Beta-adrenergic agonist forms and compositions

Abstract

The present disclosure generally relates to various forms and compositions useful as beta-adrenergic agonists and their use in treating diseases associated with adrenergic receptors. In one aspect, the present disclosure provides a crystalline solid form of Compound 1 selected from Form A and Form B, and salt forms thereof. TIFF2023528450000103.tif126162

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) of 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 incorporated by reference.

[0002] FIELD OF THE INVENTION The present disclosure relates generally to various forms and compositions useful as beta adrenergic agonists and their use in treating diseases associated with adrenergic receptors. [Background technology]

[0003] background PCT Publication No. WO2017 / 197324 (Patent Document 1) discloses "adrenergic receptor-modulating compounds and methods for treating a subject for a disease or condition associated with an adrenergic receptor, comprising administering a therapeutically effective amount of a compound of the invention."

[0004] U.S. Patent Application Publication No. 2013 / 0096126 (Patent Document 2) discloses "a method for enhancing learning, memory, or both in a mammal having impairments in learning, memory, or both due to a neurodegenerative disorder, the method comprising the step of administering at least one compound that is a β1-adrenergic receptor agonist, partial agonist, or receptor ligand, or a salt thereof, in an amount effective to improve learning, memory, or both in the mammal."

[0005] U.S. Patent Application Publication No. 2014 / 0235726 (Patent Document 3) discloses "a method for improving cognition in patients with Down syndrome, comprising administering to the patient one or more β2 adrenergic receptor agonists in an amount and at a frequency effective to improve the patient's cognition as measured by a contextual learning test."

[0006] U.S. Patent Application Publication No. 2016 / 0184241 (Patent Document 4) discloses "a method for improving cognition in a patient with Down syndrome, the method comprising intranasally administering to the patient one or more β2-ADR agonists or pharmacologically acceptable salts, or both, in an amount and frequency effective to improve the patient's cognition as measured in a contextual learning test." [Prior art documents] [Patent documents]

[0007] [Patent Document 1] PCT Application Publication No. WO2017 / 197324 [Patent Document 2] U.S. Patent Application Publication No. 2013 / 0096126 [Patent Document 3] U.S. Patent Application Publication No. 2014 / 0235726 [Patent Document 4] U.S. Patent Application Publication No. 2016 / 0184241 Summary of the Invention

[0008] It has now been found that novel forms of the present disclosure, and compositions thereof, are useful as beta-adrenergic agonists and exhibit desirable characteristics therefor. Generally, the salt or free base forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of various diseases or disorders, as described in detail herein. [The present invention 1001] Compound 1, selected from Form A and Form B: TIFF0007734700000001.tif24128 A crystalline solid form of. [The present invention 1002] A crystalline solid form of 1001 of the present invention, wherein the compound is a crystalline solid that is substantially free of amorphous Compound 1. [The present invention 1003] A crystalline solid form of 1001 of the present invention, wherein said compound is substantially free of impurities. [The present invention 1004] A crystalline solid form of any of claims 1001 to 1003 of the present invention, which is Form A of Compound 1. [The present invention 1005] A crystalline solid form of 1004 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1006] A crystalline solid form of 1004 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1007] A crystalline solid form of 1004 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1008] A crystalline solid form of 1004 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1009] A crystalline solid form of 1004 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1010] 1004. A crystalline solid form of invention 1004 having six peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1011] A crystalline solid form of 1004 of the present invention having a DSC thermogram characterized by endothermic peaks at about 100°C and about 104°C. [The present invention 1012] A crystalline solid form of 1004 of the present invention having an X-ray powder diffraction pattern substantially as shown in Figure 1A.1. [The present invention 1013] A crystalline solid form of the present invention 1004 having a DSC thermogram substantially as shown in Figure 1A.2. [The present invention 1014] The crystalline solid form of any one of 1001 to 1003 of the present invention, which is Form B. [The present invention 1015] A crystalline solid form of 1014 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1016] A crystalline solid form of 1014 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1017] A crystalline solid form of 1014 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1018] A crystalline solid form of 1014 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1019] A crystalline solid form of 1014 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1020] A crystalline solid form of 1014 of the present invention having six or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. [The present invention 1021] A crystalline solid form of 1014 of the present invention having a DSC thermogram characterized by an endothermic peak at about 100°C. [The present invention 1022] A crystalline solid form of 1014 of the present invention having an X-ray powder diffraction pattern substantially as shown in Figure 1B.1. [The present invention 1023] A crystalline solid form of the present invention 1014 having a DSC thermogram substantially as shown in Figure 1B.2. [The present invention 1024] Compound 1: TIFF0007734700000002.tif24128 a salt form of TIFF0007734700000003.tif243137TIFF0007734700000004.tif81128 A salt form of Compound 1 selected from: [The present invention 1025] The salt form of Compound 1 is Compound 2: TIFF0007734700000005.tif24128 A salt form of 1024 of the present invention, [The present invention 1026] A salt form of 1025 of the present invention that is crystalline. [The present invention 1027] A salt form of 1025 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 2. [The present invention 1028] A salt form of any one of 1025 to 1027 of the present invention, which is substantially free of impurities. [The present invention 1029] A salt form of any one of Nos. 1025 to 1028 of the present invention, which is Form A of Compound 2. [The present invention 1030] A salt form of 1029 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. [The present invention 1031] A salt form of 1029 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. [The present invention 1032] A salt form of 1029 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. [The present invention 1033] A salt form of 1029 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. [The present invention 1034] A salt form of 1029 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. [This invention 1035] A salt form of 1029 of the present invention having six peaks in its X-ray powder diffraction pattern at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. [The present invention 1036] A salt form of 1029 of the present invention having a DSC thermogram characterized by an endothermic peak at about 215°C. [This invention 1037] A salt form of 1029 of the present invention having an XRPD substantially as shown in Figure 2A.1. [The present invention 1038] A crystalline solid form of 1029 of the present invention having a DSC thermogram substantially as shown in Figure 2A.2. [This invention 1039] The salt form of Compound 1 is Compound 3: TIFF0007734700000006.tif24128 A salt form of 1024 of the present invention, [The present invention 1040] A salt form of 1039 of the present invention that is crystalline. [This invention 1041] A salt form of 1039 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 3. [The present invention 1042] A salt form of any one of 1039 to 1041 of the present invention, which is substantially free of impurities. [This invention 1043] A salt form of any one of Nos. 1039 to 1042 of the present invention, which is Form A of Compound 3. [This invention 1044] A salt form of 1043 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. [This invention 1045] A salt form of 1043 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. [The present invention 1046] A salt form of 1043 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. [This invention 1047] A salt form of 1043 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. [This invention 1048] A salt form of 1043 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. [This invention 1049] A salt form of 1043 of the present invention having six or more peaks in its X-ray powder diffraction pattern at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. [The present invention 1050] A salt form of 1043 of the present invention having seven peaks in its X-ray powder diffraction pattern at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. [This invention 1051] A salt form of invention 1043 having a DSC thermogram characterized by an endothermic peak at about 247°C. [This invention 1052] A salt form of 1043 of the present invention having an XRPD substantially as shown in Figure 3A.1. [This invention 1053] A crystalline solid form of 1043 of the present invention having a DSC thermogram substantially as shown in Figure 3A.2. [This invention 1054] The salt form of Compound 1 is Compound 4: TIFF0007734700000007.tif24128 A salt form of 1024 of the present invention, [This invention 1055] A salt form of 1054 of the present invention that is crystalline. [The present invention 1056] A salt form of 1054 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 4. [This invention 1057] A salt form of any one of 1054 to 1056 of the present invention, which is substantially free of impurities. [This invention 1058] A salt form of any one of Nos. 1054 to 1057 of the present invention, which is Form A of Compound 4. [This invention 1059] A salt form of 1058 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta. [The present invention 1060] A salt form of 1058 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta. [The present invention 1061] A salt form of 1058 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta. [The present invention 1062] A salt form of 1058 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta. [The present invention 1063] A salt form of 1058 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta. [This invention 1064] A salt form of 1058 of the present invention having six peaks in its X-ray powder diffraction pattern at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta. [This invention 1065] A salt form of 1058 of the present invention having a DSC thermogram characterized by an endothermic peak at about 173°C. [The present invention 1066] A salt form of 1058 of the present invention having an XRPD substantially as shown in Figure 4A.1. [This invention 1067] A crystalline solid form of 1058 of the present invention having a DSC thermogram substantially as shown in Figure 4A.2. [The present invention 1068] The salt form of Compound 1 is Compound 5: TIFF0007734700000008.tif34128 A salt form of 1024 of the present invention, [This invention 1069] A salt form of 1068 of the present invention that is crystalline. [The present invention 1070] A salt form of 1068 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 5. [This invention 1071] A salt form of any one of 1068 to 1070 of the present invention, which is substantially free of impurities. [This invention 1072] A salt form of any one of Nos. 1068 to 1071 of the present invention, which is Form A of Compound 5. [This invention 1073] A salt form of 1072 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta. [This invention 1074] A salt form of 1072 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta. [This invention 1075] A salt form of 1072 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta. [This invention 1076] A salt form of 1072 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta. [This invention 1077] A salt form of 1072 of the present invention having five peaks in its X-ray powder diffraction pattern at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta. [This invention 1078] A salt form of 1072 of the present invention, having a DSC thermogram characterized by an endothermic peak at about 139°C. [This invention 1079] A salt form of 1072 of the present invention, having an XRPD substantially as shown in Figure 5A.1. [The present invention 1080] A crystalline solid form of 1072 of the present invention having a DSC thermogram substantially as shown in Figure 5A.2. [This invention 1081] The salt form of Compound 1 is Compound 6: TIFF0007734700000009.tif30128 A salt form of 1024 of the present invention, [This invention 1082] A salt form of 1081 of the present invention that is crystalline. [This invention 1083] A salt form of 1081 of the present invention, which is a crystalline solid substantially free of amorphous Compound 6. [This invention 1084] A salt form of any one of 1081 to 1083 of the present invention, which is substantially free of impurities. [This invention 1085] A salt form of any one of Compounds 1081 to 1084 of the present invention, which is Form A of Compound 6. [This invention 1086] A salt form of 1085 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta. [This invention 1087] A salt form of 1085 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta. [This invention 1088] A salt form of 1085 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 77.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta. [This invention 1089] A salt form of 1085 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta. [The present invention 1090] A salt form of 1085 of the present invention having five peaks in its X-ray powder diffraction pattern at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta. [This invention 1091] A salt form of 1085 of the present invention having a DSC thermogram characterized by endothermic peaks at about 132°C and about 146°C. [This invention 1092] A salt form of 1085 of the present invention, having an XRPD substantially as shown in Figure 6A.1. [This invention 1093] A crystalline solid form of 1085 of the present invention having a DSC thermogram substantially as shown in Figure 6A.2. [This invention 1094] The salt form of Compound 1 is Compound 7: TIFF0007734700000010.tif24128 A salt form of 1024 of the present invention, [This invention 1095] A salt form of 1094 of the present invention that is crystalline. [This invention 1096] A salt form of 1094 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 7. [This invention 1097] A salt form of any one of 1094 to 1096 of the present invention, which is substantially free of impurities. [This invention 1098] A salt form of any one of Compounds 1094 to 1097 of the present invention, which is Form A of Compound 7. [This invention 1099] A salt form of 1098 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta. [The present invention 1100] A salt form of 1098 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta. [The present invention 1101] A salt form of 1098 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta. [The present invention 1102] A salt form of 1098 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta. [The present invention 1103] A salt form of 1098 of the present invention having five peaks in its X-ray powder diffraction pattern at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta. [The present invention 1104] A salt form of 1098 of the present invention having a DSC thermogram characterized by endothermic peaks at about 138°C and about 155°C. [This invention 1105] A salt form of 1098 of the present invention having an XRPD substantially as shown in Figure 7A.1. [The present invention 1106] A crystalline solid form of 1098 of the present invention having a DSC thermogram substantially as shown in Figure 7A.2. [This invention 1107] The salt form of Compound 1 is Compound 8: TIFF0007734700000011.tif24128 A salt form of 1024 of the present invention, [This invention 1108] A salt form of 1107 of the present invention that is crystalline. [This invention 1109] A salt form of 1107 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 8. [The present invention 1110] A salt form of any one of 1107 to 1109 of the present invention, which is substantially free of impurities. [The present invention 1111] A salt form of any one of Compounds 1107 to 1110 of the present invention, which is Form A of Compound 8. [The present invention 1112] A salt form of 1111 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta. [The present invention 1113] The salt form of the present invention 1111 having two or more peaks in its X-ray powder diffraction pattern selected from the peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2 theta. [The present invention 1114] The salt form of the present invention 1111 having three or more peaks in its X-ray powder diffraction pattern selected from the peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2 theta. [The present invention 1115] The salt form of the present invention 1111 having four or more peaks in its X-ray powder diffraction pattern selected from the peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2 theta. [The present invention 1116] The salt form of the present invention 1111 having five or more peaks in its X-ray powder diffraction pattern selected from the peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2 theta. [The present invention 1117] The salt form of the present invention 1111 having six peaks in its X-ray powder diffraction pattern at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2 theta. [The present invention 1118] The salt form of the present invention 1111 having a DSC thermogram characterized by endothermic peaks at about 122 °C and about 136 °C. [The present invention 1119] The salt form of the present invention 1111 having XRPD substantially as shown in Figure 8A.1. [The present invention 1120] The crystalline solid form of the present invention 1111 having a DSC thermogram substantially as shown in Figure 8A.2. [The present invention 1121] The salt form of the compound 1 is compound 9, TIFF0007734700000012.tif28128 where 0 < X ≦ 1, the salt form of the present invention 1024. [The present invention 1122] The salt form of the present invention 1121 that is crystalline. [The present invention 1123] The salt form of the present invention 1121 that is a crystalline solid substantially free of amorphous compound 9. [The present invention 1124] The salt form of any one of the present inventions 1121 to 1123 substantially free of impurities. [The present invention 1125] The salt form of any one of the present inventions 1121 to 1124, wherein the salt form is Form A of compound 9 and X = 0.5. [The present invention 1126] The salt form of the present invention 1125 having one or more peaks in its X-ray powder diffraction pattern selected from the peaks at about 11.2, about 22.0, and about 22.5 degrees 2 theta. [The present invention 1127] The salt form of the present invention 1125 having two or more peaks in its X-ray powder diffraction pattern selected from the peaks at about 11.2, about 22.0, and about 22.5 degrees 2 theta. [The present invention 1128] The salt form of the present invention 1125 having three peaks in its X-ray powder diffraction pattern at about 11.2, about 22.0, and about 22.5 degrees 2 theta. [The present invention 1129] The salt form of the present invention 1125 having a DSC thermogram characterized by an endothermic peak at about 212 °C. [The present invention 1130] The salt form of the present invention 1125 having XRPD substantially as shown in FIG. 9A.1. [The present invention 1131] The crystalline solid form of the present invention 1125 having a DSC thermogram substantially as shown in FIG. 9A.2. [The present invention 1132] The salt form of the compound 1 is compound 10, TIFF0007734700000013.tif28128 where 0 < X ≦ 1, the salt form of the present invention 1024. [The present invention 1133] The salt form of the present invention 1132 that is crystalline. [The present invention 1134] The salt form of the present invention 1132 that is a crystalline solid substantially free of amorphous compound 10. [The present invention 1135] The salt form of any one of the present inventions 1132 to 1134 substantially free of impurities. [The present invention 1136] The salt form of any one of the present inventions 1132 to 1135, wherein the salt form is Form A of compound 10 and X = 0.5. [The present invention 1137] The salt form of the present invention 1136 having one or more peaks in its X-ray powder diffraction pattern selected from the peaks 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. [The present invention 1138] The salt form of the present invention 1136 having two or more peaks in its X-ray powder diffraction pattern selected from the peaks 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. [The present invention 1139] The salt form of the present invention 1136 having three or more peaks in its X-ray powder diffraction pattern selected from the peaks 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. [The present invention 1140] A salt form of 1136 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1141] A salt form of 1136 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1142] A salt form of 1136 of the present invention having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1143] A salt form of 1136 of the present invention having seven or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1144] A salt form of 1136 of the present invention, having eight peaks in its X-ray powder diffraction pattern 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 two-theta. [Invention 1145] A salt form of 1136 of the present invention, having a DSC thermogram characterized by endothermic peaks at about 53°C, about 107°C, and about 155°C. [Invention 1146] A salt form of 1136 of the present invention having an XRPD substantially as shown in Figure 10A.1. [This invention 1147] A crystalline solid form of 1136 of the present invention having a DSC thermogram substantially as shown in Figure 10A.2. [Invention 1148] The salt form of Compound 1 is Compound 11: TIFF0007734700000014.tif28128 A salt form of 1024 of the present invention, [This invention 1149] A salt form of 1148 of the present invention that is crystalline. [This invention 1150] A salt form of 1148 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 11. [This invention 1151] A salt form of any one of 1148 to 1150 of the present invention, which is substantially free of impurities. [This invention 1152] A salt form of any one of Compounds 1148 to 1151 of the present invention, which is Form A of Compound 11. [This invention 1153] A salt form of 1152 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta. [This invention 1154] A salt form of 1152 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta. [Invention 1155] A salt form of 1152 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta. [Invention 1156] A salt form of 1152 of the present invention having four peaks in its X-ray powder diffraction pattern at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta. [This invention 1157] A salt form of 1152 of the present invention having a DSC thermogram characterized by an endothermic peak at about 142°C. [This invention 1158] A salt form of 1152 of the present invention, having an XRPD substantially as shown in Figure 11A.1. [This invention 1159] A crystalline solid form of 1152 of the present invention having a DSC thermogram substantially as shown in Figure 11A.2. [The present invention 1160] The salt form of Compound 1 is Compound 12: TIFF0007734700000015.tif27128 A salt form of 1024 of the present invention, [This invention 1161] A salt form of 1160 of the present invention that is crystalline. [This invention 1162] A salt form of 1160 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 12. [This invention 1163] A salt form of any one of 1160 to 1162 of the present invention, which is substantially free of impurities. [Invention 1164] A salt form of any one of Compounds 1160 to 1163 of the present invention, which is Form A of Compound 12. [Invention 1165] A salt form of 1164 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [Invention 1166] A salt form of 1164 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1167] A salt form of 1164 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [Invention 1168] A salt form of 1164 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1169] A salt form of 1164 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1170] A salt form of 1164 of the present invention having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1171] A salt form of 1164 of the present invention having seven or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta. [This invention 1172] A salt form of 1164 of the present invention having eight peaks in its X-ray powder diffraction pattern 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 two-theta. [This invention 1173] A salt form of 1164 of the present invention having a DSC thermogram characterized by endothermic peaks at about 39°C, about 76°C, and about 95°C. [This invention 1174] A salt form of 1164 of the present invention having an XRPD substantially as shown in Figure 12A.1. [Invention 1175] A crystalline solid form of 1164 of the present invention having a DSC thermogram substantially as shown in Figure 12A.2. [Invention 1176] The salt form of Compound 1 is Compound 13: TIFF0007734700000016.tif27128 A salt form of 1024 of the present invention, [This invention 1177] A salt form of 1176 of the present invention that is crystalline. [This invention 1178] A salt form of 1176 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 13. [This invention 1179] A salt form of any one of 1176 to 1178 of the present invention, which is substantially free of impurities. [This invention 1180] A salt form of any one of Compounds 1176 to 1179 of the present invention, which is Form A of Compound 13. [This invention 1181] A salt form of 1180 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1182] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1183] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1184] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1185] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [Invention 1186] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having six or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1187] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having seven peaks in its X-ray powder diffraction pattern at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1188] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having a DSC thermogram characterized by endothermic peaks at about 147°C and about 166°C. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1189] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1180 of the present invention having an XRPD substantially as shown in Figure 13A.1. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1190] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A crystalline solid form of the present invention 1180 having a DSC thermogram substantially as shown in Figure 13A.2. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1191] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The salt form of Compound 1 is Compound 14: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007734700000017.tif39128<h2 style=";text-align:left;direction:ltr"> A salt form of 1024 of the present invention, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1192] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1191 of the present invention that is crystalline. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1193] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1191 of the present invention, which is a crystalline solid that is substantially free of amorphous Compound 14. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1194] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of any one of 1191 to 1193 of the present invention, which is substantially free of impurities. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1195] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of any one of Compounds 1191 to 1194 of the present invention, which is Form A of Compound 14. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1196] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1195 of the present invention having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1197] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1195 of the present invention having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1198] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1195 of the present invention having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1199] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A salt form of 1195 of the present invention having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta. [The present invention 1200] A salt form of 1195 of the present invention having five peaks in its X-ray powder diffraction pattern at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta. [The present invention 1201] A salt form of 1195 of the present invention having a DSC thermogram characterized by an endothermic peak at about 182°C. [This invention 1202] A salt form of 1195 of the present invention, having an XRPD substantially as shown in Figure 14A.1. [This invention 1203] A crystalline solid form of 1195 of the present invention having a DSC thermogram substantially as shown in Figure 14A.2. [The present invention 1204] A composition comprising a crystalline solid form or salt form of any of 1001 to 1203 of the present invention and a pharmaceutically acceptable carrier or excipient. [This invention 1205] A method for modulating the activity of one or both of the β1-adrenergic receptor and the β2-adrenergic receptor in a patient, comprising administering to the patient a crystalline solid form or salt form of any of inventions 1001 to 1203, or a composition thereof. [This invention 1206] A method for treating a β1-adrenergic receptor or β2-adrenergic receptor mediated disease or disorder in a patient, comprising administering to the patient a crystalline solid form or salt form of any of inventions 1001-1203, or a composition thereof. [This invention 1207] The β1-adrenergic receptor or β2-adrenergic receptor mediated disease or disorder is 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 (Was diagnosed as a stroke or ... The method of the present invention 1206, wherein the condition is one or more selected from the group consisting of Wernicke-Korsakoff syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down's syndrome (DS). [Brief explanation of the drawings]

[0009] [Figure 1A.1] 1 shows the XRPD pattern of Form A of Compound 1. [Figure 1A.2] 1 shows the DSC thermogram and TGA trace of Compound 1 Form A. [Figure 1A.3] 1 shows the 1H NMR spectrum of Form A of Compound 1. [Figure 1B.1] 1 shows the XRPD pattern of Form B of Compound 1. [Figure 1B.2] 1 shows the DSC thermogram and TGA trace of Compound 1 Form B. [Figure 1B.3] 1 shows the 1H NMR spectrum of Form B of Compound 1. [Figure 2A.1] 1 shows the XRPD pattern of Form A of Compound 2. [Figure 2A.2] 1 shows the DSC thermogram and TGA trace of Compound 2 Form A. [Figure 2A.3] 1 shows a DVS plot of Form A of Compound 2. [Figure 2A.4] 1 shows a DVS plot of Form A of Compound 2. [Figure 3A.1] 1 shows the XRPD pattern of Form A of Compound 3. [Figure 3A.2] 1 shows the DSC thermogram and TGA trace of Compound 3 Form A. [Figure 4A.1] 1 shows the XRPD pattern of Form A of Compound 4. [Figure 4A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 4. [Figure 5A.1] 1 shows the XRPD pattern of Form A of Compound 5. [Figure 5A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 5. [Figure 5A.3] 1 shows the 1H NMR spectrum of Form A of Compound 5. [Figure 5A.4] 1 shows a DVS plot of Form A of Compound 5. [Figure 5A.5] 1 shows a DVS plot of Form A of Compound 5. [Figure 6A.1] 1 shows the XRPD pattern of Form A of Compound 6. [Figure 6A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 6. [Figure 6A.3] 1 shows the 1H NMR spectrum of Form A of Compound 6. [Figure 7A.1] 1 shows the XRPD pattern of Form A of Compound 7. [Figure 7A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 7. [Figure 7A.3] 1 shows the 1H NMR spectrum of Form A of Compound 7. [Figure 8A.1] 1 shows the XRPD pattern of Form A of Compound 8. [Figure 8A.2] 1 shows a DSC thermogram and TGA trace of Compound 8 Form A, where the DSC thermogram shows the results of two separate batches of Compound 8 Form A. [Figure 8A.3] 1 shows the 1H NMR spectrum of Form A of Compound 8. [Figure 9A.1] 1 shows the XRPD pattern of Form A of Compound 9. [Figure 9A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 9. [Figure 9A.3] 1 shows the 1H NMR spectrum of Form A of Compound 9. [Figure 9A.4] 1 shows the DVS plot of Form A of Compound 9. [Figure 9A.5] 1 shows the DVS plot of Form A of Compound 9. [Figure 10A.1] 1 shows the XRPD pattern of Form A of Compound 10. [Figure 10A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 10. [Figure 10A.3] 1 shows the 1H NMR spectrum of Form A of Compound 10. [Figure 11A.1] 1 shows the XRPD pattern of Form A of Compound 11. [Figure 11A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 11. [Figure 11A.3] 1 shows the 1H NMR spectrum of Form A of Compound 11. [Figure 12A.1] 1 shows the XRPD pattern of Form A of Compound 12. [Figure 12A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 12. [Figure 13A.1] 1 shows the XRPD pattern of Form A of Compound 13. [Figure 13A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 13. [Figure 13A.3] 1 shows the 1H NMR spectrum of Form A of Compound 13. [Figure 14A.1] 1 shows the XRPD pattern of Form A of Compound 14. [Figure 14A.2] 1 shows the DSC thermogram and TGA trace of Form A of Compound 14. [Figure 14A.3] 1 shows the 1H NMR spectrum of Form A of Compound 14. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of the Invention General Description of Certain Aspects of the Invention: The present disclosure is based, at least in part, on the identification of compounds that modulate adrenergic receptors and methods of using them to treat diseases associated with adrenergic receptors. Disclosed herein is Compound 1. TIFF0007734700000018.tif24128

[0011] Compound 1, (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile, is active in a variety of assays and therapeutic models and acts as a low-concentration partial agonist of the β2 adrenergic receptor. Compound 1 has further been found to exhibit an unexpectedly high ability to cross the blood-brain barrier and accumulate in cerebrospinal fluid.

[0012] It would be desirable to provide a solid form of Compound 1 (e.g., as the free base or a salt thereof) that offers characteristics such as improved water solubility, stability, and ease of formulation. Accordingly, the present disclosure provides both the free base and salt forms of Compound 1.

[0013] The free base form of Compound 1 It is contemplated that Compound 1 can exist in various physical forms. For example, Compound 1 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 1 is in a solid form. When Compound 1 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0014] In some embodiments, the present disclosure provides forms of Compound 1 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 1, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, at least about 95% by weight of the Compound 1 form is present. In yet other embodiments of the present disclosure, at least about 99% by weight of the Compound 1 form is present.

[0015] According to one embodiment, the Compound 1 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 1 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 1 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0016] Structures depicted for forms of Compound 1 are also meant to include all tautomeric forms of Compound 1. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0017] Compound 1 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0018] As used herein, the term "polymorph" refers to the different crystalline structures in which a compound, or a salt or solvate thereof, can crystallize.

[0019] In certain embodiments, Compound 1 is a crystalline solid. In other embodiments, Compound 1 is a crystalline solid that is substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound does not contain significant amounts of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 1 is present.

[0020] It has been found that the 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 designated herein as Form A. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form B.

[0021] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1.

[0022] Form A of Compound 1 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. Table 1: XRPD peak positions for Form A of Compound 1 TIFF0007734700000019.tif116128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0023] In some embodiments, Form A of Compound 1 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 1 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 1 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 1 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 1 is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 1 is characterized by having 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 25.1 degrees 2-theta. As used herein, the term "about," when used in reference to a 2-theta value, refers to the stated value ±0.2 degrees 2-theta.

[0024] In some embodiments, Form A of Compound 1 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 1 with a relative intensity of 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 1A.1.

[0025] A method for preparing Form A of Compound 1 is described below.

[0026] Form B of Compound 1 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. Table 2: XRPD peak positions of Form B of Compound 1 TIFF0007734700000020.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0027] In some embodiments, Form B of Compound 1 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized by having 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 2-theta.

[0028] In some embodiments, Form B of Compound 1 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 2 with a relative intensity of greater than 10%, 20%, 30%, or 40%.

[0029] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1B.1.

[0030] A method for preparing Form B of Compound 1 is described below.

[0031] In some embodiments, the present disclosure provides Compound 1, TIFF0007734700000021.tif24128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 1, wherein the compound is substantially free of amorphous Compound 1.

[0032] In some embodiments, the present disclosure provides Compound 1, wherein the compound is substantially free of impurities.

[0033] In some embodiments, the disclosure provides Compound 1, which has one or more peaks in its XRPD selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. In some such embodiments, the disclosure provides Compound 1, which has at least two peaks in its XRPD selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.1 degrees two-theta. In some such embodiments, the disclosure provides Compound 1, which is in Form A.

[0034] In some embodiments, the present disclosure provides compound 1, which has an XRPD substantially similar to that shown in Figure 1A.1.

[0035] In some embodiments, the disclosure provides Compound 1, which has one or more peaks in its XRPD selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees two-theta. In some such embodiments, the disclosure provides Compound 1, which has at least two peaks in its XRPD selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and about 25.0 degrees two-theta. In some such embodiments, the disclosure provides Compound 1, which is in Form B.

[0036] In some embodiments, Form B of Compound 1 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 2 with a relative intensity of greater than 10%, 20%, 30%, or 40%. In some embodiments, the disclosure provides Compound 1, wherein the compound has an XRPD substantially similar to that shown in Figure 1B.1.

[0037] In some embodiments, the present disclosure provides a composition comprising Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0038] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0039] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering Compound 1 or a composition thereof to the patient.

[0040] Salt forms of Compound 1 In some embodiments, the acid and Compound 1 ionically combine to form one of Compounds 2-14, described below. It is contemplated that Compounds 2-14 can exist in various 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.

[0041] Compound 2 (hydrochloride of Compound 1) According to one embodiment, the present disclosure provides Compound 2: The hydrochloride salt of Compound 1 is provided, represented by TIFF0007734700000022.tif24128.

[0042] Those skilled in the art will understand that hydrochloric acid and Compound 1 ionically combine to form Compound 2. It is contemplated that Compound 2 can exist in various physical forms. For example, Compound 2 can be in solution, suspension, or solid form. In certain embodiments, Compound 2 is in a solid form. When Compound 2 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0043] In some embodiments, the present disclosure provides forms of Compound 2 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 2, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 2. In certain embodiments, at least about 95% by weight of the Compound 2 form is present. In yet other embodiments of the present disclosure, at least about 99% by weight of the Compound 2 form is present.

[0044] According to one embodiment, the Compound 2 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 2 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 2 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0045] The structures depicted for forms of Compound 2 are also meant to include all tautomeric forms of Compound 2. In addition, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0046] Compound 2 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0047] In certain embodiments, Compound 2 is a crystalline solid. In other embodiments, Compound 2 is a crystalline solid that is substantially free of amorphous Compound 2. As used herein, the term "substantially free of amorphous Compound 2" means that the compound does not contain a significant amount of amorphous Compound 2. In certain embodiments, at least about 95% by weight of crystalline Compound 2 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 2 is present.

[0048] 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 designated herein as Form A. In certain embodiments, the present disclosure provides a polymorphic form of Compound 2 designated herein as Form B. In certain embodiments, the present disclosure provides a polymorphic form of Compound 2 designated herein as Form C.

[0049] In some embodiments, Compound 2 is amorphous. In some embodiments, Compound 2 is amorphous and substantially free of crystalline Compound 2.

[0050] Form A of Compound 2 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. Table 3: XRPD peak positions for Form A of Compound 2 TIFF0007734700000023.tif83128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0051] In some embodiments, Form A of Compound 2 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. In some embodiments, Form A of Compound 2 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. In some embodiments, Form A of Compound 2 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. In some embodiments, Compound 2 Form A is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. In some embodiments, Compound 2 Form A is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. In some embodiments, Compound 2 Form A is characterized by having six peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta.

[0052] In some embodiments, Form A of Compound 2 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 3 with a relative intensity of 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.

[0053] A method for preparing Form A of Compound 2 is described below.

[0054] In some embodiments, the present disclosure provides Compound 2, TIFF0007734700000024.tif24128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 2, wherein the compound is substantially free of amorphous Compound 2.

[0055] In some embodiments, the present disclosure provides compound 2, wherein the compound is substantially free of impurities.

[0056] In some embodiments, the disclosure provides Compound 2, which has one or more peaks in its XRPD selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. In some such embodiments, the disclosure provides Compound 2, which has at least two peaks in its XRPD selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta. In some such embodiments, the disclosure provides Compound 2, which is in Form A.

[0057] In some embodiments, the present disclosure provides compound 2, which has an XRPD substantially similar to that shown in Figure 2A.1.

[0058] In some embodiments, the present disclosure provides a composition comprising Compound 2 and a pharmaceutically acceptable carrier or excipient.

[0059] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0060] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering Compound 2 or a composition thereof to the patient.

[0061] Compound 3 (sulfate of Compound 1) According to one embodiment, the present disclosure provides compound 3: The sulfate salt of Compound 1 is provided, represented by TIFF0007734700000025.tif25128.

[0062] Those skilled in the art will understand that sulfuric acid and compound 1 ionically combine 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 a solid form. When compound 3 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0063] In some embodiments, the present disclosure provides forms of Compound 3 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 3, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 3. In certain embodiments, at least about 95% by weight of the Compound 3 form is present. In yet other embodiments of the present disclosure, at least about 99% by weight of the Compound 3 form is present.

[0064] According to one embodiment, the Compound 3 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 3 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 3 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0065] Structures depicted for forms of Compound 3 are also meant to include all tautomeric forms of Compound 3. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0066] Compound 3 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0067] In certain embodiments, Compound 3 is a crystalline solid. In other embodiments, Compound 3 is a crystalline solid that is substantially free of amorphous Compound 3. As used herein, the term "substantially free of amorphous Compound 3" means that the compound does not contain a significant amount of amorphous Compound 3. In certain embodiments, at least about 95% by weight of crystalline Compound 3 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 3 is present.

[0068] It has been found that Compound 3 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 3, designated herein as Form A.

[0069] In some embodiments, Compound 3 is amorphous. In some embodiments, Compound 3 is amorphous and substantially free of crystalline Compound 3.

[0070] Form A of Compound 3 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. Table 4: XRPD peak positions for Form A of Compound 3 TIFF0007734700000026.tif94128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0071] In some embodiments, Form A of Compound 3 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 in that it has seven peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta.

[0072] In some embodiments, Form A of Compound 3 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 4 with a relative intensity of 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.

[0073] A method for preparing Form A of Compound 3 is described below.

[0074] In some embodiments, the present disclosure provides compound 3, TIFF0007734700000027.tif25128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 3, wherein the compound is substantially free of amorphous Compound 3.

[0075] In some embodiments, the present disclosure provides compound 3, wherein the compound is substantially free of impurities.

[0076] In some embodiments, the disclosure provides Compound 3, which has one or more peaks in its XRPD selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. In some embodiments, the disclosure provides Compound 3, which has at least two peaks in its XRPD selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta. In some such embodiments, the disclosure provides Compound 3, which is in Form A.

[0077] In some embodiments, the present disclosure provides compound 3, which has an XRPD substantially similar to that shown in Figure 3A.1.

[0078] In some embodiments, the present disclosure provides a composition comprising Compound 3 and a pharmaceutically acceptable carrier or excipient.

[0079] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0080] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering Compound 3 or a composition thereof to the patient.

[0081] Compound 4 (hydrobromide salt of Compound 1) According to one embodiment, the present disclosure provides compound 4: The hydrobromide salt of Compound 1 is provided, represented by TIFF0007734700000028.tif24128.

[0082] Those skilled in the art will understand that hydrobromic acid and compound 1 ionically bond to form compound 4. It is contemplated that compound 4 can exist in various physical forms. For example, compound 4 can be a solution, a suspension, or a solid form. In certain embodiments, compound 4 is in a solid form. When compound 4 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0083] In some embodiments, the present disclosure provides forms of Compound 4 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 4, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 4. In certain embodiments, at least about 95% by weight of the form of Compound 4 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of the form of Compound 4 is present.

[0084] According to one embodiment, the Compound 4 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 4 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 4 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0085] The structures depicted for forms of compound 4 are also meant to include all tautomeric forms of compound 4. In addition, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0086] Compound 4 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0087] In certain embodiments, compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid that is substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound does not contain a significant amount of amorphous compound 4. In certain embodiments, at least about 95% by weight of crystalline compound 4 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 4 is present.

[0088] It has been found that Compound 4 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 4, designated herein as Form A.

[0089] In some embodiments, compound 4 is amorphous. In some embodiments, compound 4 is amorphous and substantially free of crystalline compound 4.

[0090] Form A of Compound 4 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. Table 5: XRPD peak positions for Form A of Compound 4 TIFF0007734700000029.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0091] In some embodiments, Form A of Compound 4 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 4 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 4 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 4 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 4 is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 4 is characterized by having six peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta.

[0092] In some embodiments, Form A of Compound 4 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 5 with a relative intensity of 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 4A.1.

[0093] A method for preparing Form A of Compound 4 is described below.

[0094] In some embodiments, the present disclosure provides compound 4, TIFF0007734700000030.tif24128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 4, wherein the compound is substantially free of amorphous Compound 4.

[0095] In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of impurities.

[0096] In some embodiments, the disclosure provides compound 4, which has one or more peaks in its XRPD selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta. In some such embodiments, the disclosure provides compound 4, which has at least two peaks in its XRPD selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees 2-theta. In some such embodiments, the disclosure provides compound 4, which is in Form A.

[0097] In some embodiments, the present disclosure provides compound 4, which has an XRPD substantially similar to that shown in Figure 4A.1.

[0098] In some embodiments, the present disclosure provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.

[0099] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0100] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 4 or a composition thereof to the patient.

[0101] Compound 5 (tosylate salt of Compound 1) According to one embodiment, the present disclosure provides compound 5: The tosylate salt of Compound 1 is provided, represented by TIFF0007734700000031.tif34128.

[0102] Those skilled in the art will understand that paratoluenesulfonic acid and compound 1 ionically bond to form compound 5. It is contemplated that compound 5 can exist in various physical forms. For example, compound 5 can be a solution, a suspension, or a solid form. In certain embodiments, compound 5 is in a solid form. When compound 5 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0103] In some embodiments, the present disclosure provides forms of Compound 5 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 5, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 5. In certain embodiments, at least about 95% by weight of a form of Compound 5 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 5 is present.

[0104] According to one embodiment, the Compound 5 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 5 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 5 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0105] The structures depicted for forms of Compound 5 are also meant to include all tautomeric forms of Compound 5. In addition, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0106] Compound 5 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0107] 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 does not contain a significant amount of amorphous Compound 5. In certain embodiments, at least about 95% by weight of crystalline Compound 5 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 5 is present.

[0108] It has been found 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, designated herein as Form A.

[0109] In some embodiments, Compound 5 is amorphous. In some embodiments, Compound 5 is amorphous and substantially free of crystalline Compound 5.

[0110] Form A of Compound 5 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. Table 6: XRPD peak positions for Form A of Compound 5 TIFF0007734700000032.tif111128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0111] In some embodiments, Form A of Compound 5 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees 2-theta. In some embodiments, Form A of Compound 5 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees 2-theta. In some embodiments, Form A of Compound 5 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees 2-theta. In some embodiments, Form A of Compound 5 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta.

[0112] In some embodiments, Form A of Compound 5 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 6 with a relative intensity of 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 5A.1.

[0113] A method for preparing Form A of Compound 5 is described below.

[0114] In some embodiments, the present disclosure provides compound 5, TIFF0007734700000033.tif34128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 5, wherein the compound is substantially free of amorphous Compound 5.

[0115] In some embodiments, the present disclosure provides compound 5, wherein the compound is substantially free of impurities.

[0116] In some embodiments, the disclosure provides compound 5, which has one or more peaks in its XRPD selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta. In some embodiments, the disclosure provides compound 5, which has at least two peaks in its XRPD selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta. In some such embodiments, the disclosure provides compound 5, which is of Form A.

[0117] In some embodiments, the present disclosure provides compound 5, which has an XRPD substantially similar to that shown in Figure 5A.1.

[0118] In some embodiments, the present disclosure provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.

[0119] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0120] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 5 or a composition thereof to the patient.

[0121] Compound 6 (maleate salt of Compound 1) According to one embodiment, the present disclosure provides compound 6: The maleate salt of Compound 1 is provided, represented by TIFF0007734700000034.tif30128.

[0122] Those skilled in the art will understand that maleic acid and compound 1 ionically bond to form compound 6. It is contemplated that compound 6 can exist in various physical forms. For example, compound 6 can be a solution, a suspension, or a solid form. In certain embodiments, compound 6 is in a solid form. When compound 6 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0123] In some embodiments, the present disclosure provides forms of Compound 6 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 6, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 6. In certain embodiments, at least about 95% by weight of a form of Compound 6 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 6 is present.

[0124] According to one embodiment, the Compound 6 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 6 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 6 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0125] The structures depicted for forms of compound 6 are also meant to include all tautomeric forms of compound 6. In addition, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0126] Compound 6 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0127] In certain embodiments, Compound 6 is a crystalline solid. In other embodiments, Compound 6 is a crystalline solid that is substantially free of amorphous Compound 6. As used herein, the term "substantially free of amorphous Compound 6" means that the compound does not contain a significant amount of amorphous Compound 6. In certain embodiments, at least about 95% by weight of crystalline Compound 6 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 6 is present.

[0128] 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, designated herein as Form A.

[0129] In some embodiments, Compound 6 is amorphous. In some embodiments, Compound 6 is amorphous and substantially free of crystalline Compound 6.

[0130] Form A of Compound 6 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. Table 7: XRPD peak positions of Form A of Compound 6 TIFF0007734700000035.tif127128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0131] In some embodiments, Form A of Compound 6 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 6 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 6 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 6 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta. In some embodiments, Form A of Compound 6 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta.

[0132] In some embodiments, Form A of Compound 6 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 7 with a relative intensity of 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 6A.1.

[0133] A method for preparing Form A of Compound 6 is described below.

[0134] In some embodiments, the present disclosure provides compound 6, TIFF0007734700000036.tif30128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 6, wherein the compound is substantially free of amorphous Compound 6.

[0135] In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of impurities.

[0136] In some embodiments, the disclosure provides Compound 6, which has one or more peaks in its XRPD selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees 2-theta. In some embodiments, the disclosure provides Compound 6, which has at least two peaks in its XRPD selected from peaks 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 disclosure provides Compound 6, which is of Form A.

[0137] In some embodiments, the present disclosure provides compound 6, which has an XRPD substantially similar to that shown in Figure 6A.1.

[0138] In some embodiments, the present disclosure provides a composition comprising compound 6 and a pharmaceutically acceptable carrier or excipient.

[0139] In some embodiments, the disclosure provides a method of activating an adrenergic receptor in a patient, comprising administering to the patient Compound 6 or a composition thereof. In some embodiments, the adrenergic receptor is selected from a β1-adrenergic receptor and a β2-adrenergic receptor.

[0140] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 6 or a composition thereof to the patient.

[0141] Compound 7 (Fumarate of Compound 1) According to one embodiment, the present disclosure provides compound 7: The fumarate salt of Compound 1 is provided, represented by TIFF0007734700000037.tif26128.

[0142] Those skilled in the art will understand that fumaric acid and compound 1 ionically bond to form compound 7. It is contemplated that compound 7 can exist in various physical forms. For example, compound 7 can be a solution, a suspension, or a solid form. In certain embodiments, compound 7 is in a solid form. When compound 7 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0143] In some embodiments, the present disclosure provides forms of Compound 7 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 7, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 7. In certain embodiments, at least about 95% by weight of the form of Compound 7 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of the form of Compound 7 is present.

[0144] According to one embodiment, the Compound 7 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 7 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 7 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0145] Structures depicted for forms of compound 7 are also meant to include all tautomeric forms of compound 7. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0146] Compound 7 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0147] In certain embodiments, compound 7 is a crystalline solid. In other embodiments, compound 7 is a crystalline solid that is substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound does not contain a significant amount of amorphous compound 7. In certain embodiments, at least about 95% by weight of crystalline compound 7 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 7 is present.

[0148] 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, designated herein as Form A.

[0149] In some embodiments, compound 7 is amorphous. In some embodiments, compound 7 is amorphous and substantially free of crystalline compound 7.

[0150] Form A of Compound 7 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. Table 8: XRPD peak positions of Form A of Compound 7 TIFF0007734700000038.tif78128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0151] 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 peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta. 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 peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta. 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 peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta. 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 peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta. In some embodiments, Form A of Compound 7 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta.

[0152] In some embodiments, Form A of Compound 7 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 8 with a relative intensity of 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 7A.1.

[0153] A method for preparing Form A of Compound 7 is described below.

[0154] In some embodiments, the present disclosure provides compound 7, TIFF0007734700000039.tif24128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 7, wherein the compound is substantially free of amorphous Compound 7.

[0155] In some embodiments, the present disclosure provides compound 7, wherein the compound is substantially free of impurities.

[0156] In some embodiments, the disclosure provides compound 7, which has one or more peaks in its XRPD selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees 2-theta. In some embodiments, the disclosure provides compound 7, which has at least two peaks in its XRPD selected from peaks 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 disclosure provides compound 7, which is of Form A.

[0157] In some embodiments, the present disclosure provides compound 7, which has an XRPD substantially similar to that shown in Figure 7A.1.

[0158] In some embodiments, the present disclosure provides a composition comprising compound 7 and a pharmaceutically acceptable carrier or excipient.

[0159] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0160] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 7 or a composition thereof to the patient.

[0161] Compound 8 (glycolate salt of Compound 1) According to one embodiment, the present disclosure provides compound 8: The glycolate salt of Compound 1 is provided, represented by TIFF0007734700000040.tif24128.

[0162] Those skilled in the art will understand that glycolic acid and Compound 1 ionically bond to form Compound 8. It is contemplated that Compound 8 can exist in a variety of physical forms. For example, Compound 8 can be a solution, a suspension, or a solid form. In certain embodiments, Compound 8 is in a solid form. When Compound 8 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0163] In some embodiments, the present disclosure provides forms of Compound 8 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 8, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 8. In certain embodiments, at least about 95% by weight of the form of Compound 8 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of the form of Compound 8 is present.

[0164] According to one embodiment, the Compound 8 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 8 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 8 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0165] Structures depicted for forms of compound 8 are also meant to include all tautomeric forms of compound 8. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0166] Compound 8 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0167] In certain embodiments, compound 8 is a crystalline solid. In other embodiments, compound 8 is a crystalline solid that is substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound does not contain a significant amount of amorphous compound 8. In certain embodiments, at least about 95% by weight of crystalline compound 8 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 8 is present.

[0168] 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, designated herein as Form A.

[0169] In some embodiments, Compound 8 is amorphous. In some embodiments, Compound 8 is amorphous and substantially free of crystalline Compound 8.

[0170] Form A of Compound 8 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. Table 9: XRPD peak positions of Form A of Compound 8 TIFF0007734700000041.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0171] In some embodiments, Form A of Compound 8 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2-theta. In some embodiments, Form A of Compound 8 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2-theta. In some embodiments, Form A of Compound 8 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2-theta. In some embodiments, Form A of Compound 8 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2-theta. In some embodiments, Form A of Compound 8 is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2-theta. In some embodiments, Form A of Compound 8 is characterized by having six peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees 2-theta.

[0172] In some embodiments, Form A of Compound 8 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 9 with a relative intensity of 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 8A.1.

[0173] A method for preparing Form A of Compound 8 is described below.

[0174] In some embodiments, the present disclosure provides compound 8, TIFF0007734700000042.tif24128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 8, wherein the compound is substantially free of amorphous Compound 8.

[0175] In some embodiments, the present disclosure provides compound 8, wherein the compound is substantially free of impurities.

[0176] In some embodiments, the disclosure provides compound 8, which has one or more peaks in its XRPD selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta. In some such embodiments, the disclosure provides compound 8, which has at least two peaks in its XRPD selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta. In some such embodiments, the disclosure provides compound 8, which is of Form A.

[0177] In some embodiments, the present disclosure provides compound 8, which has an XRPD substantially similar to that shown in Figure 8A.1.

[0178] In some embodiments, the present disclosure provides a composition comprising compound 8 and a pharmaceutically acceptable carrier or excipient.

[0179] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0180] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 8 or a composition thereof to the patient.

[0181] Compound 9 (L-tartrate salt of Compound 1) According to one embodiment, the present disclosure provides compound 9: TIFF0007734700000043.tif28128, wherein: <X≦1である。

[0182] Those skilled in the art will understand that L-(+)-tartaric acid and compound 1 ionically bond to form compound 9. It is contemplated that compound 9 can exist in various physical forms. For example, compound 9 can be a solution, a suspension, or a solid form. In certain embodiments, compound 9 is in a solid form. When compound 9 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0183] In some embodiments, the present disclosure provides forms of Compound 9 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 9, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 9. In certain embodiments, at least about 95% by weight of the form of Compound 9 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of the form of Compound 9 is present.

[0184] According to one embodiment, the Compound 9 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the Compound 9 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the Compound 9 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0185] The structures depicted for forms of compound 9 are also meant to include all tautomeric forms of compound 9. In addition, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0186] Compound 9 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0187] In certain embodiments, compound 9 is a crystalline solid. In other embodiments, compound 9 is a crystalline solid that is substantially free of amorphous compound 9. As used herein, the term "substantially free of amorphous compound 9" means that the compound does not contain a significant amount of amorphous compound 9. In certain embodiments, at least about 95% by weight of crystalline compound 9 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 9 is present.

[0188] It has been discovered that Compound 9 can exist in at least one different polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 9, designated herein as Form A.

[0189] In some embodiments, Compound 9 is amorphous. In some embodiments, Compound 9 is amorphous and substantially free of crystalline Compound 9.

[0190] In some embodiments, X is 0.5.

[0191] Form A of Compound 9 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. Table 10: XRPD peak positions of Form A of Compound 9 TIFF0007734700000044.tif67128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0192] In some embodiments, Form A of Compound 9 is a salt and X is 0.5.

[0193] In some embodiments, Form A of Compound 9 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 11.2, about 22.0, and about 22.5 degrees 2-theta. In some embodiments, Form A of Compound 9 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 11.2, about 22.0, and about 22.5 degrees 2-theta. In some embodiments, Form A of Compound 9 is characterized by having three peaks in its X-ray powder diffraction pattern selected from peaks at about 11.2, about 22.0, and about 22.5 degrees 2-theta.

[0194] In some embodiments, Form A of Compound 9 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 10 with a relative intensity of 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 9A.1.

[0195] A method for preparing Form A of Compound 9 is described below.

[0196] In some embodiments, the present disclosure provides compound 9, TIFF0007734700000045.tif28128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 9, wherein the compound is substantially free of amorphous Compound 9.

[0197] In some embodiments, the present disclosure provides compound 9, wherein the compound is substantially free of impurities.

[0198] In some embodiments, the disclosure provides compound 9, which has one or more peaks in its XRPD selected from peaks at about 11.2, about 22.0, and about 22.5 degrees two-theta. In some embodiments, the disclosure provides compound 9, which has at least two peaks in its XRPD selected from peaks at about 11.2, about 22.0, and about 22.5 degrees two-theta. In some such embodiments, the disclosure provides compound 9, which is of Form A.

[0199] In some embodiments, the present disclosure provides compound 9, which has an XRPD substantially similar to that shown in Figure 9A.1.

[0200] In some embodiments, the present disclosure provides a composition comprising compound 9 and a pharmaceutically acceptable carrier or excipient.

[0201] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0202] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 9 or a composition thereof to the patient.

[0203] Compound 10 (L-malate of Compound 1) According to one embodiment, the present disclosure provides compound 10: TIFF0007734700000046.tif28128, wherein: <X≦1である。

[0204] Those skilled in the art will understand that L-malic acid and Compound 1 ionically bond to form Compound 10. It is contemplated that Compound 10 can exist in various physical forms. For example, Compound 10 can be a solution, a suspension, or a solid form. In certain embodiments, Compound 10 is in a solid form. When Compound 10 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0205] In some embodiments, the present disclosure provides forms of Compound 10 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 10, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 10. In certain embodiments, at least about 95% by weight of a form of Compound 10 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 10 is present.

[0206] According to one embodiment, a form of Compound 10 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, a form of Compound 10 contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, a form of Compound 10 contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0207] Structures depicted for forms of compound 10 are also meant to include all tautomeric forms of compound 10. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, such as the replacement of a hydrogen by a deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0208] Compound 10 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0209] In certain embodiments, Compound 10 is a crystalline solid. In other embodiments, Compound 10 is a crystalline solid that is substantially free of amorphous Compound 10. As used herein, the term "substantially free of amorphous Compound 10" means that the compound does not contain a significant amount of amorphous Compound 10. In certain embodiments, at least about 95% by weight of crystalline Compound 10 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 10 is present.

[0210] 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, designated herein as Form A.

[0211] In some embodiments, Compound 10 is amorphous. In some embodiments, Compound 10 is amorphous and substantially free of crystalline Compound 10.

[0212] In some embodiments, X is 0.5.

[0213] Form A of Compound 10 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. Table 11: XRPD peak positions of Form A of Compound 10 TIFF0007734700000047.tif89128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0214] In some embodiments, Form A of Compound 10 is a salt and X is 0.5.

[0215] In some embodiments, Form A of Compound 10 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 10 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 10 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 10 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 10 is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 10 is characterized by having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 10 is characterized in that it has seven or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta.In some embodiments, Form A of Compound 10 is characterized in that it has eight peaks in its X-ray powder diffraction pattern selected from peaks 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.

[0216] In some embodiments, Form A of Compound 10 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 11 with a relative intensity of 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 10A.1.

[0217] A method for preparing Form A of Compound 10 is described below.

[0218] In some embodiments, the present disclosure provides compound 10, TIFF0007734700000048.tif28128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 10, wherein the compound is substantially free of amorphous Compound 10.

[0219] In some embodiments, the present disclosure provides compound 10, wherein the compound is substantially free of impurities.

[0220] In some embodiments, the disclosure provides Compound 10, which has one or more peaks in its XRPD selected from peaks 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 two-theta. In some embodiments, the disclosure provides Compound 10, which has at least two peaks in its XRPD selected from peaks 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 two-theta. In some such embodiments, the disclosure provides Compound 10, which is in Form A.

[0221] In some embodiments, the present disclosure provides compound 10, which has an XRPD substantially similar to that shown in Figure 10A.1.

[0222] In some embodiments, the present disclosure provides a composition comprising compound 10 and a pharmaceutically acceptable carrier or excipient.

[0223] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0224] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 10 or a composition thereof to the patient.

[0225] Compound 11 (D-mandelate salt of Compound 1) According to one embodiment, the present disclosure provides compound 11: The D-mandelate salt of compound 1 is provided, represented by TIFF0007734700000049.tif28128.

[0226] Those skilled in the art will understand that D-mandelic acid and compound 1 ionically bond to form compound 11. It is contemplated that compound 11 can exist in various 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 more detail below.

[0227] In some embodiments, the present disclosure provides a form of Compound 11 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 contaminants. Such contaminants may include different forms of Compound 11, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 11. In certain embodiments, at least about 95% by weight of a form of Compound 11 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 11 is present.

[0228] According to one embodiment, the compound 11 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the compound 11 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the compound 11 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0229] Structures depicted for forms of compound 11 are also meant to include all tautomeric forms of compound 11. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0230] Compound 11 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0231] In certain embodiments, compound 11 is a crystalline solid. In other embodiments, compound 11 is a crystalline solid that is substantially free of amorphous compound 11. As used herein, the term "substantially free of amorphous compound 11" means that the compound does not contain a significant amount of amorphous compound 11. In certain embodiments, at least about 95% by weight of crystalline compound 11 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 11 is present.

[0232] It has been discovered 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, designated herein as Form A.

[0233] In some embodiments, compound 11 is amorphous. In some embodiments, compound 11 is amorphous and substantially free of crystalline compound 11.

[0234] Form A of Compound 11 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. Table 12: XRPD peak positions of Form A of Compound 11 TIFF0007734700000050.tif72128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0235] In some embodiments, Form A of Compound 11 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees 2-theta. In some embodiments, Form A of Compound 11 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees 2-theta. In some embodiments, Form A of Compound 11 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees 2-theta. In some embodiments, Form A of Compound 11 is characterized by having four peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees 2-theta.

[0236] In some embodiments, Form A of Compound 11 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 12 with a relative intensity of 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 11A.1.

[0237] A method for preparing Form A of Compound 11 is described below.

[0238] In some embodiments, the present disclosure provides compound 11, TIFF0007734700000051.tif28128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 11, wherein the compound is substantially free of amorphous Compound 11.

[0239] In some embodiments, the present disclosure provides compound 11, wherein the compound is substantially free of impurities.

[0240] In some embodiments, the disclosure provides Compound 11, which has one or more peaks in its XRPD selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta. In some embodiments, the disclosure provides Compound 11, which has at least two peaks in its XRPD selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta. In some such embodiments, the disclosure provides Compound 11, which is of Form A.

[0241] In some embodiments, the present disclosure provides compound 11, which has an XRPD substantially similar to that shown in Figure 11A.1.

[0242] In some embodiments, the present disclosure provides a composition comprising compound 11 and a pharmaceutically acceptable carrier or excipient.

[0243] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0244] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 11 or a composition thereof to the patient.

[0245] Compound 12 (L-lactate of Compound 1) According to one embodiment, the present disclosure provides compound 12: The L-lactate salt of Compound 1 is provided, represented by TIFF0007734700000052.tif27128.

[0246] Those skilled in the art will understand that L-lactic acid and compound 1 ionically bond to form compound 12. It is contemplated that compound 12 can exist in various 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 more detail below.

[0247] In some embodiments, the present 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 contaminants. Such contaminants may include different forms of Compound 12, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 12. In certain embodiments, at least about 95% by weight of a form of Compound 12 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 12 is present.

[0248] According to one embodiment, the compound 12 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the compound 12 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the compound 12 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0249] Structures depicted for forms of compound 12 are also meant to include all tautomeric forms of compound 12. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0250] Compound 12 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0251] In certain embodiments, compound 12 is a crystalline solid. In other embodiments, compound 12 is a crystalline solid that is 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 certain embodiments, at least about 95% by weight of crystalline compound 12 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 12 is present.

[0252] It has been discovered 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, designated herein as Form A.

[0253] In some embodiments, Compound 12 is amorphous. In some embodiments, Compound 12 is amorphous and substantially free of crystalline Compound 12.

[0254] Form A of Compound 12 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. Table 13: XRPD peak positions of Compound 12 Form A TIFF0007734700000053.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0255] In some embodiments, Form A of Compound 12 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 12 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 12 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 12 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 12 is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 12 is characterized by having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 12 is characterized in that it has seven or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta.In some embodiments, Form A of Compound 12 is characterized in that it has eight peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta.

[0256] In some embodiments, Form A of Compound 12 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 13 with a relative intensity of 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 12A.1.

[0257] A method for preparing Form A of Compound 12 is described below.

[0258] In some embodiments, the present disclosure provides compound 12, TIFF0007734700000054.tif27128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 12, wherein the compound is substantially free of amorphous Compound 12.

[0259] In some embodiments, the present disclosure provides compound 12, wherein the compound is substantially free of impurities.

[0260] In some embodiments, the disclosure provides Compound 12, which has one or more peaks in its XRPD selected from peaks 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 embodiments, the disclosure provides Compound 12, which has at least two peaks in its XRPD selected from peaks 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 disclosure provides Compound 12, which is in Form A.

[0261] In some embodiments, the present disclosure provides compound 12, which has an XRPD substantially similar to that shown in Figure 12A.1.

[0262] In some embodiments, the present disclosure provides a composition comprising compound 12 and a pharmaceutically acceptable carrier or excipient.

[0263] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0264] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 12 or a composition thereof to the patient.

[0265] Compound 13 (D-camphor salt of Compound 1) According to one embodiment, the present disclosure provides compound 13: The D-camphor salt of Compound 1 is provided, represented by TIFF0007734700000055.tif27128.

[0266] Those skilled in the art will understand that D-camphoric acid and compound 1 ionically bond to form compound 13. It is contemplated that compound 13 can exist in various physical forms. For example, compound 13 can be in solution, suspension, or solid form. In certain embodiments, compound 13 is in a solid form. When compound 13 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0267] In some embodiments, the present disclosure provides a form of Compound 13 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 contaminants. Such contaminants may include different forms of Compound 13, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 13. In certain embodiments, at least about 95% by weight of a form of Compound 13 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 13 is present.

[0268] According to one embodiment, the compound 13 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the compound 13 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the compound 13 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0269] Structures depicted for forms of compound 13 are also meant to include all tautomeric forms of compound 13. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0270] Compound 13 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0271] In certain embodiments, compound 13 is a crystalline solid. In other embodiments, compound 13 is a crystalline solid that is substantially free of amorphous compound 13. As used herein, the term "substantially free of amorphous compound 13" means that the compound does not contain a significant amount of amorphous compound 13. In certain embodiments, at least about 95% by weight of crystalline compound 13 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 13 is present.

[0272] It has been discovered 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, designated herein as Form A.

[0273] In some embodiments, compound 13 is amorphous. In some embodiments, compound 13 is amorphous and substantially free of crystalline compound 13.

[0274] Form A of Compound 13 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. Table 14: XRPD peak positions of Form A of Compound 13 TIFF0007734700000056.tif132128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0275] In some embodiments, Form A of Compound 13 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 13 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 13 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 13 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 13 is characterized by having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 13 is characterized by having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 embodiments, Form A of Compound 13 is characterized in that it has seven peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta.

[0276] In some embodiments, Form A of Compound 13 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 14 with a relative intensity of 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.

[0277] A method for preparing Form A of Compound 13 is described below.

[0278] In some embodiments, the present disclosure provides compound 13, TIFF0007734700000057.tif27128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 13, wherein the compound is substantially free of amorphous Compound 13.

[0279] In some embodiments, the present disclosure provides compound 13, wherein the compound is substantially free of impurities.

[0280] In some embodiments, the disclosure provides compound 13, which has one or more peaks in its XRPD selected from peaks 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 embodiments, the disclosure provides compound 13, which has at least two peaks in its XRPD selected from peaks 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 disclosure provides compound 13, which is in Form A.

[0281] In some embodiments, the present disclosure provides compound 13, which has an XRPD substantially similar to that shown in Figure 13A.1.

[0282] In some embodiments, the present disclosure provides a composition comprising compound 13 and a pharmaceutically acceptable carrier or excipient.

[0283] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0284] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 13 or a composition thereof to the patient.

[0285] Compound 14 (Dibenzoyl-D-tartrate of Compound 1) According to one embodiment, the present disclosure provides compound 14: The dibenzoyl-D-tartrate salt of compound 1 is provided, represented by TIFF0007734700000058.tif38128.

[0286] Those skilled in the art will understand that dibenzoyl-D-tartaric acid and compound 1 ionically bond to form compound 14. It is contemplated that compound 14 can exist in various physical forms. For example, compound 14 can be in solution, suspension, or solid form. In certain embodiments, compound 14 is in a solid form. When compound 14 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0287] In some embodiments, the present disclosure provides a form of Compound 14 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 contaminants. Such contaminants may include different forms of Compound 14, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 14. In certain embodiments, at least about 95% by weight of a form of Compound 14 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 14 is present.

[0288] According to one embodiment, the compound 14 form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, the compound 14 form contains less than about 3.0 area percent HPLC of total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the compound 14 form contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0289] Structures depicted for forms of compound 14 are also meant to include all tautomeric forms of compound 14. In addition, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0290] Compound 14 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0291] In certain embodiments, compound 14 is a crystalline solid. In other embodiments, compound 14 is a crystalline solid that is substantially free of amorphous compound 14. As used herein, the term "substantially free of amorphous compound 14" means that the compound does not contain a significant amount of amorphous compound 14. In certain embodiments, at least about 95% by weight of crystalline compound 14 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline compound 14 is present.

[0292] It has been discovered 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, designated herein as Form A.

[0293] In some embodiments, compound 14 is amorphous. In some embodiments, compound 14 is amorphous and substantially free of crystalline compound 14.

[0294] Form A of Compound 14 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. Table 15: XRPD peak positions of Form A of Compound 14 TIFF0007734700000059.tif122128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0295] In some embodiments, Form A of Compound 14 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2-theta. In some embodiments, Form A of Compound 14 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2-theta. In some embodiments, Form A of Compound 14 is characterized by having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2-theta. In some embodiments, Form A of Compound 14 is characterized by having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2-theta. In some embodiments, Form A of Compound 14 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2-theta.

[0296] In some embodiments, Form A of Compound 14 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 15 with a relative intensity of 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 14A.1.

[0297] A method for preparing Form A of Compound 14 is described below.

[0298] In some embodiments, the present disclosure provides compound 14, TIFF0007734700000060.tif38128 The compound is crystalline. In some embodiments, the present disclosure provides Compound 14, wherein the compound is substantially free of amorphous Compound 14.

[0299] In some embodiments, the present disclosure provides compound 14, wherein the compound is substantially free of impurities.

[0300] In some embodiments, the disclosure provides compound 14, which has one or more peaks in its XRPD selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2-theta. In some embodiments, the disclosure provides compound 14, which has at least two peaks in its XRPD selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees 2-theta. In some such embodiments, the disclosure provides compound 14, which is in Form A.

[0301] In some embodiments, the present disclosure provides compound 14, which has an XRPD substantially similar to that shown in Figure 14A.1.

[0302] In some embodiments, the present disclosure provides a composition comprising compound 14 and a pharmaceutically acceptable carrier or excipient.

[0303] In some embodiments, the 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 a β1-adrenergic receptor and a β2-adrenergic receptor.

[0304] In some embodiments, the present disclosure provides a method for treating a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in a patient, comprising administering compound 14 or a composition thereof to the patient.

[0305] General Methods for Providing Salt Compounds Compound 1 can be prepared according to the general scheme provided below. TIFF0007734700000061.tif47159 Scheme 1. Preparation of compound 1

[0306] Salt compounds of general formula A, which formula includes, among others, salt compounds 2-12, and / or specific forms thereof, are prepared from compound 1 according to the following general scheme. TIFF0007734700000062.tif21128 Scheme 2. Preparation of salts of formula A

[0307] For example, compounds 2-14, and each of their forms, are prepared from compound 1 by combining compound 1 with an appropriate acid to form a salt of the acid. Accordingly, another aspect of the present disclosure provides methods for preparing compounds 2-14, and their forms.

[0308] As generally described above, in some embodiments, the present disclosure provides compounds of general formula A: TIFF0007734700000063.tif21128, comprising reacting Compound 1: TIFF0007734700000064.tif21128 with a suitable acid and optionally a suitable solvent.

[0309] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the disclosure provides a method of making the 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.

[0310] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the present disclosure provides a method of making 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.

[0311] In some embodiments, the suitable acid is hydrobromic acid. In some embodiments, the present disclosure provides a method of making the 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.

[0312] In some embodiments, the suitable acid is paratoluenesulfonic acid. In some embodiments, the present disclosure provides a method of making a tosylate salt of Compound 1. In certain embodiments, the tosylate salt of Compound 1 is Compound 5. In certain embodiments, the tosylate salt of Compound 1 is Form A of Compound 5.

[0313] In some embodiments, the suitable acid is maleic acid. In some embodiments, the present disclosure provides a method for making a maleate salt of Compound 1. In certain embodiments, the maleate salt of Compound 1 is Compound 6. In certain embodiments, the maleate salt of Compound 1 is Form A of Compound 6.

[0314] In some embodiments, the suitable acid is fumaric acid. In some embodiments, the present disclosure provides a method of making a fumarate salt of Compound 1. In certain embodiments, the fumarate salt of Compound 1 is Compound 7. In certain embodiments, the fumarate salt of Compound 1 is Form A of Compound 7.

[0315] In some embodiments, the suitable acid is glycolic acid. In some embodiments, the present disclosure provides a method of making the 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.

[0316] In some embodiments, the suitable acid is L-tartaric acid. In some embodiments, the present disclosure provides a method of making the L-tartrate salt of Compound 1. In certain embodiments, the L-tartrate salt of Compound 1 is Compound 9. In certain embodiments, the L-tartrate salt of Compound 1 is Form A of Compound 9.

[0317] In some embodiments, the suitable acid is L-malic acid. In some embodiments, the present disclosure provides a method of making the 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.

[0318] In some embodiments, the suitable acid is D-mandelic acid. In some embodiments, the present disclosure provides a method of making the 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.

[0319] In some embodiments, the suitable acid is L-lactic acid. In some embodiments, the present disclosure provides a method for making the L-lactate salt of Compound 1. In certain embodiments, the L-lactate salt of Compound 1 is Compound 12. In certain embodiments, the L-lactate salt of Compound 1 is Form A of Compound 12.

[0320] In some embodiments, the suitable acid is D-camphoric acid. In some embodiments, the present disclosure provides a method of making 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.

[0321] In some embodiments, the suitable acid is dibenzoyl-D-tartaric acid. In some embodiments, the present disclosure provides a method of making the dibenzoyl-D-tartrate salt of Compound 1. In certain embodiments, the dibenzoyl-D-tartrate salt of Compound 1 is Compound 14. In certain embodiments, the dibenzoyl-D-tartrate salt of Compound 1 is Form A of Compound 14.

[0322] A suitable solvent can be any solvent system (eg, one solvent or mixture of solvents) in which Compound 1 and / or the acid are soluble or at least partially soluble.

[0323] Examples of suitable solvents useful in the methods of the present disclosure include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, 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.

[0324] In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, or acetone, which is anhydrous or combined with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, the suitable solvent is ethanol. In some embodiments, the suitable solvent is absolute ethanol. In some embodiments, the suitable solvent is MTBE.

[0325] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is methanol. In some embodiments, the suitable solvent is methylene chloride. In some embodiments, the suitable solvent is acetonitrile. In some embodiments, the suitable solvent is isopropanol. In certain embodiments, the suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, the suitable solvent is diethyl ether. In certain embodiments, the suitable solvent is water. In certain embodiments, the suitable solvent is methyl ethyl ketone. In certain embodiments, the suitable solvent is toluene.

[0326] In some embodiments, the present disclosure provides a method for preparing a salt compound of general formula A, 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. Means for solvent removal are known in the synthetic and chemical arts and include, but are not limited to, any of those described herein and in the Examples.

[0327] In some embodiments, the method for preparing the salt compound of general formula A includes one or more steps of heating or cooling the preparation.

[0328] In some embodiments, the method for preparing a salt compound of general formula A includes one or more steps of stirring or agitating the preparation.

[0329] In some embodiments, the method for preparing a salt compound of general formula A comprises slowly evaporating the solvent. In some embodiments, the method for preparing a salt compound of general formula A comprises slowly evaporating the solvent via exposure to ambient atmosphere at room temperature. In some embodiments, the method for preparing a salt compound of general formula A comprises evaporating the solvent under a stream of inert gas, e.g., nitrogen gas.

[0330] In some embodiments, the method for preparing a salt compound of general formula A comprises adding a suitable acid to a solution or slurry of compound 1.

[0331] In some embodiments, the method for preparing a salt compound of general formula A comprises a heating step.

[0332] In certain embodiments, the salt compound of Formula A precipitates from the mixture. In other embodiments, the salt compound of Formula A crystallizes from the mixture. In other embodiments, the salt compound of Formula A crystallizes from the solution following seeding the solution (i.e., adding crystals of the salt compound of Formula A to the solution).

[0333] The salt compound of Formula A can precipitate from the reaction mixture or can be produced by removing some or all of the solvent through methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption, and reaction, by adding an antisolvent such as heptane, by cooling, or by different combinations of these methods.

[0334] As generally described above, the salt compound of formula A is optionally isolated. It will be understood that the salt compound of formula A can be isolated by any suitable physical means known to those skilled 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.

[0335] In certain embodiments, the salt compound of Formula A is separated from the supernatant by filtration.

[0336] 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 temperatures.

[0337] Uses of the Compounds and Pharmaceutically Acceptable Compositions As generally described above, Compound 1 described herein, as well as pharmaceutically acceptable solid forms and salts thereof, are adrenergic receptor-modulating compounds (e.g., adrenergic receptor agonists, partial agonists, or antagonists). The adrenergic receptor-modulating compounds of the present disclosure may, in some embodiments, be useful for modulating the activity of a target adrenergic receptor in vitro or in vivo. Aspects of the methods of the present invention include contacting a sample with an effective amount of an adrenergic receptor-modulating compound (e.g., as described herein) and determining whether a desired activity is present.

[0338] Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) widely expressed throughout the body and play important roles in regulating multiple physiological processes, including cognition, stress-related behavior, inflammation, and smooth muscle contraction / dilation, myocardial contraction, airway reactivity, and cognition. Adrenergic receptors mediate the central and peripheral actions of noradrenaline (NA) and adrenaline. There are multiple subtypes of ADRs, including α- and β-adrenergic receptors. Each subtype is expressed in a distinct pattern and is involved in different physiological processes. Therefore, ligands that selectively target one subtype are highly useful both as research tools to identify the roles of different ADR subtypes and as therapeutic agents for multiple diseases associated with dysfunction of the NA and adrenergic systems.

[0339] β-adrenergic receptors further comprise three subtypes: β1-adrenergic receptors (β1-ADRs), β2-adrenergic receptors (β2-ADRs), and β3-adrenergic receptors (β3-ADRs). Because these subtypes are expressed in different patterns and involved in different physiological processes, ligands that can selectively target one subtype have therapeutic potential for multiple diseases. However, the discovery of subtype-selective ligands is challenging due to the high level of sequence homology shared by these subtypes. Many existing agonists for β-adrenergic receptors also exhibit poor blood-brain barrier (BBB) ​​penetration, which is necessary for drug discovery efforts for central nervous system (CNS) indications.

[0340] As a class of G protein-coupled receptors, adrenergic receptors transmit signals 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 exhibit biased activation of signaling pathways. The ability of a ligand to activate a receptor and generate a response in a pathway-dependent manner has been referred to as "signaling bias" or "functional selectivity." Because G proteins and β-arrestins mediate different physiological processes, biased agonists can provide improved therapeutic selectivity with reduced side effects. Therefore, the present disclosure is directed to β-adrenergic receptor subtype-selective agonists with improved blood-brain barrier (BBB) ​​penetration.

[0341] 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 non-selective 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 non-selective β1 / β2-adrenergic receptor agonists.

[0342] The adrenergic receptor-modulating compound can be an agonist of the target adrenergic receptor. In some cases, an effective amount of the adrenergic receptor-modulating compound is an amount sufficient to activate the activity associated with the adrenergic receptor in cells by 10% or more, for example, 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, compared to a control, for example, a control cell exhibiting a known level of receptor activity.

[0343] Adrenergic receptor-modulating compound can be a partial agonist of target adrenergic receptor.In some cases, the effective amount of adrenergic receptor-modulating compound is, for example, the amount of the compound of the present invention is sufficient to achieve partial agonism of intracellular adrenergic receptor, where the compound achieves 10% or more activation of receptor, for example, 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 activation of receptor, compared to a control, for example, a fully activated receptor.Partial agonism can be evaluated by any convenient method, such as cell-based assay using a known full agonist as a 100% activation control, and the relative maximum activation of receptor can be measured against the full agonist.

[0344] 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, for example, 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 not contacted with the compound of interest.

[0345] In some embodiments, compounds of the present disclosure act as low nM partial agonists of β2 adrenergic receptors. For example, in some embodiments, compounds of the present disclosure have an EC of 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, compounds of the present disclosure act as low nM partial agonists of β2 adrenergic receptors, with an EC of about 0.001 nM to about 200 nM, 0.001 nM to about 150 nM, about 0.001 nM to about 100 nM, 0.01 nM to about 100 nM, 0.1 nM to about 100 nM, or about 0.1 nM to about 80 nM, or about 0.1 nM to about 60 nM, or about 0.1 nM to about 40 nM, or about 0.1 nM to about 30 nM, or about 0.1 nM to about 20 nM, or about 0.1 nM to about 10 nM. 50 It has.

[0346] In some embodiments, compounds of the present disclosure act as low μM partial agonists of β2 adrenergic receptors. For example, in some embodiments, compounds of the present disclosure have an EC50 of less than about 0.1 μM, less than about 0.5 μM, less than about 1.0 μM, less than about 1.5 μM, less than about 2.0 μM, less than about 2.5 μM, less than about 3.0 μM, less than about 3.5 μM, less than about 4.0 μM, less than about 4.5 μM, less than about 5.0 μM, less than about 5.5 μM, less than about 6.0 μM, less than about 6.5 μM, less than about 7.0 μM, less than about 7.5 μM, less than about 8.0 μM, less than about 8.5 μM, less than about 9.0 μM, less than about 9.5 μM, or less than about 10.0 μM. 50 It has.

[0347] In some embodiments, compounds of the present disclosure act as low μM partial agonists of β2 adrenergic receptors, with an EC of about 0.01 μM to about 10 μM, about 0.01 μM to about 9.0 μM, about 0.01 μM to about 8.0 μM, about 0.01 μM to about 7.0 μM, about 0.01 μM to about 6.0 μM, about 0.01 μM to about 5.0 μM, about 0.01 μM to about 4.0 μM, about 0.01 μM to about 3.0 μM, about 0.01 μM to about 2.0 μM, about 0.01 μM to about 1.0 μM, about 0.01 μM to about 9.0 μM, or about 0.1 μM to about 1.0 μM. 50 It has.

[0348] In some embodiments of this method, the target adrenergic receptor is a β1-adrenergic receptor. In some embodiments of this method, the target adrenergic receptor is a β2-adrenergic receptor. In some embodiments of this method, the target adrenergic receptor is a β3-adrenergic receptor. In some embodiments, the compound is an agonist of both the β1-adrenergic receptor and the β2-adrenergic receptor. In certain cases, the compound is selective for the β2-adrenergic receptor over the β1-adrenergic receptor.

[0349] The target adrenergic receptor may be responsible for mediating an intracellular signal or pathway in the cell. In some embodiments, the sample comprises a cell, and modulating the adrenergic receptor modulates a physiological process of the cell. Any convenient physiological process can be targeted for modulation in the cell using the methods of the present invention. In some embodiments, the physiological process is a process involved in cardiac function, and in certain cases, the physiological process is a process involved in cognitive function. In certain cases, the physiological process is a process involved in an inflammatory pathway or a pathology. The methods of the present invention can provide for mediating the intracellular concentration of a signaling molecule, e.g., cAMP, in the cell. The methods of the present invention can provide partial or complete blockade of the target adrenergic receptor, resulting in modulation (e.g., activation) of cAMP in the sample. In some embodiments, the method does not modulate the β-arrestin pathway in the cell. In some cases, the cell is an inflammatory cell, and the function of the cell is modulated. The methods of the present invention can provide for inhibition of an inflammatory pathway in the cell. In some cases, TNF-α is inhibited in the cell, e.g., the concentration or production of TNF-α is reduced by practicing the methods of the present invention. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulation of adrenergic receptors enhances neurogenesis.

[0350] Also disclosed are methods of treating a subject having a disease, the methods comprising administering to the subject a therapeutically effective amount of a compound 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 forms thereof. In some embodiments, the disease is a β1-adrenergic receptor or β2-adrenergic receptor-mediated disease or disorder in the patient.

[0351] In some embodiments, the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, extensor ataxia, spinal polymyalgia, progressive supranuclear penile disease, dystonia, muscle atrophy, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, intravaginal, sublingual, or rectal routes.

[0352] In some embodiments, the disease is 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), or a combination of these. and Alzheimer's disease (AD), early AD, and Down's syndrome (DS). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's 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's syndrome), The neurodegenerative disease is one or more selected from the group consisting of Korsakoff's syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), 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.

[0353] In certain embodiments of the methods disclosed herein, the methods comprise administering to a subject a compound disclosed herein and a peripherally acting beta blocker (PABRA).

[0354] As used herein, the term "peripherally acting beta-blocker (PABRA)" refers to a beta-adrenergic receptor antagonist, or simply a beta-, beta-, or non-selective beta-blocker. Examples of selective peripherally acting beta-blockers (PABRA) that may be used in certain embodiments of the methods disclosed herein 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, metaprolol, and nebivolol; in other embodiments, the methods do not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, or nebivolol as the beta-blocker.

[0355] In certain embodiments, a peripherally acting beta blocker (PABRA) is administered to a subject prior to administration of a compound of the present disclosure, while in other embodiments, a peripherally acting beta blocker (PABRA) is administered to a subject simultaneously with administration of a compound of the present disclosure.

[0356] 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 the compounds of the present disclosure to inhibit or eliminate the effects of activating peripheral beta- and / or beta-adrenergic receptors by the compounds of the present disclosure. In various embodiments, blocking peripheral beta- and / or beta-adrenergic receptors is preferred in accordance with the foregoing compositions and methods of the present disclosure to eliminate, or at least minimize, any adverse peripheral cardiac, metabolic, or muscular effects on the treated human.

[0357] In some embodiments of the methods provided herein, a beta 1 agonist and / or a beta 2 agonist, or a non-selective beta 1 / beta 2 agonist, is administered to the patient in addition to the compounds disclosed herein.

[0358] As used herein, the term "β1 agonist" refers to a β1-adrenergic receptor agonist or a β1-ADR agonist. In certain embodiments, the term β1 agonist includes compounds that are, of course, primarily β1 agonists, but may also exhibit some peripheral activating effects on other adrenergic receptors, such as the β2-adrenergic receptor. In this application, the terms "β1-adrenergic receptor agonist," "β1-ADR agonist," "β1AR agonist," and "β1 agonist" may be used interchangeably. In certain embodiments, the term β1-ADR agonist explicitly includes both selective and partial agonists, and biased and unbiased agonists. Examples of β1 adrenergic agonists include, for example, xamoterol, noradrenaline, isoprenaline, dopamine, pindolol, and dobutamine, as well as pharmacologically acceptable salts of any of the above. Partial agonists and ligands of β1-ADR are known. Furthermore, using the methodology of Kolb et al., but instead for β1-ADR, those skilled in the art can determine new ligands by structure-based discovery. See Proc. Natl. Acad. Sci. USA 2009, 106, 6843-648.

[0359] As used herein, the term β2 agonist refers to a β2-adrenergic receptor agonist or a β2-ADR agonist. In certain embodiments, the term β2 agonist includes compounds that are, of course, primarily β2 agonists, but may also exhibit some peripheral activating effects on other adrenergic receptors, such as β1-adrenergic receptors. In this application, the terms "β2-adrenergic receptor agonist," "β2-ADR agonist," "β2AR agonist," and "β2 agonist" may be used interchangeably. In some embodiments, the term β2-ADR agonist explicitly includes both selective agonists and partial agonists. β2 agonists that may be used according to various aspects and embodiments of the present disclosure may be short-acting, long-acting, or ultra-long-acting. Examples of short-acting β2 agonists that can be used include salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesilate, oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharin.Examples of long-acting β2 agonists that can be used include salmeterol, bambuterol, formoterol, and clenbuterol.Examples of ultra-long-acting β2 agonists include indacaterol, vilanterol, and olodaterol.

[0360] As used herein, "co-administration," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the described compounds may be administered simultaneously with another therapeutic agent, sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the present disclosure provides single unit dosage forms comprising the described compounds, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" when a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" when a patient or individual simultaneously exhibits therapeutically appropriate levels of the agents in specific target tissues or samples (e.g., in the brain, serum, etc.).

[0361] When the compounds of the present disclosure are administered in combination therapy with other agents, they may be administered sequentially or simultaneously to a patient. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure includes a combination of ivermectin, or any other compound described herein, and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0362] In some embodiments, the methods of the present invention include administering a therapeutically effective amount of one or more additional active agents. Combination therapy means that an adrenergic receptor modulating compound can be used in combination with another therapeutic agent to treat a single disease or condition. In certain embodiments, the compound of the present disclosure is administered simultaneously with the administration of another therapeutic agent, and the other therapeutic agent can be administered as a component of a composition containing the compound of the present disclosure or as a component of a different composition.

[0363] The compounds of the present invention can be administered in combination with other therapeutic agents in various therapeutic applications.Target therapeutic applications for combination therapy include applications in which the activity of target adrenergic receptors is a causative or compounding factor in disease progression.Therefore, the compounds of the present invention find use in combination therapy where the inhibition of target adrenergic receptors in subjects is desired.Examples of disease conditions that can be treated by combination therapy with the compounds of the present invention 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.Target drugs that can be used in conjunction with the adrenergic receptor-modulating compounds of the present invention include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, hypotensive agents, palliatives, chemotherapeutic agents, drugs used in Alzheimer's disease, and anti-inflammatory agents.

[0364] The adrenergic receptor-modulating compounds of the present invention can be used in conjunction with any drug useful in the treatment of cardiac conditions such as cardiogenic shock, hypertension, congestive heart failure, coronary heart disease, arrhythmias, myocardial infarction, or ischemic heart disease. Drugs of interest that can be used in conjunction with the adrenergic receptor-modulating compounds of the present invention include, but are not limited to, denopamine, dobutamine, xamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, carvedilol, labetalol, phentolamine, prazosin, cirazoline, methoxamine, synephrine, etilefrine, metaraminol, midrine, and coumarin.

[0365] The adrenergic receptor modulating compounds of the present invention can be used in conjunction with any drug useful for treating neurodegenerative or neurodevelopmental diseases, such as Alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue damage, Down's syndrome, or autism. Drugs of interest that can be used in conjunction with the adrenergic receptor modulating compounds of the present invention include, but are not limited to, acepromazine. In some embodiments, the adrenergic receptor modulating compounds of the present invention can be used in conjunction with cholinesterase inhibitors or NMDA receptor modulating agents to treat diseases such as neurodegenerative or neurodevelopmental diseases. Drugs of interest include, but are not limited to, donepezil, Aricept, galantamine, Razadyne, memantine, Namenda, rivastigmine, Exelon, tacrine, and Cognex. Other drugs of interest that can be used in conjunction with the adrenergic receptor modulating compounds of the present invention include 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, tolonidine, These include, but are not limited to, xylazine, xylometazoline, aripiprazole, asenapine, atipamezole, cirazoline, clozapine, efaroxan, idazoxan, lurasidone, melperone, mianlin, mirtazapine, napitan, olanzapine, paliperidone, phenoxybenzamine, phentolamine, piribedil, rauwolscine, risperidone, rotigonin, quetiapine, norquetiapine, setiptiline, tolazoline, yohimbine, ziprasidone, and zotepine.Other drugs of interest that may be used in conjunction with the adrenergic receptor-modulating compounds of the present invention 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, mirveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxuprenaline, ritodrine, salbutamol or albuterol, terbutaline, zilpeterol, ICI-118,551, and butoxamine.

[0366] The compounds utilized in the compositions and methods of the present disclosure may also be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include those that enhance 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 excretion rate.

[0367] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both 1) curing, slowing, alleviating symptoms, and / or halting progression of a diagnosed pathological condition, disease, or disorder, and 2) as well as preventative / prophylactic measures. Those in need of treatment can include individuals already with a particular medical disease or disorder, as well as those who may ultimately acquire the disorder (i.e., those at risk or in need of preventative measures).

[0368] As used herein, the term "subject" refers to any individual or patient on whom the methods of the present invention are performed. Generally, the subject is a human, and as will be understood by those skilled in the art, the subject may also be an animal.

[0369] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like refer to an amount of a compound of the present invention that elicits a desired biological or medical response in a tissue, system, animal, or human by administering the compound. Generally, the response is either an improvement in a patient's symptoms or a desired biological outcome. In some embodiments, such an amount should be sufficient to modulate adrenergic receptors.

[0370] In some embodiments, an effective amount of an adrenoceptor-modulating compound is from about 50 ng / ml to 50 pg / ml (e.g., from about 50 ng / ml to 40 pg / ml, from about 30 ng / ml to 20 pg / ml, from about 50 ng / ml to 10 μg / ml, from about 50 ng / ml to 1 μg / ml, from about 50 ng / ml to 800 ng / ml, from about 50 ng / ml to 700 ng / ml, from about 50 ng / ml to 600 ng / ml, from about 50 ng / ml to 500 ng / ml, from about 50 ng / ml to 400 ng / ml, from about 60 ng / ml to 4 The amount is in the range of about 00ng / ml, about 70ng / ml to 300ng / ml, about 60ng / ml to 100ng / ml, about 65ng / ml to 85ng / ml, about 70ng / ml to 90ng / ml, about 200ng / ml to 900ng / ml, about 200ng / ml to 800ng / ml, about 200ng / ml to 700ng / ml, about 200ng / ml to 600ng / ml, about 200ng / ml to 500ng / ml, about 200ng / ml to 400ng / ml, or about 200ng / ml to about 50ng / ml).

[0371] In some embodiments, an effective amount of an adrenoceptor modulating compound is from about 10 pg to 100 mg, e.g., from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10 ng, from about 10 ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng The amount is in the range of about 1000 mg, 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. This amount can be a single dose or a total daily amount. The total daily amount can be in the range of about 10 pg to 100 mg, about 100 mg to 500 mg, or about 500 mg to 1000 mg.

[0372] Also disclosed herein are pharmaceutical compositions comprising the compounds 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 forms thereof.

[0373] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient together with a compound of the present disclosure and that does not destroy its pharmacological activity. Pharmaceutically acceptable carriers that may 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, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, water, partial glyceride mixtures of salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0374] For pharmaceutical compositions containing only a compound described herein as an active ingredient, methods for administering these compositions may further include administering to a subject an additional drug or therapeutic agent. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapy for microbial diseases, and / or chemotherapy for neoplastic diseases. Other pharmacological therapies include any other drug or biologic found in any drug class. For example, other drug classes may include allergy / cold / ENT therapy, painkillers, anesthetics, anti-inflammatory agents, antibacterial agents, antivirals, asthma / pulmonary therapy, cardiovascular therapy, dermatological therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy, ophthalmology therapy, psychiatric therapy, or rheumatology therapy. Other examples of drugs or therapies that may be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0375] The term "therapeutically effective amount," as used herein, refers to an amount of an active compound or pharmaceutical agent that elicits the biological or pharmacological response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, including one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who is susceptible to the disease, condition, or disorder but who has not yet experienced or displayed the pathology or symptomology of the disease; (2) inhibiting the disease, e.g., inhibiting the disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology) in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder; and (3) ameliorating the disease, e.g., ameliorating the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder.

[0376] Pharmaceutically acceptable compositions 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 reducing the severity of the disorders provided above. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general health, the severity of the infection, the specific drug, 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. As used herein, the term "dosage unit form" refers to a physically discrete pharmaceutical unit appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder being treated, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the time of administration, route of administration, and excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field.

[0377] The pharmaceutically acceptable compositions of the present disclosure may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or eye drops), buccally, or as a nasal spray, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day to achieve the desired therapeutic effect.

[0378] 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 compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances.

[0379] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any smooth fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0380] Injectable preparations can be sterilized, for example, by filtration through a bacteria-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 before use.

[0381] To prolong the effect of the compounds of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which may in turn depend on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered compound form can be achieved 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 nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0382] Compositions for rectal or vaginal administration can preferably be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier which is solid at ambient temperature but liquid at body temperature, such as cocoa butter, polyethylene glycol, or a suppository wax, and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0383] 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, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, 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 may also comprise buffering agents.

[0384] Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as 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 arts. They may optionally contain opacifying agents and can be of a composition that releases 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. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0385] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical arts. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0386] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present disclosure. In addition, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable 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.

[0387] All features of each of the aspects of the present disclosure apply mutatis mutandis to all other aspects. Each of the references mentioned herein, including but not limited to patents, patent applications, and journal articles, is incorporated herein by reference as if fully set forth in its entirety.

[0388] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any way. [Example]

[0389] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods illustrate the synthesis of specific compounds of the present disclosure, it will be understood that the following general methods, and other methods known to those of skill in the art, are applicable to all compounds and each subclass and species of these compounds, as described herein.

[0390] General Procedure Solvent List TIFF0007734700000065.tif113128

[0391] Analysis method X-ray powder diffraction (XRPD) XRPD patterns were identified using an X-ray diffractometer (Bruker D8 advance). The system was equipped with a LynxEye detector. Samples were scanned from 3 to 40°2θ with a step size of 0.02°2θ. The tube voltage and current were 40 kV and 40 mA, respectively.

[0392] Differential scanning calorimetry (DSC) DSC was performed using a Discovery DSC 250 (TA Instruments, US). The sample was placed in an aluminum hermetically sealed pan with a pinhole, and the weight was accurately recorded. The sample was heated from 25°C to the final temperature at a rate of 10°C / min.

[0393] Thermogravimetric analysis (TGA) TGA analysis was performed on a Discovery TGA 55 (TA Instruments, US). Samples were placed in tared aluminum pans, automatically weighed, and inserted into the TGA oven. The samples were heated from ambient temperature to the final temperature at a rate of 10°C / min.

[0394] Dynamic Vapor Sorption (DVS) Moisture sorption / desorption data were collected on a DVS Intrinsic (SMS, UK). Samples were placed in a tared sample chamber and automatically weighed. Samples were dried at 40°C until dm / dt was less than 0.002% and then cooled to 25°C. Instrument parameters were set as follows: Step time (min): 60 min; Sample temperature: 25°C; Cycle: Full cycle; Adsorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90; Desorption: 80, 70, 60, 50, 40, 30, 20, 10, 0; Save data rate: 5 s; Total flow rate: 200 sccm; Total flow after experiment: 200 sccm.

[0395] Polarized Light Microscope (PLM) Optical microscopy was performed using a polarizing microscope ECLIPSE LV100POL (Nikon, JPN).

[0396] Proton nuclear magnetic resonance ( 1 H NMR) 1 H NMR was performed using a Bruker Advance 300 equipped with an autosampler (B-ACS 120).

[0397] High-performance liquid chromatography (HPLC) HPLC analysis was performed using an Agilent HPLC 1260 series instrument. The HPLC methods for solubility and stability testing are listed in Table 16. Table 16. HPLC methods for solubility and stability testing TIFF0007734700000066.tif105137

[0398] Example A: General Preparation of Compound 1 TIFF0007734700000067.tif76148Step 1: Synthesis of 2-cyano-6-vinylpyridine 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 N2 for 5 minutes and then heated at 80 °C overnight. After cooling, the reaction mixture was poured into an aqueous solution of KF (40 g in 200 mL) and stirred for 30 minutes. The mixture was then filtered through Celite, and the solid was washed with EtOAc (2 × 50 mL). The aqueous phase of the filtrate was separated and extracted with EtOAc (2 × 250 mL). The combined organic phase was 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 give 2-cyano-6-vinylpyridine as a pale yellow liquid (6.5 g, 86%). MS (m / z): 131.1 (M+H). + .

[0399] Step 2: Synthesis of 6-(oxiran-2-yl)picolinonitrile To a stirred solution of 2-cyano-6-vinylpyridine (6.5 g, 49.94 mmol) in DCM (300 mL) was added meta-chloroperoxybenzoic acid (mCPBA) (61.56 g, 249.72 mmol) slowly and portionwise over 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, saturated aqueous NaHCO was added, and the solution was extracted with DCM (200 mL × 2). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 90 / 10 to 80 / 20) to give 6-(oxiran-2-yl)picolinonitrile as a colorless liquid (3.85 g, 52%). MS (m / z): 147.1 (M+H). + .

[0400] Step 3: Synthesis of Compound 1 To a stirred solution of 6-(oxiran-2-yl)picolinonitrile (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 in a sealed tube at 80° C. for 3 hours while monitoring the reaction by TLC and LCMS. After completion of the reaction, the solvent was evaporated to give a residue, which was purified by reverse-phase chromatography to give the desired product as a racemic mixture. The racemic mixture was separated by SFC (Chiralpak AS-H (30*250) mm, 5μ column) using CO2:80% co-solvent:20% (0.2% isopropylamine in IPA as eluent) to give compound 1 (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile (1.05 g, 26.3%) and (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile (0.98 g, 24.5%) as white solids. Compound 1: 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)picolinonitrile: 1 H 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).

[0401] Example 1: Preparation of Free Base Forms A and B of Compound 1 TIFF0007734700000068.tif25128 Compound 1 was prepared as described elsewhere herein.

[0402] Compound 1 Form A Compound 1 Form A was prepared as described in Example A and formed directly from IPA / isopropylamine co-solvent as a white solid.

[0403] Characterization of the resulting material showed crystalline Form A of the free base of Compound 1.

[0404] Table 1 above is reproduced below showing the X-ray diffraction peaks observed for Compound 1, Form A. Table 1: XRPD peak positions for Form A of Compound 1 TIFF0007734700000069.tif132128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0405] FIG. 1A.1 shows the XRPD pattern of Form A of Compound 1.

[0406] Figure 1A.2 shows the DSC thermogram and TGA trace of Compound 1 Form A. The DSC thermogram of Compound 1 Form A was characterized by two endothermic peaks at about 100°C and about 104°C.

[0407] Figure 1A.3 shows Form A of Compound 1. 1 The H NMR spectrum is shown.

[0408] Form B of Compound 1 Form B of Compound 1 was prepared as follows.

[0409] Procedure A: A solution of compound 1 was dissolved in THF (5 volumes) and stirred at room temperature (<25°C). After 2 hours, HO (5 volumes) was added, followed by 3M aqueous HCl (2 volumes). The mixture was extracted with dichloromethane (4 x 1 volume). The pH of the resulting aqueous solution was adjusted to approximately 9 with concentrated aqueous NHOH and extracted with dichloromethane (5 x 3 volumes). The combined organics were filtered and concentrated to give compound 1 Form B as a light brown solid.

[0410] Characterization of the resulting material showed crystalline Form B of the free base of Compound 1.

[0411] Table 2 above is reproduced below showing the X-ray diffraction peaks observed for Compound 1, Form B. Table 2: XRPD peak positions of Form B of Compound 1 TIFF0007734700000070.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0412] FIG. 1B.1 shows the XRPD pattern of Form B of Compound 1.

[0413] Figure 1B.2 shows the DSC thermogram and TGA trace of Form B of Compound 1. The DSC thermogram of Form B of Compound 1 was characterized by an endothermic peak at about 100°C.

[0414] Figure 1B.3 shows Form B of Compound 1. 1 The H NMR spectrum is shown.

[0415] Example 2: Preparation of Form A of Compound 2 TIFF0007734700000071.tif25128 Compound 2 Form A Compound 2 Form A was prepared as follows.

[0416] Procedure A: Compound 1 (3.5 g) was dissolved in 35 mL of IPA at 50° C. Hydrochloric acid (1.05 equivalents) was added. The resulting mixture was cooled to room temperature. After 2 hours, the solid was collected by filtration and dried under vacuum at 50° C. for 2 hours to give Compound 2 Form A (3.28 g, 80% yield, approximately 100% purity, 0.16% IPA).

[0417] Procedure B: Compound 1 (20.0 mg) was dissolved in IPA (15 V) at 50° C. The solution was cooled to room temperature. Hydrochloric acid (1.05 equivalents) was added at room temperature. The resulting mixture was stirred for 2 hours. The solid was collected by filtration and dried under vacuum at 50° C. for 2 hours to give Form A of Compound 2 (71% yield, approximately 100% purity, 0.31% IPA).

[0418] Procedure C: Compound 1 (20.0 mg) was dissolved in IPA (10 V) 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 warmed to room temperature. After 1.5 hours, the solid was collected by filtration and dried under vacuum at 50° C. for 2 hours to give Form A of Compound 2 (77% yield, approximately 100% purity, 0.12% IPA).

[0419] Procedure D: Compound 1 (20.0 mg) was added to IPA (10 V) at room temperature. Hydrochloric acid (1.05 equivalents) was added. The resulting slurry was stirred for 2 hours. The solid was collected by filtration and dried under vacuum at 50° C. for 2 hours to give Compound 2 Form A (76% yield, approximately 100% purity, 0.20% IPA).

[0420] 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 solid was collected by filtration and dried under vacuum at 50° C. for 2 hours to give Compound 2 Form A (70% yield, approximately 100% purity, negligible solvent).

[0421] Procedure F: Compound 1 was added to EtOAc (15 V) at room temperature. Hydrochloric acid (1.05 equiv) was added. The resulting slurry was stirred for 4 hours. The solid was collected by filtration to give Compound 2 Form A.

[0422] Procedure G: Compound 1 (198.1 mg) was added to 4 mL of EtOAc at room temperature. Hydrochloric acid (1.05 equivalents) was added, and the resulting precipitate was stirred at room temperature for 3 hours. The solid was collected by filtration at 50° C. for 1 day to give Compound 2 Form A.

[0423] 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, then at room temperature for an additional 1.5 hours. The resulting solid was collected by filtration and dried overnight under vacuum at 50° C. to give compound 11 (5.8 g, 91% yield). The resulting compound 11 was added to EtOAc (2.58 V) and mixed to form a suspension. Concentrated HCl (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 seeds (10.12 mg) were added. A solid precipitated immediately. The suspension was stirred at room temperature for 3 hours. The resulting solid was collected by filtration and dried overnight under vacuum at 50° C. The solid was added to an EtOAc / MTBE solvent mixture (0.88 volumes of EtOAc + 7.92 volumes 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 give Form A of Compound 2 (2.23 g, 53% yield, 99.9% purity).

[0424] Characterization of the resulting material indicated anhydrous crystalline Form A of Compound 2.

[0425] Table 3 above is reproduced below showing the X-ray diffraction peaks observed for Compound 2 Form A. Table 3: XRPD peak positions for Form A of Compound 2 TIFF0007734700000072.tif83128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0426] FIG. 2A.1 shows the XRPD pattern of Form A of Compound 2.

[0427] Figure 2A.2 shows the DSC thermogram and TGA trace of Compound 2 Form A. The TGA trace showed little weight loss before decomposition. The DSC thermogram of Compound 2 Form A was characterized by an endothermic peak at about 215°C.

[0428] Figures 2A.3 and 2A.4 show the DVS plots of Form A of Compound 2. The DVS results showed that Form A was slightly hygroscopic, with a water uptake of 0.58% at 80% RH. The XRPD pattern did not change after the DVS test.

[0429] Ion chromatography analysis of Compound 2 Form A determined an HCl content of about 13.5%, indicating that Compound 2 Form A is the mono-HCl salt (theoretical 14.26%).

[0430] Example 3: Preparation of Form A of Compound 3 TIFF0007734700000073.tif25128 Form A of Compound 3 Compound 3 Form A was prepared as follows.

[0431] Procedure A: Compound 1 (20.4 mg) was dissolved in iPrOAc (20 V) at room temperature. Sulfuric acid (0.6 equivalents) was added. A solid precipitated quickly. The solid was collected by filtration and dried under vacuum to give Compound 3 Form A.

[0432] Characterization of the resulting material showed anhydrous crystalline Form A of compound 3 with no residual organic solvent as observed by NMR.

[0433] Table 4 above is reproduced below showing the X-ray diffraction peaks observed for Compound 3 Form A. Table 4: XRPD peak positions for Form A of Compound 3 TIFF0007734700000074.tif94128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0434] FIG. 3A.1 shows the XRPD pattern of Form A of Compound 3.

[0435] Figure 3A.2 shows the DSC thermogram and TGA trace of Compound 3 Form A. The TGA trace showed little weight loss before decomposition. The DSC thermogram of Compound 3 Form A was characterized by an endothermic peak at about 247°C.

[0436] Example 4: Preparation of Form A of Compound 4 TIFF0007734700000075.tif25128 Form A of Compound 4 Compound 4 Form A was prepared as follows.

[0437] Procedure A: Compound 1 was dissolved in EtOAc (20 V) at room temperature. HBr acid (1.05 eq.) was added, resulting in precipitation. The solid was collected by filtration and dried under vacuum at 50° C. to give Compound 4 Form A.

[0438] Characterization of the resulting material showed anhydrous crystalline Form A of compound 4 with no residual organic solvent as observed by NMR.

[0439] Table 5 above is reproduced below showing the X-ray diffraction peaks observed for Form A of Compound 4. Table 5: XRPD peak positions for Form A of Compound 4 TIFF0007734700000076.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0440] FIG. 4A.1 shows the XRPD pattern of Form A of Compound 4.

[0441] Figure 4A.2 shows the DSC thermogram and TGA trace of Compound 4 Form A. The TGA trace showed no weight loss prior to decomposition. The DSC thermogram of Compound 4 Form A was characterized by an endothermic peak at approximately 173°C.

[0442] Example 5: Preparation of Form A of Compound 5 TIFF0007734700000077.tif34128 Form A of Compound 5 Form A of Compound 5 was prepared as follows.

[0443] Procedure A: Compound 1 (20.2 mg) was added to iPrOAc (20 V) with stirring at room temperature. p-Toluenesulfonic acid (1.05 equivalents) was added, resulting in a slurry. The solid was collected by filtration and dried under vacuum to give Compound 5 Form A.

[0444] Characterization of the resulting material showed anhydrous crystalline Form A of Compound 5 with no residual organic solvent as observed by NMR. The ratio of tosylate to Compound 1 in Form A of Compound 5 was: 1 Determined to be 1:1 by 1 H NMR analysis.

[0445] Table 6 above is reproduced below showing the X-ray diffraction peaks observed for Compound 5, Form A. Table 6: XRPD peak positions for Form A of Compound 5 TIFF0007734700000078.tif111128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0446] FIG. 5A.1 shows the XRPD pattern of Form A of Compound 5.

[0447] Figure 5A.2 shows the DSC thermogram and TGA trace of Compound 5 Form A. The TGA trace showed little weight loss before decomposition. The DSC thermogram of Compound 5 Form A was characterized by an endothermic peak at approximately 139 °C.

[0448] Figure 5A.3 shows Form A of Compound 5. 1 The H NMR spectrum is shown.

[0449] Figures 5A.4 and 5A.5 show the DVS plots of Form A of Compound 5. The DVS plots showed that Form A of Compound 5 was slightly hygroscopic, with water uptakes of 1.25% and 2.77% at 80% RH and 90% RH, respectively. The XRPD patterns of the test samples remained unchanged after the DVS test.

[0450] Example 6: Preparation of Form A of Compound 6 TIFF0007734700000079.tif31128 Form A of Compound 6 Form A of Compound 6 was prepared as follows.

[0451] 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 give Compound 6 Form A.

[0452] 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 give Compound 6 Form A.

[0453] 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 equivalent) 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 give Compound 6 Form A.

[0454] 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 give Compound 6 Form A.

[0455] Characterization of the obtained material showed anhydrous crystalline Form A of Compound 6, 1 No residual organic solvent was observed by H NMR. The ratio of maleic acid to Compound 1 in Form A was: 1 It was determined to be 1:1 based on 1 H NMR analysis.

[0456] Table 7 above is reproduced below showing the X-ray diffraction peaks observed for Compound 6 Form A. Table 7: XRPD peak positions of Form A of Compound 6 TIFF0007734700000080.tif127128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0457] FIG. 6A.1 shows the XRPD pattern of Form A of Compound 6.

[0458] Figure 6A.2 shows the DSC thermogram and TGA trace of Compound 6 Form A. The TGA trace showed little weight loss before decomposition. The DSC thermogram of Compound 6 Form A was characterized by two endothermic peaks at about 132 °C and about 146 °C.

[0459] Figure 6A.3 shows Form A of Compound 6. 1 The H NMR spectrum is shown.

[0460] Example 7: Preparation of Form A of Compound 7 TIFF0007734700000081.tif24128 Form A of Compound 7 Form A of Compound 7 was prepared as follows.

[0461] 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 obtain Form A of Compound 7.

[0462] Characterization of the obtained material showed anhydrous crystalline Form A of Compound 7, 1 No residual organic solvent was observed by H NMR. The ratio of fumaric acid to Compound 1 in Form A was: 1 It was determined to be 1:1 based on 1 H NMR analysis.

[0463] Table 8 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 7. Table 8: XRPD peak positions of Form A of Compound 7 TIFF0007734700000082.tif78128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0464] FIG. 7A.1 shows the XRPD pattern of Form A of Compound 7.

[0465] Figure 7A.2 shows the DSC thermogram and TGA trace of Form A of Compound 7. The TGA trace showed little weight loss before decomposition. The DSC thermogram of Form A of Compound 7 was characterized by two endothermic peaks at about 138°C and about 155°C.

[0466] Figure 7A.3 shows Form A of Compound 7. 1 The H NMR spectrum is shown.

[0467] Example 8: Preparation of Form A of Compound 8 TIFF0007734700000083.tif25128 Form A of Compound 8 Form A of Compound 8 was prepared as follows.

[0468] 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 solid was collected by filtration and dried under vacuum to give Compound 8 Form A.

[0469] Procedure B: Compound 1 (20.0 mg) was dissolved in EtOAc (30 V) at 50° C. Glycolic acid (1.05 equiv.) was added. The solution was stirred at 50° C. for 1 day, during which time a solid precipitated. The solid was collected by filtration and dried under vacuum to give Compound 8 Form A.

[0470] Characterization of the resulting material showed anhydrous crystalline Form A of Compound 8 with no residual organic solvent as observed by NMR. The ratio of glycolic acid to Compound 1 in Form A was: 1 It was determined to be 1:1 based on 1 H NMR analysis.

[0471] Table 9 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 8. Table 9: XRPD peak positions of Form A of Compound 8 TIFF0007734700000084.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0472] FIG. 8A.1 shows the XRPD pattern of Form A of Compound 8.

[0473] Figure 8A.2 shows the DSC thermogram and TGA trace of Form A of Compound 8. The TGA trace showed little weight loss before decomposition. The DSC thermogram of Form A of Compound 8 was characterized by two endothermic peaks at about 122 °C and about 136 °C.

[0474] Figure 8A.3 shows Form A of Compound 8. 1 The H NMR spectrum is shown.

[0475] Example 9: Preparation of Form A of Compound 9 TIFF0007734700000085.tif28128 Form A of Compound 9 Form A of Compound 9 was prepared as follows.

[0476] Procedure A (Salt Screening Method): Compound 1 (180 mg) was dissolved in MeOH (6 mL) to prepare a stock solution. 100 μL of the stock solution was added to each well of a 96-well plate. One column of wells received L-tartaric acid (150 μL, 0.1 M solution, 1.1 equivalents). Each row of the plate received a different solvent (200 μL each of MeOH, IPA, THF, ACN, MTBE, acetone, water, and EtOAc). The wells were covered with a film with a pinhole on top and allowed to evaporate to dryness under ambient conditions. The dried material was collected and submitted for XRPD analysis. The wells receiving L-tartaric acid containing IPA, THF, ACN, acetone, and EtOAc each yielded Compound 9 Form A.

[0477] Procedure B: Compound 1 (approximately 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 a solid precipitated immediately after the addition of the acid solution. The solid was collected by filtration and dried under vacuum at 50° C. to obtain Form A of Compound 9.

[0478] Procedure C: Compound 1 (approximately 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 a solid precipitated immediately after the addition of the solid L-tartaric acid. The resulting precipitate was collected by filtration and dried under vacuum at 50° C. to obtain Form A of Compound 9.

[0479] Procedure D: Compound 1 (121.0 mg) was dissolved in EtOAc (20 V) at room temperature. A 1 M solution of L-tartaric acid in MeOH (303.5 μL, 0.55 equivalents) was added to the solution, and a solid precipitated immediately after the addition of 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 give Form A of Compound 9 (134.5 mg, 82.8% yield).

[0480] Characterization of the resulting material showed anhydrous crystalline Form A of Compound 9 with no residual organic solvent as observed by NMR. The ratio of L-tartaric acid to Compound 1 in Form A of Compound 9 was: 1 It was determined to be 0.5:1 based on 1 H NMR analysis.

[0481] Table 10 above is reproduced below showing the X-ray diffraction peaks observed for Form A of Compound 9. Table 10: XRPD peak positions of Form A of Compound 9 TIFF0007734700000086.tif67128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0482] FIG. 9A.1 shows the XRPD pattern of Form A of Compound 9.

[0483] Figure 9A.2 shows the DSC thermogram and TGA trace of Form A of Compound 9. The TGA trace showed little weight loss below 150°C. The DSC thermogram of Form A of Compound 9 was characterized by an endothermic peak at approximately 212°C.

[0484] Figure 9A.3 shows Form A of Compound 9. 1 The H NMR spectrum is shown.

[0485] Figures 9A.4 and 9A.5 show the DVS plots of Form A of Compound 9. The DVS plots showed that Form A of Compound 9 is slightly hygroscopic at 1.05% at 80% RH. The XRPD pattern of the test sample did not change after the DVS test.

[0486] Example 10: Preparation of Form A of Compound 10 TIFF0007734700000087.tif28128 Form A of Compound 10 Form A of Compound 10 was prepared as follows.

[0487] Procedure A: Compound 1 (approximately 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 a solid precipitated immediately after the addition of the acid solution. The solid was collected by filtration and dried under vacuum at 50° C. to obtain Form A of Compound 10.

[0488] Characterization of the resulting material showed crystalline Form A of Compound 10 as a solvate / hydrate form with a small amount of water and approximately 1% residual MeOH as observed by NMR. The ratio of L-malic acid to Compound 1 in Form A of Compound 10 is: 1 It was determined to be 0.5:1 based on 1 H NMR analysis.

[0489] Table 11 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 10. Table 11: XRPD peak positions of Form A of Compound 10 TIFF0007734700000088.tif89128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0490] FIG. 10A.1 shows the XRPD pattern of Form A of Compound 10.

[0491] Figure 10A.2 shows the DSC thermogram and TGA trace of Form A of Compound 10. The TGA trace showed two weight loss features below 155°C: a 1.0% weight loss from room temperature to 70°C and a 1.8% weight loss from 70°C to 125°C. Without intending to be limited to any particular theory, these weight losses are likely due to the loss of MeOH and water found to be part of Form A. The DSC thermogram of Form A of Compound 10 was characterized by endothermic peaks at approximately 53°C, 107°C, and 155°C.

[0492] Figure 10A.3 shows Form A of Compound 10. 1 The H NMR spectrum is shown.

[0493] Example 11: Preparation of Form A of Compound 11 TIFF0007734700000089.tif28128 Form A of Compound 11 Form A of Compound 11 was prepared as follows.

[0494] Procedure A (Salt Screening Method): Compound 1 (180 mg) was dissolved in MeOH (6 mL) to prepare a stock solution. 100 μL of the stock solution was added to each well of a 96-well plate. D-Mandelic acid (150 μL, 0.1 M solution, 1.1 equivalents) was added to one column of wells. Different solvents (200 μL each of MeOH, IPA, THF, ACN, MTBE, acetone, water, and EtOAc) were added to each row of the plate. The wells were covered with a film with a pinhole on top and allowed to evaporate to dryness under ambient conditions. The dried material was collected and submitted for XRPD analysis. Each well containing D-Mandelic acid containing THF, MTBE, and EtOAc yielded Form A of Compound 11.

[0495] Procedure B: Compound 1 (approximately 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. After stirring, no solid appeared. 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, during which time a solid precipitated. The solid was collected by filtration and dried under vacuum at 50 °C to obtain Form A of Compound 11.

[0496] Procedure C: Compound 1 (approximately 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 a solid precipitated immediately after the acid addition. Heptane (40 V) was added to increase the yield of the precipitate, and the mixture was stirred at room temperature for an additional 3 hours. The solid was collected by filtration and dried under vacuum at 50° C. to obtain Form A of Compound 11.

[0497] Characterization of the obtained material showed anhydrous crystalline Form A of Compound 11, 1No residual organic solvent was observed by H NMR. The ratio of D-mandelic acid to Compound 1 in Form A of Compound 11 was: 1 It was determined to be 1:1 based on 1 H NMR analysis.

[0498] Table 12 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 11. Table 12: XRPD peak positions of Form A of Compound 11 TIFF0007734700000090.tif72128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0499] FIG. 11A.1 shows the XRPD pattern of Form A of Compound 11.

[0500] Figure 11A.2 shows the DSC thermogram and TGA trace of Form A of Compound 11. The TGA trace showed no weight loss below 100°C. The DSC thermogram of Form A of Compound 11 was characterized by an endothermic peak at approximately 142°C.

[0501] Figure 11A.3 shows Form A of Compound 11. 1 The H NMR spectrum is shown.

[0502] Example 12: Preparation of Form A of Compound 12 TIFF0007734700000091.tif27128 Form A of Compound 12 Form A of Compound 12 was prepared as follows.

[0503] Procedure A (Salt Screening Method): Compound 1 (180 mg) was dissolved in MeOH (6 mL) to prepare a stock solution. 100 μL of the stock solution was added to each well of a 96-well plate. One column of wells received L-lactic acid (150 μL, 0.1 M solution, 1.1 equivalents). Each row of the plate received a different solvent (200 μL each of MeOH, IPA, THF, ACN, MTBE, acetone, water, and EtOAc). The wells were covered with a film with a pinhole on top and allowed to evaporate to dryness under ambient conditions. The dried material was collected and submitted for XRPD analysis. Each well containing MeOH, THF, MTBE, and acetone containing L-lactic acid yielded Form A of Compound 12.

[0504] Procedure B: Compound 1 (approximately 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. After stirring, no solids appeared. 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 a solid precipitated. The solid was collected by filtration and dried under vacuum at 50 °C to give Form A of Compound 12.

[0505] Characterization of the material obtained from Procedure B showed a form with low crystallinity, which was assigned as crystalline Form A of Compound 12. The material obtained from Procedure A showed greater crystallinity.

[0506] Table 13 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 12. Table 13: XRPD peak positions of Compound 12 Form A TIFF0007734700000092.tif105128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0507] FIG. 12A.1 shows the XRPD pattern of Form A of Compound 12.

[0508] Figure 12A.2 shows the DSC thermogram and TGA trace of Form A of Compound 12. The TGA trace showed a weight loss of about 2.9% before 100°C. The DSC thermogram of Form A of Compound 12 was complex, showing multiple overlapping endothermic peaks between room temperature and 120°C, with prominent endothermic features at about 39°C, 76°C, and 95°C.

[0509] Example 13: Preparation of Forms A and B of Compound 13 TIFF0007734700000093.tif27128 Form A of Compound 13 Form A of Compound 13 was prepared as follows.

[0510] 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. After stirring, no solid appeared. Heptane (0.8 mL) was added, and the mixture was stirred at room temperature for an additional 2 hours, during which time a solid precipitated. The solid was collected by filtration and dried under vacuum at 50° C. to obtain Form A of Compound 13.

[0511] Characterization of the obtained material showed anhydrous crystalline Form A of Compound 13, 1 No residual organic solvent was observed by H NMR. The ratio of D-camphoric acid to Compound 1 in Form A of Compound 13 was: 1 It was determined to be 1:1 based on 1 H NMR analysis.

[0512] Table 14 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 13. Table 14: XRPD peak positions of Form A of Compound 13 TIFF0007734700000094.tif133128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0513] FIG. 13A.1 shows the XRPD pattern of Form A of Compound 13.

[0514] Figure 13A.2 shows the DSC thermogram and TGA trace of Compound 13 Form A. The TGA trace showed no weight loss below 100°C. The DSC thermogram of Compound 13 Form A was characterized by a minor endothermic peak at about 147°C and a larger endothermic peak at about 166°C.

[0515] Figure 13A.3 shows Form A of Compound 13. 1 The H NMR spectrum is shown.

[0516] Example 14: Preparation of Form A of Compound 14 TIFF0007734700000095.tif39128 Form A of Compound 14 Form A of Compound 14 was prepared as follows.

[0517] Procedure A: Compound 1 (approximately 20 mg) was dissolved in IPA (0.6 mL) at room temperature. Dibenzoyl-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 a solid began to precipitate immediately after the addition of the acid. The solid was collected by filtration and dried under vacuum at 50° C. to obtain Form A of Compound 14.

[0518] Characterization of the resulting material showed anhydrous crystalline Form A of Compound 14 with no residual organic solvent as observed by NMR. The ratio of dibenzoyl-D-tartaric acid to Compound 1 in Form A of Compound 14 was: 1 It was determined to be 1:1 based on 1 H NMR analysis.

[0519] Table 15 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 14. Table 15: XRPD peak positions of Form A of Compound 14 TIFF0007734700000096.tif122128In this and all subsequent tables, positions (°2θ) are accurate to within ±0.2.

[0520] FIG. 14A.1 shows the XRPD pattern of Form A of Compound 14.

[0521] Figure 14A.2 shows the DSC thermogram and TGA trace of Compound 14 Form A. The TGA trace showed no weight loss below 150°C. The DSC thermogram of Compound 14 Form A was characterized by an endothermic peak at approximately 182°C.

[0522] Figure 14A.3 shows Form A of Compound 14. 1 The H NMR spectrum is shown.

[0523] Example 15: Chiral purification of compound 1 via formation of a chiral acid salt Several of the above crystalline salt-forming acids were tested for their ability to improve the chiral purity of a mixture of compound 1 and its enantiomers. Compound 1, (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile), and its enantiomer, (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile, were mixed together in a ratio of 80 / 20 or 90 / 10 and dissolved in a solvent at room temperature or 60° C., and one of the acid-forming salts was added to the solution, as listed in Table 17 below: Table 17: Chiral purification evaluation TIFF0007734700000097.tif87155TIFF0007734700000098.tif206155Note: Salts marked with an * were formed using 0.55 equivalents of acid; other salts were formed using 1.05 equivalents of acid.

[0524] Chiral purity was determined by HPLC analysis. Chiral purification screening showed that the addition of L-tartaric acid substantially reduced the content of (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile in the final recovered solid. Under certain conditions, the addition of L-tartaric acid could reduce the content of the undesired enantiomer by more than half.

[0525] Example 16: Solubility and stability studies Solubility Test The stability of Compound 1 Form A, Compound 2 Form A, and Compound 9 Form A was tested in three biorelevant media and water at 37°C for 0.5, 2, 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 gastrointestinal fluid (SGF), fasted-state simulated intestinal fluid (FaSSIF), fed-state simulated intestinal fluid (FeSSIF), or water. All samples were shaken at 200 rpm at 37°C for up to 24 hours. Compound 2 Form A was immediately dissolved in each of the four media at room temperature. Compound 9 Form A was dissolved in each media after shaking at 37°C for approximately 15 minutes. Compound 1 Form A was dissolved in each media during approximately 2 hours of shaking at 37°C. Compound 1 Form A, Compound 2 Form A, and Compound 9 Form A all exhibited high solubility (>5 mg / ml) in each medium. The results of the solubility tests are summarized in Table 18 below. (Table 18) Solubility evaluation results TIFF0007734700000099.tif71160Note: The pH of the water, SGF, FaSSIF, and FeSSIF controls was 5.26, 1.19, 6.53, and 5.01, respectively.

[0526] Because all samples dissolved after approximately 2 hours, a predictive solubility test was performed in which approximately 5 mg each of Compound 1 Form A, Compound 2 Form A, and Compound 9 Form A was weighed into four separate vials and each medium was added stepwise with stirring at room temperature until the solids dissolved. The results of the predictive solubility test are summarized in Table 19. (Table 19) Estimated solubility results TIFF0007734700000100.tif45160

[0527] It was found that Compound 2 Form A and Compound 9 Form A were much more soluble than the free base Compound 1 Form A, with the HCl salt Compound 2 having the highest solubility in all media.

[0528] Stability testing The solid-state 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 for 7 days. Purity was determined via HPLC. The results are summarized in Table 20 below. Compounds 2 and 9 remained very stable over the 7-day experiment, with the purity of the HCl salt of Compound 2 remaining almost unchanged. The free base showed a decrease in purity of approximately 0.3% under both sets of conditions. All tested compounds retained the same solid-state form after the 7-day experiment. (Table 20) Stability evaluation results TIFF0007734700000101.tif50160

Claims

1. Compound 1: A crystalline solid form of.

2. 2. The crystalline solid form of claim 1, wherein the compound is a crystalline solid that is substantially free of amorphous Compound 1.

3. 3. The crystalline solid form of claim 1 or 2, wherein the crystalline solid is at least about 95% by weight crystalline Compound 1.

4. 10. The crystalline solid form of claim 1, wherein the compound is substantially free of impurities.

5. The crystalline solid form of any one of claims 1 to 4, which is Form A of Compound 1, wherein Form A is characterized by: (f) having six peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and 25.1 degrees two-theta; or (g) having a DSC thermogram characterized by endothermic peaks at about 100°C and about 104°C; or (h) having an X-ray powder diffraction pattern as shown in Figure 1A.1; or (i) It has a DSC thermogram as shown in Figure 1A.

2.

6. 6. The crystalline solid form of claim 5, wherein Form A is characterized by having six peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and 25.1 degrees two-theta, wherein said peaks have a relative intensity of greater than 10%.

7. 5. The crystalline solid form of any one of claims 1 to 4, which is Form B, wherein Form B is characterized by: (f) having six peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 12.6, about 16.9, about 18.8, about 20.6, and 25.0 degrees two-theta; or (g) having a DSC thermogram characterized by an endothermic peak at about 100°C; or (h) having an X-ray powder diffraction pattern as shown in Figure 1B.1; or (i) It has a DSC thermogram as shown in Figure 1B.

2.

8. Compound 1: a salt form of A salt form of Compound 1 selected from:

9. The salt form of Compound 1 is crystalline: (A) Compound 2: wherein the salt form is crystalline or the salt form is a crystalline solid that is substantially free of amorphous Compound 2; or (B) Compound 3: wherein the salt form is crystalline or the salt form is a crystalline solid substantially free of amorphous Compound 3; or (C) Compound 4: wherein the salt form is crystalline or the salt form is a crystalline solid substantially free of amorphous Compound 4; or (D) Compound 5: wherein the salt form is crystalline or the salt form is a crystalline solid substantially free of amorphous Compound 5; or (E) Compound 6: wherein the salt form is crystalline or the salt form is a crystalline solid that is substantially free of amorphous Compound 6; or (F) Compound 7: wherein the salt form is crystalline or the salt form is a crystalline solid substantially free of amorphous Compound 7; or (G) Compound 8: wherein the salt form is crystalline or the salt form is a crystalline solid substantially free of amorphous Compound 8; or (H) Compound 9: wherein 0<X≦1 and the salt form is crystalline or the salt form is a crystalline solid substantially free of amorphous Compound 9; or (I) Compound 10: wherein 0<X≦1 and the salt form is crystalline or the salt form is a crystalline solid that is substantially free of amorphous Compound 10; or (J) Compound 11: wherein the salt form is crystalline or the salt form is a crystalline solid that is substantially free of amorphous Compound 11; or (K) Compound 12: wherein the salt form is crystalline or the salt form is a crystalline solid that is substantially free of amorphous Compound 12; or (L) Compound 13: wherein the salt form is crystalline or the salt form is a crystalline solid that is substantially free of amorphous Compound 13; or (M) Compound 14: wherein the salt form is crystalline or the salt form is a crystalline solid that is substantially free of amorphous Compound 14. The salt form of claim 8.

10. 10. The salt form of claim 9, which is substantially free of impurities.

11. The salt form is (A) Form A of Compound 2, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta; or (e) having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta; or (f) having six peaks in its X-ray powder diffraction pattern at about 10.6, about 15.6, about 19.3, about 23.8, about 28.0, and about 32.2 degrees two-theta; or (g) having a DSC thermogram characterized by an endothermic peak at about 215°C; or (h) having an XRPD as shown in Figure 2A.1; or (i) Figure It has a DSC thermogram as shown in Figure 2A.

2. (B) Form A of Compound 3, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta; or (e) having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta; or (f) having six or more peaks in its X-ray powder diffraction pattern at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta; or (g) having seven peaks in its X-ray powder diffraction pattern at about 6.4, about 11.1, about 16.1, about 18.4, about 21.9, about 22.7, and about 23.8 degrees two-theta; or (h) has a DSC thermogram characterized by an endothermic peak at about 247°C; or (i) Figure having an XRPD as shown in 3A.1; or (j) Figure 3A.2 has a DSC thermogram as shown in (C) Form A of Compound 4, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta; or (e) having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta; or (f) having six peaks in its X-ray powder diffraction pattern at about 6.8, about 10.6, about 15.6, about 18.8, about 23.5, and about 27.4 degrees two-theta; or (g) having a DSC thermogram characterized by an endothermic peak at about 173°C; or (h) having an XRPD as shown in Figure 4A.1; or (i) having a DSC thermogram as shown in Figure 4A.2; (D) Form A of Compound 5, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta; or (e) having five peaks in its X-ray powder diffraction pattern at about 7.1, about 7.6, about 15.4, about 19.9, and about 23.3 degrees two-theta; or (f) having a DSC thermogram characterized by an endothermic peak at about 139°C; or (g) having an XRPD as shown in Figure 5A.1; or (h) having a DSC thermogram as shown in Figure 5A.2; (E) Form A of Compound 6, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 77.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta; or (e) having five peaks in its X-ray powder diffraction pattern at about 7.7, about 8.6, about 10.8, about 26.0, and about 27.4 degrees two-theta; or (f) having a DSC thermogram characterized by endothermic peaks at about 132°C and about 146°C; or (g) Figure having an XRPD as shown in 6A.1; or (h) Figure 6A.2 having a DSC thermogram as shown in (F) Form A of Compound 7, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta; or (e) having five peaks in its X-ray powder diffraction pattern at about 7.4, about 10.1, about 11.1, about 23.0, and about 24.6 degrees two-theta; or (f) having a DSC thermogram characterized by endothermic peaks at about 138°C and about 155°C; or (g) having an XRPD as shown in Figure 7A.1; or (h) Figure 7 A.2 has a DSC thermogram as shown in (G) Form A of Compound 8, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta; or (e) having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta; or (f) having six peaks in its X-ray powder diffraction pattern at about 5.7, about 11.6, about 15.7, about 17.5, about 20.4, and about 23.1 degrees two-theta; or (g) having a DSC thermogram characterized by endothermic peaks at about 122°C and about 136°C; or (h) having an XRPD as shown in Figure 8A.1; or (i) has a DSC thermogram as shown in Figure 8A.2; (H) Form A of Compound 9, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 11.2, about 22.0, and about 22.5 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 11.2, about 22.0, and about 22.5 degrees two-theta; or (c) having three peaks in its X-ray powder diffraction pattern at about 11.2, about 22.0, and about 22.5 degrees two-theta; or (d) has a DSC thermogram characterized by an endothermic peak at about 212°C; or (e) having an XRPD as shown in Figure 9A.1; or (f) having a DSC thermogram as shown in Figure 9A.2; (I) Form A of Compound 10, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (e) having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (f) having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (g) having seven or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (h) having eight peaks in its X-ray powder diffraction pattern 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 two-theta; or (i) has a DSC thermogram characterized by endothermic peaks at about 53°C, about 107°C, and about 155°C; or (j) having an XRPD as shown in Figure 10A.1; or (k) Figure 10 A.2 has a DSC thermogram as shown in (J) Form A of Compound 11, wherein Form A is characterized by: (a) having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta; or (d) having four peaks in its X-ray powder diffraction pattern at about 6.5, about 14.0, about 22.8, and about 26.3 degrees two-theta; or (e) has a DSC thermogram characterized by an endothermic peak at about 142°C; or (f) having an XRPD as shown in Figure 11A.1; or (g) having a DSC thermogram as shown in Figure 11A.2; (K) Form A of Compound 12, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (e) having five or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (f) having six or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (g) having seven or more peaks in its X-ray powder diffraction pattern selected from peaks 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 two-theta; or (h) having eight peaks in its X-ray powder diffraction pattern 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 two-theta; or (i) has a DSC thermogram characterized by endothermic peaks at about 39°C, about 76°C, and about 95°C; or (j) having an XRPD as shown in Figure 12A.1; or (k) Figure 12 A.2 has a DSC thermogram as shown in (L) Form A of Compound 13, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta; or (e) having five or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta; or (f) having six or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta; or (g) having seven peaks in its X-ray powder diffraction pattern at about 7.9, about 9.5, about 11.7, about 14.737, about 17.2, about 18.5, and about 18.9 degrees two-theta; or (h) has a DSC thermogram characterized by endothermic peaks at about 147°C and about 166°C; or (i) having an XRPD as shown in Figure 13A.1; or (j) having a DSC thermogram as shown in Figure 13A.2; or (M) Form A of Compound 14, wherein Form A is characterized by: (a) has one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta; or (b) having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta; or (c) having three or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta; or (d) having four or more peaks in its X-ray powder diffraction pattern selected from peaks at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta; or (e) having five peaks in its X-ray powder diffraction pattern at about 6.3, about 8.8, about 12.2, about 12.6, and about 12.8 degrees two-theta; or (f) having a DSC thermogram characterized by an endothermic peak at about 182°C; or (g) having an XRPD as shown in Figure 14A.1; or (h) Figure 14 A.2 has a DSC thermogram as shown in The salt form of any one of claims 9 to 10.

12. A composition comprising a crystalline solid form or salt form of Compound 1 according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier or excipient.

13. 12. A composition for modulating the activity of one or both of the β1-adrenergic receptor and the β2-adrenergic receptor in a patient, comprising the crystalline solid form or salt form of any one of claims 1 to 11.

14. 12. A composition for treating a β1-adrenergic receptor or β2-adrenergic receptor mediated disease or disorder in a patient, comprising the crystalline solid form or salt form of any one of claims 1 to 11.

15. The β1-adrenergic receptor or β2-adrenergic receptor mediated disease or disorder is 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 (Wound syndrome), 15. The composition of claim 14, wherein the disease is one or more selected from the group consisting of Wernicke-Korsakoff syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down's syndrome (DS).

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