Forms and compositions of beta adrenergic agonists

Abstract

The present disclosure relates generally to various forms and compositions useful as beta adrenergic agonists and the use of the various forms and compositions in the treatment of diseases associated with adrenergic receptors. In one aspect, the present disclosure provides: crystalline solid forms of Compound 1 selected from Form A and Form B; and salt forms of Compound 1.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 034,900, filed June 4, 2020. The disclosure of the prior application is considered part of the disclosure of this application and is hereby incorporated by reference into the disclosure of this application. TECHNICAL FIELD

[0003] The present disclosure relates generally to various forms and compositions useful as beta adrenergic agonists and the use of the various forms and compositions in the treatment of diseases associated with adrenergic receptors. BACKGROUND

[0004] PCT Application Publication No. WO 2017 / 197324 discloses “[a] method of treating a subject having a disease or condition associated with an adrenergic receptor, the method comprising administering a therapeutically effective amount of a subject compound.”

[0005] U.S. Patent Application Publication No. 2013 / 0096126 discloses “A method of enhancing learning or memory, or both, in a mammal having a neurodegenerative disorder, the method involving the step of administering at least one compound or salt thereof, the compound or salt thereof being a beta 1 -adrenergic receptor agonist, partial agonist, or receptor ligand in an amount effective to improve learning or memory, or both, in the mammal.”

[0006] U.S. Patent Application Publication No. 2014 / 0235726 discloses “A method of improving cognition in a patient with Down syndrome, the method involving administering to the patient one or more beta 2 adrenergic receptor agonists in an amount and frequency effective to improve cognition in the patient as measured by a contextual learning test.”

[0007] U.S. Patent Application Publication No. 2016 / 0184241 discloses “A method of improving cognition in a patient with Down syndrome, the method involving intranasally administering to the patient one or more beta 2-ADR agonists or a pharmaceutically acceptable salt of either or both in an amount and frequency effective to improve cognition in the patient as measured by a contextual learning test.” SUMMARY

[0008] It has now been discovered that the novel forms of the present disclosure and compositions thereof are useful as beta adrenergic agonists and exhibit desirable properties with respect thereto. In general, the salt forms or free base forms and pharmaceutically acceptable compositions thereof are useful in treating or lessening the severity of a variety of diseases or disorders as described in detail herein. BRIEF DESCRIPTION OF DRAWINGS

[0009] Figure 1A.1 An XRPD pattern of Form A of Compound 1 is depicted.

[0010] Figure 1A.2 A DSC thermogram and TGA trace of Form A of Compound 1 are depicted.

[0011] Figure 1A.3 A DVS plot of Form A of Compound 1 is depicted. 1 H NMR spectrum.

[0012] Figure 1B.1 An XRPD pattern of Form B of Compound 1 is depicted.

[0013] Figure 1B.2 A DSC thermogram and TGA trace of Form B of Compound 1 are depicted.

[0014] Figure 1B.3 A DVS plot of Form B of Compound 1 is depicted. 1 H NMR spectrum.

[0015] Figure 2A.1 An XRPD pattern of Form A of Compound 2 is depicted.

[0016] Figure 2A.2 A DSC thermogram and TGA trace of Form A of Compound 2 are depicted.

[0017] Figure 2A.3 and 2A.4 A DVS plot of Form A of Compound 2 is depicted.

[0018] Figure 3A.1 An XRPD pattern of Form A of Compound 3 is depicted.

[0019] Figure 3A.2 A DSC thermogram and TGA trace of Form A of Compound 3 are depicted.

[0020] Figure 4A.1 An XRPD pattern of Form A of Compound 4 is depicted.

[0021] Figure 4A.2 A DSC thermogram and TGA trace of Form A of Compound 4 are depicted.

[0022] Figure 5A.1 An XRPD pattern of Form A of Compound 5 is depicted.

[0023] Figure 5A.2 A DSC thermogram and TGA trace of Form A of Compound 5 are depicted.

[0024] Figure 5A.3FIG. 1 depicts an XRPD pattern of Form A of compound 5. 1 H NMR spectrum.

[0025] Figure 5A.4 and 5A.5 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0026] Figure 6A.1 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0027] Figure 6A.2 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0028] Figure 6A.3 FIG. 1 depicts an XRPD pattern of Form A of compound 5. 1 H NMR spectrum.

[0029] Figure 7A.1 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0030] Figure 7A.2 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0031] Figure 7A.3 FIG. 1 depicts an XRPD pattern of Form A of compound 5. 1 H NMR spectrum.

[0032] Figure 8A.1 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0033] Figure 8A.2 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0034] Figure 8A.3 FIG. 1 depicts an XRPD pattern of Form A of compound 5. 1 H NMR spectrum.

[0035] Figure 9A.1 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0036] Figure 9A.2 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0037] Figure 9A.3 FIG. 1 depicts an XRPD pattern of Form A of compound 5. 1 H NMR spectrum.

[0038] Figure 9A.4 and 9A.5 FIG. 1 depicts an XRPD pattern of Form A of compound 5.

[0039] Figure 10A.1 An XRPD pattern of Form A of Compound 10 is depicted.

[0040] Figure 10A.2 A DSC thermogram and TGA trace of Form A of Compound 10 are depicted.

[0041] Figure 10A.3 A DSC thermogram and TGA trace of Form A of Compound 10 are depicted. 1 H NMR spectrum.

[0042] Figure 11A.1 An XRPD pattern of Form A of Compound 11 is depicted.

[0043] Figure 11A.2 A DSC thermogram and TGA trace of Form A of Compound 11 are depicted.

[0044] Figure 11A.3 A DSC thermogram and TGA trace of Form A of Compound 11 are depicted. 1 H NMR spectrum.

[0045] Figure 12A.1 An XRPD pattern of Form A of Compound 12 is depicted.

[0046] Figure 12A.2 A DSC thermogram and TGA trace of Form A of Compound 12 are depicted.

[0047] Figure 13A.1 An XRPD pattern of Form A of Compound 13 is depicted.

[0048] Figure 13A.2 A DSC thermogram and TGA trace of Form A of Compound 13 are depicted.

[0049] Figure 13A.3 A DSC thermogram and TGA trace of Form A of Compound 13 are depicted. 1 H NMR spectrum.

[0050] Figure 14A.1 An XRPD pattern of Form A of Compound 14 is depicted.

[0051] Figure 14A.2 A DSC thermogram and TGA trace of Form A of Compound 14 are depicted.

[0052] Figure 14A.3 A DSC thermogram and TGA trace of Form A of Compound 14 are depicted. 1 H NMR spectrum. DETAILED DESCRIPTION

[0053] General Description of Certain Aspects of the Invention:

[0054] The present disclosure is based, at least in part, on the identification of compounds that modulate adrenergic receptors and methods of using the compounds to treat diseases associated with adrenergic receptors. Disclosed herein is Compound 1:

[0055]

[0056] Compound 1, (S)-6-(2-(tert-butylamino)-l-hydroxyethyl)picolinitrile, has activity in a variety of assays and therapeutic models as a low concentration partial agonist of the β2 adrenergic receptor. It has further been discovered that Compound 1 exhibits an unexpected high ability to cross the blood-brain barrier and accumulate in cerebrospinal fluid.

[0057] It is desirable to provide solid forms of Compound 1 (e.g., as its free base or salts thereof) that impart properties such as improved aqueous solubility, stability, and ease of formulation. Accordingly, the present disclosure provides both free base and salt forms of Compound 1.

[0058] Free base forms of Compound 1

[0059] It is contemplated that Compound 1 can exist in a variety of physical forms. For example, Compound 1 can be in solution, suspension, or solid form. In certain embodiments, Compound 1 is in solid form. When Compound 1 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0060] In some embodiments, the present disclosure provides a certain form of Compound 1 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of extraneous materials. Such extraneous materials can include different forms of Compound 1, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 1. In certain embodiments, at least about 95% by weight of a certain form of Compound 1 is present. In still other embodiments of the present disclosure, at least about 99% by weight of a certain form of Compound 1 is present.

[0061] According to one embodiment, a certain form of Compound 1 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, wherein the percent is based on the total weight of the composition. According to another embodiment, a certain form of Compound 1 contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, a certain form of Compound 1 contains no more than about 1.0 area percent of any single impurity by HPLC, no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0062] The structure of a certain form of Compound 1 depicted also is meant to include all tautomeric forms of Compound 1. Additionally, the structure depicted herein is also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H) can be substituted for the protium (1H) present in the structures of the present application. All such isotopologues are within the scope of the present disclosure. 13 C or 14 Compounds having the structure of the present application except for the substitution of deuterium or tritium for a protium or carbon enrichment carbon are within the scope of the present disclosure.

[0063] It has been found that Compound 1 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0064] As used herein, the term "polymorph" refers to different crystal structures in which a compound or salt or solvate thereof can crystallize.

[0065] In certain embodiments, Compound 1 is a crystalline solid. In other embodiments, Compound 1 is a crystalline solid substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound contains no significant amount of amorphous Compound 1. In certain embodiments, at least about 95% by weight of the crystalline Compound 1 is present. In still other embodiments of the disclosure, at least about 99% by weight of the crystalline Compound 1 is present.

[0066] It has been found that free base Compound 1 can exist in at least two different polymorphic forms. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, which is referred to herein as Form A. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, which is referred to herein as Form B.

[0067] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1.

[0068] Form A of Compound 1

[0069] In some embodiments, Form A of Compound 1 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 1 below.

[0070] Table 1 - XRPD Peak Positions for Form A of Compound 1

[0071] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.5 3.1 23.5 11.8 9.3 100.0 23.9 3.3 9.7 15.8 25.1 23.1 10.2 7.0 25.6 6.4 11.5 1.4 25.9 3.7 12.6 20.0 26.2 1.7 13.0 1.5 27.5 1.6 14.7 2.6 28.3 11.4 15.3 1.5 29.1 3.9 15.7 3.5 29.6 6.0 16.4 12.8 30.7 2.4 16.9 21.7 31.1 2.2 17.5 8.6 32.5 1.1 18.8 20.0 32.9 1.2 19.3 1.9 34.3 2.8 20.0 2.0 35.6 0.8 20.6 47.0 36.2 1.2 21.7 1.7 37.2 2.0 22.0 2.5 38.1 1.6 22.5 6.2 38.6 0.9

[0072] In this table and all subsequent tables, the positions (°2q) are within ±0.2.

[0073] In some embodiments, Form A of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3 degrees, about 12.6 degrees, about 16.9 degrees, about 18.8 degrees, about 20.6 degrees, and about 25.1 degrees 2q. In some embodiments, Form A of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3 degrees, about 12.6 degrees, about 16.9 degrees, about 18.8 degrees, about 20.6 degrees, and about 25.1 degrees 2q. In some embodiments, Form A of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3 degrees, about 12.6 degrees, about 16.9 degrees, about 18.8 degrees, about 20.6 degrees, and about 25.1 degrees 2q. In some embodiments, Form A of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3 degrees, about 12.6 degrees, about 16.9 degrees, about 18.8 degrees, about 20.6 degrees, and about 25.1 degrees 2q. In some embodiments, Form A of Compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3 degrees, about 12.6 degrees, about 16.9 degrees, about 18.8 degrees, about 20.6 degrees, and about 25.1 degrees 2q. In some embodiments, Form A of Compound 1 is characterized by six peaks in its X-ray powder diffraction pattern at about 9.3 degrees, about 12.6 degrees, about 16.9 degrees, about 18.8 degrees, about 20.6 degrees, and about 25.1 degrees 2q. As used herein, the term“about,” when used in reference to a degree 2q value, means the stated value ± 0.2 degrees 2q.

[0074] In some embodiments, Form A of compound 1 is characterized by each of the spectral peaks listed in Table 1 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 1A.1 the XRPD provided in Table 1.

[0075] Methods for preparing Form A of compound 1 are described hereinafter.

[0076] Form B of compound 1

[0077] In some embodiments, Form B of compound 1 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 2 below.

[0078] Table 2 - XRPD peak positions for Form B of compound 1

[0079] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.9 6.7 23.9 18.3 9.3 100.0 24.1 10.8 9.6 23.7 25.0 37.7 10.6 12.0 25.4 7.3 12.6 25.2 25.9 7.3 14.7 7.3 27.4 3.8 15.7 8.2 28.4 18.6 16.4 22.3 29.1 9.8 16.9 56.5 29.6 11.6 17.5 13.0 30.6 6.8 18.1 5.0 31.6 3.6 18.8 34.2 32.4 3.9 19.3 9.5 34.3 7.0 19.9 6.8 36.1 3.6 20.6 68.2 37.3 4.9 22.0 6.6 38.3 5.0 22.4 18.3 38.5 4.4 23.5 24.3

[0080] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0081] In some embodiments, Form B of compound 1 is characterized by one or more peaks in its X- ray powder diffraction pattern selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2Q. In some embodiments, Form B of compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2Q. In some embodiments, Form B of compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2Q. In some embodiments, Form B of compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2Q. In some embodiments, Form B of compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2Q. In some embodiments, Form B of compound 1 is characterized by six peaks in its X-ray powder diffraction pattern at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2Q.

[0082] In some embodiments, Form B of compound 1 is characterized by each of the spectral peaks listed in Table 2 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%.

[0083] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1B.1 Table 1.

[0084] Methods for preparing Form B of compound 1 are described hereinafter.

[0085] In some embodiments, the present disclosure provides compound 1:

[0086]

[0087] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 1, wherein the compound is substantially free of amorphous compound 1.

[0088] In some embodiments, the present disclosure provides Compound 1, wherein the compound is substantially free of impurities.

[0089] In some embodiments, the present disclosure provides Compound 1, wherein the compound has one or more peaks in its XRPD selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 1, wherein the compound has at least two peaks in its XRPD selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 1, wherein the compound is Form A.

[0090] In some embodiments, the present disclosure provides Compound 1, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 1. Figure 1A.1 In some embodiments, the present disclosure provides Compound 1, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 1.

[0091] In some embodiments, the present disclosure provides Compound 1, wherein the compound has one or more peaks in its XRPD selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 1, wherein the compound has at least two peaks in its XRPD selected from those at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 1, wherein the compound is Form A.

[0092] In some embodiments, Form B of Compound 1 is characterized by having each of the spectral peaks listed in Table 2 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In some embodiments, the present disclosure provides Compound 1, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 2. Figure 1B.1 In some embodiments, the present disclosure provides Compound 1, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 2.

[0093] In some embodiments, the present disclosure provides a composition comprising Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0094] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient Compound 1 or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0095] In some embodiments, the present disclosure provides a method of treating a disease or disorder mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, the method comprising administering to the patient Compound 1 or a composition thereof.

[0096] Salt forms of Compound 1

[0097] In some embodiments, an acid and Compound 1 are bonded to form one of Compounds 2-14, described below. It is contemplated that Compounds 2-14 can exist in a variety of physical forms. For example, Compounds 2-14 can be in solution, suspension, or solid form. In certain embodiments, Compounds 2-14 are in solid form. When Compounds 2-14 are in solid form, the compounds can be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of Compounds 2-14 are described in more detail below.

[0098] Compound 2 (hydrochloride salt of Compound 1)

[0099] According to one embodiment, the present disclosure provides a hydrochloride salt of Compound 1, which is represented by Compound 2:

[0100]

[0101] It will be appreciated by one of ordinary skill in the art that an acid and Compound 1 are bonded to form Compound 2. It is contemplated that Compound 2 can exist in a variety of physical forms. For example, Compound 2 can be in solution, suspension, or solid form. In certain embodiments, Compound 2 is in solid form. When Compound 2 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0102] In some embodiments, the present disclosure provides Compound 2 in a certain form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous materials. Such extraneous materials can include different forms of Compound 2, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 2. In certain embodiments, at least about 95% by weight of Compound 2 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 2 in a certain form is present.

[0103] According to one embodiment, a certain form of Compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, wherein the percent is based on the total weight of the composition. According to another embodiment, a certain form of Compound 2 contains no more than about 3.0 area percent of total organic impurities by HPLC relative to the total area of the HPLC chromatogram, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC. In other embodiments, a certain form of Compound 2 contains no more than about 1.0 area percent of any single impurity by HPLC relative to the total area of the HPLC chromatogram; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC.

[0104] The structure of a certain form of Compound 2 depicted also is meant to include all tautomeric forms of Compound 2. Additionally, the structure depicted herein is also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium or tritium in place of hydrogen or carbon enriched in carbon- 13 in place of carbon are within the scope of this disclosure. 13 C or 14 Compounds having the structure of this invention except for hydrogen replaced by deuterium or tritium or carbon replaced by carbon- 13 are within the scope of this disclosure.

[0105] It has been found that Compound 2 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0106] In certain embodiments, Compound 2 is a crystalline solid. In other embodiments, Compound 2 is a crystalline solid substantially free of amorphous Compound 2. As used herein, the term "substantially free of amorphous Compound 2" means that the compound contains no significant amount of amorphous Compound 2. In certain embodiments, at least about 95% by weight of the crystalline Compound 2 is present. In still other embodiments of the disclosure, at least about 99% by weight of the crystalline Compound 2 is present.

[0107] It has been found that Compound 2 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 2, which is referred to herein as Form A. In certain embodiments, the present disclosure provides a polymorphic form of Compound 2, which is referred to herein as Form B. In certain embodiments, the present disclosure provides a polymorphic form of Compound 2, which is referred to herein as Form C.

[0108] In some embodiments, Compound 2 is amorphous. In some embodiments, Compound 2 is amorphous and substantially free of crystalline Compound 2.

[0109] Form A of Compound 2

[0110] In some embodiments, Form A of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 3 below.

[0111] Table 3 - XRPD Peak Positions for Form A of Compound 2

[0112] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.9 12.4 27.8 6.7 10.6 100.0 28.0 29.0 12.6 1.8 28.4 2.1 13.9 3.6 29.4 2.6 15.6 19.7 30.4 1.7 17.7 2.5 31.6 5.5 19.3 59.9 32.2 l8.1 19.9 8.5 34.6 2.2 21.0 8.6 35.4 2.5 21.3 6.0 36.3 1.6 23.8 83.2 36.8 1.3 25.4 6.9 37.4 3.6 25.6 4.4 38.3 2.3 26.6 2.0 39.3 2.5

[0113] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0114] In some embodiments, Form A of Compound 2 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 10.6 degrees, about 15.6 degrees, about 19.3 degrees, about 23.8 degrees, about 28.0 degrees, and about 32.2 degrees 2Θ. In some embodiments, Form A of Compound 2 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 10.6 degrees, about 15.6 degrees, about 19.3 degrees, about 23.8 degrees, about 28.0 degrees, and about 32.2 degrees 2Θ. In some embodiments, Form A of Compound 2 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 10.6 degrees, about 15.6 degrees, about 19.3 degrees, about 23.8 degrees, about 28.0 degrees, and about 32.2 degrees 2Θ. In some embodiments, Form A of Compound 2 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 10.6 degrees, about 15.6 degrees, about 19.3 degrees, about 23.8 degrees, about 28.0 degrees, and about 32.2 degrees 2Θ. In some embodiments, Form A of Compound 2 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 10.6 degrees, about 15.6 degrees, about 19.3 degrees, about 23.8 degrees, about 28.0 degrees, and about 32.2 degrees 2Θ. In some embodiments, Form A of Compound 2 is characterized by six peaks in its X-ray powder diffraction pattern selected from those at about 10.6 degrees, about 15.6 degrees, about 19.3 degrees, about 23.8 degrees, about 28.0 degrees, and about 32.2 degrees 2Θ.

[0115] In some embodiments, Form A of Compound 2 is characterized by each of the spectral peaks listed in Table 3 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 2A.1 Table 3.

[0116] Methods for preparing Form A of compound 2 are described below.

[0117] In some embodiments, the present disclosure provides compound 2:

[0118]

[0119] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 2, wherein the compound is substantially free of amorphous compound 2.

[0120] In some embodiments, the present disclosure provides compound 2, wherein the compound is substantially free of impurities.

[0121] In some embodiments, the present disclosure provides compound 2, wherein the compound has one or more peaks in its XRPD selected from those at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees 2-theta. In some such embodiments, the present disclosure provides compound 2, wherein the compound has at least two peaks in its XRPD selected from those at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees 2-theta. In some such embodiments, the present disclosure provides compound 2, wherein the compound is Form A.

[0122] In some embodiments, the present disclosure provides compound 2, wherein the XRPD of the compound is substantially similar to the XRPD depicted in Figure 2A.1 In some embodiments, the present disclosure provides compound 2, wherein the XRPD of the compound is substantially similar to the XRPD depicted in

[0123] In some embodiments, the present disclosure provides a composition comprising compound 2 and a pharmaceutically acceptable carrier or excipient.

[0124] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient compound 2 or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0125] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient compound 2 or a composition thereof.

[0126] Compound 3 (sulfate salt of compound 1)

[0127] According to one embodiment, the present disclosure provides a sulfate salt of compound 1, which is represented by compound 3:

[0128]

[0129] One of ordinary skill in the art will appreciate that sulfuric acid and compound 1 bond to form compound 3. It is contemplated that compound 3 can exist in a variety of physical forms. For example, compound 3 can be in solution, suspension, or solid form. In certain embodiments, compound 3 is in solid form. When compound 3 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0130] In some embodiments, the present disclosure provides compound 3 in a certain form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly amount of extraneous substances. Such extraneous substances can include different forms of compound 3, residual solvents, or any other impurities that can result from the preparation and / or isolation of compound 3. In certain embodiments, at least about 95% by weight of compound 3 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of compound 3 in a certain form is present.

[0131] According to one embodiment, compound 3 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, compound 3 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, compound 3 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0132] The structure of compound 3 depicted is also meant to include all tautomeric forms of compound 3. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 Compounds having the structure of the present disclosure except for the replacement of hydrogen by deuterium or tritium, or carbon by an isotopically enriched carbon are within the scope of the present disclosure.

[0133] It has been found that compound 3 can exist in a variety of solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0134] In certain embodiments, compound 3 is a crystalline solid. In other embodiments, compound 3 is a crystalline solid substantially free of amorphous compound 3. As used herein, the term "substantially free of amorphous compound 3" means that the compound contains no significant amount of amorphous compound 3. In certain embodiments, at least about 95% by weight of compound 3 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of compound 3 is crystalline.

[0135] It has been discovered that compound 3 can exist in at least one different polymorphic form. In certain embodiments, the disclosure provides a polymorphic form of compound 3, referred to herein as Form A.

[0136] In some embodiments, compound 3 is amorphous. In some embodiments, compound 3 is amorphous and substantially free of crystalline compound 3.

[0137] Form A of compound 3

[0138] In some embodiments, Form A of compound 3 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 4 below.

[0139] Table 4 - XRPD peak positions for Form A of compound 3

[0140] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.4 60.8 25.8 5.0 10.2 6.0 26.4 5.1 11.1 100.0 26.9 8.2 12.2 5.8 27.9 6.6 l3.3 12.7 28.9 5.7 15.8 15.9 30.5 4.9 16.1 37.7 31.0 5.3 17.8 18.7 31.4 4.7 18.4 35.7 31.7 5.8 19.3 5.4 31.9 7.4 21.3 12.4 32.4 6.0 21.9 32.7 33.6 7.4 22.7 39.1 34.9 4.6 23.4 15.5 35.4 4.1 23.8 73.9 36.8 5.3 24.7 13.3 37.4 3.8

[0141] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0142] In some embodiments, Form A of compound 3 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized by seven peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta.

[0143] In some embodiments, Form A of compound 3 is characterized by each of the spectral peaks listed in Table 4 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 3A.1 Table 4.

[0144] Methods for preparing Form A of compound 3 are described below.

[0145] In some embodiments, the present disclosure provides compound 3:

[0146]

[0147] In some embodiments, the present disclosure provides compound 3, wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 3, wherein the compound is substantially free of amorphous compound 3.

[0148] In some embodiments, the present disclosure provides compound 3, wherein the compound is substantially free of impurities.

[0149] In some embodiments, the present disclosure provides compound 3, wherein the compound has one or more peaks in its XRPD selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some such embodiments, the present disclosure provides compound 3, wherein the compound has at least two peaks in its XRPD selected from those at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees 2-theta. In some such embodiments, the present disclosure provides compound 3, wherein the compound is Form A.

[0150] In some embodiments, the present disclosure provides compound 3, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 1. Figure 3A.1 In some embodiments, the present disclosure provides compound 3, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 1.

[0151] In some embodiments, the present disclosure provides a composition comprising compound 3 and a pharmaceutically acceptable carrier or excipient.

[0152] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient compound 3 or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0153] In some embodiments, the present disclosure provides a method of treating a disease or condition in a patient mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor, comprising administering to the patient compound 3 or a composition thereof.

[0154] Compound 4 (hydrobromide salt of compound 1)

[0155] According to one embodiment, the present disclosure provides a hydrobromide salt of compound 1, which is represented by compound 4:

[0156]

[0157] One of ordinary skill in the art will appreciate that hydrogen bromide and compound 1 are bonded to form compound 4. It is contemplated that compound 4 can exist in a variety of physical forms. For example, compound 4 can be in solution, suspension, or solid form. In certain embodiments, compound 4 is in solid form. When compound 4 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0158] In some embodiments, the present disclosure provides compound 4 in a form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly-quantifiable amounts of extraneous substances. Such extraneous substances can include different forms of compound 4, residual solvents, or any other impurities that can result from the preparation and / or isolation of compound 4. In certain embodiments, at least about 95% by weight of compound 4 in a form is present. In still other embodiments of the present disclosure, at least about 99% by weight of compound 4 in a form is present.

[0159] According to one embodiment, compound 4 in a form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, compound 4 in a form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, compound 4 in a form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0160] The structure of compound 4 depicted is also meant to include all tautomeric forms of compound 4. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 Compounds having the structure of the application except for the replacement of hydrogen by deuterium or tritium, or carbon by an isotopically enriched carbon, are within the scope of the present disclosure.

[0161] It has been found that compound 4 can exist in a variety of solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0162] In certain embodiments, compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound contains no significant amount of amorphous compound 4. In certain embodiments, at least about 95% by weight of compound 4 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of compound 4 is crystalline.

[0163] It has been discovered that compound 4 can exist in at least one different polymorphic form. In certain embodiments, the disclosure provides a polymorphic form of compound 4, referred to herein as Form A.

[0164] In some embodiments, compound 4 is amorphous. In some embodiments, compound 4 is amorphous and substantially free of crystalline compound 4.

[0165] Form A of compound 4

[0166] In some embodiments, Form A of compound 4 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 5 below.

[0167] Table 5 - XRPD peak positions of Form A of compound 4

[0168]

[0169]

[0170] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0171] In some embodiments, Form A of compound 4 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 4 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 4 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 4 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 4 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 4 is characterized by six peaks in its X-ray powder diffraction pattern selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2Q.

[0172] In some embodiments, Form A of compound 4 is characterized by each of the spectral peaks listed in Table 5 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Table 5. Figure 4A.1

[0173] Methods for preparing Form A of compound 4 are described below.

[0174] In some embodiments, the present disclosure provides compound 4:

[0175]

[0176] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of amorphous compound 4.

[0177] ​In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of impurities.

[0178] In some embodiments, the present disclosure provides compound 4, wherein the compound has one or more peaks in its XRPD selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2-theta. In some such embodiments, the present disclosure provides compound 4, wherein the compound has at least two peaks in its XRPD selected from those at about 6.8 degrees, about 10.6 degrees, about 15.6 degrees, about 18.8 degrees, about 23.5 degrees, and about 27.4 degrees 2-theta. In some such embodiments, the present disclosure provides compound 4, wherein the compound is Form A.

[0179] In some embodiments, the present disclosure provides compound 4, wherein the XRPD of the compound is substantially similar to that depicted in Figure 4A.1 FIG. 6.

[0180] In some embodiments, the present disclosure provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.

[0181] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient compound 4 or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0182] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient compound 4 or a composition thereof.

[0183] Compound 5 (a tosylate salt of compound 1)

[0184] According to one embodiment, the present disclosure provides a tosylate salt of compound 1, which is represented by compound 5:

[0185]

[0186] One of ordinary skill in the art will appreciate that the tosylate acid and compound 1 are bonded to form compound 5. It is contemplated that compound 5 can exist in a variety of physical forms. For example, compound 5 can be in solution, suspension, or solid form. In certain embodiments, compound 5 is in solid form. When compound 5 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0187] In some embodiments, the present disclosure provides certain forms of Compound 5 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly-quantifiable amounts of extraneous substances. Such extraneous substances can include different forms of Compound 5, residual solvents or any other impurities that can result from the preparation and / or isolation of Compound 5. In certain embodiments, at least about 95% by weight of a certain form of Compound 5 is present. In still other embodiments of the present disclosure, at least about 99% by weight of a certain form of Compound 5 is present.

[0188] According to one embodiment, a certain form of Compound 5 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, a certain form of Compound 5 contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, a certain form of Compound 5 contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0189] The structure of a certain form of Compound 5 depicted is also meant to include all tautomeric forms of the compound. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 Compounds having the structure of the application except for the replacement of hydrogen by deuterium or tritium, or carbon by an isotopically enriched carbon, are within the scope of the present disclosure.

[0190] It has been found that Compound 5 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0191] In certain embodiments, Compound 5 is a crystalline solid. In other embodiments, Compound 5 is a crystalline solid that is substantially free of amorphous Compound 5. As used herein, the term "substantially free of amorphous Compound 5" means that the compound contains no significantly-quantifiable amounts of amorphous Compound 5. In certain embodiments, at least about 95% by weight of crystalline Compound 5 is present. In still other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 5 is present.

[0192] It has been discovered that compound 5 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 5, referred to herein as Form A.

[0193] In some embodiments, compound 5 is amorphous. In some embodiments, compound 5 is amorphous and substantially free of crystalline compound 5.

[0194] Form A of compound 5

[0195] In some embodiments, Form A of compound 5 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 6 below.

[0196] Table 6 - XRPD peak positions for Form A of compound 5

[0197] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 3.2 8.2 23.8 5.6 7.1 100.0 24.3 2.7 7.6 25.5 24.9 5.2 9.9 10.0 25.1 12.9 13.6 4.6 25.7 2.9 14.1 11.8 26.6 6.0 15.4 24.5 27.6 7.4 15.9 9.8 27.8 6.0 17.0 15.6 28.6 1.7 17.4 3.1 28.8 2.2 18.8 4.0 29.8 5.4 19.5 6.5 31.2 2.6 19.9 28.0 33.1 2.5 20.8 9.4 34.4 1.9 21.1 11.1 35.1 2.8 21.8 7.2 36.3 4.0 22.3 3.5 37.1 1.2 22.7 4.7 38.1 1.8 23.3 31.9 38.5 2.3

[0198] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0199] In some embodiments, Form A of compound 5 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1 degrees, about 7.6 degrees, about 15.4 degrees, about 19.9 degrees, and about 23.3 degrees 2Θ. In some embodiments, Form A of compound 5 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.094, about 7.644, about 15.432, about 19.92, and about 23254. In some embodiments, Form A of compound 5 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1 degrees, about 7.6 degrees, about 15.4 degrees, about 19.9 degrees, and about 23.3 degrees 2Θ. In some embodiments, Form A of compound 5 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1 degrees, about 7.6 degrees, about 15.4 degrees, about 19.9 degrees, and about 23.3 degrees 2Θ. In some embodiments, Form A of compound 5 is characterized by five peaks in its X-ray powder diffraction pattern selected from those at about 7.1 degrees, about 7.6 degrees, about 15.4 degrees, about 19.9 degrees, and about 23.3 degrees 2Θ.

[0200] In some embodiments, Form A of compound 5 is characterized by each of the spectral peaks listed in Table 6 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 5A.1XRPD provided in Table 1.

[0201] Methods for preparing Form A of Compound 5 are described below.

[0202] In some embodiments, the present disclosure provides Compound 5:

[0203]

[0204] wherein the compound is crystalline. In some embodiments, the present disclosure provides Compound 5, wherein the compound is substantially free of amorphous Compound 5.

[0205] In some embodiments, the present disclosure provides Compound 5, wherein the compound is substantially free of impurities.

[0206] In some embodiments, the present disclosure provides Compound 5, wherein the compound has one or more peaks in its XRPD selected from those at about 7.1 degrees, about 7.6 degrees, about 15.4 degrees, about 19.9 degrees, and about 23.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 5, wherein the compound has at least two peaks in its XRPD selected from those at about 7.1 degrees, about 7.6 degrees, about 15.4 degrees, about 19.9 degrees, and about 23.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 5, wherein the compound is Form A.

[0207] In some embodiments, the present disclosure provides Compound 5, wherein the XRPD of the compound is substantially similar to the XRPD depicted in Table 1. Figure 5A.1

[0208] In some embodiments, the present disclosure provides a composition comprising Compound 5 and a pharmaceutically acceptable carrier or excipient.

[0209] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient Compound 5 or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0210] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient Compound 5 or a composition thereof.

[0211] Compound 6 (maleate salt of Compound 1)

[0212] ​According to one embodiment, the present disclosure provides a maleate salt of Compound 1, represented by Compound 6:

[0213]

[0214] One of ordinary skill in the art will appreciate that maleic acid and Compound 1 are bonded to form Compound 6. It is contemplated that Compound 6 can exist in a variety of physical forms. For example, Compound 6 can be in solution, suspension, or solid form. In certain embodiments, Compound 6 is in solid form. When Compound 6 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0215] In some embodiments, the present disclosure provides Compound 6 in a certain form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly amount of extraneous substances. Such extraneous substances can include different forms of Compound 6, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 6. In certain embodiments, at least about 95% by weight of Compound 6 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 6 in a certain form is present.

[0216] According to one embodiment, Compound 6 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, Compound 6 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 6 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0217] The structure of Compound 6 in a certain form depicted is also meant to include all tautomeric forms of Compound 6. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 Compounds having the structure of the present disclosure except for the replacement of hydrogen by deuterium or tritium, or carbon by an isotopically enriched carbon, are within the scope of the present disclosure.

[0218] It has been discovered that compound 6 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0219] In certain embodiments, compound 6 is a crystalline solid. In other embodiments, compound 6 is a crystalline solid substantially free of amorphous compound 6. As used herein, the term "substantially free of amorphous compound 6" means that the compound contains no significant amount of amorphous compound 6. In certain embodiments, at least about 95% by weight of compound 6 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of compound 6 is crystalline.

[0220] It has been discovered that compound 6 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 6, referred to herein as Form A.

[0221] In some embodiments, compound 6 is amorphous. In some embodiments, compound 6 is amorphous and substantially free of crystalline compound 6.

[0222] Form A of compound 6

[0223] In some embodiments, Form A of compound 6 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 7 below.

[0224] Table 7 - XRPD peak positions for Form A of compound 6

[0225] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.4 2.7 24.7 2.8 7.7 100.0 25.6 4.4 8.6 22.1 26.0 28.2 10.2 4.2 26.3 17.2 10.8 40.7 27.4 20.2 129 72 291 54 14.0 1.4 30.0 3.4 14.5 12.9 30.8 3.0 15.1 4.6 31.1 4.8 15.5 7.5 32.8 2.3 16.4 5.0 33.2 2.0 17.4 5.7 33.8 2.2 18.0 19.5 34.1 3.4 18.5 9.1 34.7 2.5 19.5 2.2 35.3 5.7 19.9 16.1 36.1 1.6 20.5 4.2 36.6 2.0 21.3 2.7 37.2 1.6 22.2 2.1 37.8 1.1 22.7 8.4 38.3 2.3 23.4 16.6 38.8 1.9 24.3 5.4 39.6 2.0

[0226] In this and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0227] In some embodiments, Form A of compound 6 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.7 degrees, about 8.6 degrees, about 10.8 degrees, about 26.0 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 6 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.7 degrees, about 8.6 degrees, about 10.8 degrees, about 26.0 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 6 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.7 degrees, about 8.6 degrees, about 10.8 degrees, about 26.0 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 6 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 7.7 degrees, about 8.6 degrees, about 10.8 degrees, about 26.0 degrees, and about 27.4 degrees 2Q. In some embodiments, Form A of compound 6 is characterized by five peaks in its X-ray powder diffraction pattern selected from those at about 7.7 degrees, about 8.6 degrees, about 10.8 degrees, about 26.0 degrees, and about 27.4 degrees 2Q.

[0228] In some embodiments, Form A of compound 6 is characterized by each of the spectral peaks listed in Table 7 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Table 7. Figure 6A.1

[0229] Methods for preparing Form A of compound 6 are described below.

[0230] In some embodiments, the present disclosure provides compound 6:

[0231]

[0232] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of amorphous compound 6.

[0233] In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of impurities.

[0234] ​In some embodiments, the present disclosure provides Compound 6, wherein the compound has one or more peaks in its XRPD selected from those at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 6, wherein the compound has at least two peaks in its XRPD selected from those at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 6, wherein the compound is Form A.

[0235] In some embodiments, the present disclosure provides Compound 6, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 1. Figure 6A.1

[0236] In some embodiments, the present disclosure provides a composition comprising Compound 6 and a pharmaceutically acceptable carrier or excipient.

[0237] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering Compound 6, or a composition thereof, to the patient. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0238] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering Compound 6, or a composition thereof, to the patient.

[0239] Compound 7 (fumarate salt of Compound 1)

[0240] According to one embodiment, the present disclosure provides a fumarate salt of Compound 1, which is represented by Compound 7:

[0241]

[0242] One of ordinary skill in the art will appreciate that the fumaric acid and Compound 1 are bonded to form Compound 7. It is contemplated that Compound 7 can exist in a variety of physical forms. For example, Compound 7 can be in solution, suspension, or solid form. In certain embodiments, Compound 7 is in solid form. When Compound 7 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0243] ​In some embodiments, the present disclosure provides certain forms of Compound 7 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly objectionable amounts of extraneous substances. Such extraneous substances can include different forms of Compound 7, residual solvents or any other impurities that can result from the preparation and / or isolation of Compound 7. In certain embodiments, at least about 95% by weight of the certain form of Compound 7 is present. In still other embodiments of the disclosure, at least about 99% by weight of the certain form of Compound 7 is present.

[0244] According to one embodiment, the certain form of Compound 7 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percentage is based upon the total weight of the composition. According to another embodiment, the certain form of Compound 7 contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, the certain form of Compound 7 contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0245] The structure of the certain form of Compound 7 depicted is also meant to include all tautomeric forms of the compound. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 Compounds having the structure of the application except for the replacement of hydrogen by deuterium or tritium, or carbon by an isotopically enriched carbon, are within the scope of the present disclosure.

[0246] It has been found that Compound 7 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0247] In certain embodiments, Compound 7 is a crystalline solid. In other embodiments, Compound 7 is a crystalline solid substantially free of amorphous Compound 7. As used herein, the term "substantially free of amorphous Compound 7" means that the compound contains no significant amount of amorphous Compound 7. In certain embodiments, at least about 95% by weight of the crystalline Compound 7 is present. In still other embodiments of the disclosure, at least about 99% by weight of the crystalline Compound 7 is present.

[0248] It has been discovered that compound 7 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 7, referred to herein as Form A.

[0249] In some embodiments, compound 7 is amorphous. In some embodiments, compound 7 is amorphous and substantially free of crystalline compound 7.

[0250] Form A of compound 7

[0251] In some embodiments, Form A of compound 7 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 8 below.

[0252] Table 8 - XRPD peak positions for Form A of compound 7

[0253] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 4.9 11.3 17.5 11.3 5.5 14.7 18.3 4.1 5.8 12.0 19.5 6.4 7.4 15.5 21.4 4.3 10.1 15.7 22.6 12.1 11.1 100.0 23.0 34.5 12.2 6.3 23.9 8.4 12.8 4.7 24.6 43.3 14.0 5.5 26.4 13.3 15.0 6.6 27.1 11.3 15.7 6.4 28.2 11.7 16.0 7.1 30.8 4.7 16.7 5.1 35.5 3.1

[0254] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0255] In some embodiments, Form A of compound 7 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.4 degrees, about 10.1 degrees, about 11.1 degrees, about 23.0 degrees, and about 24.6 degrees 2Θ. In some embodiments, Form A of compound 7 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.4 degrees, about 10.1 degrees, about 11.1 degrees, about 23.0 degrees, and about 24.6 degrees 2Θ. In some embodiments, Form A of compound 7 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.4 degrees, about 10.1 degrees, about 11.1 degrees, about 23.0 degrees, and about 24.6 degrees 2Θ. In some embodiments, Form A of compound 7 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from those at about 7.4 degrees, about 10.1 degrees, about 11.1 degrees, about 23.0 degrees, and about 24.6 degrees 2Θ. In some embodiments, Form A of compound 7 is characterized by having five peaks in its X-ray powder diffraction pattern selected from those at about 7.4 degrees, about 10.1 degrees, about 11.1 degrees, about 23.0 degrees, and about 24.6 degrees 2Θ.

[0256] In some embodiments, Form A of compound 7 is characterized by having each of the spectral peaks listed in Table 8 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to:Figure 7A.1 XRPD provided in Table 1.

[0257] Methods for preparing Form A of compound 7 are described below.

[0258] In some embodiments, the present disclosure provides compound 7:

[0259]

[0260] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 7, wherein the compound is substantially free of amorphous compound 7.

[0261] In some embodiments, the present disclosure provides compound 7, wherein the compound is substantially free of impurities.

[0262] In some embodiments, the present disclosure provides compound 7, wherein the compound has one or more peaks in its XRPD selected from those at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta. In some such embodiments, the present disclosure provides compound 7, wherein the compound has at least two peaks in its XRPD selected from those at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta. In some such embodiments, the present disclosure provides compound 7, wherein the compound is Form A.

[0263] In some embodiments, the present disclosure provides compound 7, wherein the XRPD of the compound is substantially similar to the XRPD depicted in Table 1. Figure 7A.1

[0264] In some embodiments, the present disclosure provides a composition comprising compound 7 and a pharmaceutically acceptable carrier or excipient.

[0265] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient compound 7 or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0266] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient compound 7 or a composition thereof.

[0267] Compound 8 (glycolate salt of compound 1)

[0268] ​According to one embodiment, the present disclosure provides a glycolate salt of Compound 1, which is represented by Compound 8:

[0269]

[0270] One of ordinary skill in the art will appreciate that glycolic acid and Compound 1 are bonded to form Compound 8. It is contemplated that Compound 8 can exist in a variety of physical forms. For example, Compound 8 can be in solution, suspension, or solid form. In certain embodiments, Compound 8 is in solid form. When Compound 8 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0271] In some embodiments, the present disclosure provides Compound 8 in a certain form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly amount of foreign substances. Such foreign substances can include different forms of Compound 8, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 8. In certain embodiments, at least about 95% by weight of Compound 8 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 8 in a certain form is present.

[0272] According to one embodiment, Compound 8 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, Compound 8 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 8 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0273] The structure of Compound 8 depicted is also meant to include all tautomeric forms of Compound 8. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 Compounds having the structure of the present disclosure except for the replacement of hydrogen by deuterium or tritium, or carbon by an isotopically enriched carbon are within the scope of the present disclosure.

[0274] It has been discovered that compound 8 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0275] In certain embodiments, compound 8 is a crystalline solid. In other embodiments, compound 8 is a crystalline solid substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound contains no significant amount of amorphous compound 8. In certain embodiments, at least about 95% by weight of compound 8 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of compound 8 is crystalline.

[0276] It has been discovered that compound 8 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 8, referred to herein as Form A.

[0277] In some embodiments, compound 8 is amorphous. In some embodiments, compound 8 is amorphous and substantially free of crystalline compound 8.

[0278] Form A of compound 8

[0279] In some embodiments, Form A of compound 8 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 9 below.

[0280] Table 9 - XRPD peak positions for Form A of compound 8

[0281]

[0282]

[0283] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0284] In some embodiments, Form A of compound 8 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q. In some embodiments, Form A of compound 8 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q. In some embodiments, Form A of compound 8 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q. In some embodiments, Form A of compound 8 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q. In some embodiments, Form A of compound 8 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q. In some embodiments, Form A of compound 8 is characterized by six peaks in its X-ray powder diffraction pattern selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q.

[0285] In some embodiments, Form A of compound 8 is characterized by each of the spectral peaks listed in Table 9 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Table 9. Figure 8A.1

[0286] Methods for preparing Form A of compound 8 are described below.

[0287] In some embodiments, the present disclosure provides compound 8:

[0288]

[0289] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 8, wherein the compound is substantially free of amorphous compound 8.

[0290] ​In some embodiments, the present disclosure provides Compound 8, wherein the compound is substantially free of impurities.

[0291] In some embodiments, the present disclosure provides Compound 8, wherein the compound has one or more peaks in its XRPD selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q. In some such embodiments, the present disclosure provides Compound 8, wherein the compound has at least two peaks in its XRPD selected from those at about 5.7 degrees, about 11.6 degrees, about 15.7 degrees, about 17.5 degrees, about 20.4 degrees, and about 23.1 degrees 2Q. In some such embodiments, the present disclosure provides Compound 8, wherein the compound is Form A.

[0292] In some embodiments, the present disclosure provides Compound 8, wherein the XRPD of the compound is substantially similar to that depicted in Figure 8A.1

[0293] In some embodiments, the present disclosure provides a composition comprising Compound 8 and a pharmaceutically acceptable carrier or excipient.

[0294] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient Compound 8, or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0295] In some embodiments, the present disclosure provides a method of treating a disease or disorder mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient Compound 8, or a composition thereof.

[0296] Compound 9 (L-tartaric acid salt of Compound 1)

[0297] According to one embodiment, the present disclosure provides an L-tartaric acid salt of Compound 1, represented by Compound 9:

[0298]

[0299] wherein 0 < X < 1.

[0300] ​One of ordinary skill in the art will appreciate that L-(+)-tartaric acid and Compound 1 are bonded to form Compound 9. It is contemplated that Compound 9 can exist in a variety of physical forms. For example, Compound 9 can be in solution, suspension, or solid form. In certain embodiments, Compound 9 is in solid form. When Compound 9 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0301] In some embodiments, the present disclosure provides Compound 9 in a certain form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly amount of extraneous substances. Such extraneous substances can include different forms of Compound 9, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 9. In certain embodiments, at least about 95% by weight of Compound 9 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 9 in a certain form is present.

[0302] According to one embodiment, Compound 9 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, Compound 9 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 9 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0303] The structure of Compound 9 depicted is also meant to include all tautomeric forms of Compound 9. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 compounds having the structure of the application except that one or more carbon atoms are replaced by isotopes of carbon such as

[0304] It has been found that Compound 9 can exist in a variety of solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0305] In certain embodiments, Compound 9 is a crystalline solid. In other embodiments, Compound 9 is a crystalline solid substantially free of amorphous Compound 9. As used herein, the term "substantially free of amorphous Compound 9" means that the compound contains no significant amount of amorphous Compound 9. In certain embodiments, at least about 95% by weight of Compound 9 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of Compound 9 is crystalline.

[0306] It has been discovered that Compound 9 can exist in at least one different polymorphic form. In certain embodiments, the disclosure provides a polymorphic form of Compound 9, referred to herein as Form A.

[0307] In some embodiments, Compound 9 is amorphous. In some embodiments, Compound 9 is amorphous and substantially free of crystalline Compound 9.

[0308] In some embodiments, X is 0.5.

[0309] Form A of Compound 9

[0310] In some embodiments, Form A of Compound 9 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 10 below.

[0311] Table 10 - XRPD Peak Positions of Form A of Compound 9

[0312] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 3.7 16.8 20.0 7.1 5.6 12.4 20.7 4.6 10.9 14.7 21.2 3.4 11.2 100.0 22.0 27.7 12.4 6.8 22.5 21.8 13.6 8.8 23.3 8.4 14.2 5.5 24.5 11.2 16.0 10.3 27.2 4.5 16.8 6.3 28.5 2.9 17.1 6.7 32.3 2.7 18.4 10.0 33.5 4.3

[0313] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0314] In some embodiments, Form A of Compound 9 is a salt, wherein X is 0.5.

[0315] In some embodiments, Form A of Compound 9 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 11.2 degrees, about 22.0 degrees, and about 22.5 degrees 2Θ. In some embodiments, Form A of Compound 9 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 11.2 degrees, about 22.0 degrees, and about 22.5 degrees 2Θ. In some embodiments, Form A of Compound 9 is characterized by three peaks in its X-ray powder diffraction pattern selected from those at about 11.2 degrees, about 22.0 degrees, and about 22.5 degrees 2Θ.

[0316] In some embodiments, Form A of compound 9 is characterized by an X-ray powder diffraction pattern having each of the spectral peaks listed in Table 10, with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 10. Figure 9A.1

[0317] Methods for preparing Form A of compound 9 are described hereinafter.

[0318] In some embodiments, the present disclosure provides compound 9:

[0319]

[0320] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 9, wherein the compound is substantially free of amorphous compound 9.

[0321] In some embodiments, the present disclosure provides compound 9, wherein the compound is substantially free of impurities.

[0322] In some embodiments, the present disclosure provides compound 9, wherein the compound has one or more peaks in its XRPD selected from those at about 11.2 degrees, about 22.0 degrees, and about 22.5 degrees 2-theta. In some such embodiments, the present disclosure provides compound 9, wherein the compound has at least two peaks in its XRPD selected from those at about 11.2 degrees, about 22.0 degrees, and about 22.5 degrees 2-theta. In some such embodiments, the present disclosure provides compound 9, wherein the compound is Form A.

[0323] In some embodiments, the present disclosure provides compound 9, wherein the XRPD of the compound is substantially similar to the XRPD depicted in Figure 10. Figure 9A.1

[0324] In some embodiments, the present disclosure provides a composition comprising compound 9 and a pharmaceutically acceptable carrier or excipient.

[0325] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient compound 9, or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0326] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient compound 9, or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient compound 9, or a composition thereof.​

[0327] Compound 10 (L-malate salt of Compound 1)

[0328] According to one embodiment, the present disclosure provides an L-malate salt of Compound 1, which is represented by Compound 10:

[0329]

[0330] wherein 0 < X < 1.

[0331] One of ordinary skill in the art will appreciate that L-malic acid and Compound 1 are bonded to form Compound 10. It is contemplated that Compound 10 can exist in a variety of physical forms. For example, Compound 10 can be in solution, suspension, or solid form. In certain embodiments, Compound 10 is in solid form. When Compound 10 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0332] In some embodiments, the present disclosure provides Compound 10 in a certain form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous materials. Such extraneous materials can include different forms of Compound 10, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 10. In certain embodiments, at least about 95% by weight of Compound 10 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 10 in a certain form is present.

[0333] According to one embodiment, Compound 10 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percentage is based upon the total weight of the composition. According to another embodiment, Compound 10 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 10 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC, no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0334] The structure of compound 10 depicted in certain forms is also meant to encompass all tautomeric forms of compound 10. Additionally, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the compounds 13 C or 14 C enriched carbon substitution have structures according to the present disclosure.

[0335] It has been found that compound 10 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0336] In certain embodiments, compound 10 is a crystalline solid. In other embodiments, compound 10 is a crystalline solid substantially free of amorphous compound 10. As used herein, the term "substantially free of amorphous compound 10" means that the compound contains no significant amount of amorphous compound 10. In certain embodiments, at least about 95% by weight of the compound 10 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of the compound 10 is crystalline.

[0337] It has been found that compound 10 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 10, referred to herein as Form A.

[0338] In some embodiments, compound 10 is amorphous. In some embodiments, compound 10 is amorphous and substantially free of crystalline compound 10.

[0339] In some embodiments, X is 0.5.

[0340] Form A of compound 10

[0341] In some embodiments, Form A of compound 10 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 11 below.

[0342] Table 11 - XRPD peak positions for Form A of compound 10

[0343]

[0344]

[0345] In this table and all subsequent tables, position (°2Θ) is within ±0.2.

[0346] In some embodiments, Form A of compound 10 is a salt, wherein X is 0.5.

[0347] In some embodiments, Form A of compound 10 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q. In some embodiments, Form A of compound 10 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q. In some embodiments, Form A of compound 10 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q. In some embodiments, Form A of compound 10 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q. In some embodiments, Form A of compound 10 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q. In some embodiments, Form A of compound 10 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q. In some embodiments, Form A of compound 10 is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q. In some embodiments, Form A of compound 10 is characterized by eight peaks in its X-ray powder diffraction pattern selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2Q.

[0348] In some embodiments, Form A of compound 10 is characterized by an X-ray powder diffraction pattern having each of the spectral peaks listed in Table 11, with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1. Figure 10A.1

[0349] Methods for preparing Form A of compound 10 are described hereinafter.

[0350] In some embodiments, the present disclosure provides compound 10:

[0351]

[0352] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 10, wherein the compound is substantially free of amorphous compound 10.

[0353] In some embodiments, the present disclosure provides compound 10, wherein the compound is substantially free of impurities.

[0354] In some embodiments, the present disclosure provides compound 10, wherein the compound has one or more peaks in its XRPD selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2-theta. In some such embodiments, the present disclosure provides compound 10, wherein the compound has at least two peaks in its XRPD selected from those at about 10.3, about 10.8, about 11.7, about 15.0, about 16.5, about 23.7, about 25.3, and about 26.6 degrees 2-theta. In some such embodiments, the present disclosure provides compound 10, wherein the compound is Form A.

[0355] In some embodiments, the present disclosure provides compound 10, wherein the XRPD of the compound is substantially similar to the XRPD depicted in Figure 1. Figure 10A.1

[0356] In some embodiments, the present disclosure provides a composition comprising compound 10 and a pharmaceutically acceptable carrier or excipient.

[0357] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient compound 10, or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0358] ​​In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient Compound 10 or a composition thereof.

[0359] Compound 11 (D-mandelate salt of Compound 1)

[0360] According to one embodiment, the present disclosure provides a D-mandelate salt of Compound 1, represented by Compound 11:

[0361]

[0362] One of ordinary skill in the art will appreciate that the D-mandelic acid and Compound 1 bond to form Compound 11. It is contemplated that Compound 11 can exist in a variety of physical forms. For example, Compound 11 can be in solution, suspension, or solid form. In certain embodiments, Compound 11 is in solid form. When Compound 11 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0363] In some embodiments, the present disclosure provides Compound 11 in a certain form substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous substances. Such extraneous substances can include different forms of Compound 11, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 11. In certain embodiments, at least about 95% by weight of Compound 11 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 11 in a certain form is present.

[0364] According to one embodiment, Compound 11 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, Compound 11 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 11 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0365] The structure of compound 11 depicted in certain forms is also meant to encompass all tautomeric forms of compound 11. Additionally, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the compounds 13 C or 14 Compounds having the structure of the application except for isotopically enriched atoms are within the scope of the present disclosure.

[0366] It has been found that compound 11 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0367] In certain embodiments, compound 11 is a crystalline solid. In other embodiments, compound 11 is a crystalline solid substantially free of amorphous compound 11. As used herein, the term "substantially free of amorphous compound 11" means that the compound contains no significant amount of amorphous compound 11. In certain embodiments, at least about 95% by weight of the compound 11 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of the compound 11 is crystalline.

[0368] It has been found that compound 11 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 11, referred to herein as Form A.

[0369] In some embodiments, compound 11 is amorphous. In some embodiments, compound 11 is amorphous and substantially free of crystalline compound 11.

[0370] Form A of compound 11

[0371] In some embodiments, Form A of compound 11 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 12 below.

[0372] Table 12 - XRPD peak positions for Form A of compound 11

[0373] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.5 69.6 23.7 2.0 7.4 8.9 26.3 22.3 9.0 7.1 27.0 2.9 13.1 13.9 27.4 17.0 14.0 34.9 28.3 6.8 14.8 3.0 31.1 2.4 15.2 4.6 31.9 2.3 16.1 3.9 32.9 2.0 17.2 2.9 34.3 8.1 19.8 8.9 37.2 1.9 20.0 5.4 39.7 3.4 228 1000

[0374] In this and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0375] In some embodiments, Form A of compound 11 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.5 degrees, about 14.0 degrees, about 22.8 degrees, and about 26.3 degrees 2Q. In some embodiments, Form A of compound 11 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.5 degrees, about 14.0 degrees, about 22.8 degrees, and about 26.3 degrees 2Q. In some embodiments, Form A of compound 11 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.5 degrees, about 14.0 degrees, about 22.8 degrees, and about 26.3 degrees 2Q. In some embodiments, Form A of compound 11 is characterized by four peaks in its X-ray powder diffraction pattern selected from those at about 6.5 degrees, about 14.0 degrees, about 22.8 degrees, and about 26.3 degrees 2Q.

[0376] In some embodiments, Form A of compound 11 is characterized by each of the spectral peaks listed in Table 12 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Table 12. Figure 11A.1

[0377] Methods for preparing Form A of compound 11 are described below.

[0378] In some embodiments, the present disclosure provides compound 11:

[0379]

[0380] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 11, wherein the compound is substantially free of amorphous compound 11.

[0381] In some embodiments, the present disclosure provides compound 11, wherein the compound is substantially free of impurities.

[0382] ​In some embodiments, the present disclosure provides Compound 11, wherein the compound has one or more peaks in its XRPD selected from those at about 6.5, about 14.0, about 22.8, and about 26.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 11, wherein the compound has at least two peaks in its XRPD selected from those at about 6.5, about 14.0, about 22.8, and about 26.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 11, wherein the compound is Form A.

[0383] In some embodiments, the present disclosure provides Compound 11, wherein the XRPD of the compound is substantially similar to that depicted in FIG. 6. Figure 11A.1

[0384] In some embodiments, the present disclosure provides a composition comprising Compound 11 and a pharmaceutically acceptable carrier or excipient.

[0385] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient Compound 11, or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0386] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient Compound 11, or a composition thereof.

[0387] Compound 12 (L-lactate salt of Compound 1)

[0388] According to one embodiment, the present disclosure provides an L-lactate salt of Compound 1, which is represented by Compound 12:

[0389]

[0390] One of ordinary skill in the art will appreciate that L-lactic acid and Compound 1 are bonded to form Compound 12. It is contemplated that Compound 12 can exist in a variety of physical forms. For example, Compound 12 can be in solution, suspension, or solid form. In certain embodiments, Compound 12 is in solid form. When Compound 12 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0391] ​In some embodiments, this disclosure provides a form of compound 12 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound 12, residual solvents, or any other impurities that may arise from the preparation and / or separation of compound 12. In some embodiments, at least about 95% by weight of a form of compound 12 is present. In other embodiments of this disclosure, at least about 99% by weight of a form of compound 12 is present.

[0392] According to one embodiment, a certain form of compound 12 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8% by weight, wherein said percentage is based on the total weight of the composition. According to another embodiment, a certain form of compound 12 contains no more than about 3.0% of the total area of ​​the HPLC chromatogram as a percentage of total organic impurities, and in some embodiments, contains no more than about 1.5% of the total area of ​​the HPLC chromatogram as a percentage of total organic impurities. In other embodiments, a certain form of compound 12 contains no more than about 1.0% of the area of ​​the HPLC chromatogram as a percentage of total organic impurities; contains no more than about 0.6% of the area of ​​the HPLC chromatogram as a percentage of total organic impurities, and in some embodiments, contains no more than about 0.5% of the area of ​​the HPLC chromatogram as a percentage of total organic impurities.

[0393] The structure of one form of compound 12 described herein also implies the inclusion of all tautomeric forms of compound 12. Additionally, the structure described herein also implies the inclusion of compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium, or carbon by... 13 C or 14 Compounds having the structure of this invention, other than those enriched by carbon substitution, are within the scope of this disclosure.

[0394] It has been found that compound 12 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0395] In some embodiments, compound 12 is a crystalline solid. In other embodiments, compound 12 is a crystalline solid substantially free of amorphous compound 12. As used herein, the term "substantially free of amorphous compound 12" means that the compound does not contain a significant amount of amorphous compound 12. In some embodiments, at least about 95% by weight of crystalline compound 12 is present. In other embodiments of this disclosure, at least about 99% by weight of crystalline compound 12 is present.

[0396] It has been found that compound 12 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 12, referred to herein as Form A.

[0397] In some embodiments, compound 12 is amorphous. In some embodiments, compound 12 is amorphous and substantially free of crystalline compound 12.

[0398] Form A of compound 12

[0399] In some embodiments, Form A of compound 12 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 13 below.

[0400] Table 13 - XRPD peak positions for Form A of compound 12

[0401] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 5.0 58.5 22.1 59.5 6.4 18.5 22.8 27.9 7.1 15.0 23.2 19.1 10.1 100.0 24.0 15.8 10.4 77.7 24.6 29.6 10.8 47.7 25.0 19.3 11.1 56.6 25.6 29.6 13.7 25.1 25.8 19.4 15.2 28.3 26.4 20.1 15.7 23.2 27.7 22.3 16.2 53.1 28.6 16.9 17.0 24.1 29.1 13.4 17.4 26.3 30.2 9.9 17.7 27.9 31.0 13.9 19.1 16.0 31.3 13.4 19.8 24.0 31.9 12.4 20.4 29.2 32.6 12.5 21.3 65.0 35.8 11.6

[0402] In this and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0403] In some embodiments, Form A of compound 12 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q. In some embodiments, Form A of compound 12 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q. In some embodiments, Form A of compound 12 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q. In some embodiments, Form A of compound 12 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q. In some embodiments, Form A of compound 12 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q. In some embodiments, Form A of compound 12 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q. In some embodiments, Form A of compound 12 is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q. In some embodiments, Form A of compound 12 is characterized by eight peaks in its X-ray powder diffraction pattern selected from those at about 5.0 degrees, about 10.1 degrees, about 10.4 degrees, about 10.8 degrees, about 11.1 degrees, about 16.2 degrees, about 21.3 degrees, and about 22.1 degrees 2Q.

[0404] In some embodiments, Form A of compound 12 is characterized by an X-ray powder diffraction pattern having each of the spectral peaks listed in Table 13, with an intensity of greater than 10%, 20%, 30%, or 40% relative intensity. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 13. Figure 12A.1

[0405] Methods for preparing Form A of compound 12 are described hereinafter.

[0406] In some embodiments, the present disclosure provides compound 12:

[0407]

[0408] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 12, wherein the compound is substantially free of amorphous compound 12.

[0409] In some embodiments, the present disclosure provides compound 12, wherein the compound is substantially free of impurities.

[0410] In some embodiments, the present disclosure provides compound 12, wherein the compound has one or more peaks in its XRPD selected from those at about 5.0, about 10.1, about 10.4, about 10.8, about 11.1, about 16.2, about 21.3, and about 22.1 degrees 2-theta. In some such embodiments, the present disclosure provides compound 12, wherein the compound has at least two peaks in its XRPD selected from those at about 5.0, about 10.1, about 10.4, about 10.8, about 11.1, about 16.2, about 21.3, and about 22.1 degrees 2-theta. In some such embodiments, the present disclosure provides compound 12, wherein the compound is Form A.

[0411] In some embodiments, the present disclosure provides compound 12, wherein the XRPD of the compound is substantially similar to the XRPD depicted in Figure 13. Figure 12A.1

[0412] In some embodiments, the present disclosure provides a composition comprising compound 12 and a pharmaceutically acceptable carrier or excipient.

[0413] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient compound 12, or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0414] ​​In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient, comprising administering to the patient Compound 12, or a composition thereof.

[0415] Compound 13 (D-camphoric acid salt of Compound 1)

[0416] According to one embodiment, the present disclosure provides a D-camphoric acid salt of Compound 1, represented by Compound 13:

[0417]

[0418] One of ordinary skill in the art will appreciate that D-camphoric acid and Compound 1 bond to form Compound 13. It is contemplated that Compound 13 can exist in a variety of physical forms. For example, Compound 13 can be in solution, suspension, or solid form. In certain embodiments, Compound 13 is in solid form. When Compound 13 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0419] In some embodiments, the present disclosure provides Compound 13 in a certain form substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous materials. Such extraneous materials can include different forms of Compound 13, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 13. In certain embodiments, at least about 95% by weight of Compound 13 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 13 in a certain form is present.

[0420] According to one embodiment, Compound 13 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, Compound 13 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 13 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0421] The structure of compound 13 depicted in certain forms is also meant to encompass all tautomeric forms of compound 13. Additionally, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the compounds 13 C or 14 C enriched carbon in place of those compounds having the structure of the present invention are within the scope of the present disclosure.

[0422] It has been found that compound 13 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0423] In certain embodiments, compound 13 is a crystalline solid. In other embodiments, compound 13 is a crystalline solid substantially free of amorphous compound 13. As used herein, the term "substantially free of amorphous compound 13" means that the compound contains no significant amount of amorphous compound 13. In certain embodiments, at least about 95% by weight of the compound 13 is crystalline. In still other embodiments of the disclosure, at least about 99% by weight of the compound 13 is crystalline.

[0424] It has been found that compound 13 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 13, referred to herein as Form A.

[0425] In some embodiments, compound 13 is amorphous. In some embodiments, compound 13 is amorphous and substantially free of crystalline compound 13.

[0426] Form A of compound 13

[0427] In some embodiments, Form A of compound 13 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 14 below.

[0428] Table 14 - XRPD peak positions for Form A of compound 13

[0429] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 4.5 10.9 22.2 3.2 7.9 100.0 23.2 4.0 8.6 10.3 23.6 3.4 9.5 35.3 24.9 3.6 10.1 7.6 25.6 3.7 10.9 3.6 26.1 6.1 11.7 23.7 26.5 4.7 12.9 19.4 27.9 2.8 13.3 2.5 28.6 2.8 14.7 20.4 29.1 2.6 15.7 3.6 29.4 3.9 16.2 10.0 29.7 5.9 16.8 13.1 31.0 5.3 17.2 21.4 32.0 1.9 17.8 4.9 32.9 2.3 18.1 11.3 33.1 3.4 18.5 20.5 34.8 1.9 18.9 21.6 36.5 2.0 19.1 13.4 37.4 2.8 20.3 3.8 37.7 2.2 20.6 3.9 38.8 2.2 21.1 7.5 39.6 2.1 21.8 7.2

[0430] In this and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0431] In some embodiments, Form A of compound 13 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2Q. In some embodiments, Form A of compound 13 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2Q. In some embodiments, Form A of compound 13 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2Q. In some embodiments, Form A of compound 13 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2Q. In some embodiments, Form A of compound 13 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2Q. In some embodiments, Form A of compound 13 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2Q. In some embodiments, Form A of compound 13 is characterized by seven peaks in its X-ray powder diffraction pattern selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2Q.

[0432] In some embodiments, Form A of compound 13 is characterized by each of the spectral peaks listed in Table 14 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 13A.1

[0433] Methods for preparing Form A of compound 13 are described hereinafter.

[0434] ​In some embodiments, the present disclosure provides compound 13:

[0435]

[0436] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 13, wherein the compound is substantially free of amorphous compound 13.

[0437] In some embodiments, the present disclosure provides compound 13, wherein the compound is substantially free of impurities.

[0438] In some embodiments, the present disclosure provides compound 13, wherein the compound has one or more peaks in its XRPD selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2-theta. In some such embodiments, the present disclosure provides compound 13, wherein the compound has at least two peaks in its XRPD selected from those at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees 2-theta. In some such embodiments, the present disclosure provides compound 13, wherein the compound is Form A.

[0439] In some embodiments, the present disclosure provides compound 13, wherein the XRPD of the compound is substantially similar to that depicted in Figure 13A.1 FIG. 14.

[0440] In some embodiments, the present disclosure provides a composition comprising compound 13 and a pharmaceutically acceptable carrier or excipient.

[0441] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient comprising administering to the patient compound 13, or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a β1 -adrenergic receptor and a β2-adrenergic receptor.

[0442] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in a patient comprising administering to the patient compound 13, or a composition thereof.

[0443] Compound 14 (dibenzoyl-D-tartaric acid salt of compound 1)

[0444] According to one embodiment, the present disclosure provides a dibenzoyl-D-tartaric acid salt of compound 1, which is represented by compound 14:

[0445]

[0446] One of ordinary skill in the art will appreciate that dibenzoyl-D-tartaric acid and Compound 1 are bonded to form Compound 14. It is contemplated that Compound 14 can exist in a variety of physical forms. For example, Compound 14 can be in solution, suspension, or solid form. In certain embodiments, Compound 14 is in solid form. When Compound 14 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in greater detail below.

[0447] In some embodiments, the present disclosure provides Compound 14 in a certain form that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significantly amount of extraneous substances. Such extraneous substances can include different forms of Compound 14, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 14. In certain embodiments, at least about 95% by weight of Compound 14 in a certain form is present. In still other embodiments of the present disclosure, at least about 99% by weight of Compound 14 in a certain form is present.

[0448] According to one embodiment, Compound 14 in a certain form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, wherein the percent by weight is based upon the total weight of the composition. According to another embodiment, Compound 14 in a certain form contains no more than about 3.0 area percent of total organic impurities by HPLC, and in certain embodiments, no more than about 1.5 area percent of total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 14 in a certain form contains no more than about 1.0 area percent of any single impurity by HPLC; no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments, no more than about 0.5 area percent of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0449] The structure of Compound 14 depicted is also meant to include all tautomeric forms of Compound 14. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (2H) or tritium (3H), carbon isotopes such as 13 C or 14 Compounds having the structure of the present invention except for the replacement of hydrogen by deuterium or tritium, or carbon by an isotopically enriched carbon, are within the scope of the present disclosure.

[0450] It has been found that compound 14 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0451] In certain embodiments, compound 14 is a crystalline solid. In other embodiments, compound 14 is a crystalline solid substantially free of amorphous compound 14. As used herein, the term "substantially free of amorphous compound 14" means that the compound contains no significant amount of amorphous compound 14. In certain embodiments, at least about 95% by weight of crystalline compound 14 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 14 is present.

[0452] It has been found that compound 14 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of compound 14, referred to herein as Form A.

[0453] In some embodiments, compound 14 is amorphous. In some embodiments, compound 14 is amorphous and substantially free of crystalline compound 14.

[0454] Form A of compound 14

[0455] In some embodiments, Form A of compound 14 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 15 below.

[0456] Table 15 - XRPD peak positions for Form A of compound 14

[0457]

[0458]

[0459] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0460] In some embodiments, Form A of compound 14 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3 degrees, about 8.8 degrees, about 12.2 degrees, about 12.6 degrees, and about 12.8 degrees 2Q. In some embodiments, Form A of compound 14 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3 degrees, about 8.8 degrees, about 12.2 degrees, about 12.6 degrees, and about 12.8 degrees 2Q. In some embodiments, Form A of compound 14 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3 degrees, about 8.8 degrees, about 12.2 degrees, about 12.6 degrees, and about 12.8 degrees 2Q. In some embodiments, Form A of compound 14 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3 degrees, about 8.8 degrees, about 12.2 degrees, about 12.6 degrees, and about 12.8 degrees 2Q. In some embodiments, Form A of compound 14 is characterized by five peaks in its X-ray powder diffraction pattern selected from those at about 6.3 degrees, about 8.8 degrees, about 12.2 degrees, about 12.6 degrees, and about 12.8 degrees 2Q.

[0461] In some embodiments, Form A of compound 14 is characterized by each of the spectral peaks listed in Table 15 in its X-ray powder diffraction pattern with a relative intensity greater than 10%, 20%, 30%, or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Table 15. Figure 14A.1

[0462] Methods for preparing Form A of compound 14 are described hereinafter.

[0463] In some embodiments, the present disclosure provides compound 14:

[0464]

[0465] wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 14, wherein the compound is substantially free of amorphous compound 14.

[0466] In some embodiments, the present disclosure provides compound 14, wherein the compound is substantially free of impurities.

[0467] ​In some embodiments, the present disclosure provides Compound 14, wherein the compound has one or more peaks in its XRPD selected from those at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2Q. In some such embodiments, the present disclosure provides Compound 14, wherein the compound has at least two peaks in its XRPD selected from those at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2Q. In some such embodiments, the present disclosure provides Compound 14, wherein the compound is Form A.

[0468] In some embodiments, the present disclosure provides Compound 14, wherein the XRPD of the compound is substantially similar to that depicted in Figure 14A.1

[0469] In some embodiments, the present disclosure provides a composition comprising Compound 14 and a pharmaceutically acceptable carrier or excipient.

[0470] In some embodiments, the present disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient Compound 14, or a composition thereof. In some embodiments, the adrenergic receptor is selected from the group consisting of a b1 -adrenergic receptor and a b2-adrenergic receptor.

[0471] In some embodiments, the present disclosure provides a method of treating a disease or condition mediated by a b1 -adrenergic receptor or a b2-adrenergic receptor in a patient, comprising administering to the patient Compound 14, or a composition thereof.

[0472] General methods for providing salt compounds

[0473] Compound 1 can be prepared according to the general schemes provided below:

[0474]

[0475] Scheme 1. Preparation of Compound 1

[0476] Salt compounds of general formula A, which encompasses inter alia salt compounds 2 to 12 and / or specific forms thereof, are prepared from Compound 1 according to the general scheme below.

[0477]

[0478] Scheme 2. Preparation of salts of formula A

[0479] ​For example, each of compounds 2-14 and forms thereof are prepared from compound 1 by combining compound 1 with a suitable acid to form a salt of the acid. Accordingly, another aspect of the present disclosure provides a method for preparing compounds 2-14 and forms thereof.

[0480] As generally described above, in some embodiments, the present disclosure provides a method for preparing a salt compound of general formula A:

[0481]

[0482] The method comprises the steps of:

[0483] combining compound 1:

[0484]

[0485] with a suitable acid and optionally a suitable solvent under conditions suitable to form a salt of formula A.

[0486] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the present disclosure provides a method of preparing a hydrochloride salt of compound 1. In certain embodiments, the hydrochloride salt of compound 1 is compound 2. In certain embodiments, the hydrochloride salt of compound 1 is form A of compound 2. In certain embodiments, the hydrochloride salt of compound 1 is form B of compound 2. In certain embodiments, the hydrochloride salt of compound 1 is form C of compound 2.

[0487] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the present disclosure provides a method of preparing a sulfate salt of compound 1. In certain embodiments, the sulfate salt of compound 1 is compound 3. In certain embodiments, the sulfate salt of compound 1 is form A of compound 3.

[0488] In some embodiments, the suitable acid is hydrobromic acid. In some embodiments, the present disclosure provides a method of preparing a hydrobromide salt of compound 1. In certain embodiments, the hydrobromide salt of compound 1 is compound 4. In certain embodiments, the hydrobromide salt of compound 1 is form A of compound 4.

[0489] In some embodiments, the suitable acid is toluenesulfonic acid. In some embodiments, the present disclosure provides a method of preparing a toluenesulfonate salt of compound 1. In certain embodiments, the toluenesulfonate salt of compound 1 is compound 5. In certain embodiments, the toluenesulfonate salt of compound 1 is form A of compound 5.

[0490] In some embodiments, a suitable acid is maleic acid. In some embodiments, the present disclosure provides a method of preparing a maleic acid salt of Compound 1. In certain embodiments, the maleic acid salt of Compound 1 is Compound 6. In certain embodiments, the maleic acid salt of Compound 1 is Form A of Compound 6.

[0491] In some embodiments, a suitable acid is fumaric acid. In some embodiments, the present disclosure provides a method of preparing a fumaric acid salt of Compound 1. In certain embodiments, the fumaric acid salt of Compound 1 is Compound 7. In certain embodiments, the fumaric acid salt of Compound 1 is Form A of Compound 7.

[0492] In some embodiments, a suitable acid is glycolic acid. In some embodiments, the present disclosure provides a method of preparing a glycolic acid salt of Compound 1. In certain embodiments, the glycolic acid salt of Compound 1 is Compound 8. In certain embodiments, the glycolic acid salt of Compound 1 is Form A of Compound 8.

[0493] In some embodiments, a suitable acid is L-tartaric acid. In some embodiments, the present disclosure provides a method of preparing an L-tartaric acid salt of Compound 1. In certain embodiments, the L-tartaric acid salt of Compound 1 is Compound 9. In certain embodiments, the L-tartaric acid salt of Compound 1 is Form A of Compound 9.

[0494] In some embodiments, a suitable acid is L-malic acid. In some embodiments, the present disclosure provides a method of preparing an L-malic acid salt of Compound 1. In certain embodiments, the L-malic acid salt of Compound 1 is Compound 10. In certain embodiments, the L-malic acid salt of Compound 1 is Form A of Compound 10.

[0495] In some embodiments, a suitable acid is D-mandelic acid. In some embodiments, the present disclosure provides a method of preparing a D-mandelic acid salt of Compound 1. In certain embodiments, the D-mandelic acid salt of Compound 1 is Compound 11. In certain embodiments, the D-mandelic acid salt of Compound 1 is Form A of Compound 11.

[0496] In some embodiments, a suitable acid is L-lactic acid. In some embodiments, the present disclosure provides a method of preparing an L-lactic acid salt of Compound 1. In certain embodiments, the L-lactic acid salt of Compound 1 is Compound 12. In certain embodiments, the L-lactic acid salt of Compound 1 is Form A of Compound 12.

[0497] In some embodiments, a suitable acid is D-camphoric acid. In some embodiments, the disclosure provides a method of preparing a D-camphoric acid salt of Compound 1. In certain embodiments, the D-camphoric acid salt of Compound 1 is Compound 13. In certain embodiments, the D-camphoric acid salt of Compound 1 is Form A of Compound 13. In certain embodiments, the D-camphoric acid salt of Compound 1 is Form B of Compound 13.

[0498] In some embodiments, a suitable acid is dibenzoyl-D-tartaric acid. In some embodiments, the disclosure provides a method of preparing a dibenzoyl-D-tartaric acid salt of Compound 1. In certain embodiments, the dibenzoyl-D-tartaric acid salt of Compound 1 is Compound 14. In certain embodiments, the dibenzoyl-D-tartaric acid salt of Compound 1 is Form A of Compound 14.

[0499] A suitable solvent can be any solvent system (e.g., one solvent or a mixture of solvents) in which Compound 1 and / or the acid is soluble or at least partially soluble.

[0500] Examples of suitable solvents that can be used in the presently disclosed methods include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, a suitable solvent includes an ether, an ester, an alcohol, a ketone, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0501] In certain embodiments, a suitable solvent is methanol, ethanol, isopropanol, or acetone, wherein the solvent is anhydrous or combined with water or heptane. In some embodiments, a suitable solvent includes tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glycol dimethyl ether, diglycol dimethyl ether, methyl tert-butyl ether, tert-butyl alcohol, n-butyl alcohol, and acetonitrile. In some embodiments, a suitable solvent is ethanol. In some embodiments, a suitable solvent is anhydrous ethanol. In some embodiments, a suitable solvent is MTBE.

[0502] In some embodiments, a suitable solvent is ethyl acetate. In some embodiments, a suitable solvent is methanol. In some embodiments, a suitable solvent is dichloromethane. In some embodiments, a suitable solvent is acetonitrile. In some embodiments, a suitable solvent is isopropanol. In certain embodiments, a suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, a suitable solvent is diethyl ether. In certain embodiments, a suitable solvent is water. In certain embodiments, a suitable solvent is methyl ethyl ketone. In certain embodiments, a suitable solvent is toluene.

[0503] In some embodiments, the present disclosure provides a method for preparing a salt compound of Formula A, the method comprising one or more steps of removing a solvent and adding a solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. Methods of solvent removal are known in the art of synthesis and chemistry and include, but are not limited to, any of those methods described herein and in the Examples.

[0504] In some embodiments, a method for preparing a salt compound of Formula A comprises one or more steps of heating or cooling the preparation.

[0505] In some embodiments, a method for preparing a salt compound of Formula A comprises one or more steps of agitating or stirring the preparation.

[0506] In some embodiments, a method for preparing a salt compound of Formula A comprises slow evaporation of the solvent. In some embodiments, a method for preparing a salt compound of Formula A comprises slow evaporation of the solvent by exposure to ambient atmosphere at room temperature. In some embodiments, a method for preparing a salt compound of Formula A comprises evaporation of the solvent under a stream of inert gas, such as nitrogen.

[0507] In some embodiments, a method for preparing a salt compound of Formula A comprises the step of adding a suitable acid to a solution or slurry of Compound 1.

[0508] In some embodiments, a method for preparing a salt compound of Formula A comprises a heating step.

[0509] In certain embodiments, the salt compound of Formula A is precipitated from a mixture. In another embodiment, the salt compound of Formula A is crystallized from a mixture. In other embodiments, the salt compound of Formula A is crystallized from a solution after seeding the solution (i.e., adding a crystal of the salt compound of Formula A to the solution).

[0510] The salt compound of Formula A can be precipitated from the reaction mixture or produced by partial or complete removal of solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, adsorption, and reaction, by addition of an antisolvent such as heptane, by cooling, or by different combinations of these methods.

[0511] As generally described above, the salt compound of Formula A is optionally isolated. It is understood that the salt compound of Formula A can be isolated by any suitable physical means known to one of ordinary skill in the art. In certain embodiments, the precipitated solid salt compound of Formula A is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of Formula A is separated from the supernatant by decanting the supernatant.

[0512] In certain embodiments, the salt compound of Formula A is separated from the supernatant by filtration.

[0513] In certain embodiments, the isolated salt compound of Formula A is dried in air. In other embodiments, the isolated salt compound of Formula A is dried under reduced pressure, optionally at elevated temperature.

[0514] Uses of Compounds and Pharmaceutically Acceptable Compositions

[0515] As generally described above, the compounds 1 described herein, and pharmaceutically acceptable solid forms and salts thereof, are adrenergic receptor modulating compounds (e.g., agonists, partial agonists, or antagonists of adrenergic receptors). In some embodiments, the adrenergic receptor modulating compounds of the present disclosure are found to be useful for modulating the activity of target adrenergic receptors in vitro or in vivo. Aspects of the subject methods include contacting a sample with an effective amount of an adrenergic receptor modulating compound (e.g., as described herein) to determine whether a desired activity is present.

[0516] Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the body and play important roles in modulating a variety of physiological processes, including cognition, stress-related behaviors, inflammation, smooth muscle contraction / dilation, cardiac muscle contraction, airway reactivity, and cognition. Adrenergic receptors mediate the central and peripheral effects of norepinephrine (NA) and epinephrine. There are multiple subtypes of ADRs, including alpha- and beta-adrenergic receptors. Each subtype is expressed in different patterns and is involved in different physiological processes. Thus, ligands that selectively target one subtype are valuable both as research tools to identify the roles of different ADR subtypes and as therapeutic agents for a variety of diseases associated with dysfunction of the NA and epinephrine systems.

[0517] Beta-adrenergic receptors further include three subtypes: beta 1 -adrenergic receptors (β1-ADR), beta 2-adrenergic receptors (β2-ADR), and beta 3-adrenergic receptors (β3-ADR). Because these subtypes are expressed in different patterns and are involved in different physiological processes, ligands that selectively target one subtype have the potential to treat a variety of diseases. However, due to the high level of sequence homology among these subtypes, the discovery of subtype-selective ligands has been challenging. Many existing beta-adrenergic receptor agonists also exhibit poor blood-brain barrier (BBB) penetration, which is necessary for central nervous system (CNS) indications drug discovery.

[0518] As a class of G protein-coupled receptors, adrenergic receptors signal through G protein and β-arrestin dependent pathways. G protein or β-arrestin signaling can mediate different physiological responses. Recently, it has become clear that agonists can display biased activation of signaling pathways. The ability of a ligand to activate a receptor in a pathway-dependent manner and generate a response is referred to as "signaling bias" or "functional selectivity." Because G protein and β-arrestin mediate different physiological processes, biased agonists can provide improved therapeutic selectivity and reduced adverse effects. Accordingly, the present disclosure relates to β-adrenergic receptor subtype selective agonists with improved blood brain barrier (BBB) penetration.

[0519] In certain embodiments, the compounds disclosed herein are agonists, partial agonists, or antagonists of adrenergic receptors; in some embodiments, the compounds are β1 -adrenergic receptor agonists, β2-adrenergic receptor agonists, or nonselective β1 / β2-adrenergic receptor agonists; in some embodiments, the compounds are β1 -adrenergic receptor agonists; in some embodiments, the compounds are β2-adrenergic receptor agonists; in some embodiments, the compounds are nonselective β1 / β2-adrenergic agonists.

[0520] An adrenergic receptor modulating compound can be an agonist of the target adrenergic receptor. In some cases, an effective amount of an adrenergic receptor modulating compound is an amount sufficient to activate an activity associated with an adrenergic receptor in a cell by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or even more relative to a control, e.g., a control cell exhibiting a known level of receptor activity.

[0521] An adrenergic receptor modulating compound can be a partial agonist of the target adrenergic receptor. In some cases, an effective amount of an adrenergic receptor modulating compound is an amount sufficient to achieve partial agonism of an adrenergic receptor in a cell relative to a control, e.g., a receptor that is fully activated, e.g., where the subject compound achieves 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of receptor activation. Partial agonism can be assessed using any convenient method, such as a cell-based assay using a known full agonist as a 100% activation control, where the relative maximum activation of the receptor can be measured relative to the full agonist.

[0522] The adrenergic receptor modulating compound can be an antagonist of the target adrenergic receptor. In some cases, an effective amount of the adrenergic receptor modulating compound is an amount sufficient to inhibit or reduce the activity of the target adrenergic receptor in a sample by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or even more relative to a control, e.g., a sample that has not been contacted with the compound of interest.

[0523] In some embodiments, the compounds of the present disclosure act as low nM partial agonists of the β2 adrenergic receptor. For example, in some embodiments, the EC50of a compound of the present disclosure is less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 15 nM, less than about 20 nM, less than 25 nM, less than 30 nM, less than 35 nM, less than 40 nM, less than 45 nM, less than 50 nM, less than 55 nM, less than 60 nM, less than 65 nM, less than 70 nM, less than 75 nM, less than 80 nM, less than 85 nM, less than 90 nM, less than 95 nM, or less than 100 nM. 50 In some embodiments, the compounds of the present disclosure act as low nM partial agonists of the β2 adrenergic receptor and the EC50is less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 15 nM, less than about 20 nM, less than 25 nM, less than 30 nM, less than 35 nM, less than 40 nM, less than 45 nM, less than 50 nM, less than 55 nM, less than 60 nM, less than 65 nM, less than 70 nM, less than 75 nM, less than 80 nM, less than 85 nM, less than 90 nM, less than 95 nM, or less than 100 nM. 50 In some embodiments, the compounds of the present disclosure act as low nM partial agonists of the β2 adrenergic receptor and the EC50is less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 15 nM, less than about 20 nM, less than 25 nM, less than 30 nM, less than 35 nM, less than 40 nM, less than 45 nM, less than 50 nM, less than 55 nM, less than 60 nM, less than 65 nM, less than 70 nM, less than 75 nM, less than 80 nM, less than 85 nM, less than 90 nM, less than 95 nM, or less than 100 nM.

[0524] In some embodiments, the compounds of the present disclosure act as low μΜ partial agonists of the β2 adrenergic receptor. For example, in some embodiments, the EC50of a compound of the present disclosure is less than about 0.1 μΜ, less than about 0.5 μΜ, less than about 1.0 μΜ, less than about 1.5 μΜ, less than about 2.0 μΜ, less than about 2.5 μΜ, less than about 3.0 μΜ, less than about 3.5 μΜ, less than about 4.0 μΜ, less than about 4.5 μΜ, less than about 5.0 μΜ, less than about 5.5 μΜ, less than about 6.0 μΜ, less than about 6.5 μΜ, less than about 7.0 μΜ, less than about 7.5 μΜ, less than about 8.0 μΜ, less than about 8.5 μΜ, less than about 9.0 μΜ, less than about 9.5 μΜ, or less than about 10.0 μΜ. 50 In some embodiments, the compounds of the present disclosure act as low μΜ partial agonists of the β2 adrenergic receptor and the EC50is less than about 0.1 μΜ, less than about 0.5 μΜ, less than about 1.0 μΜ, less than about 1.5 μΜ, less than about 2.0 μΜ, less than about 2.5 μΜ, less than about 3.0 μΜ, less than about 3.5 μΜ, less than about 4.0 μΜ, less than about 4.5 μΜ, less than about 5.0 μΜ, less than about 5.5 μΜ, less than about 6.0 μΜ, less than about 6.5 μΜ, less than about 7.0 μΜ, less than about 7.5 μΜ, less than about 8.0 μΜ, less than about 8.5 μΜ, less than about 9.0 μΜ, less than about 9.5 μΜ, or less than about 10.0 μΜ.

[0525] In some embodiments, the compounds of the present disclosure act as low μΜ partial agonists of the β2 adrenergic receptor and the EC50is less than about 0.1 μΜ, less than about 0.5 μΜ, less than about 1.0 μΜ, less than about 1.5 μΜ, less than about 2.0 μΜ, less than about 2.5 μΜ, less than about 3.0 μΜ, less than about 3.5 μΜ, less than about 4.0 μΜ, less than about 4.5 μΜ, less than about 5.0 μΜ, less than about 5.5 μΜ, less than about 6.0 μΜ, less than about 6.5 μΜ, less than about 7.0 μΜ, less than about 7.5 μΜ, less than about 8.0 μΜ, less than about 8.5 μΜ, less than about 9.0 μΜ, less than about 9.5 μΜ, or less than about 10.0 μΜ. 50from about 0.01 μΜ to about 10 μΜ, from about 0.01 μΜ to about 9.0 μΜ, from about 0.01 μΜ to about 8.0 μΜ, from about 0.01 μΜ to about 7.0 μΜ, from about 0.01 μΜ to about 6.0 μΜ, from about 0.01 μΜ to about 5.0 μΜ, from about 0.01 μΜ to about 4.0 μΜ, from about 0.01 μΜ to about 3.0 μΜ, from about 0.01 μΜ to about 2.0 μΜ, from about 0.01 μΜ to about 1.0 μΜ, from about 0.01 μΜ to about 9.0 μΜ, from about 0.1 μΜ to about 1.0 μΜ.

[0526] In some embodiments of the method, the target adrenergic receptor is a β1 -adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β2-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β3-adrenergic receptor. In some embodiments, the compound is an agonist of both β1 -adrenergic receptor and β2-adrenergic receptor. In certain cases, the compound is selective for the β2-adrenergic receptor over the β1 -adrenergic receptor.

[0527] The target adrenergic receptor can be a receptor responsible for mediating an intracellular signal or pathway in a cell. In some embodiments, the sample comprises a cell and modulating the adrenergic receptor modulates a physiological process in the cell. Any convenient physiological process can be targeted for modulation in the cell using the subject methods. In some embodiments, the physiological process is a process related to cardiac function, in certain cases, the physiological process is a process related to cognitive function. In certain cases, the physiological process is a process related to an inflammatory pathway or condition. The subject methods can provide mediation of intracellular concentrations of signaling molecules in the cell, such as cAMP. The subject methods can provide partial or complete blockade of the target adrenergic receptor to produce modulation (e.g., activation) of cAMP in the sample. In some embodiments, the method does not modulate the β-arrestin pathway of the cell. In some cases, the cell is an inflammatory cell and the function of the cell is modulated. The subject methods can provide inhibition of an inflammatory pathway in the cell. In some cases, TNF-α is inhibited in the cell, e.g., by reducing the concentration or production of TNF-α by practicing the subject methods. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulating the adrenergic receptor enhances neurogenesis.

[0528] Further disclosed is a method of treating a subject having a disease, the method comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, i.e., a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and any polymorphic form thereof. In some embodiments, the disease is a disease or disorder mediated by a β1 -adrenergic receptor or a β2-adrenergic receptor in the patient.

[0529] In some embodiments, the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, other demyelination-related disorders, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementia, cerebrovascular inflammation, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject by oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epidermal, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernous, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route.

[0530] In some embodiments, the disease is a neurodegenerative disease that is one or more selected from the group consisting of MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett Syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / drowsiness, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (CJD, etc.), depression, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (dementia with PD), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down's syndrome (DS). In some embodiments, the disease is a neurodegenerative disease that is one or more selected from the group consisting of MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett Syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / drowsiness, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (CJD, etc.), depression, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (dementia with PD), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not have Alzheimer's disease (AD). In some embodiments, the subject does not have Down's syndrome.

[0531] In certain embodiments of the methods disclosed herein, the methods comprise administering to the subject a compound as disclosed herein and a peripherally acting beta-blocker (PABRA).

[0532] As used herein, the term "peripherally acting beta-blocker (PABRA)" means a beta adrenergic receptor antagonist or simply means a beta1-, beta2-, or non-selective beta- blocker. Examples of selective peripherally acting beta-blockers (PABRAs) that can be used in the methods disclosed herein in certain embodiments include nadolol, atenolol, sotalol, and labetalol. In certain embodiments, the beta-blocker that can be used in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, and nevivolol; in other embodiments, the methods do not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, or nevivolol as the beta-blocker.

[0533] In certain embodiments, a peripherally acting beta-blocker (PABRA) is administered to the subject prior to administration of a compound of the disclosure; in other embodiments, a peripherally acting beta-blocker (PABRA) is administered to the subject concurrently with administration of a compound of the disclosure.

[0534] In certain embodiments of the compositions and methods provided herein, one or more peripherally acting beta-blockers (PABRAs) are administered prior to or concurrently with a compound of the disclosure in order to inhibit or preclude agonism of peripheral beta1 and / or beta2 adrenergic receptors by the compounds of the disclosure. In various embodiments, it is preferred that the compositions and methods according to the disclosure block peripheral beta1 and / or beta2 adrenergic receptors in order to preclude or at least minimize any adverse peripheral cardiac, metabolic, or muscle effects on a human receiving treatment.

[0535] In some embodiments of the methods provided herein, a patient is administered a beta1 agonist and / or a beta2 agonist or a non-selective beta1 / beta2 agonist in addition to a compound as disclosed herein.

[0536] As used herein, the term "β1 agonist" is used to mean a β1 -adrenergic receptor agonist or a β1 -ADR agonist. In certain embodiments, the term β1 agonist is understood to include compounds that are primarily β1 agonists, but which can also exhibit some peripheral agonism of other adrenergic receptors, such as β2-adrenergic receptors. In the present application, the terms "β1 -adrenergic receptor agonist," "β1 -ADR agonist," "β1 AR agonist," and "β1 agonist" can be used interchangeably. In certain embodiments, the term β1 -ADR agonist expressly includes both selective and partial agonists, as well as biased and unbiased agonists. Examples of β1 adrenergic agonists include, for example, xamoterol, norepinephrine, isoprenaline, dopamine, pindolol, and dobutamine, and pharmaceutically acceptable salts of any of the above drugs. Partial agonists and ligands of β1 -ADR are known. Further, using the methods of Kolb et al., but for β1 -ADR, one of skill in the art can determine new ligands through structure-based discovery. See Proc. Natl. Acad. Sci. USA 2009, 106, 6843-648.

[0537] As used herein, the term beta2 agonist is used to mean a beta2-adrenergic receptor agonist or a beta2-ADR agonist. In certain embodiments, the term beta2 agonist is understood to include compounds that are primarily beta2 agonists, but which can also exhibit some peripheral agonism of other adrenergic receptors, such as beta1-adrenergic receptors. In this application, the terms "beta2-adrenergic receptor agonist," "beta2-ADR agonist," "beta2AR agonist," and "beta2 agonist" can be used interchangeably. In some embodiments, the term beta2-ADR agonist expressly includes both selective and partial agonists. Beta2 agonists that can be used in accordance with various aspects and embodiments of the present disclosure can be short-acting, long-acting, or ultra-long-acting. Examples of short-acting beta2 agonists that can be used are salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharine. Examples of long-acting beta2 agonists that can be used are salmeterol, bambuterol, formoterol, and clenbuterol. Examples of ultra-long-acting beta2 agonists include indacaterol, vilanterol, and olodaterol.

[0538] As used herein, the terms "in combination," "in combination with," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, a described compound can be administered with another therapeutic agent either simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form that includes a described compound, another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two agents are generally considered to be "administered in combination" when a patient or subject is simultaneously exposed to both agents. In many embodiments, two or more agents are considered to be "administered in combination" when a patient or subject simultaneously shows therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in the brain, in serum, etc.).

[0539] When the compounds of the disclosure are administered in combination therapy with other agents, the compounds can be administered sequentially or simultaneously to the patient. Alternatively, a pharmaceutical or prophylactic composition according to the disclosure includes ivermectin or any other compound described herein in combination with another therapeutic or prophylactic agent. The additional therapeutic agent that is typically administered to treat a particular disease or condition can be referred to as an "agent appropriate for the disease or condition being treated."

[0540] In some embodiments, the subject methods comprise administration of a therapeutically effective amount of one or more additional active agents. Combination therapy means that the adrenergic receptor modulating compound can be used in combination with another therapeutic agent to treat a single disease or condition. In particular embodiments, administration of a compound of the disclosure is administered concurrently with administration of another therapeutic agent, which can be administered as a component of a composition comprising a compound of the disclosure or as a component of a different composition.

[0541] In various therapeutic applications, the subject compounds can be administered in combination with other therapeutic agents. Therapeutic applications of interest for combination therapy include those in which the activity of the target adrenergic receptor is a cause or contributing factor in the progression of the disease. As such, the subject compounds find use in combination therapies in which inhibition of a target adrenergic receptor in a subject is desired. Examples of disease conditions that can be treated by combination therapy comprising a subject compound include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory disorders, asthma, memory disorders, depression, inflammatory diseases, stroke, ischemic brain or tissue damage, and cancer. Agents of interest that can be used in combination with the subject adrenergic receptor modulating compounds include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, antihypertensives, decongestants, chemotherapeutic agents, agents for Alzheimer's disease, and anti-inflammatory agents.

[0542] The subject adrenergic receptor modulating compounds can be used in combination with any agent used to treat a cardiac condition, such as cardiogenic shock, hypertension, congestive heart failure, coronary heart disease, cardiac arrhythmias, myocardial infarction, or ischemic heart disease. Agents of interest that can be used in combination with the subject adrenergic receptor modulating compounds include, but are not limited to, denopamine, dobutamine, zarno lol, acebutolol, atenolol, betalol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, Carvedilol, labetalol, Phentolamine, Prazosin, Cirazoline, Methoxamine, Synephrine, Etilefrine, Metaraminol, Midodrine, and cumarin.

[0543] The subject adrenergic receptor modulating compounds can be used in combination with any agent used to treat neurodegenerative or neurodevelopmental diseases, such as Alzheimer's disease, memory disorders, cognitive disorders, depression, stroke and ischemic brain or tissue damage, Down's syndrome, or autism. Agents of interest that can be used in combination with the subject adrenergic receptor modulating compounds include, but are not limited to, acepromazine. In some embodiments, the subject adrenergic receptor modulating compounds can be combined with cholinesterase inhibitors or NMDA receptor modulators for the treatment of diseases, such as neurodegenerative or neurodevelopmental diseases. Agents of interest include, but are not limited to: Donepezil, Aricept, Galantamine, Razadyne, Memantine, Namenda, Rivastigmine, Exelon, Tacrine, and Cognex.Other agents of interest that can be used in combination with the subject adrenergic receptor modulating compounds include, but are not limited to: 4-NEMD, 7-methyl-marsanidine, Agmatine, Apraclonidine, Brimonidine, Cannabigerol, Clonidine, Detomidine, Dexmedetomidine, Fadolmidine, Guanabenz, Guanfacine, Lofexidine, Marsanidine, Medetomidine, Methamphetamine, Mivazerol, Rilmenidine, Romifidine, Talipexole, Tiamenidine, Tizanidine, Tolonidine, Xylazine, Xylometazoline, Aripiprazole, Asenapine, Atipamezole, Cirazoline, Clozapine, Efaroxan, Idazoxan, lurasidone, Melperone, Mianserin, Mirtazapine, Napitane, Olanzapine, Paliperidone, Phenoxybenzamine, Phentolamine, Piribedil, Rauwolscine, Risperidone, Rotigotine, Quetiapine, Norquetiapine, Setiptiline, Tolazoline, Yohimbine, Ziprasidone, and Zotepine.Other agents of interest that can be used in combination with the subject adrenergic receptor modulating compounds include, but are not limited to: bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol or levalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, milveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxsuprine, ritodrine, salbutamol, terbutaline, zilpaterol, ICI-118,551, and butoxamine.

[0544] The compounds used in the compositions and methods of the present disclosure can also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and / or alter rate of excretion.

[0545] The term "treatment" is used interchangeably with the term "method of treatment" herein, and refers to both 1) therapeutic treatment or measure for curing, slowing, alleviating, stopping the progression of, or reducing symptoms of a diagnosed pathological condition, disease, or disorder, and 2) prophylactic / preventive measures as well. Patients in need of treatment can include individuals already afflicted with a particular medical disease or disorder, as well as individuals who can eventually acquire the disorder (i.e., individuals who are at risk or in need of prophylactic measures).

[0546] The term "subject" as used herein refers to any individual or patient on whom the subject methods are performed. Typically, the subject is a human, but as will be appreciated by those in the art, the subject can be an animal.

[0547] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like, refer to the amount of the subject compound which will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the administration of the compound. Typically, the response is improvement of the patient's symptoms or the desired biological result. In some embodiments, such amount should be sufficient to modulate an adrenergic receptor.

[0548] In some embodiments, the effective amount of the adrenergic receptor modulating compound is an amount ranging from about 50 ng / ml to 50 pg / ml (e.g., about 50 ng / ml to 40 pg / ml, about 30 ng / ml to 20 pg / ml, about 50 ng / ml to 10 pg / ml, about 50 ng / ml to 1 pg / ml, about 50 ng / ml to 800 ng / ml, about 50 ng / ml to 700 ng / ml, about 50 ng / ml to 600 ng / ml, about 50 ng / ml to 500 ng / ml, about 50 ng / ml to 400 ng / ml, about 60 ng / ml to 400 ng / ml, about 70 ng / ml to 300 ng / ml, about 60 ng / ml to 100 ng / ml, about 65 ng / ml to 85 ng / ml, about 70 ng / ml to 90 ng / ml, about 200 ng / ml to 900 ng / ml, about 200 ng / ml to 800 ng / ml, about 200 ng / ml to 700 ng / ml, about 200 ng / ml to 600 ng / ml, about 200 ng / ml to 500 ng / ml, about 200 ng / ml to 400 ng / ml, or about 200 ng / ml to about ng / ml).

[0549] In some embodiments, the effective amount of the adrenergic receptor modulating compound is an amount ranging from about 10 pg to 100 mg, e.g., about 10 pg to 50 pg, about 50 pg to 150 pg, about 150 pg to 250 pg, about 250 pg to 500 pg, about 500 pg to 750 pg, about 750 pg to 1 ng, about 1 ng to 10 ng, about 10 ng to 50 ng, about 50 ng to 150 ng, about 150 ng to 250 ng, about 250 ng to 500 ng, about 500 ng to 750 ng, about 750 ng to 1 mg, about 1 pg to 10 pg, about 10 pg to 50 pg, about 50 pg to 150 pg, about 150 pg to 250 pg, about 250 pg to 500 pg, about 500 pg to 750 pg, about 750 pg to 1 mg, about 1 mg to 50 mg, about 1 mg to 100 mg, or about 50 mg to 100 mg. The amount can be a single dose amount or can be a total amount per day. The total amount per day can range from about 10 pg to 100 mg, or can range from about 100 mg to 500 mg, or can range from about 500 mg to 1000 mg.

[0550] Also disclosed herein are pharmaceutical compositions comprising a compound as disclosed herein, e.g., any one of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and any polymorphic form thereof.

[0551] The term "pharmaceutically acceptable carrier" means a non-toxic carrier with which the compounds of the present disclosure are administered to a patient and which does not destroy the pharmacological activity thereof. Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0552] In pharmaceutical compositions comprising only the compounds described herein as the active ingredient, the methods for administering these compositions can additionally include the step of administering to the subject an additional agent or therapy. Such therapies include, but are not limited to, anemia therapies, diabetes therapies, hypertension therapies, cholesterol therapies, neuropharmacological drugs, drugs that modulate cardiovascular function, drugs that modulate inflammation, immune function, blood cell production; hormones and antagonists, drugs that affect gastrointestinal function, chemotherapy drugs for microbial diseases, and / or chemotherapy drugs for neoplastic diseases. Other drug therapies can include any other drug or biological agent found in any drug class. For example, other drug classes can include allergy / cold / ENT therapies, analgesics, anesthetics, anti-inflammatory drugs, anti-bacterial drugs, anti-viral drugs, asthma / lung therapies, cardiovascular therapies, dermatological therapies, endocrine / metabolic therapies, gastrointestinal therapies, cancer therapies, immunological therapies, neurology therapies, ophthalmic therapies, psychiatric therapies, or rheumatology therapies. Other examples of agents or therapies that can be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferation compounds.

[0553] The term "therapeutically effective amount" as used herein refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that is predisposed to the disease, condition or disorder but has not yet experienced or expressed the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) relieving the disease; for example, alleviating the disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0554] Pharmaceutically acceptable compositions

[0555] According to the methods of the present disclosure, the compounds and compositions are administered using any amount and any route of administration effective for treating or lessening the severity of the disorders described above. The precise amount required can vary depending on the subject, according to factors such as the species, age, and general condition of the subject, the severity of the infection, the particular agent being employed, its mode of administration and the like. The compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed; and like factors well known in the medical arts.

[0556] The pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral spray, or nasally, etc., in dosage unit formulations containing non-toxic pharmaceutically-acceptable carriers or diluents. In certain embodiments, the compounds of the present disclosure are orally or parenterally administered at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0557] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, baby oil, olive oil, castor oil and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0558] Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0559] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0560] In order to prolong the effect of the compounds of the present disclosure, it is often desirable to slow their absorption from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer, and the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

[0561] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0562] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically-acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0563] Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polethylene glycols and the like.

[0564] The active compounds can also be in micro-encapsulated form, with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings and other coatings known to those skilled in the art of pharmaceutical formulation. In such solid dosage forms the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids, such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents. The compositions can optionally contain opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0565] Dosage forms for topical or transdermal administration of a compound of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as can be required. Ophthalmic formulations, eardrops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0566] All of the features of each of the aspects of the present disclosure apply to all of the other aspects, mutatis mutandis. Each of the references mentioned herein, including but not limited to patents, patent applications, and journal articles, are incorporated by reference herein as if fully set forth in their entirety.

[0567] In order that the disclosure herein described can be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

[0568] Example

[0569] As depicted in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and sub-classes and species of each of these compounds as described herein.

[0570] General procedure

[0571] Solvent list

[0572] Solvent Abbreviation Methanol MeOH Ethanol EtOH 2-Propanol IPA Isobutanol IBA 2-Butanone MEK Tetrahydrofuran THF Acetonitrile ACN Tert-Butyl methyl ether MTBE Acetone - Water - Toluene Tol Ethyl acetate EtOAc Isopropyl acetate iPrOAc n-Heptane Hept

[0573] Analytical methods

[0574] X-ray powder diffraction (XRPD)

[0575] XRPD patterns were identified with an X-ray diffractometer (Bruker D8 advance). The system was equipped with a LynxEye detector. The samples were scanned from 3 to 40° 2theta with a step of 0.02° 2theta. The tube voltage and current were 40 KV and 40 mA, respectively.

[0576] Differential scanning calorimetry (DSC)

[0577] DSC was performed using a Discovery DSC 250 (TA Instruments, US). The sample was placed in an aluminum pin-holed sealed pan and the weight was recorded accurately. The sample was heated from 25 °C to the final temperature at 10 °C / min.

[0578] Thermogravimetric analysis (TGA)

[0579] TGA analysis was performed using a Discovery TGA 55 (TA Instruments, US). The sample was placed in an open tared aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated from ambient temperature to the final temperature at 10 °C / min.

[0580] Dynamic vapor sorption (DVS)

[0581] Moisture sorption / desorption data were collected on a DVS Intrinsic (SMS, UK). The sample was placed in a tared sample chamber and automatically weighed. The sample was dried at 40 °C until dm / dt was less than 0.002% and cooled to 25 °C. Instrument parameter settings details are as follows. Step time (min): 60 min; sample temperature: 25 °C; cycle: full cycle; sorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90; desorption: 80, 70, 60, 50, 40, 30, 20, 10, 0; save data rate: 5 sec; total flow rate: 200 sccm; post experiment total flow: 200 sccm.

[0582] Polarized light microscopy (PLM)

[0583] Light microscopy was performed with a polarized light microscope ECLIPSE LV100 POL (Nikon, JPN).

[0584] Proton nuclear magnetic resonance 1 H NMR

[0585] 1 H NMR was performed using a Bruker Advance 300 equipped with an automation sample (B-ACS 120).

[0586] High performance liquid chromatography (HPLC)

[0587] HPLC analysis was performed with an Agilent HPLC 1260 series instrument. The HPLC method used for solubility and stability testing is listed in Table 16.

[0588] Table 16. HPLC method used for solubility and stability testing

[0589]

[0590]

[0591] Example A: General preparation of compound 1

[0592]

[0593] Step 1: Synthesis of 2-cyano-6-vinylpyridine

[0594] A stirred mixture of 2-chloro-6-cyanopyridine (8.0 g, 69.3 mmol), 1-vinyltri-n- butyltin (21.97 g, 69.29 mmol, 20.34 mL) and Pd(PPh3)4(3.34 g, 3.61 mmol) in anhydrous toluene (150 mL) was bubbled with N2for 5 min and then heated to 80 °C overnight. After cooling, the reaction mixture was poured into an aqueous KF solution (40 g in 200 mL) and stirred for 30 min. The mixture was then filtered through celite and the solid was washed with EtOAc (2 x 50 mL). The aqueous phase of the filtrate was separated and extracted with EtOAc (2 x 250 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 95 / 5 to 90 / 10) to afford 2-cyano-6-vinylpyridine (6.5 g, 86%) as a light yellow liquid. MS (m / z): 131.1 (M+H) + .

[0595] Step 2: Synthesis of 6-(oxirane-2-yl)picolinonitrile

[0596] To a stirred solution of 2-cyano-6-vinylpyridine (6.5 g, 49.94 mmol) in DCM (300 mL) was added mCPBA (61.56 g, 249.72 mmol) portion wise slowly over a period of 30 min at 0 °C and the mixture was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was cooled to 5 °C and saturated aqueous NaHC03solution was added and the solution was extracted with DCM (200 mL x 2). The organic layers were combined, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 90 / 10 to 80 / 20) to afford 6-(oxirane-2-yl)pyridinecarbonitrile (3.85 g, 52%) as a colorless liquid. MS (m / z): 147.1 (M+H) + .

[0597] Step 3: Synthesis of compound 1

[0598] To a stirred solution of 6-(oxirane-2-yl)pyridinecarbonitrile (3.5 g, 18.2 mmol) in ethanol (25 mL) was added tert-butylamine (6.66 g, 91.0 mmol). The reaction mixture was stirred at 80 °C in a sealed tube for 3 h while monitoring the reaction by TLC and LCMS. After completion of the reaction, the solvent was evaporated to yield a residue which was purified by reverse phase chromatography to afford the desired product as a racemic mixture. The racemic mixture was separated by SFC (Chiralpak AS-H (30*250) mm, 5 μ column) using C02: 80% co-solvent: 20% (0.2% isopropylamine in IPA as eluent) to afford compound 1 (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)pyridinecarbonitrile (1.05 g, 26.3%) and (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)pyridinecarbonitrile (0.98 g, 24.5%) as white solids. 1 H NMR 400 MHz, DMSO-d6: δ 8.03 (t, J = 8.0 Hz, 1H), 7.90 (dd, J = 0.8 Hz, 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 5.63 (s, 1H), 4.60 (q, J = 4.4 Hz, 1H), 2.86-2.80 (m, 1H), 2.67-2.49 (m, 1H), 1.44-1.40 (m, 1H), 0.98 (s, 9H). (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)pyridinecarbonitrile: 1H NMR 400 MHz, DMSO-d6: δ 8.03 (t, J = 7.6 Hz, 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H), 4.6 (s, 1H), 2.81-2.82 (m, 1H), 2.62-2.64 (m, 1H), 1.44 (s, 1H), 0.98 (s, 9H).

[0599] Example 1: Preparation of Compound 1 Free Base Forms A and B

[0600]

[0601] Compound 1 was prepared as described elsewhere herein.

[0602] Form A of Compound 1

[0603] Form A of Compound 1 was prepared as described in Example A and formed as a white solid directly from IPA / isopropylamine cosolvent.

[0604] Characterization of the resulting material exhibited crystalline Form A of Compound 1 free base.

[0605] Table 1 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 1.

[0606] Table 1 - XRPD Peak Positions for Form A of Compound 1

[0607]

[0608]

[0609] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0610] Figure 1A.1 An XRPD pattern of Form A of Compound 1 is depicted.

[0611] Figure 1A.2 A DSC thermogram and TGA trace of Form A of Compound 1 are depicted. The DSC thermogram of Form A of Compound 1 is characterized by two endothermic peaks at about 100 °C and about 104 °C.

[0612] Figure 1A.3 A DSC thermogram and TGA trace of Form A of Compound 1 are depicted. The DSC thermogram of Form A of Compound 1 is characterized by two endothermic peaks at about 100 °C and about 104 °C. 1 H NMR spectrum.

[0613] Form B of Compound 1

[0614] Form B of Compound 1 was prepared as follows:

[0615] Procedure A: A solution of compound 1 was dissolved in THF (5 volumes) and stirred at room temperature (<25 °C). After 2 hours, H2O (5 volumes) was added, followed by 3M aqueous HC1 (2 volumes). The mixture was extracted with dichloromethane (4 x 1 volumes). The pH of the resulting aqueous solution was adjusted to about 9 with concentrated aqueous NH4OH solution and extracted with dichloromethane (5 x 3 volumes). The combined organics were filtered and concentrated to yield Form B of compound 1 as a light brown solid.

[0616] Characterization of the resulting material exhibited crystalline Form B of compound 1 free base.

[0617] Table 2 above is reproduced below and lists the X-ray diffraction peaks observed for Form B of compound 1.

[0618] Table 2 - XRPD peak positions for Form B of compound 1

[0619] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.9 6.7 23.9 18.3 9.3 100.0 24.1 10.8 9.6 23.7 25.0 37.7 10.6 12.0 25.4 7.3 12.6 25.2 25.9 7.3 14.7 7.3 27.4 3.8 15.7 8.2 28.4 18.6 16.4 22.3 29.1 9.8 16.9 56.5 29.6 11.6 17.5 13.0 30.6 6.8 18.1 5.0 31.6 3.6 18.8 34.2 32.4 3.9 19.3 9.5 34.3 7.0 19.9 6.8 36.1 3.6 20.6 68.2 37.3 4.9 22.0 6.6 38.3 5.0 22.4 18.3 38.5 4.4 23.5 24.3

[0620] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0621] Figure 1B.1 An XRPD pattern of Form B of compound 1 is depicted.

[0622] Figure 1B.2 A DSC thermogram and TGA trace of Form B of compound 1 are depicted. The DSC thermogram of Form B of compound 1 is characterized by an endothermic peak at about 100 °C.

[0623] Figure 1B.3 A DSC thermogram and TGA trace of Form B of compound 1 are depicted. The DSC thermogram of Form B of compound 1 is characterized by an endothermic peak at about 100 °C. 1 H NMR spectrum.

[0624] Example 2: Preparation of Form A of compound 2

[0625]

[0626] Form A of compound 2

[0627] Form A of compound 2 was prepared as follows:

[0628] Procedure A: Compound 1 (3.5 g) was dissolved in 35 mL IPA at 50 °C. Hydrochloric acid (1.05 equivalents) was added. The resulting mixture was cooled to room temperature. After 2 hours, the solids were collected by filtration and dried under vacuum at 50 °C for 2 hours to yield Form A of compound 2 (3.28 g, 80% yield, about 100% purity, 0.16% IPA).

[0629] Procedure B: Compound 1 (20.0 mg) was dissolved in IPA (15V) at 50 °C. The solution was allowed to cool to room temperature. Hydrochloric acid (1.05 equivalents) was added at room temperature. The resulting mixture was stirred for 2 hours. The solids were collected by filtration and dried under vacuum at 50 °C for 2 hours to yield Compound 2 Form A (71% yield, ~100% purity, 0.31% IPA).

[0630] Procedure C: Compound 1 (20.0 mg) was dissolved in IPA (10V) at 50 °C. Hydrochloric acid (1.05 equivalents) was added at 50 °C. The resulting mixture was stirred at 50 °C for 0.5 hours and then allowed to warm to room temperature after 1.5 hours, the solids were collected by filtration and dried under vacuum at 50 °C for 2 hours to yield Compound 2 Form A (77% yield, ~100% purity, 0.12% IPA).

[0631] Procedure D: Compound 1 (20.0 mg) was added to IPA (10V) at room temperature. Hydrochloric acid (1.05 equivalents) was added. The resulting slurry was allowed to stir for 2 hours. The solids were collected by filtration and dried under vacuum at 50 °C for 2 hours to yield Compound 2 Form A (76% yield, ~100% purity, 0.20% IPA).

[0632] Procedure E: Compound 1 (20.0 mg) was mostly dissolved in EtOH / EtOAc (1:3; 10V) at room temperature. Hydrochloric acid (1.05 equivalents) was added. The resulting mixture was stirred at room temperature for 2 hours. The solids were collected by filtration and dried under vacuum at 50 °C for 2 hours to yield Compound 2 Form A (70% yield, ~100% purity, negligible solvent).

[0633] Procedure F: Compound 1 was added to EtOAc (15V) at room temperature. Hydrochloric acid (1.05 equivalents) was added. The resulting slurry was stirred for 4 hours. The solids were collected by filtration to yield Compound 2 Form A.

[0634] Procedure G: Compound 1 (198.1 mg) was added to EtOAc (4 mL) at room temperature. Hydrochloric acid (1.05 equivalents) was added and the resulting precipitate was stirred at room temperature for 3 hours. The solids were collected by filtration at 50 °C for 1 day to yield Compound 2 Form A.

[0635] Procedure H: Compound 1 (4 g) was dissolved in EtOAc (8 V). D- mandelic acid (2.4 g) was then added to the solution. The mixture was stirred at room temperature for 10 minutes. Heptane (25 V) was added to the mixture at room temperature and the suspension was stirred at 50 °C for 2 hours and then at room temperature for another 1.5 hours. The resulting solid was collected by filtration and dried under vacuum at 50 °C overnight to yield Compound 11 (5.8 g, 91% yield). The resulting Compound 11 was added to EtOAc (2.58 V) and mixed to make a suspension. Concentrated HC1 (1.2 mL) was added and the suspension became clear. The solution was stirred at room temperature for 10 minutes and MTBE (25.8 V) and Compound 2 Form A seed (10.12 mg) were added. The solid precipitated immediately. The suspension was stirred at room temperature for 3 hours. The resulting solid was collected by filtration and dried under vacuum at 50 °C overnight. The solid was added to an EtOAc / MTBE solvent mixture (0.88 volume of EtOAc + 7.92 volume of MTBE) and stirred at room temperature for 10 minutes. The solid was filtered and dried under vacuum at 50 °C for 3 hours to yield Compound 2 Form A (2.23 g, 53% yield, 99.9% purity).

[0636] The characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 2.

[0637] Table 3 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 2.

[0638] Table 3 - XRPD peak positions for Form A of Compound 2

[0639] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.9 12.4 27.8 6.7 10.6 100.0 28.0 29.0 12.6 1.8 28.4 2.1 13.9 3.6 29.4 2.6 15.6 19.7 30.4 1.7 17.7 2.5 31.6 5.5 19.3 59.9 32.2 18.1 19.9 8.5 34.6 2.2 21.0 8.6 35.4 2.5 21.3 6.0 36.3 1.6 23.8 83.2 36.8 1.3 25.4 6.9 37.4 3.6 25.6 4.4 38.3 2.3 26.6 2.0 39.3 2.5

[0640] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0641] Figure 2A.1 An XRPD pattern of Form A of Compound 2 is depicted.

[0642] Figure 2A.2 A DSC thermogram and TGA trace of Form A of Compound 2 are depicted. The TGA trace shows little weight loss prior to decomposition. The DSC thermogram of Form A of Compound 2 is characterized by an endothermic peak at about 215 °C.

[0643] Figure 2A.3 and 2A.4 A DVS plot of Form A of Compound 2 is depicted. The DVS results indicate that Form A is slightly hygroscopic with a water uptake of 0.58% at 80% RH. The XRPD pattern remained unchanged after the DVS test.

[0644] Ion chromatography analysis of Form A of Compound 2 determined the HC1 content to be about 13.5%, indicating that Form A of Compound 2 is a mono-HC1 salt (theoretical value of 14.26%).

[0645] Example 3: Preparation of Form A of Compound 3

[0646]

[0647] Form A of Compound 3

[0648] Form A of Compound 3 was prepared as follows:

[0649] Procedure A: Compound 1 (20.4 mg) was dissolved in iPrOAc (20 V) at room temperature. Sulfuric acid (0.6 equivalents) was added. The solid precipitated rapidly. The solid was collected by filtration and dried under vacuum to yield Compound 3 Form A.

[0650] Characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 3 with no residual organic solvent observed by NMR.

[0651] Table 4 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 3.

[0652] Table 4 - XRPD Peak Positions for Form A of Compound 3

[0653] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.4 60.8 25.8 5.0 10.2 6.0 26.4 5.1 11.1 100.0 26.9 8.2 12.2 5.8 27.9 6.6 13.3 12.7 28.9 5.7 15.8 15.9 30.5 4.9 16.1 37.7 31.0 5.3 17.8 18.7 31.4 4.7 18.4 35.7 31.7 5.8 19.3 5.4 31.9 7.4 21.3 12.4 32.4 6.0 21.9 32.7 33.6 7.4 22.7 39.1 34.9 4.6 23.4 15.5 35.4 4.1 23.8 73.9 36.8 5.3 24.7 13.3 37.4 3.8

[0654] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0655] Figure 3A.1 An XRPD pattern of Form A of Compound 3 is depicted.

[0656] Figure 3A.2 A DSC thermogram and TGA trace of Form A of Compound 3 are depicted. The TGA trace shows little weight loss prior to decomposition. The DSC thermogram of Form A of Compound 3 is characterized by an endothermic peak at about 247 °C.

[0657] Example 4: Preparation of Form A of Compound 4

[0658]

[0659] Form A of Compound 4

[0660] Form A of Compound 4 was prepared as follows:

[0661] Procedure A: Compound 1 was dissolved in EtOAc (20V) at room temperature. HBr acid (1.05 equivalents) was added, resulting in a precipitate. The solid was collected by filtration and dried under vacuum at 50 °C to yield Compound 4 Form A.

[0662] Characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 4, with no residual organic solvent observed by NMR.

[0663] Table 5 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 4.

[0664] Table 5 - XRPD peak positions for Form A of Compound 4

[0665] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.8 42.7 28.9 3.2 10.6 100.0 30.1 3.7 11.5 11.5 30.4 3.4 13.6 5.9 30.9 11.7 15.6 31.1 31.3 6.3 17.5 5.6 31.6 6.1 18.8 40.0 32.1 11.7 19.5 10.7 32.5 2.8 20.5 2.4 34.1 3.4 21.1 2.6 34.5 6.0 21.3 8.4 35.2 3.3 23.5 55.9 35.5 4.0 24.9 13.5 36.7 2.6 25.4 15.2 37.1 4.3 26.8 4.7 37.4 5.1 27.4 48.2 38.2 5.0 28.1 4.8 39.2 1.6 286 100 397 21

[0666] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0667] Figure 4A.1 An XRPD pattern of Form A of Compound 4 is depicted.

[0668] Figure 4A.2 A DSC thermogram and TGA trace of Form A of Compound 4 are depicted. The TGA trace shows no weight loss prior to decomposition. The DSC thermogram of Form A of Compound 4 is characterized by an endothermic peak at about 173 °C.

[0669] Example 5: Preparation of Form A of Compound 5

[0670]

[0671] Form A of Compound 5

[0672] Form A of Compound 5 was prepared as follows:

[0673] Procedure A: Compound 1 (20.2 mg) was added to iPrOAc (20V) at room temperature and stirred. p-toluenesulfonic acid (1.05 equivalents) was added, resulting in a slurry. The solid was collected by filtration and dried under vacuum to yield Compound 5 Form A.

[0674] Characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 5, with no residual organic solvent observed by NMR. By 1 H NMR analysis determined the ratio of toluenesulfonate to Compound 1 in Form A of Compound 5 was 1 : 1.

[0675] Table 6 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 5.

[0676] Table 6 - XRPD peak positions for Form A of Compound 5

[0677] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 3.2 8.2 23.8 5.6 7.1 100.0 24.3 2.7 7.6 25.5 24.9 5.2 9.9 10.0 25.1 12.9 13.6 4.6 25.7 2.9 14.1 11.8 26.6 6.0 15.4 24.5 27.6 7.4 15.9 9.8 27.8 6.0 17.0 15.6 28.6 1.7 17.4 3.1 28.8 2.2 18.8 4.0 29.8 5.4 19.5 6.5 31.2 2.6 19.9 28.0 33.1 2.5 20.8 9.4 34.4 1.9 21.1 11.1 35.1 2.8 21.8 7.2 36.3 4.0 22.3 3.5 37.1 1.2 22.7 4.7 38.1 1.8 23.3 31.9 38.5 2.3

[0678] In this and all subsequent tables, the positions (°2Q) are within ±0.2.

[0679] Figure 5A.1 An XRPD pattern of Form A of Compound 5 is depicted.

[0680] Figure 5A.2 A DSC thermogram and TGA trace of Form A of Compound 5 are depicted. The TGA trace shows little weight loss prior to decomposition. The DSC thermogram of Form A of Compound 5 is characterized by an endothermic peak at about 139 °C.

[0681] Figure 5A.3 A DVS plot of Form A of Compound 5 is depicted. The DVS plot indicates that Form A of Compound 5 is slightly hygroscopic with water uptake of 1.25% and 2.77% at 80% RH and 90% RH, respectively. The XRPD pattern of the tested sample remained unchanged after the DVS test. 1 H NMR spectrum.

[0682] Figure 5A.4 and 5A.5 A DVS plot of Form A of Compound 5 is depicted. The DVS plot indicates that Form A of Compound 5 is slightly hygroscopic with water uptake of 1.25% and 2.77% at 80% RH and 90% RH, respectively. The XRPD pattern of the tested sample remained unchanged after the DVS test.

[0683] Example 6: Preparation of Form A of Compound 6

[0684]

[0685] Form A of Compound 6

[0686] Form A of Compound 6 was prepared as follows:

[0687] Procedure A: Compound 1 (20 mg) was dissolved in EtOAc (15 V) at room temperature. Solid maleic acid (1.05 equivalents) was added. The solution was stirred for 4 hours during which time a solid precipitated. The solid was collected by filtration and dried under vacuum to yield Compound 6 Form A.

[0688] Procedure B: Compound 1 (20 mg) was dissolved in EtOAc (20 V) at room temperature. A solution of maleic acid (1 M in MeOH, 1.05 equivalents) was added. The solution was stirred for 3 hours. MTBE (150 V) was added and the solution was stirred for an additional hour. The resulting precipitate was collected by filtration and dried under vacuum to yield Compound 6 Form A.

[0689] Procedure C: Compound 1 (20 mg) was dissolved in EtOAc (20 V) at 50 °C. A solution of maleic acid (1 M in MeOH, 1.0 equivalents) was added. The solution was stirred for 1 hour. MTBE (150 V) was added and the solution was stirred at 50 °C for 1 day. The resulting precipitate was collected by filtration and dried under vacuum to yield Compound 6 Form A.

[0690] Procedure D: Compound 1 (20 mg) was dissolved in EtOAc (20 V) at 50 °C. A solution of maleic acid (1 M in MeOH, 0.55 equivalents) was added. The solution was stirred for 1 hour, MTBE (150 V) was added and the solution was stirred at 50 °C for 1 day. The resulting precipitate was collected by filtration and dried under vacuum to yield Compound 6 Form A.

[0691] Characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 6 by 1 No residual organic solvent was observed by H NMR. Based on the 1 H NMR analysis determined the ratio of maleate to Compound 1 in Form A was 1 : 1.

[0692] Table 7 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 6.

[0693] Table 7 - XRPD peak positions for Form A of Compound 6

[0694]

[0695]

[0696] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0697] Figure 6A.1 An XRPD pattern of Form A of Compound 6 is depicted.

[0698] Figure 6A.2 A DSC thermogram and TGA trace of Form A of Compound 6 are depicted. The TGA trace shows little weight loss prior to decomposition. The DSC thermogram of Form A of Compound 6 is characterized by two endothermic peaks at about 132 °C and about 146 °C.

[0699] Figure 6A.3 An XRPD pattern of Form A of Compound 6 is depicted. 1 H NMR spectrum.

[0700] Example 7: Preparation of Form A of Compound 7

[0701]

[0702] Form A of compound 7

[0703] Form A of compound 7 was prepared as follows:

[0704] Procedure A: Compound 1 (20.3 mg) was dissolved in EtOH (20 V) at room temperature. Fumaric acid (1.05 equivalents) was added. The solution was stirred at room temperature for 3 hours. MTBE (250 V) was added and the solution was stirred at 50 °C for 1 day. The resulting precipitate was collected by filtration and dried under vacuum at 50 °C to yield compound 7 Form A.

[0705] Characterization of the resulting material exhibited an anhydrous crystalline Form A of compound 7 by 1 No residual organic solvent was observed by H NMR. Based on the weight of the fumarate salt, the ratio of fumarate to compound 1 in Form A was determined to be 1:1 by H NMR analysis. 1 No residual organic solvent was observed by H NMR. Based on the weight of the fumarate salt, the ratio of fumarate to compound 1 in Form A was determined to be 1:1 by H NMR analysis.

[0706] Table 8 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of compound 7.

[0707] Table 8 - XRPD peak positions for Form A of compound 7

[0708] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 4.9 11.3 17.5 11.3 5.5 14.7 18.3 4.1 5.8 12.0 19.5 6.4 7.4 15.5 21.4 4.3 10.1 15.7 22.6 12.1 11.1 100.0 23.0 34.5 12.2 6.3 23.9 8.4 12.8 4.7 24.6 43.3 14.0 5.5 26.4 13.3 15.0 6.6 27.1 11.3 15.7 6.4 28.2 11.7 16.0 7.1 30.8 4.7 16.7 5.1 35.5 3.1

[0709] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0710] Figure 7A.1 An XRPD pattern of Form A of compound 7 is depicted.

[0711] Figure 7A.2 A DSC thermogram and TGA trace of Form A of compound 7 are depicted. The TGA trace shows little weight loss prior to decomposition. The DSC thermogram of Form A of compound 7 is characterized by two endothermic peaks at about 138 °C and about 155 °C.

[0712] Figure 7A.3 A DSC thermogram and TGA trace of Form A of compound 7 are depicted. The TGA trace shows little weight loss prior to decomposition. The DSC thermogram of Form A of compound 7 is characterized by two endothermic peaks at about 138 °C and about 155 °C. 1 H NMR spectrum of Form A of compound 7.

[0713] Example 8: Preparation of Form A of compound 8

[0714]

[0715] Form A of compound 8

[0716] Form A of compound 8 was prepared as follows:

[0717] Procedure A: Compound 1 (20.1 mg) was dissolved in EtOAc (20 V) at room temperature. Glycolic acid (1.05 equivalents) was added. The resulting slurry was stirred at room temperature for 4 hours and the solids were collected by filtration and dried under vacuum to yield Compound 8 Form A.

[0718] Procedure B: Compound 1 (20.0 mg) was dissolved in EtOAc (30 V) at 50 °C. Glycolic acid (1.05 equivalents) was added. The solution was stirred at 50 °C for 1 day during which time solids precipitated. The solids were collected by filtration and dried under vacuum to yield Compound 8 Form A.

[0719] Characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 8 with no residual organic solvent observed by NMR. Based on the XRPD pattern, the Form A of Compound 8 was assigned a crystalline structure with a 1:1 ratio of glycolic acid ester to Compound 1. 1 H NMR analysis determined the ratio of glycolic acid ester to Compound 1 in Form A was 1:1.

[0720] Table 9 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 8.

[0721] Table 9 - XRPD peak positions for Form A of Compound 8

[0722] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 3.7 25.0 24.3 19.6 5.7 55.2 25.1 13.3 6.4 11.3 25.5 13.9 10.1 14.1 25.8 19.3 10.9 19.9 26.3 5.9 11.6 68.6 27.2 7.1 12.0 20.3 27.6 5.7 15.4 12.9 29.6 13.1 15.7 100.0 31.4 5.3 16.7 12.5 31.8 6.0 17.5 68.4 32.6 6.9 18.4 12.1 32.9 8.3 18.7 8.4 34.2 5.7 19.8 12.6 35.1 4.4 20.4 40.4 37.2 5.7 22.2 8.9 38.5 4.8 22.7 8.0 39.5 7.8 23.1 70.5

[0723] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0724] Figure 8A.1 An XRPD pattern of Form A of Compound 8 is depicted.

[0725] Figure 8A.2 A DSC thermogram and TGA trace of Form A of Compound 8 are depicted. The TGA trace shows little weight loss prior to decomposition. The DSC thermogram of Form A of Compound 8 is characterized by two endothermic peaks at about 122 °C and about 136 °C.

[0726] Figure 8A.3 A DSC thermogram of Form A of Compound 8 is depicted. 1 H NMR spectrum.

[0727] Example 9: Preparation of Form A of Compound 9

[0728]

[0729] Form A of Compound 9

[0730] Form A of Compound 9 was prepared as follows:

[0731] Procedure A (Salt Screening Method): Compound 1 (about 180 mg) was dissolved in MeOH (6 mL) to make a stock solution. The stock solution (100 pL) was added to each well of a 96-well plate. L-tartaric acid (150 pL of a 0.1 M solution, 1.1 equivalents) was added to one column of wells. Different solvents (MeOH, IPA, THF, ACN, MTBE, acetone, water, and EtOAc, 200 pL of each) were added to each row of the plate. The wells were covered with a membrane having pinholes on top and evaporated to dryness at ambient conditions. The dried material was collected and submitted for XRPD analysis. The wells containing IPA, THF, ACN, acetone, and EtOAc with L-tartaric acid each resulted in Compound 9 Form A.

[0732] Procedure B: Compound 1 (about 20 mg) was dissolved in EtOAc (22 V) at room temperature. L-tartaric acid (1 M solution in MeOH, 1.05 equivalents) was added to the solution, and the solution was stirred at room temperature for 3 hours, during which time the solid precipitated immediately upon addition of the acid solution. The solid was collected by filtration and dried under vacuum at 50 °C to yield Compound 9 Form A.

[0733] Procedure C: Compound 1 (about 20 mg) was dissolved in acetone (25 V) at room temperature. L-tartaric acid (solid, 1.05 equivalents) was added to the solution, and the solution was stirred at room temperature for 3 hours, during which time the solid precipitated shortly after addition of the L-tartaric acid. The resulting precipitate was collected by filtration and dried under vacuum at 50 °C to yield Compound 9 Form A.

[0734] Procedure D: Compound 1 (121.0 mg) was dissolved in EtOAc (20 V) at room temperature. 1 M L-tartaric acid in MeOH (303.5 pL, 0.55 equivalents) was added to the solution, and the solid precipitated shortly after addition of the solid L-tartaric acid. The suspension was stirred at room temperature for 3 hours, after which the resulting precipitate was collected by filtration and dried under vacuum at 50 °C to yield Compound 9 Form A (134.5 mg, 82.8% yield).

[0735] Characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 9, with no residual organic solvent observed by NMR. Based on the XRPD pattern, the Form A of Compound 9 was determined to be a crystalline solid. 1 H NMR analysis determined the ratio of L-tartaric ester to Compound 1 in Compound 9 Form A to be 0.5:1.

[0736] Table 10 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 9.

[0737] Table 10 - XRPD Peak Positions for Form A of Compound 9

[0738] Table 10 - XRPD Peak Positions for Form A of Compound 9

[0739]

[0740] In this table and all subsequent tables, the position (°2q) is within ±0.2.

[0741] Figure 9A.1 An XRPD pattern of Form A of compound 9 is depicted.

[0742] Figure 9A.2 A DSC thermogram and TGA trace of Form A of compound 9 are depicted. The TGA trace shows little weight loss below 150 °C. The DSC thermogram of Form A of compound 9 is characterized by an endothermic peak at about 212 °C.

[0743] Figure 9A.3 A DVS plot of Form A of compound 9 is depicted. The DVS plot indicates that Form A of compound 9 is slightly hygroscopic with a water uptake of 1.05% at 80% RH. The XRPD pattern of the tested sample remained unchanged after the DVS test. 1 H NMR spectrum.

[0744] Figure 9A.4 and 9A.5 A DVS plot of Form A of compound 9 is depicted. The DVS plot indicates that Form A of compound 9 is slightly hygroscopic with a water uptake of 1.05% at 80% RH. The XRPD pattern of the tested sample remained unchanged after the DVS test.

[0745] Example 10: Preparation of Form A of compound 10

[0746]

[0747] Form A of compound 10

[0748] Form A of compound 10 was prepared as follows:

[0749] Procedure A: Compound 1 (about 20 mg) was dissolved in EtOAc (22 V) at room temperature. L-malic acid (1 M solution in MeOH, 1.05 equivalents) was added to the solution and the solution was stirred at room temperature for 3 hours during which time the solid precipitated shortly after the addition of the acid solution. The solid was collected by filtration and dried under vacuum at 50 °C to yield compound 10 Form A.

[0750] Characterization of the resulting material revealed that the crystalline Form A of compound 10 was a solvate / hydrate form with a small amount of water and about 1% residual MeOH as observed by NMR. Based on the NMR analysis, the ratio of L-malate to compound 1 in compound 10 Form A was determined to be 0.5:1. 1 H NMR analysis determined the ratio of L-malate to compound 1 in compound 10 Form A to be 0.5:1.

[0751] Table 11 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of compound 10.

[0752] Table 11 - XRPD peak positions for Form A of compound 10

[0753] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 5.7 44.9 21.6 29.5 10.3 100.0 22.0 16.4 10.8 41.3 22.4 34.9 11.1 16.9 23.1 22.5 11.5 36.4 23.7 75.8 11.7 63.5 24.6 17.5 12.7 13.8 25.3 53.5 14.4 39.3 26.6 35.6 15.0 47.3 27.9 9.6 16.5 64.4 29.2 10.7 17.5 15.3 29.9 9.8 18.8 13.5 31.5 12.4 19.6 39.8 32.1 11.1 20.3 21.6 32.9 15.3 21.3 32.9

[0754] In this table and all subsequent tables, the positions (°2Θ) are within ±0.2.

[0755] Figure 10A.1 An XRPD pattern of Form A of compound 10 is depicted.

[0756] Figure 10A.2 A DSC thermogram and TGA trace of Form A of compound 10 are depicted. The TGA curve shows two weight loss features below 155 °C: a 1.0% weight loss between room temperature and 70 °C and a 1.8% weight loss between 70 °C and 125 °C. Without intending to be bound by any particular theory, these weight losses can be attributed to the loss of MeOH and water found to be part of Form A. The DSC thermogram of Form A of compound 10 is characterized by endothermic peaks at about 53 °C, 107 °C, and 155 °C.

[0757] Figure 10A.3 An XRPD pattern of Form A of compound 10 is depicted. 1 H NMR spectrum.

[0758] Example 11: Preparation of Form A of compound 11

[0759]

[0760] Form A of compound 11

[0761] Form A of compound 11 was prepared as follows:

[0762] Procedure A (Salt screen method): Compound 1 (about 180 mg) was dissolved in MeOH (6 mL) to make a stock solution. The stock solution (100 μL) was added to each well of a 96-well plate. D- mandelic acid (150 μL of a 0.1 M solution, 1.1 equivalents) was added to one column of wells. Different solvents (MeOH, IPA, THF, ACN, MTBE, acetone, water, and EtOAc, 200 μL each) were added to each row of the plate. The wells were covered with a membrane having pinholes on top and evaporated to dryness under ambient conditions. The dried material was collected and submitted for XRPD analysis. The wells containing THF, MTBE, and EtOAc with D-mandelic acid each resulted in Form A of compound 11.

[0763] Procedure B: Compound 1 (about 20 mg) was dissolved in acetone (25 V) at room temperature. D- mandelic acid (1.05 equivalents) was added to the solution and the solution was stirred at room temperature for 3 hours. No solids appeared after stirring. The solvent was evaporated under N2 flow and the dry material was dissolved in EtOAc (25 V) and stirred at room temperature for another 3 hours during which time solids precipitated. The solids were collected by filtration and dried under vacuum at 50 °C to yield Compound 11 Form A.

[0764] Procedure C: Compound 1 (about 20 mg) was dissolved in EtOAc (20 V) at room temperature. D- mandelic acid (1.05 equivalents) was added to the solution and the solution was stirred at room temperature for 3 hours during which time solids precipitated shortly after the acid was added. Heptane (40 V) was added to increase the yield of precipitant and the mixture was stirred at room temperature for another 3 hours. The solids were collected by filtration and dried under vacuum at 50 °C to yield Compound 11 Form A.

[0765] Characterization of the resulting material exhibited an anhydrous crystalline Form A of Compound 11 without residual organic solvents as observed by 1 H NMR. The ratio of D-mandelic ester to Compound 1 in Compound 11 Form A was determined to be 1 : 1 based on 1 H NMR analysis.

[0766] Table 12 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 11.

[0767] Table 12 - XRPD peak positions for Form A of Compound 11

[0768] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 6.5 69.6 23.7 2.0 7.4 8.9 26.3 22.3 9.0 7.1 27.0 2.9 13.1 13.9 27.4 17.0 14.0 34.9 28.3 6.8 14.8 3.0 31.1 2.4 15.2 4.6 31.9 2.3 16.1 3.9 32.9 2.0 17.2 2.9 34.3 8.1 19.8 8.9 37.2 1.9 20.0 5.4 39.7 3.4 22.8 100.0

[0769] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0770] Figure 11A.1 An XRPD pattern of Form A of Compound 11 is depicted.

[0771] Figure 11A.2 A DSC thermogram and TGA trace of Form A of Compound 11 are depicted. The TGA trace shows no weight loss below 100 °C. The DSC thermogram of Form A of Compound 11 is characterized by an endothermic peak at about 142 °C.

[0772] Figure 11A.3 A 1 H NMR spectrum of Form A of Compound 11 is depicted.

[0773] Example 12: Preparation of Form A of Compound 12

[0774]

[0775] Form A of Compound 12

[0776] Form A of Compound 12 was prepared as follows:

[0777] Procedure A (Salt Screening Method): Compound 1 (about 180 mg) was dissolved in MeOH (6 mL) to make a stock solution. The stock solution (100 pL) was added to each well of a 96-well plate. L-lactic acid (150 pL of a 0.1 M solution, 1.1 equivalents) was added to one column of wells. Different solvents (MeOH, IPA, THF, ACN, MTBE, acetone, water, and EtOAc, 200 pL of each) were added to each row of the plate. The wells were covered with a membrane having pinholes on top and evaporated to dryness at ambient conditions. The dried material was collected and submitted for XRPD analysis. The wells containing MeOH, THF, MTBE, and acetone for L-lactic acid each produced Form A of Compound 12.

[0778] Procedure B: Compound 1 (about 20 mg) was dissolved in acetone (25 V) at room temperature. L-lactic acid (1.05 equivalents) was added to the solution, and the solution was stirred at room temperature for 3 hours. No solids appeared after stirring. The solvent was evaporated under a stream of N2, and the dried material was dissolved in EtOAc (25 V) and stirred at room temperature for an additional 3 hours. Heptane (80 V) was added, and the mixture was stirred at room temperature for 1 day during which time solids precipitated. The solids were collected by filtration and dried under vacuum at 50 °C to produce Form A of Compound 12.

[0779] Characterization of the resulting material from Procedure B exhibited a form with low crystallinity, which was assigned as crystalline Form A of Compound 12. The material obtained from Procedure A exhibited higher crystallinity.

[0780] Table 13 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of Compound 12.

[0781] Table 13 - XRPD Peak Positions for Form A of Compound 12

[0782]

[0783]

[0784] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0785] Figure 12A.1 An XRPD pattern of Form A of Compound 12 is depicted.

[0786] Figure 12A.2A DSC thermogram and TGA trace of Form A of compound 12 are depicted. The TGA trace shows a weight loss of about 2.9% prior to 100 °C. The DSC thermogram of Form A of compound 12 is complex and shows multiple overlapping endothermic peaks between room temperature and 120 °C with prominent endothermic features at about 39 °C, 76 °C, and 95 °C.

[0787] Example 13: Preparation of Form A and B of compound 13

[0788]

[0789] Form A of compound 13

[0790] Form A of compound 13 was prepared as follows:

[0791] Procedure A: Compound 1 (20 mg) was dissolved in EtOAc (20 V) at room temperature. D-camphoric acid (1.05 equivalents) was added to the solution and the solution was stirred at room temperature for 2 hours. No solids appeared upon stirring. Heptane (0.8 mL) was added and the mixture was stirred at room temperature for an additional 2 hours during which time solids precipitated. The solids were collected by filtration and dried under vacuum at 50 °C to yield Form A of compound 13.

[0792] Characterization of the resulting material exhibited an anhydrous crystalline Form A of compound 13 without residual organic solvents as observed by 1 H NMR. The ratio of D-camphoric acid ester to compound 1 in Form A of compound 13 was determined to be 1 : 1 based on 1 H NMR analysis.

[0793] Table 14 above is reproduced below and lists the X-ray diffraction peaks observed for Form A of compound 13.

[0794] Table 14 - XRPD peak positions for Form A of compound 13

[0795] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 4.5 10.9 22.2 3.2 7.9 100.0 23.2 4.0 8.6 10.3 23.6 3.4 9.5 35.3 24.9 3.6 10.1 7.6 25.6 3.7 10.9 3.6 26.1 6.1 11.7 23.7 26.5 4.7 12.9 19.4 27.9 2.8 13.3 2.5 28.6 2.8 14.7 20.4 29.1 2.6 15.7 3.6 29.4 3.9 16.2 10.0 29.7 5.9 16.8 13.1 31.0 5.3 17.2 21.4 32.0 1.9 17.8 4.9 32.9 2.3 18.1 11.3 33.1 3.4 18.5 20.5 34.8 1.9 18.9 21.6 36.5 2.0 19.1 13.4 37.4 2.8 20.3 3.8 37.7 2.2 20.6 3.9 38.8 2.2 21.1 7.5 39.6 2.1 21.8 7.2

[0796] In this table and all subsequent tables, the positions (°2Q) are within ±0.2.

[0797] Figure 13A.1 An XRPD pattern of Form A of compound 13 is depicted.

[0798] Figure 13A.2 A DSC thermogram and TGA trace of Form A of compound 13 are depicted. The TGA trace shows no weight loss below 100 °C. The DSC thermogram of Form A of compound 13 is characterized by a smaller endothermic peak at about 147 °C and a larger endothermic peak at about 166 °C.

[0799] Figure 13A.3 The form A of compound 13 is described. 1 H NMR spectrum.

[0800] Example 14: Preparation of form A of compound 14

[0801]

[0802] Form A of compound 14

[0803] Compound 14 was prepared in form A as follows:

[0804] Procedure A: Compound 1 (approximately 20 mg) was dissolved in IPA (0.6 mL) at room temperature. Benzoyl-D-tartaric acid (1.05 equivalents) was added to the solution, and the solution was stirred at room temperature for 2 hours, during which time the solid began to precipitate shortly after the addition of the acid. The solid was collected by filtration and dried under vacuum at 50 °C to yield compound 14, form A.

[0805] Characterization of the obtained material revealed that compound 14 exists in its anhydrous crystalline form A, without any residual organic solvent, as observed by NMR. Based on 1 1H NMR analysis determined that the ratio of dibenzoyl-D-tartrate to compound 1 in form A of compound 14 was 1:1.

[0806] Table 15 above is reproduced below and lists the X-ray diffraction peaks observed for form A of compound 14.

[0807] Table 15 - XRPD peak positions of form A of compound 14

[0808] Position (°2Θ) Intensity % Position (°2Θ) Intensity % 4.9 8.6 19.6 5.6 6.3 100.0 20.3 2.9 6.8 9.6 20.7 5.6 8.8 36.1 21.1 2.8 11.2 7.7 22.3 4.6 12.2 26.9 22.6 5.7 12.6 34.7 23.0 7.5 12.8 25.3 23.4 7.9 14.0 18.0 23.8 8.8 14.2 12.8 24.3 10.5 14.8 4.3 24.6 4.4 15.3 4.4 25.1 6.9 15.6 9.0 25.3 5.4 16.2 4.9 25.9 4.3 16.5 7.3 26.2 4.7 16.9 18.1 26.5 5.0 17.2 13.8 27.2 5.1 17.6 7.7 27.8 3.2 18.2 7.7 28.2 2.5 18.9 13.7 32.5 2.4 19.3 11.7

[0809] In this table and all subsequent tables, the position (°2θ) is within ±0.2.

[0810] Figure 14A.1 An XRPD plot of compound 14 in form A was depicted.

[0811] Figure 14A.2 The DSC thermogram and TGA trace of compound 14 in form A were depicted. The TGA trace showed no weight loss below 150 °C. The DSC thermogram of compound 14 in form A is characterized by an endothermic peak at approximately 182 °C.

[0812] Figure 14A.3 The form A of compound 14 is described. 1 H NMR spectrum.

[0813] Example 15: Chiral purification of compound 1 by forming chiral acid salts

[0814] Several of the crystalline salts described above were tested for their ability to increase the chiral purity of Compound 1 and mixtures of its enantiomers. Compound 1 (S)-6-(2-(tert- butylamino)-l-hydroxyethyl)picolinitrile and its enantiomer, (R)-6-(2-(tert- butylamino)-l-hydroxyethyl)picolinitrile, were mixed together in an 80 / 20 or 90 / 10 ratio, dissolved in a solvent at room temperature or 60 °C, and one of the acid salts was added to the solution, as described in Table 17 below:

[0815] Table 17 - Chiral purification evaluation

[0816]

[0817]

[0818] Note: salts denoted with * were formed using 0.55 equivalents of acid and other salts were formed using 1.05 equivalents of acid.

[0819] Chiral purity was determined by HPLC analysis. The results of the chiral purification screen indicated that the addition of L-tartaric acid significantly reduced the content of (R)-6-(2-(tert-butylamino)-l-hydroxyethyl)picolinitrile in the final collected solids. In certain conditions, the addition of L-tartaric acid was able to reduce the content of the undesired enantiomer by more than half.

[0820] Example 16: Solubility and stability testing

[0821] Solubility testing

[0822] Compound 1 Form A, Compound 2 Form A, and Compound 9 Form A were tested for their stability in three biorelevant media and water at 37 °C for 0.5 hours, 2 hours, and 24 hours. Approximately 15 mg of Compound 1 Form A, Compound 2 Form A, and Compound 9 Form A were each weighed into four separate vials and 3 mL of one of the following biorelevant media was added to each set of vials: simulated gastric and intestinal fluids (SGF), fasted state simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF), and water. All samples were shaken at 200 rpm for up to 24 hours at 37 °C. Compound 2 Form A dissolved immediately in each of the four media at room temperature. Compound 9 Form A dissolved in each of the media after approximately 15 minutes of shaking at 37 °C. Compound 1 Form A dissolved in each of the media over the course of approximately 2 hours of shaking at 37 °C. Compound 1 Form A, Compound 2 Form A, and Compound 9 Form A all showed high solubility (>5 mg / ml) in each of the media. The results of the solubility testing are summarized in Table 18 below:

[0823] Table 18 - Solubility Assessment Results

[0824]

[0825] Note: pH of water, SGF, FaSSIF and FeSSIF controls were 5.26, 1.19, 6.53 and 5.01, respectively.

[0826] When all samples were dissolved after about 2 hours, an estimated solubility test was performed in which about 5 mg of Compound 1 Form A, Compound 2 Form A and Compound 9 Form A were each weighed into four separate vials and each medium was added stepwise while stirring at room temperature until the solid was dissolved. The results of the estimated solubility test are summarized in Table 19:

[0827] Table 19 - Estimated Solubility Results

[0828]

[0829] Compound 2 Form A and Compound 9 Form A were found to be more soluble than free base Compound 1 Form A, and the HC1 salt of Compound 2 had the highest solubility in all media.

[0830] Stability Testing

[0831] The 7-day solid stability of Compound 1 Form A, Compound 2 Form A and Compound 9 Form A was evaluated at 60 °C and 40 °C / 75% RH. Purity was determined by HPLC. The results are summarized in Table 20 below. Compound 2 and Compound 9 remained highly stable over the 7-day experiment, with the purity of the Compound 2 HC1 salt remaining nearly unchanged. The free base showed a decrease in purity of about 0.3% under both sets of conditions. All tested compounds remained in the same solid form after the 7-day experiment.

[0832] Table 20 - Stability Assessment Results

[0833]

Claims

1. A crystalline solid form of Compound 1: having an X-ray powder diffraction pattern substantially as shown in FIG. 1A.

1.

2. A crystalline solid form of Compound 1: having an X-ray powder diffraction pattern substantially as shown in FIG. 1B.

1.

3. A salt form of Compound 1: wherein said salt form is Compound 2: has an XRPD substantially as shown in Figure 2A.

1.

4. A salt form of Compound 1: wherein said salt form is Compound 3: has an XRPD substantially as shown in Figure 3A.

1.

5. A salt form of Compound 1: wherein said salt form is Compound 4: has an XRPD substantially as shown in Figure 4A.

1.

6. A salt form of Compound 1: wherein said salt form is Compound 5: has an XRPD substantially as shown in Figure 5A.

1.

7. A salt form of Compound 1: wherein said salt form is Compound 6: has an XRPD substantially as shown in Figure 6A.

1.

8. A salt form of Compound 1: wherein said salt form is compound 7: has an XRPD substantially as shown in Figure 7A.

1.

9. A salt form of Compound 1: wherein said salt form is Compound 8: has an XRPD substantially as shown in Figure 8A.

1.

10. A salt form of Compound 1: wherein the salt form is Compound 9: wherein X = 0.5, has an XRPD substantially as shown in Figure 9A.

1.

11. A salt form of Compound 1: wherein the salt form is Compound 10: wherein X = 0.5, has an XRPD substantially as shown in Figure 10A.

1.

12. A salt form of Compound 1: wherein said salt form is Compound 11: has an XRPD substantially as shown in Figure 11A.

1.

13. A salt form of Compound 1: wherein said salt form is Compound 12: has an XRPD substantially as shown in Figure 12A.

1.

14. A salt form of Compound 1: wherein said salt form is Compound 13: has an XRPD substantially as shown in Figure 13A.

1.

15. A salt form of Compound 1: wherein said salt form is Compound 14: has an XRPD substantially as shown in Figure 14A.

1.

16. A composition comprising a crystalline solid form or salt form according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier or excipient.

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