1-2-2

[0375] [ka]

[0376] To a solution of (2S)-3-aminopropane-1,2-diol (1 equiv., 14.4 g, 158.1 mmol) and EtN (1.01 equiv., 22.2 mL, 159.6 mmol) in anhydrous MeOH (245 mL) was added a solution of BocO (1.2 equiv., 41.4 g, 189.7 mmol) in anhydrous DCM (41 mL) under an argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to give B1-2-2 as a pale yellow oil (30.2 g, quantitative). The crude product was considered quantitative and was used as is.

[0377] LC / MS (AN01_001_012): Rt=1.69 min, non-UV active, [M+Na]+ =214.1.

[0378] Concentration under reduced pressure gave B1-2-2 as a pale yellow oil (30.2 g, quantitative). The crude product was deemed quantitative and was used as is.

[0379] LC / MS (AN01_001_012): Rt=1.69 min, non-UV active, [M+Na] + =214.1.

[0380] tert-Butyl N-[(2S)-3-[(tert-butyldimethylsilyl)oxy)-2-hydroxypropyl]carbamate B1-2-15

[0381] [ka]

[0382] To a solution of B1-2-2 (1 equiv., 10.0 g, 47.6 mmol) and EtN (1.2 equiv., 7.94 mL, 57.1 mmol) in anhydrous DCM (76 mL) was added TBDMSCl (1.1 equiv., 7.90 g, 52.4 mmol) and DMAP (0.05 equiv., 0.290 g, 2.38 mmol) under an argon atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The resulting mixture was diluted with DCM (50 mL) and water (150 mL), and the two layers were separated. The aqueous layer was extracted with DCM (2 × 50 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (220 g, gradient: 100:0 to 65:35 cyclohexane / EtOAc) to afford B1-2-15 as a colorless oil (12.4 g, 86%).

[0383] LC / MS (AN01_001_012): Rt=2.68 min, non-UV active, [M-C4H8+H] + =250.2.

[0384] tert-Butyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methylidene-1,4-oxazepane-4-carboxylate B1-2-4

[0385] [ka]

[0386] To a suspension of 60% NaH in oil (2.1 equiv., 1.65 g, 41.3 mmol) in anhydrous DMF (35 mL) was added 3-chloro-2-chloromethyl-1-propene (1 equiv., 2.27 mL, 19.6 mmol) under an argon atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, after which a solution of B1-2-15 (1 equiv., 6.00 g, 19.6 mmol) in THF (24 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with water (150 mL) and extracted with EtO (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (220 g, gradient: 100:0 to 91:9 cyclohexane / EtOAc) to afford B1-2-4 as a colorless oil (1.90 g, 27%).

[0387] LC / MS(AN01_001_012): Rt=3.17 min, 88%, [M-C5H8O2+H] + =258.2.

[0388] tert-Butyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-oxo-1,4-oxazepane-4-carboxylate B1-2-5

[0389] [ka]

[0390] To a solution of B1-2-4 (1 equiv., 880 mg, 2.46 mmol) in a mixture of DCM (15 mL) and acetonitrile (15 mL), 2,6-lutidine (2 equiv., 0.570 mL, 4.92 mmol), water (22 mL), and sodium periodate (4 equiv., 2.10 g, 9.84 mmol) were added sequentially at room temperature. A solution of RuCl3·3H2O (0.035 equiv., 22.5 mg, 0.086 mmol) in water (2.5 mL) was then added dropwise, and the resulting brown suspension was vigorously stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (40 g, gradient: 100:0 to 90:10 cyclohexane / EtOAc) to afford B1-2-5 as a colorless oil (737 mg, 83%).

[0391] LC / MS(AN01_001_012): Rt=3.02 min, 100%, [M-C4H8+H] + =304.1.

[0392] tert-Butyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-1,4-oxazepane-4-carboxylate B1-2-6

[0393] [ka]

[0394] To a solution of B1-2-5 (1 equiv., 730 mg, 2.03 mmol) in absolute absolute EtOH (21 mL) was added NaBH (2 equiv., 154 mg, 4.06 mmol) under an argon atmosphere at 0 °C. The resulting solution was warmed to room temperature and stirred for 5 h. The reaction mixture was quenched with saturated aqueous NH Cl (20 mL) at room temperature and then diluted with water (100 mL) and DCM (100 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 × 100 mL). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to afford B1-2-6 as a colorless oil (734 mg, 100%, diastereomeric mixture).

[0395] LC / MS (AN01_001_012): Rt=2.80 min, non-UV active, [M-C4H8+H] + =306.2.

[0396] Example 2 Synthesis of -(2S,6S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (INSM-201) INSM-201 was synthesized as follows.

[0397] [ka]

[0398] Experimental procedure tert-Butyl (2S)-2-(hydroxymethyl)-6-methylidene-1,4-oxazepane-4-carboxylate B1-2-11

[0399] [ka]

[0400] Starting from B1-2-4 (1 equiv., 1.90 g, 5.31 mmol), general procedure A was used to afford B1-2-11 as a colorless oil (1.09 g, 84%) after purification by silica gel flash chromatography (25 g, gradient: 95:5 to 50:50 cyclohexane / EtOAc).

[0401] LC / MS (AN01_001_012): Rt=2.04 min, 100%, [M+Na] + =266.2.

[0402] (2S)-4-[(tert-butoxy)carbonyl]-6-oxo-1,4-oxazepane-2-carboxylic acid B1-2-12

[0403] [ka]

[0404] To a solution of B1-2-11 (1 equiv., 440 mg, 1.81 mmol) in a mixture of DCM (5 mL), ACN (7.5 mL), and HO (4 mL) was added sodium periodate (5 equiv., 1.93 g, 9.04 mmol) and RuCl (0.2 equiv., 75.0 mg, 0.36 mmol) at room temperature. The resulting mixture was vigorously stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (20 mL) and a saturated aqueous solution of NaHCO (20 mL). The two layers were separated, and the aqueous layer was washed with DCM (20 mL). The aqueous layer was then acidified to pH 1 with 3 M aqueous HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to provide B1-2-12 as a colorless oil (225 mg, 48%).

[0405] LC / MS (AN01_001_012): Rt=1.88 min, non-UV active, [M+H] + =258.1.

[0406] (2S)-4-[(tert-butoxy)carbonyl]-6-hydroxy-1,4-oxazepane-2-carboxylic acid B1-2-10

[0407] [ka]

[0408] To an argon-purged solution of B1-2-12 (1 equiv., 240 mg, 0.926 mmol) in MeOH (9.3 mL) was added 10% Pd / C (0.2 equiv., 197 mg, 0.185 mmol) at room temperature. The resulting mixture was purged with argon (3 times) and then with H (3 times). The reaction mixture was stirred at room temperature under atmospheric pressure of H for 18 hours. The reaction mixture was purged with argon, filtered through a pad of Celite, and rinsed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure to afford B1-2-10 as a white solid (227 mg, 94%, diastereomeric mixture).

[0409] LC / MS (AN01_001_012): Rt=1.76 min, non-UV active, [M+H] + =260.1.

[0410] tert-Butyl (2S,6S * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-1,4-oxazepane-4-carboxylate B1-2-11-(S) * and tert-butyl (2S,6R * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-1,4-oxazepane-4-carboxylate B1-2-11-(R) *

[0411] [ka]

[0412] Starting from BB01 (1 equiv., 264 mg, 0.802 mmol) and B1-2-10 (1.05 equiv., 220 mg, 0.842 mmol) using general procedure B, the resulting diastereomeric mixture was separated by purification by silica gel flash chromatography (25 g, gradient: 100:0 to 96:4 DCM / MeOH) to give B1-2-11-(S). * (100 mg, 23%) and B1-2-11-(R) * (121 mg, 28%) was obtained as a pale yellow solid. Stereochemistry (S) * is arbitrarily assigned to the first eluted product by flash chromatography, and then the second eluted product is assigned to (R) * was assigned to.

[0413] B1-2-11-(S) * :LC / MS(AN01_001_012):Rt=2.30 min, 100%, [M-C4H8+H] + =481.2.

[0414] B1-2-11-(R) * :LC / MS(AN01_001_012):Rt=2.30 min, 100%, [M-C4H8+H] + =481.2.

[0415] (2S,6S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-1,4-oxazepane-2-carboxamide (INSM-201).

[0416] [ka]

[0417] B1-2-11-(S) *INSM-201 was prepared using general procedure C starting from (1 equiv., 50.0 mg, 0.093 mmol). The crude residue was purified by preparative HPLC (gradient: 85:15 to 70:30 HO (+0.1% TFA) / acetonitrile, column: XBridge C18 (30 × 150 (5 μm)), flow rate: 43 mL / min). The collected fractions containing INSM-201 were combined, and the organic solvent was removed under reduced pressure. The resulting aqueous layer was basified with solid NaHCO3 to pH 8 and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in a HO / MeOH mixture (90:10, 2 mL) and lyophilized to give INSM-201 as a white solid (15.7 mg, 39%).

[0418] LC / MS (AN01_001_026): Rt=6.44 min, 100%, [M+H] + =437.6.

[0419] 1 H NMR (DMSO-d6,400MHz): δppm8.61(d,J=8.4Hz,1H),7.66(d,J=8.3Hz,2H),7.58-7.56(m,1H),7.41-7. 37(m,4H),5.02(q,J=8.0Hz,1H),4.76(d,J=5.3Hz,1H),4.00(dd,J=7.7,4.1Hz,1H),3.88(dd,J=12.3 ,4.8Hz,1H),3.76-3.69(m,1H),3.47(dd,J=12.2,7.8Hz,1H),3.41(s,3H),3.25-3.15(m,2H),3.03(d d,J=14.2,4.0Hz,1H),2.81(dd,J=13.7,3.8Hz,1H),2.62(dd,J=13.7,5.9Hz,1H),2.54-2.50(m,2H).

[0420] Example 3 Synthesis of -(2S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (INSM-202) INSM-202 was synthesized as follows.

[0421] [ka]

[0422] Experimental procedure tert-Butyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methoxy-1,4-oxazepane-4-carboxylate B1-3-1

[0423] [ka]

[0424] To a solution of B1-2-6 (1 equiv., 500 mg, 1.38 mmol) and MeI (2 equiv., 0.172 mL, 2.77 mmol) in anhydrous DMF (8 mL) was added 60% NaH / oil (1.1 equiv., 60.8 mg, 1.52 mmol) under an argon atmosphere at 0 °C. The resulting mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) at room temperature and then diluted with water (50 mL) and EtOAc (50 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (25 g, gradient: 100:0 to 90:10 cyclohexane / EtOAc) to afford B1-3-1 as a colorless oil (412 mg, 79%, mixture of diastereomers).

[0425] LC / MS (AN01_001_012): Rt=3.06 min, non-UV active, [M-C4H8+H] + =320.2.

[0426] tert-Butyl (2S)-2-(hydroxymethyl)-6-methoxy-1,4-oxazepane-4-carboxylate B1-3-2

[0427] [ka]

[0428] Starting from B1-3-1 (1 equiv., 410 mg, 1.09 mmol), general procedure A was used to obtain B1-3-2 as a colorless oil (211 mg, 74%, diastereomeric mixture) after purification by silica gel flash chromatography (25 g, gradient: 100:0 to 25:75 cyclohexane / EtOAc).

[0429] LC / MS (AN01_001_012): Rt=1.93 min, non-UV active, [M+Na] + =284.2.

[0430] 4-[(tert-butoxy)carbonyl]-6-methoxy-1,4-oxazepane(2S)-2-carboxylic acid B1-3-3

[0431] [ka]

[0432] To a solution of B1-3-2 (1 equiv., 210 mg, 0.804 mmol) in acetone (14 mL), sodium bromide (0.3 equiv., 25.2 mg, 0.245 mmol) and saturated aqueous NaHCO3 (2 mL) were added sequentially at room temperature. To the resulting mixture, trichlorocyanuric acid (2.2 equiv., 411 mg, 1.77 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl (0.03 equiv., 3.76 mg, 0.0245 mmol) were added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. Isopropanol (15 mL) was added at room temperature, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The two layers were separated, and the aqueous layer was washed with EtOAc (100 mL). The aqueous layer was then acidified with 3 M aqueous HCl to pH 1 and extracted with DCM (2 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give B1-3-3 as a pale yellow oil (208 mg, 94%, diastereomeric mixture).

[0433] LC / MS (AN01_001_012): Rt=1.91 min, non-UV active, [M+Na] + =298.1.

[0434] tert-Butyl-(2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazepane-4-carboxylate B1-3-4

[0435] [ka]

[0436] Starting from BB01 (1 equiv., 302 mg, 0.916 mmol) and B1-3-3 (1.05 equiv., 265 mg, 0.962 mmol), general procedure B was used to afford B1-3-4 as an orange solid (271 mg, 54%, mixture of diastereomers) after two purifications by silica gel flash chromatography (first purification: 25 g, gradient: 100:0 to 98:2 DCM / MeOH; second purification: 25 g, gradient: 100:0 to 40:60 cyclohexane / EtOAc).

[0437] LC / MS (AN01_001_012): Rt=2.49 min, 100%, [M-C4H8+H] + =495.3.

[0438] (6-rac)-(2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazepane-2-carboxamide INSM-202

[0439] [ka]

[0440] Starting from B1-3-4 (1 equiv., 92.5 mg, 0.168 mmol), INSM-202 was prepared using general procedure C. The crude residue was first purified by C18 reverse-phase flash chromatography (12 g, gradient: 100:0 to 50:50 HO (+0.1% TFA) / acetonitrile). The collected fractions containing INSM-202 were combined, and the organic solvent was removed under reduced pressure. The resulting aqueous layer was basified to pH ∼8 with solid NaHCO and extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (gradient: 85:15 to 70:30 HO (+0.1% TFA) / acetonitrile, column: XBridge PFP (30 × 150 (5 μm)), flow rate: 43 mL / min). The collected fractions containing INSM-202 were combined and the organic solvent was removed under reduced pressure. The resulting aqueous layer was basified with solid NaHCO to pH 8 and extracted with DCM (3 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in a HO / MeOH mixture (90:10, 2 mL) and lyophilized to give INSM-202 as a white solid (15.3 mg, 20%, diastereomeric mixture, 1 H NMR ratio: 4:6).

[0441] LC / MS (AN01_001_026): Rt=6.60 min, 99.9%, [M+H] + =451.6.

[0442] 1H NMR(DMSO-d6,400MHz):δppm8.64-8.61(m,1H),7.67-7.63(m,2H),7.58-7.56(m,1H),7. 43-7.35(m,4H),5.04-4.98(m,1H),4.01-3.89(m,2H),3.76(dd,J=13.5,3.6Hz,0.4H),3. 56(dd,J=12.6,7.6Hz,0.6H),3.46-3.41(m,1H),3.40(s,3H),3.25(s,3H),3.22-3.02(m ,4H),2.87(dd,J=14.1,4.9Hz,0.5H),2.73(dd,J=14.1,3.5Hz,0.5H),2.47-2.30(m,2H).

[0443] Example 4 Synthesis of -(2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (INSM-203) Synthetic scheme for the preparation of INSM-203:

[0444] [ka]

[0445] Experimental procedure tert-Butyl (2S,6R * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazepane-4-carboxylate B1-3-4-(R) * &tert-Butyl (2S,6S * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazepane-4-carboxylate B1-3-4-(S) *

[0446] [ka]

[0447] The diastereomeric mixture B1-3-4 (170 mg) was separated by preparative SFC (column: Chiralcel OD-H (30 × 250 mm); eluent: i-PrOH / CO2, 30:70 isocratic condition; flow rate: 160 mL / min; T °C: 35 °C) to give B1-3-4-(S). * (63.5 mg, 37%) & B1-3-4-(R) * (79 mg, 46%) was obtained as a yellow solid. Stereochemistry (S) * was arbitrarily assigned to the first elution product by preparative SFC, and then the second elution product was assigned to (R) * was assigned to.

[0448] B1-3-4-(S) * Chiral SFC purity analysis: Rt = 1.49 min, 100%, [M+Na] + =573.2. LC / MS(AN01_001_012): Rt=2.48 min, 100%, [M-C4H8+H] + =495.2.

[0449] B1-3-4-(R) * Chiral SFC purity analysis: Rt = 2.27 min, 100%, [M+Na] + =573.2. LC / MS(AN01_001_012): Rt=2.47 min, 100%, [M-C4H8+H] + =495.2.

[0450] (2S,6R * )-N-[(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazepane-2-carboxamide INSM-203

[0451] [ka]

[0452] B1-3-4-(R) * Starting with (1 equiv., 70.0 mg, 0.127 mmol), general procedure C was used to afford INSM-202 as a white solid (42.5 mg, 74%) after purification by silica gel flash chromatography (4 g, gradient: 100:0 to 93:7 DCM / MeOH).

[0453] LC / MS (AN01_001_026): Rt=6.56 min, 99.9%, [M+H] + =451.5.

[0454] 1 H NMR (DMSO-d6,400MHz): δppm8.63(d,J=8.5Hz,1H),7.66(d,J=8.2Hz,2H),7.58-7.55(m,1H),7.4 3-7.37(m,4H),5.01(q,J=8.5Hz,1H),4.01-3.96(m,2H),3.56(dd,J=12.5,7.0Hz,1H),3.46-3.4 1(m,1H),3.40(s,3H),3.25(s,3H),3.22-3.14(m,2H),3.04(dd,J=14.0,3.5Hz,1H),2.87(dd,J= 14.2,4.9Hz,1H),2.73(dd,J=14.2,3.6Hz,1H),2.43(dd,J=14.2,8.4Hz,1H),2.35-2.22(m,1H).

[0455] Example 3 - DPP1 IC50 measurement The following compounds were tested:

[0456] [Table 3]

[0457] Human DPP1 enzyme IC50 assay Recombinant human DPP1 enzyme (R&D Systems, Minneapolis, MN) was first proteolytically processed to its mature form using recombinant human cathepsin L (R&D Systems) in a buffer consisting of 20 mM citrate pH 4.5, 150 mM NaCl, 1 mM EDTA, and 10 mM DTT. Alternatively, crude HL-60 cell lysates (ATCC, Manassas, VA) were used as a source of human DPP1 enzyme in the assay. Lysates were prepared in 1% Triton X-100 in PBS at a concentration of 20,000 viable cells per μL of lysis buffer and centrifuged at 16,000 × g for 10 minutes at 4°C. The supernatant was then collected and flash-frozen in liquid nitrogen.

[0458] Test substances were applied to activated human DPP1 enzyme in assay buffer (25 mM MES pH 6.0, 50 mM NaCl, 5 mM DTT) in a total reaction volume of 125 μL. 25 μL of compound in assay buffer + 5% DMSO was first added to 50 μL of activated human DPP1 enzyme at a concentration of 1 ng / μL and preincubated at 37°C for 10 minutes, after which 50 μL of 1000 μM H-Gly-Arg-AMC substrate (Bachem, St. Torrance, CA) was added, resulting in a final substrate concentration of 400 μM and a final DMSO concentration of 1%. Substrate cleavage was measured for 90 minutes at 37°C, and fluorescence at excitation / emission 350 / 450 nm was measured every 5 minutes. DPP1 concentrations were interpolated based on their activity against a standard curve of activated human recombinant DPP1 enzyme. The IC50 value for each compound was calculated via XLFit (IDBS version 5.3.1.3). The four-parameter fit equation y = (A + ((B A) / (1 + ((C / x)), which appears as equation number 205 in XLFit (four-parameter logistic model or sigmoidal dose-response model). ^ D)))) was added to Microsoft Excel using the add-on. Default constraints were used for each parameter. IC50 was defined as the compound concentration at which 50% of the enzyme activity was inhibited compared to a compound-free control.

[0459] Mouse DPP1 enzyme IC50 assay Test substances were applied to active mouse DPP1 enzyme (R&D Systems, Minneapolis, MN) in assay buffer (50 mM MES pH 5.5, 50 mM NaCl, 5 mM DTT) in a total reaction volume of 125 μL. 25 μL of compound in assay buffer + 5% DMSO was first added to 50 μL of active mouse DPP1 enzyme at a concentration of 62.5 pg / μL and preincubated at 37°C for 10 minutes, after which 50 μL of 1000 μM H-Gly-Arg-AMC substrate (Bachem, St. Torrance, CA) was added, resulting in a final substrate concentration of 400 μM and a final DMSO concentration of 1%. Substrate cleavage was measured for 90 minutes at 37°C, and fluorescence at excitation / emission 350 / 450 nm was measured every 5 minutes. DPP1 concentrations were interpolated based on their activity against a standard curve of recombinant active mouse DPP1 enzyme. The IC50 value for each compound was calculated via XLFit (IDBS version 5.3.1.3). The four-parameter fit equation y = (A + ((B A) / (1 + ((C / x)), which appears as equation number 205 in XLFit (four-parameter logistic model or sigmoidal dose-response model). ^ D)))) was added to Microsoft Excel using the add-on. Default constraints were used for each parameter. IC50 was defined as the compound concentration at which 50% of the enzyme activity was inhibited compared to a compound-free control.

[0460] DPP1 cellular IC50 assay HL-60 cells (ATCC, Manassas, VA) were maintained in RPMI-1640 supplemented with 20% heat-inactivated FBS and 1× antibiotic-antimycotic (Cytiva, Marlborough, MA). Medium was changed every 3–4 days and cells were cultured at a density of 1×10 per mL. 6 Prior to the assay, cells were harvested by centrifugation at 500 rcf for 3 minutes, resuspended in RPMI, and counted. Cells were collected at 5 x 10 per mL in RPMI. 5The cells were diluted to a concentration of 100 μL per well and transferred to a black 96-well plate at 60 μL per well for the assay. Test substances were diluted in RPMI + 0.5% DMSO, and 20 μL was added to each assay well. Compounds were preincubated with the cells at 37°C for 60 minutes with gentle shaking at 100 rpm in a cell culture incubator maintained at 5% CO2, after which 20 μL of 500 μM H-Gly-Phe-AFC substrate (MP Biomedicals, Solon, OH) in RPMI was added to each well. The plate was returned to the incubator for 30 minutes with shaking at 100 rpm, after which fluorescence was measured at excitation / emission 400 / 505 nm. Percent inhibition (%) was calculated from RFU values ​​compared to control cell wells that received only RPMI + 0.5% DMSO. IC50 values ​​for each compound were calculated via XLFit (IDBS version 5.3.1.3). The four-parameter fit equation y = (A + ((B A) / (1 + ((C / x), which appears as equation number 205 in XLFit (four-parameter logistic model or sigmoidal dose-response model) ^ D)))) into Microsoft Excel using the add-on. IC50 was defined as the compound concentration at which 50% of the enzyme activity was inhibited compared to a compound-free control.

[0461] result The IC50 values ​​for INSM-201, INSM-202, INSM-203, and INSM-204 are provided in Table 1. IC50 curves are also provided in Figures 1-9 for INSM-201 (Figures 1-3), INSM-202 (Figures 4-6), and INSM-203 (Figures 7-9).

[0462] [Table 4]

[0463] Example 4 - In vivo activity of compounds of formula (I). Bone marrow cell pellet collection: Male or female C57BL / 6 mice aged 8-14 weeks were used.

[0464] Two femurs and two tibiae were removed from one mouse and cleaned of muscle and residual tissue using gauze. Surgical instruments and facilities were maintained in a sterile environment. The bones were placed in a 15 mL tube containing cold sterile RPMI medium and placed on ice until further processing.

[0465] Place a new 50 mL tube on ice and insert a new 40 / 70 μm cell strainer (CLS431750, Sigma) into the top of the Falcon tube. Cut both ends of two femurs and two tibias with a bone cutter, and place fresh bone marrow from all bones from one mouse into the cell strainer. Five mL of ice-cold RPMI (RPMI medium containing 10 mM HEPES, pH 7.4) was added to each femur or tibia using a blunt needle (25G needle), for a total of approximately 20 mL per tube.

[0466] Centrifuge the cell suspension at 600 xg for 5 minutes at 4°C and carefully discard the supernatant.

[0467] Myeloid lineage cell depletion protocol The cell pellet is resuspended in 400 μL of ice-cold MACS buffer (pH 7.2 PBS+0.5% BSA and 2 mM EDTA) per adult mouse (optimized for 4 bones / mouse).

[0468] Add 100 µL of direct lineage cell depletion cocktail (enough for 100 million cell depletion). Mix the components well and incubate at 2 °C–8 °C for 10 min.

[0469] Prepare a magnetic separation LS column (MACS, Miltenyi, 130042401) by placing it in the magnetic field of a MACS separator and rinsing with 3 mL of ice-cold MACS buffer.

[0470] The cell suspension is applied to the column and the flow-through containing unlabeled cells, representing enriched lineage-negative cells, is collected.

[0471] Wash the column with 3 x 3 mL of ice-cold MACS buffer. Collect the unlabeled cells that pass through, representing enriched lineage-negative cells, and combine them with the flow-through from the previous step.

[0472] The cell suspension is centrifuged at 600 x g for 5 minutes at 4°C and the supernatant is carefully discarded. The pellet is washed once with 10 mL of ice-cold IMDM medium (IMDM GlutaMax (Gibco, 31980030) + 10% FCS and 1% PS).

[0473] The cell pellet is resuspended in 2 mL of ice-cold complete IMDM medium and the cells are counted. The cells are then ready for neutrophil differentiation.

[0474] Treatment of bone marrow progenitor cells and their differentiation into neutrophils by DPP1 inhibitors The resulting undifferentiated bone marrow cells were placed in complete IMDM medium (IMDM containing 10% FBS and 1% antibiotics) at a cell concentration of 1 × 10 5 The medium was adjusted to 100 cells / mL and supplemented with 50 ng / mL SCF (BioLegend, 579704) and 50 ng / mL IL3 (BioLegend, 575504). Cells were subgrouped and the respective DPP1 inhibitors were added accordingly. The cells were then cultured in flasks at 37°C for 3 days.

[0475] Cells were checked daily for proliferation and plated at 2–10 × 10 5 Maintain a final concentration of 10 cells / ml. On day 3, count the cells. Harvest 3-4 million cells for each group and prepare lysates for NSP activity detection. Dissolve the remaining cells at 2 x 10 in fresh medium supplemented with 50 ng / ml SCF, 50 ng / ml IL3, and 50 ng / ml G-CSF (BioLegend, 574604). 5 The cells are resuspended at 100 cells / mL. The DPP1 inhibitor in the medium is refreshed. The cells are then cultured in the flask for an additional 2 days at 37°C.

[0476] On day 5, count the cells. Harvest 3-4 million cells / condition and lyse the cells to prepare samples for NSP activity detection. Harvest the remaining cells by centrifugation at 600 x g for 5 minutes. Wash the remaining cells once in 1x PBS. After washing, dissolve the pelleted cells in a 4-6 x 10 solution in complete IMDM medium supplemented with 50 ng / ml G-CSF only. 5 Resuspend cells at 100 cells / mL. Refresh the DPP1 inhibitor in the medium. Incubate the cells for an additional 2 days, for a total of 7 days from the day of harvest. On day 7, count the cells. Harvest 3-4 million cells / condition, lyse the cells, and prepare samples for NSP activity detection.

[0477] Preserving cell lysates for the NSP activity assessment protocol Collect 3-4 million cells in an Eppendorf tube. Spin down the sample at 600 x g for 5 minutes at 4°C. Remove the supernatant and resuspend in 1 mL of PBS. Spin down the sample at 600 x g for 5 minutes at 4°C and remove the supernatant. Lyse the sample in 100 μL of ice-cold 1% (v / v) Triton X-100 in PBS and incubate on ice for 15 minutes. Spin down the sample at 16,000 x g for 10 minutes at 4°C. Collect the lysate, flash freeze it in liquid nitrogen, and store it at -80°C.

[0478] Enzyme activity Neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G The enzymatic activity of the NE and PR3 subunits (CatG, CatG) was determined in mouse progenitor cell lysates via kinetic assays using the following peptide substrates (final concentrations indicated): 100 μM N-methoxysuccinyl-Ala-Ala-Pro-Val-7-amido-4-methylcoumarin (Sigma, St. Louis, MO, excitation / emission at 350 / 450 nm) for NE, 40 μM (7-methoxycoumarin-4-yl)acetyl-lysyl-(picolinoyl)-Tyr-Asp-Ala-Lys-Gly-Asp-N-3-(2-4-dinitrophenyl)-2-3-diaminopropionyl-NH2) (GenScript, Piscataway, NJ, excitation / emission at 340 / 430 nm) for PR3, and 200 μM N-succinyl-Ala-Ala-Pro-Phe for CatG. p-nitroanilide (Sigma, absorbance at 405 nm).

[0479] Fluorescence or absorbance was quantified using a Synergy microplate reader (BioTek, Winooski, VT). Specific NSP activity in each sample was calculated by subtracting from the total activity the activity measured in the presence of specific NSP inhibitors—elastase inhibitor (Abcam) for NE, sivelestat (Abcam) for PR3, and cathepsin G inhibitor I (Cayman Chemical, Ann Arbor, MI) for CatG. Active NSP concentrations were interpolated based on their activity against standard curves generated using active human NE protein (Sigma), active human PR3 protein (Sigma), and active human CatG protein (Sigma), respectively. Due to the unavailability of commercially available mouse NE, PR3, and CatG proteins, the corresponding human proteins were used because their catalytic properties are largely conserved across species. A portion of each cell lysate sample was also set aside for protein quantification using the Pierce BCA Protein Assay Kit (Thermo Fisher). NSP activity was normalized to cell lysate protein concentration. Data analysis was performed using an internally developed macro Excel program by first determining the linear portion of the kinetic experiment. Slope values ​​were calculated from the linear portion of the experiment, and a standard curve was constructed using the standard slope values ​​and their respective known concentrations. Unknown sample concentrations were then calculated using a second-order polynomial line of best fit from the appropriate standard curve.

[0480] The results of the enzyme assays are provided in Tables 2-4 below.

[0481] A concentration-dependent reduction in NE activity was observed with INSM-201, with maximum inhibition observed at 0.1 μM, regardless of day, being approximately 85%. At lower doses of INSM-201, variability in inhibition was observed depending on day (range: 42-78%). INSM-202 appeared to reach a plateau of NE inhibition by 0.02 μM, with maximum inhibition observed at approximately 85% regardless of day. INSM-203 appeared to reach a plateau of inhibition by 0.02 μM, with maximum inhibition observed at approximately 85% regardless of day.

[0482] The results of the PR3 activity assay are provided in Table 3. A concentration-dependent reduction in PR3 activity was observed with INSM-201, with maximal inhibition observed at 1 μM on D5 and D7 being approximately 95%. Low dose variation in inhibition was observed with INSM-201, depending on the day (range: 36%-72%). INSM-202 appeared to reach an inhibition plateau by 0.02 μM, with maximal inhibition observed being approximately 95%, regardless of day. INSM-203 appeared to reach an inhibition plateau by 0.02 μM, with maximal inhibition observed being approximately 90%, regardless of day.

[0483] The results of the CatG activity assay are provided in Table 4. A concentration-dependent reduction in CatG activity was observed with INSM-201, with maximum inhibition observed at 1 μM, approximately 95% regardless of day. At lower doses of INSM-201, variability in inhibition was observed depending on the day (range: 27-78%). INSM-202 appeared to reach an inhibition plateau by 0.02 μM, with maximum inhibition observed at approximately 95% regardless of day. INSM-203 appeared to reach an inhibition plateau by 0.02 μM, with maximum inhibition observed at approximately 95% regardless of day.

[0484] [Table 5]

[0485] [Table 6]

[0486] [Table 7] *******

[0487] All references, patents, patent applications, publications, product descriptions, and protocols cited throughout this application are hereby incorporated by reference in their entirety for all purposes.

[0488] The embodiments illustrated and discussed herein are intended only to teach those skilled in the art the best mode known to the inventors of making and using the invention. Modifications and variations of the above-described embodiments of the invention are possible without departing from the invention, as will be understood by those skilled in the art in light of the above teachings. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Claims

1. 1. A method of treating a disorder mediated by dipeptidyl peptidase 1 (DPP1) in a subject in need thereof, comprising administering to the subject a composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for an administration period; 【Chemistry 1】 During the ceremony, G is a 5- to 12-membered carbocycle, a 5- to 12-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, or O, or a group of the formula 【Chemistry 2】 and L is a fused ring of １ is bonded to G by replacing any hydrogen atom on ring G, and a bond, C １～３ Alkylene, -NH-, -N(C １～４ alkyl)-, —O—, —S—, C ２～６ Ortho-alkenyl, C ２～６ ortho-alkynyl, -CO-, or -CONH-, wherein said alkylene, ortho-alkenyl, or ortho-alkynyl optionally contains 1 to 3 halogens, C １～４ Alkyl, cyano, hydroxyl, NH ２ and is substituted with a —COOH group, R １ , R ２ , and R ３ are independently H, deuterium, halogen, C １～４ Alkyl, C １～４ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ cycloalkyl, and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are selected from halogen, C １～４ Alkyl, cyano, hydroxyl, NH ２ and COOH, or alternatively, R １ and R ２ But C ３～６ Forms a cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein said cycloalkyl or heterocycle optionally contains ═O, halogen, cyano, hydroxyl, NH ２ , COOH, C １～４ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C ３～６ cycloalkyl; Y １ and Y ２ However, both are independent of CR ４ or N, Each R ４ are independently H, deuterium, halogen, C １～４ Alkyl, C １～４ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, cyano, hydroxyl, NH ２ , N.H.C. １～４ Alkyl, N(C １～４ alkyl) ２ , COOH, COC １～４ Alkyl, COOC １～４ Alkyl, CONHC １～４ Alkyl, CON(C １～４ alkyl) ２ , NHCOC １～４ alkyl, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O; R ４ wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are optionally selected from the group consisting of deuterium, halogen, cyano, hydroxyl, NH ２ and COOH, X １ , X ２ , X ３ , and X ４ each independently represents a bond, NR ５ , O., C.R. ６ R ７ , S, S(O), and S(O) ２ is selected from X １ , X ２ , X ３ , and X ４ at most one of is a bond, Rc is H, ═O, halogen, cyano, hydroxyl, NH ２ , -COOH, C １～４ Alkyl, halogenated C １～４ Alkyl, Hydroxyl C １～４ Alkyl, C １～４ Alkoxy, C １～６ Alkoxyalkyl or halogenated C １～４ is an alkoxy, Each R ５ However, independently, H, C １～４ Alkyl, -COC １～４ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C ３～６ and cycloalkyl, wherein said alkyl, alkenyl, alkynyl, and cycloalkyl are optionally selected from deuterium, halogen, cyano, hydroxyl, NH ２ and COOH, R ６ and R ７ are each independently H, deuterium, halogen, C １～４ Alkyl, C １～４ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, cyano, hydroxyl, NH ２ , COOH, and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are optionally selected from deuterium, halogen, cyano, hydroxyl, NH ２ and -COOH, or Alternatively, R ６ and R ７ forms =O or Alternatively, X １ , X ２ , X ３ , and X ４ Two R on adjacent ring atoms in ５ or two R on adjacent ring atoms ６ or R of an atom on an adjacent ring ５ and R ６ and the atom to which they are bonded form a double bond, or Alternatively, the R ６ and R ７ are connected to the carbon atoms and C ３～１２ Forms a carbocyclic ring or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, or O, wherein the carbocyclic ring or heterocyclic ring is not ═O, halogen, cyano, hydroxyl, NH ２ , -COOH, C １～４ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C ３～６ cycloalkyl; Z is CH or N; A is, 【Transformation 3】 a 6-atom heteroaryl or a 5- to 7-membered non-aromatic monocyclic heterocycle, wherein the heteroaryl and non-aromatic monocyclic heterocycle contain 1 to 3 heteroatoms selected from N, S, or O; ＊ " represents a terminal bond to an alkyl carbon, B is C ４～６ a carbocycle or a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O; Each R ８ are independently H, ═O, deuterium, halogen, C １～４ Alkyl, C １～４ Alkoxy, SC １～４ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, cyano, hydroxyl, —COOH, NH ２ , and C ３～６ cycloalkyl, wherein said alkyl, alkoxy, alkenyl, alkynyl, or cycloalkyl is selected from the group consisting of deuterium, halogen, cyano, hydroxyl, NH ２ and COOH, optionally substituted with 1 to 3 groups selected from

2. The compound of formula (I) is a compound of formula (1a) or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 During the ceremony, R １ , R ２ , R ３ and G is defined above for formula (I), Rc is ═O, halogen, cyano, hydroxyl, NH ２ , -COOH, C １～４ Alkyl, halogenated C １～４ Alkyl, Hydroxyl C １～４ Alkyl, C １～４ Alkoxy, C １～６ Alkoxyalkyl or halogenated C １～４ The method of claim 1 , wherein the alkyl group is alkoxy.

3. The compound of formula (I) is a compound of formula (1b) or a pharmaceutically acceptable salt thereof, 【Transformation 5】 During the ceremony, R １ , R ２ , R ３ , Z, and G are defined above for formula (I); Rc is ═O, halogen, cyano, hydroxyl, NH ２ , -COOH, C １～４ Alkyl, halogenated C １～４ Alkyl, Hydroxyl C １～４ Alkyl, C １～４ Alkoxy, C １～６ Alkoxyalkyl or halogenated C １～４ The method of claim 1 , wherein the alkyl group is alkoxy.

4. G, 【Transformation 6】 The method according to any one of claims 1 to 3, wherein

5. G, 【Transformation 7】 The method according to any one of claims 1 to 3, wherein

6. G, 【Transformation 8】 The method according to any one of claims 1 to 3, wherein

7. G, 【Chemistry 9】 The method according to any one of claims 1 to 3, wherein

8. G is a substituted cyclopentane, cyclohexane, cycloheptane, or benzene; 【Chemistry 10】 The method according to any one of claims 1 to 3, wherein

9. G, 【Chemistry 11】 The method according to any one of claims 1 to 3, wherein

10. G, 【Chemistry 12】 The method according to any one of claims 1 to 3, wherein

11. G, 【Chemistry 13】 The method according to any one of claims 1 to 3, wherein

12. G, 【Chemistry 14】 The method according to any one of claims 1 to 3, wherein

13. R １ The method of any one of claims 1 to 12, wherein is H.

14. R ２ The method of any one of claims 1 to 13, wherein is H.

15. R ３ The method of any one of claims 1 to 14, wherein is H.

16. Rc is hydroxyl, C １～４ Alkyl, or C １～４ The method of any one of claims 1 to 15, wherein the alkyl group is alkoxy.

17. Rc is halogen, C １～２ Alkyl, or C １～２ The method of any one of claims 1 to 15, wherein the alkyl group is alkoxy.

18. The method of any one of claims 1 to 15, wherein Rc is methoxy.

19. The method of any one of claims 1 to 15, wherein Rc is ethoxy.

20. The method of any one of claims 1 to 15, wherein Rc is propoxy.

21. The method of any one of claims 1 to 15, wherein Rc is halogen.

22. The method of any one of claims 1 to 15, wherein Rc is hydroxyl.

23. Rc is C １～２ The method of any one of claims 1 to 15, wherein the alkyl is alkyl.

24. Rc is C １～２ The method of any one of claims 1 to 15, wherein the alkyl group is alkoxy.

25. 25. The method of any one of claims 3 to 24, wherein Z is CH.

26. L １ The method of any one of claims 1 and 4 to 25, wherein is a bond.

27. A is, 【Chemistry 15】 and During the ceremony, 27. The method of any one of claims 1 and 4 to 26, wherein r is an integer from 1 to 3 and E is NH, S, or O.

28. 28. The method of claim 27, wherein r is 1.

29. 28. The method of claim 27, wherein r is 2.

30. 28. The method of claim 27, wherein r is 3.

31. 31. The method of any one of claims 27 to 30, wherein E is NH.

32. 31. The method of any one of claims 27 to 30, wherein E is S.

33. The method of any one of claims 27 to 30, wherein E is O.

34. A is, 【Chemistry 16】 The method according to any one of claims 1 and 4 to 26, wherein

35. A is, 【Chemistry 17】 The method according to any one of claims 1 and 4 to 26, wherein

36. A is, [Chemistry 18] The method according to any one of claims 1 and 4 to 26, wherein

37. The compound of formula (I) is the following compound: 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 or 【Chemistry 23】 or a pharmaceutically acceptable salt thereof.

38. The compound of formula (I) 【Chemistry 24】 or a pharmaceutically acceptable salt thereof.

39. The compound of formula (I) 【Chemistry 25】 or a pharmaceutically acceptable salt thereof.

40. The compound of formula (I) 【Chemistry 26】 or a pharmaceutically acceptable salt thereof.

41. The compound of formula (I) 【Chemistry 27】 or a pharmaceutically acceptable salt thereof.

42. The compound of formula (I) 【Chemistry 28】 or a pharmaceutically acceptable salt thereof.

43. The compound of formula (I) 【Chemistry 29】 or a pharmaceutically acceptable salt thereof.

44. The compound of formula (I) 【Transformation 30】 or a pharmaceutically acceptable salt thereof.

45. The compound of formula (I) 【Chemistry 31】 or a pharmaceutically acceptable salt thereof.

46. The compound of formula (I) 【Chemistry 32】 or a pharmaceutically acceptable salt thereof.

47. The compound of formula (I) 【Transformation 33】 or a pharmaceutically acceptable salt thereof.

48. The compound of formula (I) 【Transformation 34】 or a pharmaceutically acceptable salt thereof.

49. The compound of formula (I) 【Chemistry 35】 or a pharmaceutically acceptable salt thereof.

50. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is bronchitis, emphysema, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, pulmonary fibrosis, complications of lung transplantation, vasculitic and thrombotic disorders of the pulmonary 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 drug-induced rhinitis, and vasomotor rhinitis; neurogenic rhinitis (hay fever), perennial and seasonal allergic rhinitis including nasal polyposis; acute viral infections including the common cold and infections caused by respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

51. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is asthma.

52. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is acute respiratory distress syndrome (ARDS).

53. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is bronchitis.

54. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is pulmonary fibrosis.

55. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is emphysema.

56. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is cystic fibrosis (CF).

57. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is bronchiectasis.

58. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is sarcoidosis.

59. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is alpha-1 antitrypsin (A1AT) deficiency.

60. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is farmer's lung.

61. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is hypersensitivity pneumonitis.

62. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is a complication of lung transplantation.

63. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is a vasculitic or thrombotic disorder of the pulmonary vasculature.

64. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is pulmonary hypertension.

65. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is iatrogenic cough.

66. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is iatrogenic cough.

67. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is acute rhinitis.

68. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is chronic rhinitis.

69. 51. The method of claim 50, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is nasal polyposis.

70. 52. The method of claim 51, wherein the asthma is bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, or drug-induced asthma.

71. 54. The method of claim 53, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

72. 55. The method of claim 54, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, fibrosing alveolitis of unknown cause, idiopathic interstitial pneumonia, or anti-tumor therapy-associated fibrosis or chronic infection.

73. 58. The method of claim 57, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

74. 58. The method of claim 57, wherein the bronchiectasis is associated with cystic fibrosis.

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

76. 57. The method of claim 56, wherein said treating comprises improving pulmonary function of said patient compared to said patient's pulmonary function before said administration period.

77. Improving the patient's pulmonary function is characterized by an increase in the patient's forced forced expiratory volume in one second (FEV1) compared to the patient's respective value prior to the administration period. １ increasing the patient's forced vital capacity (FVC); increasing the patient's peak expiratory flow rate (PEFR); or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC. （２５～７５％） 77. The method of claim 76, comprising increasing

78. 78. The method of claim 76 or 77, wherein the pulmonary function is measured by spirometry.

79. 75. The method of claim 73 or 74, wherein treating comprises improving pulmonary function of the patient compared to the patient's pulmonary function before the administration period.

80. Improving the patient's pulmonary function is characterized by an increase in the patient's forced forced expiratory volume in one second (FEV1) compared to the patient's respective value prior to the administration period. １ increasing the patient's forced vital capacity (FVC); increasing the patient's peak expiratory flow rate (PEFR); or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC. （２５～７５％） 80. The method of claim 79, comprising increasing

81. 81. The method of claim 79 or 80, wherein the pulmonary function is measured by spirometry.

82. 82. The method of any one of claims 73-74 and 79-81, wherein treating comprises reducing the pulmonary exacerbation rate compared to the patient's pulmonary exacerbation rate before the administration period.

83. 83. The method of any one of claims 73-74 and 79-82, wherein treating comprises increasing the time to first pulmonary exacerbation compared to an untreated patient.

84. 84. The method of claim 82 or 83, wherein the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited by the patient for at least 48 hours: (1) increased coughing, (2) increased sputum volume or change in sputum consistency, (3) increased sputum purulence, (4) increased shortness of breath and / or decreased exercise tolerance, (5) fatigue and / or malaise, and (6) hemoptysis.

85. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is chronic rhinosinusitis (CRS).

86. 86. The method of claim 85, wherein the chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

87. 86. The method of claim 85, wherein the chronic sinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

88. The method according to any one of claims 85 to 87, wherein the chronic sinusitis is intractable chronic sinusitis.

89. 89. The method of any one of claims 85-88, wherein treating comprises reducing one or more symptoms of CRS, reducing its severity, delaying its onset, or eliminating it.

90. 90. The method of claim 89, wherein the one or more symptoms of CRS are selected from nasal congestion, nasal obstruction, runny nose, postnasal drip, facial pressure, facial pain, facial fullness, reduced odor, depression, mucosal edema, mucopurulent secretions, obstruction of the middle nasal meatus, mucosal changes in the middle meatus ostium and sinuses, or rhinorrhea.

91. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is hidradenitis suppurativa (HS).

92. 92. The method of claim 91, wherein the hidradenitis suppurativa (HS) is Hurley Stage I.

93. 92. The method of claim 91, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

94. 92. The method of claim 91, wherein the hidradenitis suppurativa (HS) is Hurley Stage III.

95. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is cancer.

96. 96. The method of claim 95, wherein the cancer is a metastatic cancer.

97. 97. The method of claim 96, wherein the metastatic cancer is metastatic cancer from the breast to the lung.

98. 97. The method of claim 96, wherein the metastatic cancer comprises breast cancer metastasis to the brain, bone, pancreas, lymph nodes, or liver.

99. 97. The method of claim 96, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

100. 97. The method of claim 96, wherein the metastatic cancer comprises colorectal cancer metastasis to the peritoneum, pancreas, stomach, lung, liver, kidney, or spleen.

101. 97. The method of claim 96, wherein the metastatic cancer comprises gastric cancer metastasis to the mesentery, spleen, pancreas, lung, liver, adrenal gland, or ovary.

102. 97. The method of claim 96, wherein the metastatic cancer comprises liver cancer metastasis to the intestine, spleen, pancreas, stomach, lung, or kidney.

103. 97. The method of claim 96, wherein the metastatic cancer comprises lymphoma metastasis to the kidney, ovary, liver, bladder, or spleen.

104. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is lupus nephritis.

105. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is rheumatoid arthritis.

106. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is inflammatory bowel disease (IBD).

107. 107. The method of claim 106, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

108. 107. The method of claim 106, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

109. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is granulomatosis with polyangiitis (GPA).

110. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is hidradenitis suppurativa (HS).

111. 50. The method of any one of claims 1 to 49, wherein the disorder mediated by dipeptidyl peptidase 1 (DPP1) is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture's disease), systemic sclerosis, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatosis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

112. 112. The method of any one of claims 1-111, wherein the composition is administered once daily during the administration period.

113. 112. The method of any one of claims 1-111, wherein the composition is administered twice daily during the administration period.

114. 112. The method of any one of claims 1-111, wherein the composition is administered every other day during the administration period.

115. 112. The method of any one of claims 1-111, wherein the composition is administered once per week during the administration period.

116. 116. The method of any one of claims 1 to 115, wherein the composition is in an oral dosage form.

117. 117. The method of claim 116, wherein the composition is administered orally.

118. 118. The method of any one of claims 1-117, wherein the composition comprises about 10 mg to about 50 mg of the compound.

119. 119. The method of any one of claims 1-118, wherein the administration period is from about 1 year to about 30 years.

120. 119. The method of any one of claims 1-118, wherein the administration period is from about 1 year to about 20 years.

121. 119. The method of any one of claims 1-118, wherein the administration period is from about 1 year to about 15 years.

122. 119. The method of any one of claims 1-118, wherein the administration period is from about 1 year to about 10 years.

123. 119. The method of any one of claims 1-118, wherein the administration period is from about 1 year to about 5 years.

124. 119. The method of any one of claims 1-118, wherein the administration period is from about 1 year to about 5 years.

125. The administration period is about 119. The method of any one of claims 1 to 118, wherein the treatment is for 1 year to about 3 years.

126. 119. The method of any one of claims 1-118, wherein the administration period is from about 2 years to about 10 years.

127. 119. The method of any one of claims 1-118, wherein the administration period is from about 2 years to about 8 years.

128. 119. The method of any one of claims 1-118, wherein the administration period is from about 2 years to about 5 years.

129. 119. The method of any one of claims 1-118, wherein the administration period is from about 2 years to about 4 years.

130. 119. The method of any one of claims 1-118, wherein the administration period is from about 2 years to about 3 years.

131. 119. The method of any one of claims 1-118, wherein the administration period is at least about 30 days.

132. 119. The method of any one of claims 1-118, wherein the administration period is at least about 60 days.

133. 119. The method of any one of claims 1-118, wherein the administration period is at least about 90 days.

134. 119. The method of any one of claims 1-118, wherein the administration period is at least about 4 months.

135. 119. The method of any one of claims 1-118, wherein the administration period is at least about 6 months.

136. 119. The method of any one of claims 1-118, wherein the administration period is at least about 8 months.

137. 119. The method of any one of claims 1-118, wherein the administration period is at least about 10 months.

138. 119. The method of any one of claims 1-118, wherein the administration period is at least about 1 year.

139. 119. The method of any one of claims 1-118, wherein the administration period is at least about 2 years.

140. 119. The method of any one of claims 1-118, wherein the administration period is at least about 3 years.

141. 119. The method of any one of claims 1-118, wherein the administration period is at least about 4 years.

142. 119. The method of any one of claims 1-118, wherein the administration period is at least about 5 years.

143. 119. The method of any one of claims 1-118, wherein the administration period is at least about 10 years. 【Request Item 144】 【Chemistry 36】 or a pharmaceutically acceptable salt or deuterated form thereof.

145. compound 【Chemistry 37】 or a pharmaceutically acceptable salt or deuterated form thereof.

146. compound 【Transformation 38】 or a pharmaceutically acceptable salt or deuterated form thereof.

147. compound 【Chemistry 39】 or a pharmaceutically acceptable salt or deuterated form thereof.

148. compound 【Chemistry 40】 or a pharmaceutically acceptable salt or deuterated form thereof.

149. compound 【Chemistry 41】 or a pharmaceutically acceptable salt or deuterated form thereof.

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