Stabilization of integrin inhibitors

Abstract

Provided herein is a formulation comprising a hygroscopic or deliquescent component, wherein the hygroscopic or deliquescent component is a compound of formula (A) JPEG2025518533000077.jpg43164 or a salt thereof. Also provided herein is a method for preparing a formulation comprising a hygroscopic or deliquescent component, wherein the hygroscopic or deliquescent component is a compound of formula (A).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 343,454, filed May 18, 2022, the entire content of which is hereby incorporated by reference herein.

[0002] Provided herein are formulations that include hygroscopic or deliquescent components such as integrin inhibitors.

Background Art

[0003] Fibrosis, a pathological feature of many diseases, results from a dysfunction of the body's natural ability to repair damaged tissues. If left untreated, fibrosis can lead to irreversible damage and scarring of vital organs that can cause ultimate organ failure.

[0004] Patients with non - alcoholic fatty liver disease (NAFLD) can progress from simple fatty liver to non - alcoholic steatohepatitis (NASH) and then to fibrosis. Hepatic fibrosis is reversible in its early stages, but progressive hepatic fibrosis can lead to cirrhosis.

[0005] Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common outcome of a variety of chronic kidney diseases (CKD). Regardless of the initial cause, progressive CKD often results in extensive tissue scarring leading to destruction of the renal parenchyma, end - stage renal disease, and a devastating state requiring dialysis or renal replacement.

[0006] Scleroderma encompasses a complex and diverse set of conditions characterized primarily by fibrosis, vascular abnormalities, and autoimmunity. The spectrum of scleroderma disorders shares common features of fibrosis, with hardening or thickening of the skin occurring. This hardening occurs in only limited areas in some patients, but in other patients, it can spread to other major organs.

[0007] Cardiac structural remodeling after myocardial infarction is associated with an inflammatory response, resulting in scar formation at the infarct site. This scar formation is the result of fibrous tissue deposition and can lead to a decline in cardiac function and disruption of electrical activity within the heart.

[0008] Crohn's disease is a chronic disease of unknown etiology that tends to progress in both medical or surgical treatment settings. Enterofibrosis is one of the most common complications of Crohn's disease, with strictures forming in the small intestine and colon.

[0009] Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic disease of unknown etiology that occurs in adults and is localized to the lungs. In IPF, lung tissue thickens, hardens, and scars. As pulmonary fibrosis progresses, it becomes difficult for the lungs to deliver oxygen to the bloodstream, and organs are unable to receive the oxygen necessary for proper function. Currently, approximately 200,000 people in the United States are affected by IPF, and 40,000 die annually. Patients diagnosed with IPF experience progressive shortness of breath and ultimately develop complete respiratory failure.

[0010] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic liver disease that causes damage and fibrosis to the liver. PBC occurs when the small bile ducts in the liver are slowly and progressively destroyed, causing bile and other toxins to accumulate in the liver, resulting in a condition called cholestasis. Over time, scarring and fibrosis occur in both the liver and biliary tract.

[0011] Nonspecific interstitial pneumonia (NSIP) is a rare disease that affects the tissue surrounding and separating the small air sacs of the lungs. These air sacs, called alveoli, are the sites where oxygen and carbon dioxide are exchanged between the lungs and the bloodstream. Interstitial pneumonia is a disease in which the reticular walls of the alveoli become inflamed. The pleura (a thin membrane that protects and cushions the lungs and the individual lobes of the lungs) can also become inflamed. NSIP has two main forms: cellular and fibrotic. The cellular form is mainly defined by inflammation of the interstitial cells. The fibrotic form is defined by thickening and scarring of the lung tissue. This scarring, known as fibrosis, is irreversible. When the lung tissue thickens or scars, the lungs no longer function effectively. Breathing becomes less efficient, and the oxygen concentration in the blood decreases. (Kim et al., Proc. Am. Thorac. Soc. (2006) 3:285-292; Lynch, D., Radiology (2001) 221:583-584; Kinder et al., Am. J. Respir. Crit. Care Med. (2007) 176:691-697).

[0012] Currently, the available treatment courses are limited because there are no options on the market that have been proven effective for the long-term survival or overall symptoms of patients. Still, there is a need for treatment of fibrotic diseases.

[0013] α V αβ6 integrin is expressed in epithelial cells, binds to the latent peptide of transforming growth factor β1 (TGFβ1), and mediates the activation of TGFβ1. Its expression level increases significantly after injury to the lungs and bile duct cells and plays an important role in vivo in tissue fibrosis. The increase in levels is also associated with an increased mortality rate in patients with IPF and NSIP.

[0014] Primary sclerosing cholangitis (PSC) is associated with bile duct inflammation and fibrosis that obstructs the bile ducts. As a result, the flow of bile into the intestine is inhibited, leading to cirrhosis, which can subsequently result in complications such as liver failure and liver cancer. α V The expression of β6 is elevated in the livers and bile ducts of PSC patients.

[0015] There is still a need for agents that utilize a new mechanism of action and can have good outcomes with respect to symptom relief, safety, and patient mortality in both the short and long term.

[0016] To make such compounds readily usable in practical pharmaceuticals, it is important to provide stable compositions containing such compounds that are stable under temperature and humidity conditions related to production, distribution, and storage. Therefore, further improvement is needed.

Summary of the Invention

[0017] There is a need for a method of acceptably formulating deliquescent and / or hygroscopic integrin inhibitors suitable for production and dosage forms.

[0018] Provided herein are formulations and methods for preparing the same, comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A)

Chemical Formula

[0019] In some embodiments, the compound of formula (A) is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid:

Chemical formula

[0020] In some embodiments, the method includes formulating a hygroscopic or deliquescent component with one or more hygroscopic excipients. In some embodiments, the one or more hygroscopic excipients are selected from the group consisting of sorbitol, citric acid, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, polyethylene glycol, polyglycolized glycerides, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, magnesium aluminum silicate, calcium carbonate, cyclodextrin, or carbomer.

[0021] In some embodiments, the method includes coating a hygroscopic or deliquescent component with one or more moisture barrier coatings. In some embodiments, the one or more moisture barrier coatings are selected from the group consisting of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, copolymer dispersion of methyl methacrylate and diethylamino-ethyl methacrylate, hydroxypropyl cellulose, polyvinyl acetate, ethyl cellulose, cellulose acetate, ammonio methacrylate, ammonio methacrylate copolymer, poly(ethyl acrylate-co-methyl methacrylate), shellac, cellulose acetate phthalate, cellulose acetate butyrate, methacrylic acid copolymer, aminodiethyl-methacrylate copolymer, acrylic acid copolymer, sodium alginate, and carboxymethyl cellulose.

[0022] In some embodiments, the method includes tableting a hygroscopic or deliquescent component using a dry granulation process.

[0023] In another aspect, there is provided a substantially non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A)

Chemical formula

[0024] In some embodiments, a non-deliquescent formulation is provided that includes a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A). In some embodiments, a substantially non-hygroscopic formulation is provided that includes a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A). In some embodiments, a non-hygroscopic formulation is provided that includes a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A).

[0025] In some embodiments, the compound of formula (A) is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid:

Chemical formula

[0026] In some embodiments, the compound of formula (A) is a salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. In some embodiments, the compound of formula (A) is a crystalline form of a salt or a solvate of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. In some embodiments, the compound of formula (A) is a crystalline form of a phosphate salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. In some embodiments, the compound of formula (A) is a crystalline form of a hydrate of a phosphate salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. In some embodiments, the compound of formula (A) is a crystalline form of an isopropyl alcohol and water mixed solvate of a phosphate salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. In some embodiments, the compound of formula (A) is a crystalline form of a fumarate salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. In some embodiments, the compound of formula (A) is a crystalline form of a 1,5-naphthalenedisulfonate salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Specific examples of such crystalline forms and methods for their preparation can be found, for example, in U.S. Patent Application Publication US2022 / 0177468A1, the content of which is hereby incorporated by reference in its entirety.In some embodiments, the compound of formula (A) is in Form I, Form II, Form III, or Form IV as described in U.S. Patent Application Publication US2022 / 0177468A1, the content of which is hereby incorporated by reference in its entirety.

[0027] In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations comprise one or more hygroscopic excipients. In some embodiments, the one or more hygroscopic excipients are selected from the group consisting of sorbitol, citric acid, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, polyethylene glycol, polyglycolized glycerides, alpha starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, magnesium aluminum silicate, calcium carbonate, cyclodextrin, or carbomer.

[0028] In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations comprise a core and a coating shell. In some embodiments, the core comprises at least about 50 w / w%, at least about 60 w / w%, at least about 70 w / w%, at least about 80 w / w%, at least about 90 w / w%, at least about 95 w / w%, at least about 96 w / w%, at least about 97 w / w%, at least about 98 w / w%, at least about 99 w / w%, or at least about 99.9 w / w% of the compound of formula (A).

[0029] In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations include one or more moisture-barrier coatings. In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations include one or more moisture-barrier solid coatings. In some embodiments, the one or more moisture-barrier coatings are selected from the group consisting of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, copolymer dispersion of methyl methacrylate and diethylamino-ethyl methacrylate, hydroxypropyl cellulose, polyvinyl acetate, ethyl cellulose, cellulose acetate, ammonio methacrylate, ammonio methacrylate copolymer, poly(ethyl acrylate-co-methyl methacrylate), shellac, cellulose acetate phthalate, cellulose acetate butyrate, methacrylic acid copolymer, aminodiethyl-methacrylate copolymer, acrylic acid copolymer, sodium alginate, and carboxymethyl cellulose.

[0030] In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations are tablets in a tablet formulation. In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations include a dry coating. In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations include a press coating or a compression coating. In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations include a coating that does not contain any aqueous or organic solvents.

[0031] In some embodiments, there is provided a method of treating a fibrotic disease in an individual in need thereof, the method comprising administering any one of the formulations described herein. In some embodiments, there is provided a method of treating a fibrotic disease in an individual in need thereof, the method comprising administering a formulation prepared according to any of the methods described herein.

Brief Description of the Drawings

[0032]

Figure 1

Modes for Carrying Out the Invention

[0033] Provided herein is a method for preparing a substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic composition comprising a hygroscopic or deliquescent component and one or more excipients or coatings. In some embodiments, the hygroscopic or deliquescent component is an integrin inhibitor. In some embodiments, the hygroscopic or deliquescent component is a compound disclosed in US20190276449. In some embodiments, the hygroscopic or deliquescent component is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. For example, US20190276449 (the entire content of which is incorporated herein by reference) discloses compounds comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, an α V β6 integrin inhibitor, and methods of treatment using the same.

[0034] Compounds and compositions that are hygroscopic or deliquescent are difficult to handle and formulate. Such compounds also have stability issues because they can change into an undesirable form when exposed to moisture. Considerations regarding hygroscopic or deliquescent compounds can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), and Pharmaceutics: The science of dosage form design, M.E. Aulton, (1988), both of which are hereby incorporated by reference.

[0035] Definitions For use herein, unless otherwise specified, the use of terms such as "a", "an", etc. refers to one or more.

[0036] References to "about" a value or parameter herein include (and describe) embodiments that target the value or parameter itself. For example, a description that refers to "about X" includes a description of "X".

[0037] As used herein, "alkyl", unless otherwise specified, refers to a straight-chain (i.e., unbranched) or branched monovalent saturated hydrocarbon chain having the specified number of carbon atoms (i.e., C1-C 10 which means 1 to 10 carbon atoms), or a combination thereof, including these. Specific alkyl groups include groups having 1 to 20 carbon atoms ("C1-C 20 alkyl"), groups having 1 to 10 carbon atoms ("C1-C 10 alkyl"), groups having 6 to 10 carbon atoms ("C6-C 10"(alkyl)", a group having 1 to 6 carbon atoms ("C1-C6 alkyl"), a group having 2 to 6 carbon atoms ("C2-C6 alkyl"), or a group having 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.

[0038] As used herein, "alkylene" refers to the same residue as alkyl but is divalent. Specific alkylene groups include a group having 1 to 20 carbon atoms ("C1-C 20 alkylene"), a group having 1 to 10 carbon atoms ("C1-C 10 alkylene"), a group having 6 to 10 carbon atoms ("C6-C 10 alkylene"), a group having 1 to 6 carbon atoms ("C1-C6 alkylene"), a group having 1 to 5 carbon atoms ("C1-C5 alkylene"), a group having 1 to 4 carbon atoms ("C1-C4 alkylene") or a group having 1 to 3 carbon atoms ("C1-C3 alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), etc.

[0039] As used herein, "alkenyl", unless otherwise specified, has at least one olefinic unsaturated site (i.e., has at least one moiety of the formula C=C) and has the specified number of carbon atoms (i.e., C2-C 10(which means 2 to 10 carbon atoms), a linear (i.e., unbranched) or branched monounsaturated hydrocarbon chain or a combination thereof, and includes these. The alkenyl group can have a "cis" configuration or a "trans" configuration, or can have an "E" configuration or a "Z" configuration. Specific alkenyl groups are groups having 2 to 20 carbon atoms ( "C2-C 20 alkenyl"), groups having 6 to 10 carbon atoms ( "C6-C 10 alkenyl"), groups having 2 to 8 carbon atoms ( "C2-C8 alkenyl"), groups having 2 to 6 carbon atoms ( "C2-C6 alkenyl"), or groups having 2 to 4 carbon atoms ( "C2-C4 alkenyl"). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, etc.

[0040] As used herein, "alkenylene" refers to the same residue as alkenyl, but has divalency. Specific alkenylene groups are groups having 2 to 20 carbon atoms ( "C2-C 20 alkenylene"), groups having 2 to 10 carbon atoms ( "C2-C 10 alkenylene"), groups having 6 to 10 carbon atoms ( "C6-C 10"(an "alkenylene"), a group having 2 to 6 carbon atoms ("C2-C6 alkenylene"), a group having 2 to 4 carbon atoms ("C2-C4 alkenylene"), or a group having 2 to 3 carbon atoms ("C2-C3 alkenylene"). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-1-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-1-enylene (-CH=CH-(CH2)3CH2-).

[0041] As used herein, "alkynyl", unless otherwise specified, has at least one acetylenic unsaturated site (i.e., has at least one moiety of the formula C≡C) and has the specified number of carbon atoms (i.e., C2-C 10 means 2 to 10 carbon atoms), and refers to a linear (i.e., unbranched) or branched monounsaturated hydrocarbon chain or a combination thereof, including these. Specific alkynyl groups are groups having 2 to 20 carbon atoms ("C2-C 20 alkynyl"), groups having 6 to 10 carbon atoms ("C6-C 10 alkynyl"), groups having 2 to 8 carbon atoms ("C2-C8 alkynyl"), groups having 2 to 6 carbon atoms ("C2-C6 alkynyl"), or groups having 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl.

[0042] As used herein, "alkynylene" refers to the same residue as alkynyl but is divalent. Specific alkynylene groups are groups having 2 to 20 carbon atoms ("C2-C 20 alkynylene"), groups having 2 to 10 carbon atoms ("C2-C 10("alkynylene"), a group having 6 to 10 carbon atoms ("C6-C 10 "alkynylene"), a group having 2 to 6 carbon atoms ("C2-C6 alkynylene"), a group having 2 to 4 carbon atoms ("C2-C4 alkynylene") or a group having 2 to 3 carbon atoms ("C2-C3 alkynylene"). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH2-), etc.

[0043] As used herein, "cycloalkyl", unless otherwise specified, refers to a cyclic monovalent saturated hydrocarbon structure having the specified number of carbon atoms (i.e., C3-C 10 means 3 to 10 carbon atoms) and includes these. Cycloalkyl can be composed of one ring such as cyclohexyl, or multiple rings such as adamantyl. Cycloalkyl containing two or more rings can be a fused ring, a spiro ring or a bridged ring, or a combination thereof. Specific cycloalkyl groups are groups having 3 to 12 ring carbon atoms. Preferred cycloalkyl is a cyclic hydrocarbon having 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), a cyclic hydrocarbon having 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or a cyclic hydrocarbon having 3 to 4 ring carbon atoms ("C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, etc.

[0044] As used herein, "cycloalkylene" refers to the same residue as cycloalkyl but is divalent. Cycloalkylene may be composed of one ring or may be composed of multiple rings which may be fused rings, spiro rings or bridged rings, or combinations thereof. Specific cycloalkylene groups are groups having 3 to 12 ring carbon atoms. Preferred cycloalkylene is a cyclic hydrocarbon having 3 to 8 ring carbon atoms ("C3-C8 cycloalkylene"), a cyclic hydrocarbon having 3 to 6 carbon atoms ("C3-C6 cycloalkylene"), or a cyclic hydrocarbon having 3 to 4 ring carbon atoms ("C3-C4 cycloalkylene"). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, etc. Cycloalkylene may be bonded to the remaining structure via the same ring carbon atom or different ring carbon atoms. When cycloalkylene is bonded to the remaining structure via two different ring carbon atoms, the connecting bonds may be cis or trans to each other. For example, cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene), or mixtures thereof.

[0045] "Cycloalkenyl", unless otherwise specified, has at least one olefinic unsaturated site (i.e., has at least one moiety of the formula C=C) and has a specified number of carbon atoms (i.e., C3-C 10 means 3 to 10 carbon atoms), and refers to a cyclic non-aromatic monounsaturated hydrocarbon structure, including these. Cycloalkenyl may be composed of one ring such as cyclohexenyl or may be composed of multiple rings such as norbornenyl. Preferred cycloalkenyl is a cyclic unsaturated hydrocarbon having 3 to 8 ring carbon atoms ("C3-C8 cycloalkenyl"). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, etc.

[0046] As used herein, "cycloalkenylene" refers to the same residue as cycloalkenyl, but is divalent.

[0047] As used herein, "aryl" or "Ar" refers to an aromatic unsaturated carbocyclic group having a monocyclic ring (e.g., phenyl) or a plurality of fused rings (e.g., naphthyl or anthryl), and the fused rings may or may not be aromatic. Specific aryl groups are groups having 6 to 14 ring carbon atoms ("C6-C 14 aryl"). An aryl group having two or more rings, with at least one ring being non-aromatic, can be connected to the parent structure at either the position of the aromatic ring or the position of the non-aromatic ring. In one variant form, an aryl group having two or more rings, with at least one ring being non-aromatic, is connected to the parent structure at the position of the aromatic ring.

[0048] As used herein, "arylene" refers to the same residue as aryl, but is divalent. Specific arylene groups are groups having 6 to 14 ring carbon atoms ("C6-C 14 arylene").

[0049] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having from 1 to 14 ring carbon atoms and at least one individual ring heteroatom including, but not limited to, heteroatoms such as nitrogen, oxygen, and sulfur. The heteroaryl group may have a monocyclic ring (e.g., pyridyl, furyl) or a plurality of fused rings (e.g., indolizinyl, benzothienyl), and the fused rings may or may not be aromatic. Specific heteroaryl groups include a 5- to 14-membered ring having from 1 to 12 ring carbon atoms and from 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 10-membered ring having from 1 to 8 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-, 6-, or 7-membered ring having from 1 to 5 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, specific heteroaryl groups are monocyclic aromatic 5-, 6-, or 7-membered rings having from 1 to 6 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, specific heteroaryl groups are polycyclic aromatic rings having from 1 to 12 ring carbon atoms and from 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group having two or more rings, at least one of which is non-aromatic, may be connected to the parent structure at either the position of the aromatic ring or the position of the non-aromatic ring. In one variation, a heteroaryl group having two or more rings, at least one of which is non-aromatic, is connected to the parent structure at the position of the aromatic ring. The heteroaryl group may be connected to the parent structure by a ring carbon atom or a ring heteroatom.

[0050] As used herein, "heteroarylene" refers to the same residue as heteroaryl but having a divalent nature.

[0051] As used herein, "heterocyclic", "heterocyclic ring", or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a monocyclic or polycondensed ring, 1 to 14 ring carbon atoms, and 1 to 6 ring heteroatoms such as nitrogen, sulfur or oxygen. A heterocyclic ring containing two or more rings can be a fused ring, a bridged ring or a spiro ring, or a combination thereof, but heteroaryl groups are excluded. The heterocyclyl group can be independently optionally substituted with one or more substituents described herein. Specific heterocyclyl groups include 3- to 14-membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; 3- to 12-membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; 3- to 10-membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; 3- to 8-membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; or 3- to 6-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variant, the heterocyclyl includes a 3-, 4-, 5-, 6- or 7-membered monocyclic ring having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variant, the heterocyclyl includes a polycyclic non-aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0052] As used herein, "heterocyclylene" refers to the same residue as heterocyclyl, but having a divalent nature.

[0053] "Halo" or "halogen" refers to Group 17 elements having atomic numbers from 9 to 85. Preferred halo groups include radicals of fluorine, chlorine, bromine and iodine. When a residue is substituted with two or more halogens, it may be designated by using a prefix according to the number of the attached halogen moieties. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may or may not be the same halogen. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halo group is called "perhaloalkyl". A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which each H in the hydrocarbon constituting the alkyl portion of the alkoxy group is replaced by a halogen. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0054] "Carbonyl" refers to the group C=O.

[0055] "Thiocarbonyl" refers to the group C=S.

[0056] "Oxo" refers to the moiety =O.

[0057] "D" refers to deuterium ( 2 H).

[0058] "T" refers to tritium ( 3 H).

[0059] An alkyl group in which each hydrogen is replaced by deuterium is called "perdeuterated". An alkyl group in which each hydrogen is replaced by tritium is called "pertriated".

[0060] "Optionally substituted" means that, unless otherwise specified, the group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, and the substituents may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, the optionally substituted group is unsubstituted.

[0061] It is understood that the optionally substituted moiety may be substituted with six or more substituents, provided that the number of valences available for substitution at that moiety permits. For example, a propyl group may be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents may be the same or different.

[0062] "Pharmaceutically acceptable salts" are salts that retain at least some of the biological activities of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. Such salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid; (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions, for example, alkali metal ions, alkaline earth metal ions, or aluminum ions, or when coordinated with organic bases. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process or by separately reacting the purified compounds described herein in the form of their organic acids or organic bases with suitable organic or inorganic bases or acids, respectively, and isolating the salts thus formed during subsequent purification.

[0063] As used herein, the term "excipient" means an inert or inactive substance that can be used in the manufacture of drugs or pharmaceuticals such as tablets containing the compounds described herein as active ingredients. The term excipient can include a variety of substances including, but not limited to, binders, disintegrants, coating agents, compression / capsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable agents, sweetening or flavoring agents, suspending / gelling agents, or any substance used as a wet granulating agent. Examples of binders include, for example, carbomers, povidone, xanthan gum, etc.; examples of coating agents include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; examples of compression / capsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; examples of disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; examples of creams or lotions include, for example, maltodextrin, carrageenan, etc.; examples of lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; examples of materials for chewable agents include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; examples of suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; examples of sweetening agents include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and examples of wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0064] It should be understood that the aspects and embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" from the embodiments.

[0065] Compound In one aspect, a method for preparing a substantially non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings is provided, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a method for preparing a non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings is provided, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof, or a pharmaceutically acceptable salt thereof.

[0066] In another aspect, a method for preparing a substantially non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings is provided, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a method for preparing a non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings is provided, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof, or a pharmaceutically acceptable salt thereof.

[0067] In another aspect, a substantially non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings is provided, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof or a pharmaceutically acceptable salt thereof. In some embodiments, a non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings is provided, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof or a pharmaceutically acceptable salt thereof.

[0068] In another aspect, there is provided a substantially non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof or a pharmaceutically acceptable salt thereof. In some embodiments, there is provided a non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over a given time at a given relative humidity (RH) and a given temperature. In some embodiments, the given RH is about 60%. In some embodiments, the given RH is about 55% to about 65%. In some embodiments, the given relative humidity is about 75%. In some embodiments, the relative humidity is about 70% to 80%. In some embodiments, the given temperature is about 20°C to 25°C. In some embodiments, the given temperature is about 23°C to about 27°C. In some embodiments, the given temperature is about 38°C to 42°C. In some embodiments, the given time is about 24 hours, about 48 hours, about 72 hours, about 96 hours, about one week, about two weeks, about three weeks, or about one month.

[0070] In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of about 60%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of from about 55% to about 65%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of about 75%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of from about 70% to about 80%.

[0071] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 60%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of from about 55% to about 65%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 75%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of from about 70% to about 80%.

[0072] In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 60%. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 55% to about 65%. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 75%. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 70% to about 80%.

[0073] In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 60%. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 55% to about 65%. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 75%. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 70% to about 80%.

[0074] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 60%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 55% to about 65%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 75%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 70% to about 80%.

[0075] In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about two weeks at a relative humidity (RH) of about 60%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about two weeks at a relative humidity (RH) of about 55% to about 65%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about two weeks at a relative humidity (RH) of about 75%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about two weeks at a relative humidity (RH) of about 70% to about 80%.

[0076] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 60%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 55% to about 65%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 75%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 70% to about 80%.

[0077] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 60%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 55% to about 65%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 75%. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 70% to about 80%.

[0078] In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of about 60% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of about 75% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits a moisture uptake of less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% over about 24 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20°C to 25°C.

[0079] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 60% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 75% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20°C to 25°C.

[0080] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 60% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 75% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20°C to 25°C.

[0081] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 60% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 75% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20°C to 25°C.

[0082] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 60% and a temperature of about 20° C. to 25° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20° C. to 25° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 75% and a temperature of about 20° C. to 25° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20° C. to 25° C.

[0083] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 60% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 75% and a temperature of about 20°C to 25°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20°C to 25°C.

[0084] In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 60% and a temperature of about 20°C to 25°C. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20°C to 25°C. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 75% and a temperature of about 20°C to 25°C. In some embodiments, a "substantially non-hygroscopic" formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 3 weeks at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20°C to 25°C.

[0085] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 60% and a temperature of about 20° C. to 25° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 55% to about 65% and a temperature of about 20° C. to 25° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 75% and a temperature of about 20° C. to 25° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 70% to about 80% and a temperature of about 20° C. to 25° C.

[0086] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 24 hours at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 24 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 24 hours at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 24 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0087] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0088] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0089] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 96 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0090] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about one week at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about one week at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about one week at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about one week at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0091] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about two weeks at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about two weeks at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about two weeks at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about two weeks at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0092] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about three weeks at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about three weeks at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about three weeks at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about three weeks at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0093] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 60% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 55% to about 65% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 75% and a temperature of about 23°C to about 27°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 70% to about 80% and a temperature of about 23°C to about 27°C.

[0094] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 24 hours at a relative humidity (RH) of about 60% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 24 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 24 hours at a relative humidity (RH) of about 75% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 24 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38°C to 42°C.

[0095] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 60% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 75% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 48 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38°C to 42°C.

[0096] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 60% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 75% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 72 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38°C to 42°C.

[0097] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 60% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 75% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% moisture uptake over about 96 hours at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38°C to 42°C.

[0098] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 60% and a temperature of about 38° C. to 42° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38° C. to 42° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 75% and a temperature of about 38° C. to 42° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one week at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38° C. to 42° C.

[0099] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 60% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 75% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about two weeks at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38°C to 42°C.

[0100] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 3 weeks at a relative humidity (RH) of about 60% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 3 weeks at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 3 weeks at a relative humidity (RH) of about 75% and a temperature of about 38°C to 42°C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about 3 weeks at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38°C to 42°C.

[0101] In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 60% and a temperature of about 38° C. to 42° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 55% to about 65% and a temperature of about 38° C. to 42° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 75% and a temperature of about 38° C. to 42° C. In some embodiments, a “substantially non-hygroscopic” formulation exhibits less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, less than about 4%, or less than about 5% water uptake over about one month at a relative humidity (RH) of about 70% to about 80% and a temperature of about 38° C. to 42° C.

[0102] In any of the aspects or embodiments provided herein, a hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof [Chemical formula] or a salt thereof (wherein, R 1 is C6-C 14 aryl or 5- to 10-membered heteroaryl, where C6-C 14 aryl and 5- to 10-membered heteroaryl are optionally substituted by R 1a ; R 2 is hydrogen; deuterium; C1-C6 alkyl optionally substituted by R 2a ; -OH; R 2a-O-C1-C6 alkyl optionally substituted by; R 2b C3-C6 cycloalkyl optionally substituted by; R 2b -O-C3-C6 cycloalkyl optionally substituted by; R 2c 3- to 12-membered heterocyclyl optionally substituted by; or -S(O)2R 2d wherein any carbon atom directly bonded to a nitrogen atom is optionally substituted by an R other than halogen 2a and each R 1a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)2NR 4 R 5 , or -P(O)(OR 4 )(OR 5 ) and where each R 1a is, when possible, independently deuterium, halogen, oxo, -OR6 、 -NR 6 R 7 、 -C(O)R 6 、 -CN, -S(O)R 6 、 -S(O)₂R 6 、 -P(O)(OR 6 )(OR 7 )、 C₃ - C₈ cycloalkyl, 3 - 12 membered heterocyclyl, 5 - 10 membered heteroaryl, C₆ - C 14 aryl, or optionally substituted by deuterium, oxo, -OH or halogen and optionally substituted by C₁ - C₆ alkyl each R 2a 、 R 2b 、 R 2c 、 R 2e 、 and R 2f is independently oxo or R 1a and R 2d is C₁ - C₆ alkyl optionally substituted by R 2e or C₃ - C₅ cycloalkyl optionally substituted by R 2f and R 3 is independently hydrogen, deuterium, C₁ - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, C₃ - C₆ cycloalkyl, C₆ - C 14 aryl, 5 - 6 membered heteroaryl or 3 - 6 membered heterocyclyl, where the C₁ - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, C₃ - C₆ cycloalkyl, C₆ - C 3 aryl, 5 - 6 membered heteroaryl and 3 - 6 membered heterocyclyl of R 14 are independently halogen, deuterium, oxo, -CN, -OR 8 、 -NR 8 R 9 、 -P(O)(OR 8 )(OR 9 )、 or optionally substituted by deuterium, halogen, -OH or oxo and optionally substituted by C₁ - C₆ alkyl R 4 and R 5are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, where R 4 and R 5 of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each independently deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , or are optionally substituted by C1-C6 alkyl optionally substituted by deuterium, halogen, -OH or oxo, or alternatively, R 4 and R 5 together with the atom to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 , or by C1-C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH, R 6 and R 7 are each independently hydrogen; deuterium; C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted by deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted by deuterium, halogen, or oxo, or alternatively, R 6 and R 7 together with the atom to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or by C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo, R 8 and R 9is, independently of one another, hydrogen; deuterium; C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted by deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted by deuterium, halogen, or oxo, or alternatively, R 8 and R 9 together with the atom to which they are attached, form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, oxo, or halogen, each R 10 、R 11 、R 12 and R 13 is independently hydrogen or deuterium, R 14 is deuterium, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, each R 15 is independently selected from hydrogen, deuterium, or halogen, each R 16 is independently selected from hydrogen, deuterium, or halogen, p is 3, 4, 5, 6, 7, 8, or 9).

[0103] In one variant form, the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof, or a salt thereof, in which the carbon having the CO2H and NHR 1 moiety is in the "S" configuration. In another variant form, the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof, or a salt thereof, in which the carbon having the CO2H and NHR 1 moiety is in the "R" configuration. Embodiments in which the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof are also included, as well as racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0104] In one variant form of formula (A) or its sub-formulas, R 2 has the condition that any carbon atom directly bonded to the nitrogen atom is either unsubstituted or substituted with deuterium.

[0105] In the description of this specification, all descriptions, variant forms, embodiments or aspects of a certain part can be combined with all descriptions, variant forms, embodiments or aspects of other parts in the same way as if all combinations of the descriptions were specifically and individually listed. For example, all descriptions, variant forms, embodiments or aspects provided in this specification regarding R 1 can be combined with all descriptions, variant forms, embodiments or aspects of R 2 in the same way as if all combinations were specifically and individually listed.

[0106] In some embodiments of formula (A), the compound is a compound of formula (I)

Chemical formula

[0107] In some embodiments of formula (A), the compound is a compound of formula (I) or a salt thereof, wherein the carbon atom having the CO2H and NHR 1 moieties is in the "S" configuration. In another variation, the compound of formula (A) is a compound of formula (I) or a salt thereof, wherein the carbon atom having the CO2H and NHR 1 moieties is in the "R" configuration. Mixtures of compounds of formula (I) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0108] In one variation of formula (I), R 2 is such that any carbon atom directly bonded to the nitrogen atom is optionally substituted with an R 2a moiety other than halogen. In one variation of formula (I), R 2 is such that any carbon atom directly bonded to the nitrogen atom is either unsubstituted or substituted with deuterium.

[0109] In the descriptions herein, it should be understood that all descriptions, variations, embodiments or aspects of one part can be combined with all descriptions, variations, embodiments or aspects of other parts, just as if all combinations were specifically and individually listed. For example, all descriptions, variations, embodiments or aspects provided herein regarding R 1 in formula (I) can be combined with all descriptions, variations, embodiments or aspects of R 2 just as if all combinations were specifically and individually listed.

[0110] In some embodiments of the compound of formula (I) or a salt thereof, R 1a , R 2a , R 2b , R 2c , R 2e , R 2f , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , or R 16 is at least one of deuterium.

[0111] In some embodiments of the compound of formula (I) or a salt thereof, R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a . In some embodiments, R 1 is pyrimidin-4-yl optionally substituted by R 1a . In some embodiments, R 1 is pyrimidin-4-yl optionally substituted by R 1a , where R 1a is a 5- to 10-membered heteroaryl (e.g., pyrazolyl) or a C1-C6 alkyl optionally substituted by a halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R 1 is pyrimidin-4-yl optionally substituted by R 1a , where R 1a is a 5- to 10-membered heteroaryl (e.g., pyrazolyl or pyridinyl) or a C1-C6 alkyl optionally substituted by a halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R 1is a pyrimidin-4-yl substituted by both methyl and trifluoromethyl. In some embodiments, R 1 is a pyrimidin-4-yl substituted by both methyl and pyridinyl. In some embodiments, R 1 is R 1a is a pyrimidin-4-yl optionally substituted by R 1a wherein R 14 is C6-C 1 is R 1a is a pyrimidin-4-yl optionally substituted by R 1a wherein R 1 is R 1a is a pyrimidin-2-yl optionally substituted by R 1 is R 1a is a pyrimidin-2-yl optionally substituted by R 1a wherein R 1 is R 1a is a quinazolin-4-yl optionally substituted by R 1 is R 1a is a quinazolin-4-yl optionally substituted by R 1a wherein R 1 is R 1a is a quinazolin-4-yl optionally substituted by R 1ais a 5- to 10-membered heteroaryl (e.g., pyridinyl). In some embodiments, R 1 is pyrazolopyrimidinyl optionally substituted by R 1a . In some embodiments, R 1 is pyrazolopyrimidinyl optionally substituted by R 1a , where R 1a is C1-C6 alkyl (e.g., methyl). In some embodiments where R 1 is shown to be optionally substituted by R 1a , the R 1 moiety is unsubstituted. In some embodiments where R 1 is shown to be optionally substituted by R 1a , the R 1 moiety is substituted by one R 1a . In some embodiments where R 1 is shown to be optionally substituted by R 1a , the R 1 moiety is substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R 1a moieties which may be the same or different.

[0112] In some embodiments of formula (I) including embodiments describing the variable elements of R 1 , R 10 , R 11 , R 12 and R 13 are hydrogen. In some embodiments of formula (I) including embodiments describing the variable elements of R 1 and / or the variable elements of R 10 , R 11 , R 12 and R 13 , q is 0. In some embodiments including embodiments describing the variable elements of R 1 and / or the variable elements of R 10 , R 11 , R 12 and R 13 and / or the variable elements of q, p is 3, 4 or 5.

[0113] In some embodiments of formula (I), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II):

Chemical formula

[0114] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-A):

Chemical formula

[0115] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-A) or a salt thereof, wherein the carbon having the CO2H and NH moieties has the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-A) or a salt thereof, wherein the carbon having the CO2H and NH moieties has the "R" configuration. Mixtures of compounds of formula (I-A) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0116] In some embodiments of the compound of formula (I-A), m is 0, 1, 2, or 3, and each R 1a is, independently when applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compound of formula (I-A), m is 0, 1, 2, or 3, and each R 1a is, independently when applicable, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variant form), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-A), m is 1, 2 or 3.

[0117] In some embodiments of the compound of formula (I-A), m is 0. In some embodiments of the compound of formula (I-A), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-A), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-A), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-A), m is 2 and the R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-A), m is 2 and the R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-A), m is 2 and the R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-A), m is 3 and the R 1a groups are at the 2-, 5-, and 6-positions. Two or more R1a When a base is present, it is always R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (I-A) or a salt thereof, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0118] R 1a In some embodiments of formula (I-A), including embodiments that describe the variable elements of R and m, R 10 、R 11 、R 12 and R 13 each is hydrogen. R 1a and the variable elements of m, and / or R 10 、R 11 、R 12 and R 13 In some embodiments of formula (I-A), including embodiments that describe the variable elements of R and m, and / or the variable elements of R 1a and R 10 、R 11 、R 12 and R 13 q is 0. In some embodiments of formula (I-A), including embodiments that describe the variable elements of R and m, and / or the variable elements of R

[0119] In some embodiments of formula (I-A), R 10 、R 11 、R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-A):

Chemical formula

[0120] R 1 is R 1a In some embodiments of the compounds of formula (I) which is a 5- to 10-membered heteroaryl optionally substituted by R, the compound is of formula (I-B):

Chemical formula

[0121] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-B) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-B) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-B) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0122] In some embodiments of the compounds of formula (I-B), m is 0, 1, 2, 3, 4, or 5, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted by deuterium. In further embodiments of the compounds of formula (I-B), m is 0, 1, 2, 3, 4, or 5, and each R 1ais, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant form), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where R 1a the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-B), m is 1, 2, 3, 4, or 5.

[0123] In some embodiments of the compound of formula (I-B), m is 0. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 7-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 8-position. In some embodiments of the compound of formula (I-B), m is 2 and the R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-B), m is 2 and the R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-B), m is 2 and the R 1a groups are at the 2- and 7-positions. In some embodiments of the compound of formula (I-B), m is 2 and the R 1a groups are at the 2- and 8-positions. In some embodiments of the compound of formula (I-B), m is 2 and the R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-B), m is 2 and the R 1a groups are at the 5- and 7-positions. In some embodiments of the compound of formula (I-B), m is 2 and R1a The group is at the 5- and 8-positions. In some embodiments of the compound of formula (I-B), m is 2, and R 1a The group is at the 6- and 7-positions. In some embodiments of the compound of formula (I-B), m is 2, and R 1a The group is at the 6- and 8-positions. In some embodiments of the compound of formula (I-B), m is 2, and R 1a The group is at the 7- and 8-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 2-, 5-, and 6-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 2-, 5-, and 7-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 2-, 5-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 2-, 6-, and 7-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 2-, 6-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 2-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is at the 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, and R 1a The group is at the 2-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-B), m is 4, and R 1aThe group is at the 2-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, R 1a The group is at the 2-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, R 1a The group is at the 2-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, R 1a The group is at the 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 5, R 1a The group is at the 2-, 5-, 6-, 7-, and 8-positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compound of formula (I-B) or its salt, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0124] R 1a In some embodiments of formula (I-B) including the embodiments describing the variable elements of R and m, R 10 , R 11 , R 12 and R 13 are each hydrogen. In some embodiments of formula (I-B) including the embodiments describing the variable elements of R and m, and / or the variable elements of R 1a , R 10 , R 11 , R 12 and R 13 , q is 0. In some embodiments of formula (I-B) including the embodiments describing the variable elements of R and m, and / or the variable elements of R 1a , R 10 , R 11 , R 12 and R 13 , and / or the variable elements of q, p is 3, 4, or 5.

[0125] In some embodiments of formula (I-B), R 10 , R 11 , R 12 and R13 is hydrogen, p is 3, q is 0, and the compound is of formula (II-B):

Chem.

[0126] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a . In some embodiments of the compound of formula (I), the compound is of formula (I-C):

Chem.

[0127] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-C) or a salt thereof in which the carbon having the CO2H and NH moieties has the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-C) or a salt thereof in which the carbon having the CO2H and NH moieties has the "R" configuration. Mixtures of compounds of formula (I-C) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0128] In some embodiments of the compound of formula (I-C), m is 0, 1, 2, 3, or 4, and each R 1a , when applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted by deuterium. In further embodiments of the compound of formula (I-C), m is 0, 1, 2, 3, or 4, and each R 1a , when applicable, is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-C), m is 1, 2, 3, or 4.

[0129] In some embodiments of the compound of formula (I-C), m is 0. In some embodiments of the compound of formula (I-C), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-C), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-C), m is 1 and R 1a is at the 7-position. In some embodiments of the compound of formula (I-C), m is 1 and R 1a is at the 8-position. In some embodiments of the compound of formula (I-C), m is 2 and the R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-C), m is 2 and the R 1a groups are at the 2- and 7-positions. In some embodiments of the compound of formula (I-C), m is 2 and R 1aThe groups are at the 2- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a The groups are at the 6- and 7-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a The groups are at the 6- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a The groups are at the 7- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a The groups are at the 2-, 6-, and 7-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a The groups are at the 2-, 6-, and 8-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a The groups are at the 2-, 7-, and 8-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a The groups are at the 6-, 7-, and 8-positions. In some embodiments of the compounds of formula (I-C), m is 4, and R 1a The groups are at the 2-, 6-, 7-, and 8-positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compounds of formula (I-C) or salts thereof, the carbon having the CO2H and NH moieties can be in the “S” configuration or the “R” configuration.

[0130] R 1a In some embodiments of formula (I-C) including the embodiments describing the variable elements of R 10 and m, each of R 11 and R 12 and R 13 is hydrogen. In some embodiments of formula (I-C) including the embodiments describing the variable elements of R 1a and m, and / or the variable elements of R 10 and R 11 and R 12 and R 13 q is 0. In some embodiments of formula (I-C) including the embodiments describing the variable elements of R 1a and m, and / or the variable elements of R 10 and R11 , R 12 and R 13 In some embodiments of formula (I-C) that describe variable elements of p, and / or variable elements of q, p is 3, 4, or 5.

[0131] In some embodiments of formula (I-C), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-C):

Chemical formula

[0132] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-D):

Chemical formula

[0133] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-D) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-D) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-D) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0134] In some embodiments of the compound of formula (I-D), m is 0, 1, 2, 3, or 4, and each R 1a , when applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted by deuterium. In a further embodiment of the compound of formula (I-D), m is 0, 1, 2, 3, or 4, and each R 1a , when applicable, is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-D), m is 1, 2, 3, or 4.

[0135] In some embodiments of the compound of formula (I-D), m is 0. In some embodiments of the compound of formula (I-D), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-D), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-D), m is 1 and R 1ais in the 6th position. In some embodiments of the compound of formula (I-D), m is 1, and R 1a is in the 8th position. In some embodiments of the compound of formula (I-D), m is 2, and R 1a groups are in the 2nd and 5th positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a groups are in the 2nd and 6th positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a groups are in the 2nd and 8th positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a groups are in the 5th and 6th positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a groups are in the 5th and 8th positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a groups are in the 6th and 8th positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a groups are in the 2nd, 5th, and 6th positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a groups are in the 2nd, 5th, and 8th positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a groups are in the 2nd, 6th, and 8th positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a groups are in the 5th, 6th, and 8th positions. In some embodiments of the compound of formula (I-D), m is 4, and R 1a groups are in the 2nd, 5th, 6th, and 8th positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compound of formula (I-D) or its salt, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0136] R 1a and some embodiments of formula (I-D) including embodiments describing the variable elements of m, R 10 、R11 , R 12 and R 13 each is hydrogen. R 1a and variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-D) including embodiments describing variable elements of and m, and / or R 1a and variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-D) including embodiments describing variable elements of and / or variable elements of q, p is 3, 4, or 5.

[0137] In some embodiments of formula (I-D), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-D):

Chemical formula

[0138] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-E):

Chemical formula

[0139] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-E) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-E) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-E) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0140] In some embodiments of the compound of formula (I-E), m is 0, 1, 2, 3, or 4, and each R 1a , when applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted by deuterium. In a further embodiment of the compound of formula (I-E), m is 0, 1, 2, 3, or 4, and each R 1a , when applicable, is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-E), m is 1, 2, 3, or 4.

[0141] In some embodiments of the compound of formula (I-E), m is 0. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is at the 7-position. In some embodiments of the compound of formula (I-E), m is 2 and R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-E), m is 2 and R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-E), m is 2 and R 1a groups are at the 2- and 7-positions. In some embodiments of the compound of formula (I-E), m is 2 and R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-E), m is 2 and R 1a groups are at the 5- and 7-positions. In some embodiments of the compound of formula (I-E), m is 2 and R 1a groups are at the 6- and 7-positions. In some embodiments of the compound of formula (I-E), m is 3 and R 1a groups are at the 2-, 5-, and 6-positions. In some embodiments of the compound of formula (I-E), m is 3 and R 1a groups are at the 2-, 5-, and 7-positions. In some embodiments of the compound of formula (I-E), m is 3 and R 1a groups are at the 2-, 6-, and 7-positions. In some embodiments of the compound of formula (I-E), m is 3 and R 1a groups are at the 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-E), m is 4 and R 1a groups are at the 2-, 5-, 6-, and 7-positions. When two or more R 1a groups are present, always R 1aThe groups can be independently selected. In any of these embodiments of the compound of formula (I-E) or a salt thereof, the carbon atom having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0142] R 1a In some embodiments of formula (I-E), including embodiments that describe the variable elements of R and m, 10 R 11 R 12 and 13 R 1a each of and the variable elements of m, and / or 10 R 11 R 12 and 13 R 1a each of and the variable elements of m, and / or 10 R 11 R 12 and 13 R, and / or including embodiments that describe the variable elements of q, in some embodiments of formula (I-E), p is 3, 4, or 5.

[0143] In some embodiments of formula (I-E), 10 R 11 R 12 and 13 R are hydrogen, p is 3, q is 0, and the compound is of formula (II-E):

Chemical formula

[0144] R 1 is R 1a In some embodiments of the compound of formula (I), which is a 5- to 10-membered heteroaryl optionally substituted by R, the compound is of formula (I-F):

Chemical formula

[0145] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-F) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-F) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-F) are also included, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[0146] In some embodiments of the compound of formula (I-F), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a , when applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted by deuterium. In further embodiments of the compound of formula (I-F), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1ais, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant form), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where R 1a the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-F), m is 1, 2, 3, 4, 5, or 6.

[0147] In some embodiments of the compound of formula (I-F), m is 0. In some embodiments of the compound of formula (I-F), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-F), m is 1 and R 1a is at the 3-position. In some embodiments of the compound of formula (I-F), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-F), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-F), m is 1 and R 1a is at the 7-position. In some embodiments of the compound of formula (I-F), m is 1 and R 1a is at the 8-position. In some embodiments of the compound of formula (I-F), m is 2 and the R 1a groups are at the 2- and 3-positions. In some embodiments of the compound of formula (I-F), m is 2 and the R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-F), m is 2 and the R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-F), m is 2 and the R 1a groups are at the 2- and 7-positions. In some embodiments of the compound of formula (I-F), m is 2 and the R 1a groups are at the 2- and 8-positions. In some embodiments of the compound of formula (I-F), m is 2 and the R1a The groups are at the 3- and 5-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 3- and 6-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 3- and 7-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 3- and 8-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 5- and 6-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 5- and 7-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 5- and 8-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 6- and 7-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 6- and 8-positions. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The groups are at the 7- and 8-positions. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The groups are at the 2-, 3-, and 5-positions. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The groups are at the 2-, 3-, and 6-positions. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The groups are at the 2-, 3-, and 7-positions. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The groups are at the 2-, 3-, and 8-positions. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The groups are at the 2-, 5-, and 6-positions. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The groups are at the 2-, 5-, and 7-positions. In some embodiments of the compounds of formula (I-F), m is 3, and R 1aThe group is at the 2-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 2-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 2-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 2-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 3-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 3-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 3-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 3-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 3-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 3-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3, R 1a The group is at the 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, R 1a The group is at the 2-position, 3-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-F), m is 4, R 1aThe groups are at the 2-, 3-, 5-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 3-, 5-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 3-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 3-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 3-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, R 1a The groups are at the 2-, 3-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 5, R1a The groups are at the 2-, 3-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The groups are at the 2-, 3-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The groups are at the 2-, 3-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The groups are at the 2-, 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The groups are at the 3-, 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 6, and R 1a The groups are at the 2-, 3-, 5-, 6-, 7-, and 8-positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compound of formula (I-F) or its salt, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0148] R 1a In some embodiments of formula (I-F), including the embodiments describing the variable elements of R 10 and m, each of R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I-F), including the embodiments describing the variable elements of R 1a and m, and / or the variable elements of R 10 , R 11 , R 12 and R 13 , q is 0. In some embodiments of formula (I-F), including the embodiments describing the variable elements of R 1a and m, and / or the variable elements of R 10 , R 11 , R 12 and R 13 , and / or the variable elements of q, p is 3, 4, or 5.

[0149] In some embodiments of formula (I-F), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-F):

Chemical formula

[0150] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a . In some embodiments of the compound of formula (I), the compound is of formula (I-G):

Chemical formula

[0151] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-G) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-G) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-G) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0152] In some embodiments of the compound of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted by deuterium. In a further embodiment of the compound of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a is, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-G), m is 1, 2, 3, 4, 5, or 6.

[0153] In some embodiments of the compound of formula (I-G), m is 0. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is at the 3-position. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is at the 4-position. In some embodiments of the compound of formula (I-G), m is 1 and R1a is in the 5th position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is in the 6th position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is in the 7th position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is in the 8th position. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 3rd and 4th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 4th and 5th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 4th and 6th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 4th and 7th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 4th and 8th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 3rd and 5th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 3rd and 6th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 3rd and 7th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 3rd and 8th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 5th and 6th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 5th and 7th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 5th and 8th positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are in the 6th and 7th positions. In some embodiments of the compound of formula (I-G), m is 2, and R1a The group is at the 6- and 8-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a The group is at the 7- and 8-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-, 4-, and 5-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-, 4-, and 6-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-, 4-, and 7-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-, 4-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-, 5-, and 6-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-, 5-, and 7-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-, 5-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-, 6-, and 7-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-, 6-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-, 7-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-, 5-, and 6-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-, 5-, and 7-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-, 5-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 3, and R 1aThe group is at the 3-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, R 1a The group is at the 3-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, R 1a The group is at the 3-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, R 1a The group is at the 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, R 1a The group is at the 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, R 1a The group is at the 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, R 1a The group is at the 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3-position, 4-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3-position, 4-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3-position, 4-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3-position, 4-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 4-position, 3-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3-position, 4-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 4-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 4-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4, R 1aThe group is at the 4th, 5th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 4th, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3rd, 5th, 6th, and 7th positions. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3rd, 5th, 6th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3rd, 5th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 3rd, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, R 1a The group is at the 5th, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3rd, 4th, 5th, 6th, and 7th positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3rd, 4th, 5th, 6th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3rd, 4th, 5th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3rd, 4th, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 4th, 5th, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3rd, 5th, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 6, R 1a The group is at the 3rd, 4th, 5th, 6th, 7th, and 8th positions. When two or more R 1a groups are present, always R 1aThe groups can be independently selected. In any of these embodiments of the compound of formula (I-G) or a salt thereof, the carbon atom having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0154] R 1a In some embodiments of formula (I-G), including embodiments that describe the variable elements of R and m, 10 R 11 R 12 and R 13 each is hydrogen. R 1a and the variable elements of m, and / or R 10 R 11 R 12 and R 13 In some embodiments of formula (I-G), including embodiments that describe the variable elements of R and m, and / or the variable elements of R 1a and R 10 R 11 R 12 and R 13 q is 0. In some embodiments of formula (I-G), including embodiments that describe the variable elements of R and m, and / or the variable elements of R

[0155] and / or the variable elements of q, p is 3, 4, or 5. 10 R 11 R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-G):

Chemical formula

[0156] R1 is R 1a In some embodiments of the compounds of formula (I), which is a 5- to 10-membered heteroaryl optionally substituted by R, the compound is of formula (I-H):

Chemical formula

[0157] In some embodiments of formula (A), the compound of formula (A) is a compound of formula (I-H) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, the compound of formula (A) is a compound of formula (I-H) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-H) are also included, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[0158] In some embodiments of the compounds of formula (I-H), m is 0, 1, or 2, and each R 1a is, independently where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted by deuterium. In further embodiments of the compounds of formula (I-H), m is 0, 1, or 2, and each R 1ais, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant form), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where R 1a the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-H), m is 1 or 2.

[0159] In some embodiments of the compound of formula (I-H), m is 0. In some embodiments of the compound of formula (I-H), m is 1 and R 1a is at the 3-position. In some embodiments of the compound of formula (I-H), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-H), m is 2 and R 1a groups are at the 3-position and 6-position. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compound of formula (I-H) or its salt, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0160] R 1a and in some embodiments of formula (I-H) including embodiments describing the variable elements of m, R 10 R 11 R 12 and R 13 each is hydrogen. R 1a and the variable elements of m, and / or R 10 R 11 R 12 and R 13 In some embodiments of formula (I-H) including embodiments describing the variable elements, q is 0. R 1a and the variable elements of m, and / or R 10 R 11 R12 and R 13 In some embodiments of formula (I-H) that include embodiments describing the variable elements of p and / or the variable elements of q, p is 3, 4, or 5.

[0161] In some embodiments of formula (I-H), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-H):

Chemical formula

[0162] In some embodiments, the compound is a compound of formula (A), (I) or (II), or a salt thereof, wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a . In some embodiments, R 1 is an unsubstituted 5- to 10-membered heteroaryl (e.g., pyridinyl, pyrimidinyl, quinoxalinyl, quinazolinyl, pyrazolopyrimidinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzothiazolyl, isoquinolinyl, purinyl, or benzoxazolyl). In some embodiments, R 1 is a 5- to 10-membered heteroaryl substituted by 1, 2, 3, 4, or 5 R 1a groups, which may be the same or different, where each R 1ais selected independently from halogen (e.g., fluoro, chloro, or bromo), C1-C6 alkyl optionally substituted by halogen (e.g., -CH3, -CHF2, -CF3, or C(CH3)3), C3-C6 cycloalkyl (e.g., cyclopropyl), 5- to 10-membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 14 aryl (e.g., phenyl), -CN, -OR 3 (e.g., -OCH3), and -NR 4 R 5 (e.g., -N(CH3)2). In some embodiments, R 1 is 1, 2, 3, or 4 R groups, which may be the same or different, selected from -CH3, -CH2F, -CHF2, and -CF3, and is a 5-membered heteroaryl (e.g., pyrazolyl) substituted by the R groups. In some embodiments, R 1a is halogen (e.g., fluoro, chloro, or bromo), C3-C6 cycloalkyl (e.g., cyclopropyl), 5- to 6-membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 1 aryl (e.g., phenyl), C1-C4 alkyl optionally substituted by halogen (e.g., -CH3, -CF3 or C(CH3)3), -CN, -OR 10 (e.g., -OCH3), and -NR 3 (e.g., -N(CH3)2), and is a 6-membered heteroaryl (e.g., pyridinyl, pyrimidinyl, or pyrazinyl) substituted by 1, 2, 3, 4, or 5 R groups, which may be the same or different. In some embodiments, R 4 R 5 is 1, 2, 3, 4, or 5 R groups, which may be the same or different, selected from -CH3, -CH2F, -CHF2, and -CF3, and is a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzimidazolyl) substituted by the R groups. In some embodiments, R 1a is 1, 2, 3, 4, or 5 R groups, which may be the same or different, selected from -CH3, -CH2F, -CHF2, and -CF3, and is a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzimidazolyl) substituted by the R groups. In some embodiments, R 1 is 1, 2, 3, 4, or 5 R groups, which may be the same or different, selected from -CH3, -CH2F, -CHF2, and -CF3, and is a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzimidazolyl) substituted by the R groups. In some embodiments, R 1a is 1, 2, 3, 4, or 5 R groups, which may be the same or different, selected from -CH3, -CH2F, -CHF2, and -CF3, and is a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzimidazolyl) substituted by the R groups. In some embodiments, R1 is halogen (e.g., fluoro or chloro), 5-6 membered heteroaryl (e.g., pyridinyl), C alkyl optionally substituted with halogen (e.g., -CH or -CF), and -OR 3 (e.g., -OCH3), 1, 2, 3, 4, or 5 R, which may be the same or different, selected from 1a and 10-membered heteroaryl substituted by a group (eg, quinazolinyl).

[0163] In some embodiments, the compound is a compound of formula (A), (I) or (II), or a salt thereof, wherein R 1 teeth, [ka] and any of the preceding groups in which any one or more hydrogen atoms are replaced with a deuterium atom. In some embodiments, the compound is a compound of formula (A), (I) or (II), or a salt thereof, wherein R 1 is selected from the group consisting of any of the aforementioned groups in which any one or more hydrogen atoms are replaced with a tritium atom. For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned groups, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned groups can be perdeuterated groups in which all hydrogens are replaced with deuterium, or pertritiated groups in which all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons in the aforementioned groups can be 13 For example, in the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that is directly bonded to the remainder of the compound may be replaced with 13 In the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that replace or are fused to the ring that is attached to the remainder of the compound may be replaced by13 It may be replaced by C. Further, for example, all ring carbons in the aforementioned group may be 13 replaced by C.

[0164] In some embodiments, the compound is a compound of formula (A), (I) or (II), or a salt thereof, wherein R 1 is

Chemical formula

[0165] In some embodiments, the compound is a compound of formula (A), (I) or (II), or a salt thereof, wherein R 1 is

Chemical formula

[0166] replaced by 1 is

Chemical formula

[0167] In some embodiments, the compound is a compound of formula (A), (I) or (II), or a salt thereof, wherein R 1 is

Chemical formula

[0168] The R 1 group described herein as part (symbol

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0169] In some embodiments of the compounds of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or salts thereof, R 2 is C1-C6 alkyl optionally substituted by R 2a . In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 . In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclyl optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluoro), -S(O)2R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ; oxo; or -OR 3 In some embodiments, R 2 is C1-C6 alkyl optionally substituted by -OR 3 , where R 3 is hydrogen; C1-C6 alkyl optionally substituted by halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted by halogen (e.g., cyclopropyl substituted by fluoro); C6-C 14 aryl optionally substituted by halogen (e.g., phenyl optionally substituted by fluoro); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted by fluoro or methyl). In some embodiments, R 2 is -CH2CH2OCH3. In some embodiments, R 2 is C1-C6 alkyl substituted by both halogen and OR 3 . In some embodiments, R 2 is n-propyl substituted by both halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). In some embodiments where R 2 is shown to be optionally substituted by R 2a , R 2The moiety is unsubstituted. R 2 is R 2a In some embodiments where it is optionally substituted by R 2 the moiety is substituted by one R 2a . R 2 is R 2a In some embodiments where it is optionally substituted by R 2 the moiety may be substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R 2a moieties which may be the same or different.

[0170] In some embodiments of the compounds of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or salts thereof, R 2 is C1-C6 alkyl optionally substituted by R 2a . In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 . In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3-12 membered heterocyclyl optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluoro); -S(O)2R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ; oxo; or -OR 3 wherein. In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a wherein R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); C6-C 14 aryl (e.g., phenyl); 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., thiazolyl or pyrazolyl optionally substituted by methyl); 3-12 membered heterocyclyl optionally substituted by halogen or oxo (e.g., R 2a is oxetanyl optionally substituted by fluoro; tetrahydrofuranyl; pyrrolidinyl optionally substituted by oxo; morpholinyl optionally substituted by oxo; or dioxanyl); -S(O)2R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ; oxo; -OR 3 ; or -CN. In some embodiments, R 2 is C1-C6 alkyl optionally substituted by -OR 3 wherein R 3is hydrogen; C1-C6 alkyl optionally substituted by halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted by halogen (e.g., cyclopropyl substituted by fluoro); C6-C 14 aryl (e.g., phenyl optionally substituted by fluoro); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted by fluoro or methyl). In some embodiments, R 2 is -CH2CH2OCH3. In some embodiments, R 2 is C1-C6 alkyl substituted by both halogen and OR 3 . In some embodiments, R 2 is n-propyl substituted by both halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). When R 2 is shown to be optionally substituted by R 2a , in some embodiments, the R 2 moiety is unsubstituted. When R 2 is shown to be optionally substituted by R 2a , in some embodiments, the R 2 moiety is substituted by one R 2a . When R 2 is shown to be optionally substituted by R 2a , in some embodiments, the R 2 moiety is substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R 2a moieties which may be the same or different. In some embodiments, R 2 is C1-C6 alkyl substituted by 2 halogen groups (e.g., 2 fluoro groups) which may be the same or different. In some embodiments, R 2 is C1-C6 alkyl substituted by 2 -OR 3It is C1-C6 alkyl substituted by a group (for example, two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups). In some embodiments, R 2 is C1-C6 alkyl substituted by one halogen group (for example, fluoro) and one -OR 3 group (for example, -OH or -OCH3). In some embodiments, R 2 is C1-C6 alkyl substituted by two halogen groups (for example, two fluoro groups) which may be the same or different, and one -OR 3 group (for example, -OH or -OCH3). In some embodiments, R 2 is C1-C6 alkyl substituted by one halogen group (for example, fluoro) and two -OR 3 groups (for example, two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups) which may be the same or different.

[0171] In some embodiments of the compounds of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or salts thereof, R 2 is C3-C6 cycloalkyl optionally substituted by R 2b . In some embodiments, R 2 is C3-C6 cycloalkyl substituted by one or two R 2b moieties which may be the same or different. In some embodiments, R 2 is C3-C4 cycloalkyl optionally substituted by halogen (for example, unsubstituted cyclopropyl or cyclobutyl optionally substituted by fluoro). In some embodiments, R 2is C3-C4 cycloalkyl optionally substituted by deuterium or tritium atom(s). For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned group can be replaced by the corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned group, such as the carbon of methyl or methoxy, can be replaced by the corresponding isotope, such as deuterium or tritium. Further, for example, the aforementioned group may be a perdeuterated group in which all hydrogens are replaced by deuterium, or a pertritium group in which all hydrogens are replaced by tritium. In some embodiments, one or more ring carbons in the aforementioned group are 13 may be replaced by C. For example, in the polycyclic ring of the aforementioned group, one or more ring carbons in the ring directly bonded to the rest of the compound may be 13 replaced by C. In the polycyclic ring of the aforementioned group, one or more ring carbons that substitute or are fused to the ring bonded to the rest of the compound may be 13 replaced by C. Further, for example, all ring carbons in the aforementioned group may be 13 replaced by C.

[0172] In some embodiments of the compounds of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or salts thereof, R 2 is hydrogen.

[0173] In some embodiments of the compounds of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or salts thereof, R 2 is R 2ais -O-C1-C6 alkyl optionally substituted by. In some embodiments, R 2 is -OCH3.

[0174] In some embodiments, the hygroscopic or deliquescent component is a compound of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or a salt thereof, wherein R 2 is

Chemical formula

[0175] In some embodiments, the hygroscopic or deliquescent component is a compound of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or a salt thereof, wherein R 2 is

Chemical formula

[0176] In some embodiments, the hygroscopic or deliquescent component is a compound of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or a salt thereof, wherein R 2 is

Chemical formula

[0177] In some embodiments, the hygroscopic or deliquescent component is a compound of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or a salt thereof, wherein R 2 is

Chemical formula

[0178] In some embodiments, the hygroscopic or deliquescent component is a compound of formula (A), (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H), or a salt thereof, wherein R 2 is

Chemical formula

[0179] In one embodiment of formula (I), the tetrahydronaphthyridine group is disubstituted with deuterium at the 2-position.

[0180] In some embodiments, the compound is of formula (II):

Chemical formula

[0181] In some embodiments, the compound is of formula (II): [Chem.] or a salt thereof, wherein R 1 is selected from the group consisting of [Chem.] and R 2 is selected from the group consisting of [Chem.] ).

[0182] In some embodiments, the compound is of formula (II): [Chem.] or a salt thereof, wherein R 1 is [Chem.] and R 2 is selected from the group consisting of [Chem.] ).

[0183] Any variant or combination listed herein for the compound of formula (I) also includes any possible combination of R 15 and R 16 and is also applicable to formula (A) or its sub-formulas.

[0184] Representative compounds are listed in Figure 1.

[0185] In some embodiments, the compound is selected from compound numbers 1 - 66 in Figure 1, or its stereoisomers (including mixtures of two or more of its stereoisomers), or its salts. In some embodiments, the compound is a salt of a compound selected from compound numbers 1 - 66 in Figure 1 or its stereoisomers.

[0186] In some embodiments, the compound is selected from compound numbers 1 - 147 in Figure 1, or its stereoisomers (including mixtures of two or more of its stereoisomers), or its salts. In some embodiments, the compound is a salt of a compound selected from compound numbers 1 - 147 or its stereoisomers.

[0187] In some embodiments, the compound is selected from compound numbers 1 - 665 in Figure 1, or its stereoisomers (including mixtures of two or more of its stereoisomers), or its salts. In some embodiments, the compound is a salt of a compound selected from compound numbers 1 - 665 or its stereoisomers.

[0188] In some embodiments, the compound is selected from compound numbers 1 - 780 in Figure 1, or its stereoisomers (including mixtures of two or more of its stereoisomers), or its salts. In some embodiments, the compound is a salt of a compound selected from compound numbers 1 - 780 or its stereoisomers.

[0189] In one variant, the compound is selected from the group consisting of: 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,4-d]pyrimidin-4-ylamino)butanoic acid; 2-((5-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6,7-Difluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(Difluoromethyl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((3,3-Difluorocyclobutyl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 2-(Isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Difluoromethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoic acid; 2-((7-Chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-Chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-(quinazolin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methoxyquinazolin-4-yl)amino)butanoic acid; 4-((2-(2,2-difluorocyclopropoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methoxyquinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((8-Chloroquinazolin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-(pyrido[3,2-d]pyrimidin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((6-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-((5-Fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((6-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((5-Fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid.

[0190] In another variant form, the compounds detailed herein are selected from the group consisting of: 2-((3-Cyanopyrazin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Hydroxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((3-Cyanopyrazin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Fluoropyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-Pyrazolo[4,3-d]pyrimidin-7-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((Oxetan-2-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-Hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(4-Fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-(((3-Fluorooxetan-3-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid.

[0191] Method Provided herein is a method for preparing a substantially non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a hygroscopic or deliquescent compound. Also provided herein is a method for preparing a non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a hygroscopic or deliquescent compound. Also provided herein is a method for preparing a substantially non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a hygroscopic or deliquescent compound. Also provided herein is a method for preparing a non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a hygroscopic or deliquescent compound.

[0192] Provided herein is a method for preparing a substantially non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof. Also provided herein is a method for preparing a non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof. Also provided herein is a method for preparing a substantially non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof. Also provided herein is a method for preparing a non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof.

[0193] In some embodiments, the method includes treating a hygroscopic or deliquescent component according to a formulation process to provide a substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulation. In some embodiments, the formulation process includes a single processing step. In some embodiments, the formulation process includes two or more processing steps. In some embodiments, the method includes restricting exposure of the hygroscopic or deliquescent component to any moisture source during the formulation process. In some embodiments, an intermediate composition is generated during the formulation process. In some embodiments, the intermediate composition is stored in a low moisture environment between processing steps. In some embodiments, the intermediate composition is stored in a sealed moisture-proof container. In some embodiments, the container is a bag, bottle, canister, desiccator, or any other suitable moisture-proof container. In some embodiments, the container is an aluminum bag with a heat seal. In some embodiments, the intermediate composition is stored with one or more additional packaging materials. In some embodiments, the one or more additional packaging materials are desiccants. In some embodiments, the intermediate composition is stored under an inert gas. In some embodiments, the inert gas is selected from the group consisting of nitrogen and argon.

[0194] In some embodiments, the method includes performing any or all of the formulation steps in an environment of low relative humidity. In some embodiments, the method includes performing any or all of the formulation steps in an inert environment. In some embodiments, the atmosphere of the inert environment includes an inert gas. In some embodiments, the inert gas is selected from the group consisting of nitrogen or argon.

[0195] In some embodiments, the hygroscopic or deliquescent component is absorbed onto a solid support prior to further formulation. In some embodiments, the solid support is selected from the group consisting of silicon dioxide, magnesium aluminum silicate, cellulose powder, microcrystalline cellulose, or any other suitable solid support. In some embodiments, the hygroscopic or deliquescent component is absorbed onto a silicon dioxide solid support. In some embodiments, the process of absorbing the hygroscopic or deliquescent component onto the solid support comprises dissolving or suspending the hygroscopic or deliquescent component in a non-aqueous solvent, mixing with the solid support, and removing the solvent. In some embodiments, the solvent is removed using evaporation under vacuum. In some embodiments, the solvent is removed using spray drying. In some embodiments, the solvent is removed using fluid bed drying. In some embodiments, the solvent is removed using filtration. In some embodiments, the resulting composition is stored until further processing according to any of the embodiments described above.

[0196] In some embodiments, the method comprises formulating the hygroscopic or deliquescent component with excipients having a low moisture content and / or excipients that are non-hygroscopic. In some embodiments, the method comprises formulating the hygroscopic or deliquescent component with one or more excipients or coatings selected from the group consisting of anhydrous lactose, calcium phosphate, and mannitol.

[0197] In some embodiments, the method comprises formulating a hygroscopic or deliquescent component, or a composition containing the same, together with one or more hygroscopic excipients. In some embodiments, the one or more hygroscopic excipients are selected from the group consisting of sorbitol, citric acid, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, polyethylene glycol, polyglycolized glyceride, alpha starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, magnesium aluminum silicate, calcium carbonate, cyclodextrin, or carbomer.

[0198] In some embodiments, the method comprises coating a hygroscopic or deliquescent component, or a composition containing the same, with one or more moisture-proof coatings. In some embodiments, the one or more moisture coatings are polymers. In some embodiments, the one or more moisture-proof coatings are selected from the group consisting of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, copolymer dispersion of methyl methacrylate and diethylamino-ethyl methacrylate, hydroxypropyl cellulose, polyvinyl acetate, ethyl cellulose, cellulose acetate, ammonium methacrylate, ammonium methacrylate copolymer, poly(ethyl acrylate-co-methyl methacrylate), shellac, cellulose acetate phthalate, cellulose acetate butyrate, methacrylic acid copolymer, aminodiethyl-methacrylate copolymer, acrylic acid copolymer, sodium alginate, and carboxymethyl cellulose.

[0199] In some embodiments, the method includes encapsulating a hygroscopic or deliquescent component, or a composition containing the same, with a polymer. In some embodiments, the polymer is a hydrophilic polymer. In some embodiments, the polymer is an enteric polymer. In some embodiments, the polymer is an amphiphilic polymer. In some embodiments, the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinylpyrrolidone (PVP), and copovidone. In some embodiments, the method includes mixing a hygroscopic or deliquescent component, or a composition containing the same, with a polymer and heating the mixture to form a melt. In some embodiments, the method further includes extruding the melt to form granules. In some embodiments, the method includes suspending or dissolving a hygroscopic or deliquescent component, or a composition containing the same, and a polymer in a water-insoluble solvent. In some embodiments, the method further includes removing the solvent. In some embodiments, the method further includes treating the resulting solid. In some embodiments, the solvent is removed using evaporation under vacuum. In some embodiments, the solvent is removed using spray drying. In some embodiments, the solvent is removed using fluidized bed drying. In some embodiments, the solvent is removed using filtration. In some embodiments, the polymer is formulated at a ratio of about 1:1 of the active pharmaceutical ingredient to the polymer. In some embodiments, the polymer is formulated at a ratio of 1:1 of the active pharmaceutical ingredient to the polymer. In some embodiments, the polymer is formulated at a ratio of about 1:4 of the active pharmaceutical ingredient to the polymer. In some embodiments, the polymer is formulated at a ratio of 1:4 of the active pharmaceutical ingredient to the polymer. In some embodiments, the polymer is formulated at a ratio of about 1:1 to about 1:4 of the active pharmaceutical ingredient to the polymer. In some embodiments, the polymer is formulated at a ratio of 1:1 to 1:4 of the active pharmaceutical ingredient to the polymer.

[0200] In some embodiments, the method includes formulating a hygroscopic or deliquescent component using a dry granulation process to form tablets.

[0201] In some embodiments, the method includes formulating a hygroscopic or deliquescent component into one or more tablet cores. In some embodiments, the method includes applying a low hygroscopic coating to one or more tablet cores. In some embodiments, the coating is a film coating. In some embodiments, the coating is a dry coating. In some embodiments, the coating is a compression coating. In some embodiments, the coating is a hot melt coating. In some embodiments, the coating formulation includes one or more components selected from the group consisting of a film-forming polymer, a hydrophobic plasticizer, and a pigment that functions as a moisture barrier layer. In some embodiments, the coating formulation includes a coating polymer selected from the group consisting of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose, hydroxyethyl cellulose, PVA-PEG (polyethylene glycol), hydroxypropyl cellulose (HPC), methyl methacrylate and other acrylate copolymers, polyvinyl acetate, ethyl cellulose, cellulose acetate, cellulose acetate phthalate / butyrate, shellac, sodium alginate, and carboxymethyl cellulose. In some embodiments, the coating formulation includes one or more waxes. In some embodiments, the coating formulation includes one or more oils. In some embodiments, the coating formulation includes one or more fatty acids.

[0202] In some embodiments, the hygroscopic or deliquescent component is formulated into a capsule, where the capsule comprises low moisture HPMC. In some embodiments, the capsule is a Quali-V® Extra Dry capsule. In some embodiments, an intermediate composition comprising a hygroscopic or deliquescent component is formulated into a capsule, where the capsule comprises low moisture HPMC. In some embodiments, the intermediate composition comprises a hygroscopic or deliquescent component absorbed onto a solid support according to any of the methods described herein. In some embodiments, the capsule is a Quali-V® Extra Dry capsule.

[0203] Further formulation techniques are disclosed in U.S. Patent Nos. 5,037,698, 6,204,255, 8,299,271, 8,916,214, 3,553,114, or 4,223,006, or PCT Publication WO2004 / 060353, the entire disclosures of which are incorporated herein by reference.

[0204] In some embodiments, any of the substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations described herein are further packaged to limit exposure of the formulation to moisture. In some embodiments, the formulation is packaged in a moisture-proof bottle. In some embodiments, the formulation is packaged in a moisture-proof blister package. In some embodiments, the moisture-proof blister package is an Alu-Alu package. In some embodiments, the formulation is packaged with one or more additional packaging materials. In some embodiments, the one or more additional packaging materials comprise a desiccant.

[0205] In some embodiments, the package is an HDPE bottle. In some embodiments, the package is an HDPE bottle further comprising a desiccant. In some embodiments, the package is an HDPE bottle and the formulation is sealed within the HDPE bottle using heat or induction. In some embodiments, the package is an HDPE bottle and the formulation and desiccant are sealed together within the HDPE bottle using heat or induction.

[0206] In some embodiments, the package is a blister pack. In some embodiments, the blister pack is a thermoformed blister. In some embodiments, the blister pack is a cold formed blister. In some embodiments, the package is a blister pack further comprising a desiccant. In some embodiments, the package is a blister pack further comprising a desiccant, and the desiccant is included as a film inside each cavity of the blister pack. In some embodiments, the package is a blister pack further comprising a desiccant, and the desiccant is disposed in a dedicated cavity connected via a channel to each cavity containing the formulation.

[0207] In some embodiments, the package comprises a material having a high moisture barrier capacity. In some embodiments, the package comprises a material having a low water vapor transmission rate (MVTR).

[0208] In some embodiments, the package comprises a desiccant.

[0209] In some embodiments, the method includes dissolving a hygroscopic or deliquescent compound in absolute ethanol to a concentration of 95 - 105 mg / mL, placing silicon dioxide in a fluid bed dryer, and spraying the compound onto the solid silicon dioxide particles while fluidizing. In some embodiments, the method further includes drying until the loss on drying is 2% or less to provide a pharmaceutical intermediate. In some embodiments, the method further includes storing the obtained pharmaceutical intermediate in a sealed foil pouch together with a desiccant. In some embodiments, the method further includes mixing the pharmaceutical intermediate with about 5 - 50 w / w% mannitol and 1 - 10 w / w% sodium croscarmellose to provide an intragranular blend. In some embodiments, the method includes mixing the pharmaceutical intermediate with about 25 w / w% mannitol and 5 w / w% sodium croscarmellose to provide an intragranular blend. In some embodiments, the method further includes transferring the intragranular blend to a roller compactor and compressing it to provide granules. In some embodiments, the method further includes blending the granules with 0.1 - 5 w / w% magnesium stearate to provide a granule blend. In some embodiments, the method further includes blending the granules with 1 w / w% magnesium stearate to provide a granule blend. In some embodiments, the final blend is stored in a sealed foil pouch containing a desiccant. In some embodiments, the method further includes compressing the granule blend using a tableting machine to provide tablets. In some embodiments, the method further includes storing the tablets in a sealed foil pouch containing a desiccant. In some embodiments, the method further includes coating the tablets with an Opadry® suspension until a weight gain of 3 - 5 w / w% of the tablets is achieved. In some embodiments, the method further includes coating the tablets with an Opadry® suspension until a weight gain of 4 w / w% of the tablets is achieved.

[0210] In some embodiments, the method comprises dissolving a compound of formula (A) or any of its sub-formulas in absolute ethanol to a concentration of 95 - 105 mg / mL, placing silicon dioxide in a fluid bed dryer, and spraying the compound onto the solid silicon dioxide particles while fluidizing. In some embodiments, the method further comprises drying until the loss on drying is 2% or less to provide a pharmaceutical intermediate. In some embodiments, the method further comprises storing the obtained pharmaceutical intermediate in a sealed foil pouch together with a desiccant. In some embodiments, the method further comprises mixing the pharmaceutical intermediate with about 5 - 50 w / w% mannitol and 1 - 10 w / w% croscarmellose sodium to provide an intragranular blend. In some embodiments, the method comprises mixing the pharmaceutical intermediate with about 25 w / w% mannitol and 5 w / w% croscarmellose sodium to provide an intragranular blend. In some embodiments, the method further comprises transferring the intragranular blend to a roller compactor and compressing it to provide granules. In some embodiments, the method further comprises blending the granules with 0.1 - 5 w / w% magnesium stearate to provide a granule blend. In some embodiments, the method further comprises blending the granules with 1 w / w% magnesium stearate to provide a granule blend. In some embodiments, the final blend is stored in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises compressing the granule blend using a tableting machine to provide tablets. In some embodiments, the method further comprises storing the tablets in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises coating the tablets with an Opadry® suspension until a weight gain of 3 - 5 w / w% of the tablets is achieved. In some embodiments, the method further comprises coating the tablets with an Opadry® suspension until a weight gain of 4 w / w% of the tablets is achieved.

[0211] In some embodiments, the method comprises dissolving (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid in absolute ethanol to a concentration of 95 - 105 mg / mL, placing silicon dioxide in a fluid bed dryer, and spraying the compound onto the solid silicon dioxide particles while fluidizing. In some embodiments, the method further comprises drying until the loss on drying is 2% or less to provide a pharmaceutical intermediate. In some embodiments, the method further comprises storing the obtained pharmaceutical intermediate in a sealed foil pouch together with a desiccant. In some embodiments, the method further comprises mixing the pharmaceutical intermediate with about 5 - 50 w / w% mannitol and 1 - 10 w / w% croscarmellose sodium to provide an intragranular blend. In some embodiments, the method comprises mixing the pharmaceutical intermediate with about 25 w / w% mannitol and 5 w / w% croscarmellose sodium to provide an intragranular blend. In some embodiments, the method further comprises transferring the intragranular blend to a roller compactor and compressing it to provide granules. In some embodiments, the method further comprises blending the granules with 0.1 - 5 w / w% magnesium stearate to provide a granule blend. In some embodiments, the method further comprises blending the granules with 1 w / w% magnesium stearate to provide a granule blend. In some embodiments, the final blend is stored in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises compressing the granule blend using a tableting machine to provide tablets. In some embodiments, the method further comprises storing the tablets in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises coating the tablets with Opadry® suspension until a weight gain of 3 - 5 w / w% of the tablets is achieved. In some embodiments, the method further comprises coating the tablets with Opadry® suspension until a weight gain of 4 w / w% of the tablets is achieved.

[0212] In some embodiments, the method comprises dissolving a hygroscopic or deliquescent compound in absolute ethanol to a concentration of about 95 - 105 mg / mL, placing silicon dioxide in a fluid bed dryer, and spraying the compound onto the solid silicon dioxide particles while fluidizing. In some embodiments, the method further comprises drying until the loss on drying is about 2% or less to provide a pharmaceutical intermediate. In some embodiments, the method further comprises storing the obtained pharmaceutical intermediate in a sealed foil pouch together with a desiccant. In some embodiments, the method further comprises mixing the pharmaceutical intermediate with about 5 - 50 w / w% mannitol and about 1 - 10 w / w% sodium croscarmellose to provide an intragranular blend. In some embodiments, the method comprises mixing the pharmaceutical intermediate with about 25 w / w% mannitol and about 5 w / w% sodium croscarmellose to provide an intragranular blend. In some embodiments, the method further comprises transferring the intragranular blend to a roller compactor and compressing it to provide granules. In some embodiments, the method further comprises blending the granules with about 0.1 - 5 w / w% magnesium stearate to provide a granule blend. In some embodiments, the method further comprises blending the granules with about 1 w / w% magnesium stearate to provide a granule blend. In some embodiments, the final blend is stored in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises compressing the granule blend using a tableting machine to provide tablets. In some embodiments, the method further comprises storing the tablets in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises coating the tablets with an Opadry® suspension until a weight gain of about 3 - 5 w / w% of the tablets is achieved. In some embodiments, the method further comprises coating the tablets with an Opadry® suspension until a weight gain of about 4 w / w% of the tablets is achieved.

[0213] In some embodiments, the method comprises dissolving a compound of formula (A) or any of its sub-formulas in absolute ethanol to a concentration of about 95 - 105 mg / mL, placing silicon dioxide in a fluid bed dryer, and spraying the compound onto the solid silicon dioxide particles while fluidizing. In some embodiments, the method further comprises drying until the loss on drying is about 2% or less to provide a pharmaceutical intermediate. In some embodiments, the method further comprises storing the obtained pharmaceutical intermediate in a sealed foil pouch together with a desiccant. In some embodiments, the method further comprises mixing the pharmaceutical intermediate with about 5 - 50 w / w% mannitol and about 1 - 10 w / w% sodium croscarmellose to provide an intragranular blend. In some embodiments, the method comprises mixing the pharmaceutical intermediate with about 25 w / w% mannitol and about 5 w / w% sodium croscarmellose to provide an intragranular blend. In some embodiments, the method further comprises transferring the intragranular blend to a roller compactor and compressing it to provide granules. In some embodiments, the method further comprises blending the granules with about 0.1 - 5 w / w% magnesium stearate to provide a granule blend. In some embodiments, the method further comprises blending the granules with about 1 w / w% magnesium stearate to provide a granule blend. In some embodiments, the final blend is stored in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises compressing the granule blend using a tableting machine to provide tablets. In some embodiments, the method further comprises storing the tablets in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises coating the tablets with an Opadry® suspension until a weight gain of about 3 - 5 w / w% of the tablets is achieved. In some embodiments, the method further comprises coating the tablets with an Opadry® suspension until a weight gain of about 4 w / w% of the tablets is achieved.

[0214] In some embodiments, the method comprises dissolving (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid in absolute ethanol to a concentration of about 95 - 105 mg / mL, placing silicon dioxide in a fluid bed dryer, and spraying the compound onto the solid silicon dioxide particles while fluidizing. In some embodiments, the method further comprises drying until the loss on drying is about 2% or less to provide a pharmaceutical intermediate. In some embodiments, the method further comprises storing the obtained pharmaceutical intermediate in a sealed foil pouch together with a desiccant. In some embodiments, the method further comprises mixing the pharmaceutical intermediate with about 5 - 50 w / w% mannitol and about 1 - 10 w / w% croscarmellose sodium to provide an intragranular blend. In some embodiments, the method comprises mixing the pharmaceutical intermediate with about 25 w / w% mannitol and about 5 w / w% croscarmellose sodium to provide an intragranular blend. In some embodiments, the method further comprises transferring the intragranular blend to a roller compactor and compressing it to provide granules. In some embodiments, the method further comprises blending the granules with about 0.1 - 5 w / w% magnesium stearate to provide a granule blend. In some embodiments, the method further comprises blending the granules with about 1 w / w% magnesium stearate to provide a granule blend. In some embodiments, the final blend is stored in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises compressing the granule blend using a tableting machine to provide tablets. In some embodiments, the method further comprises storing the tablets in a sealed foil pouch containing a desiccant. In some embodiments, the method further comprises coating the tablets with Opadry® suspension until a weight gain of about 3 - 5 w / w% of the tablets is achieved. In some embodiments, the method further comprises coating the tablets with Opadry® suspension until a weight gain of about 4 w / w% of the tablets is achieved.

[0215] Composition In another aspect, there is provided a substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) or a sub-formula thereof.

[0216] In some embodiments, the substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulation comprises one or more hygroscopic excipients. In some embodiments, the one or more hygroscopic excipients are selected from the group consisting of sorbitol, citric acid, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, polyethylene glycol, polyglycolated glycerides, pre-gelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, magnesium aluminum silicate, calcium carbonate, cyclodextrin, or carbomer.

[0217] In some embodiments, substantially non-deliquescent, non-deliquescent, substantially non-hygroscopic, and / or non-hygroscopic formulations comprise one or more moisture-barrier coatings. In some embodiments, the one or more moisture-barrier coatings are selected from the group consisting of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, copolymer dispersion of methyl methacrylate and diethylamino-ethyl methacrylate, hydroxypropyl cellulose, polyvinyl acetate, ethyl cellulose, cellulose acetate, ammonio methacrylate, ammonio methacrylate copolymer, poly(ethyl acrylate-co-methyl methacrylate), shellac, cellulose acetate phthalate, cellulose acetate butyrate, methacrylic acid copolymer, aminodiethyl-methacrylate copolymer, acrylic acid copolymer, sodium alginate, and carboxymethyl cellulose. In some embodiments, the moisture-barrier coating comprises Opadry®. In some embodiments, the moisture-barrier coating comprises Opadry QX® or Opadry AMB II®.

[0218] Formulation A pharmaceutical composition comprising a compound of formula (A), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H) or a salt thereof, any of the compounds detailed herein, or any of the compounds of Figure 1, or a salt thereof, or a mixture thereof, is encompassed herein. A pharmaceutical composition comprising a compound of formula (A), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H) or a salt thereof, any of the compounds detailed herein, or any of the compounds of Figure 1, or a salt thereof, or a mixture thereof, is encompassed herein. A pharmaceutical composition comprising a compound of formula (A) or a sub-formula thereof, or a salt thereof, or a mixture thereof, is encompassed by the present invention. Provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt such as a salt formed with an inorganic acid or an organic acid. The pharmaceutical compositions described herein may take a form suitable for oral administration, buccal administration, parenteral administration, nasal administration, topical administration, or rectal administration, or a form suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is a controlled release composition of any of the compounds detailed herein.

[0219] The compounds detailed herein can, in one aspect, be in a purified form, and compositions containing the compounds in purified form are described herein. In one embodiment, the composition can have 35% or less impurities, where impurities refer to compounds other than the compound that makes up the majority of the composition or its salt. For example, a composition of a compound selected from the compound of Figure 1 can contain 35% or less impurities, where impurities refer to compounds other than the compound of Figure 1 or its salt. In one embodiment, the composition can have 35% or less impurities, where impurities refer to compounds other than the compound that makes up the majority of the composition or its salt. For example, a composition of a compound selected from the compound of Figure 1 can contain 35% or less impurities, where impurities refer to compounds other than the compound of Figure 1 or its salt. In one embodiment, the composition can contain 25% or less impurities. In one embodiment, the composition can contain 20% or less impurities. In still further embodiments, a composition containing the compounds detailed herein or their salts is provided as a composition of substantially pure compound. A "substantially pure" composition contains 10% or less impurities, for example, a composition containing 9%, 7%, 5%, 3%, 1%, or less than 0.5% impurities. In some embodiments, a composition containing the compounds detailed herein or their salts is in a substantially pure form. In yet another variant, a composition of substantially pure compound or its salt is provided, where the composition contains 10% or less impurities. In a further variant, a composition of substantially pure compound or its salt is provided, where the composition contains 9% or less impurities. In a further variant, a composition of substantially pure compound or its salt is provided, where the composition contains 7% or less impurities. In a further variant, a composition of substantially pure compound or its salt is provided, where the composition contains 5% or less impurities. In another variant, a composition of substantially pure compound or its salt is provided, where the composition contains 3% or less impurities. In yet another variant, a composition of substantially pure compound or its salt is provided, where the composition contains 1% or less impurities.In a further variant form, a composition of a substantially pure compound or a salt thereof is provided, where the composition contains 0.5% or less impurities. In yet another variant form, a composition of a substantially pure compound means that the composition contains 10% or less, or preferably 5% or less, or more preferably 3% or less, or even more preferably 1% or less, or most preferably 0.5% or less impurities, and the impurities can be compounds of different stereochemical forms. For example, a composition of a substantially pure (S) compound means that the composition contains 10% or less or 5% or less or 3% or less or 1% or less or 0.5% or less of the (R) form of the compound.

[0220] The compounds described in detail herein can, in one aspect, be in a purified form, and compositions containing the compounds in a purified form are described herein. In one embodiment, the composition can have up to about 35% impurities, where impurities refer to compounds other than the compound that makes up the majority of the composition or its salt. For example, a composition of a compound selected from the compound of Figure 1 can contain up to about 35% impurities, where impurities refer to compounds other than the compound of Figure 1 or its salt. In one embodiment, the composition can have up to about 35% impurities, where impurities refer to compounds other than the compound that makes up the majority of the composition or its salt. For example, a composition of a compound selected from the compound of Figure 1 can contain up to about 35% impurities, where impurities refer to compounds other than the compound of Figure 1 or its salt. In one embodiment, the composition can contain up to about 25% impurities. In one embodiment, the composition can contain up to about 20% impurities. In yet further embodiments, a composition containing the compound described in detail herein or its salt is provided as a composition of a substantially pure compound. A "substantially pure" composition contains up to about 10% impurities, for example, a composition containing up to about 9%, about 7%, about 5%, about 3%, about 1%, or less than about 0.5% impurities. In some embodiments, the composition containing the compound described in detail herein or its salt is in a substantially pure form. In yet another variant, a composition of a substantially pure compound or its salt is provided, where the composition contains up to about 10% impurities. In a further variant, a composition of a substantially pure compound or its salt is provided, where the composition contains up to about 9% impurities. In a further variant, a composition of a substantially pure compound or its salt is provided, where the composition contains up to about 7% impurities. In a further variant, a composition of a substantially pure compound or its salt is provided, where the composition contains up to about 5% impurities. In another variant, a composition of a substantially pure compound or its salt is provided, where the composition contains up to about 3% impurities. In yet another variant, a composition of a substantially pure compound or its salt is provided, where the composition contains up to about 1% impurities.In a further variant form, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains impurities of about 0.5% or less. In yet another variant form, a composition of a substantially pure compound means that the composition contains impurities of about 10% or less, or preferably about 5% or less, or more preferably 3% or less, or even more preferably about 1% or less, or most preferably about 0.5% or less, and the impurities can be compounds in different stereochemical forms. For example, a composition of a substantially pure (S) compound means that the composition contains a compound in the (R) form of about 10% or less or about 5% or less or about 3% or less or about 1% or less or about 0.5% or less.

[0221] In one variant form, the compounds herein are synthetic compounds prepared for administration to an individual such as a human. In another variant form, a composition containing a compound in substantially pure form is provided. In another variant form, provided herein is a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variant form, a method of administering the compound is provided. The purified form, the pharmaceutical composition and the method of administering the compound are suitable for any compound or its form detailed herein.

[0222] The compounds or salts thereof detailed herein can be formulated for any available delivery route including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. The compound or its salt can be formulated with a carrier suitable for providing a delivery form including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (wet dressings), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0223] One or more of the compounds or salts thereof described herein can be used in the preparation of pharmaceutical formulations such as pharmaceutical preparations by combining one or more compounds or salts thereof as active ingredients with pharmaceutically acceptable carriers such as those described above. Depending on the form of treatment of the system (e.g., whether it is a transdermal patch or an oral tablet), the carrier can be in various forms. In addition, the pharmaceutical formulation can contain preservatives, solubilizing agents, stabilizing agents, rewetting agents, emulsifying agents, sweetening agents, coloring agents, adjusting agents, and salts for adjusting osmotic pressure, buffering agents, coating agents, or antioxidants. The formulation containing the compound can also contain other substances having beneficial therapeutic properties. The pharmaceutical formulation can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), which is hereby incorporated by reference herein.

[0224] The compounds described herein can be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions such as tablets, coating agents, and hard or soft shell gel capsule agents, emulsions or suspensions. Examples of carriers that can be used in the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Carriers acceptable for soft shell gel capsule agents are, for example, vegetable oils, waxes, fats, semi - solids and liquid polyols, etc. In addition, the pharmaceutical formulation can contain preservatives, solubilizing agents, stabilizing agents, rewetting agents, emulsifying agents, sweetening agents, coloring agents, adjusting agents, and salts for adjusting osmotic pressure, buffering agents, coating agents, or antioxidants.

[0225] Any of the compounds described herein can be formulated into tablets of any of the described dosage forms. For example, the compounds or pharmaceutically acceptable salts thereof described herein can be formulated as 10 mg tablets.

[0226] Compositions comprising the compounds provided herein are also described. In one variant form, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variant form, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicine. In some embodiments, the composition is for use in the methods described herein. In some embodiments, the composition is for use in the treatment of the diseases or disorders described herein.

[0227] In some embodiments, a formulation is provided that comprises mannitol, croscarmellose sodium, magnesium stearate, and Opadry®.

[0228] In some embodiments, a formulation is provided that comprises from about 1 to 75 w / w% mannitol, from about 0.1 to 20 w / w% croscarmellose sodium, from about 0.05 to 10 w / w% magnesium stearate, and from about 1 to 10% Opadry®.

[0229] In some embodiments, a formulation is provided that comprises from about 5 to 50 w / w% mannitol, from about 1 to 10 w / w% croscarmellose sodium, from about 0.1 to 5 w / w% magnesium stearate, and from about 3 to 5% Opadry®.

[0230] In some embodiments, a formulation is provided that comprises about 25 w / w% mannitol, about 5 w / w% croscarmellose sodium, about 1 w / w% magnesium stearate, and about 4% Opadry®.

[0231] In some embodiments, a formulation is provided that comprises 5 to 50 w / w% mannitol, 1 to 10 w / w% croscarmellose sodium, 0.1 to 5 w / w% magnesium stearate, and 3 to 5% Opadry®.

[0232] In some embodiments, there is provided a formulation comprising 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, and 4% Opadry®.

[0233] In some embodiments, there is provided a formulation comprising mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and Opadry®.

[0234] In some embodiments, there is provided a formulation comprising about 1 - 75 w / w% mannitol, about 0.1 - 20 w / w% croscarmellose sodium, about 0.05 - 10 w / w% magnesium stearate, about 0.1 - 90% silicon dioxide, and about 1 - 10% Opadry®.

[0235] In some embodiments, there is provided a formulation comprising about 5 - 50 w / w% mannitol, about 1 - 10 w / w% croscarmellose sodium, about 0.1 - 5 w / w% magnesium stearate, about 1 - 75% silicon dioxide, and about 3 - 5% Opadry®.

[0236] In some embodiments, there is provided a formulation comprising 5 - 50 w / w% mannitol, 1 - 10 w / w% croscarmellose sodium, 0.1 - 5 w / w% magnesium stearate, 0.1 - 90% silicon dioxide, and 3 - 5% Opadry®.

[0237] In some embodiments, there is provided a formulation comprising 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, 1 - 75% silicon dioxide, and 4% Opadry®.

[0238] In some embodiments, there is provided a formulation comprising mannitol, croscarmellose sodium, magnesium stearate, and Opadry® QX.

[0239] In some embodiments, a formulation is provided that includes from about 1 to 75 w / w% mannitol, from about 0.1 to 20 w / w% croscarmellose sodium, from about 0.05 to 10 w / w% magnesium stearate, and from about 1 to 10% Opadry® QX.

[0240] In some embodiments, a formulation is provided that includes from about 5 to 50 w / w% mannitol, from about 1 to 10 w / w% croscarmellose sodium, from about 0.1 to 5 w / w% magnesium stearate, and from about 3 to 5% Opadry® QX.

[0241] In some embodiments, a formulation is provided that includes about 25 w / w% mannitol, about 5 w / w% croscarmellose sodium, about 1 w / w% magnesium stearate, and about 4% Opadry® QX.

[0242] In some embodiments, a formulation is provided that includes 5 to 50 w / w% mannitol, 1 to 10 w / w% croscarmellose sodium, 0.1 to 5 w / w% magnesium stearate, and 3 to 5% Opadry® QX.

[0243] In some embodiments, a formulation is provided that includes 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, and 4% Opadry® QX.

[0244] In some embodiments, a formulation is provided that includes mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and Opadry® QX.

[0245] In some embodiments, a formulation is provided that includes about 1 to 75 w / w% mannitol, about 0.1 to 20 w / w% croscarmellose sodium, about 0.05 to 10 w / w% magnesium stearate, about 0.1 to 90% silicon dioxide, and about 1 to 10% Opadry® QX.

[0246] In some embodiments, a formulation is provided that includes about 5 to 50 w / w% mannitol, about 1 to 10 w / w% croscarmellose sodium, about 0.1 to 5 w / w% magnesium stearate, about 1 to 75% silicon dioxide, and about 3 to 5% Opadry® QX.

[0247] In some embodiments, a formulation is provided that includes 5 to 50 w / w% mannitol, 1 to 10 w / w% croscarmellose sodium, 0.1 to 5 w / w% magnesium stearate, 0.1 to 90% silicon dioxide, and 3 to 5% Opadry® QX.

[0248] In some embodiments, a formulation is provided that includes 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, 1 to 75% silicon dioxide, and 4% Opadry® QX.

[0249] In some embodiments, a formulation is provided that includes mannitol, croscarmellose sodium, magnesium stearate, and Opadry® AMB II.

[0250] In some embodiments, a formulation is provided that includes about 1 to 75 w / w% mannitol, about 0.1 to 20 w / w% croscarmellose sodium, about 0.05 to 10 w / w% magnesium stearate, and about 1 to 10% Opadry® AMB II.

[0251] In some embodiments, a formulation is provided that comprises about 5 to 50 w / w% mannitol, about 1 to 10 w / w% croscarmellose sodium, about 0.1 to 5 w / w% magnesium stearate, and about 3 to 5% Opadry® AMB II.

[0252] In some embodiments, a formulation is provided that comprises about 25 w / w% mannitol, about 5 w / w% croscarmellose sodium, about 1 w / w% magnesium stearate, and about 4% Opadry® AMB II.

[0253] In some embodiments, a formulation is provided that comprises 5 to 50 w / w% mannitol, 1 to 10 w / w% croscarmellose sodium, 0.1 to 5 w / w% magnesium stearate, and 3 to 5% Opadry® AMB II.

[0254] In some embodiments, a formulation is provided that comprises 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, and 4% Opadry® AMB II.

[0255] In some embodiments, a formulation is provided that comprises mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and Opadry® AMB II.

[0256] In some embodiments, a formulation is provided that comprises about 1 to 75 w / w% mannitol, about 0.1 to 20 w / w% croscarmellose sodium, about 0.05 to 10 w / w% magnesium stearate, about 0.1 to 90% silicon dioxide, and about 1 to 10% Opadry® AMB II.

[0257] In some embodiments, there is provided a formulation comprising about 5 to 50 w / w% mannitol, about 1 to 10 w / w% croscarmellose sodium, about 0.1 to 5 w / w% magnesium stearate, about 1 to 75% silicon dioxide, and about 3 to 5% Opadry® AMB II.

[0258] In some embodiments, there is provided a formulation comprising 5 to 50 w / w% mannitol, 1 to 10 w / w% croscarmellose sodium, 0.1 to 5 w / w% magnesium stearate, 0.1 to 90% silicon dioxide, and 3 to 5% Opadry® AMB II.

[0259] In some embodiments, there is provided a formulation comprising 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, 1 to 75% silicon dioxide, and 4% Opadry® AMB II.

[0260] In some embodiments, there is provided a formulation comprising mannitol, croscarmellose sodium, magnesium stearate, and a polyethylene glycol - polyvinyl alcohol copolymer.

[0261] In some embodiments, there is provided a formulation comprising about 1 to 75 w / w% mannitol, about 0.1 to 20 w / w% croscarmellose sodium, about 0.05 to 10 w / w% magnesium stearate, and about 1 to 10% polyethylene glycol - polyvinyl alcohol copolymer.

[0262] In some embodiments, there is provided a formulation comprising about 5 to 50 w / w% mannitol, about 1 to 10 w / w% croscarmellose sodium, about 0.1 to 5 w / w% magnesium stearate, and about 3 to 5% polyethylene glycol - polyvinyl alcohol copolymer.

[0263] In some embodiments, a formulation is provided that comprises about 25 w / w% mannitol, about 5 w / w% croscarmellose sodium, about 1 w / w% magnesium stearate, and about 4% polyethylene glycol - polyvinyl alcohol copolymer.

[0264] In some embodiments, a formulation is provided that comprises 5 - 50 w / w% mannitol, 1 - 10 w / w% croscarmellose sodium, 0.1 - 5 w / w% magnesium stearate, and 3 - 5% polyethylene glycol - polyvinyl alcohol copolymer.

[0265] In some embodiments, a formulation is provided that comprises 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, and 4% polyethylene glycol - polyvinyl alcohol copolymer.

[0266] In some embodiments, a formulation is provided that comprises mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and polyethylene glycol - polyvinyl alcohol copolymer.

[0267] In some embodiments, a formulation is provided that comprises about 1 - 75 w / w% mannitol, about 0.1 - 20 w / w% croscarmellose sodium, about 0.05 - 10 w / w% magnesium stearate, about 0.1 - 90% silicon dioxide, and about 1 - 10% polyethylene glycol - polyvinyl alcohol copolymer.

[0268] In some embodiments, a formulation is provided that comprises about 5 - 50 w / w% mannitol, about 1 - 10 w / w% croscarmellose sodium, about 0.1 - 5 w / w% magnesium stearate, about 1 - 75% silicon dioxide, and about 3 - 5% polyethylene glycol - polyvinyl alcohol copolymer.

[0269] In some embodiments, there is provided a formulation comprising 5 to 50 w / w% mannitol, 1 to 10 w / w% croscarmellose sodium, 0.1 to 5 w / w% magnesium stearate, 0.1 to 90% silicon dioxide, and 3 to 5% polyethylene glycol-polyvinyl alcohol copolymer.

[0270] In some embodiments, there is provided a formulation comprising 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, 1 to 75% silicon dioxide, and 4% polyethylene glycol-polyvinyl alcohol copolymer.

[0271] In some embodiments, there is provided a formulation comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and polyethylene glycol-polyvinyl alcohol copolymer.

[0272] In some embodiments, there is provided a formulation comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, about 1 to 75 w / w% mannitol, about 0.1 to 20 w / w% croscarmellose sodium, about 0.05 to 10 w / w% magnesium stearate, about 0.1 to 90% silicon dioxide, and about 1 to 10% polyethylene glycol-polyvinyl alcohol copolymer.

[0273] In some embodiments, there is provided a formulation comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, about 5 to 50 w / w% mannitol, about 1 to 10 w / w% croscarmellose sodium, about 0.1 to 5 w / w% magnesium stearate, about 1 to 75% silicon dioxide, and about 3 to 5% polyethylene glycol-polyvinyl alcohol copolymer.

[0274] In some embodiments, there is provided a formulation comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, 5 to 50 w / w% mannitol, 1 to 10 w / w% croscarmellose sodium, 0.1 to 5 w / w% magnesium stearate, 0.1 to 90% silicon dioxide, and 3 to 5% polyethylene glycol-polyvinyl alcohol copolymer.

[0275] In some embodiments, there is provided a formulation comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, 25 w / w% mannitol, 5 w / w% croscarmellose sodium, 1 w / w% magnesium stearate, 1 to 75% silicon dioxide, and 4% polyethylene glycol-polyvinyl alcohol copolymer.

[0276] Treatment method In some embodiments, there is provided a method of treating a fibrotic disease in an individual in need thereof, the method comprising administering any one of the formulations described herein. In some embodiments, there is provided a method of treating a fibrotic disease, the method comprising administering a formulation prepared according to any of the methods described herein. In some embodiments, the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. In some embodiments, the fibrotic disease is liver fibrosis, cardiac fibrosis, primary sclerosing cholangitis, or biliary fibrosis.

[0277] In some embodiments, there is provided a kit comprising any one of the formulations described herein. In some embodiments, there is provided a kit comprising a formulation prepared according to any of the methods described herein.

[0278] In some embodiments, there is provided a method of inhibiting αvβ6 integrin in an individual, the method comprising administering any one of the formulations described herein. In some embodiments, there is provided a method of inhibiting αvβ6 integrin in an individual, the method comprising administering a formulation prepared according to any of the methods described herein. In some embodiments, the individual has or is at risk of a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, interstitial lung disease associated with systemic sclerosis, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's disease. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease is primary sclerosing cholangitis.

[0279] In some embodiments, provided is a method of inhibiting TGFβ activation in a cell, the method comprising any one of the formulations described herein. In some embodiments, provided is a method of inhibiting TGFβ activation in a cell, the method comprising a formulation prepared according to any of the methods described herein.

[0280] A method of treatment comprising a compound of formula (A) is disclosed, for example, in U.S. Patent No. 10,793,564, which is hereby incorporated by reference in its entirety.

[0281] General synthetic methods The compounds described herein can be prepared by many processes (such as the schemes provided in the following examples) outlined below and detailed in the following examples. In the description of the following processes, it should be understood that the symbols used in the indicated formulas represent the groups described above in connection with the formulas herein.

[0282] If it is desired to obtain a specific enantiomer of a compound, this can be achieved using any conventional procedure suitable for separating or resolving enantiomers from the corresponding enantiomeric mixture. Thus, for example, diastereomeric derivatives can be generated by reaction of an enantiomeric mixture, such as a racemate, with a suitable chiral compound. The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer recovered. In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate. Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the described processes.

[0283] If it is desired to obtain a specific isomer of a compound or otherwise generate a reaction product, chromatography, recrystallization and other conventional separation procedures may be used on the intermediate or final product.

[0284] Solvates and / or polymorphs of the compounds provided herein or pharmaceutically acceptable salts thereof are also contemplated. Solvates contain either a stoichiometric or non-stoichiometric amount of solvent and are often formed during the crystallization process. When the solvent is water, a hydrate is formed, and when the solvent is an alcohol, an alcoholate is formed. Polymorphs contain different crystal packing arrangements for compounds of the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and / or solubility. The formation of single crystals can be favored by various factors such as the recrystallization solvent, crystallization rate, and storage temperature.

[0285] The compounds provided herein can be prepared according to General Schemes A, B, C, and D, General Procedures A, B, C, D, E, F, G, H, and P, and the Examples herein.

[0286] The compounds provided herein can be prepared according to General Schemes A, B, C, and D, General Procedures A, B, C, D, E, F, G, H, P, Q, R, S, T, and U, and the Examples herein.

[0287] The compound of Formula 11A can be prepared according to General Scheme A, wherein R 1 and R 2 are as defined for Formula (I) or any applicable variant detailed herein. General Scheme A

Chemical Formula

[0288] In the presence of a suitable coupling agent, coupling of a compound of 1A and a compound of Formula 2A gives a compound of Formula 3A, which upon reduction gives a compound of Formula 4A. Reductive amination of the compound of Formula 4A with compound 5A gives a compound of Formula 6A. Exposure of the compound of Formula 6A to a suitable acid to remove the N-Boc protecting group gives a compound of Formula 7A, which upon coupling with a compound of Formula 8A gives a compound of Formula 10A. Hydrolysis of the compound of Formula 10A in the presence of a suitable source of hydroxide gives a compound of Formula 11A.

[0289] The reaction conditions for the conversions of General Scheme A are provided in the following general procedures, specifically, General Procedures A, D, E, F, G, H, and P.

[0290] Modifying General Scheme A, variants of the compound of Formula 11A can be prepared starting from variants of 1A that contain 5- and 6-carbon linkers between the nitrogen having the R 2 group and the tetrahydronaphthyridine group. These variants of the compound of Formula 11A can be synthesized by replacing 1A with either 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid or 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid and using the route described in General Scheme A. Condensing 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst gives 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, and subsequent hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature gives the 5,6,7,8-tetrahydronaphthyridine ring.

[0291] Alternatively, the compound of Formula 11A can be prepared according to General Scheme B, wherein R 1 and R 2 are as defined for Formula (I) or any applicable variant detailed herein. General Scheme B

Chem.

[0292] In the presence of a suitable base and di-tert-butyl dicarbonate, the N-Boc group of 1B is introduced to obtain a compound of formula 2B, which is reduced to obtain a compound of formula 3B. Oxidation of the compound of formula 3B with a suitable oxidizing agent gives a compound of formula 4B. Reductive amination of the compound of formula 4B with compound 2A gives a compound of formula 5B. Reductive amination of the compound of formula 5B with compound 5A gives a compound of formula 7B. Exposure of the compound of formula 7B to a suitable acid to remove the N-Boc protecting group gives a compound of formula 7A, which is coupled with a compound of formula 8A to give a compound of formula 10A. Hydrolysis of the compound of formula 10A in the presence of a suitable source of hydroxide gives a compound of formula 11A.

[0293] The reaction conditions for the conversions of General Scheme B are provided in the following general procedures, specifically, General Procedures B, D, F, G, H, and P.

[0294] Modify General Scheme B such that R 2Starting from variants of 1B that contain five and six carbon linkers between the nitrogen having a base and the tetrahydronaphthyridinyl group, variants of the compound of formula 11A can be prepared. These variants of the compound of formula 11A can be synthesized by replacing 1B with either ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate or ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate and using the route described in General Scheme B. Condensing ethyl 6-oxoheptanoate and ethyl 7-oxooctanoate with 2-aminonicotinaldehyde in the presence of a suitable catalyst converts them to ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate and ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate, respectively. Subsequently, hydrogenating the resulting naphthyridine ring using procedures known in the chemical literature gives the 5,6,7,8-tetrahydronaphthyridine ring.

[0295] The compound of formula 10C can be prepared according to General Scheme C, wherein R is C1-C5 alkyl optionally substituted by 2a and R 1 and R 2a are as defined for formula (I) or any applicable variant detailed herein. General Scheme C

Chemical formula

[0296] In the presence of a suitable coupling agent, coupling of a 1C compound with a 4C compound gives a 2C compound, which upon reduction gives a 3C compound. Reductive amination of the 3C compound with compound 5A gives a 5C compound. Exposure of the 5C compound to a suitable acid to remove the N-Boc protecting group globally gives a 6C compound, which upon coupling with a compound 8A gives a 9C compound. Hydrolysis of the 9C compound in the presence of a suitable hydroxide source gives a 10C compound.

[0297] The reaction conditions for the conversions of General Scheme C are provided in the following general procedures, in particular, General Procedures B, D, F, G, H, and P.

[0298] General Scheme C can be modified to prepare variants of the 10C compound starting from variants of 1C containing 5- and 6-carbon linkers between the nitrogen having a -CH2R group and the tetrahydronaphthyridine group. These variants of the 10C compound can be synthesized by replacing 1C with either 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in General Scheme C. Condensation of 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst converts them to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively. Subsequently, hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature gives a 5,6,7,8-tetrahydronaphthyridine ring. The resulting carboxylic acids can be converted to primary amines by a two-step procedure involving coupling of the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0299] Alternatively, the compound of Formula 10C can be prepared according to General Scheme D, wherein R is C1-C5 alkyl optionally substituted by 2a R 1 and R 2a are as defined for Formula (I) or any applicable variant detailed herein. General Scheme D

Chemical Formula

[0300] Alkylation of 1C with a compound of Formula 2D in the presence of a suitable alkyl halide gives a compound of Formula 3C. Reductive amination of the compound of Formula 3C with compound 5A gives a compound of Formula 5C. Exposure of the compound of Formula 5C to a suitable acid to remove the N-Boc protecting group gives a compound of Formula 6C, which is coupled with a compound of Formula 9A to give a compound of Formula 9C. Hydrolysis of the compound of Formula 8A in the presence of a suitable source of hydroxide gives a compound of Formula 10C.

[0301] The reaction conditions for the conversions of General Scheme D are provided in the following general procedures, in particular, General Procedures C, F, G, H, and P.

[0302] By modifying general scheme D, variants of the compound of formula 10C can be prepared starting from 1C variants containing 5- and 6-carbon linkers between the nitrogen having a -CH2R group and the tetrahydronaphthyridine group. These variants of the compound of formula 10C can be synthesized by replacing 1C with either 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in general scheme D. Condensing 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst converts them to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively. Subsequently, hydrogenating the resulting naphthyridine ring using procedures known in the chemical literature gives the 5,6,7,8-tetrahydronaphthyridine ring. The resulting carboxylic acids can be converted to primary amines by a two-step procedure involving coupling of the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0303] The compound of formula 1f can be prepared according to general scheme E. It is understood that the ring having the Het description can be any aromatic heterocyclic ring. General scheme E

Chemical formula

[0304] Hydrolysis of the compound of formula 1a gives the compound of formula 1b, which upon alkylation with a suitable electrophile gives the compound of formula 1c. Deprotection of the compound of formula 1c under reducing conditions gives the compound of formula 1d. Metal-catalyzed cross-coupling of an aryl halide with the compound of formula 1d gives the compound of formula 1e, which upon hydrolysis under acidic conditions gives the compound of formula 1f.

[0305] The reaction conditions for the conversion of general scheme E are provided in the following general procedures, in particular, general procedures Q, R, S, T, and U.

[0306] It is understood that by modifying the above scheme and selecting appropriate reagents and starting materials, various compounds described herein can be reached. For a general description of protecting groups and their use, see P.G.M.Wuts and T.W.Greene, Greene’s Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.

[0307] Additional methods for preparing the compounds according to formula (I) and their salts are provided in the examples. As will be recognized by those skilled in the art, the preparation methods taught herein can be varied, for example, by selecting starting materials that will provide the desired compounds, to provide additional compounds within the scope of formula (I).

[0308] Further synthetic methods for preparing the compounds described herein are disclosed in U.S. Patent No. 10,793,564, which is hereby incorporated by reference in its entirety.

[0309] General Procedures The compounds provided herein can be prepared according to the general schemes illustrated by the general procedures and examples. When following the general procedures, some variations may occur in temperature, concentration, reaction time, and other parameters, but they do not substantially affect the results of the procedures.

[0310] It is understood that when a specific stereoisomer, or an unspecified stereoisomer, or a mixture of stereoisomers is shown by the following general procedure, a similar chemical transformation can be carried out on other specific stereoisomers, or unspecified stereoisomers, or mixtures thereof. For example, the hydrolysis reaction of (S)-methyl 4-aminobutanoate to (S)-4-aminobutanoic acid can be carried out on (R)-methyl 4-aminobutanoate to similarly prepare (R)-4-aminobutanoic acid, or on a mixture of (S)-methyl 4-aminobutanoate and (R)-methyl 4-aminobutanoate to prepare a mixture of (S)-4-aminobutanoic acid and (R)-4-aminobutanoic acid.

[0311] Some of the following general procedures use specific compounds to illustrate general reactions (e.g., a compound having an amine protected with Boc is deprotected using an acid to a compound having a deprotected amine). The general reaction can be carried out on other specific compounds having the same functional group (e.g., a different compound having a protected amine whose Boc protecting group can be similarly removed using an acid), provided that such other specific compounds do not contain additional functional groups that would be affected by the general reaction (i.e., such other specific compounds do not contain acid-sensitive functional groups), or the effect of the general reaction on such additional functional groups is desired (e.g., such other specific compounds have another group that is affected by the acid and the reaction of the acid on the other group is a desired reaction).

[0312] If a specific reagent or solvent is specified for a reaction in the general procedure, one of ordinary skill in the art will recognize that, if desired, it can be replaced with another reagent or solvent. For example, if hydrochloric acid is used for the removal of the Boc group, trifluoroacetic acid can be used instead. As another example, if HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) is used as a coupling reagent, BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) or PyBOP (benzotriazol-1-yl-oxytrypyrrolidinophosphonium hexafluorophosphate) can be used instead.

[0313] General Procedure A

Chem.

Chem.

[0314] N-(4-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (351 mg, 1.71 mmol) and formic acid (0.09 mL, 2.22 mmol) in 4:1 THF / DMF (5 mL) was added HATU (844 mg, 2.22 mmol), followed by DIPEA (0.89 mL, 5.13 mmol), and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and purified by normal-phase silica gel chromatography to afford N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide.

[0315] General procedure C [Chemical formula] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (300 mg, 1.46 mmol), 1-bromo-2-methoxyethane (0.11 mL, 1.17 mmol) and DIPEA (0.25 mL, 1.46 mmol) in i-PrOH (3 mL) was heated to 70 °C for 18 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum and purified by normal-phase silica gel chromatography to afford N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0316] General procedure D [Chemical formula] N-Methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. To a solution of N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide (200 mg, 0.86 mmol) in THF (2 mL) at room temperature was added dropwise a solution of borane tetrahydrofuran complex (1.0 M in THF, 4.0 mL, 4.0 mmol). The resulting mixture was then heated to 60 °C for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted with MeOH and concentrated under vacuum. The crude residue was purified by normal phase silica gel chromatography to give N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0317] General procedure E

Chemical formula

Chemical formula

[0318] (S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a mixture of N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5) (187 mg, 0.85 mmol) in MeOH (5 mL) at room temperature was added acetic acid (0.12 mL, 2.05 mmol), followed by methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol). The resulting mixture was stirred at room temperature for 15 minutes, at which point sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture, stirred for 30 minutes, and then concentrated under vacuum. The crude residue was purified by normal-phase silica gel chromatography to give (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. General Procedure G [Chemical formula]

[0319] (S)-Methyl 2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (152 mg, 0.35 mmol) in CH2Cl2 (2 mL) at room temperature was added 4N HCl in 1,4-dioxane (1 mL, 4 mmol), and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under vacuum to give (S)-methyl 2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate as the trihydrochloride salt. General Procedure H [Chemical formula] A solution of methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate trihydrochloride (80 mg, 0.16 mmol), 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine (64 mg, 0.33 mmol) and DIPEA (0.23 mL, 1.31 mmol) in i-PrOH (1 mL) was heated at 60 °C overnight. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoate.

[0320] General procedure P

Chemical formula

[0321] General procedure Q

Chemical formula

Chemical formula

[0322] (S)-2-(((Benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 523.84 μmol, HOAc salt) in DMA (4 mL) were added N-benzyl-N,N-diethylethanaminium chloride (119.32 mg, 523.84 μmol), K2CO3 (1.88 g, 13.62 mmol), and 2-bromo-2-methylpropane (3.45 g, 25.14 mmol). The mixture was stirred at 55 °C for 18 h and then allowed to cool to room temperature. The reaction mixture was concentrated under vacuum, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by preparative TLC to give (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl. LCMS (ESI+): m / z = 569.3 (M+H) + . General Procedure S

Chemical formula

[0323] (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl. To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl (107 mg, 188.13 μmol) in i-PrOH (2 mL) was added Pd(OH)2 (26 mg) under an N2 atmosphere. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at room temperature for 15 h under H2 (15 psi). The mixture was filtered and concentrated under vacuum to afford (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl. LCMS (ESI+): m / z = 435.5 (M+H) + . 1 H NMR (400 MHz, CDCl3): δ ppm 7.06 (d, J = 7.34 Hz, 1 H) 6.34 (d, J = 7.34 Hz, 1 H) 4.98 (br s, 1 H) 3.38 - 3.44 (m, 4 H) 3.34 (s, 3 H) 2.69 (t, J = 6.30 Hz, 2 H) 2.51 - 2.59 (m, 5 H) 2.31 (dd, J = 13.39, 5.56 Hz, 1 H) 1.86 - 1.94 (m, 5 H) 1.49 - 1.69 (m, 6 H) 1.47 (s, 9 H) 1.13 (d, J = 6.11 Hz, 3 H). General procedure T

Chemical formula

[0324] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid tert-butyl. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl To a solution of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl (100 mg, 230.09 umol) and 2-chloro-5-methyl-pyrimidine (24.65 mg, 191.74 umol) in 2-methyl-2-butanol (2 mL) were added t-BuONa (2 M in THF, 191.74 uL) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.23 mg, 19.17 umol), and the resulting mixture was stirred at 100 °C for 14 h. The mixture was concentrated under vacuum to give (S)-4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid tert-butyl. LCMS (ESI+): m / z = 527.3 (M+H) + . General Procedure U

Chemical Structure

[0325] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. To a solution of tert-butyl (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate (80 mg, 151.89 μmol) in DCM (2 mL) was added TFA (254.14 mg, 2.23 mmol) at 0 °C. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated under vacuum and the resulting crude residue was purified by preparative HPLC to give the compound (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. LCMS (ESI+): m / z = 471.2 (M+H) + . 1 H NMR (400 MHz, methanol-d4) δ ppm 8.57 (br s, 2 H) 7.60 (d, J = 7.28 Hz, 1 H) 6.67 (d, J = 7.28 Hz, 1 H) 4.81 - 4.86 (m, 1 H) 3.86 (br s, 1 H) 3.41 - 3.59 (m, 4 H) 3.39 (s, 3 H) 3.33 - 3.38 (m, 1 H) 3.12 - 3.30 (m, 3 H) 2.76 - 2.86 (m, 4 H) 2.54 (br s, 1 H) 2.39 (br d, J = 8.82 Hz, 1 H) 2.30 (s, 3 H) 1.76 - 1.99 (m, 6 H) 1.22 (d, J = 5.95 Hz, 3 H). Further general procedures for preparing the compounds described herein are disclosed in U.S. Patent No. 10,793,564, which is hereby incorporated by reference in its entirety.

Example

[0326] Example 1 - Synthesis of Compounds 1 - 10 Compound 1: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with cyclopropylamine and Procedure H with 4-chloro-6-(difluoromethyl)pyrimidine. LCMS calculated m / z = 475.3. [M+H]+, found 475.2. Scheme 1, Compound 2: [Chemical Structure]

[0327] Step 1: 7-(4-(Cyclopropylamino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylic acid tert-butyl. A solution of cyclopropanamine (22.8 mL, 328.5 mmol), AcOH (18.8 mL, 328.5 mmol), and NaBH3CN (4.13 g, 65.7 mmol) in MeOH (100 mL) at 0 °C was added to a solution of 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylic acid tert-butyl (10.0 g, 32.9 mmol) in MeOH (100 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated NaHCO3, stirred until gas evolution ceased, and then concentrated in vacuo to remove volatiles. The aqueous layer was extracted with EtOAc, the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the title compound. LCMS calculated m / z = 346.3. [M+H]+, found 346.5.

[0328] Step 2: N-(4-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)butyl)cyclopropanamine. To a solution of tert-butyl 7-(4-(cyclopropylamino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (2.5 g, 7.24 mmol) in EtOAc (10 mL) was added 4M HCl in EtOAc (1.8 mL), and the resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The crude residue was used without further purification. LCMS calculated m / z = 246.2. [M+H]+, found 246.0.

[0329] Step 3: Methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a mixture of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (2.59 g, 9.8 mmol) and N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)cyclopropanamine hydrochloride (2.5 g, 8.9 mmol) in DCE (40 mL) was added AcOH (761 μL, 13.3 mmol) at 0 °C, then NaBH(OAc)3 (2.82 g, 13.3 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 and stirred until gas evolution ceased, then extracted with CH2Cl2. The combined organic extracts were washed with brine, then dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by normal-phase silica gel chromatography to afford the title compound. LCMS calculated m / z = 495.3. [M+H]+, found 495.4.

[0330] Step 4: (S)-2-(((Benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (4 g, 7.9 mmol) in 1:1:1 THF / MeOH / H2O (36 mL) was added LiOH·H2O (664 mg, 15.8 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. The mixture was then adjusted to pH = 6 by carefully adding 1N HCl and then concentrated under vacuum to afford the title compound. LCMS calculated m / z = 480.3 [M]+, found 480.1.

[0331] Step 5: (S)-2-Amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a flask containing (S)-2-(((benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (4.5 g, 9.4 mmol) was added 20 wt% Pd(OH)2 / C (4.5 g), then diluted with i-PrOH (300 mL), and stirred at room temperature for 48 h under a H2 atmosphere of 50 psi. The reaction mixture was filtered through a pad of CELITE® and rinsed with MeOH and then concentrated under vacuum. The crude residue was purified by reverse phase preparative HPLC to afford the title compound. LCMS calculated m / z = 347.2. [M+H]+, found 347.2.

[0332] Step 6: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid trifluoroacetate (150 mg, 0.3 mmol) in 4:1 THF / H2O (3 mL) were added 5-bromo-4-chloro-pyrimidine (69 mg, 0.4 mmol) and NaHCO3 (137 mg, 1.63 mmol), then the mixture was stirred at 70 °C for 2 h, then allowed to cool to room temperature and concentrated in vacuo. The crude residue was used without further purification.

[0333] Step 7: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid. To a flask containing (S)-2-((5-bromopyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (157 mg, 0.3 mmol) was added 20 wt% Pd / C (200 mg), then the mixture was diluted with MeOH (20 mL), and the resulting mixture was stirred at room temperature for 4 h under a H2 atmosphere, then filtered and concentrated in vacuo. The crude residue was purified by reverse-phase preparative HPLC to give the title compound. LCMS (ESI+): m / z = 425.2 (M+H) + . 11H NMR (400 MHz, methanol-d4): δ ppm 8.34 (s, 1 H) 7.96 (br s, 1 H) 7.18 (d, J = 7.21 Hz, 1 H) 6.52 (br s, 1 H) 6.39 (d, J = 7.21 Hz, 1 H) 3.87 - 4.65 (m, 1 H) 3.34 - 3.42 (m, 2 H) 2.76 - 2.96 (m, 2 H) 2.70 (br t, J = 6.11 Hz, 4 H) 2.54 (br t, J = 7.03 Hz, 2 H) 2.14 - 2.26 (m, 1 H) 1.96 - 2.08 (m, 1 H) 1.87 (q, J = 5.87 Hz, 3 H) 1.62 (br d, J = 4.40 Hz, 4 H) 0.37 - 0.59 (m, 4 H). LCMS calculated m / z = 425.3. [M+H]+, found 425.2.

[0334] Compound 3: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid. A mixture of (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (170 mg, 0.4 mmol) in 4:1 THF / H2O (2.5 mL) was treated with 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (75 mg, 0.4 mmol) and NaHCO3 (112 mg, 1.33 mmol), and the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting crude residue was purified by reverse-phase preparative HPLC to afford the title compound as the trifluoroacetate salt. 11H NMR (400 MHz, D2O): δ ppm 8.32 - 8.47 (m, 2 H) 7.51 (br d, J=6.60 Hz, 1 H) 6.56 (br s, 1 H) 4.85 (br s, 1 H) 4.03 (br s, 3 H) 3.29 - 3.63 (m, 6 H) 2.38 - 2.91 (m, 7 H) 1.64 - 1.95 (m, 6 H) 0.90 - 1.09 (m, 4 H). LCMS calculated value m / z = 479.3. [M+H]+, measured value 479.2.

[0335] Compound 4: (S)-4-((2-Hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid. Prepared according to Scheme A using procedure A with 1-amino-2-methylpropan-2-ol, procedure H with 4-chloropyrimidine, and procedure P. LCMS calculated value m / z = 457.3. [M+H]+, measured value 457.2.

[0336] Compound 5: (S)-4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using procedure A with 2-methoxyethan-1-amine, procedure H with 4-chloroquinazoline, and procedure P. LCMS calculated value m / z = 493.1. [M+H]+, measured value 493.1.

[0337] Compound 6: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using procedure A with cyclopropylamine, procedure H with 4-chloroquinazoline, and procedure P. LCMS calculated value m / z = 475.3. [M+H]+, measured value 475.3.

[0338] Compound 7: (S)-2-((7-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-7-fluoroquinazoline, and Procedure P. LCMS calculated m / z = 511.3. [M+H]+, found 511.3.

[0339] Compound 8: (S)-4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 2,2-difluoroethan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS calculated m / z = 499.3. [M+H]+, found 499.3.

[0340] Compound 9: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 3,3-difluorocyclobutan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS calculated m / z = 523.3. [M+H]+, found 525.3.

[0341] Compound 10: (S)-4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-2-methylquinazoline, and Procedure P. LCMS calculated m / z = 507.3. [M+H]+, found 507.3.

[0342] Example 2 - Preparation of a formulation containing Compound 5 Compound 5 was dissolved in absolute ethanol to a concentration of 95 - 105 mg / mL. Silicon dioxide was placed in a fluidized bed dryer and while fluidizing, the ethanol solution of Compound 5 was sprayed onto the solid particles. Drying was continued until the weight loss on drying was 2% or less. The obtained pharmaceutical intermediate of Compound 5 (50 - 70 w / w%, preferably 60 w / w%) was put into a foil pouch together with a desiccant, sealed, and stored for further use.

[0343] A pharmaceutical intermediate of Compound 5, mannitol (5 - 50 w / w% of the batch size, preferably 25 w / w%), and croscarmellose sodium (1 - 10 w / w% of the batch size, preferably 5 w / w%) were blended. The obtained in - granule blend was transferred to a roller compactor and compressed into granules. The granules were blended with magnesium stearate (0.1 - 5 w / w% of the batch size, preferably 1 w / w%), and the final blend was transferred to a foil pouch containing a desiccant, sealed, and stored for later use.

[0344] Using a tab...

Claims

1. A substantially non-deliquescent formulation comprising a hygroscopic or deliquescent component and one or more excipients or coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) 【Chemical Formula 1】 or a salt thereof, wherein (in the formula), R １ is C ６ -C １４ aryl or 5- to 10-membered heteroaryl, where the C ６ -C １４ aryl and 5- to 10-membered heteroaryl are optionally substituted by R １ａ ; R ２ is hydrogen; deuterium; C ２ａ -C １ alkyl optionally substituted by R ６ ; -OH; -O-C ２ａ -C １ alkyl optionally substituted by R ６ ; C ２ｂ -C ３ cycloalkyl optionally substituted by R ６ ; -O-C ２ｂ -C ３ cycloalkyl optionally substituted by R ６ ; 3- to 12-membered heterocyclyl optionally substituted by R ２ｃ ; or -S(O) ２ R ２ｄ provided that any carbon atom directly bonded to a nitrogen atom is optionally substituted by an R ２ａ moiety other than halogen; Each R １ａ is independently C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ８ cycloalkyl, C ４ -C ８Cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６ -C １４ Aryl, deuterium, halogen, -CN, -OR ３ -SR ３ -NR ４ R ５ -NO ２ -C=NH(OR ３ ), -C(O)R ３ -OC(O)R ３ -C(O)OR ３ -C(O)NR ４ R ５ -NR ３ C(O)R ４ -NR ３ C(O)OR ４ -NR ３ C(O)NR ４ R ５ -S(O)R ３ -S(O) ２ R ３ -NR ３ S(O)R ４ -NR ３ S(O) ２ R ４ -S(O)NR ４ R ５ -S(O) ２ NR ４ R ５ 、 or -P(O)(OR ４ )(OR ５ ), where each R １ａ is, when possible, independently deuterium, halogen, oxo, -OR ６ 、 -NR ６ R ７ 、 -C(O)R ６ 、 -CN, -S(O)R ６ 、 -S(O) ２ R ６ 、 -P(O)(OR ６ )(OR ７ ), C ３ -C ８ Cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６ -C １４Aryl, or C optionally substituted by deuterium, oxo, -OH or halogen １ -C ６ optionally substituted by alkyl, each R ２ａ , R ２ｂ , R ２ｃ , R ２ｅ , and R ２ｆ is independently oxo or R １ａ , R ２ｄ is C optionally substituted by R ２ｅ -C １ -C ６ alkyl or C optionally substituted by R ２ｆ -C ３ -C ５ cycloalkyl, R ３ is independently hydrogen, deuterium, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, where the C of R ３ -C １ -C １０ alkyl, C ２ -C １２ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl are independently halogen, deuterium, oxo, -CN, -OR ８ , -NR ８ R ９ , -P(O)(OR ８ )(OR ９ ), or C optionally substituted by deuterium, halogen, -OH or oxo １ -C ６ optionally substituted by alkyl, R ４ and R ５ are each independently hydrogen, deuterium, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, where the C ４ and R ５ of said C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently deuterium, halogen, oxo, -CN, -OR ８ , -NR ８ R ９ , or optionally substituted by deuterium, halogen, -OH or oxo C １ -C ６ alkyl optionally substituted by, or, R ４ and R ５ together with the atom to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR ８ , -NR ８ R ９ , or optionally substituted by deuterium, halogen, oxo or -OH C １ -C ６ alkyl, R ６ and R ７is, independently of each other, hydrogen; deuterium; C optionally substituted by deuterium, halogen, or oxo １ -C ６ alkyl; C optionally substituted by deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by deuterium, halogen, or oxo ２ -C ６ alkynyl, or alternatively, R ６ and R ７ together with the atom to which they are attached, form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C optionally substituted by deuterium, halogen, or oxo １ -C ６ alkyl, and R ８ and R ９ are, independently of each other, hydrogen; deuterium; C optionally substituted by deuterium, halogen, or oxo １ -C ６ alkyl; C optionally substituted by deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by deuterium, halogen, or oxo ２ -C ６ alkynyl, or alternatively, R ８ and R ９ together with the atom to which they are attached, form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C optionally substituted by deuterium, oxo, or halogen １ -C ６ alkyl, and each R １０ 、R １１ 、R １２ and R １３ is independently hydrogen or deuterium, and R １４ is deuterium, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, and each R １５ is independently selected from hydrogen, deuterium, or a halogen, each R １６ is independently selected from hydrogen, deuterium, or a halogen, p is 3, 4, 5, 6, 7, 8, or 9). **Claim 2** R ２ is optionally substituted by R ２ａ to form C １ -C ６ alkyl; R ２ｂ is optionally substituted by R ３ to form C ６ cycloalkyl; R ２ｃ is optionally substituted by R ２ to form a 3- to 12-membered heterocyclyl; or -S(O) ２ｄ R R ３ is independently hydrogen, deuterium, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, a 5- to 6-membered heteroaryl or a 3- to 6-membered heterocyclyl, where the C ３ of said R １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently halogen, deuterium, oxo, -CN, -OR ８ , -NR ８ R ９ , -P(O)(OR ８ )(OR ９ ), or C optionally substituted by deuterium, halogen, -OH or oxo １ -C ６ optionally substituted by alkyl, each R １５ is hydrogen, each R １６ is hydrogen, the compound of formula (A) is of formula (I): [Chemical Formula 2] The formulation according to claim 1, represented by

3. R １０ 、R １１ 、R １２ 、and R １３ are hydrogen, p is 3, q is 0, and the compound of formula (A) is of formula (II): [Chemical Formula 3] The formulation according to claim 1 or claim 2, represented by

4. The compound of formula (A) is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid: [Chemical Formula 4] The formulation according to claim 1, which is

5. The formulation according to any one of claims 1 to 4, wherein the composition comprises one or more hygroscopic excipients and a moisture-proof coating.

6. The preparation according to any one of claims 1 to 5, wherein the one or more hygroscopic excipients include sorbitol, citric acid, sodium carboxymethylcellulose, polyvinylpolypyrrolidone, polyethylene glycol, polyglycolized glyceride, α-starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, magnesium aluminum silicate, calcium carbonate, cyclodextrin, or carbomer.

7. The preparation according to any one of claims 1 to 6, wherein the hygroscopic or deliquescent component is supported on a solid support.

8. The preparation according to claim 7, wherein the solid support is silicon dioxide.

9. The preparation according to any one of claims 1 to 8, wherein the composition includes one or more moisture-proof coatings.

10. The preparation according to any one of claims 1 to 9, wherein the one or more moisture-proof coatings include polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol-polyethylene glycol copolymer, copolymer dispersion of methyl methacrylate and diethylamino-ethyl methacrylate, hydroxypropylcellulose, polyvinyl acetate, ethylcellulose, cellulose acetate, ammonium methacrylate, ammonium methacrylate copolymer, poly(ethyl acrylate-co-methyl methacrylate), shellac, cellulose acetate phthalate, cellulose acetate butyrate, methacrylic acid copolymer, aminodiethyl-methacrylate copolymer, acrylic acid copolymer, sodium alginate, and carboxymethylcellulose.

11. (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; Mannitol; Croscarmellose; Magnesium stearate; and a polyethylene glycol - polyvinyl alcohol copolymer The preparation according to any one of claims 1 to 10, comprising Claim 12 (S)-4-(((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; about 5 to 50 w / w% mannitol; about 1 to 10 w / w% croscarmellose; about 0.1 to 5 w / w% magnesium stearate; and about 3 to 5% polyethylene glycol-polyvinyl alcohol copolymer A formulation according to any one of claims 11, comprising: Claim 13 The formulation according to any one of claims 1 to 12, wherein the formulation is a tablet. Claim 14 The formulation according to any one of claims 1 to 13, wherein the formulation is a tablet in a tablet formulation. Claim 15 The formulation according to any one of claims 1 to 14, wherein the formulation is packaged in a moisture-proof package. Claim 16 The formulation according to claim 15, wherein the moisture-proof package is an HDPE bottle. Claim 17 The formulation according to claim 15, wherein the moisture-proof package is a moisture-proof blister package. Claim 18 The formulation according to any one of claims 15 to 17, wherein the package contains a desiccant. Claim 19 A method for preparing a formulation containing a hygroscopic or deliquescent component, the method comprising at least one of the following: (i) mixing the hygroscopic or deliquescent component with one or more excipients, and / or (ii) coating the hygroscopic or deliquescent component with one or more moisture-proof coatings, wherein the hygroscopic or deliquescent component is a compound of formula (A) [Chemical Formula 5] (wherein R １ is C ６ - C １４ aryl or 5- to 10-membered heteroaryl, wherein the C ６ - C １４ aryl and 5- to 10-membered heteroaryl are optionally substituted by R １ａ ; R ２ is hydrogen; deuterium; C ２ａ optionally substituted by R １ - C ６ alkyl; -OH; -O-C ２ａ optionally substituted by R １ - C ６ alkyl; C ２ｂ optionally substituted by R ３ - C ６ cycloalkyl; C ２ｂ optionally substituted by R ３ - C ６ cycloalkyl; 3- to 12-membered heterocyclyl optionally substituted by R ２ｃ ; or -S(O) ２ R ２ｄ provided that any carbon atom directly bonded to a nitrogen atom is optionally substituted by an R ２ａ moiety other than halogen; each R １ａ is independently C １ - C ６ alkyl, C ２ - C ６ alkenyl, C ２ - C ６ alkynyl, C ３ - C ８ cycloalkyl, C ４ - C ８ cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６-C １４ aryl, deuterium, halogen, -CN, -OR ３ , -SR ３ , -NR ４ R ５ , -NO ２ , -C=NH(OR ３ ), -C(O)R ３ , -OC(O)R ３ , -C(O)OR ３ , -C(O)NR ４ R ５ , -NR ３ C(O)R ４ , -NR ３ C(O)OR ４ , -NR ３ C(O)NR ４ R ５ , -S(O)R ３ , -S(O) ２ R ３ , -NR ３ S(O)R ４ , -NR ３ S(O) ２ R ４ , -S(O)NR ４ R ５ , -S(O) ２ NR ４ R ５ , or -P(O)(OR ４ )(OR ５ ), where each R １ａ , when possible, is independently deuterium, halogen, oxo, -OR ６ , -NR ６ R ７ , -C(O)R ６ , -CN, -S(O)R ６ , -S(O) ２ R ６ , -P(O)(OR ６ )(OR ７ ), C ３ -C ８ cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６ -C １４ aryl, or C １ -C ６Optionally substituted by alkyl, each R ２ａ , R ２ｂ , R ２ｃ , R ２ｅ , and R ２ｆ is independently oxo or R １ａ and R ２ｄ is C ２ｅ optionally substituted by R １ -C ６ alkyl or C ２ｆ optionally substituted by R ３ -C ５ cycloalkyl, R ３ is independently hydrogen, deuterium, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, where the C ３ of R １ -C １０ alkyl, C ２ -C １２ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are independently halogen, deuterium, oxo, -CN, -OR ８ , -NR ８ R ９ , -P(O)(OR ８ )(OR ９ ), or C １ -C ６ optionally substituted by deuterium, halogen, -OH or oxo and alkyl, R ４ and R ５ each independently is hydrogen, deuterium, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, where the C ４ of R ５ and R １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each independently deuterium, halogen, oxo, -CN, -OR ８ , -NR ８ R ９ , or C １ -C ６ alkyl optionally substituted by deuterium, halogen, -OH or oxo, or alternatively, R ４ and R ５ together with the atom to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR ８ , -NR ８ R ９ , or C １ -C ６ alkyl optionally substituted by deuterium, halogen, oxo or -OH, and R ６ and R ７ each independently is hydrogen; deuterium; C １ -C ６ Alkyl; C optionally substituted by deuterium, halogen, or oxo ２ -C ６ Alkenyl; or C optionally substituted by deuterium, halogen, or oxo ２ -C ６ is alkynyl, or, R ６ and R ７ together with the atom to which they are attached, form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C １ -C ６ alkyl optionally substituted by deuterium, halogen, or oxo, R ８ and R ９ are each independently hydrogen; deuterium; C optionally substituted by deuterium, halogen, or oxo １ -C ６ alkyl; C optionally substituted by deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by deuterium, halogen, or oxo ２ -C ６ is alkynyl, or, R ８ and R ９ together with the atom to which they are attached, form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C １ -C ６ alkyl optionally substituted by deuterium, oxo, or halogen, each R １０ 、R １１ 、R １２ and R １３ is independently hydrogen or deuterium, R １４ is deuterium, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, each R １５is independently selected from hydrogen, deuterium, or a halogen, each R １６ is independently selected from hydrogen, deuterium, or a halogen, and p is 3, 4, 5, 6, 7, 8, or 9), said method.

20. R ２ is optionally substituted C ２ａ -C １ -C ６ alkyl; R ２ｂ is optionally substituted C ３ -C ６ cycloalkyl; R ２ｃ is optionally substituted 3- to 12-membered heterocyclyl; or -S(O) ２ R ２ｄ is, R ３ is independently hydrogen, deuterium, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, where the C ３ of R １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ６ -C １４ aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently halogen, deuterium, oxo, -CN, -OR ８ -, -NR ８ R ９ -, -P(O)(OR ８ )(OR ９), or C optionally substituted by deuterium, halogen, -OH or oxo １ -C ６ optionally substituted by alkyl, each R １５ is hydrogen, each R １６ is hydrogen, the compound of formula (A) is of formula (I): 【Chemical Formula 6】 represented by, the method according to claim 19.

21. R １０ 、R １１ 、R １２ 、and R １３ are hydrogen, p is 3, q is 0, and the compound of formula (A) is of formula (II): 【Chemical Formula 7】 represented by, the method according to claim 19 or claim 20.

22. the compound of formula (A) is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid: 【Chemical Formula 8】 is, the method according to claim 21.

23. the method includes supporting the hygroscopic or deliquescent component on a solid support, the method according to any one of claims 19 to 22.

24. the solid support is silicon dioxide, the method according to claim 23.

25. the method includes formulating the hygroscopic or deliquescent component together with one or more excipients, the method according to any one of claims 19 to 24.

26. The method according to any one of claims 19 to 25, wherein the method comprises formulating the hygroscopic or deliquescent component together with one or more hygroscopic excipients. **Claim 27** The method according to any one of claims 19 to 26, wherein the one or more hygroscopic excipients include sorbitol, citric acid, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, polyethylene glycol, polyglycolized glyceride, alpha starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, magnesium aluminum silicate, calcium carbonate, cyclodextrin, or carbomer. **Claim 28** The method according to any one of claims 19 to 27, wherein the method comprises coating the hygroscopic or deliquescent component with one or more moisture-proof coatings. **Claim 29** The method according to any one of claims 19 to 28, wherein the one or more moisture-proof coatings include polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol - polyethylene glycol copolymer, copolymer dispersion of methyl methacrylate and diethylamino - ethyl methacrylate, hydroxypropyl cellulose, polyvinyl acetate, ethyl cellulose, cellulose acetate, ammonio methacrylate, ammonio methacrylate copolymer, poly(ethyl acrylate - co - methyl methacrylate), shellac, cellulose acetate phthalate, cellulose acetate butyrate, methacrylic acid copolymer, aminodiethyl - methacrylate copolymer, acrylic acid copolymer, sodium alginate, and carboxymethyl cellulose. **Claim 30** The method according to any one of claims 19 to 29, wherein the method comprises tableting the hygroscopic or deliquescent component using a dry granulation process.

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