WO2022232420A1 - Certain n-(1-cyano-2-phenylethyl)-1,4-oxazepane-2-carboxamides for treating cancer - Google Patents

Certain n-(1-cyano-2-phenylethyl)-1,4-oxazepane-2-carboxamides for treating cancer Download PDF

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WO2022232420A1
WO2022232420A1 PCT/US2022/026769 US2022026769W WO2022232420A1 WO 2022232420 A1 WO2022232420 A1 WO 2022232420A1 US 2022026769 W US2022026769 W US 2022026769W WO 2022232420 A1 WO2022232420 A1 WO 2022232420A1
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cancer
subject
alkyl
composition
oxazepane
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PCT/US2022/026769
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French (fr)
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Kuan-Ju CHEN
Jimin Zhang
David Cipolla
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Insmed Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Cancer is a complex disease that often results from dysfunction in multiple regulatory systems, such as, DNA repair, apoptosis and immune cells.
  • neutrophils are immune cells, which can play an important role in the development of at least some cancers, particularly metastatic cancers.
  • Serine proteases released from neutrophils, and neutrophil extracellular traps (NETs) are thought to be pivotal players in tumor initiation and progression.
  • NETs neutrophil extracellular traps
  • the present disclosure provides a method of inhibiting dipeptidyl peptidase (DPP1) in a subject having cancer or at risk of developing cancer, comprising: administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
  • R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl, or C 1-3 alkyl
  • R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH 2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring
  • X is O, S or CF 2
  • Y is O or S
  • Q is CH or N
  • R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, and tetrahydropyran
  • R 7 is hydrogen, F, Cl or CH 3, thereby inhibiting DPP1 in the subject.
  • the present disclosure provides a method of treating cancer in a subject in need of treatment.
  • the method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • the method further comprises administering radiation therapy to the subject.
  • the present disclosure provides a method of treating cancer- induced pain in a subject having cancer.
  • the method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • the cancer-induced pain is cancer-induced bone pain (CIBP).
  • the method further comprises administering radiation therapy to the subject.
  • a method for improving a radiation response in a subject having cancer includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.; and administering radiation therapy to the subject.
  • the cancer in the subject has previously been treated with radiation therapy.
  • improving the radiation response comprises reducing radioresistance of the cancer.
  • the radiation therapy is administered prior to the administration period. In another embodiment, the radiation therapy is administered subsequent to the administration period.
  • the radiation therapy is administered during the administration period. In even another embodiment, the radiation therapy is administered prior to the administration period and either (i) during the administration period or (ii) subsequent to the administration period.
  • the radiation therapy in one embodiment, comprises external beam radiation.
  • the external beam radiation therapy comprises three-dimensional conformal radiation therapy (3D-CRT), image guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), helical-tomotherapy, photon beam radiation therapy, proton beam radiation therapy or stereotactic radiosurgery.
  • the radiation therapy comprises brachytherapy.
  • the radiation therapy in one embodiment, is carried out for about 1 week to about 10 weeks, for about 1 week to about 8 weeks, for about 1 week to about 6 weeks, for about 1 week to about 4 weeks or for about 1 week to about 2 weeks. In another embodiment, the radiation therapy is carried out 5 days per week while radiation therapy is being administered.
  • DPP1 is expressed by cancerous cells, neutrophils, macrophages, monocytes, or mast cells of the subject.
  • the cancer comprises a primary solid tumor, a liquid tumor, a metastatic cancer, or a combination thereof.
  • the cancer comprises a primary solid tumor.
  • the cancer is selected from the group consisting of breast cancer, bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibroid cancer, lymphoma, virus-induced cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, melanoma, and bone cancer.
  • the cancer is bone cancer.
  • the cancer comprises a liquid tumor.
  • the cancer comprising a 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, a myeloproliferative disorder, 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).
  • AML acute myeloid leukemia
  • AML acute lymphoblastic leukemia
  • acute lymphocytic leukemia acute promyelocytic leukemia
  • chronic myeloid leukemia hairy cell leukemia
  • a myeloproliferative disorder Natural Killer cell leukemia, blastic plasmacytoid dendritic cell n
  • the pediatric cancer comprises neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma.
  • the cancer comprises a metastatic cancer.
  • the subject is at a risk for developing a metastatic cancer.
  • the metastatic cancer comprises a metastatic breast cancer, e.g., metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, and/or liver.
  • the metastatic cancer comprises metastasis of breast cancer to the bone.
  • the metastatic cancer comprises a metastatic bone cancer, e.g., metastasis of bone cancer to the lung.
  • the metastatic cancer comprises a metastatic prostate cancer, e.g., metastasis of prostate cancer to the lung, the pancreas, the kidney, the spleen, the intestine, the liver, the bone, and/or the lymph nodes.
  • the metastatic cancer comprises metastasis of prostate cancer to the bone.
  • the metastatic cancer comprises a metastatic myeloma, e.g., metastasis of myeloma to the bone.
  • the metastatic cancer comprises a metastatic lung cancer, e.g., metastasis of lung cancer to the bone, the brain, the lymph nodes, the liver, the ovary, and/or the intestine. In a further embodiment, the metastatic cancer comprises metastasis of lung cancer to the bone.
  • the metastatic cancer comprises a metastatic bladder cancer, e.g., metastasis of bladder cancer to the bone, the liver and/or the lung. In a further embodiment, the metastatic cancer comprises metastasis of bladder cancer to the bone.
  • the metastatic cancer comprises a metastatic thyroid cancer, e.g., metastasis of thyroid cancer to the bone, the liver and/or the lung. In a further embodiment, the metastatic cancer comprises metastasis of thyroid cancer to the bone. [0025] In some embodiments, the metastatic cancer comprises a metastatic pancreatic cancer, e.g., metastasis of pancreatic cancer to the mesentery, the ovary, the kidney, the spleen, the lymph nodes, the stomach, and/or the liver. [0026] In some embodiments, administration of the composition diminishes the severity of, delays the onset of, or eliminates a symptom of cancer.
  • the symptom of cancer is cancer-induced bone pain. In some embodiments, the symptom of cancer is allodynia. In some embodiments, the allodynia is tactile allodynia. In some embodiments, the tactile allodynia is static mechanical allodynia. In some embodiments, the tactile allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastasis to the bone.
  • the subject has bone cancer or metastasis to the bone, and the subject experiences decreased bone pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition.
  • the subject undergoes surgery and/or is administered chemotherapy, immunotherapy, targeted therapy, an immune checkpoint inhibitor, hormone therapy, or any combination thereof.
  • the compound of Formula (I) is (2S)-N- ⁇ (1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ - 1,4-oxazepane-2-carboxamide, referred to herein by its international nonproprietary name (INN), brensocatib (and formerly known as INS1007 and AZD7986), , or a pharmaceutically acceptable salt thereof.
  • the composition is administered orally.
  • the administration period is at least about 30 days, 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 18 months, at least about 24 months or at least about 30 months.
  • the subject does not have breast- to-lung metastasis.
  • FIG. 2 depicts the study design to evaluate the treatment of cancer-induced bone pain by administering brensocatib.
  • FIG.3 shows the body weight change as a function of time for the six groups of animals tested in Example 1.
  • FIG. 4 is a bar graph showing the mechanical allodynia paw withdrawal threshold (PWT) (g) at Day 0 for each of the 6 groups tested in Example 1.
  • FIG. 5 is a bar graph showing the mechanical allodynia paw withdrawal threshold (PWT) (g) at Day 7 for each of the 6 groups tested in Example 1.
  • FIG. 6 is a bar graph showing the mechanical allodynia paw withdrawal threshold (PWT) (g) at Day 14 for each of the 6 groups tested in Example 1.
  • FIGS. 7-12 are graphs showing the PWT (g) as a function of time for the individual animals in each of the six groups tested in Example 1.
  • FIG. 7 Morphine group (group 4 in Table 1);
  • FIG. 8 Leave alone control (group 6 in Table 1);
  • FIG. 9 Placebo (group 5 in Table 1);
  • FIG. 10 Brensocatib: day -7 – day 13 (group 1 in Table 1);
  • FIG. 11 Brensocatib: day 0 – day 13 (group 2 in Table 1);
  • FIG. 12 Brensocatib day 7 – day 13 (group 3 in Table 1).
  • FIG. 7 Morphine group (group 4 in Table 1);
  • FIG. 8 Leave alone control (group 6 in Table 1);
  • FIG. 9 Placebo (group 5 in Table 1);
  • FIG. 10 Brensocatib: day -7 – day 13 (group 1 in Table 1);
  • FIG. 11 Brensocatib: day 0 – day 13 (group 2 in Table
  • FIG. 13 is a graph showing the percentage of rats in each group reaching the effective paw withdrawal threshold (PWT) on Day 0, Day 7 and Day 14.
  • FIGS. 14 provides a study schematic examining the effects of brensocatib on cancer- induced pain.
  • FIG.15 depicts the study design to evaluate the treatment of metastatic cancer in mouse models by administering brensocatib. The metastatic cancer mouse models are generated by intravenously injecting tumor cells.
  • FIG. 16 depicts the general study design to evaluate the treatment of spontaneous metastasis mouse models with brensocatib. The treatment of lung, colon, prostate, pancreatic, and other cancer types by brensocatib will be evaluated using this general study design.
  • FIG.17 depicts the study design to evaluate anti-primary and metastatic tumor effect of brensocatib using a BX-PC3 pancreatic cancer orthotopic spontaneous metastasis xenograft mouse model.
  • FIG. 18 is a graphic representation of in vivo imaging data of the BX-PC3 pancreatic cancer orthotopic spontaneous metastasis xenograft mouse model treated with placebo or brensocatib. The bioluminescent intensity for placebo control group was statistically greater than those of the brensocatib treatment groups on day 33 and day 36 (p ⁇ 0.005).
  • the present disclosure provides reversible inhibitors of dipeptidyl peptidase 1 (DPP1) or cathepsin C, and methods of use thereof.
  • the methods of use are methods of treating cancer.
  • DPP1 catalyses excision of dipeptides from the N-terminus of protein and peptide substrates. Through this enzymatic function, DPP1 activates many serine proteases in immune/inflammatory cells, such as neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and neutrophil serine protease 4 (NSP4).
  • NSPs neutrophil serine proteases
  • NE neutrophil elastase
  • PR3 proteinase 3
  • CatG cathepsin G
  • NSP4 neutrophil serine protease 4
  • Neutrophil serine proteases can mediate tumor initiation, tumor progression and/or tumor metastasis.
  • neutrophils play an important role in stages of metastasis, such as intravascular dissemination, extravasation, and metastatic growth.
  • Neutrophils can aid cancer cell adhesion to the endothelium in metastatic sites with their surface expression of selectins and integrins.
  • Neutrophil-derived IL- ⁇ FDQ ⁇ SURPRWH ⁇ WXPRU ⁇ FHOO ⁇ H[WUDYDVDWLRQ ⁇ )XUWKHUPRUH ⁇ neutrophil extracellular traps (NETs) can induce invasive and migratory behaviors of tumor cells.
  • NETs can also result in the degradation of thrombospondin-1, which in turn facilitates metastatic cancer growth.
  • inhibition of DPP1 function by the disclosed DPP1 inhibitors can result in inhibition of NSPs and/or the pro-cancerous functions of neutrophils, and therefore, inhibit the development, growth and progression of a variety of cancers, and stages of cancer metastasis (such as intravascular dissemination, extravasation).
  • the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
  • alkyl refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).
  • C 1-3 means a carbon group having 1, 2 or 3 carbon atoms.
  • alkyl includes both straight and branched chain alkyl groups and may be substituted or non-substituted. “Alkyl” groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl.
  • a pharmaceutically acceptable moiety e.g., a salt, dosage form, or excipient
  • a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
  • treatment or “treating,” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit.
  • Therapeutic benefit refers to any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment.
  • treating includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (3) relieving the condition (for example, by causing regression, or reducing the severity of the state, disorder or condition or at least one of its clinical or subclinical symptoms).
  • the term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to achieve an outcome, for example, to effect beneficial or desired results.
  • the therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like.
  • the terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, such as a mammal.
  • the mammal may be, for example, a mouse, a rat, a rabbit, a cat, a dog, a pig, a sheep, a horse, a non-human primate (e.g., cynomolgus monkey, chimpanzee), or a human.
  • a subject s tissues, cells, or derivatives thereof, obtained in vivo or cultured in vitro are also encompassed.
  • a human subject may be an adult, a teenager, a child (2 years to 14 years of age), an infant (1 month to 24 months), or a neonate (up to 1 month). In some embodiments, the adults are seniors about 65 years or older, or about 60 years or older.
  • cancer-induced pain is pain that is associated, correlated, or caused by cancer.
  • cancer-induced pain results from the growth of the cancer into or adjacent to nearby cells, tissues, or organs.
  • cancer-induced pain is caused by the tumor pressing against nerves, bones or other tissues.
  • the cancer releases chemicals that cause pain.
  • the cancer-induced pain is cancer-induced bone pain.
  • cancer-induced bone pain refers to a pain state having features of both inflammatory and neuropathic pain seen in subjects with primary bone cancer, or cancer metastasis to the bone.
  • the CIBP comprises steady background pain, and/or pain that is exacerbated by weight bearing or movement (incident or episodic pain).
  • CIBP is experienced in the lower back, pelvis, long bones, and/or ribs.
  • the CIBP is a presenting feature of the cancer.
  • the CIBP highlights cancer recurrence in a previously treated subject.
  • the present disclosure provides a method of inhibiting DPP1 in a subject diagnosed with a cancer.
  • the method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
  • R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl, or C 1-3 alkyl
  • R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH 2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring
  • X is O, S or CF 2
  • Y is O or S
  • Q is CH or N
  • R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, and tetrahydropyran
  • R 7 is hydrogen, F, Cl or CH 3,
  • the subject has cancer or is at risk of developing cancer.
  • the administration results in the treatment or delay in the onset of cancer in the subject.
  • the subject has previously been administered radiation therapy prior to administration of the composition comprising an effective amount of a compound of Formula (I).
  • the present disclosure provides a method of treating cancer in a subject in need of treatment. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • the present disclosure further provides a method of treating cancer in a subject in need of treatment.
  • the method includes (a) determining a level of DPP1 in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • the level of DPP1 determined in step (a), or the level of DPP1 in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about
  • the level of DPP1 determined in step (a) is in the range of about 1 ng/mL to about 100 ng/mL. In a further embodiment, the level of DPP1 determined in step (a) is in the range of about 5 ng/mL to about 20 ng/mL. In the present disclosure, in some embodiments, the level of DPP1 refers to the level of total DPP1, including both active and inactive DPP1. In other embodiments, the level of DPP1 refers to the level of active DPP1.
  • the level or activity of DPP1 determined in step (a), or the level or activity of DPP1 in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of DPP1 in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the level or activity of DPP1 determined in step (a), or the level or activity of DPP1 in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000%, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of DPP1 in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the disclosure further provides a method of treating cancer in a subject in need of treatment.
  • the method includes (a) determining a level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • NETs neutrophil extracellular traps
  • the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about
  • the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the present disclosure further provides a method of treating cancer in a subject in need of treatment.
  • the method includes (a) determining a level of a neutrophil serine protease (NSP) in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • NSP neutrophil serine protease
  • the level of the NSP determined in step (a), or the level of the NSP in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about
  • the level of an NSP refers to the level of total NSP, including both the active and inactive forms of the NSP. In other embodiments, the level of an NSP refers to the level of the active form(s) of the NSP.
  • the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the method further comprises administering radiation therapy to the subject.
  • the present disclosure provides a method of treating cancer- induced pain in a subject having cancer. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • the cancer-induced pain is cancer-induced bone pain (CIBP).
  • the method further comprises administering radiation therapy to the subject.
  • CIBP cancer-induced bone pain
  • a method for improving a radiation response in a subject having cancer is provided.
  • the method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.; and administering radiation therapy to the subject.
  • the present disclosure further provides a method for improving a radiation response in a subject having cancer. The method includes (a) determining a level of NETs in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein; and administering radiation therapy to the subject.
  • the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about
  • the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the present disclosure further provides a method for improving a radiation response in a subject having cancer.
  • the method includes (a) determining a level of an NSP in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein; and administering radiation therapy to the subject.
  • the level of the NSP determined in step (a), or the level of the NSP in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about
  • the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer.
  • the cancer in the subject has previously been treated with radiation therapy.
  • improving the radiation response comprises reducing radioresistance of the cancer.
  • the radiation therapy is administered prior to the administration period.
  • the radiation therapy is administered subsequent to the administration period.
  • the radiation therapy is administered during the administration period.
  • the radiation therapy is administered prior to the administration period and either (i) during the administration period or (ii) subsequent to the administration period.
  • the radiation therapy in one embodiment, comprises external beam radiation.
  • the external beam radiation therapy comprises three-dimensional conformal radiation therapy (3D-CRT), image guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), helical-tomotherapy, photon beam radiation therapy, proton beam radiation therapy or stereotactic radiosurgery.
  • the radiation therapy comprises brachytherapy.
  • the radiation therapy in one embodiment, is carried out for about 1 week to about 10 weeks, for about 1 week to about 8 weeks, for about 1 week to about 6 weeks, for about 1 week to about 4 weeks or for about 1 week to about 2 weeks. In another embodiment, the radiation therapy is carried out 5 days per week while radiation therapy is being administered.
  • DPP1 is expressed by cancerous cells, neutrophils, macrophages, monocytes, or mast cells of the subject.
  • a level of DPP1 in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL, or about 1 ng/mL to about 100 ng/mL, before administration of the composition.
  • the activity of DPP1 in a biological sample obtained from the subject after administration of the composition is less than: (a) the activity of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • the activity of DPP1 in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) the activity of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • a level of DPP1 in a biological sample obtained from the subject after administration of the composition is less than: (a) a level of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • a level of DPP1 in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a level of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • a level of NETs in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL before administration of the composition.
  • a level of NETs in a biological sample obtained from the subject after administration of the composition is less than: (a) a level of NETs in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of NETs in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • a level of NETs in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a level of NETs in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of NETs in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • the level of NETs is the level of circulating plasma NETs.
  • the level of NETs is determined by measuring DNA complexed with NET- molecules like myeloperoxidase (MPO-DNA) or neutrophil elastase (NE-DNA) using enzyme- linked immunosorbent assays (ELISAs), measuring the presence of citrullinated histones by fluorescence microscopy, flow cytometric detection of NET-components, immunofluorescence to detect the colocalization of NET-associated molecules (NE, MPO, CitH3) with extracellular DNA or using flow cytometry or confocal microscopy-based methods.
  • MPO-DNA myeloperoxidase
  • NE-DNA neutrophil elastase
  • ELISAs enzyme- linked immunosorbent assays
  • a level of an NSP in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL before administration of the composition.
  • the activity of an NSP in a biological sample obtained from the subject after administration of the composition is less than: (a) the activity of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • the activity of the NSP in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) the activity of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • a level of an NSP in a biological sample obtained from the subject after administration of the composition is less than: (a) a level of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • a level of the NSP in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a level of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition.
  • the NSP is a secreted NSP, or an NSP in the cytoplasmic granules.
  • the NSP is a proform of the NSP.
  • the NSP is the active form of the NSP.
  • the NSP is a secreted proform of the NSP.
  • the NSP comprises neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), neutrophil serine protease 4 (NSP4), or any combination thereof.
  • the NSP is cell surface-localized NSP, intracellular NSP, or a combination thereof.
  • the level of the cell surface-localized NSP or intracellular NSP is measured using flow cytometry.
  • the biological sample comprises blood, serum, white blood cells, neutrophils, a cancer tissue, tumor cells, tumor T-cells, or any combination thereof.
  • the level or activity of a cytokine or an inflammatory cytokine in a biological sample obtained from the subject is determined before administration of the composition.
  • the present disclosure further provides methods of treating cancer in a subject in need thereof, comprising: (a) determining a level or activity of a cytokine or an inflammatory cytokine in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as disclosed herein.
  • a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as disclosed herein.
  • the inflammatory cytokines include IL-6, IL-1, and TNF- ⁇ ,Q ⁇ VRPH ⁇ embodiments
  • the cytokine is a cytokine described in Berraondo et al., British Journal of Cancer volume 120, pages 6–15(2019).
  • the level or activity of the cytokine or inflammatory cytokine is altered (lower or higher), as compared to a healthy subject who does not have cancer.
  • a level or activity of a biomarker in a biological sample obtained from the subject is determined before administration of the composition.
  • the present disclosure further provides methods of treating cancer in a subject in need thereof, comprising: (a) determining a level or activity of a biomarker in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as disclosed herein.
  • biomarkers include biomarkers which can be evaluated based on immunocytochemistry or immunohistochemistry (such as, for example, Her2, ER, PR, PD-L1, PD-1, TIM3, MMR, c-MET, ALK, EGFR, CTLA4, Foxp3, PTEN, P16, Ki67, CD20, PAX-5, CD3, CD5, CD8, CD10, CD13, CD16,CD22, CD23, CD33, CD34, POX (MPO), CD79a, TdT, CD11b, CD45, CD68, GL7, GrazymeB, Ly- ⁇ * ⁇ &' ⁇ 1. ⁇ $3 ⁇ -Catenin, CXCR4, CXCL12, LAG3, total Rb, and CyclinD1), biomarkers that can be evaluated by fluorescence in-situ hybridization (such as, for example, Her2, EGFR, FGFR1, ALK, MET, ROS1,AXL, Bcl-2, Bcl-6), biomarkers that can be evaluated based on
  • the level or activity of the biomarker is altered (lower or higher), as compared to a healthy subject who does not have cancer.
  • the cancer comprises a primary solid tumor, a liquid tumor, a metastatic cancer, or a combination thereof.
  • the cancer comprises a primary solid tumor.
  • the cancer is selected from the group consisting of breast cancer, bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibroid cancer, lymphoma, virus-induced cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, melanoma, and bone cancer.
  • the cancer is bladder cancer.
  • the cancer is lung cancer.
  • the cancer is brain cancer.
  • the cancer is ovarian cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibroid cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is virus-induced cancer. In some embodiments, the cancer is oropharyngeal cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is thymus cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer.
  • the fibroid cancer is leiomyosarcoma.
  • the cancer is breast cancer.
  • the breast cancer comprises ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer.
  • the breast cancer comprises ductal carcinoma.
  • the breast cancer comprises lobular carcinoma.
  • the breast cancer comprises medullary carcinoma.
  • the breast cancer comprises colloid carcinoma.
  • the breast cancer comprises tubular carcinoma.
  • the breast cancer comprises inflammatory breast cancer.
  • the breast cancer is triple-negative breast cancer.
  • the breast cancer does not respond to hormonal therapy or therapeutics that target the HER2 protein receptors.
  • the lymphoma is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, Natural Killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma or Kaposi’s Sarcoma.
  • the lymphoma is Hodgkin’s lymphoma.
  • the lymphoma is non-Hodgkin’s lymphoma.
  • the lymphoma is diffuse large B-cell lymphoma.
  • the lymphoma is B-cell immunoblastic lymphoma. In some embodiments, the lymphoma is Natural Killer cell lymphoma. In some embodiments, the lymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma. In some embodiments, the lymphoma is Kaposi’s Sarcoma. [0106] In some embodiments, the brain cancer is astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma.
  • 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. [0107] In some embodiments, the cancer comprises a liquid tumor.
  • the cancer comprising a 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, a myeloproliferative disorder, 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).
  • AML acute myeloid leukemia
  • AML acute lymphoblastic leukemia
  • acute lymphocytic leukemia acute promyelocytic leukemia
  • chronic myeloid leukemia hairy cell leukemia
  • a myeloproliferative disorder Natural Killer cell leukemia
  • the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is acute lymphocytic leukemia. In some embodiments, the cancer is acute promyelocytic leukemia. In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is hairy cell leukemia. In some embodiments, the cancer is a myeloproliferative disorder. In some embodiments, the cancer is Natural Killer cell leukemia. In some embodiments, the cancer is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the cancer is chronic myelogenous leukemia (CML). In some embodiments, the cancer is mastocytosis.
  • CML chronic myelogenous leukemia
  • the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the cancer is myelodysplastic syndrome (MDS). [0108] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer comprises neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma. In some embodiments, the pediatric cancer comprises neuroblastoma. In some embodiments, the pediatric cancer comprises Wilms tumor. In some embodiments, the pediatric cancer comprises rhabdomyosarcoma.
  • the pediatric cancer comprises retinoblastoma. In some embodiments, the pediatric cancer comprises osteosarcoma. In some embodiments, the pediatric cancer comprises Ewing sarcoma.
  • the cancer comprises a metastatic cancer. In other embodiments, the subject is at a risk for developing a metastatic cancer. In some embodiments, the subject does not have breast-to-lung metastasis.
  • the metastatic cancer comprises a metastatic breast cancer, e.g., metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, and/or liver. In a further embodiment, the metastatic cancer comprises metastasis of breast cancer to the bone.
  • the metastatic cancer comprises a metastatic bone cancer, e.g., metastasis of bone cancer to the lung.
  • the metastatic cancer comprises a metastatic colorectal cancer, e.g., metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, and/or the spleen.
  • the metastatic cancer comprises a metastatic stomach cancer, e.g., metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, and/or the ovary.
  • the metastatic cancer comprises a metastatic leukemia, e.g., metastasis of leukemia to the lymph nodes, the lung, the liver, the limb, the brain, the kidney, and/or the spleen.
  • the metastatic cancer comprises a metastatic liver cancer, e.g., metastasis of liver cancer to the intestine, the spleen, the pancreas, the stomach, the lung, and/or the kidney.
  • the metastatic cancer comprises a metastatic lymphoma, e.g., metastasis of lymphoma to the kidney, the ovary, the liver, the bladder, and/or the spleen.
  • the metastatic cancer comprises a metastatic hematopoietic cancer, e.g., metastasis of hematopoietic cancer to the intestine, the lung, the liver, the spleen, the kidney, and/or the stomach.
  • the metastatic cancer comprises a metastatic melanoma, e.g., metastasis of melanoma to lymph nodes and/or the lung.
  • the metastatic cancer comprises a metastatic pancreatic cancer, e.g., metastasis of pancreatic cancer to the mesentery, the ovary, the kidney, the spleen, the lymph nodes, the stomach, and/or the liver.
  • the metastatic cancer comprises a metastatic prostate cancer, e.g., metastasis of prostate cancer to the lung, the pancreas, the kidney, the spleen, the intestine, the liver, the bone, and/or the lymph nodes.
  • the metastatic cancer comprises metastasis of prostate cancer to the bone.
  • the metastatic cancer comprises a metastatic ovarian cancer, e.g., metastasis of ovarian cancer to the diaphragm, the liver, the intestine, the stomach, the lung, the pancreas, the spleen, the kidney, the lymph nodes, and/or the uterus.
  • the metastatic cancer comprises a metastatic myeloma, e.g., metastasis of myeloma to the bone.
  • the metastatic cancer comprises a metastatic lung cancer, e.g., metastasis of lung cancer to the bone, the brain, the lymph nodes, the liver, the ovary, and/or the intestine. In a further embodiment, the metastatic cancer comprises metastasis of lung cancer to the bone.
  • the metastatic cancer comprises a metastatic kidney cancer, e.g., metastasis of kidney cancer to the liver, the lung, the pancreas, the stomach, the brain, and/or the spleen.
  • the metastatic cancer comprises a metastatic bladder cancer, e.g., metastasis of bladder cancer to the bone, the liver and/or the lung.
  • the metastatic cancer comprises metastasis of bladder cancer to the bone.
  • the metastatic cancer comprises a metastatic thyroid cancer, e.g., metastasis of thyroid cancer to the bone, the liver and/or the lung.
  • the metastatic cancer comprises metastasis of thyroid cancer to the bone.
  • the methods disclosed herein comprise treating cancer-induced bone pain (CIBP) in a subject having metastasis of a cancer to the bone.
  • the subject has metastasis of breast cancer, prostate cancer, lung cancer, bladder cancer, thyroid cancer, or myeloma to the bone.
  • the subject has metastasis of breast cancer to the bone.
  • the subject is identified as having metastasis to the bone by the use of any one of the following methods: plain film radiography, computed tomography, technetium-99m bone scan, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, fluorine positron emission tomography, and/or choline positron emission tomography, but is not yet feeling cancer-induced bone pain.
  • the subject is suffering from cancer-induced bone pain, which is indicative of metastasis of a previously treated or untreated primary tumor to the bone.
  • the cancer has metastasized to vertebrae, pelvis, long bones, or ribs.
  • administration of the composition diminishes the severity of, delays the onset of, or eliminates a symptom of cancer.
  • the symptom of cancer is cancer-induced bone pain (CIBP).
  • the CIBP is neuropathic pain.
  • the CIBP is inflammatory pain.
  • the CIBP is spontaneous pain.
  • the symptom of cancer is nociceptive hypersensitivity.
  • the symptom of cancer is allodynia.
  • the allodynia is tactile allodynia.
  • the tactile allodynia is static mechanical allodynia.
  • the tactile allodynia is dynamic mechanical allodynia.
  • the subject has bone cancer or metastasis to the bone.
  • the cancer comprises a solid tumor, and a volume of the solid tumor in the subject after administration of the composition is less than: (a) a volume of the solid tumor in the subject before administration of the composition, and/or (b) a volume of a solid tumor in a control subject, wherein the control subject has the solid tumor and is not administered the composition.
  • the cancer comprises a solid tumor
  • a volume of the solid tumor in the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a volume of the solid tumor in the subject before administration of the composition, and/or (b) a volume of a solid tumor in a control subject, wherein the control subject has the solid tumor and is not administered the composition.
  • the cancer comprises a plurality of solid tumors, and the subject exhibits fewer solid tumors after administration of the composition as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has a plurality of solid tumors and is not administered the composition.
  • the cancer comprises a plurality of solid tumors
  • the subject exhibits at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) fewer solid tumors after administration of the composition as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has a plurality of solid tumors and is not administered the composition.
  • the cancer induces a weight loss in the subject, and the weight loss is alleviated after administration of the composition, as compared to before administration of the composition.
  • the cancer-induced weight loss in the subject is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower after administration of the composition, as compared to before administration of the composition.
  • an overall survival period of the subject after administration of the composition is longer than an overall survival period of a control subject, wherein the control subject has cancer and is not administered the composition.
  • all survival is defined as the time from randomization until death from any cause and is measured in the intent-to-treat population, and is further described in the FDA guidance document titled “Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, Guidance for Industry, December 2018” which is incorporated herein by reference in its entirety for all purposes.
  • an overall survival period of the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, or about 500%, including all values and subranges that lie therebetween) longer than an overall survival period of a control subject, wherein the control subject has cancer and is not administered the composition.
  • the subject has bone cancer or metastasis to the bone, and the subject shows an increased bone mineral density after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition.
  • the subject has bone cancer or metastasis to the bone, and shows at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500% about 600%, about 700%, about 800%, about 900% or about 1000%, including all values and subranges that lie therebetween) higher bone mineral density after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition.
  • 2% for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%
  • the subject experiences decreased cancer-induced pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has cancer-induced pain and is not administered the composition.
  • the subject experiences at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has cancer-induced pain and is not administered the composition.
  • 2% for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween
  • the subject has bone cancer or metastasis to the bone, and experiences decreased bone pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition.
  • the subject has bone cancer or metastasis to the bone, and experiences at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower bone pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition.
  • at least about 2% for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 9
  • the subject has prostate cancer, and a blood level of prostate-specific antigen (PSA) in the subject is lower after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has prostate cancer and is not administered the composition.
  • PSA prostate-specific antigen
  • the subject has prostate cancer
  • a blood level of prostate-specific antigen (PSA) in the subject is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has prostate cancer and is not administered the composition.
  • PSA prostate-specific antigen
  • any one or more of the clinical endpoints described in the FDA guidance document titled “Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, Guidance for Industry, December 2018” which is incorporated herein by reference in its entirety for all purposes, may be used to evaluate the effect of administering the pharmaceutical composition comprising a compound of Formula (I) or its pharmaceutically acceptable salt, e.g., brensocatib, to the subject.
  • the rate of clinical improvement upon administering the composition is calculated over a period of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, about 21 days or about 28 days.
  • Embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, that can be used according to the methods disclosed herein are described below. It is noted that one or more DPP1 inhibitors other than the compounds of Formula (I), or pharmaceutically acceptable salts thereof, may also be used in place of, or in combination with, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, according to the disclosed treatment methods.
  • Non-limiting examples of DPP1 inhibitors other than the compounds of Formula (I), or pharmaceutically acceptable salts thereof contemplated for use include those disclosed in Chen et al., Journal of Medicinal Chemistry 64(16):11857-11885 (2021); Banerjee et al., Bioorganic & Medicinal Chemistry Letters 47:128202 (2021); Bondebjerg J et al., Bioorg Med Chem. 13:4408-4424 (2005); Bondejberg J et al., Bioorg Med Chem Lett. 16:3614-3617 (2006); Guarino C et al., Biochem Pharmacol.
  • the compound of Formula (I) is an S,S diastereomer.
  • the compound of Formula (I) has the following stereochemistry: (S,S diastereomer).
  • the other diastereomeric forms are also contemplated by the present invention.
  • the compound of Formula (I) is the R,R diastereomer: (R,R diastereomer).
  • the compound of Formula (I) is the R,S diastereomer: (R,S diastereomer).
  • the compound of Formula (I) is the S,R diastereomer: (S,R diastereomer).
  • the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an S,R diastereomer of a compound of Formula (I).
  • the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,S diastereomer of a compound of Formula (I). [0146] In one embodiment, the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,R diastereomer of a compound of Formula (I).
  • R 3 is hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl, or C 1- 3 alkyl; R 3 is hydrogen, F, Cl, Br, CN, CF3, SO 2 C 1-3 alkyl, CONH2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.
  • R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.
  • hydrogen, F, Cl or C 1-3 alkyl; and R 3 is hydrogen, F, Cl, CN or SO 2 C 1-3 alkyl.
  • 3 hydrogen, F or C 1-3 alkyl; and R is hydrogen, F or CN.
  • R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, and tetrahydropyran; and R 7 is hydrogen, F, Cl or CH 3 .
  • [0151] is O or S; R 6 is C 1-3 alkyl, optionally substituted by 1, 2 or 3 F and optionally substituted by OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, or tetrahydropyran; and R 7 is hydrogen, F, Cl or CH 3 .
  • R 1 ; X is O, S or CF 2 ; R 6 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F; and R 7 is hydrogen, F, Cl or CH 3 .
  • R 1 X is O; R 6 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F; and R 7 is hydrogen.
  • R 6 is C 1-3 alkyl, i.e., methyl, ethyl, or propyl.
  • R 6 is methyl.
  • R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl or C 1-3 alkyl.
  • R 2 is hydrogen, F, Cl or C 1-3 alkyl.
  • R 2 is hydrogen, F or C 1-3 alkyl.
  • R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl CONH2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.
  • R 3 is hydrogen, F, Cl, CN or SO 2 C 1-3 alkyl.
  • R 3 is hydrogen, F or CN.
  • R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1- 3alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, and tetrahydropyran.
  • R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F.
  • R 6 is methyl or ethyl.
  • R 6 is methyl.
  • R 7 is hydrogen, F, Cl or CH 3 .
  • the composition administered to the patient comprises an effective amount of (2S)-N- ⁇ (1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3- dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide (referred to herein by its international nonproprietary name (INN), brensocatib): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is brensocatib.
  • the compound of Formula (I) is: [0165] (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, [0166] (2S)-N- ⁇ (1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide, [0167] (2S)-N- ⁇ (1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide, [0168] 4’-[(2S)-N-[(1
  • the compound of Formula (I) is brensocatib.
  • brensocatib is in polymorphic Form A as disclosed in U.S. PatentNo. 9,522,894, the disclosure of which is incorporated herein by reference in its entirety for all purposes.
  • brensocatib is characteSzed by an X-ray powder diffraction pattern having a peak at about 12.2 ⁇ 0.2 (° 2-theta), measured using CuKa radiation.
  • brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 20.6 ⁇ 0.2 (° 2-theta), measured using CuKa radiation.
  • brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 12.2 ⁇ 0.2 and about 20.6 ⁇ 0.2 (° 2-theta), measured using CuKa radiation. In some embodiments, brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 12.2 ⁇ 0.2, about 14.3 ⁇ 0.2, about 16.2 ⁇ 0.2, about 19.1 ⁇ 0.2 and about 20.6 ⁇ 0.2 (° 2-theta), measured using CuKa radiation.
  • a compound of Formula (I) can be administered as a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt of a compound of Formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in diffeSng temperatures and humidities, or a desirable solubility in H 2 O, oil, or other solvent.
  • a salt may be used to aid in the isolation or puSfication of the compound of Formula (I).
  • pharmaceutically acceptable salts include, but are not limited to, an alkali metal salt, e.g., Na or K, an alkali earth metal salt, e.g., Ca or Mg, or an organic amine salt.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.
  • the compounds of Formula (I) may form mixtures of its salt and co-crystal forms. It is also to be understood that the methods provided herein can employ such salt/co-crystal mixtures of the compound of Formula (I).
  • Salts and co-crystals may be characterized using well known techniques, for example X-ray powder diffraction, single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state NMR, (to evaluate for example, C, N or P chemical shifts) or spectroscopic techniques (to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding).
  • compounds of Formula (I) may exist in solvated form, e.g., hydrates, including solvates of a pharmaceutically acceptable salt of a compound of Formula (I).
  • compounds of Formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. It is to be understood that the present disclosure encompasses all such isomeric forms.
  • the backbone of the compounds of Formula (I) has two chiral centers. Chiral center 1 is the most substituted carbon atom on the 1,4-oxazepane ring.
  • Chiral center 2 is the substituted carbon atom to which a cyano group, -NH-, and a benzyl group are attached.
  • the present disclosure encompasses the compounds of Formula (I) with the (S)-configuration for the ring substituent at chiral center 1 and the (S)-configuration for the benzyl substituent at chiral center 2 (i.e., the S,S diastereomer disclosed herein); the (S)-configuration for the ring substituent at chiral center 1 and the (R)-configuration for the benzyl substituent at chiral center 2 (i.e., the S,R diastereomer disclosed herein); the (R)-configuration for the ring substituent at chiral center 1 and the (S)-configuration for the benzyl substituent at chiral center 2 (i.e., the R,S diastereomer disclosed herein); and the (R)-configuration for the ring substituent at chiral center 1 and the (R)-configuration for the benzyl substituent at chiral center 2 (i.e., the R,R diastereomer disclosed herein
  • the compound of Formula (I) is (2S)-N- ⁇ (1S)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane- 2-carboxamide (i.e., brensocatib, the S,S isomer), shown below. pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is (2R)-N- ⁇ (1R)-1-Cyano-2-[4-(3- methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide (i.e., the R,R isomer), shown below. pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is (2S)-N- ⁇ (1R)-1-Cyano-2-[4-(3- methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide (i.e., the S,R isomer), shown below. pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is (2R)-N- ⁇ (1S)-1-Cyano-2-[4-(3- methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide (i.e., the R,S isomer), shown below. pharmaceutically acceptable salt thereof.
  • the composition comprises a mixture of two or more of the aforementioned stereoisomers.
  • the mixture in one embodiment, comprises the S,S isomer (brensocatib) and the S,R isomer of a compound of Formula (I).
  • composition comprises a mixture of the S,S isomer (brensocatib) and the R,S isomer. In yet another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,R isomer.
  • Certain compounds of Formula (I) may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g., restriction resulting from the presence of a ring bond or double bond. Accordingly, it is to be understood that the present disclosure encompasses all such isomers. Certain compounds of Formula (I) may also contain multiple tautomeric forms.
  • the compounds of Formula (I) encompass any isotopically-labeled (or “radio-labelled”) derivatives of a compound of Formula (I).
  • a derivative is a derivative of a compound of Formula (I) wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include 2 H (also written as “D” for deuterium).
  • a compound of Formula (I) is provided where one or more hydrogen atoms are replaced by one or more deuterium atoms; and the deuterated compound is used in one of the methods provided herein.
  • the compounds of Formula (I) may be prepared, in known manner, in a variety of ways.
  • compounds of Formula (I) are prepared according to the methods set forth in U.S. Patent No. 9,522,894, incorporated by reference herein in its entirety for all purposes.
  • Combination Therapies [0216]
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be used on their own, or in conjunction with the standard-of-care administered by a treating physician.
  • any standard-of-care therapeutic may be used in combination with the compounds disclosed herein.
  • the subject has undergone or will undergo surgery for treating the cancer.
  • the compound of Formula (I), or a pharmaceutically acceptable salts thereof is administered in combination with a neutrophil elastase (NE) inhibitor.
  • the NE inhibitor is sivelestat.
  • the compound of Formula (I) is brensocatib.
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof are administered in combination with chemotherapy, immunotherapy, targeted therapy, an immune checkpoint inhibitor, radiation therapy, hormone therapy, phototherapy, virotherapy, or any combination thereof.
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof are administered in combination with a tyrosine kinase inhibitor, e.g., erlotinib.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, or any combination thereof.
  • Exemplary anti-PD-1 antibodies include, for example, nivolumab (Opdivo®, Bristol-Myers Squibb Co.), pembrolizumab (Keytruda®, Merck Sharp & Dohme Corp.), PDR001 (Novartis Pharmaceuticals), and pidilizumab (CT-011, Cure Tech).
  • Exemplary anti-PD-L1 antibodies include, for example, atezolizumab (Tecentriq®, Genentech), duvalumab (AstraZeneca), MEDI4736, avelumab, and BMS 936559 (Bristol Myers Squibb Co.).
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof, e.g., brensocatib are administered in combination with an immunosuppressive drug.
  • immunosuppressive drugs include tacrolimus, cyclosporine, mycophenolate mofetil, mycophenolate sodium, azathioprine, and sirolimus.
  • the subject is administered corticosteroids, e.g., prednisone.
  • the compound of Formula (I), or pharmaceutically acceptable salts thereof, e.g., brensocatib is administered in combination with a cancer therapeutic selected from the group consisting of a BTK inhibitor, an HDAC inhibitor, an mTOR inhibitor, a proteasome inhibitor, a JAK inhibitor, a JAK/STAT inhibitor, a BCL-2 inhibitor, a MEK inhibitor, an anti-folate, a farnesyl transferase inhibitor, an antibody, an antibody-drug conjugate, a cytotoxic agent, and a chemotherapeutic agent.
  • a cancer therapeutic selected from the group consisting of a BTK inhibitor, an HDAC inhibitor, an mTOR inhibitor, a proteasome inhibitor, a JAK inhibitor, a JAK/STAT inhibitor, a BCL-2 inhibitor, a MEK inhibitor, an anti-folate, a farnesyl transferase inhibitor, an antibody, an antibody-drug conjugate, a cytotoxic agent, and a chemotherapeutic agent.
  • the BTK inhibitor is ibrutinib, RN-486 (6-cyclopropyl-8-fluoro- 2-(2-hydroxymethyl-3- ⁇ 1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo- 1,6-dihydro-pyridin-3-yl ⁇ -phenyl)-2H-isoquinolin-1-one), GDC-0834 ([R—N-(3-(6-(4-(1,4- dimethyl-3-oxopiperazin-2-yl) phenylamino)-4-methyl-5-oxo-4,5-dihydropy-razin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]), CGI-560 (N-[3-(8- anilinoimidazo[1,2-a]pyrazin-6-yl
  • the HDAC inhibitor is belinostat, vorinostat, panobinostat, romidepsin, or any combination thereof.
  • the mTOR inhibitor is everolimus.
  • the proteasome inhibitor is bortezomib, carfilzomib, or a combination thereof.
  • the JAK/STAT inhibitor is tofacitinib, INCB16562, AZD1480, or any combination thereof.
  • the BCL-2 inhibitor is ABT-737, ABT-263, navitoclax, or any combination thereof.
  • the MEK inhibitor is AZD8330 or ARRY-424704.
  • the anti-folate is pralatrexate.
  • the farnesyl transferase inhibitor is tipifarnib.
  • the antibody is obinutuzumab, alemtuzumab, rituximab, ofatumumab, brentuximab vedotin, or any combination thereof.
  • the antibody-drug conjugate is inotuzumab, ozogamicin, brentuximab vedotin, or any combination thereof.
  • the cytotoxic agent is bendamustine, gemcitabine, oxaliplatin, cyclophosphamide, vincristine, vinblastine, anthracycline, daunorubicin, daunomycin, doxorubicin, actinomycin dactinomycin, bleomycin, clofarabine, nelarabine, cladribine, asparaginase, methotrexate, pralatrexate, or any combination thereof.
  • the chemotherapeutic agent is fludarabine, ibrutinib, fostamatinib, lenalidomide, thalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, cyclophosphamide, doxorubicin hydroxydaunomycin, vincristine, oncovin, prednisone, or any combination thereof.
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof, e.g., brensocatib are administered in combination with a therapeutic targeting bone pain, such as, cancer-induced bone pain.
  • a therapeutic targeting bone pain such as, cancer-induced bone pain.
  • the therapeutic targeting bone pain is sivelestat.
  • the therapeutic targeting bone pain is an analgesic, an opiod (such as, morphine, fentanyl, buprenophine, oxycodone) or a non-steroidal anti-inflammatory drug.
  • the therapeutic targeting bone pain is radiotherapy, such as, using radioisotopes.
  • the therapeutic targeting bone pain is bisphosphonates (such as, pamidronate and zoledronate).
  • the therapeutic targeting bone pain is denosumab. Further examples of therapeutics targeting bone pain are described in Kane et al., BMJ 2015;350:h315, which is incorporated herein by reference in its entirety for all purposes.
  • the term administered “in combination,” as used herein, is understood to mean that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder (such as, cancer), such that the effects of the treatments on the patient overlap at a point in time. In certain embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent” delivery.
  • the delivery of one treatment ends before the delivery of the other treatment begins, which may be referred to as “sequential” or “serial” delivery.
  • the treatment is more effective because of combined administration.
  • the second treatment is more effective; for e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (synergistic).
  • the dosage administered will vary with the compound employed, the mode of administration, the treatment desired and the type of cancer being treated.
  • the subject is administered a compound of Formula (I) at a daily dosage of about 10 mgs to about 100 mgs, for example, about 15 mgs, about 20 mgs, about 25 mgs, about 30 mgs, about 35 mgs, about 40 mgs, about 45 mgs, about 50 mgs, about 55 mgs, about 60 mgs, about 65 mgs, about 70 mgs, about 75 mgs, about 80 mgs, about 85 mgs, about 90 mgs, about 95 mgs, or about 100 mgs, including all values and subranges that lie therebetween.
  • the subject is administered a compound of Formula (I) at a daily dosage of about 10 mgs to about 65 mgs.
  • the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • the daily dosage of a compound of the disclosure is in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg), for example, about 0.05 ⁇ g/kg, 0.1 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 5 ⁇ g/kg, 10 ⁇ g/kg, 20 ⁇ g/kg, 30 ⁇ g/kg, 40 ⁇ g/kg, 50 ⁇ g/kg, 60 ⁇ g/kg, 70 ⁇ g/kg, 80 ⁇ g/kg, 90 ⁇ g/kg, 100 ⁇ g/kg, 200 ⁇ g/kg, 300 ⁇ g/kg, 400 ⁇ g/kg, 500 ⁇ g/kg, 600 ⁇ g/kg, 700 ⁇ g/kg, 800 ⁇ g/kg, 900 ⁇ g/kg, 1 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70
  • the compound of Formula (I) is administered in an oral dosage form.
  • the compound of Formula (I) is administered as a 10 mg to 50 mg dosage form, for example, a 5 mg dosage form, a 10 mg dosage form, a 15 mg dosage form, a 20 mg dosage form, a 25 mg dosage form, a 30 mg dosage form, 35 mg dosage form, a 40 mg dosage form, a 45 mg dosage form or a 50 mg dosage form.
  • the dosage form is a 10 mg, 25 mg or 40 mg dosage form.
  • the dosage form is administered once daily.
  • the compound is brensocatib, or a pharmaceutically acceptable salt thereof.
  • Administration routes include oral, enteral, transmucosal, rectal, intranasal, inhalation (e.g., via an aerosol), buccal (e.g., sublingual), vaginal, intrathecal, intraocular, transdermal, in utero (or in ovo), parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular (including administration to skeletal, diaphragm and/or cardiac muscle), intradermal, intrapleural, intracerebral, intraarticular, intravascular or via infusion), topical (e.g., to both skin and mucosal surfaces, including airway surfaces, and transdermal administration), intralymphatic, and the like, as well as direct tissue or organ injection (e.g., to liver, skeletal muscle, cardiac muscle, diaphragm muscle or brain).
  • direct tissue or organ injection e.g., to liver, skeletal muscle, cardiac muscle, diaphragm muscle or brain.
  • the administration is by injection into the central nervous system. In one embodiment, administration is via the enteral route and is conducted through a nasogastric (NG) tube. [0241] In some embodiments, the administration is via intraosseous injection. In some embodiments, the subject administered the compounds disclosed herein via intraosseous injection has bone cancer, metastasis to the bone and/or cancer-induced bone pain. [0242] The length of the administration period in any given case may depend on the nature and severity of the condition being treated and/or prevented and be determined by the physician.
  • the compounds or compositions disclosed herein may be administered for a period of about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 week, about 2 weeks, about 3 weeks, 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 1 year, about 18 months, about 2 years, about 30 months, about 3 years, about 4 years, about 5 years, or more than 5 years.
  • the administration period for the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, 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 1 year, at least about 18 months, at least about 2 years, at least about 30 months, at least about 3 years, at least about 4 years, at least about 5 years.
  • the administration period for the methods provided herein, in another embodiment is from about 30 days to about 180 days.
  • 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. .
  • Administration schedules, including frequency of dosage may be determined by the physician.
  • the composition may be administered to the subject once a day or more than once a day during the administration period.
  • the composition may be administered to the subject twice a day.
  • the composition may be administered to the subject every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some embodiments, the composition may be administered to the subject weekly, bi-weekly or every three weeks. In some embodiments, the dosage form is administered at approximately the same time every day. [0245] In one embodiment, the composition is administered once daily during the administration period. In another embodiment, the composition is administered twice daily during the administration period. In another embodiment, the composition is administered every other day during the administration period. In another embodiment, the composition is administered once weekly, twice weekly, thrice weekly, four times weekly, five times weekly or six times weekly. [0246] The present disclosure provides compositions comprising any one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof.
  • the present disclosure further provides pharmaceutical compositions, comprising an effective amount of any one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) are generally administered in the form of a pharmaceutical composition in which the Formula (I) compound/salt (active pharmaceutical ingredient (API)) is in a composition comprising a pharmaceutically acceptable adjuvant(s), diluents(s) and/or carrier(s).
  • a pharmaceutically acceptable adjuvant(s), diluents(s) and/or carrier(s Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals – The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2 nd Ed. 2002, incorporated by reference herein in its entirety for all purposes.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.
  • the pharmaceutical composition may comprise from about 0.05 to about 99 wt%, for example, about 0.5 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 98 wt%, or about 99 wt%, from about 0.05 to about 80 wt%, or from about 0.10 to about 70 wt%, or from about 0.10 to about 50 wt%, of API, all percentages by weight being based on the total weight of the pharmaceutical composition.
  • compositions disclosed herein further comprise at least one pharmaceutically acceptable carrier, excipient, and/or vehicle, for example, solvents, buffers, solutions, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
  • the pharmaceutically acceptable carrier, excipient, and/or vehicle may comprise saline, buffered saline, dextrose, water, glycerol, sterile isotonic aqueous buffer, and combinations thereof.
  • the pharmaceutically acceptable carrier, excipient, and/or vehicle comprises phosphate buffered saline, sterile saline, lactose, sucrose, calcium phosphate, dextran, agar, pectin, peanut oil, sesame oil, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like) or suitable mixtures thereof.
  • the compositions disclosed herein further comprise minor amounts of emulsifying or wetting agents, or pH buffering agents.
  • compositions disclosed herein further comprise other conventional pharmaceutical ingredients, such as preservatives, or chemical stabilizers, such as chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, the parabens, ethyl vanillin, glycerin, phenol, parachlorophenol or albumin.
  • the compositions disclosed herein may further comprise antibacterial and antifungal agents, such as, parabens, chlorobutanol, phenol, sorbic acid or thimerosal; isotonic agents, such as, sugars or sodium chloride and/or agents delaying absorption, such as, aluminum monostearate and gelatin.
  • the adjuvant(s), diluent(s) or carrier(s) present in the pharmaceutical composition are selected based on the mode of administration.
  • the compound of the present disclosure may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, corn starch or amylopectin; cellulose derivative; binder, for example, gelatine or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and/or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets.
  • adjuvant(s), diluent(s) or carrier(s) for example, lactose, saccharose, sorbitol, mannitol
  • starch for example, potato starch, corn starch or amylope
  • the cores may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s).
  • the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the compound of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using pharmaceutical excipients like the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules.
  • the form of the pharmaceutical composition depends on the mode of administration.
  • the oral dosage form is a film-coated oral tablet.
  • the dosage form is an immediate release dosage form with rapid dissolution characteristics under in vitro test conditions.
  • the composition is an oral disintegrating tablet (ODT). ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole.
  • the composition is an oral thin film or an oral disintegrating film (ODF). Such formulations, when placed on the tongue, hydrate via interaction with saliva, and releases the active compound from the dosage form.
  • the ODF in one embodiment, contains a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA) or sodium alginate.
  • a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA) or sodium alginate.
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropyl cellulose
  • pullulan carboxymethyl cellulose
  • CMC carboxymethyl cellulose
  • PVA polyvinyl acetate
  • Na alginate sodium alginate.
  • Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example, may contain the compound of the disclosure, the balance being sugar and
  • the pharmaceutical composition is one of the compositions described in International Application Publication No. WO 2019/166626, the disclosure of which is incorporated herein by reference in its entirety for all purposes.
  • the pharmaceutical composition administered to the patient is Composition (A) comprising: (a) from about 1 to about 30 wt% of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; (b) from about 45 to about 85 wt% of a pharmaceutical diluent; (c) from about 6 to about 30 wt% of a compression aid; (d) from about 1 to about 15 wt% of a pharmaceutical disintegrant; (e) from about 0.00 to about 2 wt% of a pharmaceutical glidant; and (f) from about 1 to about 10 wt% of a pharmaceutical lubricant; wherein the components add up to 100 wt%.
  • the compound of Formula (I) is brensocatib.
  • brensocatib is in polymorphic Form A.
  • brensocatib is characterized by one of the X-ray powder diffraction patterns described above.
  • Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 1 to about 25 wt %; from about 1 to about 20 wt %; from about 1 to about 15 wt %; from about 1 to about 10 wt %; from about 1 to about 5 wt%, or from about 1 to about 3 wt % of the total weight of the composition.
  • Formula (I) e.g., brensocatib
  • Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 1.5 to about 30 wt%; from about 1.5 to about 25 wt%; from about 1.5 to about 20 wt%; from about 1.5 to about 15 wt%; from about 1.5 to about 10 wt %; or from about 1.5 to about 5 wt% of the total weight of the composition.
  • Formula (I) e.g., brensocatib
  • Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 3 to about 30 wt%; from about 3 to about 25 wt %; from about 3 to about 20 wt%; from about 3 to about 15 wt %; from about 3 to about 10 wt %; or from about 3 to about 5 wt% of the total weight of the composition.
  • the compound of Formula (I)) is present at from about 3 to about 10 wt % of the total weight of the composition.
  • the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt% or about 30 wt% of the total weight
  • Composition (A) comprises one or more pharmaceutical diluents selected from the group consisting of microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose, xylitol, and a combination of the foregoing.
  • pharmaceutical diluents selected from the group consisting of microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin
  • Composition (A) comprises two or more pharmaceutical diluents. In another embodiment, Composition (A) comprises one pharmaceutical diluent. In a further embodiment, the pharmaceutical diluent is microcrystalline cellulose. Microcrystalline cellulose is a binder/diluent in oral tablet and capsule formulations and can be used in dry-granulation, wet-granulation, and direct- compression processes.
  • Composition (A) comprises one or more pharmaceutical diluents in an amount from about 45 to about 80 wt%, from about 45 to about 75 wt%, from about 45 to about 70 wt%, from about 45 to about 65 wt%, from about 45 to about 60 wt%, or from about 45 to about 55 wt% of the total weight of the composition.
  • the one or more pharmaceutical diluents comprises microcrystalline cellulose.
  • the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • Composition (A) comprises one or more pharmaceutical diluents in an amount from about 50 to about 85 wt%, from about 50 to about 75 wt%, from about 55 to about 85 wt%, from about 55 to about 70 wt%, from about 60 to about 85 wt%, from about 65 to about 85 wt%, from about 70 to about 85 wt%, or from about 75 to about 85 wt% of the total weight of the composition.
  • the one or more pharmaceutical diluents is present at from about 55 to about 70 wt% of the total weight of the composition.
  • the one or more pharmaceutical diluents comprises microcrystalline cellulose.
  • Composition (A) comprises one or more pharmaceutical diluents in an amount of about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt% or about 85 wt% of the total weight of the composition.
  • the one or more pharmaceutical diluents in Composition (A) is microcrystalline cellulose.
  • the one or more pharmaceutical diluents comprises calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol.
  • a disintegrant in the Composition (A) may be, for example: alginic acid, calcium alginate, carboxymethylcellulose calcium, chitosan, croscarmellose sodium, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, starch, or a combination thereof.
  • the one or more disintegrants in Composition (A) is sodium starch glycolate.
  • the amount of the disintegrants present in Composition (A) is between 2% and 8% of the total weight of the composition. In a further embodiment, the amount of the disintegrants is about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt% or about 4.5 wt% of the total weight of the composition.
  • the physical properties of sodium starch glycolate, and hence its effectiveness as a disintegrant, are affected by the degree of crosslinkage, extent of carboxymethylation, and purity.
  • the one or more pharmaceutical disintegrants in Composition (A) comprises croscarmellose sodium.
  • Composition (A) comprises one or more pharmaceutical disintegrants in an amount from about 2 to about 14 wt%, from about 2 to about 13 wt%, from about 2 to about 12 wt%, from about 2 to about 11 wt%, from about 2 to about 10 wt%, from about 2 to about 9 wt%, from about 2 to about 8 wt%, from about 2 to about 7 wt%, from about 2 to about 6 wt%, from about 2 to about 5 wt%, from about 3.5 to about 4.5 wt% of the total weight of the composition.
  • the one or more pharmaceutical disintegrants is present at from about 3.5 to about 4.5 wt% of the total weight of the pharmaceutical composition.
  • the one or more pharmaceutical disintegrants is sodium starch glycolate.
  • the one or more pharmaceutical diluents comprises microcrystalline cellulose.
  • the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • a glidant in Composition (A) may be, for example: silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate and talc.
  • the one or more pharmaceutical glidants in Composition (A) is selected from silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, talc, or a combination of the foregoing.
  • the glidant is silicon dioxide.
  • Typical silicon dioxide concentrations for use herein range from about 0.05 to about 1.0 wt%.
  • Porous silica gel particles may also be used as a glidant, which may be an advantage for some formulations, with typical concentrations of 0.25-1%.
  • Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.00 to about 1.75 wt%; from about 0.00 to about 1.50 wt%; from about 0.00 to about 1.25 wt%; from about 0.00 to about 1.00 wt%; from about 0.00 to about 0.75 wt%; from about 0.00 to about 0.50 wt%; from about 0.00 to about 0.25 wt%; from about 0.00 to about 0.20 wt% of the total weight of the composition.
  • the one or more pharmaceutical glidants comprises silicon dioxide.
  • the one or more pharmaceutical disintegrants is sodium starch glycolate.
  • Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.05 to about 2 wt%; from about 0.05 to about 1.75 wt%; from about 0.05 to about 1.50 wt%; from about 0.05 to about 1.25 wt%; from about 0.05 to about 1.00 wt%; from about 0.05 to about 0.75 wt%; from about 0.05 to about 0.50 wt%; from about 0.05 to about 0.25 wt%; or from about 0.05 to about 0.20 wt% of the total weight of the composition.
  • the one or more pharmaceutical glidants is present at from about 0.05 to about 0.25 wt% of the total weight of the composition.
  • the one or more pharmaceutical glidants comprises silicon dioxide.
  • the one or more pharmaceutical disintegrants is sodium starch glycolate.
  • the one or more pharmaceutical diluents comprises microcrystalline cellulose.
  • the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.05 to about 2 wt%; from about 0.10 to about 2 wt%; from about 0.2 to about 2 wt%; from about 0.3 to about 2 wt%; or from about 0.40 to about 2 wt% of the total weight of the composition.
  • the one or more pharmaceutical glidants comprises silicon dioxide.
  • the one or more pharmaceutical disintegrants is sodium starch glycolate.
  • the one or more pharmaceutical diluents comprises microcrystalline cellulose.
  • the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • a lubricant may be, for example calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g.
  • glyceryl bihenehate, tribehenin and glyceryl behenate leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin and zinc stearate.
  • the one or more pharmaceutical lubricants in Composition (A) are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin and zinc stearate.
  • glyceryl behenate e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate
  • leucine magnesium stearate
  • myristic acid palmi
  • the one or more pharmaceutical lubricants are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, stearic acid, talc, tribehenin and zinc stearate.
  • Composition (A) comprises one or more pharmaceutical lubricants and the lubricant is not sodium stearyl fumarate.
  • the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • Composition (A) includes glycerol behenate as the lubricant.
  • the one or more pharmaceutical lubricants in Composition (A) comprises glyceryl behenate, magnesium stearate, stearic acid, or a combination thereof.
  • the lubricant in Composition (A) is glyceryl behenate, magnesium stearate, or a combination thereof.
  • the one or more pharmaceutical lubricants in Composition (A) comprises sodium stearyl fumarate and/or one or more behenate esters of glycerine.
  • Composition (A) comprises one or more pharmaceutical lubricants in an amount from about 1 wt% to about 9 wt %, from about 1 wt% to about 8 wt %, from about 1 wt% to about 7 wt %, from about 1 wt% to about 6 wt %, from about 1 wt% to about 5 wt %, from about 2 wt% to about 10 wt %, from about 2.5 wt% to about 10 wt %, from about 2 wt% to about 8 wt %, from about 2 wt% to about 7 wt %, from about 2 wt% to about 6 wt %, from about 2 wt% to about 5 wt %, from about 2 wt% to about 4.5 wt %, or from about 2.5 wt% to about 4.5 wt % of the total weight of the composition.
  • the one or more pharmaceutical lubricants is present at from about 2.5 to about 4.5 wt% of the total weight of the composition.
  • the one or more pharmaceutical lubricants in Composition (A) is glycerol behenate.
  • the one or more pharmaceutical glidants in Composition (A) comprises silicon dioxide.
  • the one or more pharmaceutical disintegrants in Composition (A) is sodium starch glycolate.
  • the one or more pharmaceutical diluents in Composition (A) comprises microcrystalline cellulose.
  • the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
  • the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate and/or one or more behenate esters of glycerine or a mixture thereof.
  • the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate, glyceryl dibehenate, glyceryl behenate, tribehenin or any mixture thereof.
  • the one or more pharmaceutical lubricants in Composition (A) comprises sodium stearyl fumarate.
  • the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate.
  • the one or more pharmaceutical lubricants in Composition (A) comprises one or more behenate esters of glycerine (i.e., one or more of glyceryl dibehenate, tribehenin and glyceryl behenate).
  • the compression aid in Composition (A) is dicalcium phosphate dihydrate (also known as dibasic calcium phosphate dihydrate) (DCPD). DCPD is used in tablet formulations both as an excipient and as a source of calcium and phosphorus in nutritional supplements.
  • Composition (A) comprises the compression aid, e.g., DCPD, in an amount from about 10 to about 30 wt%, including about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, or about 24 wt% of the total weight of the composition.
  • the compression aid is present at about 20 wt % of the total weight of the composition.
  • Composition (A) comprises the compression aid, e.g., DCPD, in an amount from about 10 to about 25 wt%, from about 10 to about 20 wt%, from about 10 to about 15 wt%, from about 15 to about 25 wt%, or from about 20 to about 25 wt%, or from about 18 to about 22 wt% of the total weight of the composition.
  • the compression aid is present at from about 18 to about 22 wt% of the total weight of the composition.
  • the compression aid is DCPD.
  • the one or more pharmaceutical lubricants in Composition (A) is glycerol behenate.
  • the one or more pharmaceutical glidants in Composition (A) comprises silicon dioxide.
  • the one or more pharmaceutical disintegrants in Composition (A) is sodium starch glycolate.
  • the one or more pharmaceutical diluents in Composition (A) comprises microcrystalline cellulose.
  • the compound of Formula (I) in the exemplary composition is brensocatib, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition administered to the patient is Composition (B) comprising: (a) from about 1 to about 30 wt% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; (b) from about 55 to about 75 wt% of a pharmaceutical diluent; (c) from about 15 to about 25 wt% of a compression aid; (d) from about 3 to about 5 wt% of a pharmaceutical disintegrant; (e) from about 0.00 to about 1 wt% of a pharmaceutical glidant; and (f) from about 2 to about 6 wt% of a pharmaceutical lubricant; wherein the components add up to 100 wt%.
  • composition (B) in some embodiments of the methods where Composition (B) is administered to the patient, the identity of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical glidant, and pharmaceutical lubricant in the composition may be one of those described above for Composition (A). In other embodiments, the amount of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical glidant, and pharmaceutical lubricant in Composition (B) may also be one of those described above for Composition (A), as long as the amount is within the corresponding broader range recited above for Composition (B). [0295]
  • the pharmaceutical compositions disclosed herein, including Compositions (A) and (B) may be in a solid dosage form suitable for oral administration to a human being.
  • the pharmaceutical composition is a pharmaceutical tablet.
  • Pharmaceutical tablets may be prepared using methods known to those skilled in the art including, for example, dry mixing / direct compression process as described in International Application Publication No. WO 2019/166626.
  • the pharmaceutical tablet comprises a tablet core wherein the tablet core comprises the pharmaceutical composition as disclosed herein and wherein the tablet core has a coating.
  • the coating is a film coating.
  • the film coating may be applied using conventional methods known to those skilled in the art.
  • a functional coating can be used to provide protection against, for example, moisture ingress or degradation by light. Additionally, a functional coating may be used to modify or control the release of the compound of Formula (I), e.g., brensocatib, from the composition.
  • the coating may comprise, for example, about 0.2 to about 10 wt% of the total weight of the pharmaceutical composition, e.g., from about 0.2 to about 4 wt%, from about 0.2 to about 3 wt%, from about 1 to about 6 wt%, or from about 2 to about 5 wt% of the total weight of the pharmaceutical composition.
  • FIGS. 4 Day 0
  • 5 Day 7
  • 6 Day 14
  • FIGS. 4 and 13 The results of the mechanical allodynia assessments are provided in FIGS. 4 (Day 0), 5 (Day 7) and 6 (Day 14).
  • all groups showed normal (100%) tolerance to the pain achieving the pain threshold (FIGs. 4 and 13).
  • brensocatib pre-treatment to Group 1 showed a statistically significant anti-neuropathic pain effect compared to placebo control on Day 7 and Day 14.
  • FIGS 7-12 Time-course monitoring for individual rats of each group is summarized in FIGS 7-12. By setting an effective threshold based on the data from the morphine, placebo, and no tumor leave alone control groups, the therapeutic response rate per group was calculated.
  • FIG. 13 At Day 0, all groups showed normal (100%) tolerance to the pain achieving the effective threshold.
  • Group 3 which had 100% of the rats failing to achieve the pain response threshold at Day 7, showed improvement with recovery to the same degree as Group 1, which had the longest duration of brensocatib treatment.
  • brensocatib treatment had a positive anti- neuropathic pain effect in the cancer-induced bone pain rat model, with more than 50% of the rats showing improvement in pain tolerance and a 7-day dosing regimen adequate to recover the maximum effect.
  • FIG. 14 provides a schematic of a follow-on study assessing mechanical allodynia in animals treated with brensocatib, the neutrophil elastase (NE) inhibitor sivelestat or a combination of brensocatib and morphine. The follow-on study will evaluate brensocatib treatment with or without the combination of morphine compared to morphine alone or sivelestat alone.
  • NE neutrophil elastase
  • Animals are pretreated 7 days before tumor inoculation on Day -7, and the tumor is inoculated on Day 0. Brensocatib treatment effects are evaluated on Day 7 compared to morphine at 3 mg/kg or NE inhibitor sivelestat. Additionally, the combination of brensocatib and morphine at 1 mg/kg will be evaluated and compared to morphine only at 1 mg/kg to investigate whether there is any synergistic effect of the two.
  • the timepoint for pain evaluation on Day 7 will be performed at 1 hr., 6 hr., and 24 hr. post-morphine treatment to investigate time-dependent response.
  • Example 2 Treatment of Intravenous (IV) Metastasis Mouse Model By Administration of Brensocatib
  • Mouse models are used to evaluate the effect of administering brensocatib on the treatment of cancer.
  • mouse models with thyroid cancer which show high DPP1 expression levels in the cancer cells, are used to evaluate the effects of administering brensocatib (10 mg/kg) twice daily.
  • the cancer cells injected in this experiment may be transfected with luciferase to enable monitoring of their location and cancer progression via in vivo imaging and ex vivo imaging. Further, this study also evaluates how brensocatib affects neutrophil-derived DPP1 and tumor- derived DPP1.
  • Downstream endpoint analyses include measuring brensocatib concentration and circulating NETs in plasma, measuring the level of NSPs and DPP1 in bone marrow pellet, histopathology analysis of tumor tissues including primary and metastatic sites, hematoxylin and eosin staining of tissues, immunohistochemistry of NETs, myeloperoxidase (MPO), neutrophil elastase (NE), neutrophil biomarker Ly6G, and Cathepsin C (CTSC).
  • MPO myeloperoxidase
  • NE neutrophil elastase
  • CTSC Cathepsin C
  • Example 3 Treatment of Spontaneous Metastasis Mouse Model By Administration of Brensocatib
  • An orthotopic spontaneous metastasis mouse model in either Balb/c or Balb/c nude mice is used to evaluate the treatment of metastatic cancer by the administration of brensocatib.
  • the general study design is shown in FIG.16.
  • the cancer cells injected in this experiment may be transfected with luciferase to enable monitoring of their location and cancer progression via in vivo imaging and ex vivo imaging.
  • H460 cells are orthotopically injected into mice on Day 0 as shown in FIG. 16. H460 cells are a fast growing non-small-cell lung cancer cell line. Treatment with brensocatib starts on Day -7, which is a week before tumor injection as prophylactic pre-treatment, or on Day 0 along with tumor cells injection as prophylactic co-treatment. Overall study lasts 5-7 weeks based on historical data; however, the termination timepoint in our study design is one day after more than 40% of animals die within any of the group in order to evaluate the progression of metastasis.
  • HCT116 cells are orthotopically injected into the cecal wall of mice on Day 0 as shown in FIG. 16.
  • HCT116 is a human colorectal carcinoma cell line that can form primary tumors and distant metastases upon transplantation into immunocompromised mice.
  • Treatment with brensocatib starts on Day -7, which is a week before tumor injection as prophylactic pre- treatment, or on Day 0 along with tumor cells injection as prophylactic co-treatment.
  • BX-PC-3-Luc2 is a light-producing cell line derived from BX-PC3 human pancreatic adenocarcinoma.
  • Group 1 mice received twice-daily brensocatib treatment at 10 mg/kg via oral gavage that lasted from Day -7, which was a week before tumor injection as prophylactic pre-treatment, to the end of study.
  • Group 2 mice received twice-daily placebo treatment via oral gavage from Day -7 to Day -1, followed by twice-daily brensocatib treatment at 10 mg/kg via oral gavage from Day 0 to the end of study.
  • mice received twice-daily placebo treatment via oral gavage from Day -7 to the end of study.
  • the study ended one day after 2 animals died in any of the three groups, which was day 38. Endpoints of the study include primary tumor and metastatic tumor progression, survival rate, NSP levels and activity in bone marrow cells, and histopathology analysis of primary tumor and metastatic tumor tissues.
  • One mouse from Group 2 died on day 29; two mice from group 2 died on day 38, and one mouse from Group 3 died on day 26.
  • In vivo imaging data of the mice presented in FIG. 18 demonstrated that brensocatib treatment, whether initiated on Day -7 in Group 1 or initiated on Day 0 in Group 2, inhibited overall tumor progression up to Day 36. IV.
  • PC-3M cells are orthotopically injected into the prostate of mice on Day 0 as shown in FIG. 16.
  • the PC3 cell line was originally derived from bone metastasis of human prostatic adenocarcinoma.
  • PC-3M-Luc-C6 is a subline of PC3 that has increased metastatic ability and is transfected with luciferase. Further details on the PC-3M cell line is provided in Zacharias, N.M., et al., Sci Rep 7, 16159 (2017), which is incorporated herein by reference in its entirety for all purposes.
  • Treatment with brensocatib starts on Day -7, which is a week before tumor injection as prophylactic pre-treatment, or on Day 0 along with tumor cells injection as prophylactic co-treatment. Overall study lasts 6-8 weeks based on historical data; however, the termination timepoint in our study design is one day after more than 40% of animals die within any of the group in order to evaluate the progression of metastasis.
  • the start day of brensocatib administration as a therapeutic for primary tumor or a prophylactic for metastatic tumor is 7 days post tumor engraftment. Treatment efficacy will be monitored by assaying different parameters as described herein.
  • Example 4 In vivo test of anti-tumor efficacy of brensocatib in the subcutaneous MB49 murine bladder cancer syngeneic model in female C57BL/6 mice [0315] The in vivo therapeutic efficacy of brensocatib in the treatment of the MB49 murine bladder cancer syngeneic model in female C57BL/6 mice is assessed. [0316] Tumor inoculation and treatment: Each mouse is inoculated subcutaneously at the right flank with MB49 tumor cells (1 x 10 6 /mouse) in 0.1 mL of PBS for tumor development. The test article administration and the animal numbers in each group are shown in the Table 4. The treatments start on Day 0 (the same day of tumor cell injection).

Abstract

The present disclosure relates to methods for treating cancer or cancer-induced bone pain, with a composition comprising an effective amount of a N-(1-cyano-2-phenylethyl)-1,4-oxazepane-2-carboxamide DPP1 inhibitor compound of Formula (I), or a pharmaceutically acceptable salt thereof, (Formula (I)). In one embodiment, the compound of Formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (brensocatib).

Description

CERTAIN N-(1-CYANO-2-PHENYLETHYL)-1,4-OXAZEPANE-2- CARBOXAMIDES FOR TREATING CANCER CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority from U.S. Provisional Application Serial No. 63/181,815, filed April 29, 2021, U.S. Provisional Application Serial No. 63/234,961, filed August 19, 2021, and U.S. Provisional Application Serial No. 63/241,754, filed September 8, 2021, the disclosure of each of which is incorporated by reference herein in its entirety. BACKGROUND OF THE INVENTION [0002] Cancer is among the leading causes of death worldwide. In 2020, over 1.8 million new cases of cancer were diagnosed in the United States and more than half a million people died from the disease. [0003] Cancer is a complex disease that often results from dysfunction in multiple regulatory systems, such as, DNA repair, apoptosis and immune cells. For instance, neutrophils are immune cells, which can play an important role in the development of at least some cancers, particularly metastatic cancers. Serine proteases released from neutrophils, and neutrophil extracellular traps (NETs) are thought to be pivotal players in tumor initiation and progression. [0004] Therefore, targeting immune cells with pro-cancerous functions promises to have therapeutic potential. Given the heterogeneous and dynamic nature of cancer, there continues to be a need to develop a therapeutic that could potentially target multiple cancer types at different stages of cancer progression, and that could also be used in combination with established treatment methods such as radiation therapy. SUMMARY OF THE INVENTION [0005] In one aspect, the present disclosure provides a method of inhibiting dipeptidyl peptidase (DPP1) in a subject having cancer or at risk of developing cancer, comprising: administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000004_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3, thereby inhibiting DPP1 in the subject. [0006] In another aspect, the present disclosure provides a method of treating cancer in a subject in need of treatment. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. In one embodiment, the method further comprises administering radiation therapy to the subject. [0007] In still another aspect, the present disclosure provides a method of treating cancer- induced pain in a subject having cancer. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the cancer-induced pain is cancer-induced bone pain (CIBP). In some embodiments, the method further comprises administering radiation therapy to the subject. [0008] In still another aspect, a method for improving a radiation response in a subject having cancer is provided. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.; and administering radiation therapy to the subject. In one embodiment, the cancer in the subject has previously been treated with radiation therapy. In one embodiment, improving the radiation response comprises reducing radioresistance of the cancer. [0009] In one embodiment of the methods involving administration of radiation therapy disclosed herein, the radiation therapy is administered prior to the administration period. In another embodiment, the radiation therapy is administered subsequent to the administration period. In yet another embodiment, the radiation therapy is administered during the administration period. In even another embodiment, the radiation therapy is administered prior to the administration period and either (i) during the administration period or (ii) subsequent to the administration period. [0010] The radiation therapy, in one embodiment, comprises external beam radiation. In a further embodiment, the external beam radiation therapy comprises three-dimensional conformal radiation therapy (3D-CRT), image guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), helical-tomotherapy, photon beam radiation therapy, proton beam radiation therapy or stereotactic radiosurgery. In another embodiment, the radiation therapy comprises brachytherapy. [0011] The radiation therapy, in one embodiment, is carried out for about 1 week to about 10 weeks, for about 1 week to about 8 weeks, for about 1 week to about 6 weeks, for about 1 week to about 4 weeks or for about 1 week to about 2 weeks. In another embodiment, the radiation therapy is carried out 5 days per week while radiation therapy is being administered. [0012] In some embodiments of the methods disclosed herein, DPP1 is expressed by cancerous cells, neutrophils, macrophages, monocytes, or mast cells of the subject. [0013] In some embodiments of the methods disclosed herein, the cancer comprises a primary solid tumor, a liquid tumor, a metastatic cancer, or a combination thereof. [0014] In some embodiments, the cancer comprises a primary solid tumor. In a further embodiment, the cancer is selected from the group consisting of breast cancer, bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibroid cancer, lymphoma, virus-induced cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, melanoma, and bone cancer. In a further embodiment, the cancer is bone cancer. [0015] In some embodiments, the cancer comprises a liquid tumor. In some embodiments, the cancer comprising a 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, a myeloproliferative disorder, 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). [0016] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer comprises neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma. [0017] In some embodiments of the methods disclosed herein, the cancer comprises a metastatic cancer. In other embodiments, the subject is at a risk for developing a metastatic cancer. [0018] In some embodiments, the metastatic cancer comprises a metastatic breast cancer, e.g., metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, and/or liver. In a further embodiment, the metastatic cancer comprises metastasis of breast cancer to the bone. [0019] In some embodiments, the metastatic cancer comprises a metastatic bone cancer, e.g., metastasis of bone cancer to the lung. [0020] In some embodiments, the metastatic cancer comprises a metastatic prostate cancer, e.g., metastasis of prostate cancer to the lung, the pancreas, the kidney, the spleen, the intestine, the liver, the bone, and/or the lymph nodes. In a further embodiment, the metastatic cancer comprises metastasis of prostate cancer to the bone. [0021] In some embodiments, the metastatic cancer comprises a metastatic myeloma, e.g., metastasis of myeloma to the bone. [0022] In some embodiments, the metastatic cancer comprises a metastatic lung cancer, e.g., metastasis of lung cancer to the bone, the brain, the lymph nodes, the liver, the ovary, and/or the intestine. In a further embodiment, the metastatic cancer comprises metastasis of lung cancer to the bone. [0023] In some embodiments, the metastatic cancer comprises a metastatic bladder cancer, e.g., metastasis of bladder cancer to the bone, the liver and/or the lung. In a further embodiment, the metastatic cancer comprises metastasis of bladder cancer to the bone. [0024] In some embodiments, the metastatic cancer comprises a metastatic thyroid cancer, e.g., metastasis of thyroid cancer to the bone, the liver and/or the lung. In a further embodiment, the metastatic cancer comprises metastasis of thyroid cancer to the bone. [0025] In some embodiments, the metastatic cancer comprises a metastatic pancreatic cancer, e.g., metastasis of pancreatic cancer to the mesentery, the ovary, the kidney, the spleen, the lymph nodes, the stomach, and/or the liver. [0026] In some embodiments, administration of the composition diminishes the severity of, delays the onset of, or eliminates a symptom of cancer. In some embodiments, the symptom of cancer is cancer-induced bone pain. In some embodiments, the symptom of cancer is allodynia. In some embodiments, the allodynia is tactile allodynia. In some embodiments, the tactile allodynia is static mechanical allodynia. In some embodiments, the tactile allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastasis to the bone. [0027] In some embodiments, the subject has bone cancer or metastasis to the bone, and the subject experiences decreased bone pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition. [0028] In some embodiments, the subject undergoes surgery and/or is administered chemotherapy, immunotherapy, targeted therapy, an immune checkpoint inhibitor, hormone therapy, or any combination thereof. [0029] In one embodiment of the methods disclosed herein, the compound of Formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide, referred to herein by its international nonproprietary name (INN), brensocatib (and formerly known as INS1007 and AZD7986),
Figure imgf000008_0001
, or a pharmaceutically acceptable salt thereof. In a further embodiment, the composition is administered orally. [0030] In one embodiment of the methods disclosed herein, the administration period is at least about 30 days, 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 18 months, at least about 24 months or at least about 30 months. [0031] In one embodiment of the methods disclosed herein, the subject does not have breast- to-lung metastasis. BRIEF DESCRIPTION OF THE FIGURES [0032] FIG. 1 depicts the chiral centers of the compounds of Formula (I). [0033] FIG. 2 depicts the study design to evaluate the treatment of cancer-induced bone pain by administering brensocatib. [0034] FIG.3 shows the body weight change as a function of time for the six groups of animals tested in Example 1. [0035] FIG. 4 is a bar graph showing the mechanical allodynia paw withdrawal threshold (PWT) (g) at Day 0 for each of the 6 groups tested in Example 1. [0036] FIG. 5 is a bar graph showing the mechanical allodynia paw withdrawal threshold (PWT) (g) at Day 7 for each of the 6 groups tested in Example 1. [0037] FIG. 6 is a bar graph showing the mechanical allodynia paw withdrawal threshold (PWT) (g) at Day 14 for each of the 6 groups tested in Example 1. [0038] FIGS. 7-12 are graphs showing the PWT (g) as a function of time for the individual animals in each of the six groups tested in Example 1. FIG. 7: Morphine group (group 4 in Table 1); FIG. 8: Leave alone control (group 6 in Table 1); FIG. 9: Placebo (group 5 in Table 1); FIG. 10: Brensocatib: day -7 – day 13 (group 1 in Table 1); FIG. 11: Brensocatib: day 0 – day 13 (group 2 in Table 1); FIG. 12 Brensocatib day 7 – day 13 (group 3 in Table 1). [0039] FIG. 13 is a graph showing the percentage of rats in each group reaching the effective paw withdrawal threshold (PWT) on Day 0, Day 7 and Day 14. [0040] FIGS. 14 provides a study schematic examining the effects of brensocatib on cancer- induced pain. [0041] FIG.15 depicts the study design to evaluate the treatment of metastatic cancer in mouse models by administering brensocatib. The metastatic cancer mouse models are generated by intravenously injecting tumor cells. [0042] FIG. 16 depicts the general study design to evaluate the treatment of spontaneous metastasis mouse models with brensocatib. The treatment of lung, colon, prostate, pancreatic, and other cancer types by brensocatib will be evaluated using this general study design. [0043] FIG.17 depicts the study design to evaluate anti-primary and metastatic tumor effect of brensocatib using a BX-PC3 pancreatic cancer orthotopic spontaneous metastasis xenograft mouse model. [0044] FIG. 18 is a graphic representation of in vivo imaging data of the BX-PC3 pancreatic cancer orthotopic spontaneous metastasis xenograft mouse model treated with placebo or brensocatib. The bioluminescent intensity for placebo control group was statistically greater than those of the brensocatib treatment groups on day 33 and day 36 (p< 0.005). DETAILED DESCRIPTION OF THE INVENTION [0045] The present disclosure provides reversible inhibitors of dipeptidyl peptidase 1 (DPP1) or cathepsin C, and methods of use thereof. In some embodiments, the methods of use are methods of treating cancer. DPP1 catalyses excision of dipeptides from the N-terminus of protein and peptide substrates. Through this enzymatic function, DPP1 activates many serine proteases in immune/inflammatory cells, such as neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and neutrophil serine protease 4 (NSP4). Neutrophil serine proteases can mediate tumor initiation, tumor progression and/or tumor metastasis. [0046] Moreover, neutrophils play an important role in stages of metastasis, such as intravascular dissemination, extravasation, and metastatic growth. Neutrophils can aid cancer cell adhesion to the endothelium in metastatic sites with their surface expression of selectins and integrins. Neutrophil-derived IL-^ȕ^FDQ^SURPRWH^ WXPRU^FHOO^H[WUDYDVDWLRQ^^)XUWKHUPRUH^^ neutrophil extracellular traps (NETs) can induce invasive and migratory behaviors of tumor cells. NETs can also result in the degradation of thrombospondin-1, which in turn facilitates metastatic cancer growth. [0047] Without wishing to be bound by a theory, it is thought that inhibition of DPP1 function by the disclosed DPP1 inhibitors can result in inhibition of NSPs and/or the pro-cancerous functions of neutrophils, and therefore, inhibit the development, growth and progression of a variety of cancers, and stages of cancer metastasis (such as intravascular dissemination, extravasation). [0048] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. [0049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the present application belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, representative methods and materials are herein described. [0050] Following long-standing patent law convention, the terms “a”, “an”, and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a carrier” includes mixtures of one or more carriers, two or more carriers, and the like and reference to “the method” includes reference to equivalent steps and/or methods known to those skilled in the art, and so forth. [0051] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the present application. Generally, the term “about”, as used herein in references to a measurable value such as an amount of weight, time, dose, etc. is meant to encompass values within an acceptable degree of variability in the art. In some embodiments, degree of variability is based on FDA guidelines. [0052] Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). [0053] As used herein, “C1-3” means a carbon group having 1, 2 or 3 carbon atoms. [0054] The term “alkyl”, unless otherwise noted, includes both straight and branched chain alkyl groups and may be substituted or non-substituted. “Alkyl” groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl. [0055] The term “pharmaceutically acceptable”, unless otherwise noted, is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications. [0056] As used herein, “treatment” or “treating,” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. The term “treating” in one embodiment, includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (3) relieving the condition (for example, by causing regression, or reducing the severity of the state, disorder or condition or at least one of its clinical or subclinical symptoms). [0057] The term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to achieve an outcome, for example, to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like. [0058] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, such as a mammal. The mammal may be, for example, a mouse, a rat, a rabbit, a cat, a dog, a pig, a sheep, a horse, a non-human primate (e.g., cynomolgus monkey, chimpanzee), or a human. A subject’s tissues, cells, or derivatives thereof, obtained in vivo or cultured in vitro are also encompassed. A human subject may be an adult, a teenager, a child (2 years to 14 years of age), an infant (1 month to 24 months), or a neonate (up to 1 month). In some embodiments, the adults are seniors about 65 years or older, or about 60 years or older. In some embodiments, the subject is a pregnant woman or a woman intending to become pregnant. [0059] As used herein, “cancer-induced pain” is pain that is associated, correlated, or caused by cancer. In some embodiments, cancer-induced pain results from the growth of the cancer into or adjacent to nearby cells, tissues, or organs. In some embodiments, cancer-induced pain is caused by the tumor pressing against nerves, bones or other tissues. In some embodiments, the cancer releases chemicals that cause pain. [0060] In some embodiments, the cancer-induced pain is cancer-induced bone pain. As used herein, “cancer-induced bone pain (CIBP)” refers to a pain state having features of both inflammatory and neuropathic pain seen in subjects with primary bone cancer, or cancer metastasis to the bone. In some embodiments, the CIBP comprises steady background pain, and/or pain that is exacerbated by weight bearing or movement (incident or episodic pain). In some embodiments, CIBP is experienced in the lower back, pelvis, long bones, and/or ribs. In some embodiments, the CIBP is a presenting feature of the cancer. In some embodiments, the CIBP highlights cancer recurrence in a previously treated subject. For instance, persistent pain in a bone (e.g., lower back, pelvis, long bones, and/or ribs) may be indicative of CIBP due to metastasis to the bone in a subject who was previously treated for a primary tumor. [0061] In one aspect, the present disclosure provides a method of inhibiting DPP1 in a subject diagnosed with a cancer. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000013_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3, [0062] The compounds of Formula (I) and their pharmaceutically acceptable salts are reversible inhibitors of DPP1 activity. In some embodiments, the subject has cancer or is at risk of developing cancer. In some embodiments, the administration results in the treatment or delay in the onset of cancer in the subject. In one embodiment, the subject has previously been administered radiation therapy prior to administration of the composition comprising an effective amount of a compound of Formula (I). [0063] In another aspect, the present disclosure provides a method of treating cancer in a subject in need of treatment. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. [0064] The present disclosure further provides a method of treating cancer in a subject in need of treatment. The method includes (a) determining a level of DPP1 in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the level of DPP1 determined in step (a), or the level of DPP1 in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about 550 ng/mL, about 600 ng/mL, about 650 ng/mL, about 700 ng/mL, about 750 ng/mL, about 800 ng/mL, about 850 ng/mL, about 900 ng/mL, about 950 ng/mL, or about 1000 ng/mL, including all values and subranges that lie therebetween. In a further embodiment, the level of DPP1 determined in step (a) is in the range of about 1 ng/mL to about 100 ng/mL. In a further embodiment, the level of DPP1 determined in step (a) is in the range of about 5 ng/mL to about 20 ng/mL. In the present disclosure, in some embodiments, the level of DPP1 refers to the level of total DPP1, including both active and inactive DPP1. In other embodiments, the level of DPP1 refers to the level of active DPP1. [0065] In some embodiments, the level or activity of DPP1 determined in step (a), or the level or activity of DPP1 in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of DPP1 in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0066] In some embodiments, the level or activity of DPP1 determined in step (a), or the level or activity of DPP1 in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000%, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of DPP1 in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0067] The disclosure further provides a method of treating cancer in a subject in need of treatment. The method includes (a) determining a level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about 550 ng/mL, about 600 ng/mL, about 650 ng/mL, about 700 ng/mL, about 750 ng/mL, about 800 ng/mL, about 850 ng/mL, about 900 ng/mL, about 950 ng/mL, or about 1000 ng/mL, including all values and subranges that lie therebetween. [0068] In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0069] In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0070] The present disclosure further provides a method of treating cancer in a subject in need of treatment. The method includes (a) determining a level of a neutrophil serine protease (NSP) in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the level of the NSP determined in step (a), or the level of the NSP in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about 550 ng/mL, about 600 ng/mL, about 650 ng/mL, about 700 ng/mL, about 750 ng/mL, about 800 ng/mL, about 850 ng/mL, about 900 ng/mL, about 950 ng/mL, or about 1000 ng/mL, including all values and subranges that lie therebetween. In the present disclosure, in some embodiments, the level of an NSP refers to the level of total NSP, including both the active and inactive forms of the NSP. In other embodiments, the level of an NSP refers to the level of the active form(s) of the NSP. [0071] In some embodiments, the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0072] In some embodiments, the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0073] In one embodiment of the methods for treating cancer, the method further comprises administering radiation therapy to the subject. [0074] In still another aspect, the present disclosure provides a method of treating cancer- induced pain in a subject having cancer. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the cancer-induced pain is cancer-induced bone pain (CIBP). In some embodiments, the method further comprises administering radiation therapy to the subject. [0075] In still another aspect, a method for improving a radiation response in a subject having cancer is provided. The method includes administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.; and administering radiation therapy to the subject. [0076] The present disclosure further provides a method for improving a radiation response in a subject having cancer. The method includes (a) determining a level of NETs in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein; and administering radiation therapy to the subject. In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about 550 ng/mL, about 600 ng/mL, about 650 ng/mL, about 700 ng/mL, about 750 ng/mL, about 800 ng/mL, about 850 ng/mL, about 900 ng/mL, about 950 ng/mL, or about 1000 ng/mL, including all values and subranges that lie therebetween. [0077] In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0078] In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level of NETs in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0079] The present disclosure further provides a method for improving a radiation response in a subject having cancer. The method includes (a) determining a level of an NSP in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein; and administering radiation therapy to the subject. In some embodiments, the level of the NSP determined in step (a), or the level of the NSP in a biological sample obtained from the subject before administration of the composition is in the range of about 1 ng/mL to about 1000 ng/mL, for example about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 10 ng/mL, about 13 ng/mL, about 15 ng/mL, about 17 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250 ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450 ng/mL, about 500 ng/mL, about 550 ng/mL, about 600 ng/mL, about 650 ng/mL, about 700 ng/mL, about 750 ng/mL, about 800 ng/mL, about 850 ng/mL, about 900 ng/mL, about 950 ng/mL, or about 1000 ng/mL, including all values and subranges that lie therebetween. [0080] In some embodiments, the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 1.2 fold (for example, about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold, about 8 fold, about 8.5 fold, about 9 fold, about 9.5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, or about 30 fold, including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0081] In some embodiments, the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject before administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000% including all values and subranges that lie therebetween) higher than the level or activity, respectively, of the NSP in a counterpart biological sample obtained from a healthy subject who does not have cancer. [0082] In one embodiment of the methods for improving a radiation response in a subject having cancer, the cancer in the subject has previously been treated with radiation therapy. In one embodiment, improving the radiation response comprises reducing radioresistance of the cancer. [0083] In one embodiment of the methods involving administration of radiation therapy disclosed herein, the radiation therapy is administered prior to the administration period. In another embodiment, the radiation therapy is administered subsequent to the administration period. In yet another embodiment, the radiation therapy is administered during the administration period. In even another embodiment, the radiation therapy is administered prior to the administration period and either (i) during the administration period or (ii) subsequent to the administration period. [0084] The radiation therapy, in one embodiment, comprises external beam radiation. In a further embodiment, the external beam radiation therapy comprises three-dimensional conformal radiation therapy (3D-CRT), image guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), helical-tomotherapy, photon beam radiation therapy, proton beam radiation therapy or stereotactic radiosurgery. In another embodiment, the radiation therapy comprises brachytherapy. [0085] The radiation therapy, in one embodiment, is carried out for about 1 week to about 10 weeks, for about 1 week to about 8 weeks, for about 1 week to about 6 weeks, for about 1 week to about 4 weeks or for about 1 week to about 2 weeks. In another embodiment, the radiation therapy is carried out 5 days per week while radiation therapy is being administered. [0086] In some embodiments of the methods disclosed herein, DPP1 is expressed by cancerous cells, neutrophils, macrophages, monocytes, or mast cells of the subject. [0087] In some embodiments of the methods, a level of DPP1 in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL, or about 1 ng/mL to about 100 ng/mL, before administration of the composition. [0088] In some embodiments of the methods, the activity of DPP1 in a biological sample obtained from the subject after administration of the composition is less than: (a) the activity of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. In some embodiments, the activity of DPP1 in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) the activity of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. [0089] In some embodiments of the methods, a level of DPP1 in a biological sample obtained from the subject after administration of the composition is less than: (a) a level of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. In some embodiments, a level of DPP1 in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a level of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. [0090] In some embodiments of the methods, a level of NETs in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL before administration of the composition. [0091] In some embodiments, a level of NETs in a biological sample obtained from the subject after administration of the composition is less than: (a) a level of NETs in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of NETs in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. In some embodiments, a level of NETs in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a level of NETs in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of NETs in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. [0092] In some embodiments, the level of NETs is the level of circulating plasma NETs. In some embodiments, the level of NETs is determined by measuring DNA complexed with NET- molecules like myeloperoxidase (MPO-DNA) or neutrophil elastase (NE-DNA) using enzyme- linked immunosorbent assays (ELISAs), measuring the presence of citrullinated histones by fluorescence microscopy, flow cytometric detection of NET-components, immunofluorescence to detect the colocalization of NET-associated molecules (NE, MPO, CitH3) with extracellular DNA or using flow cytometry or confocal microscopy-based methods. Further details on determining the levels of NETs are provided in Arends et al., J. Vis. Exp. (143), e59150, (2019); Gál, Z., et al., Sci Rep 10, 4320 (2020); and Thålin, et al., Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:1724–1738, each of which is incorporated herein by reference in its entirety for all purposes. [0093] In some embodiments of the methods, a level of an NSP in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL before administration of the composition. [0094] In some embodiments, the activity of an NSP in a biological sample obtained from the subject after administration of the composition is less than: (a) the activity of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. In some embodiments, the activity of the NSP in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) the activity of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. [0095] In some embodiments, a level of an NSP in a biological sample obtained from the subject after administration of the composition is less than: (a) a level of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. In some embodiments, a level of the NSP in a biological sample obtained from the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a level of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. [0096] In some embodiments, the NSP is a secreted NSP, or an NSP in the cytoplasmic granules. In some embodiments, the NSP is a proform of the NSP. In some embodiments, the NSP is the active form of the NSP. In some embodiments, the NSP is a secreted proform of the NSP. In some embodiments, the NSP comprises neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), neutrophil serine protease 4 (NSP4), or any combination thereof. In some embodiments, the NSP is cell surface-localized NSP, intracellular NSP, or a combination thereof. In some embodiments, the level of the cell surface-localized NSP or intracellular NSP is measured using flow cytometry. [0097] In some embodiments, the biological sample comprises blood, serum, white blood cells, neutrophils, a cancer tissue, tumor cells, tumor T-cells, or any combination thereof. [0098] In some embodiments, the level or activity of a cytokine or an inflammatory cytokine in a biological sample obtained from the subject is determined before administration of the composition. The present disclosure further provides methods of treating cancer in a subject in need thereof, comprising: (a) determining a level or activity of a cytokine or an inflammatory cytokine in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as disclosed herein. Non-limiting examples of the inflammatory cytokines include IL-6, IL-1, and TNF-Į^^,Q^VRPH^ embodiments, the cytokine is a cytokine described in Berraondo et al., British Journal of Cancer volume 120, pages 6–15(2019). In some embodiments, the level or activity of the cytokine or inflammatory cytokine is altered (lower or higher), as compared to a healthy subject who does not have cancer. [0099] In some embodiments, a level or activity of a biomarker in a biological sample obtained from the subject is determined before administration of the composition. The present disclosure further provides methods of treating cancer in a subject in need thereof, comprising: (a) determining a level or activity of a biomarker in a biological sample obtained from the subject, and (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as disclosed herein. Non-limiting examples of biomarkers include biomarkers which can be evaluated based on immunocytochemistry or immunohistochemistry (such as, for example, Her2, ER, PR, PD-L1, PD-1, TIM3, MMR, c-MET, ALK, EGFR, CTLA4, Foxp3, PTEN, P16, Ki67, CD20, PAX-5, CD3, CD5, CD8, CD10, CD13, CD16,CD22, CD23, CD33, CD34, POX (MPO), CD79a, TdT, CD11b, CD45, CD68, GL7, GrazymeB, Ly-^*^^&'^^^^1.^^^^^<$3^^^ȕ-Catenin, CXCR4, CXCL12, LAG3, total Rb, and CyclinD1), biomarkers that can be evaluated by fluorescence in-situ hybridization (such as, for example, Her2, EGFR, FGFR1, ALK, MET, ROS1,AXL, Bcl-2, Bcl-6), biomarkers that can be evaluated by dual in situ hybridization (such as, Her2), biomarkers that can be evaluated by immunofluorescence (such as, for example, CD4, PD1, PD-L1, Foxp3, CD11b, CD3, CD8, CD45R), biomarkers that can be evaluated using RNA scope (such as, for example, Her 2, PD- 1, PD-L1, MET exon 14 skipping, RIPK2, TRPM5, STING), or any combination thereof. In some embodiments, the level or activity of the biomarker is altered (lower or higher), as compared to a healthy subject who does not have cancer. [0100] In some embodiments of the methods disclosed herein, the cancer comprises a primary solid tumor, a liquid tumor, a metastatic cancer, or a combination thereof. [0101] In some embodiments, the cancer comprises a primary solid tumor. In a further embodiment, the cancer is selected from the group consisting of breast cancer, bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibroid cancer, lymphoma, virus-induced cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, melanoma, and bone cancer. [0102] In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibroid cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is virus-induced cancer. In some embodiments, the cancer is oropharyngeal cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is thymus cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, the fibroid cancer is leiomyosarcoma. [0103] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer comprises ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, the breast cancer comprises ductal carcinoma. In some embodiments, the breast cancer comprises lobular carcinoma. In some embodiments, the breast cancer comprises medullary carcinoma. In some embodiments, the breast cancer comprises colloid carcinoma. In some embodiments, the breast cancer comprises tubular carcinoma. In some embodiments, the breast cancer comprises inflammatory breast cancer. [0104] In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer does not respond to hormonal therapy or therapeutics that target the HER2 protein receptors. [0105] In some embodiments, the lymphoma is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, Natural Killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma or Kaposi’s Sarcoma. In some embodiments, the lymphoma is Hodgkin’s lymphoma. In some embodiments, the lymphoma is non-Hodgkin’s lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the lymphoma is B-cell immunoblastic lymphoma. In some embodiments, the lymphoma is Natural Killer cell lymphoma. In some embodiments, the lymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma. In some embodiments, the lymphoma is Kaposi’s Sarcoma. [0106] 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. [0107] In some embodiments, the cancer comprises a liquid tumor. In some embodiments, the cancer comprising a 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, a myeloproliferative disorder, 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 cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is acute lymphocytic leukemia. In some embodiments, the cancer is acute promyelocytic leukemia. In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is hairy cell leukemia. In some embodiments, the cancer is a myeloproliferative disorder. In some embodiments, the cancer is Natural Killer cell leukemia. In some embodiments, the cancer is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the cancer is chronic myelogenous leukemia (CML). In some embodiments, the cancer is mastocytosis. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the cancer is myelodysplastic syndrome (MDS). [0108] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer comprises neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma. In some embodiments, the pediatric cancer comprises neuroblastoma. In some embodiments, the pediatric cancer comprises Wilms tumor. In some embodiments, the pediatric cancer comprises rhabdomyosarcoma. In some embodiments, the pediatric cancer comprises retinoblastoma. In some embodiments, the pediatric cancer comprises osteosarcoma. In some embodiments, the pediatric cancer comprises Ewing sarcoma. [0109] In some embodiments of the methods disclosed herein, the cancer comprises a metastatic cancer. In other embodiments, the subject is at a risk for developing a metastatic cancer. In some embodiments, the subject does not have breast-to-lung metastasis. [0110] In some embodiments, the metastatic cancer comprises a metastatic breast cancer, e.g., metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, and/or liver. In a further embodiment, the metastatic cancer comprises metastasis of breast cancer to the bone. [0111] In some embodiments, the metastatic cancer comprises a metastatic bone cancer, e.g., metastasis of bone cancer to the lung. [0112] In some embodiments, the metastatic cancer comprises a metastatic colorectal cancer, e.g., metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, and/or the spleen. [0113] In some embodiments, the metastatic cancer comprises a metastatic stomach cancer, e.g., metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, and/or the ovary. [0114] In some embodiments, the metastatic cancer comprises a metastatic leukemia, e.g., metastasis of leukemia to the lymph nodes, the lung, the liver, the limb, the brain, the kidney, and/or the spleen. [0115] In some embodiments, the metastatic cancer comprises a metastatic liver cancer, e.g., metastasis of liver cancer to the intestine, the spleen, the pancreas, the stomach, the lung, and/or the kidney. [0116] In some embodiments, the metastatic cancer comprises a metastatic lymphoma, e.g., metastasis of lymphoma to the kidney, the ovary, the liver, the bladder, and/or the spleen. [0117] In some embodiments, the metastatic cancer comprises a metastatic hematopoietic cancer, e.g., metastasis of hematopoietic cancer to the intestine, the lung, the liver, the spleen, the kidney, and/or the stomach. [0118] In some embodiments, the metastatic cancer comprises a metastatic melanoma, e.g., metastasis of melanoma to lymph nodes and/or the lung. [0119] In some embodiments, the metastatic cancer comprises a metastatic pancreatic cancer, e.g., metastasis of pancreatic cancer to the mesentery, the ovary, the kidney, the spleen, the lymph nodes, the stomach, and/or the liver. [0120] In some embodiments, the metastatic cancer comprises a metastatic prostate cancer, e.g., metastasis of prostate cancer to the lung, the pancreas, the kidney, the spleen, the intestine, the liver, the bone, and/or the lymph nodes. In a further embodiment, the metastatic cancer comprises metastasis of prostate cancer to the bone. [0121] In some embodiments, the metastatic cancer comprises a metastatic ovarian cancer, e.g., metastasis of ovarian cancer to the diaphragm, the liver, the intestine, the stomach, the lung, the pancreas, the spleen, the kidney, the lymph nodes, and/or the uterus. [0122] In some embodiments, the metastatic cancer comprises a metastatic myeloma, e.g., metastasis of myeloma to the bone. [0123] In some embodiments, the metastatic cancer comprises a metastatic lung cancer, e.g., metastasis of lung cancer to the bone, the brain, the lymph nodes, the liver, the ovary, and/or the intestine. In a further embodiment, the metastatic cancer comprises metastasis of lung cancer to the bone. [0124] In some embodiments, the metastatic cancer comprises a metastatic kidney cancer, e.g., metastasis of kidney cancer to the liver, the lung, the pancreas, the stomach, the brain, and/or the spleen. [0125] In some embodiments, the metastatic cancer comprises a metastatic bladder cancer, e.g., metastasis of bladder cancer to the bone, the liver and/or the lung. In a further embodiment, the metastatic cancer comprises metastasis of bladder cancer to the bone. [0126] In some embodiments, the metastatic cancer comprises a metastatic thyroid cancer, e.g., metastasis of thyroid cancer to the bone, the liver and/or the lung. In a further embodiment, the metastatic cancer comprises metastasis of thyroid cancer to the bone. [0127] In some embodiments, the methods disclosed herein comprise treating cancer-induced bone pain (CIBP) in a subject having metastasis of a cancer to the bone. In some embodiments, the subject has metastasis of breast cancer, prostate cancer, lung cancer, bladder cancer, thyroid cancer, or myeloma to the bone. In a further embodiment, the subject has metastasis of breast cancer to the bone. In some embodiments, the subject is identified as having metastasis to the bone by the use of any one of the following methods: plain film radiography, computed tomography, technetium-99m bone scan, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, fluorine positron emission tomography, and/or choline positron emission tomography, but is not yet feeling cancer-induced bone pain. In some embodiments, the subject is suffering from cancer-induced bone pain, which is indicative of metastasis of a previously treated or untreated primary tumor to the bone. In some embodiments, the cancer has metastasized to vertebrae, pelvis, long bones, or ribs. [0128] In some embodiments, administration of the composition diminishes the severity of, delays the onset of, or eliminates a symptom of cancer. In some embodiments, the symptom of cancer is cancer-induced bone pain (CIBP). In some embodiments, the CIBP is neuropathic pain. In some embodiments, the CIBP is inflammatory pain. In some embodiments, the CIBP is spontaneous pain. In some embodiments, the symptom of cancer is nociceptive hypersensitivity. In some embodiments, the symptom of cancer is allodynia. In some embodiments, the allodynia is tactile allodynia. In some embodiments, the tactile allodynia is static mechanical allodynia. In some embodiments, the tactile allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastasis to the bone. [0129] In some embodiments, the cancer comprises a solid tumor, and a volume of the solid tumor in the subject after administration of the composition is less than: (a) a volume of the solid tumor in the subject before administration of the composition, and/or (b) a volume of a solid tumor in a control subject, wherein the control subject has the solid tumor and is not administered the composition. In some embodiments, the cancer comprises a solid tumor, and a volume of the solid tumor in the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower than: (a) a volume of the solid tumor in the subject before administration of the composition, and/or (b) a volume of a solid tumor in a control subject, wherein the control subject has the solid tumor and is not administered the composition. [0130] In some embodiments, the cancer comprises a plurality of solid tumors, and the subject exhibits fewer solid tumors after administration of the composition as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has a plurality of solid tumors and is not administered the composition. In some embodiments, the cancer comprises a plurality of solid tumors, and the subject exhibits at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) fewer solid tumors after administration of the composition as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has a plurality of solid tumors and is not administered the composition. [0131] In some embodiments, the cancer induces a weight loss in the subject, and the weight loss is alleviated after administration of the composition, as compared to before administration of the composition. In some embodiments, the cancer-induced weight loss in the subject is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower after administration of the composition, as compared to before administration of the composition. [0132] In some embodiments, an overall survival period of the subject after administration of the composition is longer than an overall survival period of a control subject, wherein the control subject has cancer and is not administered the composition. As used herein, “overall survival” is defined as the time from randomization until death from any cause and is measured in the intent-to-treat population, and is further described in the FDA guidance document titled “Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, Guidance for Industry, December 2018” which is incorporated herein by reference in its entirety for all purposes. [0133] In some embodiments, an overall survival period of the subject after administration of the composition is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, or about 500%, including all values and subranges that lie therebetween) longer than an overall survival period of a control subject, wherein the control subject has cancer and is not administered the composition. [0134] In some embodiments, the subject has bone cancer or metastasis to the bone, and the subject shows an increased bone mineral density after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition. In some embodiments, the subject has bone cancer or metastasis to the bone, and shows at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500% about 600%, about 700%, about 800%, about 900% or about 1000%, including all values and subranges that lie therebetween) higher bone mineral density after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition. [0135] In some embodiments, the subject experiences decreased cancer-induced pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has cancer-induced pain and is not administered the composition. In some embodiments, the subject experiences at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has cancer-induced pain and is not administered the composition. [0136] In some embodiments, the subject has bone cancer or metastasis to the bone, and experiences decreased bone pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition. In some embodiments, the subject has bone cancer or metastasis to the bone, and experiences at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower bone pain after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition. [0137] In some embodiments, the subject has prostate cancer, and a blood level of prostate- specific antigen (PSA) in the subject is lower after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has prostate cancer and is not administered the composition. In some embodiments, the subject has prostate cancer, and a blood level of prostate-specific antigen (PSA) in the subject is at least about 2% (for example, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and subranges that lie therebetween) lower after administration of the composition, as compared to: (a) before administration of the composition, and/or (b) a control subject, wherein the control subject has prostate cancer and is not administered the composition. [0138] In some embodiments, any one or more of the clinical endpoints described in the FDA guidance document titled “Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, Guidance for Industry, December 2018” which is incorporated herein by reference in its entirety for all purposes, may be used to evaluate the effect of administering the pharmaceutical composition comprising a compound of Formula (I) or its pharmaceutically acceptable salt, e.g., brensocatib, to the subject. In some embodiments, the rate of clinical improvement upon administering the composition is calculated over a period of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, about 21 days or about 28 days. [0139] Embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, that can be used according to the methods disclosed herein are described below. It is noted that one or more DPP1 inhibitors other than the compounds of Formula (I), or pharmaceutically acceptable salts thereof, may also be used in place of, or in combination with, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, according to the disclosed treatment methods. Non-limiting examples of DPP1 inhibitors other than the compounds of Formula (I), or pharmaceutically acceptable salts thereof contemplated for use include those disclosed in Chen et al., Journal of Medicinal Chemistry 64(16):11857-11885 (2021); Banerjee et al., Bioorganic & Medicinal Chemistry Letters 47:128202 (2021); Bondebjerg J et al., Bioorg Med Chem. 13:4408-4424 (2005); Bondejberg J et al., Bioorg Med Chem Lett. 16:3614-3617 (2006); Guarino C et al., Biochem Pharmacol. 131:52-67 (2017); Guay D et al., Bioorg Med Chem Lett Guay D et al., Curr Top Med Chem. 10:708-716 (2010); Méthot N et al., J. Biol Chem.282:20836–20846 (2007); Méthot N et al., Mol. Pharm. 73:1857–1865 (2008); Miller et al., Br J Clin Pharmacol. 83:2813-2820 (2017); U.S. Patent Nos. 8,871,783, 8,877,775, 8,889,708, 8,987,249, 8,999,975, 9,073,869, 9,440,960, 9,713,606, 9,879,026, RE47,636E1, 10,238,633, 9,856,228, and 10,479,781; Chinese Patent Application No: CN202110129457.2A; each of which is incorporated herein by reference in its entirety for all purposes. [0140] In one embodiment of the methods provided herein, the compound of Formula (I) is an S,S diastereomer. In other words, the compound of Formula (I) has the following stereochemistry: (S,S diastereomer).
Figure imgf000033_0001
[0141] The other diastereomeric forms are also contemplated by the present invention. For example, in one embodiment, the compound of Formula (I) is the R,R diastereomer: (R,R diastereomer).
Figure imgf000033_0002
[0142] In another embodiment, the compound of Formula (I) is the R,S diastereomer: (R,S diastereomer).
Figure imgf000033_0003
[0143] In even another embodiment, the compound of Formula (I) is the S,R diastereomer:
Figure imgf000034_0001
(S,R diastereomer). [0144] In one embodiment, the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an S,R diastereomer of a compound of Formula (I). [0145] In one embodiment, the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,S diastereomer of a compound of Formula (I). [0146] In one embodiment, the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,R diastereomer of a compound of Formula (I). [0147] In one embodiment
Figure imgf000034_0002
hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1- 3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring. [0148] In one embodiment,
Figure imgf000034_0003
hydrogen, F, Cl or C1-3alkyl; and R3 is hydrogen, F, Cl, CN or SO2C1-3alkyl. [0149] In one embodiment, 3
Figure imgf000034_0004
hydrogen, F or C1-3alkyl; and R is hydrogen, F or CN.
Figure imgf000035_0004
is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. In a further embodiment,
Figure imgf000035_0001
[0151] In one embodiment,
Figure imgf000035_0002
is O or S; R6 is C1-3alkyl, optionally substituted by 1, 2 or 3 F and optionally substituted by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. In a further embodiment,
Figure imgf000035_0003
[0152] In one embodiment, R1 ; X is O, S or CF2; R6 is C1-3alkyl, wherein
Figure imgf000035_0005
the C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7 is hydrogen, F, Cl or CH3. [0153] In another embodiment, R1 X is O; R6 is C1-3alkyl, wherein the
Figure imgf000036_0001
C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7 is hydrogen. In a further embodiment, R6 is C1-3alkyl, i.e., methyl, ethyl, or propyl. In still a further embodiment, R6 is methyl. [0154] In one embodiment, R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl or C1-3alkyl. [0155] In a further embodiment, R2 is hydrogen, F, Cl or C1-3alkyl. [0156] In still a further embodiment, R2 is hydrogen, F or C1-3alkyl. [0157] In one embodiment, R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring. [0158] In a further embodiment, R3 is hydrogen, F, Cl, CN or SO2C1-3alkyl. [0159] In still a further embodiment, R3 is hydrogen, F or CN. [0160] In one embodiment, R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1- 3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran. [0161] In a further embodiment, R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F. In still a further embodiment, R6 is methyl or ethyl. In still a further embodiment, R6 is methyl. [0162] In one embodiment, R7 is hydrogen, F, Cl or CH3. In a further embodiment R7 is hydrogen. [0163] In one embodiment of the methods provided herein, the composition administered to the patient comprises an effective amount of (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3- dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (referred to herein by its international nonproprietary name (INN), brensocatib): or a pharmaceutically acceptable salt thereof. In a further
Figure imgf000037_0001
embodiment, the compound of Formula (I) is brensocatib. [0164] In one embodiment, the compound of Formula (I) is: [0165] (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, [0166] (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0167] (2S)-N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0168] 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate, [0169] (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide, [0170] (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide, [0171] (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2- carboxamide, [0172] (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide, [0173] (2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0174] (2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0175] (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0176] (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0177] (2S)-N-[(1S)-1-Cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide, [0178] (2S)-N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0179] (2S)-N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0180] (2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0181] (2S)-N-[(1S)-1-Cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0182] (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol- 5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0183] (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0184] (2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0185] (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol- 5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0186] (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide, [0187] (2S)-N-[(1S)-2-(4’-Carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane- 2-carboxamide, [0188] (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide, [0189] (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro- 1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0190] (2S)-N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, [0191] (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol- 5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0192] (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, [0193] (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [0194] (2S)-/V-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide,
[0195] (2S)-/V-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4- oxazepane-2-carboxamide,
[0196] (2S)-/V-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2- carboxamide,
[0197] (2S)-/V-{(1S)-2-[4-(l,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide, or
[0198] (2S)-/V-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, or a pharmaceutically acceptable salt of one of the foregoing compounds.
[0199] In one embodiment, the compound of Formula (I) is brensocatib. In some embodiments, brensocatib is in polymorphic Form A as disclosed in U.S. PatentNo. 9,522,894, the disclosure of which is incorporated herein by reference in its entirety for all purposes. In some embodiments, brensocatib is characteSzed by an X-ray powder diffraction pattern having a peak at about 12.2 ± 0.2 (° 2-theta), measured using CuKa radiation. In some embodiments, brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 20.6 ± 0.2 (° 2-theta), measured using CuKa radiation. In some embodiments, brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 12.2 ± 0.2 and about 20.6 ± 0.2 (° 2-theta), measured using CuKa radiation. In some embodiments, brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 12.2 ± 0.2, about 14.3 ± 0.2, about 16.2 ± 0.2, about 19.1 ± 0.2 and about 20.6 ± 0.2 (° 2-theta), measured using CuKa radiation.
[0200] As provided throughout, according to the methods provided herein, a compound of Formula (I) can be administered as a pharmaceutically acceptable salt. A pharmaceutically acceptable salt of a compound of Formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in diffeSng temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent. In some instances, a salt may be used to aid in the isolation or puSfication of the compound of Formula (I).
[0201] Where the compound of Formula (I) is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, an alkali metal salt, e.g., Na or K, an alkali earth metal salt, e.g., Ca or Mg, or an organic amine salt. Where the compound of Formula (I) is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts. [0202] There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. [0203] For reviews on suitable salts, and pharmaceutically acceptable salts amenable for use herein, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or “Handbook of Pharmaceutical Salts: Properties, selection and use”, P.H. Stahl, P.G. Vermuth, IUPAC, Wiley-VCH, 2002, incorporated by reference herein in its entirety for all purposes. [0204] The compounds of Formula (I) may form mixtures of its salt and co-crystal forms. It is also to be understood that the methods provided herein can employ such salt/co-crystal mixtures of the compound of Formula (I). [0205] Salts and co-crystals may be characterized using well known techniques, for example X-ray powder diffraction, single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state NMR, (to evaluate for example, C, N or P chemical shifts) or spectroscopic techniques (to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding). [0206] It is also to be understood that compounds of Formula (I) may exist in solvated form, e.g., hydrates, including solvates of a pharmaceutically acceptable salt of a compound of Formula (I). [0207] In one embodiment, compounds of Formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. It is to be understood that the present disclosure encompasses all such isomeric forms. As shown in FIG. 1, irrespective of R1, the backbone of the compounds of Formula (I) has two chiral centers. Chiral center 1 is the most substituted carbon atom on the 1,4-oxazepane ring. Chiral center 2 is the substituted carbon atom to which a cyano group, -NH-, and a benzyl group are attached. The present disclosure encompasses the compounds of Formula (I) with the (S)-configuration for the ring substituent at chiral center 1 and the (S)-configuration for the benzyl substituent at chiral center 2 (i.e., the S,S diastereomer disclosed herein); the (S)-configuration for the ring substituent at chiral center 1 and the (R)-configuration for the benzyl substituent at chiral center 2 (i.e., the S,R diastereomer disclosed herein); the (R)-configuration for the ring substituent at chiral center 1 and the (S)-configuration for the benzyl substituent at chiral center 2 (i.e., the R,S diastereomer disclosed herein); and the (R)-configuration for the ring substituent at chiral center 1 and the (R)-configuration for the benzyl substituent at chiral center 2 (i.e., the R,R diastereomer disclosed herein), as well as a mixture of any two or more of the foregoing diastereomers. [0208] Accordingly, in one embodiment, the compound of Formula (I) is (2S)-N-{(1S)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane- 2-carboxamide (i.e., brensocatib, the S,S isomer), shown below.
Figure imgf000041_0002
pharmaceutically acceptable salt thereof. [0209] In one embodiment, the compound of Formula (I) is (2R)-N-{(1R)-1-Cyano-2-[4-(3- methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the R,R isomer), shown below. pharmaceutically acceptable salt thereof.
Figure imgf000041_0001
[0210] In one embodiment, the compound of Formula (I) is (2S)-N-{(1R)-1-Cyano-2-[4-(3- methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the S,R isomer), shown below. pharmaceutically acceptable salt thereof.
Figure imgf000041_0003
[0211] In one embodiment, the compound of Formula (I) is (2R)-N-{(1S)-1-Cyano-2-[4-(3- methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the R,S isomer), shown below. pharmaceutically acceptable salt thereof.
Figure imgf000042_0001
[0212] In one embodiment, the composition comprises a mixture of two or more of the aforementioned stereoisomers. The mixture in one embodiment, comprises the S,S isomer (brensocatib) and the S,R isomer of a compound of Formula (I). In another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,S isomer. In yet another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,R isomer. [0213] Certain compounds of Formula (I) may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g., restriction resulting from the presence of a ring bond or double bond. Accordingly, it is to be understood that the present disclosure encompasses all such isomers. Certain compounds of Formula (I) may also contain multiple tautomeric forms. It is to be understood that the present disclosure encompasses all such tautomeric forms. Stereoisomers may be separated using conventional techniques, e.g., chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis. [0214] In a further embodiment, the compounds of Formula (I) encompass any isotopically-labeled (or “radio-labelled”) derivatives of a compound of Formula (I). Such a derivative is a derivative of a compound of Formula (I) wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include 2H (also written as “D” for deuterium). As such, in one embodiment, a compound of Formula (I) is provided where one or more hydrogen atoms are replaced by one or more deuterium atoms; and the deuterated compound is used in one of the methods provided herein. [0215] The skilled person will recognize that the compounds of Formula (I) may be prepared, in known manner, in a variety of ways. For example, in one embodiment, compounds of Formula (I) are prepared according to the methods set forth in U.S. Patent No. 9,522,894, incorporated by reference herein in its entirety for all purposes. Combination Therapies [0216] The compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be used on their own, or in conjunction with the standard-of-care administered by a treating physician. Any standard-of-care therapeutic may be used in combination with the compounds disclosed herein. In some embodiments, the subject has undergone or will undergo surgery for treating the cancer. [0217] In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salts thereof, is administered in combination with a neutrophil elastase (NE) inhibitor. In a further embodiment, the NE inhibitor is sivelestat. In a further embodiment, the compound of Formula (I) is brensocatib. [0218] In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, e.g., brensocatib, are administered in combination with chemotherapy, immunotherapy, targeted therapy, an immune checkpoint inhibitor, radiation therapy, hormone therapy, phototherapy, virotherapy, or any combination thereof. In certain embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are administered in combination with a tyrosine kinase inhibitor, e.g., erlotinib. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, or any combination thereof. Exemplary anti-PD-1 antibodies include, for example, nivolumab (Opdivo®, Bristol-Myers Squibb Co.), pembrolizumab (Keytruda®, Merck Sharp & Dohme Corp.), PDR001 (Novartis Pharmaceuticals), and pidilizumab (CT-011, Cure Tech). Exemplary anti-PD-L1 antibodies include, for example, atezolizumab (Tecentriq®, Genentech), duvalumab (AstraZeneca), MEDI4736, avelumab, and BMS 936559 (Bristol Myers Squibb Co.). [0219] In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, e.g., brensocatib, are administered in combination with an immunosuppressive drug. Exemplary immunosuppressive drugs include tacrolimus, cyclosporine, mycophenolate mofetil, mycophenolate sodium, azathioprine, and sirolimus. In some embodiments, the subject is administered corticosteroids, e.g., prednisone. [0220] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salts thereof, e.g., brensocatib, is administered in combination with a cancer therapeutic selected from the group consisting of a BTK inhibitor, an HDAC inhibitor, an mTOR inhibitor, a proteasome inhibitor, a JAK inhibitor, a JAK/STAT inhibitor, a BCL-2 inhibitor, a MEK inhibitor, an anti-folate, a farnesyl transferase inhibitor, an antibody, an antibody-drug conjugate, a cytotoxic agent, and a chemotherapeutic agent. [0221] In some embodiments, the BTK inhibitor is ibrutinib, RN-486 (6-cyclopropyl-8-fluoro- 2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo- 1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), GDC-0834 ([R—N-(3-(6-(4-(1,4- dimethyl-3-oxopiperazin-2-yl) phenylamino)-4-methyl-5-oxo-4,5-dihydropy-razin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]), CGI-560 (N-[3-(8- anilinoimidazo[1,2-a]pyrazin-6-yl)phenyl]-4-tert-butylbenzamide), CGI-1746 (4-(tert-butyl)- N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5- dihydropyrazin-2-yl)phenyl)benzamide), HM-712245, ONO-40595, CNX-774 (4-(4-((4-((3- acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), LFM-A13 (2Z-cyano-N-(2,5-dibromophenyl)3-hydroxy-2-butenamide), AVL-292 (N-(3-((5- fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide), or any combination thereof. [0222] In some embodiments, the HDAC inhibitor is belinostat, vorinostat, panobinostat, romidepsin, or any combination thereof. [0223] In some embodiments, the mTOR inhibitor is everolimus. [0224] In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or a combination thereof. [0225] In some embodiments, the JAK/STAT inhibitor is tofacitinib, INCB16562, AZD1480, or any combination thereof. [0226] In some embodiments, the BCL-2 inhibitor is ABT-737, ABT-263, navitoclax, or any combination thereof. [0227] In some embodiments, the MEK inhibitor is AZD8330 or ARRY-424704. [0228] In some embodiments, the anti-folate is pralatrexate. [0229] In some embodiments, the farnesyl transferase inhibitor is tipifarnib. [0230] In some embodiments, the antibody is obinutuzumab, alemtuzumab, rituximab, ofatumumab, brentuximab vedotin, or any combination thereof. [0231] In some embodiments, the antibody-drug conjugate is inotuzumab, ozogamicin, brentuximab vedotin, or any combination thereof. [0232] In some embodiments, the cytotoxic agent is bendamustine, gemcitabine, oxaliplatin, cyclophosphamide, vincristine, vinblastine, anthracycline, daunorubicin, daunomycin, doxorubicin, actinomycin dactinomycin, bleomycin, clofarabine, nelarabine, cladribine, asparaginase, methotrexate, pralatrexate, or any combination thereof. [0233] In some embodiments, the chemotherapeutic agent is fludarabine, ibrutinib, fostamatinib, lenalidomide, thalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, cyclophosphamide, doxorubicin hydroxydaunomycin, vincristine, oncovin, prednisone, or any combination thereof. [0234] In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, e.g., brensocatib, are administered in combination with a therapeutic targeting bone pain, such as, cancer-induced bone pain. In some embodiments, the therapeutic targeting bone pain is sivelestat. In some embodiments, the therapeutic targeting bone pain is an analgesic, an opiod (such as, morphine, fentanyl, buprenophine, oxycodone) or a non-steroidal anti-inflammatory drug. In some embodiments, the therapeutic targeting bone pain is radiotherapy, such as, using radioisotopes. In some embodiments, the therapeutic targeting bone pain is bisphosphonates (such as, pamidronate and zoledronate). In some embodiments, the therapeutic targeting bone pain is denosumab. Further examples of therapeutics targeting bone pain are described in Kane et al., BMJ 2015;350:h315, which is incorporated herein by reference in its entirety for all purposes. [0235] The term administered “in combination,” as used herein, is understood to mean that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder (such as, cancer), such that the effects of the treatments on the patient overlap at a point in time. In certain embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent” delivery. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins, which may be referred to as “sequential” or “serial” delivery. [0236] In some embodiments, the treatment is more effective because of combined administration. For example, the second treatment is more effective; for e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (synergistic).
Dosage and Administration
[0237] The dosage administered will vary with the compound employed, the mode of administration, the treatment desired and the type of cancer being treated. In some embodiments, the subject is administered a compound of Formula (I) at a daily dosage of about 10 mgs to about 100 mgs, for example, about 15 mgs, about 20 mgs, about 25 mgs, about 30 mgs, about 35 mgs, about 40 mgs, about 45 mgs, about 50 mgs, about 55 mgs, about 60 mgs, about 65 mgs, about 70 mgs, about 75 mgs, about 80 mgs, about 85 mgs, about 90 mgs, about 95 mgs, or about 100 mgs, including all values and subranges that lie therebetween. In some embodiments, the subject is administered a compound of Formula (I) at a daily dosage of about 10 mgs to about 65 mgs. In a further embodiment, the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
[0238] In some embodiments, the daily dosage of a compound of the disclosure is in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg), for example, about 0.05 μg/kg, 0.1 μg/kg, 0.5 μg/kg, 1 μg/kg, 5 μg/kg, 10 μg/kg, 20 μg/kg, 30 μg/kg, 40 μg/kg, 50 μg/kg, 60 μg/kg, 70 μg/kg, 80 μg/kg, 90 μg/kg, 100 μg/kg, 200 μg/kg, 300 μg/kg, 400 μg/kg, 500 μg/kg, 600 μg/kg, 700 μg/kg, 800 μg/kg, 900 μg/kg, 1 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, or 100 mg/kg, including all values and subranges that lie therebetween. In a further embodiment, the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
[0239] In one embodiment, the compound of Formula (I) is administered in an oral dosage form. In a further embodiment, the compound of Formula (I) is administered as a 10 mg to 50 mg dosage form, for example, a 5 mg dosage form, a 10 mg dosage form, a 15 mg dosage form, a 20 mg dosage form, a 25 mg dosage form, a 30 mg dosage form, 35 mg dosage form, a 40 mg dosage form, a 45 mg dosage form or a 50 mg dosage form. In a further embodiment, the dosage form is a 10 mg, 25 mg or 40 mg dosage form. In a further embodiment, the dosage form is administered once daily. In a further embodiment, the compound is brensocatib, or a pharmaceutically acceptable salt thereof. [0240] The most suitable route in any given case will depend on the nature and severity of the condition being treated and/or prevented and the cancer tissue that is being targeted. Administration routes include oral, enteral, transmucosal, rectal, intranasal, inhalation (e.g., via an aerosol), buccal (e.g., sublingual), vaginal, intrathecal, intraocular, transdermal, in utero (or in ovo), parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular (including administration to skeletal, diaphragm and/or cardiac muscle), intradermal, intrapleural, intracerebral, intraarticular, intravascular or via infusion), topical (e.g., to both skin and mucosal surfaces, including airway surfaces, and transdermal administration), intralymphatic, and the like, as well as direct tissue or organ injection (e.g., to liver, skeletal muscle, cardiac muscle, diaphragm muscle or brain). In some embodiments, the administration is by injection into the central nervous system. In one embodiment, administration is via the enteral route and is conducted through a nasogastric (NG) tube. [0241] In some embodiments, the administration is via intraosseous injection. In some embodiments, the subject administered the compounds disclosed herein via intraosseous injection has bone cancer, metastasis to the bone and/or cancer-induced bone pain. [0242] The length of the administration period in any given case may depend on the nature and severity of the condition being treated and/or prevented and be determined by the physician. In some embodiments, the compounds or compositions disclosed herein may be administered for a period of about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 week, about 2 weeks, about 3 weeks, 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 1 year, about 18 months, about 2 years, about 30 months, about 3 years, about 4 years, about 5 years, or more than 5 years. [0243] In some embodiments, the administration period for the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, 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 1 year, at least about 18 months, at least about 2 years, at least about 30 months, at least about 3 years, at least about 4 years, at least about 5 years. The administration period for the methods provided herein, in another embodiment, is from about 30 days to about 180 days. In another embodiment, the administration period is from about 30 days to about 36 months, or from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months. . [0244] Administration schedules, including frequency of dosage, may be determined by the physician. In some embodiments, the composition may be administered to the subject once a day or more than once a day during the administration period. In some embodiments, the composition may be administered to the subject twice a day. In some embodiments, the composition may be administered to the subject every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some embodiments, the composition may be administered to the subject weekly, bi-weekly or every three weeks. In some embodiments, the dosage form is administered at approximately the same time every day. [0245] In one embodiment, the composition is administered once daily during the administration period. In another embodiment, the composition is administered twice daily during the administration period. In another embodiment, the composition is administered every other day during the administration period. In another embodiment, the composition is administered once weekly, twice weekly, thrice weekly, four times weekly, five times weekly or six times weekly. [0246] The present disclosure provides compositions comprising any one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof. The present disclosure further provides pharmaceutical compositions, comprising an effective amount of any one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof. [0247] The compounds of Formula (I) are generally administered in the form of a pharmaceutical composition in which the Formula (I) compound/salt (active pharmaceutical ingredient (API)) is in a composition comprising a pharmaceutically acceptable adjuvant(s), diluents(s) and/or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals – The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002, incorporated by reference herein in its entirety for all purposes. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994. [0248] Depending on the mode of administration, the pharmaceutical composition may comprise from about 0.05 to about 99 wt%, for example, about 0.5 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 98 wt%, or about 99 wt%, from about 0.05 to about 80 wt%, or from about 0.10 to about 70 wt%, or from about 0.10 to about 50 wt%, of API, all percentages by weight being based on the total weight of the pharmaceutical composition. Unless otherwise provided herein, API weight percentages provided herein are for the respective free base form of the compound of Formula (I). [0249] In some embodiments, the compositions disclosed herein further comprise at least one pharmaceutically acceptable carrier, excipient, and/or vehicle, for example, solvents, buffers, solutions, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. In some embodiments, the pharmaceutically acceptable carrier, excipient, and/or vehicle may comprise saline, buffered saline, dextrose, water, glycerol, sterile isotonic aqueous buffer, and combinations thereof. In some embodiments, the pharmaceutically acceptable carrier, excipient, and/or vehicle comprises phosphate buffered saline, sterile saline, lactose, sucrose, calcium phosphate, dextran, agar, pectin, peanut oil, sesame oil, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like) or suitable mixtures thereof. In some embodiments, the compositions disclosed herein further comprise minor amounts of emulsifying or wetting agents, or pH buffering agents. [0250] In some embodiments, the compositions disclosed herein further comprise other conventional pharmaceutical ingredients, such as preservatives, or chemical stabilizers, such as chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, the parabens, ethyl vanillin, glycerin, phenol, parachlorophenol or albumin. In some embodiments, the compositions disclosed herein may further comprise antibacterial and antifungal agents, such as, parabens, chlorobutanol, phenol, sorbic acid or thimerosal; isotonic agents, such as, sugars or sodium chloride and/or agents delaying absorption, such as, aluminum monostearate and gelatin. [0251] In some embodiments, the adjuvant(s), diluent(s) or carrier(s) present in the pharmaceutical composition are selected based on the mode of administration. For instance, for oral administration the compound of the present disclosure may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, corn starch or amylopectin; cellulose derivative; binder, for example, gelatine or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and/or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s). Alternatively, the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. [0252] For the preparation of soft gelatine capsules, the compound of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using pharmaceutical excipients like the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules. [0253] In some embodiments, the form of the pharmaceutical composition depends on the mode of administration. For instance, in one oral administration embodiment, the oral dosage form is a film-coated oral tablet. In a further embodiment, the dosage form is an immediate release dosage form with rapid dissolution characteristics under in vitro test conditions. [0254] In one embodiment, the composition is an oral disintegrating tablet (ODT). ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole. [0255] In one embodiment, the composition is an oral thin film or an oral disintegrating film (ODF). Such formulations, when placed on the tongue, hydrate via interaction with saliva, and releases the active compound from the dosage form. The ODF, in one embodiment, contains a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA) or sodium alginate. [0256] Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example, may contain the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and/or carboxymethylcellulose as a thickening agent. [0257] In one embodiment of the methods, the pharmaceutical composition is one of the compositions described in International Application Publication No. WO 2019/166626, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [0258] In another embodiment of the methods, the pharmaceutical composition administered to the patient is Composition (A) comprising: (a) from about 1 to about 30 wt% of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; (b) from about 45 to about 85 wt% of a pharmaceutical diluent; (c) from about 6 to about 30 wt% of a compression aid; (d) from about 1 to about 15 wt% of a pharmaceutical disintegrant; (e) from about 0.00 to about 2 wt% of a pharmaceutical glidant; and (f) from about 1 to about 10 wt% of a pharmaceutical lubricant; wherein the components add up to 100 wt%. [0259] In a further embodiment, the compound of Formula (I) is brensocatib. In one embodiment, brensocatib is in polymorphic Form A. In another embodiment, brensocatib is characterized by one of the X-ray powder diffraction patterns described above. [0260] In some embodiments of the methods, Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 1 to about 25 wt %; from about 1 to about 20 wt %; from about 1 to about 15 wt %; from about 1 to about 10 wt %; from about 1 to about 5 wt%, or from about 1 to about 3 wt % of the total weight of the composition. [0261] In some embodiments of the methods, Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 1.5 to about 30 wt%; from about 1.5 to about 25 wt%; from about 1.5 to about 20 wt%; from about 1.5 to about 15 wt%; from about 1.5 to about 10 wt %; or from about 1.5 to about 5 wt% of the total weight of the composition. [0262] In some embodiments of the methods, Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 3 to about 30 wt%; from about 3 to about 25 wt %; from about 3 to about 20 wt%; from about 3 to about 15 wt %; from about 3 to about 10 wt %; or from about 3 to about 5 wt% of the total weight of the composition. In a further embodiment, the compound of Formula (I)) is present at from about 3 to about 10 wt % of the total weight of the composition. In a further embodiment, the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof. [0263] In some embodiments of the methods, Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt% or about 30 wt% of the total weight of the composition. [0264] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical diluents selected from the group consisting of microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose, xylitol, and a combination of the foregoing. In one embodiment, Composition (A) comprises two or more pharmaceutical diluents. In another embodiment, Composition (A) comprises one pharmaceutical diluent. In a further embodiment, the pharmaceutical diluent is microcrystalline cellulose. Microcrystalline cellulose is a binder/diluent in oral tablet and capsule formulations and can be used in dry-granulation, wet-granulation, and direct- compression processes. [0265] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical diluents in an amount from about 45 to about 80 wt%, from about 45 to about 75 wt%, from about 45 to about 70 wt%, from about 45 to about 65 wt%, from about 45 to about 60 wt%, or from about 45 to about 55 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical diluents comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof. [0266] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical diluents in an amount from about 50 to about 85 wt%, from about 50 to about 75 wt%, from about 55 to about 85 wt%, from about 55 to about 70 wt%, from about 60 to about 85 wt%, from about 65 to about 85 wt%, from about 70 to about 85 wt%, or from about 75 to about 85 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical diluents is present at from about 55 to about 70 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical diluents comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof. [0267] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical diluents in an amount of about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt% or about 85 wt% of the total weight of the composition. [0268] In some embodiments of the methods, the one or more pharmaceutical diluents in Composition (A) is microcrystalline cellulose. In other embodiments, the one or more pharmaceutical diluents comprises calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol. [0269] In the present disclosure, the terms “disintegrant” and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Accordingly, a disintegrant in the Composition (A) may be, for example: alginic acid, calcium alginate, carboxymethylcellulose calcium, chitosan, croscarmellose sodium, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, starch, or a combination thereof. [0270] In some embodiments of the methods, the one or more disintegrants in Composition (A) is sodium starch glycolate. In one embodiment, the amount of the disintegrants present in Composition (A) is between 2% and 8% of the total weight of the composition. In a further embodiment, the amount of the disintegrants is about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt% or about 4.5 wt% of the total weight of the composition. The physical properties of sodium starch glycolate, and hence its effectiveness as a disintegrant, are affected by the degree of crosslinkage, extent of carboxymethylation, and purity. [0271] In some embodiments of the methods, the one or more pharmaceutical disintegrants in Composition (A) comprises croscarmellose sodium. [0272] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical disintegrants in an amount from about 2 to about 14 wt%, from about 2 to about 13 wt%, from about 2 to about 12 wt%, from about 2 to about 11 wt%, from about 2 to about 10 wt%, from about 2 to about 9 wt%, from about 2 to about 8 wt%, from about 2 to about 7 wt%, from about 2 to about 6 wt%, from about 2 to about 5 wt%, from about 3.5 to about 4.5 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical disintegrants is present at from about 3.5 to about 4.5 wt% of the total weight of the pharmaceutical composition. In a further embodiment, the one or more pharmaceutical disintegrants is sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof. [0273] In the present disclosure, the terms “glidants” and “gliding agents” are intended to be interpreted in the context of pharmaceutical formulation science. Accordingly, a glidant in Composition (A) may be, for example: silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate and talc. [0274] Accordingly, in some embodiments of the methods, the one or more pharmaceutical glidants in Composition (A) is selected from silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, talc, or a combination of the foregoing. In one embodiment, the glidant is silicon dioxide. Its small particle size and large specific surface area give it desirable flow characteristics that are exploited to improve the flow properties of dry powders in a number of processes such as tableting and capsule filling. Typical silicon dioxide concentrations for use herein range from about 0.05 to about 1.0 wt%. Porous silica gel particles may also be used as a glidant, which may be an advantage for some formulations, with typical concentrations of 0.25-1%. [0275] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.00 to about 1.75 wt%; from about 0.00 to about 1.50 wt%; from about 0.00 to about 1.25 wt%; from about 0.00 to about 1.00 wt%; from about 0.00 to about 0.75 wt%; from about 0.00 to about 0.50 wt%; from about 0.00 to about 0.25 wt%; from about 0.00 to about 0.20 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical glidants comprises silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants is sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof. [0276] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.05 to about 2 wt%; from about 0.05 to about 1.75 wt%; from about 0.05 to about 1.50 wt%; from about 0.05 to about 1.25 wt%; from about 0.05 to about 1.00 wt%; from about 0.05 to about 0.75 wt%; from about 0.05 to about 0.50 wt%; from about 0.05 to about 0.25 wt%; or from about 0.05 to about 0.20 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical glidants is present at from about 0.05 to about 0.25 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical glidants comprises silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants is sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof. [0277] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.05 to about 2 wt%; from about 0.10 to about 2 wt%; from about 0.2 to about 2 wt%; from about 0.3 to about 2 wt%; or from about 0.40 to about 2 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical glidants comprises silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants is sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof. [0278] In the present disclosure, the terms “lubricant” and “lubricants”, as used herein, are intended to be interpreted in the context of pharmaceutical formulation science. Accordingly, a lubricant may be, for example calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g. a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin and zinc stearate. [0279] Accordingly, in some embodiments of the methods, the one or more pharmaceutical lubricants in Composition (A) are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin and zinc stearate. In other embodiments, the one or more pharmaceutical lubricants are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, stearic acid, talc, tribehenin and zinc stearate. [0280] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical lubricants and the lubricant is not sodium stearyl fumarate. In a further embodiment, the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof. [0281] In one embodiment of the methods, Composition (A) includes glycerol behenate as the lubricant. [0282] In some embodiments of the methods, the one or more pharmaceutical lubricants in Composition (A) comprises glyceryl behenate, magnesium stearate, stearic acid, or a combination thereof. [0283] In one embodiment of the methods, the lubricant in Composition (A) is glyceryl behenate, magnesium stearate, or a combination thereof. [0284] In one embodiment of the methods, the one or more pharmaceutical lubricants in Composition (A) comprises sodium stearyl fumarate and/or one or more behenate esters of glycerine. [0285] In some embodiments of the methods, Composition (A) comprises one or more pharmaceutical lubricants in an amount from about 1 wt% to about 9 wt %, from about 1 wt% to about 8 wt %, from about 1 wt% to about 7 wt %, from about 1 wt% to about 6 wt %, from about 1 wt% to about 5 wt %, from about 2 wt% to about 10 wt %, from about 2.5 wt% to about 10 wt %, from about 2 wt% to about 8 wt %, from about 2 wt% to about 7 wt %, from about 2 wt% to about 6 wt %, from about 2 wt% to about 5 wt %, from about 2 wt% to about 4.5 wt %, or from about 2.5 wt% to about 4.5 wt % of the total weight of the composition. In a further embodiment, the one or more pharmaceutical lubricants is present at from about 2.5 to about 4.5 wt% of the total weight of the composition. In a further embodiment, the one or more pharmaceutical lubricants in Composition (A) is glycerol behenate. In a further embodiment, the one or more pharmaceutical glidants in Composition (A) comprises silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants in Composition (A) is sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents in Composition (A) comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof. [0286] In one embodiment of the methods, the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate and/or one or more behenate esters of glycerine or a mixture thereof. [0287] In another embodiment of the methods, the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate, glyceryl dibehenate, glyceryl behenate, tribehenin or any mixture thereof. [0288] In one embodiment of the methods, the one or more pharmaceutical lubricants in Composition (A) comprises sodium stearyl fumarate. In another embodiment, the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate. [0289] In one embodiment of the methods, the one or more pharmaceutical lubricants in Composition (A) comprises one or more behenate esters of glycerine (i.e., one or more of glyceryl dibehenate, tribehenin and glyceryl behenate). [0290] In one embodiment of the methods, the compression aid in Composition (A) is dicalcium phosphate dihydrate (also known as dibasic calcium phosphate dihydrate) (DCPD). DCPD is used in tablet formulations both as an excipient and as a source of calcium and phosphorus in nutritional supplements. [0291] In one embodiment of the methods, Composition (A) comprises the compression aid, e.g., DCPD, in an amount from about 10 to about 30 wt%, including about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, or about 24 wt% of the total weight of the composition. In a further embodiment, the compression aid is present at about 20 wt % of the total weight of the composition. [0292] In one embodiment of the methods, Composition (A) comprises the compression aid, e.g., DCPD, in an amount from about 10 to about 25 wt%, from about 10 to about 20 wt%, from about 10 to about 15 wt%, from about 15 to about 25 wt%, or from about 20 to about 25 wt%, or from about 18 to about 22 wt% of the total weight of the composition. In a further embodiment, the compression aid is present at from about 18 to about 22 wt% of the total weight of the composition. In a further embodiment, the compression aid is DCPD. In a further embodiment, the one or more pharmaceutical lubricants in Composition (A) is glycerol behenate. In a further embodiment, the one or more pharmaceutical glidants in Composition (A) comprises silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants in Composition (A) is sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents in Composition (A) comprises microcrystalline cellulose. In even a further embodiment, the compound of Formula (I) in the exemplary composition is brensocatib, or a pharmaceutically acceptable salt thereof. [0293] In one embodiment of the methods, the pharmaceutical composition administered to the patient is Composition (B) comprising: (a) from about 1 to about 30 wt% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; (b) from about 55 to about 75 wt% of a pharmaceutical diluent; (c) from about 15 to about 25 wt% of a compression aid; (d) from about 3 to about 5 wt% of a pharmaceutical disintegrant; (e) from about 0.00 to about 1 wt% of a pharmaceutical glidant; and (f) from about 2 to about 6 wt% of a pharmaceutical lubricant; wherein the components add up to 100 wt%. [0294] In some embodiments of the methods where Composition (B) is administered to the patient, the identity of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical glidant, and pharmaceutical lubricant in the composition may be one of those described above for Composition (A). In other embodiments, the amount of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical glidant, and pharmaceutical lubricant in Composition (B) may also be one of those described above for Composition (A), as long as the amount is within the corresponding broader range recited above for Composition (B). [0295] The pharmaceutical compositions disclosed herein, including Compositions (A) and (B), may be in a solid dosage form suitable for oral administration to a human being. For example, the pharmaceutical composition is a pharmaceutical tablet. Pharmaceutical tablets may be prepared using methods known to those skilled in the art including, for example, dry mixing / direct compression process as described in International Application Publication No. WO 2019/166626. In some embodiments, the pharmaceutical tablet comprises a tablet core wherein the tablet core comprises the pharmaceutical composition as disclosed herein and wherein the tablet core has a coating. In some embodiments, the coating is a film coating. The film coating may be applied using conventional methods known to those skilled in the art. A functional coating can be used to provide protection against, for example, moisture ingress or degradation by light. Additionally, a functional coating may be used to modify or control the release of the compound of Formula (I), e.g., brensocatib, from the composition. The coating may comprise, for example, about 0.2 to about 10 wt% of the total weight of the pharmaceutical composition, e.g., from about 0.2 to about 4 wt%, from about 0.2 to about 3 wt%, from about 1 to about 6 wt%, or from about 2 to about 5 wt% of the total weight of the pharmaceutical composition. EXAMPLES [0296] The present disclosure is further illustrated by reference to the following Examples. However, it should be noted that the Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way. Example 1 – Treatment of Cancer-Induced Bone Pain By Administration of Brensocatib [0297] FIG. 2 and Table 1 show the design for this 22-day study (day -7 to day 14). Female Wistar rats (150-170 g) received Walker 256 rat breast cancer cells via intraosseous injection into the bone marrow of the right tibia on Day 0 (groups 1-5 in Table 1). Group 6 did not receive the cancer cells. Rats in groups 1-5 were administered either placebo or brensocatib orally twice daily starting on Day -7 until study ended (n=12 for all groups besides leave alone control group, which was n=8).
Figure imgf000060_0001
[0298] Body weight was monitored daily starting Day -7. Behavior check was done on Day 0, Day 7, and Day 14. Pain was assessed by evaluating tactile allodynia. Tumor progression was followed using magnetic resonance imaging (MRI), and the levels and activity of biomarkers were measured in plasma, white blood cells and bone marrow cells. The behavior endpoint was tactile allodynia, and the primary endpoint was the measurement of hind paw withdrawal threshold (PWT) using Von Frey Fibers. [0299] Bone marrow cell pellets were collected 24 hr post-last AM dose, and the level and activity of neutrophil serine proteases and DPP1 were measured in each of the samples. [0300] Further, the effect of brensocatib on cancer-induced bone pain is evaluated by assaying the spontaneous nocifensive behaviour of the rodents, and other methods, as described in Bali et al., Pain. 2017 Nov; 158(11): 2243–2258; and Yu et al., Exp Ther Med. 2017 Aug; 14(2): 1531–1537, each of which is herein incorporated by its reference in its entirety for all purposes. [0301] The body weight for each group as a function of time is shown in FIG. 3. As expected, the leave alone healthy control group without tumor injection had the most weight gain; however, there were no differences for all tumor inoculated groups. No unexpected side effects were observed for the 40 mg/kg/day brensocatib treatment groups. [0302] The mechanical allodynia was assessed using a von Frey test. A decrease in the mechanical paw withdrawal threshold (PWT) as measured by the test means an increased pain sensitivity. The results of the mechanical allodynia assessments are provided in FIGS. 4 (Day 0), 5 (Day 7) and 6 (Day 14). At Day 0, all groups showed normal (100%) tolerance to the pain achieving the pain threshold (FIGs. 4 and 13). As shown in FIGs. 5 and 6, brensocatib pre-treatment to Group 1 showed a statistically significant anti-neuropathic pain effect compared to placebo control on Day 7 and Day 14. [0303] Time-course monitoring for individual rats of each group is summarized in FIGS 7-12. By setting an effective threshold based on the data from the morphine, placebo, and no tumor leave alone control groups, the therapeutic response rate per group was calculated. As shown in FIG. 13, at Day 0, all groups showed normal (100%) tolerance to the pain achieving the effective threshold. However, on Day 7, both the placebo group (Group 5) and brensocatib: day 7- day 13 group (Group 3) showed a decline in pain tolerance with no rats achieving the pain tolerance threshold. In contrast, for both the brensocatib: day -7 – day 13 (pre-treatment) group (Group 1) and brensocatib: day 0- day 13 group (Group 2), approximately 50% of the rats achieved the effective threshold. The morphine treatment group performed as expected with a response that was similar to the healthy leave alone control group, with 100% of the rats achieving the effective response threshold. On Day 14, all three brensocatib-treated groups (Groups 1-3) showed approximately 50% of the rats achieving the effective threshold. Notably, Group 3, which had 100% of the rats failing to achieve the pain response threshold at Day 7, showed improvement with recovery to the same degree as Group 1, which had the longest duration of brensocatib treatment. In summary, brensocatib treatment had a positive anti- neuropathic pain effect in the cancer-induced bone pain rat model, with more than 50% of the rats showing improvement in pain tolerance and a 7-day dosing regimen adequate to recover the maximum effect. [0304] NSP activity in the bone marrow samples from the right (tumor implantation) and the left side of the limb were measured. There was no increase in NSP activity in the bone marrow of the diseased animals (placebo control group) compared to the healthy controls. A significant reduction in NSP activity in the bone marrow was observed for PR3 in the brensocatib treated groups compared to the placebo group. Smaller and non-significant reductions in CatG and NE activity were also observed in the brensocatib treated groups. [0305] FIG. 14 provides a schematic of a follow-on study assessing mechanical allodynia in animals treated with brensocatib, the neutrophil elastase (NE) inhibitor sivelestat or a combination of brensocatib and morphine. The follow-on study will evaluate brensocatib treatment with or without the combination of morphine compared to morphine alone or sivelestat alone. Animals are pretreated 7 days before tumor inoculation on Day -7, and the tumor is inoculated on Day 0. Brensocatib treatment effects are evaluated on Day 7 compared to morphine at 3 mg/kg or NE inhibitor sivelestat. Additionally, the combination of brensocatib and morphine at 1 mg/kg will be evaluated and compared to morphine only at 1 mg/kg to investigate whether there is any synergistic effect of the two. The timepoint for pain evaluation on Day 7 will be performed at 1 hr., 6 hr., and 24 hr. post-morphine treatment to investigate time-dependent response. Example 2 – Treatment of Intravenous (IV) Metastasis Mouse Model By Administration of Brensocatib [0306] Mouse models are used to evaluate the effect of administering brensocatib on the treatment of cancer. For example, mouse models with thyroid cancer, which show high DPP1 expression levels in the cancer cells, are used to evaluate the effects of administering brensocatib (10 mg/kg) twice daily. [0307] The cancer cells injected in this experiment may be transfected with luciferase to enable monitoring of their location and cancer progression via in vivo imaging and ex vivo imaging. Further, this study also evaluates how brensocatib affects neutrophil-derived DPP1 and tumor- derived DPP1. The study design is shown in FIG.15, and the experimental details are provided in Table 2 below.
Figure imgf000063_0001
[0308] Secretomic profiling analysis of DPP1 along with confirmation using Western blot and qPCR is done. In vivo imaging of metastatic sites and body weight measurements are conducted before and after treatment, and different time points during the administration period. Endpoint measurements include ex vivo organ imaging, survival rate, and quantification of tumor cells in metastatic sites. Downstream endpoint analyses include measuring brensocatib concentration and circulating NETs in plasma, measuring the level of NSPs and DPP1 in bone marrow pellet, histopathology analysis of tumor tissues including primary and metastatic sites, hematoxylin and eosin staining of tissues, immunohistochemistry of NETs, myeloperoxidase (MPO), neutrophil elastase (NE), neutrophil biomarker Ly6G, and Cathepsin C (CTSC). Example 3 – Treatment of Spontaneous Metastasis Mouse Model By Administration of Brensocatib [0309] An orthotopic spontaneous metastasis mouse model in either Balb/c or Balb/c nude mice is used to evaluate the treatment of metastatic cancer by the administration of brensocatib. The general study design is shown in FIG.16. The cancer cells injected in this experiment may be transfected with luciferase to enable monitoring of their location and cancer progression via in vivo imaging and ex vivo imaging. The start day of brensocatib administration as a therapeutic for primary tumor or as a prophylactic for metastatic tumor, indicated as “X” in FIG. 16, depends on the type of the mouse model and the cancer cell line used in the experiment. The start day of brensocatib treatment and the study duration for each cancer type - lung, colon, prostate, and pancreatic cancers – is detailed below. I. Orthotopic Injection of Lung Cancer Cells [0310] H460 cells are orthotopically injected into mice on Day 0 as shown in FIG. 16. H460 cells are a fast growing non-small-cell lung cancer cell line. Treatment with brensocatib starts on Day -7, which is a week before tumor injection as prophylactic pre-treatment, or on Day 0 along with tumor cells injection as prophylactic co-treatment. Overall study lasts 5-7 weeks based on historical data; however, the termination timepoint in our study design is one day after more than 40% of animals die within any of the group in order to evaluate the progression of metastasis. The start day of brensocatib administration as a therapeutic for primary tumor or a prophylactic for metastatic tumor is 7 days post tumor engraftment. Treatment efficacy will be monitored by assaying different parameters as described herein. II. Orthotopic Injection of Colon Cancer Cells [0311] HCT116 cells are orthotopically injected into the cecal wall of mice on Day 0 as shown in FIG. 16. HCT116 is a human colorectal carcinoma cell line that can form primary tumors and distant metastases upon transplantation into immunocompromised mice. Treatment with brensocatib starts on Day -7, which is a week before tumor injection as prophylactic pre- treatment, or on Day 0 along with tumor cells injection as prophylactic co-treatment. Overall study lasts 6-8 weeks based on historical data; however, the termination timepoint in our study design is one day after more than 40% of animals die within any of the group in order to evaluate the progression of metastasis. The start day of brensocatib administration as a therapeutic for primary tumor or a prophylactic for metastatic tumor is 14 days post tumor engraftment. Treatment efficacy will be monitored by assaying different parameters as described herein. III. Orthotopic Injection of Pancreatic Cancer Cells [0312] A BX-PC3 human pancreatic cancer orthotopic spontaneous metastasis xenograft model in female BALB/c nude mice was used to evaluate anti-primary and metastatic tumor effect of brensocatib. Three groups of female BALB/c nude mice were orthotopically injected with BX-PC3-Luc2 cells on Day 0 as shown in FIG. 17. BX-PC-3-Luc2 is a light-producing cell line derived from BX-PC3 human pancreatic adenocarcinoma. Group 1 mice received twice-daily brensocatib treatment at 10 mg/kg via oral gavage that lasted from Day -7, which was a week before tumor injection as prophylactic pre-treatment, to the end of study. Group 2 mice received twice-daily placebo treatment via oral gavage from Day -7 to Day -1, followed by twice-daily brensocatib treatment at 10 mg/kg via oral gavage from Day 0 to the end of study. Group 3 mice received twice-daily placebo treatment via oral gavage from Day -7 to the end of study. The study ended one day after 2 animals died in any of the three groups, which was day 38. Endpoints of the study include primary tumor and metastatic tumor progression, survival rate, NSP levels and activity in bone marrow cells, and histopathology analysis of primary tumor and metastatic tumor tissues. One mouse from Group 2 died on day 29; two mice from group 2 died on day 38, and one mouse from Group 3 died on day 26. [0313] In vivo imaging data of the mice presented in FIG. 18 demonstrated that brensocatib treatment, whether initiated on Day -7 in Group 1 or initiated on Day 0 in Group 2, inhibited overall tumor progression up to Day 36. IV. Orthotopic Injection of Prostate Cancer Cells [0314] PC-3M cells are orthotopically injected into the prostate of mice on Day 0 as shown in FIG. 16. The PC3 cell line was originally derived from bone metastasis of human prostatic adenocarcinoma. PC-3M-Luc-C6 is a subline of PC3 that has increased metastatic ability and is transfected with luciferase. Further details on the PC-3M cell line is provided in Zacharias, N.M., et al., Sci Rep 7, 16159 (2017), which is incorporated herein by reference in its entirety for all purposes. Treatment with brensocatib starts on Day -7, which is a week before tumor injection as prophylactic pre-treatment, or on Day 0 along with tumor cells injection as prophylactic co-treatment. Overall study lasts 6-8 weeks based on historical data; however, the termination timepoint in our study design is one day after more than 40% of animals die within any of the group in order to evaluate the progression of metastasis. The start day of brensocatib administration as a therapeutic for primary tumor or a prophylactic for metastatic tumor is 7 days post tumor engraftment. Treatment efficacy will be monitored by assaying different parameters as described herein. Example 4 – In vivo test of anti-tumor efficacy of brensocatib in the subcutaneous MB49 murine bladder cancer syngeneic model in female C57BL/6 mice [0315] The in vivo therapeutic efficacy of brensocatib in the treatment of the MB49 murine bladder cancer syngeneic model in female C57BL/6 mice is assessed. [0316] Tumor inoculation and treatment: Each mouse is inoculated subcutaneously at the right flank with MB49 tumor cells (1 x 106/mouse) in 0.1 mL of PBS for tumor development. The test article administration and the animal numbers in each group are shown in the Table 4. The treatments start on Day 0 (the same day of tumor cell injection). [0317] Endpoint analysis: Tumor growth via caliper measurement, histopathology analysis, and NSP activities in bone marrow are assessed in the study.
Figure imgf000066_0001
* * * * * * * [0318] All papers, publications and patents cited in this specification are herein incorporated by reference as if each individual paper, publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world. [0319] The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. Modifications and variation of the above-described embodiments of the invention are possible without departing from the invention, as appreciated 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

CLAIMS 1. A method of treating cancer in a subject in need thereof, comprising, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000068_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. 2. A method of treating cancer in a subject in need thereof, comprising, (a) determining a level of DPP1 in a biological sample obtained from the subject, and if the level of DPP1 determined in step (a) is in the range of about 1 ng/mL to about 100 ng/mL, then (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000069_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. 3. A method of treating cancer in a subject in need thereof, comprising: (a) determining a level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject, and if the level of NETs determined in step (a) is in the range of about 1 ng/mL to about 1000 ng/mL, then (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000070_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. 4. A method of treating cancer in a subject in need thereof, comprising: (a) determining a level of a neutrophil serine protease (NSP) in a biological sample obtained from the subject, and if the level of the NSP determined in step (a) is in the range of about 1 ng/mL to about 1000 ng/mL, then (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000071_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. 5. A method of treating cancer-induced bone pain (CIBP) in a subject having cancer, comprising, administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000072_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. 6. The method of any one of claims 1-5, wherein the method further comprises administering radiation therapy to the subject. 7. A method of improving a radiation response in a subject having cancer, wherein the cancer has previously been treated with radiation therapy, the method comprising: administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000073_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3; and administering radiation therapy to the subject. 8. A method for improving a radiation response in a subject having cancer, wherein the cancer has previously been treated with radiation therapy, the method comprising: (a) determining a level of NETs in a biological sample obtained from the subject, and if the level of NETs determined in step (a) is in the range of about 1 ng/mL to about 1000 ng/mL, then (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000074_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3; and administering radiation therapy to the subject. 9. A method for improving a radiation response in a subject having cancer, wherein the cancer has previously been treated with radiation therapy, the method comprising: (a) determining a level of an NSP in a biological sample obtained from the subject, and if the level of the NSP determined in step (a) is in the range of about 1 ng/mL to about 1000 ng/mL, then (b) administering to the subject for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000075_0001
R2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3, and administering radiation therapy to the subject.
10. The method of any one of claims 7-9, wherein improving the radiation response comprises reducing radioresistance of the cancer. 11. The method of any one of claims of 6-10, wherein administering radiation therapy is carried out prior to the administration period. 12. The method of any one of claims 6-11, wherein administering radiation therapy is carried out during the administration period. 13. The method of any one of claims 6-12, wherein administering radiation therapy is carried out subsequent to the administration period. 14. The method of any one of claims 6-13, wherein administering radiation therapy is carried out for about 1 week to about 10 weeks. 15. The method of claim 14, wherein administering radiation therapy is carried out for about 1 week to about 8 weeks. 16. The method of claim 15, wherein administering radiation therapy is carried out for about 1 week to about 6 weeks. 17. The method of claim 16, wherein administering radiation therapy is carried out for about 1 week to about 4 weeks. 18. The method of claim 17, wherein administering radiation therapy is carried out for about 1 week to about 2 weeks. 19. The method of any one of claims 6-18, wherein administering radiation therapy is carried out 5 days per week. 20. The method of any one of claims 6-19, wherein the radiation therapy comprises external beam radiation. 21. The method of claim 20, wherein the external beam radiation comprises three- dimensional conformal radiation therapy (3D-CRT), image guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), helical-tomotherapy, photon beam radiation therapy, proton beam radiation therapy or stereotactic radiosurgery.
22. The method of any one of claims 6-21, wherein the radiation therapy comprises brachytherapy. 23. The method of any one of claims 1-22, wherein DPP1 is expressed by cancerous cells, neutrophils, macrophages, monocytes, or mast cells of the subject. 24. The method of any one of claims 1-23, wherein a level of DPP1 in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 100 ng/mL prior to the administration period. 25. The method of any one of claims 1-24, wherein the activity of DPP1 in a biological sample obtained from the subject after administration of the composition is less than: (a) the activity of DPP1 in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of DPP1 in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. 26. The method of any one of claims 1-25, wherein a level of NETs in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL prior to the administration period. 27. The method of any one of claims 1-26, wherein a level of NETs in a biological sample obtained from the subject after administration of the composition is less than: (a) a level of NETs in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) a level of NETs in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. 28. The method of any one of claims 1-27, wherein a level of an NSP in a biological sample obtained from the subject is in the range of about 1 ng/mL to about 1000 ng/mL prior to the administration period. 29. The method of any one of claims 1-28, wherein the activity of an NSP in a biological sample obtained from the subject after administration of the composition is less than: (a) the activity of the NSP in a counterpart biological sample obtained from the subject before administration of the composition, and/or (b) the activity of the NSP in a counterpart biological sample obtained from a control subject, wherein the control subject has cancer and is not administered the composition. 30. The method of any one of claims 4, 9, 28, and 29, wherein the NSP comprises one selected from the group consisting of neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), neutrophil serine protease 4 (NSP4), and any combination thereof. 31. The method of claim 30, wherein the NSP comprises NE. 32. The method of claim 30, wherein the NSP comprises PR3. 33. The method of claim 30, wherein the NSP comprises CatG. 34. The method of claim 30, wherein the NSP comprises NSP4. 35. The method of any one of claims 2, 3, 4, 8, 9, 24, 25, 26, 27, 28, and 29, wherein the biological sample comprises one selected from the group consisting of blood, serum, white blood cells, neutrophils, a cancer tissue, tumor cells, tumor T-cells, and a combination thereof. 36. The method of claim 35, wherein the biological sample comprises blood. 37. The method of claim 35, wherein the biological sample comprises serum. 38. The method of claim 35, wherein the biological sample comprises white blood cells. 39. The method of claim 35, wherein the biological sample comprises neutrophils. 40. The method of claim 35, wherein the biological sample comprises a cancer tissue. 41. The method of claim 35, wherein the biological sample comprises tumor cells. 42. The method of claim 35, wherein the biological sample comprises tumor T-cells. 43. The method of any one of claims 1-42, wherein the cancer comprises a primary solid tumor, a liquid tumor, a metastatic cancer, or a combination thereof. 44. The method of claim 43, wherein the cancer comprises a primary solid tumor. 45. The method of claim 44, wherein the cancer is selected from the group consisting of breast cancer, bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibroid cancer, lymphoma, virus-induced cancer, oropharyngeal cancer, testicular cancer, thymus cancer, thyroid cancer, melanoma, and bone cancer. 46. The method of claim 45, wherein the cancer is breast cancer. 47. The method of claim 46, wherein the breast cancer comprises ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer. 48. The method of claim 47, wherein the breast cancer comprises ductal carcinoma. 49. The method of claim 47, wherein the breast cancer comprises lobular carcinoma. 50. The method of claim 47, wherein the breast cancer comprises medullary carcinoma. 51. The method of claim 47, wherein the breast cancer comprises colloid carcinoma. 52. The method of claim 47, wherein the breast cancer comprises tubular carcinoma. 53. The method of claim 47, wherein the breast cancer comprises inflammatory breast cancer. 54. The method of claim 45, wherein the cancer is bladder cancer. 55. The method of claim 45, wherein the cancer is lung cancer. 56. The method of claim 45, wherein the cancer is brain cancer. 57. The method of claim 56, wherein the brain cancer comprises astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. 58. The method of claim 57, wherein the brain cancer comprises astrocytoma. 59. The method of claim 57, wherein the brain cancer comprises anaplastic astrocytoma. 60. The method of claim 57, wherein the brain cancer comprises glioblastoma multiforme. 61. The method of claim 57, wherein the brain cancer comprises oligodendroglioma.
62. The method of claim 57, wherein the brain cancer comprises ependymoma. 63. The method of claim 57, wherein the brain cancer comprises meningioma. 64. The method of claim 57, wherein the brain cancer comprises schwannoma. 65. The method of claim 57, wherein the brain cancer comprises medulloblastoma. 66. The method of claim 45, wherein the cancer is ovarian cancer. 67. The method of claim 45, wherein the cancer is pancreatic cancer. 68. The method of claim 45, wherein the cancer is colorectal cancer. 69. The method of claim 45, wherein the cancer is prostate cancer. 70. The method of claim 45, wherein the cancer is liver cancer. 71. The method of claim 45, wherein the cancer is hepatocellular carcinoma. 72. The method of claim 45, wherein the cancer is kidney cancer. 73. The method of claim 45, wherein the cancer is stomach cancer. 74. The method of claim 45, wherein the cancer is skin cancer. 75. The method of claim 45, wherein the cancer is fibroid cancer. 76. The method of claim 75, wherein the fibroid cancer is leiomyosarcoma. 77. The method of claim 45, wherein the cancer is lymphoma. 78. The method of claim 77, wherein the lymphoma comprises Hodgkin’s lymphoma, non- Hodgkin’s lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, Natural Killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma or Kaposi's Sarcoma. 79. The method of claim 78, wherein the lymphoma comprises Hodgkin’s lymphoma. 80. The method of claim 78, wherein the lymphoma comprises non-Hodgkin’s lymphoma.
81. The method of claim 78, wherein the lymphoma comprises diffuse large B-cell lymphoma. 82. The method of claim 78, wherein the lymphoma comprises B-cell immunoblastic lymphoma. 83. The method of claim 78, wherein the lymphoma comprises Natural Killer cell lymphoma. 84. The method of claim 78, wherein the lymphoma comprises T-cell lymphoma. 85. The method of claim 78, wherein the lymphoma comprises Burkitt lymphoma. 86. The method of claim 78, wherein the lymphoma comprises Kaposi's Sarcoma. 87. The method of claim 45, wherein the cancer is virus-induced cancer. 88. The method of claim 45, wherein the cancer is oropharyngeal cancer. 89. The method of claim 45, wherein the cancer is testicular cancer. 90. The method of claim 45, wherein the cancer is thymus cancer. 91. The method of claim 45, wherein the cancer is thyroid cancer. 92. The method of claim 45, wherein the cancer is melanoma. 93. The method of claim 45, wherein the cancer is bone cancer. 94. The method of claim 43, wherein the cancer comprises a liquid tumor. 95. The method of claim 94, wherein the cancer 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, a myeloproliferative disorder, 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). 96. The method of claim 95, wherein the cancer is acute myeloid leukemia (AML).
97. The method of claim 95, wherein the cancer is acute lymphoblastic leukemia. 98. The method of claim 95, wherein the cancer is acute lymphocytic leukemia. 99. The method of claim 95, wherein the cancer is acute promyelocytic leukemia. 100. The method of claim 95, wherein the cancer is chronic myeloid leukemia. 101. The method of claim 95, wherein the cancer is hairy cell leukemia. 102. The method of claim 95, wherein the cancer is a myeloproliferative disorder. 103. The method of claim 95, wherein the cancer is Natural Killer cell leukemia. 104. The method of claim 95, wherein the cancer is blastic plasmacytoid dendritic cell neoplasm. 105. The method of claim 95, wherein the cancer is chronic myelogenous leukemia (CML). 106. The method of claim 95, wherein the cancer is mastocytosis. 107. The method of claim 95, wherein the cancer is chronic lymphocytic leukemia (CLL). 108. The method of claim 95, wherein the cancer is multiple myeloma (MM). 109. The method of claim 95, wherein the cancer is myelodysplastic syndrome (MDS). 110. The method of any one of claims 1-109, wherein the cancer is a pediatric cancer. 111. The method of claim 110, wherein the pediatric cancer comprises neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma or Ewing sarcoma. 112. The method of claim 111, wherein the pediatric cancer comprises neuroblastoma. 113. The method of claim 111, wherein the pediatric cancer comprises Wilms tumor. 114. The method of claim 111, wherein the pediatric cancer comprises rhabdomyosarcoma. 115. The method of claim 111, wherein the pediatric cancer comprises retinoblastoma. 116. The method of claim 111, wherein the pediatric cancer comprises osteosarcoma.
117. The method of claim 111, wherein the pediatric cancer comprises Ewing sarcoma. 118. The method of any one of claims 1-42, wherein the subject is at a risk for developing a metastatic cancer. 119. The method of claim 43, wherein the cancer comprises a metastatic cancer. 120. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, and/or liver. 121. The method of claim 120, wherein the metastatic cancer comprises metastasis of breast cancer to the brain. 122. The method of claim 120, wherein the metastatic cancer comprises metastasis of breast cancer to the bone. 123. The method of claim 120, wherein the metastatic cancer comprises metastasis of breast cancer to the pancreas. 124. The method of claim 120, wherein the metastatic cancer comprises metastasis of breast cancer to the lymph nodes. 125. The method of claim 120, wherein the metastatic cancer comprises metastasis of breast cancer to the liver. 126. The method of claim 118 or 119, wherein the metastatic cancer comprises a metastatic bone cancer. 127. The method of claim 118, 119 or 126, wherein the metastatic cancer comprises metastasis of bone cancer to the lung. 128. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, and/or the spleen. 129. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, and/or the ovary.
130. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of leukemia to the lymph nodes, the lung, the liver, the limb, the brain, the kidney, and/or the spleen. 131. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, the spleen, the pancreas, the stomach, the lung, and/or the kidney. 132. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of lymphoma to the kidney, the ovary, the liver, the bladder, and/or the spleen. 133. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of hematopoietic cancer to the intestine, the lung, the liver, the spleen, the kidney, and/or the stomach. 134. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of melanoma to lymph nodes and/or the lung. 135. The method of claim 118 or 119, wherein the metastatic cancer comprises a metastatic pancreatic cancer. 136. The method of claim 135, wherein the metastatic pancreatic cancer comprises metastasis of pancreatic cancer to the mesentery, the ovary, the kidney, the spleen, the lymph nodes, the stomach, and/or the liver. 137. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of prostate cancer to the lung, the pancreas, the kidney, the spleen, the intestine, the liver, the bone, and/or the lymph nodes. 138. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of ovarian cancer to the diaphragm, the liver, the intestine, the stomach, the lung, the pancreas, the spleen, the kidney, the lymph nodes, and/or the uterus. 139. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of myeloma to the bone. 140. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of lung cancer to the bone, the brain, the lymph nodes, the liver, the ovary, and/or the intestine.
141. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of kidney cancer to the liver, the lung, the pancreas, the stomach, the brain, and/or the spleen. 142. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of bladder cancer to the bone, the liver and/or the lung. 143. The method of claim 118 or 119, wherein the metastatic cancer comprises metastasis of thyroid cancer to the bone, the liver and/or the lung. 144. The method of any one of claims 1-143, wherein the administration of the composition diminishes the severity of, delays the onset of, or eliminates a symptom of cancer. 145. The method of claim 144, wherein the symptom of cancer is cancer-induced bone pain. 146. The method of claim 144, wherein the symptom of cancer is allodynia. 147. The method of claim 146, wherein the allodynia is tactile allodynia. 148. The method of claim 147, wherein the tactile allodynia is static mechanical allodynia. 149. The method of claim 147, wherein the tactile allodynia is dynamic mechanical allodynia. 150. The method of any one of claims 1-93 and 110-149, wherein the cancer comprises a solid tumor, and wherein a volume of the solid tumor in the subject after administration of the composition is less than: (a) a volume of the solid tumor in the subject before administration of the composition, and/or (b) a volume of a solid tumor in a control subject, wherein the control subject has the solid tumor and is not administered the composition. 151. The method of any one of claims 1-93 and 110-150, wherein the cancer comprises a plurality of solid tumors, and wherein the subject exhibits fewer solid tumors after administration of the composition as compared to: (a) before the administration period, and/or (b) a control subject, wherein the control subject has a plurality of solid tumors and is not administered the composition. 152. The method of any one of claims 1-151, wherein the cancer induces a weight loss in the subject, and the weight loss is alleviated during the administration period or subsequent to the administration period, as compared to prior to the administration period.
153. The method of any one of claims 1-152, wherein an overall survival period of the subject subsequent to the administration period is longer than an overall survival period of a control subject, wherein the control subject has cancer and is not administered the composition. 154. The method of any one of claims 1-153, wherein the subject has bone cancer or metastasis to the bone, and wherein the subject shows an increased bone mineral density during the administration period or subsequent to the administration period, as compared to: (a) a bone mineral density of the subject prior to the administration period, and/or (b) a bone mineral density of a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition. 155. The method of any one of claims 1-154, wherein the subject has bone cancer or metastasis to the bone, and wherein the subject experiences decreased bone pain during the administration period or subsequent to the administration period, as compared to: (a) bone pain of the subject prior to the administration period, and/or (b) bone pain of a control subject, wherein the control subject has bone cancer or metastasis to the bone and is not administered the composition. 156. The method of any one of claims 1-155, wherein the subject has prostate cancer, and wherein a blood level of prostate-specific antigen (PSA) in the subject is lower during the administration period or subsequent to the administration period, as compared to: (a) a blood level of PSA in the subject before the administration period, and/or (b) a blood level of PSA in a control subject, wherein the control subject has prostate cancer and is not administered the composition. 157. The method of any one of claims 1-156, wherein the method further comprises administering to the subject chemotherapy, immunotherapy, targeted therapy, an immune checkpoint inhibitor, hormone therapy, performing surgery on the subject, or any combination thereof. 158. The method of claim 157, wherein the method further comprises administering to the subject an immune checkpoint inhibitor. 159. The method of claim 158, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, or any combination thereof.
160. The method of any one of claims 1-159, wherein the method further comprises administering a neutrophil elastase inhibitor to the subject. 161. The method of claim 160, wherein the neutrophil elastase inhibitor is sivelestat. 162. The method of any one of claims 1-161, wherein the subject is administered a cancer therapeutic selected from the group consisting of a BTK inhibitor, an HDAC inhibitor, an mTOR inhibitor, a proteasome inhibitor, a JAK inhibitor, a JAK/STAT inhibitor, a BCL-2 inhibitor, a MEK inhibitor, an anti-folate, a farnesyl transferase inhibitor, an antibody, an antibody-drug conjugate, a cytotoxic agent, and a chemotherapeutic agent. 163. The method of claim 162, wherein the BTK inhibitor is ibrutinib, RN-486 (6- cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)- pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), GDC- 0834 ([R—N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl) phenylamino)-4-methyl-5-oxo-4,5- dihydropy-razin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide]), CGI-560 (N-[3-(8-anilinoimidazo[1,2-a]pyrazin-6-yl)phenyl]-4-tert- butylbenzamide), CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4- carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), HM-71224 5, ONO-4059 5, CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2- yl)amino)phenoxy)-N-methylpicolinamide), LFM-A13 (2Z-cyano-N-(2,5-dibromophenyl)3- hydroxy-2-butenamide), AVL-292 (N-(3-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide), or any combination thereof. 164. The method of claim 162, wherein the HDAC inhibitor is belinostat, vorinostat, panobinostat, romidepsin, or any combination thereof. 165. The method of claim 162, wherein the mTOR inhibitor is everolimus. 166. The method of claim 162, wherein the proteasome inhibitor is bortezomib, carfilzomib, or a combination thereof. 167. The method of claim 162, wherein the JAK/STAT inhibitor is tofacitinib, INCB16562, AZD1480, or any combination thereof.
168. The method of claim 162, wherein the BCL-2 inhibitor is ABT-737, ABT-263, navitoclax, or any combination thereof. 169. The method of claim 162, wherein the MEK inhibitor is AZD8330 or ARRY-424704. 170. The method of claim 162, wherein the anti-folate is pralatrexate. 171. The method of claims 162, wherein the farnesyl transferase inhibitor is tipifarnib. 172. The method of claim 162, wherein the antibody is obinutuzumab, alemtuzumab, rituximab, ofatumumab, brentuximab vedotin, or any combination thereof. 173. The method of claim 162, wherein the antibody-drug conjugate is inotuzumab, ozogamicin, brentuximab vedotin, or any combination thereof. 174. The method of claim 162, wherein the cytotoxic agent is bendamustine, gemcitabine, oxaliplatin, cyclophosphamide, vincristine, vinblastine, anthracycline, daunorubicin, daunomycin, doxorubicin, actinomycin dactinomycin, bleomycin, clofarabine, nelarabine, cladribine, asparaginase, methotrexate, pralatrexate, or any combination thereof. 175. The method of claim 162, wherein the chemotherapeutic agent is fludarabine, ibrutinib, fostamatinib, lenalidomide, thalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, cyclophosphamide, doxorubicin hydroxydaunomycin, vincristine, oncovin, prednisone, or any combination thereof. 176. The method of any one of claims 1-175, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is the S,S diastereomer:
Figure imgf000088_0001
177. The method of any one of claims 1-175, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is the S,R diastereomer:
Figure imgf000089_0001
. 178. The method of any one of claims 1-175, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is the R,S diastereomer:
Figure imgf000089_0002
. 179. The method of any one of claims 1-175, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is the R,R diastereomer:
Figure imgf000089_0003
. 180. The method of any one of claims 1-175, wherein the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an S,R diastereomer of a compound of Formula (I). 181. The method of any one of claims 1-175, wherein the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,S diastereomer of a compound of Formula (I). 182. The method of any one of claims 1-175, wherein the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,R diastereomer of a compound of Formula (I). 183. The method of any one of claims 1-182, wherein,
Figure imgf000090_0001
X is O, S or CF2; Y is O or S; Q is CH or N; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. 184. The method of any one of claims 1-183, wherein,
Figure imgf000090_0002
X is O, S or CF2; Y is O or S; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from the group consisting of OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, and tetrahydropyran; and R7 is hydrogen, F, Cl or CH3. 185. The method of any one of claims 1-184, wherein,
Figure imgf000090_0003
186. The method of claim 1-185, wherein X is O; R6 is C1-3alkyl; and R7 is hydrogen. 187. The method of any one of claims 1-185, wherein,
Figure imgf000091_0003
X is O; R6 is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7 is hydrogen. 188. The method of any one of claims 1-185, wherein,
Figure imgf000091_0002
X is O, S or CF2; R6 is C1-3alkyl, wherein the C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7 is hydrogen, F, Cl or CH3. 189. The method of claim 176, wherein the compound of Formula (I) is brensocatib:
Figure imgf000091_0001
191. The method of claim 176, wherein the compound of Formula (I) is selected from the group consisting of (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol- 5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-2-(4'-Carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1- cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharmaceutically acceptable salts thereof. 192. The method of claim 177, wherein the compound of Formula (I) is (2S)-N-{(1R)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane- 2-carboxamide:
Figure imgf000094_0001
pharmaceutically acceptable salt thereof. 193. The method of claim 192, wherein the compound of Formula (I) is (2S)-N-{(1R)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane- 2-carboxamide:
Figure imgf000094_0002
194. The method of claim 178, wherein the compound of Formula (I) is (2R)-N-{(1S)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane- 2-carboxamide: or a pharmaceutically acceptable salt thereof.
Figure imgf000094_0003
195. The method of claim 194, wherein the compound of Formula (I) is (2R)-N-{(1S)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane- 2-carboxamide:
Figure imgf000094_0004
196. The method of claim 179, wherein the compound of Formula (I) is (2R)-N-{(1R)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane- 2-carboxamide: pharmaceutically acceptable salt thereof.
Figure imgf000095_0001
197. The method of claim 196, wherein the compound of Formula (I) is (2R)-N-{(1R)-1- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane- 2-carboxamide:
Figure imgf000095_0002
198. The method of any one of claims 1-175, wherein the composition comprises a mixture of brensocatib, or a pharmaceutically acceptable salt thereof and (2S)-N-{(1R)-1-Cyano-2-[4- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide: pharmaceutically acceptable salt thereof.
Figure imgf000095_0003
199. The method of any one of claims 1-175, wherein the composition comprises a mixture of brensocatib, or a pharmaceutically acceptable salt thereof and (2R)-N-{(1S)-1-Cyano-2-[4- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide: or a pharmaceutically acceptable salt
Figure imgf000095_0004
thereof. 200. The method of any one of claims 1-175, wherein the composition comprises a mixture of brensocatib, or a pharmaceutically acceptable salt thereof and (2R)-N-{(1R)-1-Cyano-2-[4- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide: pharmaceutically acceptable salt thereof.
Figure imgf000096_0001
201. The method of any one of claims 1-200, wherein the composition comprises a pharmaceutically acceptable adjuvant, diluent or carrier. 202. The method of any one of claims 1-201, wherein the composition comprises: (a) from about 1 to about 30 wt% of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (b) from about 55 to about 75 wt% of a pharmaceutical diluent, (c) from about 15 to about 25 wt% of a compression aid, (d) from about 3 to about 5 wt% of a pharmaceutical disintegrant, (e) from about 0.00 to about 1 wt% of a pharmaceutical glidant; and (f) from about 2 to about 6 wt% of a pharmaceutical lubricant, wherein the component weights add up to 100 wt%. 203. The method of claim 202, wherein the pharmaceutical lubricant is glycerol behenate. 204. The method of claim 202 or 203, wherein the pharmaceutical diluent is microcrystalline cellulose. 205. The method of any one of claims 202-204, wherein the compression aid is dibasic calcium phosphate dihydrate. 206. The method of any one of claims 202-205, wherein the pharmaceutical disintegrant is sodium starch glycolate. 207. The method of any one of claims 202-206, wherein the pharmaceutical glidant is silicon dioxide. 208. The method of any one of claims 202-207, wherein the composition is in tablet form.
209. The method of claim 208, wherein the composition further comprises a tablet coating. 210. The method of any one of claims 202-209, wherein the compound of Formula (I) is present at about 3 to about 10 wt% of the total weight of the pharmaceutical composition. 211. The method of claim 210, wherein the pharmaceutical lubricant is glycerol behenate and the glycerol behenate is present at about 2.5 to about 4.5 wt% of the total weight of the composition. 212. The method of claim 210 or 211, wherein the pharmaceutical glidant is silicon dioxide and the silicon dioxide is present at about 0.05 to about 0.25 wt% of the total weight of the composition. 213. The method of any one of claims 210-212, wherein the pharmaceutical disintegrant is sodium starch glycolate and the sodium starch glycolate is present at about 3.5 to about 4.5 wt% of the total weight of the composition. 214. The method of any one of claims 210-213, wherein the compression aid is dibasic calcium phosphate dihydrate and the dibasic calcium phosphate dihydrate is present at about 18 to about 22 wt% of the total weight of the composition. 215. The method of any one of claims 210-214, wherein the pharmaceutical diluent is microcrystalline cellulose and the microcrystalline cellulose is present at about 55 to about 70 wt% of the total weight of the composition. 216. The method of any one of claims 1-215, wherein the composition is administered once- a-day during the administration period. 217. The method of any one of claims 1-215, wherein the composition is administered twice- a-day during the administration period. 218. The method of any one of claims 1-215, wherein the composition is administered every other day during the administration period. 219. The method of any one of claims 1-218, wherein the composition is administered orally, parenterally, enterally, or through a nasogastric tube. 220. The method of claim 219, wherein the composition is administered orally.
221. The method of any one of claims 1-220, wherein the administration period is about 30 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 18 months, about 24 months or about 30 months. 222. The method of any one of claims 1-220, wherein the administration period is at least about 30 days, 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 18 months, at least about 24 months or at least about 30 months. 223. The method of any one of claims 1-222, wherein the subject does not have breast-to- lung metastasis.
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US11673872B2 (en) 2014-01-24 2023-06-13 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11680049B2 (en) 2014-01-24 2023-06-20 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11773069B2 (en) 2014-01-24 2023-10-03 Astrazeneca Ab Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11814359B2 (en) 2014-01-24 2023-11-14 Astrazeneca Ab Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
WO2024008131A1 (en) * 2022-07-07 2024-01-11 上海汇伦医药股份有限公司 New use of sivelestat

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