Fumarate, tartrate, malate and citrate of EGFR inhibitors

Abstract

Provided are salts and crystalline forms and polymorphic crystalline forms of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl) piperidin-1-yl)-5-((6-(3-(3, 5-difluorophenyl) isoxazolidin-2-yl) pyrimidin-4-yl) amino)-4-methoxyphenyl) acrylamide, compositions thereof, methods of making the same, and methods of using the same.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 422,361, filed on November 3, 2022, and U.S. Provisional Application No. 63 / 464,130, filed on May 4, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Provided herein are salts and crystalline forms and polymorphic crystalline forms of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide (hereinafter referred to as "Compound I"), compositions thereof, methods for preparing the same and methods for using the same. Background Art

[0003] Compound 1 is an inhibitor of epidermal growth factor receptor (EGFR) and can be used to treat various cancers in individuals in need thereof, including humans. The present disclosure relates to the identification of novel salt forms of Compound 1 and novel polymorphic forms of the disclosed salt forms. The disclosed salt forms and their disclosed polymorphic forms have physical properties that make it advantageous to develop Compound 1 as a therapy for treating cancer in individuals in need thereof.

[0004] Disclosure of the Invention

[0005] Problem Solving

[0006] In one aspect, provided herein is a fumarate salt of Compound 1.

[0007] In one aspect, provided herein is a tartrate salt of Compound 1.

[0008] In one aspect, provided herein is a malate salt of Compound 1.

[0009] In one aspect, provided herein is a citrate salt of Compound 1.

[0010] In another aspect, provided herein are compositions containing a fumarate, tartrate, malate, or citrate salt of Compound I as described herein.

[0011] In another aspect, provided herein are methods of using a fumarate, tartrate, malate, or citrate salt of Compound I to treat cancer in an individual in need thereof.

[0012] In another aspect, provided herein are methods of treating cancer in an individual in need thereof using a fumarate, tartrate, malate, or citrate salt of Compound I, or a pharmaceutical composition comprising such a salt.

[0013] In another aspect, provided herein are methods of using a fumarate, tartrate, malate, or citrate salt of Compound I, or a pharmaceutical composition comprising such a salt, in the manufacture of a medicament for treating cancer in an individual in need thereof.

[0014] In another aspect, provided herein is a method for preparing a fumarate, tartrate, malate or citrate salt of Compound I.

[0015] Various embodiments are contemplated herein. For example, in Embodiment 1, a fumarate salt of (R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is provided.

[0016] Embodiment 2: The fumarate salt of Embodiment 1, wherein the salt is a hemifumarate salt.

[0017] Embodiment 3: The fumarate salt of Embodiment 1 or 2, wherein the salt is in crystalline form.

[0018] Embodiment 4: The fumarate salt of any one of Embodiments 1-3, wherein the solubility of the fumarate salt in an aqueous solution having a pH of about 1.5 at a temperature of about 25° C. is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0019] Embodiment 5: The fumarate salt of any one of Embodiments 1-4, wherein the solubility of the fumarate salt in an aqueous solution having a pH of about 4.7 at a temperature of about 25° C. is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0020] Embodiment 6: The fumarate salt of any one of Embodiments 1-5, wherein the fumarate salt has a solubility of about 0.2 mg / mL in an aqueous solution at a pH of about 6.6 at a temperature of about 25° C., calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0021] Embodiment 7: The fumarate salt of any one of Embodiments 3-6, wherein the fumarate salt exhibits an XRPD pattern comprising a peak at 5.0±0.2° 2θ.

[0022] Embodiment 8: The fumarate salt of Embodiment 7, further comprising a peak at 17.1±0.2° 2θ in the XRPD pattern.

[0023] Embodiment 9: The fumarate salt of Embodiment 8, further comprising a peak at 20.5±0.2° 2θ in the XRPD pattern.

[0024] Embodiment 10: The fumarate salt of Embodiment 9, further comprising peaks at 15.4±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2 and 22.0±0.2° 2θ in the XRPD pattern.

[0025] Embodiment 11: The fumarate salt of Embodiment 10, further comprising peaks at 8.4±0.2, 17.6±0.2, 21.7±0.2, 24.0±0.2 and 27.7±0.2° 2θ in the XRPD pattern.

[0026] Embodiment 12: The fumarate salt of any of Embodiments 1-11, wherein the fumarate salt exhibits a differential scanning calorimetry trace comprising a peak at about 172°C to about 185°C.

[0027] Embodiment 13: The fumarate salt of Embodiment 12, further comprising an endothermic onset in the differential scanning calorimetry trace at about 165°C to about 180°C.

[0028] Embodiment 14: A crystalline form of a fumarate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 5.0±0.2° 2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 172°C to about 185°C.

[0029] Embodiment 15: The fumarate salt of Embodiment 14, further comprising a peak at 17.1±0.2° 2θ in the XRPD pattern.

[0030] Embodiment 16: The fumarate salt of Embodiment 15, further comprising a peak at 20.5±0.2° 2θ in the XRPD pattern.

[0031] Embodiment 17: The fumarate salt of Embodiment 16, further comprising peaks at 15.4±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2 and 22.0±0.2° 2θ in the XRPD pattern.

[0032] Embodiment 18: The fumarate salt of Embodiment 17, further comprising peaks at 8.4±0.2, 17.6±0.2, 21.7±0.2, 24.0±0.2 and 27.7±0.2° 2θ in the XRPD pattern.

[0033] Embodiment 19: The fumarate salt of any of Embodiments 14-18, further comprising an endothermic onset of about 165°C to about 180°C in the differential scanning calorimetry trace.

[0034] Embodiment 20: The fumarate salt of any one of Embodiments 14-19, wherein the solubility of the fumarate salt in an aqueous solution having a pH of about 1.2 at a temperature of about 25° C. is greater than about 9.2 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0035] Embodiment 21: The fumarate salt of any one of Embodiments 14-20, wherein the fumarate salt has a solubility of about 7.2 mg / mL in an aqueous solution at a pH of about 4.6 at a temperature of about 25°C, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0036] Embodiment 22: The fumarate salt of any one of Embodiments 14-21, wherein the fumarate salt has a solubility of about 0.1 mg / mL in an aqueous solution at a pH of about 6.8 at a temperature of about 25°C, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0037] Embodiment 23: Tartrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0038] Embodiment 24: The tartrate salt of Embodiment 23, wherein the salt is a hemi-tartrate salt.

[0039] Embodiment 25: The tartrate salt of Embodiment 23 or 24, wherein the salt is in crystalline form.

[0040] Embodiment 26: The tartrate salt of any one of Embodiments 23-25, wherein the solubility of the tartrate salt in an aqueous solution having a pH of about 1.4 at a temperature of about 25°C is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0041] Embodiment 27: The tartrate salt of any one of Embodiments 23-26, wherein the solubility of the tartrate salt in an aqueous solution having a pH of about 4.7 at a temperature of about 25°C is about 0.3 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0042] Embodiment 28: The tartrate salt of any one of Embodiments 23-27, wherein the solubility of the tartrate salt in an aqueous solution having a pH of about 6.6 at a temperature of about 25°C is about 0.2 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0043] Embodiment 29: The tartrate salt of any one of Embodiments 25-28, wherein the tartrate salt exhibits an XRPD pattern comprising a peak at 17.9±0.2° 2θ.

[0044] Embodiment 30: The tartrate salt of Embodiment 29, further comprising a peak at 5.8±0.2° 2θ in the XRPD pattern.

[0045] Embodiment 31: The tartrate salt of Embodiment 30, further comprising a peak at 7.4±0.2° 2θ in the XRPD pattern.

[0046] Embodiment 32: The tartrate salt of Embodiment 31, further comprising peaks at 16.1±0.2, 16.7±0.2, 19.1±0.2, 19.9±0.2 and 21.3±0.2° 2θ in the XRPD pattern.

[0047] Embodiment 33: The tartrate salt of Embodiment 32, further comprising peaks at 12.9±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2 and 24.0±0.2° 2θ in the XRPD pattern.

[0048] Embodiment 34: The tartrate salt of any of Embodiments 23-33, wherein the tartrate salt exhibits a differential scanning calorimetry trace comprising a peak from about 218°C to about 230°C.

[0049] Embodiment 35: The tartrate salt of Embodiment 34, further comprising an exothermic onset of about 215°C to about 230°C in the differential scanning calorimetry trace.

[0050] Embodiment 36: A crystalline form of the tartrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 17.9±0.2° 2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 218°C to about 230°C.

[0051] Embodiment 37: The tartrate salt of Embodiment 36, further comprising a peak at 5.8±0.2° 2θ in the XRPD pattern.

[0052] Embodiment 38: The tartrate salt of Embodiment 37, further comprising a peak at 7.4±0.2° 2θ in the XRPD pattern.

[0053] Embodiment 39: The tartrate salt of Embodiment 38, further comprising peaks at 16.1±0.2, 16.7±0.2, 19.1±0.2, 19.9±0.2 and 21.3±0.2° 2θ in the XRPD pattern.

[0054] Embodiment 40: The tartrate salt of Embodiment 39, further comprising peaks at 12.9±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2 and 24.0±0.2° 2θ in the XRPD pattern.

[0055] Embodiment 41: The tartrate salt of any of Embodiments 36-40, further comprising an exothermic onset of about 215°C to about 230°C in a differential scanning calorimetry trace.

[0056] Embodiment 42: The tartrate salt of any one of Embodiments 36-41, wherein the solubility of the tartrate salt in an aqueous solution having a pH of about 1.4 at a temperature of about 25°C is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0057] Embodiment 43: The tartrate salt of any one of Embodiments 36-42, wherein the solubility of the tartrate salt in an aqueous solution having a pH of about 4.7 at a temperature of about 25°C is about 0.3 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0058] Embodiment 44: The tartrate salt of any one of Embodiments 36-43, wherein the solubility of the tartrate salt in an aqueous solution having a pH of about 6.6 at a temperature of about 25°C is about 0.2 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0059] Embodiment 45: Malate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0060] Embodiment 46: The malate salt of Embodiment 45, wherein the salt is a hemimalate salt.

[0061] Embodiment 47: The malate salt of Embodiment 45 or 46, wherein the salt is in crystalline form.

[0062] Embodiment 48: The malate salt of any one of Embodiments 45-47, wherein the solubility of the malate salt in an aqueous solution having a pH of about 1.4 at a temperature of about 25°C is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0063] Embodiment 49: The malate salt of any one of Embodiments 45-48, wherein the solubility of the malate salt in an aqueous solution having a pH of about 4.8 and at about 25°C is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0064] Embodiment 50: The malate salt of any one of Embodiments 45-49, wherein the solubility of the malate salt in an aqueous solution having a pH of about 6.4 at a temperature of about 25°C is about 0.3 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0065] Embodiment 51: The malate salt of any of Embodiments 47-50, wherein the malate salt exhibits an XRPD pattern comprising a peak at 6.0±0.2° 2θ.

[0066] Embodiment 52: The malate salt of Embodiment 51, further comprising a peak at 20.2±0.2° 2θ in the XRPD pattern.

[0067] Embodiment 53: The malate salt of Embodiment 52, further comprising a peak at 19.5±0.2° 2θ in the XRPD pattern.

[0068] Embodiment 54: The malate salt of Embodiment 53, further comprising peaks at 9.7±0.2, 16.2±0.2, 18.9±0.2, 22.4±0.2 and 22.6±0.2° 2θ in the XRPD pattern.

[0069] Embodiment 55: The malate salt of Embodiment 54, further comprising peaks at 8.4±0.2, 14.5±0.2, 16.5±0.2, 18.2±0.2 and 21.9±0.2° 2θ in the XRPD pattern.

[0070] Embodiment 56: The malate salt of any of Embodiments 45-55, wherein the malate salt exhibits a differential scanning calorimetry trace comprising a peak at about 146°C to about 160°C.

[0071] Embodiment 57: The malate salt of Embodiment 56, further comprising an endothermic onset in the differential scanning calorimetry trace of about 134°C to about 147°C.

[0072] Embodiment 58: A crystalline form of a malate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 6.0±0.2° 2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 146°C to about 160°C.

[0073] Embodiment 59: The malate salt of Embodiment 58, further comprising a peak at 20.2±0.2° 2θ in the XRPD pattern.

[0074] Embodiment 60: The malate salt of Embodiment 59, further comprising a peak at 19.5±0.2° 2θ in the XRPD pattern.

[0075] Embodiment 61: The malate salt of Embodiment 60, further comprising peaks at 9.7±0.2, 16.2±0.2, 18.9±0.2, 22.4±0.2 and 22.6±0.2° 2θ in the XRPD pattern.

[0076] Embodiment 62: The malate salt of Embodiment 61, further comprising peaks at 8.4±0.2, 14.5±0.2, 16.5±0.2, 18.2±0.2 and 21.9±0.2° 2θ in the XRPD pattern.

[0077] Embodiment 63: The malate salt of any of Embodiments 58-62, further comprising an endothermic onset of about 134°C to about 147°C in a differential scanning calorimetry trace.

[0078] Embodiment 64: The malate salt of any one of Embodiments 58-63, wherein the solubility of the malate salt in an aqueous solution having a pH of about 1.4 at a temperature of about 25°C is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0079] Embodiment 65: The malate salt of any one of Embodiments 58-64, wherein the solubility of the malate salt in an aqueous solution having a pH of about 4.8 at a temperature of about 25°C is greater than about 20 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0080] Embodiment 66: The malate salt of any one of Embodiments 58-65, wherein the solubility of the malate salt in an aqueous solution having a pH of about 6.4 at a temperature of about 25°C is about 0.3 mg / mL, calculated as the amount of the free base of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0081] Embodiment 67: (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide citrate salt.

[0082] Embodiment 68: The citrate salt of Embodiment 67, wherein the salt is a hemi-citrate salt.

[0083] Embodiment 69: The citrate salt of Embodiment 67 or 68, wherein the salt is in crystalline form.

[0084] Embodiment 70: The citrate salt of Embodiment 69, wherein the citrate salt exhibits an XRPD pattern comprising a peak at 7.3±0.2° 2θ.

[0085] Embodiment 71: The citrate salt of Embodiment 70, further comprising a peak at 7.4±0.2° 2θ in the XRPD pattern.

[0086] Embodiment 72: The citrate salt of Embodiment 71, further comprising a peak at 18.6±0.2° 2θ in the XRPD pattern.

[0087] Embodiment 73: The citrate salt of Embodiment 72, further comprising peaks at 3.7±0.2, 11.2±0.2, 18.2±0.2, 21.8±0.2 and 22.4±0.2° 2θ in the XRPD pattern.

[0088] Embodiment 74: The citrate salt of Embodiment 73, further comprising peaks at 10.9±0.2, 25.5±0.2, 26.1±0.2, and 33.0±0.2° 2θ in the XRPD pattern.

[0089] Embodiment 75: The citrate salt of any of Embodiments 67-74, wherein the citrate salt exhibits a differential scanning calorimetry trace comprising a peak at about 175°C to about 179°C.

[0090] Embodiment 76: The citrate salt of Embodiment 75, further comprising an endothermic onset of about 124°C to about 128°C in the differential scanning calorimetry trace.

[0091] Embodiment 77: A crystalline form of a citrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 7.3±0.2° 2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 175°C to about 179°C.

[0092] Embodiment 78: The citrate salt of Embodiment 77, further comprising a peak at 7.4±0.2° 2θ in the XRPD pattern.

[0093] Embodiment 79: The citrate salt of Embodiment 78, further comprising a peak at 18.6±0.2° 2θ in the XRPD pattern.

[0094] Embodiment 80: The citrate salt of Embodiment 79, further comprising peaks at 3.7±0.2, 11.2±0.2, 18.2±0.2, 21.8±0.2 and 22.4±0.2° 2θ in the XRPD pattern.

[0095] Embodiment 81: The citrate salt of Embodiment 80, further comprising peaks at 10.9±0.2, 25.5±0.2, 26.1±0.2, and 33.0±0.2° 2θ in the XRPD pattern.

[0096] Embodiment 82: The citrate salt of any of Embodiments 77-81, further comprising an endothermic onset of about 124°C to about 128°C in the differential scanning calorimetry trace.

[0097] Embodiment 83: A pharmaceutical composition comprising the fumarate salt of any one of Embodiments 1-22 and a pharmaceutically acceptable carrier.

[0098] Embodiment 84: A pharmaceutical composition comprising the tartrate salt of any one of Embodiments 23-44 and a pharmaceutically acceptable carrier.

[0099] Embodiment 85: A pharmaceutical composition comprising the malate salt of any one of Embodiments 45-66 and a pharmaceutically acceptable carrier.

[0100] Embodiment 86: A pharmaceutical composition comprising the citrate salt of any one of Embodiments 67-82 and a pharmaceutically acceptable carrier.

[0101] Embodiment 87: A method for treating cancer in an individual in need thereof, comprising administering to the individual (a) a fumarate salt of any one of Embodiments 1-22, (b) a tartrate salt of any one of Embodiments 23-44, (c) a malate salt of any one of Embodiments 45-66, (d) a citrate salt of any one of Embodiments 67-82, (e) a pharmaceutical composition of Embodiment 83, (f) a pharmaceutical composition of Embodiment 84, (g) a pharmaceutical composition of Embodiment 85, or (h) a pharmaceutical composition of Embodiment 86.

[0102] Embodiment 88: The method of Embodiment 87, wherein the cancer comprises an epidermal growth factor receptor (EGFR) mutation, or one or more wild-type or mutant kinases selected from ERBB2 and ERBB4.

[0103] Embodiment 89: The method of embodiment 87 or 88, wherein the cancer comprises one or more mutations of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR exon 20ins NPH, EGFR exon 20ins SVD, EGFR exon 20ins FQEA, EGFR exon 20ins H, EGFR exon 20ins ASV, and ERBB2 mutation (which is Her2 exon 20ins YVMA).

[0104] Embodiment 90: The method of any one of Embodiments 87-89, wherein the cancer is selected from pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer. cancer), non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, pediatric lymphoma, pediatric leukemia, small intestinal cancer, meningioma, esophageal cancer, glioma, renal carcinoma, kidney cancer cancer), heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymus cancer.

[0105] Embodiment 91: The method of Embodiment 90, wherein the cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer.

[0106] Embodiment 92: The method of Embodiment 91, wherein the cancer is metastatic brain cancer.

[0107] Embodiment 93: The method of Embodiment 91, wherein the cancer is breast cancer.

[0108] Embodiment 94: The method of Embodiment 91, wherein the cancer is non-small cell lung cancer.

[0109] Embodiment 95: The method of any one of Embodiments 87-94, wherein the cancer is a locally advanced cancer.

[0110] Embodiment 96: The method of any one of Embodiments 87-95, wherein the cancer is unresectable.

[0111] Embodiment 97: The method of any one of Embodiments 87-96, wherein the cancer comprises one or more central nervous system (CNS) metastases (eg, brain metastases).

[0112] Embodiment 98: The method of any one of Embodiments 87-97, wherein the cancer comprises one or more mutations in the epidermal growth factor receptor (EGFR) protein.

[0113] Embodiment 99: The method of embodiment 98, wherein the one or more mutations in the EGFR protein include one or more mutations selected from the group consisting of: G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Del19, EGFR L858R / C797S, EGFR Del19 / C797S, EGFR exon 20ins NPH, EGFR exon 20ins SVD, EGFR exon 20ins FQEA, EGFR exon 20ins H, and EGFR exon 20ins ASV.

[0114] Embodiment 100: The method of any one of Embodiments 87-99, wherein the cancer comprises one or more mutations in a HER2 protein, wherein the one or more mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG.

[0115] Embodiment 101: The method of any one of Embodiments 87-100, wherein prior to administration of the salt or pharmaceutical composition to the individual, the individual has not received one or more prior therapies for treating the cancer.

[0116] Embodiment 102: The method of any one of Embodiments 87-101, wherein prior to administering the salt or pharmaceutical composition to the individual, the individual has received one or more prior therapies for treating cancer.

[0117] Embodiment 103: The method of Embodiment 102, wherein the one or more prior therapies comprise one or more anti-HER2 based regimens.

[0118] Embodiment 104: The method of Embodiment 103, wherein one or more anti-HER2 based regimens are administered to the individual in the metastatic setting.

[0119] Embodiment 105: The method of any one of Embodiments 102-104, wherein prior to administering the salt or pharmaceutical composition to the individual, the individual has failed one or more prior therapies.

[0120] Embodiment 106: The method of any one of Embodiments 87-105, wherein the method further comprises administering one or more additional anti-cancer agents to the individual in need thereof.

[0121] Embodiment 107: The method of embodiment 106, wherein the one or more additional anti-cancer agents include one or more agents selected from the following: HER2 inhibitors, HER2-CD3 bispecific antibodies, HER2 immune-targeted bispecific antibodies, anti-HER2 chimeric antigen receptor (CAR) T cells, anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocytes (CTLs), anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells, anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells, epidermal growth factor receptor (EGFR) inhibitors, poly ADP ribose polymerase (PARP) inhibitors, PD-1 inhibitors, PD-L1 inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors and chemotherapeutic agents.

[0122] Embodiment 108: The method of embodiment 107, wherein the one or more additional anticancer agents are selected from trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, margetuximab, trastuzumab emtansine, trastuzumab deruxtecan, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumabduocarmazine, zanidatamab (ZW25), zenocutuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, necituzumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib (iniparib), pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0123] Embodiment 109: The method of Embodiment 108, wherein the one or more additional anti-cancer agents are selected from antibody-drug conjugates.

[0124] Embodiment 110: The method of Embodiment 109, wherein the antibody-drug conjugate is selected from trastuzumab emtansine and trastuzumab depot.

[0125] Embodiment 111: The method of Embodiment 108, wherein the one or more additional anti-cancer agents comprises one or more chemotherapeutic agents.

[0126] Embodiment 112: The method of Embodiment 111, wherein the one or more chemotherapeutic agents are selected from doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxaliplatin and eribulin.

[0127] Embodiment 113: The method of Embodiment 108, wherein the one or more additional anticancer agents comprise trastuzumab and capecitabine.

[0128] Embodiment 114: The method of any one of Embodiments 87-113, wherein the method further comprises treating the individual in need thereof with radiation.

[0129] Embodiment 115: The method of Embodiment 87, wherein (a) the fumarate salt of any one of Embodiments 1-22, (b) the tartrate salt of any one of Embodiments 23-44, (c) the malate salt of any one of Embodiments 45-66, (d) the citrate salt of any one of Embodiments 67-82, (e) the pharmaceutical composition of Embodiment 83, (f) the pharmaceutical composition of Embodiment 84, (g) the pharmaceutical composition of Embodiment 85, or (h) the pharmaceutical composition of Embodiment 86 is administered orally, parentally, intravenously, subcutaneously, or intracerebrally to a subject in need thereof.

[0130] Embodiment 116: The method of any one of Embodiments 87-115, wherein the individual is a human.

[0131] Embodiment 117: A method for preparing a fumarate salt of any one of Embodiments 1-22, comprising:

[0132] (1) forming a mixture of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide and fumaric acid in a solvent; and

[0133] (2) removing the solvent from step (1) to obtain a fumarate salt.

[0134] Embodiment 118: The method of Embodiment 117, wherein the molar ratio of fumaric acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 0.5:1.

[0135] Embodiment 119: The method of Embodiment 117, wherein the molar ratio of fumaric acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 1:1.

[0136] Embodiment 120: A method for preparing the tartrate salt of any one of Embodiments 23-44, comprising:

[0137] (1) forming a mixture of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide and tartaric acid in a solvent; and

[0138] (2) removing the solvent from step (1) to obtain a tartrate salt.

[0139] Embodiment 121: The method of Embodiment 120, wherein the molar ratio of tartaric acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 0.5:1.

[0140] Embodiment 122: The method of Embodiment 120, wherein the molar ratio of tartaric acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 1:1.

[0141] Embodiment 123: A method for preparing the malate salt of any one of Embodiments 45-66, comprising:

[0142] (1) forming a mixture of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide and malic acid in a solvent; and

[0143] (2) removing the solvent from step (1) to obtain a malate salt.

[0144] Embodiment 124: The method of Embodiment 123, wherein the molar ratio of malic acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 0.5:1.

[0145] Embodiment 125: The method of Embodiment 123, wherein the molar ratio of malic acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 1:1.

[0146] Embodiment 126: A method for preparing the citrate salt of any one of Embodiments 67-82, comprising:

[0147] (1) forming a mixture of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide and citric acid in a solvent; and

[0148] (2) removing the solvent from step (1) to obtain a citrate salt.

[0149] Embodiment 127: The method of Embodiment 126, wherein the molar ratio of citric acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 0.5:1.

[0150] Embodiment 128: The method of Embodiment 126, wherein the molar ratio of citric acid to (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is about 1:1.

[0151] Embodiment 129: The method of any one of Embodiments 117-128, wherein the solvent of step (1) comprises an aprotic solvent or a protic solvent.

[0152] Embodiment 130: The method of Embodiment 129, wherein the solvent comprises an aprotic solvent.

[0153] Embodiment 131: The method of Embodiment 130, wherein the aprotic solvent is acetone.

[0154] Embodiment 132: The method of Embodiment 130, wherein the aprotic solvent is acetonitrile.

[0155] Embodiment 133: The method of Embodiment 130, wherein the aprotic solvent is ethyl acetate.

[0156] Embodiment 134: The method of Embodiment 129, wherein the solvent comprises a protic solvent.

[0157] Embodiment 135: The method of Embodiment 134, wherein the protic solvent is ethanol.

[0158] Embodiment 136: The method of any one of Embodiments 117-135, wherein the mixture of step (1) is stirred at 20-60°C.

[0159] Embodiment 137: The method of any of Embodiments 117-135, wherein removing the solvent comprises vacuum drying.

[0160] Embodiment 138: The method of any one of Embodiments 117-137, wherein step (2) further comprises vacuum filtration. BRIEF DESCRIPTION OF THE DRAWINGS

[0161] Figure 1A The experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound 1 prepared according to Example 2 is shown.

[0162] Figure 1B The experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound I prepared according to Example 3 is shown.

[0163] Figure 1C The experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound 1 prepared according to Example 4 is shown.

[0164] Figure 1D The experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound I prepared according to Example 5 is shown.

[0165] Figure 1E The experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound 1 prepared according to Example 6 is shown.

[0166] Figure 1F A differential scanning calorimetry (DSC) graph of the fumarate salt of Compound I prepared according to Example 2 is shown.

[0167] Figure 1G A differential scanning calorimetry (DSC) graph of the fumarate salt of Compound I prepared according to Example 5 is shown.

[0168] Figure 1H A differential scanning calorimetry (DSC) graph of the fumarate salt of Compound I prepared according to Example 6 is shown.

[0169] Fig. 1I Thermogravimetric analysis (TGA) chart of the fumarate salt of Compound I prepared according to Example 2 is shown.

[0170] Figure 1J Thermogravimetric analysis (TGA) chart of the fumarate salt of Compound I prepared according to Example 5 is shown.

[0171] Figure 1K A thermogravimetric analysis (TGA) chart of the fumarate salt of Compound I prepared according to Example 6 is shown.

[0172] Figure 1L Thermogravimetric analysis (TGA) graph of the fumarate salt of Compound I at room temperature at 92.5% relative humidity (RH) for 24 hours is shown, and the fumarate salt of Compound I was prepared according to Example 5.

[0173] Figure 1M Thermogravimetric analysis (TGA) graph of the fumarate salt of Compound I at room temperature at 92.5% relative humidity (RH) for 24 hours is shown, and the fumarate salt of Compound I was prepared according to Example 6.

[0174] Figure 2A The experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound 1 prepared according to Example 7 is shown.

[0175] Figure 2B The experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound 1 prepared according to Example 8 is shown.

[0176] Figure 2C The experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound 1 prepared according to Example 9 is shown.

[0177] Figure 2D The experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound 1 prepared according to Example 10 is shown.

[0178] Figure 2E A differential scanning calorimetry (DSC) graph of the tartrate salt of Compound 1 prepared according to Example 9 is shown.

[0179] Figure 2F A differential scanning calorimetry (DSC) graph of the tartrate salt of Compound I prepared according to Example 10 is shown.

[0180] Figure 2G Thermogravimetric analysis (TGA) graph of the tartrate salt of Compound 1 prepared according to Example 9 is shown.

[0181] Figure 2H A thermogravimetric analysis (TGA) graph of the tartrate salt of Compound I prepared according to Example 10 is shown.

[0182] Fig.2I Thermogravimetric analysis (TGA) graph of the tartrate salt of Compound I at room temperature at 92.5% relative humidity (RH) for 24 hours is shown, and the tartrate salt of Compound I was prepared according to Example 9.

[0183] Figure 2J Thermogravimetric analysis (TGA) graph of the tartrate salt of Compound I at room temperature at 92.5% relative humidity (RH) for 24 hours is shown, and the tartrate salt of Compound I was prepared according to Example 10.

[0184] Figure 3A The experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound 1 prepared according to Example 11 is shown.

[0185] Figure 3B The experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound 1 prepared according to Example 12 is shown.

[0186] Figure 3C The experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound 1 prepared according to Example 13 is shown.

[0187] Figure 3D The experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound 1 prepared according to Example 14 is shown.

[0188] Figure 3E A differential scanning calorimetry (DSC) graph of the malate salt of Compound 1 prepared according to Example 13 is shown.

[0189] Figure 3F A differential scanning calorimetry (DSC) graph of the malate salt of Compound 1 prepared according to Example 14 is shown.

[0190] Figure 3G A thermogravimetric analysis (TGA) chart of the malate salt of Compound 1 prepared according to Example 13 is shown.

[0191] Figure 3H A thermogravimetric analysis (TGA) chart of the malate salt of Compound 1 prepared according to Example 14 is shown.

[0192] Fig. 3IThermogravimetric analysis (TGA) graph of the malate salt of Compound I at room temperature at 92.5% relative humidity (RH) for 24 hours is shown, and the malate salt of Compound I was prepared according to Example 13.

[0193] Figure 3J Thermogravimetric analysis (TGA) graph of the malate salt of Compound I at room temperature at 92.5% relative humidity (RH) for 24 hours is shown, and the malate salt of Compound I was prepared according to Example 14.

[0194] Figure 4A The experimental X-ray powder diffraction (XRPD) pattern of the citrate salt of Compound 1 prepared according to Example 15 is shown.

[0195] Figure 4B The experimental X-ray powder diffraction (XRPD) pattern of the citrate salt of Compound 1 prepared according to Example 16 is shown.

[0196] Figure 4C The experimental X-ray powder diffraction (XRPD) pattern of the citrate salt of Compound 1 prepared according to Example 17 is shown.

[0197] Figure 4D A differential scanning calorimetry (DSC) graph of the citrate salt of Compound 1 prepared according to Example 17 is shown.

[0198] Figure 4E A thermogravimetric analysis (TGA) graph of the citrate salt of Compound 1 prepared according to Example 17 is shown.

[0199] Figure 5 The bioavailability and concentration of unbound tucatinib and Compound I in the brain or plasma at 1 hour, 4 hours, and 8 hours following oral administration of a single dose of tucatinib (50 mg / kg) or Compound I (3 mg / kg) to mice are provided.

[0200] Figure 6 The sensitivity of 25 breast cancer cell lines (including cell lines exhibiting amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein and / or overexpression of the HER2 protein) to treatment with Compound I (compared to tucatinib and lapatinib) is shown as measured by the calculated half maximal effective concentration (EC 50 ) indicated.

[0201] Fig. 7A The mean tumor volumes of mice in the Compound 1, Tucatinib and Vehicle control groups after 28 days of treatment according to Example 20 are shown.

[0202] Figure 7B Tumor volumes of individual mice in the vehicle control group according to Example 20 are shown.

[0203] Figure 7C Tumor volumes of individual mice in the Compound 1 group according to Example 20 are shown.

[0204] Fig.7D Tumor volumes of individual mice in the tucatinib group according to Example 20 are shown.

[0205] Fig. 7E The average body weight of mice in each of the Compound 1 group, the Tucatinib group, and the vehicle control group according to Example 20 is shown (wherein the vehicle group is represented by circles, the Compound 1 group is represented by triangles, and the Tucatinib group is represented by squares).

[0206] Fig. 8A It shows that in deuterated methanol (CD 3 OD) after recrystallization of the fumarate 1 H-NMR spectrum.

[0207] Figure 8B It shows that in deuterated methanol (CD 3 OD) of fumarate (fumarate enlargement) 1 H-NMR spectrum.

[0208] Figure 8C It shows that in deuterated methanol (CD 3 OD) of tartrate 1 H-NMR spectrum.

[0209] Fig.8D It shows that in deuterated methanol (CD 3 OD) of tartrate (tartrate amplification) 1 H-NMR spectrum.

[0210] Fig. 8E It shows that in deuterated methanol (CD 3 OD) of malate 1 H-NMR spectrum.

[0211] Figure 8F It shows that in deuterated methanol (CD 3 OD) of malate (malate amplification) 1 H-NMR spectrum. DETAILED DESCRIPTION

[0212] Unless otherwise expressly stated, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which this application belongs. In addition, any method or material similar or equivalent to the method or material described herein can be used in the practice of this application. For the purpose of this application, the following terms are defined.

[0213] It should be understood that the embodiments of the present application described herein include "consisting of" and / or "consisting essentially of" the embodiments.

[0214] Reference herein to "about" a value or parameter includes (and describes) variations with respect to that value or parameter itself. For example, description referring to "about X" includes description of "X".

[0215] As used herein, the term "about XY" has the same meaning as "about X to about Y." As used herein, the expression "about X, Y and / or Z" has the same meaning as "about X, about Y and / or about Z."

[0216] As used herein, reference to "not" a value or parameter generally means and describes "other than" a value or parameter. For example, the method is not used to treat type X cancer means that the method is used to treat types of cancer other than X.

[0217] As used herein, the terms "a," "an," or "the" include not only aspects having one member, but also aspects having more than one member. For example, the singular forms "a," "an," or "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the agent" includes reference to one or more agents known to those skilled in the art, and so forth.

[0218] As used herein, the term "polymorph" or "polymorphic form" refers to the crystalline form of a compound. Different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate and / or vibrational spectra, which is due to the arrangement or conformation of molecules or ions in the crystal lattice. The physical property differences exhibited by polymorphs can affect drug parameters such as storage stability, compressibility, density (important in formulation and product manufacturing) and dissolution rate (an important factor in bioavailability). Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, so that the dosage form changes color faster when composed of one polymorph than when composed of another polymorph), mechanical changes (e.g., tablets break during storage because the kinetically favorable polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more easily decomposed at high humidity). Due to differences in solubility / dissolution, in extreme cases, some polymorphic transitions can lead to insufficient efficacy, or in another extreme case, toxicity. Additionally, the physical properties of the crystalline form may be important in processing; for example, one polymorph may form solvates more easily or may be difficult to filter and wash free of impurities (eg, particle shape and size distribution may differ between polymorphs).

[0219] As used herein, the term "substantially as shown in..." when referring to, for example, an XRPD pattern, a DSC pattern, a TGA pattern, or a GVS pattern, includes patterns or patterns that are not necessarily the same as the patterns or patterns described herein, but that are within the limits of experimental error or deviation as deemed by a person skilled in the art.

[0220] In some embodiments, the term "substantially pure" refers to a salt form or polymorphic form containing about less than 30%, about less than 20%, about less than 15%, about less than 10%, about less than 5%, or about less than 1% impurities by weight. In other embodiments, "substantially pure" refers to a substance that is free of impurities. Impurities may include, for example, byproducts or remaining reagents from chemical reactions, contaminants, degradation products, other salt forms, other polymorphic forms, water, and solvents.

[0221] As used herein, the term "substantially free" means that the composition comprising a salt form or a polymorphic form contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the indicated substance or substances.

[0222] As used herein, "treatment" or "treating" is a method for obtaining beneficial or desired results (including clinical results). For the purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the deterioration of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, reducing the recurrence rate of the disease, delaying or slowing the progression of the disease, improving the disease state, providing relief of the disease (partial or complete), reducing the dosage of one or more other drugs required for the treatment of the disease, delaying the progression of the disease, improving the quality of life and / or prolonging the survival period. In some embodiments, the treatment reduces the severity of one or more symptoms associated with cancer compared to the corresponding symptoms of the same subject before treatment or compared to the corresponding symptoms of other subjects who have not received treatment: at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. "Treatment" also includes reducing the pathological consequences of cancer. The method of the present application covers any one or more of these aspects of treatment.

[0223] The term "effective amount" as used herein refers to an amount of a compound or composition sufficient to treat a particular disorder, condition or disease, such as to improve, alleviate, reduce and / or delay one or more symptoms in an individual. With respect to cancer, an effective amount includes an amount sufficient to cause a tumor to shrink and / or reduce a tumor growth rate (e.g., inhibit tumor growth) or to prevent or delay other unwanted cell proliferation in a cancer in an individual. In some embodiments, an effective amount is an amount sufficient to delay the development of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to prevent or delay the recurrence of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to reduce the recurrence rate of cancer in an individual. The effective amount can be administered to an individual in one or more administrations. An effective amount of the drug or composition can: (i) reduce the number of cancer cells; (ii) reduce the size of tumors; (iii) inhibit, delay, slow down and preferably prevent to some extent the infiltration of cancer cells into peripheral organs; (iv) inhibit (i.e., slow down and preferably prevent to some extent) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay tumor occurrence and / or recurrence; (vii) reduce the recurrence rate of tumors, and / or (viii) alleviate to some extent one or more symptoms associated with cancer in an individual.

[0224] As understood in the art, an "effective amount" can be one or more doses, that is, a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents, and if the desired or beneficial result can be achieved or achieved in combination with one or more other agents, it can be considered that the compound or composition described herein is given in an effective amount. The components (e.g., the first and second therapies) in the combination therapy of the present application can be administered to an individual sequentially, simultaneously or in parallel, and each component uses the same or different routes of administration. Therefore, the effective amount of the combination therapy includes the amount of the first therapy and the amount of the second therapy that produce the desired result in an individual when administered sequentially, simultaneously or in parallel to the individual.

[0225] As used herein, "therapeutically effective amount" refers to an amount administered to an individual that produces the desired pharmacological and / or physiological effect on the individual's condition. The effect in the individual can be preventive, in terms of completely or partially preventing the condition or its symptoms, and / or can be therapeutic, in terms of partially or completely curing the condition and / or adverse effects caused by the condition.

[0226] As used herein, "subject" refers to a mammal, including a human, dog, cat, or livestock. In one embodiment, the subject is a human.

[0227] "In conjunction with" or "combination" refers to the administration of one treatment modality in addition to another treatment modality, for example, administering a compound or composition described herein to the same individual in addition to other agents under the same treatment plan. Thus, "in conjunction with" or "combination" refers to the administration of one treatment modality before, during, or after the delivery of the other treatment modality to the individual.

[0228] As used herein, the term "simultaneous administration" means that the time interval between the administration of the first therapy and the second therapy in the combination therapy is no more than about 15 minutes, such as no more than about any of the following: 10, 5 or 1 minute. When the first and second therapies are administered simultaneously, the first and second therapies can be contained in the same composition (e.g., a composition containing the first and second therapies) or contained in separate compositions (e.g., the first therapy is contained in one composition, and the second therapy is contained in another composition).

[0229] As used herein, the term "sequential administration" refers to the time interval between the administration of the first therapy and the second therapy in the combination therapy being greater than about 15 minutes, for example greater than about any of the following: 20, 30, 40, 50, 60 or more minutes. The first therapy or the second therapy may be administered first. The first therapy and the second therapy are contained in separate compositions, which may be contained in the same or different packages or kits.

[0230] As used herein, the term "concurrent administration" means that the administration of a first therapy and the administration of a second therapy in a combination therapy overlap with each other.

[0231] As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to a material that is not biologically or otherwise undesirable, for example, the material can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effect or interacting in a deleterious manner with any other component of the composition in which the material is contained. Pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicology and manufacturing testing and / or are included in the inactive ingredient guidelines established by the U.S. Food and Drug Administration.

[0232] The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety.

[0233] Compound I

[0234] Compound I is a compound that has been shown to have inhibitory activity against epidermal growth factor receptor (EGFR) variants and HER2 variants. The chemical name of Compound I is N-[2-[4-(4-cyclopropyl-1-piperazinyl)-1-piperidinyl]-5-[[6-[(3R)-3-(3,5-difluorophenyl)-2-isoxazolidinyl]-4-pyrimidinyl]amino]-4-methoxyphenyl]-2-acrylamide. Compound I has the following structure:

[0235]

[0236] Compound I may also be named (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide. Compound I has been assigned the CAS registry number 2489185-38-6.

[0237] Compound I has been described in WO2020 / 190119 and can be prepared by the methods described therein. For this purpose, the contents of WO2020 / 190119 are hereby incorporated by reference herein. Alternatively, Compound I can be prepared by methods known to those skilled in the art.

[0238] Salt

[0239] In one aspect, provided herein are salts of Compound 1. The salts may possess chemical or physical properties, such as improved bioavailability and stability under certain conditions suitable for medical or pharmaceutical use.

[0240] The salt of Compound I can provide advantages in bioavailability and stability, and can be suitable for use as an active agent in a pharmaceutical composition. Changes in the form of drug salts can affect the dissolution rate (which can affect bioavailability, etc.), manufacturability (e.g., easy to handle, easy to purify, the ability to consistently prepare doses of known strength, etc.) and stability (e.g., thermal stability, shelf life (including anti-degradability), etc.) of the drug product. Such changes can affect the preparation or formulation of pharmaceutical compositions of different dosage forms or delivery forms (e.g., solid oral dosage forms including tablets and capsules). The salt form of the drug can provide desired or suitable hygroscopicity, dissolution rate, solubility, absorption, purity, physical and chemical stability, manufacturability, yield, reproducibility and / or process control. Therefore, the salt of the compound can provide the following advantages: improve the stability or storability of the manufacturing process of the active agent or the drug product form of the active agent, or have suitable bioavailability and / or stability as an active agent.

[0241] Using certain conditions (e.g., using different solvents and / or temperatures) has been found to produce different salts of Compound I and different polymorphic forms of these salts, including the fumarate, tartrate, malate and citrate salts described herein, which may exhibit one or more of the advantageous properties described herein. The preparation methods of the fumarate, tartrate, malate and citrate salts described herein and the characterization of these salts will be described in more detail below.

[0242] Fumarate

[0243] In some embodiments, provided herein are fumarate salts of Compound 1.

[0244] In some embodiments, the fumarate salt of Compound 1 is a hemifumarate salt.

[0245] In some embodiments, the fumarate salt of Compound 1 is in crystalline form.

[0246] In some embodiments, the solubility of the fumarate salt in an aqueous solution at a pH of about 1.5 at a temperature of about 25° C. is about 20 mg / mL (e.g., about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, about 20 mg / mL, about 20.5 mg / mL, about 21 mg / mL, about 21.5 mg / mL, or about 22 mg / mL), calculated based on the amount of the free base of Compound I. In some embodiments, the solubility of the fumarate salt in an aqueous solution at a pH of about 4.7 at a temperature of about 25° C. is about 20 mg / mL (about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, about 20 mg / mL, about 20.5 mg / mL, about 21 mg / mL, about 21.5 mg / mL, or about 22 mg / mL), calculated based on the amount of the free base of Compound I. In some embodiments, the solubility of the fumarate salt in an aqueous solution at a pH of about 6.6 at a temperature of about 25° C. is about 0.2 mg / mL (e.g., about 0.1 mg / mL, about 0.125 mg / mL, 0.15 mg / mL, about 0.175 mg / mL, about 0.225 mg / mL, about 0.25 mg / mL, about 0.275 mg / mL, or about 0.3 mg / mL), calculated as the amount of the free base of Compound I.

[0247] In some embodiments, the solubility of the fumarate salt in an aqueous solution at a pH of about 1.2 at a temperature of about 25° C. is about 9.2 mg / mL (e.g., about 8.0 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL, about 11 mg / mL, about 11.5 mg / mL, or about 12 mg / mL), calculated based on the amount of the free base of Compound I. In some embodiments, the solubility of the fumarate salt in an aqueous solution at a pH of about 4.6 at a temperature of about 25° C. is about 7.2 mg / mL (e.g., about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, or about 9 mg / mL), calculated based on the amount of the free base of Compound I. In some embodiments, the solubility of the fumarate salt in an aqueous solution at a pH of about 6.8 at a temperature of about 25° C. is about 0.1 mg / mL (e.g., about 0.05 mg / mL, about 0.075 mg / mL, 0.125 mg / mL, about 0.15 mg / mL, about 0.175 mg / mL, or about 0.2 mg / mL), calculated as the amount of the free base of Compound I.

[0248] In some embodiments, the XRPD pattern of the fumarate salt is substantially as follows Figure 1ATable 1 shows the angles (as measured in °2θ) and peak intensities of fumarate salts observable using XRPD.

[0249] Table 1

[0250]

[0251] In some embodiments, the fumarate salt has a Figure 1A In the XRPD spectrum shown in or as provided in Table 1 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignments listed herein (including fumarate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0252] In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 9.0±0.2, 9.9±0.2, 10.6±0.2, 13.1±0.2, 13.5±0.2, 14.8±0.2, 16.5±0.2, 17.5±0.2, 17.9±0.2, 19.3±0.2, 19.7±0.2, 20.4±0.2, 21.6±0.2, 22.5±0.2, 23.5±0.2, 24.5±0.2, 26.6±0.2, 27.0±0.2, 29.0±0.2, 29.7±0.2, 30.8±0.2, and 31.6±0.2 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 9.0±0.2, 9.9±0.2, 16.5±0.2, 17.9±0.2, 19.3±0.2, 19.7±0.2, 20.4±0.2, 21.6±0.2, 22.5±0.2, 23.5±0.2, 24.5±0.2, 26.6±0.2, 27.0±0.2, 29.0±0.2, and 31.6±0.2 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 9.9±0.2, 19.3±0.2, 19.7±0.2, 20.4±0.2, 22.5±0.2, 24.5±0.2, 26.6±0.2, and 27.0±0.2°2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 9.9±0.2, 22.5±0.2, 26.6±0.2, and 27.0±0.2°2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 9.0±0.4, 9.9±0.4, 10.6±0.4, 13.1±0.4, 13.5±0.4, 14.8±0.4, 16.5±0.4, 17.5±0.4, 17.9±0.4, 19.3±0.4, 19.7±0.4, 20.4±0.4, 21.6±0.4, 22.5±0.4, 23.5±0.4, 24.5±0.4, 26.6±0.4, 27.0±0.4, 29.0±0.4, 29.7±0.4, 30.8±0.4, and 31.6±0.4 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 9.0±0.4, 9.9±0.4, 16.5±0.4, 17.9±0.4, 19.3±0.4, 19.7±0.4, 20.4±0.4, 21.6±0.4, 22.5±0.4, 23.5±0.4, 24.5±0.4, 26.6±0.4, 27.0±0.4, 29.0±0.4, and 31.6±0.4 °2θ.In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 9.9±0.4, 19.3±0.4, 19.7±0.4, 20.4±0.4, 22.5±0.4, 24.5±0.4, 26.6±0.4, and 27.0±0.4° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 9.9±0.4, 22.5±0.4, 26.6±0.4, and 27.0±0.4° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 9.0±0.6, 9.9±0.6, 10.6±0.6, 13.1±0.6, 13.5±0.6, 14.8±0.6, 16.5±0.6, 17.5±0.6, 17.9±0.6, 19.3±0.6, 19.7±0.6, 20.4±0.6, 21.6±0.6, 22.5±0.6, 23.5±0.6, 24.5±0.6, 26.6±0.6, 27.0±0.6, 29.0±0.6, 29.7±0.6, 30.8±0.6, and 31.6±0.6 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 9.0±0.6, 9.9±0.6, 16.5±0.6, 17.9±0.6, 19.3±0.6, 19.7±0.6, 20.4±0.6, 21.6±0.6, 22.5±0.6, 23.5±0.6, 24.5±0.6, 26.6±0.6, 27.0±0.6, 29.0±0.6, and 31.6±0.6 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 9.9 ± 0.6, 19.3 ± 0.6, 19.7 ± 0.6, 20.4 ± 0.6, 22.5 ± 0.6, 24.5 ± 0.6, 26.6 ± 0.6, and 27.0 ± 0.6 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 9.9 ± 0.6, 22.5 ± 0.6, 26.6 ± 0.6, and 27.0 ± 0.6 ° 2θ. It should be understood that except. Figure 1A In addition to those peaks shown in or provided in Table 1, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0253] In some embodiments, the XRPD pattern of the fumarate salt is substantially as follows Figure 1B Table 2 shows the angles (as measured in °2θ) and peak intensities of the fumarate salts observable using XRPD.

[0254] Table 2

[0255]

[0256] In some embodiments, the fumarate salt has a Figure 1B In the XRPD spectrum shown in or as provided in Table 2 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignments listed herein (including fumarate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0257] In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.4±0.2, 8.7±0.2, 9.6±0.2, 10.1±0.2, 11.1±0.2, 12.9±0.2, 13.2±0.2, 17.1±0.2, 17.7±0.2, 19.2±0.2, 22.1±0.2, 25.1±0.2, 26.6±0.2, 27.2±0.2, and 31.1±0.2 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 8.7±0.2, 9.6±0.2, 10.1±0.2, 17.1±0.2, 17.7±0.2, 19.2±0.2, 22.1±0.2, 25.1±0.2, 26.6±0.2, and 27.2±0.2° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 17.7±0.2, 19.2±0.2, 22.1±0.2, 25.1±0.2, and 26.6±0.2° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.4±0.4, 8.7±0.4, 9.6±0.4, 10.1±0.4, 11.1±0.4, 12.9±0.4, 13.2±0.4, 17.1±0.4, 17.7±0.4, 19.2±0.4, 22.1±0.4, 25.1±0.4, 26.6±0.4, 27.2±0.4, and 31.1±0.4 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 8.7±0.4, 9.6±0.4, 10.1±0.4, 17.1±0.4, 17.7±0.4, 19.2±0.4, 22.1±0.4, 25.1±0.4, 26.6±0.4, and 27.2±0.4° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 17.7±0.4, 19.2±0.4, 22.1±0.4, 25.1±0.4, and 26.6±0.4° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.4±0.6, 8.7±0.6, 9.6±0.6, 10.1±0.6, 11.1±0.6, 12.9±0.6, 13.2±0.6, 17.1±0.6, 17.7±0.6, 19.2±0.6, 22.1±0.6, 25.1±0.6, 26.6±0.6, 27.2±0.6, and 31.1±0.6 °2θ.In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 8.7 ± 0.6, 9.6 ± 0.6, 10.1 ± 0.6, 17.1 ± 0.6, 17.7 ± 0.6, 19.2 ± 0.6, 22.1 ± 0.6, 25.1 ± 0.6, 26.6 ± 0.6, and 27.2 ± 0.6 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 17.7 ± 0.6, 19.2 ± 0.6, 22.1 ± 0.6, 25.1 ± 0.6, and 26.6 ± 0.6 ° 2θ. It should be understood that except. Figure 1B In addition to those peaks shown in or provided in Table 2, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0258] In some embodiments, the XRPD pattern of the fumarate salt is substantially as follows Figure 1C Table 3 shows the angles (as measured in °2θ) and peak intensities of the fumarate salts observable using XRPD.

[0259] Table 3

[0260]

[0261] In some embodiments, the fumarate salt has a Figure 1C In the XRPD pattern shown in or as provided in Table 3 at least one, at least two or all peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignments listed herein (including fumarate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0262] In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.5 ± 0.2, 8.9 ± 0.2, and 22.3 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.5 ± 0.2 and 22.3 ± 0.2 ° 2θ. The fumarate salt has an XRPD pattern comprising a peak at 22.3 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at: 4.5 ± 0.4, 8.9 ± 0.4, and 22.3 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at: 4.5 ± 0.4 and 22.3 ± 0.4 ° 2θ. The fumarate salt has an XRPD pattern comprising a peak at 22.3 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.5 ± 0.6, 8.9 ± 0.6, and 22.3 ± 0.6 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.5 ± 0.6 and 22.3 ± 0.6 ° 2θ. The fumarate salt has an XRPD pattern comprising a peak at 22.3 ± 0.6 ° 2θ. It should be understood that except for Figure 1C In addition to those peaks shown in or provided in Table 3, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0263] In some embodiments, the XRPD pattern of the fumarate salt is substantially as follows Figure 1D Table 4 shows the angles (as measured in °2θ) and peak intensities of the fumarate salts observable using XRPD.

[0264] Table 4

[0265]

[0266] In some embodiments, the fumarate salt has a Figure 1D In the XRPD spectrum shown in or as provided in Table 4 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignments listed herein (including fumarate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0267] In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 9.9 ± 0.2, 13.8 ± 0.2, 16.6 ± 0.2, 18.4 ± 0.2, 19.9 ± 0.2, and 37.3 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 13.8 ± 0.2, 18.4 ± 0.2, and 19.9 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.2, 5.0 ± 0.2, and 13.8 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.4, 5.0 ± 0.4, 9.2 ± 0.4, 9.9 ± 0.4, 13.8 ± 0.4, 16.6 ± 0.4, 18.4 ± 0.4, 19.9 ± 0.4, and 37.3 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.4, 5.0 ± 0.4, 9.2 ± 0.4, 13.8 ± 0.4, 18.4 ± 0.4, and 19.9 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.4, 5.0 ± 0.4, and 13.8 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.6, 5.0 ± 0.6, 9.2 ± 0.6, 9.9 ± 0.6, 13.8 ± 0.6, 16.6 ± 0.6, 18.4 ± 0.6, 19.9 ± 0.6, and 37.3 ± 0.6 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.6, 5.0 ± 0.6, 9.2 ± 0.6, 13.8 ± 0.6, 18.4 ± 0.6, and 19.9 ± 0.6 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 4.6 ± 0.6, 5.0 ± 0.6, and 13.8 ± 0.6 ° 2θ. It should be understood that except for Figure 1D In addition to those peaks shown in or provided in Table 4, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0268] In some embodiments, the XRPD pattern of the fumarate salt is substantially as follows Figure 1E Table 5 shows the angles (as measured in °2θ) and peak intensities of the fumarate salts observable using XRPD.

[0269] Table 5

[0270]

[0271] In some embodiments, the fumarate salt has a Figure 1E In the XRPD spectrum shown in or as provided in Table 5 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensity and peak assignment may vary within experimental error. In some embodiments, the peak assignments listed herein (including fumarate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0272] In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.2, 8.4±0.2, 8.9±0.2, 10.6±0.2, 11.0±0.2, 11.7±0.2, 12.7±0.2, 13.7±0.2, 14.2±0.2, 15.4±0.2, 16.3±0.2, 17.1±0.2, 17.6 ± 0.2, 18.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.5 ± 0.2, 21.3 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 23.4 ± 0.2, 24.0 ± 0.2, 25.7 ± 0.2, 27.2 ± 0.2, 27.7 ± 0.2, and 28.7 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.2, 8.4±0.2, 12.7±0.2, 13.7±0.2, 15.4±0.2, 17.1±0.2, 17.6±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2, 20.5±0.2, 21.3±0.2, 21.7±0.2, 22.0±0.2, 23.4±0.2, 24.0±0.2, 25.7±0.2, and 27.7±0.2 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.2, 15.4±0.2, 17.1±0.2, 17.6±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2, 20.5±0.2, and 22.0±0.2° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.4, 8.4±0.4, 8.9±0.4, 10.6±0.4, 11.0±0.4, 11.7±0.4, 12.7±0.4, 13.7±0.4, 14.2±0.4, 15.4±0.4, 16.3±0.4, 17.1±0.4, 17.6 ± 0.4, 18.1 ± 0.4, 18.8 ± 0.4, 19.5 ± 0.4, 19.8 ± 0.4, 20.5 ± 0.4, 21.3 ± 0.4, 21.7 ± 0.4, 22.0 ± 0.4, 23.4 ± 0.4, 24.0 ± 0.4, 25.7 ± 0.4, 27.2 ± 0.4, 27.7 ± 0.4, and 28.7 ± 0.4 ° 2θ.In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.4, 8.4±0.4, 12.7±0.4, 13.7±0.4, 15.4±0.4, 17.1±0.4, 17.6±0.4, 18.1±0.4, 18.8±0.4, 19.8±0.4, 20.5±0.4, 21.3±0.4, 21.7±0.4, 22.0±0.4, 23.4±0.4, 24.0±0.4, 25.7±0.4, and 27.7±0.4 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.4, 15.4±0.4, 17.1±0.4, 17.6±0.4, 18.1±0.4, 18.8±0.4, 19.8±0.4, 20.5±0.4, and 22.0±0.4° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.6, 8.4±0.6, 8.9±0.6, 10.6±0.6, 11.0±0.6, 11.7±0.6, 12.7±0.6, 13.7±0.6, 14.2±0.6, 15.4±0.6, 16.3±0.6, 17.1±0.6, 17.6 ± 0.6, 18.1 ± 0.6, 18.8 ± 0.6, 19.5 ± 0.6, 19.8 ± 0.6, 20.5 ± 0.6, 21.3 ± 0.6, 21.7 ± 0.6, 22.0 ± 0.6, 23.4 ± 0.6, 24.0 ± 0.6, 25.7 ± 0.6, 27.2 ± 0.6, 27.7 ± 0.6, and 28.7 ± 0.6° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.6, 8.4±0.6, 12.7±0.6, 13.7±0.6, 15.4±0.6, 17.1±0.6, 17.6±0.6, 18.1±0.6, 18.8±0.6, 19.8±0.6, 20.5±0.6, 21.3±0.6, 21.7±0.6, 22.0±0.6, 23.4±0.6, 24.0±0.6, 25.7±0.6, and 27.7±0.6 °2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.6, 15.4±0.6, 17.1±0.6, 17.6±0.6, 18.1±0.6, 18.8±0.6, 19.8±0.6, 20.5±0.6, and 22.0±0.6° 2θ. It should be understood that except for. Figure 1E In addition to those peaks shown in or provided in Table 5, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0273] In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at 5.0 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at: 5.0 ± 0.2 and 17.1 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at: 5.0 ± 0.2, 17.1 ± 0.2, and 20.5 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at: 5.0 ± 0.2, 15.4 ± 0.2, 17.1 ± 0.2, 18.1 ± 0.2, 18.8 ± 0.2, 19.8 ± 0.2, 20.5 ± 0.2, and 22.0 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0 ± 0.2, 8.4 ± 0.2, 15.4 ± 0.2, 17.1 ± 0.2, 17.6 ± 0.2, 18.1 ± 0.2, 18.8 ± 0.2, 19.8 ± 0.2, 20.5 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, and 27.7 ± 0.2 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0 ± 0.4 and 17.1 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.4, 17.1±0.4, and 20.5±0.4° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.4, 15.4±0.4, 17.1±0.4, 18.1±0.4, 18.8±0.4, 19.8±0.4, 20.5±0.4, and 22.0±0.4° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0 ± 0.4, 8.4 ± 0.4, 15.4 ± 0.4, 17.1 ± 0.4, 17.6 ± 0.4, 18.1 ± 0.4, 18.8 ± 0.4, 19.8 ± 0.4, 20.5 ± 0.4, 21.7 ± 0.4, 22.0 ± 0.4, 24.0 ± 0.4, and 27.7 ± 0.4 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0 ± 0.6 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0 ± 0.6 and 17.1 ± 0.6 ° 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.6, 17.1±0.6, and 20.5±0.6° 2θ.In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.6, 15.4±0.6, 17.1±0.6, 18.1±0.6, 18.8±0.6, 19.8±0.6, 20.5±0.6, and 22.0±0.6°2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at: 5.0±0.6, 8.4±0.6, 15.4±0.6, 17.1±0.6, 17.6±0.6, 18.1±0.6, 18.8±0.6, 19.8±0.6, 20.5±0.6, 21.7±0.6, 22.0±0.6, 24.0±0.6, and 27.7±0.6°2θ.

[0274] In some embodiments, the fumarate salt has substantially Figure 1F In some embodiments, the fumarate salt has substantially Figure 1G In some embodiments, the fumarate salt has substantially Figure 1HIn some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 172°C to about 185°C. In some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 172±4°C (e.g., 172±3°C, 172±2°C, or 172±1°C). In some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 174±4°C (e.g., 174±3°C, 174±2°C, or 174±1°C). In some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 176±4°C (e.g., 176±3°C, 176±2°C, or 176±1°C). In some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 178 ± 4 ° C (e.g., 178 ± 3 ° C, 178 ± 2 ° C, or 178 ± 1 ° C). In some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 180 ± 4 ° C (e.g., 180 ± 3 ° C, 180 ± 2 ° C, or 180 ± 1 ° C). In some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 182 ± 4 ° C (e.g., 182 ± 3 ° C, 182 ± 2 ° C, or 182 ± 1 ° C). In some embodiments, the fumarate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 184 ± 4 ° C (e.g., 184 ± 3 ° C, 184 ± 2 ° C, or 184 ± 1 ° C). In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 185±4°C (eg, 185±3°C, 185±2°C, or 185±1°C).

[0275] In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 172°C to about 185°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 172°C to about 184°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 172°C to about 182°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 172°C to about 180°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 174°C to about 184°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 174°C to about 182°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 174°C to about 180°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 176°C to about 184°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 176°C to about 182°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 176°C to about 180°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 178°C to about 184°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 178°C to about 182°C. In some embodiments, the fumarate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 178°C to about 180°C.

[0276] In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 165°C to about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 165±4°C (e.g., 165±3°C, 165±2°C, or 165±1°C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 167±4°C (e.g., 167±3°C, 167±2°C, or 167±1°C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 169±4°C (e.g., 169±3°C, 169±2°C, or 169±1°C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 171±4°C (e.g., 171±3°C, 171±2°C, or 171±1°C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 173 ± 4 ° C (e.g., 173 ± 3 ° C, 173 ± 2 ° C, or 173 ± 1 ° C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 175 ± 4 ° C (e.g., 175 ± 3 ° C, 175 ± 2 ° C, or 175 ± 1 ° C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 177 ± 4 ° C (e.g., 177 ± 3 ° C, 177 ± 2 ° C, or 177 ± 1 ° C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 179 ± 4 ° C (e.g., 179 ± 3 ° C, 179 ± 2 ° C, or 179 ± 1 ° C). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 180±4°C (eg, 180±3°C, 180±2°C, or 180±1°C).

[0277] In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 165°C to about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 165°C to about 175°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 167°C to about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 167°C to about 175°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 169°C to about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 169°C to about 175°C.

[0278] In some embodiments of the fumarate salt, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply:

[0279] (a) the fumarate is a hemifumarate;

[0280] (b) the fumarate salt is in crystalline form;

[0281] (c) the fumarate salt has a solubility of greater than about 20 mg / mL, calculated as the free base of Compound I, in an aqueous solution at a pH of about 1.5 at a temperature of about 25° C.;

[0282] (d) the fumarate salt has a solubility of greater than about 20 mg / mL, calculated as the free base of Compound I, in an aqueous solution having a pH of about 4.7 at a temperature of about 25° C.;

[0283] (e) the fumarate salt has a solubility of about 0.2 mg / mL in an aqueous solution at a pH of about 6.6 at a temperature of about 25° C., calculated as the free base of Compound I;

[0284] (f) The fumarate salt exhibits an XRPD pattern comprising:

[0285] (i) peak at 5.0 ± 0.2° 2θ;

[0286] (ii) peaks at 5.0 ± 0.2 and 17.1 ± 0.2° 2θ;

[0287] (iii) peaks at 5.0 ± 0.2, 17.1 ± 0.2, and 20.5 ± 0.2° 2θ;

[0288] (iv) peaks at 5.0±0.2, 15.4±0.2, 17.1±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2, 20.5±0.2, and 22.0±0.2° 2θ; or

[0289] (v) peaks at 5.0±0.2, 8.4±0.2, 15.4±0.2, 17.1±0.2, 17.6±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2, 20.5±0.2, 21.7±0.2, 22.0±0.2, 24.0±0.2, and 27.7±0.2 degrees 2θ; and

[0290] (g) The fumarate salt exhibits a differential scanning calorimetry trace comprising:

[0291] (i) a peak from about 172°C to about 185°C; or

[0292] (ii) a peak from about 172°C to about 185°C and an endothermic onset from about 165°C to about 180°C.

[0293] In some embodiments, (a) and (b) apply. In some embodiments, (a), (b) and (c) apply. In some embodiments, (a), (b), (c) and (d) apply. In some embodiments, (a), (b), (c), (d) and (e) apply. In some embodiments, (a), (b), (c), (d), (e) and (f) apply. In some embodiments, (a), (b), (c), (d), (e), (f) and (g) apply. In some embodiments, (f) and (g) apply. In some embodiments, (f)(i) and (g)(i) apply. In some embodiments, (f)(ii) and (g)(i) apply. In some embodiments, (f)(iii) and (g)(i) apply. In some embodiments, (f)(iv) and (g)(i) apply. In some embodiments, (f)(v) and (g)(i) apply. In some embodiments, (f)(i) and (g)(ii) apply. In some embodiments, (f)(ii) and (g)(ii) apply. In some embodiments, (f)(iii) and (g)(ii) apply. In some embodiments, (f)(iv) and (g)(ii) apply. In some embodiments, (f)(v) and (g)(ii) apply. In some embodiments, (c), (f) and (g) apply. In some embodiments, (c), (f)(i) and (g)(i) apply. In some embodiments, (c), (f)(ii) and (g)(i) apply. In some embodiments, (c), (f)(iii) and (g)(i) apply. In some embodiments, (c), (f)(iv) and (g)(i) apply. In some embodiments, (c), (f)(v) and (g)(i) apply. In some embodiments, (c), (f)(i) and (g)(ii) apply. In some embodiments, (c), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (f)(v) and (g)(ii) apply. In some embodiments, (d), (f) and (g) apply. In some embodiments, (d), (f)(i) and (g)(i) apply. In some embodiments, (d), (f)(ii) and (g)(i) apply. In some embodiments, (d), (f)(iii) and (g)(i) apply. In some embodiments, (d), (f)(iv) and (g)(i) apply. In some embodiments, (d), (f)(v) and (g)(i) apply. In some embodiments, (d), (f)(i) and (g)(ii) apply.In some embodiments, (d), (f)(ii) and (g)(ii) apply. In some embodiments, (d), (f)(iii) and (g)(ii) apply. In some embodiments, (d), (f)(iv) and (g)(ii) apply. In some embodiments, (d), (f)(v) and (g)(ii) apply. In some embodiments, (e), (f) and (g) apply. In some embodiments, (e), (f)(i) and (g)(i) apply. In some embodiments, (e), (f)(ii) and (g)(i) apply. In some embodiments, (e), (f)(iii) and (g)(i) apply. In some embodiments, (e), (f)(iv) and (g)(i) apply. In some embodiments, (e), (f)(v) and (g)(i) apply. In some embodiments, (e), (f)(i) and (g)(ii) apply. In some embodiments, (e), (f)(ii) and (g)(ii) apply. In some embodiments, (e), (f)(iii) and (g)(ii) apply. In some embodiments, (e), (f)(iv) and (g)(ii) apply. In some embodiments, (e), (f)(v) and (g)(ii) apply. In some embodiments, (c), (d), (f) and (g) apply. In some embodiments, (c), (d), (f)(i) and (g)(i) apply. In some embodiments, (c), (d), (f)(ii) and (g)(i) apply. In some embodiments, (c), (d), (f)(iii) and (g)(i) apply. In some embodiments, (c), (d), (f)(iv) and (g)(i) apply. In some embodiments, (c), (d), (f)(v) and (g)(i) apply. In some embodiments, (c), (d), (f)(i) and (g)(ii) apply. In some embodiments, (c), (d), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (d), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (d), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (d), (f)(v) and (g)(ii) apply. In some embodiments, (c), (e), (f) and (g) apply. In some embodiments, (c), (e), (f)(i) and (g)(i) apply. In some embodiments, (c), (e), (f)(ii) and (g)(i) apply. In some embodiments, (c), (e), (f)(iii) and (g)(i) apply. In some embodiments, (c), (e), (f)(iv) and (g)(i) apply.In some embodiments, (c), (e), (f)(v) and (g)(i) apply. In some embodiments, (c), (e), (f)(i) and (g)(ii) apply. In some embodiments, (c), (e), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (e), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (e), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (e), (f)(v) and (g)(ii) apply. In some embodiments, (d), (e), (f) and (g) apply. In some embodiments, (d), (e), (f)(i) and (g)(i) apply. In some embodiments, (d), (e), (f)(ii) and (g)(i) apply. In some embodiments, (d), (e), (f)(iii) and (g)(i) apply. In some embodiments, (d), (e), (f)(iv) and (g)(i) apply. In some embodiments, (d), (e), (f)(v) and (g)(i) apply. In some embodiments, (d), (e), (f)(i) and (g)(ii) apply. In some embodiments, (d), (e), (f)(ii) and (g)(ii) apply. In some embodiments, (d), (e), (f)(iii) and (g)(ii) apply. In some embodiments, (d), (e), (f)(iv) and (g)(ii) apply. In some embodiments, (d), (e), (f)(v) and (g)(ii) apply. In some embodiments, (c), (d), (e), (f) and (g) apply. In some embodiments, (c), (d), (e), (f) and (g) apply. In some embodiments, (c), (d), (e), (f)(i) and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(ii) and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(iii) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(iv) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(v) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(i) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(ii) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(iii) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(iv) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(v) and (g)(ii) are applicable.

[0294] Tartrate

[0295] In some embodiments, provided herein is a tartrate salt of Compound 1.

[0296] In some embodiments, the tartrate salt of Compound 1 is a hemi-tartrate salt.

[0297] In some embodiments, the tartrate salt of Compound 1 is in crystalline form.

[0298] In some embodiments, the solubility of the tartaric acid salt in an aqueous solution at a pH of about 1.4 at a temperature of about 25° C. is about 20 mg / mL (e.g., about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, about 20 mg / mL, about 20.5 mg / mL, about 21 mg / mL, about 21.5 mg / mL, or about 22 mg / mL), calculated as the amount of the free base of Compound I. In some embodiments, the solubility of the tartrate salt in an aqueous solution at a pH of about 4.7 at a temperature of about 25° C. is about 0.3 mg / mL (e.g., about 0.2 mg / mL, about 0.225 mg / mL, about 0.25 mg / mL, about 0.26 mg / mL, about 0.275 mg / mL, about 0.325 mg / mL, about 0.35 mg / mL, about 0.375 mg / mL, or about 0.4 mg / mL), calculated as the amount of the free base of Compound I. In some embodiments, the solubility of the tartrate salt in an aqueous solution at a pH of about 6.6 at a temperature of about 25° C. is about 0.2 mg / mL (e.g., about 0.1 mg / mL, about 0.125 mg / mL, 0.15 mg / mL, about 0.175 mg / mL, about 0.225 mg / mL, about 0.25 mg / mL, about 0.275 mg / mL, or about 0.3 mg / mL), calculated as the amount of the free base of Compound I.

[0299] In some embodiments, the XRPD pattern of the tartrate salt is substantially as follows Figure 2A Table 6 shows the angles (as measured in °2θ) and peak intensities of the tartrate salts observable using XRPD.

[0300] Table 6

[0301]

[0302] In some embodiments, the tartrate salt has a Figure 2AIn the XRPD pattern shown in or as provided in Table 6 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensity and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including tartrate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0303] In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.2, 7.4 ± 0.2, 11.7 ± 0.2, 16.1 ± 0.2, 17.9 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 21.4 ± 0.2, 22.8 ± 0.2, and 23.5 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.2, 7.4 ± 0.2, 11.7 ± 0.2, 17.9 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, and 21.4 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9±0.2, 17.9±0.2, 20.0±0.2, and 21.4±0.2° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9±0.4, 7.4±0.4, 11.7±0.4, 16.1±0.4, 17.9±0.4, 19.1±0.4, 20.0±0.4, 21.4±0.4, 22.8±0.4, and 23.5±0.4° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9±0.4, 7.4±0.4, 11.7±0.4, 17.9±0.4, 19.1±0.4, 20.0±0.4, and 21.4±0.4° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9±0.4, 17.9±0.4, 20.0±0.4, and 21.4±0.4° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.6, 7.4 ± 0.6, 11.7 ± 0.6, 16.1 ± 0.6, 17.9 ± 0.6, 19.1 ± 0.6, 20.0 ± 0.6, 21.4 ± 0.6, 22.8 ± 0.6, and 23.5 ± 0.6 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.6, 7.4 ± 0.6, 11.7 ± 0.6, 17.9 ± 0.6, 19.1 ± 0.6, 20.0 ± 0.6, and 21.4 ± 0.6 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9±0.6, 17.9±0.6, 20.0±0.6, and 21.4±0.6° 2θ. It is understood that except for Figure 2A In addition to those peaks shown in or provided in Table 6, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0304] In some embodiments, the XRPD pattern of the tartrate salt is substantially as follows Figure 2B Table 7 shows the angles (as measured in °2θ) and peak intensities for the tartrate salt observed using XRPD.

[0305] Table 7

[0306]

[0307] In some embodiments, the tartrate salt has a Figure 2B In the XRPD pattern shown in or as provided in Table 7 at least one peak at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensity and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including tartrate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 °, or ± 0.1 ° 2θ.

[0308] In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 26.1 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 26.1 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 26.1 ± 0.6 ° 2θ. It should be understood that except for Figure 2B In addition to those peaks shown in or provided in Table 7, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0309] In some embodiments, the XRPD pattern of the tartrate salt is substantially as follows Figure 2C Table 8 shows the angles (as measured in °2θ) and peak intensities for the tartrate salt observed using XRPD.

[0310] Table 8

[0311]

[0312] In some embodiments, the tartrate salt has a Figure 2CIn the XRPD pattern shown in or as provided in Table 8 at least one, at least two, at least three, at least four, at least five, at least six, at least seven or at least eight peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including tartrate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0313] In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.2, 11.7 ± 0.2, 16.1 ± 0.2, 18.0 ± 0.2, 18.8 ± 0.2, 20.0 ± 0.2, 21.4 ± 0.2, and 23.4 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.2, 16.1 ± 0.2, 18.0 ± 0.2, 20.0 ± 0.2, 21.4 ± 0.2, and 23.4 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 16.1 ± 0.2, 20.0 ± 0.2, and 21.4 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.4, 11.7 ± 0.4, 16.1 ± 0.4, 18.0 ± 0.4, 18.8 ± 0.4, 20.0 ± 0.4, 21.4 ± 0.4, and 23.4 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.4, 16.1 ± 0.4, 18.0 ± 0.4, 20.0 ± 0.4, 21.4 ± 0.4, and 23.4 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 16.1 ± 0.4, 20.0 ± 0.4, and 21.4 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.6, 11.7 ± 0.6, 16.1 ± 0.6, 18.0 ± 0.6, 18.8 ± 0.6, 20.0 ± 0.6, 21.4 ± 0.6, and 23.4 ± 0.6 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.9 ± 0.6, 16.1 ± 0.6, 18.0 ± 0.6, 20.0 ± 0.6, 21.4 ± 0.6, and 23.4 ± 0.6 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 16.1 ± 0.6, 20.0 ± 0.6, and 21.4 ± 0.6 ° 2θ. It should be understood that except for Figure 2C In addition to those peaks shown in or provided in Table 8, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0314] In some embodiments, the XRPD pattern of the tartrate salt is substantially as follows Figure 2D Table 9 shows the angles (as measured in °2θ) and peak intensities for the tartrate salt observed using XRPD.

[0315] Table 9

[0316]

[0317] In some embodiments, the tartrate salt has a Figure 2D In the XRPD pattern shown in or as provided in Table 9 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including tartrate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0318] In some embodiments, the tartrate salt has an XRPD pattern comprising peaks of 5.8±0.2, 7.4±0.2, 8.9±0.2, 11.1±0.2, 11.6±0.2, 12.6±0.2, 12.9±0.2, 14.0±0.2, 16.1±0.2, 16.7±0.2, 17.4±0.2, 17.9±0.2, 18.2±0. .2, 18.8±0.2, 19.1±0.2, 19.9±0.2, 20.7±0.2, 21.3±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2, 23.3±0.2, 23.5±0.2, 24.0±0.2, 24.3±0.2, 26.5±0.2, 27.8±0.2, and 28.3±0.2° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.2, 7.4±0.2, 8.9±0.2, 11.6±0.2, 12.9±0.2, 16.1±0.2, 16.7±0.2, 17.9±0.2, 18.8±0.2, 19.1±0.2, 19.9±0.2, 20.7±0.2, 21.3±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2, 23.3±0.2, 23.5±0.2, 24.0±0.2, and 26.5±0.2 °2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8±0.2, 7.4±0.2, 16.1±0.2, 16.7±0.2, 17.9±0.2, 19.1±0.2, 19.9±0.2, 21.3±0.2, 22.3±0.2, and 22.8±0.2° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8±0.4, 7.4±0.4, 8.9±0.4, 11.1±0.4, 11.6±0.4, 12.6±0.4, 12.9±0.4, 14.0±0.4, 16.1±0.4, 16.7±0.4, 17.4±0.4, 17.9±0.4, 18.2±0.4, 0.4, 18.8±0.4, 19.1±0.4, 19.9±0.4, 20.7±0.4, 21.3±0.4, 21.7±0.4, 22.3±0.4, 22.8±0.4, 23.3±0.4, 23.5±0.4, 24.0±0.4, 24.3±0.4, 26.5±0.4, 27.8±0.4, and 28.3±0.4° 2θ.In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.4, 7.4±0.4, 8.9±0.4, 11.6±0.4, 12.9±0.4, 16.1±0.4, 16.7±0.4, 17.9±0.4, 18.8±0.4, 19.1±0.4, 19.9±0.4, 20.7±0.4, 21.3±0.4, 21.7±0.4, 22.3±0.4, 22.8±0.4, 23.3±0.4, 23.5±0.4, 24.0±0.4, and 26.5±0.4 °2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8±0.4, 7.4±0.4, 16.1±0.4, 16.7±0.4, 17.9±0.4, 19.1±0.4, 19.9±0.4, 21.3±0.4, 22.3±0.4, and 22.8±0.4° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8±0.6, 7.4±0.6, 8.9±0.6, 11.1±0.6, 11.6±0.6, 12.6±0.6, 12.9±0.6, 14.0±0.6, 16.1±0.6, 16.7±0.6, 17.4±0.6, 17.9±0.6, 18.2±0.6, 0.6, 18.8±0.6, 19.1±0.6, 19.9±0.6, 20.7±0.6, 21.3±0.6, 21.7±0.6, 22.3±0.6, 22.8±0.6, 23.3±0.6, 23.5±0.6, 24.0±0.6, 24.3±0.6, 26.5±0.6, 27.8±0.6, and 28.3±0.6° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.6, 7.4±0.6, 8.9±0.6, 11.6±0.6, 12.9±0.6, 16.1±0.6, 16.7±0.6, 17.9±0.6, 18.8±0.6, 19.1±0.6, 19.9±0.6, 20.7±0.6, 21.3±0.6, 21.7±0.6, 22.3±0.6, 22.8±0.6, 23.3±0.6, 23.5±0.6, 24.0±0.6, and 26.5±0.6 °2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.6, 7.4±0.6, 16.1±0.6, 16.7±0.6, 17.9±0.6, 19.1±0.6, 19.9±0.6, 21.3±0.6, 22.3±0.6, and 22.8±0.6° 2θ. It should be understood that except for. Figure 2DIn addition to those peaks shown in or provided in Table 9, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0319] In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 17.9 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at: 5.8 ± 0.2 and 17.9 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at: 5.8 ± 0.2, 7.4 ± 0.2, and 17.9 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at: 5.8 ± 0.2, 7.4 ± 0.2, and 17.9 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at: 5.8 ± 0.2, 7.4 ± 0.2, 16.1 ± 0.2, 16.7 ± 0.2, 17.9 ± 0.2, 19.1 ± 0.2, 19.9 ± 0.2, and 21.3 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8 ± 0.2, 7.4 ± 0.2, 12.9 ± 0.2, 16.1 ± 0.2, 16.7 ± 0.2, 17.9 ± 0.2, 19.1 ± 0.2, 19.9 ± 0.2, 21.3 ± 0.2, 21.7 ± 0.2, 22.3 ± 0.2, 22.8 ± 0.2, and 24.0 ± 0.2 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 17.9 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8 ± 0.4 and 17.9 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8 ± 0.4, 7.4 ± 0.4, and 17.9 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8 ± 0.4, 7.4 ± 0.4, 16.1 ± 0.4, 16.7 ± 0.4, 17.9 ± 0.4, 19.1 ± 0.4, 19.9 ± 0.4, and 21.3 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8 ± 0.4, 7.4 ± 0.4, 12.9 ± 0.4, 16.1 ± 0.4, 16.7 ± 0.4, 17.9 ± 0.4, 19.1 ± 0.4, 19.9 ± 0.4, 21.3 ± 0.4, 21.7 ± 0.4, 22.3 ± 0.4, 22.8 ± 0.4, and 24.0 ± 0.4 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 17.9 ± 0.6 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8 ± 0.6 and 17.9 ± 0.6 ° 2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.6, 7.4±0.6, and 17.9±0.6° 2θ.In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8±0.6, 7.4±0.6, 16.1±0.6, 16.7±0.6, 17.9±0.6, 19.1±0.6, 19.9±0.6, and 21.3±0.6°2θ. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at: 5.8±0.6, 7.4±0.6, 12.9±0.6, 16.1±0.6, 16.7±0.6, 17.9±0.6, 19.1±0.6, 19.9±0.6, 21.3±0.6, 21.7±0.6, 22.3±0.6, 22.8±0.6, and 24.0±0.6°2θ.

[0320] In some embodiments, the tartrate salt has substantially Figure 2E In some embodiments, the tartrate salt has substantially Figure 2F In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 218°C to about 230°C. In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 218±4°C (e.g., 218±3°C, 218±2°C, or 218±1°C). In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 220±4°C (e.g., 220±3°C, 220±2°C, or 220±1°C). In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 222±4°C (e.g., 222±3°C, 222±2°C, or 222±1°C). In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 224 ± 4 ° C (e.g., 224 ± 3 ° C, 224 ± 2 ° C, or 224 ± 1 ° C). In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 226 ± 4 ° C (e.g., 226 ± 3 ° C, 226 ± 2 ° C, or 226 ± 1 ° C). In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 228 ± 4 ° C (e.g., 226 ± 3 ° C, 226 ± 2 ° C, or 226 ± 1 ° C). In some embodiments, the tartrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 230 ± 4 ° C (e.g., 226 ± 3 ° C, 226 ± 2 ° C, or 226 ± 1 ° C).

[0321] In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 218°C to about 230°C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 218°C to about 228°C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 218°C to about 226°C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 218°C to about 224°C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 220°C to about 228°C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 220°C to about 226°C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 220°C to about 224°C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at about 222° C. to about 228° C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at about 222° C. to about 226° C. In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at about 222° C. to about 224° C.

[0322] In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset of about 215°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 215±4°C (e.g., 215±3°C, 215±2°C, or 215±1°C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 217±4°C (e.g., 217±3°C, 217±2°C, or 217±1°C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 219±4°C (e.g., 219±3°C, 219±2°C, or 219±1°C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 221±4°C (e.g., 221±3°C, 221±2°C, or 221±1°C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 223 ± 4 ° C (e.g., 223 ± 3 ° C, 223 ± 2 ° C, or 223 ± 1 ° C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 225 ± 4 ° C (e.g., 225 ± 3 ° C, 225 ± 2 ° C, or 225 ± 1 ° C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 227 ± 4 ° C (e.g., 227 ± 3 ° C, 227 ± 2 ° C, or 227 ± 1 ° C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 229 ± 4 ° C (e.g., 229 ± 3 ° C, 229 ± 2 ° C, or 229 ± 1 ° C). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset at 230±4°C (eg, 230±3°C, 230±2°C, or 230±1°C).

[0323] In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset of about 215°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset of about 215°C to about 228°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset of about 217°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset of about 217°C to about 228°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset of about 219°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exothermic onset of about 219°C to about 228°C.

[0324] In some embodiments of the tartrate salt, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply:

[0325] (a) tartrate is hemi-tartrate;

[0326] (b) the tartrate salt is in crystalline form;

[0327] (c) the tartrate salt has a solubility of greater than about 20 mg / mL, calculated as the free base of Compound I, in an aqueous solution having a pH of about 1.4 at a temperature of about 25° C.;

[0328] (d) the tartrate salt has a solubility of about 0.3 mg / mL in an aqueous solution at a pH of about 4.7 at a temperature of about 25° C., calculated as the free base of Compound I;

[0329] (e) the tartrate salt has a solubility of about 0.2 mg / mL in an aqueous solution at a pH of about 6.6 at a temperature of about 25° C., calculated as the free base of Compound I;

[0330] (f) The tartrate salt exhibits an XRPD pattern comprising:

[0331] (i) peak at 17.9 ± 0.2° 2θ;

[0332] (ii) peaks at 5.8 ± 0.2 and 17.9 ± 0.2° 2θ;

[0333] (iii) peaks at 5.8 ± 0.2, 7.4 ± 0.2, and 17.9 ± 0.2° 2θ;

[0334] (iv) peaks at 5.8±0.2, 7.4±0.2, 16.1±0.2, 16.7±0.2, 17.9±0.2, 19.1±0.2, 19.9±0.2, and 21.3±0.2° 2θ; or

[0335] (v) peaks at 5.8±0.2, 7.4±0.2, 12.9±0.2, 16.1±0.2, 16.7±0.2, 17.9±0.2, 19.1±0.2, 19.9±0.2, 21.3±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2, and 24.0±0.2 degrees 2θ; and

[0336] (g) The tartrate salt exhibits a differential scanning calorimetry trace comprising:

[0337] (i) a peak from about 218°C to about 230°C; or

[0338] (ii) a peak from about 218°C to about 230°C and an exotherm onset from about 215°C to about 230°C.

[0339] In some embodiments, (a) and (b) apply. In some embodiments, (a), (b) and (c) apply. In some embodiments, (a), (b), (c) and (d) apply. In some embodiments, (a), (b), (c), (d) and (e) apply. In some embodiments, (a), (b), (c), (d), (e) and (f) apply. In some embodiments, (a), (b), (c), (d), (e), (f) and (g) apply. In some embodiments, (f) and (g) apply. In some embodiments, (f)(i) and (g)(i) apply. In some embodiments, (f)(ii) and (g)(i) apply. In some embodiments, (f)(iii) and (g)(i) apply. In some embodiments, (f)(iv) and (g)(i) apply. In some embodiments, (f)(v) and (g)(i) apply. In some embodiments, (f)(i) and (g)(ii) apply. In some embodiments, (f)(ii) and (g)(ii) apply. In some embodiments, (f)(iii) and (g)(ii) apply. In some embodiments, (f)(iv) and (g)(ii) apply. In some embodiments, (f)(v) and (g)(ii) apply. In some embodiments, (c), (f) and (g) apply. In some embodiments, (c), (f)(i) and (g)(i) apply. In some embodiments, (c), (f)(ii) and (g)(i) apply. In some embodiments, (c), (f)(iii) and (g)(i) apply. In some embodiments, (c), (f)(iv) and (g)(i) apply. In some embodiments, (c), (f)(v) and (g)(i) apply. In some embodiments, (c), (f)(i) and (g)(ii) apply. In some embodiments, (c), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (f)(v) and (g)(ii) apply. In some embodiments, (d), (f) and (g) apply. In some embodiments, (d), (f)(i) and (g)(i) apply. In some embodiments, (d), (f)(ii) and (g)(i) apply. In some embodiments, (d), (f)(iii) and (g)(i) apply. In some embodiments, (d), (f)(iv) and (g)(i) apply. In some embodiments, (d), (f)(v) and (g)(i) apply. In some embodiments, (d), (f)(i) and (g)(ii) apply.In some embodiments, (d), (f)(ii) and (g)(ii) apply. In some embodiments, (d), (f)(iii) and (g)(ii) apply. In some embodiments, (d), (f)(iv) and (g)(ii) apply. In some embodiments, (d), (f)(v) and (g)(ii) apply. In some embodiments, (e), (f) and (g) apply. In some embodiments, (e), (f)(i) and (g)(i) apply. In some embodiments, (e), (f)(ii) and (g)(i) apply. In some embodiments, (e), (f)(iii) and (g)(i) apply. In some embodiments, (e), (f)(iv) and (g)(i) apply. In some embodiments, (e), (f)(v) and (g)(i) apply. In some embodiments, (e), (f)(i) and (g)(ii) apply. In some embodiments, (e), (f)(ii) and (g)(ii) apply. In some embodiments, (e), (f)(iii) and (g)(ii) apply. In some embodiments, (e), (f)(iv) and (g)(ii) apply. In some embodiments, (e), (f)(v) and (g)(ii) apply. In some embodiments, (c), (d), (f) and (g) apply. In some embodiments, (c), (d), (f)(i) and (g)(i) apply. In some embodiments, (c), (d), (f)(ii) and (g)(i) apply. In some embodiments, (c), (d), (f)(iii) and (g)(i) apply. In some embodiments, (c), (d), (f)(iv) and (g)(i) apply. In some embodiments, (c), (d), (f)(v) and (g)(i) apply. In some embodiments, (c), (d), (f)(i) and (g)(ii) apply. In some embodiments, (c), (d), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (d), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (d), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (d), (f)(v) and (g)(ii) apply. In some embodiments, (c), (e), (f) and (g) apply. In some embodiments, (c), (e), (f)(i) and (g)(i) apply. In some embodiments, (c), (e), (f)(ii) and (g)(i) apply. In some embodiments, (c), (e), (f)(iii) and (g)(i) apply. In some embodiments, (c), (e), (f)(iv) and (g)(i) apply.In some embodiments, (c), (e), (f)(v) and (g)(i) apply. In some embodiments, (c), (e), (f)(i) and (g)(ii) apply. In some embodiments, (c), (e), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (e), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (e), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (e), (f)(v) and (g)(ii) apply. In some embodiments, (d), (e), (f) and (g) apply. In some embodiments, (d), (e), (f)(i) and (g)(i) apply. In some embodiments, (d), (e), (f)(ii) and (g)(i) apply. In some embodiments, (d), (e), (f)(iii) and (g)(i) apply. In some embodiments, (d), (e), (f)(iv) and (g)(i) apply. In some embodiments, (d), (e), (f)(v) and (g)(i) apply. In some embodiments, (d), (e), (f)(i) and (g)(ii) apply. In some embodiments, (d), (e), (f)(ii) and (g)(ii) apply. In some embodiments, (d), (e), (f)(iii) and (g)(ii) apply. In some embodiments, (d), (e), (f)(iv) and (g)(ii) apply. In some embodiments, (d), (e), (f)(v) and (g)(ii) apply. In some embodiments, (c), (d), (e), (f) and (g) apply. In some embodiments, (c), (d), (e), (f) and (g) apply. In some embodiments, (c), (d), (e), (f)(i) and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(ii) and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(iii) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(iv) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(v) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(i) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(ii) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(iii) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(iv) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(v) and (g)(ii) are applicable.

[0340] Malate

[0341] In some embodiments, provided herein is a malate salt of Compound 1.

[0342] In some embodiments, the malate salt of Compound 1 is a hemimalate salt.

[0343] In some embodiments, the malate salt of Compound 1 is in crystalline form.

[0344] In some embodiments, the solubility of the malate salt in an aqueous solution having a pH of about 1.4 at a temperature of about 25° C. is about 20 mg / mL (e.g., about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, about 20 mg / mL, about 20.5 mg / mL, about 21 mg / mL, about 21.5 mg / mL, or about 22 mg / mL), calculated based on the amount of the free base of Compound I. In some embodiments, the solubility of the malate salt in an aqueous solution having a pH of about 4.8 at a temperature of about 25° C. is about 20 mg / mL (e.g., about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, about 20 mg / mL, about 20.5 mg / mL, about 21 mg / mL, about 21.5 mg / mL, or about 22 mg / mL), calculated based on the amount of the free base of Compound I. In some embodiments, the solubility of the malate salt in an aqueous solution having a pH of about 6.4 at a temperature of about 25° C. is about 0.3 mg / mL (e.g., about 0.2 mg / mL, about 0.225 mg / mL, 0.25 mg / mL, about 0.275 mg / mL, about 0.325 mg / mL, about 0.35 mg / mL, about 0.375 mg / mL, or about 0.4 mg / mL), calculated as the amount of the free base of Compound I.

[0345] In some embodiments, the XRPD pattern of the malate salt is substantially as follows Figure 3A Table 10 shows the angles (as measured in °2θ) and peak intensities of the malate salts observable using XRPD.

[0346] Table 10

[0347]

[0348] In some embodiments, the malate salt has a Figure 3A10 or as provided in Table 10 at least one or at least two peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including malate) may vary by about ± 0.6°, ± 0.4°, ± 0.2°, or ± 0.1° 2θ.

[0349] In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.3±0.2 and 23.4±0.2°2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.3±0.4 and 23.4±0.4°2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.3±0.6 and 23.4±0.6°2θ. It should be understood that except for Figure 3A In addition to those peaks shown in or provided in Table 10, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0350] In some embodiments, the XRPD pattern of the malate salt is substantially as follows Figure 3B Table 11 shows the angles (as measured in °2θ) and peak intensities of the malate salt observable using XRPD.

[0351] Table 11

[0352]

[0353] In some embodiments, the malate salt has a Figure 3B 100% 2θ , or as provided in Table 11 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including malate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 °, or ± 0.1 ° 2θ.

[0354] In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.2±0.2, 6.8±0.2, 8.0±0.2, 9.1±0.2, 10.3±0.2, 13.2±0.2, 15.5±0.2, 17.7±0.2, 18.2±0.2, 20.8±0.2, 21.3±0.2, 21.9±0.2, 21.9±0.2, 22.7±0.2, 23.3±0.2, 23.6±0.2, 25.2±0.2, and 38.1±0.2 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.2±0.2, 8.0±0.2, 13.2±0.2, 15.5±0.2, 17.7±0.2, 20.8±0.2, 21.3±0.2, 21.9±0.2, 22.7±0.2, 23.3±0.2, 23.6±0.2, and 25.2±0.2° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.2±0.2, 8.0±0.2, 17.7±0.2, 22.7±0.2, 23.3±0.2, and 23.6±0.2° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.2±0.4, 6.8±0.4, 8.0±0.4, 9.1±0.4, 10.3±0.4, 13.2±0.4, 15.5±0.4, 17.7±0.4, 18.2±0.4, 20.8±0.4, 21.3±0.4, 21.9±0.4, 21.9±0.4, 22.7±0.4, 23.3±0.4, 23.6±0.4, 25.2±0.4, and 38.1±0.4 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.2±0.4, 8.0±0.4, 13.2±0.4, 15.5±0.4, 17.7±0.4, 20.8±0.4, 21.3±0.4, 21.9±0.4, 22.7±0.4, 23.3±0.4, 23.6±0.4, and 25.2±0.4° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.2±0.4, 8.0±0.4, 17.7±0.4, 22.7±0.4, 23.3±0.4, and 23.6±0.4° 2θ.In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.2±0.6, 6.8±0.6, 8.0±0.6, 9.1±0.6, 10.3±0.6, 13.2±0.6, 15.5±0.6, 17.7±0.6, 18.2±0.6, 20.8±0.6, 21.3±0.6, 21.9±0.6, 21.9±0.6, 22.7±0.6, 23.3±0.6, 23.6±0.6, 25.2±0.6, and 38.1±0.6 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.2 ± 0.6, 8.0 ± 0.6, 13.2 ± 0.6, 15.5 ± 0.6, 17.7 ± 0.6, 20.8 ± 0.6, 21.3 ± 0.6, 21.9 ± 0.6, 22.7 ± 0.6, 23.3 ± 0.6, 23.6 ± 0.6, and 25.2 ± 0.6 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.2 ± 0.6, 8.0 ± 0.6, 17.7 ± 0.6, 22.7 ± 0.6, 23.3 ± 0.6, and 23.6 ± 0.6 ° 2θ. It should be understood that except. Figure 3B In addition to those peaks shown in or provided in Table 11, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0355] In some embodiments, the XRPD pattern of the malate salt is substantially as follows Figure 3C Table 12 shows the angles (as measured in °2θ) and peak intensities of the malate salt observable using XRPD.

[0356] Table 12

[0357]

[0358] In some embodiments, the malate salt has a Figure 3C 100% 2θ , or as provided in Table 12 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors, including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including malate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 °, or ± 0.1 ° 2θ.

[0359] In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.1±0.2, 6.0±0.2, 7.9±0.2, 9.7±0.2, 10.2±0.2, 14.6±0.2, 15.2±0.2, 16.3±0.2, 17.5±0.2, 18.2±0.2, 18.9±0.2, 19.5±0.2, 20.0±0.2, 20.3±0.2, 21.0±0.2, 22.4±0.2, 23.4±0.2, 23.9±0.2, 24.6±0.2, 24.9±0.2, 26.1±0.2, and 27.6±0.2 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.1 ± 0.2, 6.0 ± 0.2, 17.5 ± 0.2, 18.2 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, 20.0 ± 0.2, 20.3 ± 0.2, 21.0 ± 0.2, 22.4 ± 0.2, 23.4 ± 0.2, 23.9 ± 0.2, 24.9 ± 0.2, and 26.1 ± 0.2 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.1 ± 0.2, 18.2 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, 20.3 ± 0.2, 21.0 ± 0.2, and 23.9 ± 0.2 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.1±0.4, 6.0±0.4, 7.9±0.4, 9.7±0.4, 10.2±0.4, 14.6±0.4, 15.2±0.4, 16.3±0.4, 17.5±0.4, 18.2±0.4, 18.9±0.4, 19.5±0.4, 20.0±0.4, 20.3±0.4, 21.0±0.4, 22.4±0.4, 23.4±0.4, 23.9±0.4, 24.6±0.4, 24.9±0.4, 26.1±0.4, and 27.6±0.4 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.1 ± 0.4, 6.0 ± 0.4, 17.5 ± 0.4, 18.2 ± 0.4, 18.9 ± 0.4, 19.5 ± 0.4, 20.0 ± 0.4, 20.3 ± 0.4, 21.0 ± 0.4, 22.4 ± 0.4, 23.4 ± 0.4, 23.9 ± 0.4, 24.9 ± 0.4, and 26.1 ± 0.4 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.1 ± 0.4, 18.2 ± 0.4, 18.9 ± 0.4, 19.5 ± 0.4, 20.3 ± 0.4, 21.0 ± 0.4, and 23.9 ± 0.4 ° 2θ.In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.1±0.6, 6.0±0.6, 7.9±0.6, 9.7±0.6, 10.2±0.6, 14.6±0.6, 15.2±0.6, 16.3±0.6, 17.5±0.6, 18.2±0.6, 18.9±0.6, 19.5±0.6, 20.0±0.6, 20.3±0.6, 21.0±0.6, 22.4±0.6, 23.4±0.6, 23.9±0.6, 24.6±0.6, 24.9±0.6, 26.1±0.6, and 27.6±0.6 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.1 ± 0.6, 6.0 ± 0.6, 17.5 ± 0.6, 18.2 ± 0.6, 18.9 ± 0.6, 19.5 ± 0.6, 20.0 ± 0.6, 20.3 ± 0.6, 21.0 ± 0.6, 22.4 ± 0.6, 23.4 ± 0.6, 23.9 ± 0.6, 24.9 ± 0.6, and 26.1 ± 0.6 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 5.1 ± 0.6, 18.2 ± 0.6, 18.9 ± 0.6, 19.5 ± 0.6, 20.3 ± 0.6, 21.0 ± 0.6, and 23.9 ± 0.6 ° 2θ. It should be understood that except. Figure 3C In addition to those peaks shown in or provided in Table 12, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0360] In some embodiments, the XRPD pattern of the malate salt is substantially as follows Figure 3D Table 13 shows the angles (as measured in °2θ) and peak intensities of the malate salt observable using XRPD.

[0361] Table 13

[0362]

[0363] In some embodiments, the malate salt has a Figure 3DIn some embodiments, the peak assignments listed herein (including malate) may vary by about ± 0.6°, ± 0.4°, ± 0.2°, or ± 0.1° 2θ.

[0364] In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.2, 8.4±0.2, 9.7±0.2, 11.7±0.2, 12.4±0.2, 12.8±0.2, 14.1±0.2, 14.5±0.2, 15.7±0.2, 15.9±0.2, 16.2±0.2, 16.5±0.2, 17.0±0.2, 0.2, 17.7 ± 0.2, 18.2 ± 0.2, 18.4 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.4 ± 0.2, 22.6 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, 24.9 ± 0.2, 26.0 ± 0.2, and 30.3 ± 0.2° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.2, 8.4±0.2, 9.7±0.2, 14.5±0.2, 16.2±0.2, 16.5±0.2, 17.7±0.2, 18.2±0.2, 18.4±0.2, 18.9±0.2, 19.5±0.2, 20.2±0.2, 21.0±0.2, 21.9±0.2, 22.4±0.2, 22.6±0.2, 23.8±0.2, 24.9±0.2, and 26.0±0.2 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.2, 8.4±0.2, 9.7±0.2, 16.2±0.2, 18.2±0.2, 18.9±0.2, 19.5±0.2, 20.2±0.2, 22.4±0.2, and 22.6±0.2° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.4, 8.4±0.4, 9.7±0.4, 11.7±0.4, 12.4±0.4, 12.8±0.4, 14.1±0.4, 14.5±0.4, 15.7±0.4, 15.9±0.4, 16.2±0.4, 16.5±0.4, 17.0±0. 0.4, 17.7 ± 0.4, 18.2 ± 0.4, 18.4 ± 0.4, 18.9 ± 0.4, 19.5 ± 0.4, 20.2 ± 0.4, 21.0 ± 0.4, 21.9 ± 0.4, 22.4 ± 0.4, 22.6 ± 0.4, 23.8 ± 0.4, 24.5 ± 0.4, 24.9 ± 0.4, 26.0 ± 0.4, and 30.3 ± 0.4 ° 2θ.In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.4, 8.4±0.4, 9.7±0.4, 14.5±0.4, 16.2±0.4, 16.5±0.4, 17.7±0.4, 18.2±0.4, 18.4±0.4, 18.9±0.4, 19.5±0.4, 20.2±0.4, 21.0±0.4, 21.9±0.4, 22.4±0.4, 22.6±0.4, 23.8±0.4, 24.9±0.4, and 26.0±0.4 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.4, 8.4±0.4, 9.7±0.4, 16.2±0.4, 18.2±0.4, 18.9±0.4, 19.5±0.4, 20.2±0.4, 22.4±0.4, and 22.6±0.4 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.6, 8.4±0.6, 9.7±0.6, 11.7±0.6, 12.4±0.6, 12.8±0.6, 14.1±0.6, 14.5±0.6, 15.7±0.6, 15.9±0.6, 16.2±0.6, 16.5±0.6, 17.0±0.6 0.6, 17.7 ± 0.6, 18.2 ± 0.6, 18.4 ± 0.6, 18.9 ± 0.6, 19.5 ± 0.6, 20.2 ± 0.6, 21.0 ± 0.6, 21.9 ± 0.6, 22.4 ± 0.6, 22.6 ± 0.6, 23.8 ± 0.6, 24.5 ± 0.6, 24.9 ± 0.6, 26.0 ± 0.6, and 30.3 ± 0.6° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.6, 8.4±0.6, 9.7±0.6, 14.5±0.6, 16.2±0.6, 16.5±0.6, 17.7±0.6, 18.2±0.6, 18.4±0.6, 18.9±0.6, 19.5±0.6, 20.2±0.6, 21.0±0.6, 21.9±0.6, 22.4±0.6, 22.6±0.6, 23.8±0.6, 24.9±0.6, and 26.0±0.6 °2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.6, 8.4±0.6, 9.7±0.6, 16.2±0.6, 18.2±0.6, 18.9±0.6, 19.5±0.6, 20.2±0.6, 22.4±0.6, and 22.6±0.6° 2θ. It should be understood that except for. Figure 3DIn addition to those peaks shown in or provided in Table 13, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0365] In some embodiments, the malate salt has an XRPD pattern comprising a peak at 6.0 ± 0.2 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising a peak at: 6.0 ± 0.2 and 20.2 ± 0.2 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising a peak at: 6.0 ± 0.2, 19.5 ± 0.2, and 20.2 ± 0.2 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising a peak at: 6.0 ± 0.2, 9.7 ± 0.2, 16.2 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 22.4 ± 0.2, and 22.6 ± 0.2 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0 ± 0.2, 8.4 ± 0.2, 9.7 ± 0.2, 14.5 ± 0.2, 16.2 ± 0.2, 16.5 ± 0.2, 18.2 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, 20.2 ± 0.2, 21.9 ± 0.222.4 ± 0.2, and 22.6 ± 0.2 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0 ± 0.4 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0 ± 0.4 and 20.2 ± 0.4 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0 ± 0.4, 19.5 ± 0.4, and 20.2 ± 0.4 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.4, 9.7±0.4, 16.2±0.4, 18.9±0.4, 19.5±0.4, 20.2±0.4, 22.4±0.4, and 22.6±0.4° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.4, 8.4±0.4, 9.7±0.4, 14.5±0.4, 16.2±0.4, 16.5±0.4, 18.2±0.4, 18.9±0.4, 19.5±0.4, 20.2±0.4, 21.9±0.4 22.4±0.4, and 22.6±0.4° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising a peak at 6.0 ± 0.6 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0 ± 0.6 and 20.2 ± 0.6 ° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0 ± 0.6, 19.5 ± 0.6, and 20.2 ± 0.6 ° 2θ.In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.6, 9.7±0.6, 16.2±0.6, 18.9±0.6, 19.5±0.6, 20.2±0.6, 22.4±0.6, and 22.6±0.6° 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at: 6.0±0.6, 8.4±0.6, 9.7±0.6, 14.5±0.6, 16.2±0.6, 16.5±0.6, 18.2±0.6, 18.9±0.6, 19.5±0.6, 20.2±0.6, 21.9±0.6 22.4±0.6, and 22.6±0.6° 2θ.

[0366] In some embodiments, the malate salt has substantially Figure 3E In some embodiments, the malate salt has substantially Figure 3F In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at about 146°C to about 160°C. In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 146±4°C (e.g., 146±3°C, 146±2°C, or 146±1°C). In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 148±4°C (e.g., 148±3°C, 148±2°C, or 148±1°C). In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 150±4°C (e.g., 150±3°C, 150±2°C, or 150±1°C). In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 152±4°C (e.g., 152±3°C, 152±2°C, or 152±1°C). In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 154±4°C (e.g., 154±3°C, 154±2°C, or 154±1°C). In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 156±4°C (e.g., 156±3°C, 156±2°C, or 156±1°C). In some embodiments, the malate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 158±4°C (e.g., 158±3°C, 158±2°C, or 158±1°C). In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 160±4°C (eg, 160±3°C, 160±2°C, or 160±1°C).

[0367] In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 146°C to about 160°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 146°C to about 158°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 146°C to about 156°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 146°C to about 154°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 148°C to about 158°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 148°C to about 156°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 148°C to about 154°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at about 150° C. to about 158° C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at about 150° C. to about 156° C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at about 150° C. to about 154° C.

[0368] In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 147°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 134±4°C (e.g., 134±3°C, 134±2°C, or 134±1°C). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 136±4°C (e.g., 136±3°C, 136±2°C, or 136±1°C). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 138±4°C (e.g., 138±3°C, 138±2°C, or 138±1°C). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 140±4°C (e.g., 140±3°C, 140±2°C, or 140±1°C). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 142 ± 4 ° C (e.g., 142 ± 3 ° C, 142 ± 2 ° C, or 142 ± 1 ° C). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 144 ± 4 ° C (e.g., 144 ± 3 ° C, 144 ± 2 ° C, or 144 ± 1 ° C). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 146 ± 4 ° C (e.g., 146 ± 3 ° C, 146 ± 2 ° C, or 146 ± 1 ° C). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at 147 ± 4 ° C (e.g., 147 ± 3 ° C, 147 ± 2 ° C, or 147 ± 1 ° C).

[0369] In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 147°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 136°C to about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 136°C to about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 138°C to about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 140°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 136°C to about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 138°C to about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 140°C to about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 138°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 136°C to about 140°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 138°C to about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 140°C to about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 142°C to about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 134°C to about 136°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 136°C to about 138°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 138°C to about 140°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 140°C to about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 142°C to about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset at about 144°C to about 146°C.

[0370] In some embodiments of the malate salt, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply:

[0371] (a) Malate is hemimalate;

[0372] (b) the malate salt is in crystalline form;

[0373] (c) the malate salt has a solubility of greater than about 20 mg / mL, calculated as the free base of Compound I, in an aqueous solution having a pH of about 1.4 at a temperature of about 25° C.;

[0374] (d) the malate salt has a solubility of greater than about 20 mg / mL, calculated as the free base of Compound I, in an aqueous solution having a pH of about 4.8 at a temperature of about 25° C.;

[0375] (e) the malate salt has a solubility of about 0.3 mg / mL, calculated as the amount of the free base of Compound I, in an aqueous solution having a pH of about 6.4 at a temperature of about 25° C.;

[0376] (f) The malate salt exhibits an XRPD pattern comprising:

[0377] (i) peak at 6.0 ± 0.2° 2θ;

[0378] (ii) peaks at 6.0 ± 0.2 and 20.2 ± 0.2° 2θ;

[0379] (iii) peaks at 6.0 ± 0.2, 19.5 ± 0.2, and 20.2 ± 0.2° 2θ;

[0380] (iv) peaks at 6.0±0.2, 9.7±0.2, 16.2±0.2, 18.9±0.2, 19.5±0.2, 20.2±0.2, 22.4±0.2, and 22.6±0.2 degrees 2θ; or

[0381] (v) peaks at 6.0±0.2, 8.4±0.2, 9.7±0.2, 14.5±0.2, 16.2±0.2, 16.5±0.2, 18.2±0.2, 18.9±0.2, 19.5±0.2, 20.2±0.2, 21.9±0.2 22.4±0.2, and 22.6±0.2 degrees 2θ; and

[0382] (g) The malate salt exhibits a differential scanning calorimetry trace comprising:

[0383] (i) a peak from about 146°C to about 160°C; or

[0384] (ii) a peak from about 146°C to about 160°C and an endothermic onset from about 134°C to about 147°C.

[0385] In some embodiments, (a) and (b) apply. In some embodiments, (a), (b) and (c) apply. In some embodiments, (a), (b), (c) and (d) apply. In some embodiments, (a), (b), (c), (d) and (e) apply. In some embodiments, (a), (b), (c), (d), (e) and (f) apply. In some embodiments, (a), (b), (c), (d), (e), (f) and (g) apply. In some embodiments, (f) and (g) apply. In some embodiments, (f)(i) and (g)(i) apply. In some embodiments, (f)(ii) and (g)(i) apply. In some embodiments, (f)(iii) and (g)(i) apply. In some embodiments, (f)(iv) and (g)(i) apply. In some embodiments, (f)(v) and (g)(i) apply. In some embodiments, (f)(i) and (g)(ii) apply. In some embodiments, (f)(ii) and (g)(ii) apply. In some embodiments, (f)(iii) and (g)(ii) apply. In some embodiments, (f)(iv) and (g)(ii) apply. In some embodiments, (f)(v) and (g)(ii) apply. In some embodiments, (c), (f) and (g) apply. In some embodiments, (c), (f)(i) and (g)(i) apply. In some embodiments, (c), (f)(ii) and (g)(i) apply. In some embodiments, (c), (f)(iii) and (g)(i) apply. In some embodiments, (c), (f)(iv) and (g)(i) apply. In some embodiments, (c), (f)(v) and (g)(i) apply. In some embodiments, (c), (f)(i) and (g)(ii) apply. In some embodiments, (c), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (f)(v) and (g)(ii) apply. In some embodiments, (d), (f) and (g) apply. In some embodiments, (d), (f)(i) and (g)(i) apply. In some embodiments, (d), (f)(ii) and (g)(i) apply. In some embodiments, (d), (f)(iii) and (g)(i) apply. In some embodiments, (d), (f)(iv) and (g)(i) apply. In some embodiments, (d), (f)(v) and (g)(i) apply. In some embodiments, (d), (f)(i) and (g)(ii) apply.In some embodiments, (d), (f)(ii) and (g)(ii) apply. In some embodiments, (d), (f)(iii) and (g)(ii) apply. In some embodiments, (d), (f)(iv) and (g)(ii) apply. In some embodiments, (d), (f)(v) and (g)(ii) apply. In some embodiments, (e), (f) and (g) apply. In some embodiments, (e), (f)(i) and (g)(i) apply. In some embodiments, (e), (f)(ii) and (g)(i) apply. In some embodiments, (e), (f)(iii) and (g)(i) apply. In some embodiments, (e), (f)(iv) and (g)(i) apply. In some embodiments, (e), (f)(v) and (g)(i) apply. In some embodiments, (e), (f)(i) and (g)(ii) apply. In some embodiments, (e), (f)(ii) and (g)(ii) apply. In some embodiments, (e), (f)(iii) and (g)(ii) apply. In some embodiments, (e), (f)(iv) and (g)(ii) apply. In some embodiments, (e), (f)(v) and (g)(ii) apply. In some embodiments, (c), (d), (f) and (g) apply. In some embodiments, (c), (d), (f)(i) and (g)(i) apply. In some embodiments, (c), (d), (f)(ii) and (g)(i) apply. In some embodiments, (c), (d), (f)(iii) and (g)(i) apply. In some embodiments, (c), (d), (f)(iv) and (g)(i) apply. In some embodiments, (c), (d), (f)(v) and (g)(i) apply. In some embodiments, (c), (d), (f)(i) and (g)(ii) apply. In some embodiments, (c), (d), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (d), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (d), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (d), (f)(v) and (g)(ii) apply. In some embodiments, (c), (e), (f) and (g) apply. In some embodiments, (c), (e), (f)(i) and (g)(i) apply. In some embodiments, (c), (e), (f)(ii) and (g)(i) apply. In some embodiments, (c), (e), (f)(iii) and (g)(i) apply. In some embodiments, (c), (e), (f)(iv) and (g)(i) apply.In some embodiments, (c), (e), (f)(v) and (g)(i) apply. In some embodiments, (c), (e), (f)(i) and (g)(ii) apply. In some embodiments, (c), (e), (f)(ii) and (g)(ii) apply. In some embodiments, (c), (e), (f)(iii) and (g)(ii) apply. In some embodiments, (c), (e), (f)(iv) and (g)(ii) apply. In some embodiments, (c), (e), (f)(v) and (g)(ii) apply. In some embodiments, (d), (e), (f) and (g) apply. In some embodiments, (d), (e), (f)(i) and (g)(i) apply. In some embodiments, (d), (e), (f)(ii) and (g)(i) apply. In some embodiments, (d), (e), (f)(iii) and (g)(i) apply. In some embodiments, (d), (e), (f)(iv) and (g)(i) apply. In some embodiments, (d), (e), (f)(v) and (g)(i) apply. In some embodiments, (d), (e), (f)(i) and (g)(ii) apply. In some embodiments, (d), (e), (f)(ii) and (g)(ii) apply. In some embodiments, (d), (e), (f)(iii) and (g)(ii) apply. In some embodiments, (d), (e), (f)(iv) and (g)(ii) apply. In some embodiments, (d), (e), (f)(v) and (g)(ii) apply. In some embodiments, (c), (d), (e), (f) and (g) apply. In some embodiments, (c), (d), (e), (f) and (g) apply. In some embodiments, (c), (d), (e), (f)(i) and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(ii) and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(iii) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(iv) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(v) and (g)(i) are applicable. In some embodiments, (c), (d), (e), (f)(i) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(ii) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(iii) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(iv) and (g)(ii) are applicable. In some embodiments, (c), (d), (e), (f)(v) and (g)(ii) are applicable.

[0386] Citrate

[0387] In some embodiments, provided herein is a citrate salt of Compound 1.

[0388] In some embodiments, the citrate salt of Compound 1 is a hemi-citrate salt.

[0389] In some embodiments, the citrate salt of Compound 1 is in crystalline form.

[0390] In some embodiments, the XRPD pattern of the citrate salt is substantially as follows Figure 4A Table 14 shows the angles (as measured in °2θ) and peak intensities for citrate salts observable using XRPD.

[0391] Table 14

[0392]

[0393] In some embodiments, the citrate salt has a Figure 4A In the XRPD pattern shown in or as provided in Table 14 at least one, at least two, at least three, at least four, at least five or at least six peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including citrate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0394] In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.2, 11.4 ± 0.2, 18.9 ± 0.2, 22.7 ± 0.2, 26.4 ± 0.2, and 28.1 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.2, 11.4 ± 0.2, 18.9 ± 0.2, and 22.7 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.2 and 18.9 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.4, 11.4 ± 0.4, 18.9 ± 0.4, 22.7 ± 0.4, 26.4 ± 0.4, and 28.1 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.4, 11.4 ± 0.4, 18.9 ± 0.4, and 22.7 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.4 and 18.9 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.6, 11.4 ± 0.6, 18.9 ± 0.6, 22.7 ± 0.6, 26.4 ± 0.6, and 28.1 ± 0.6 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6 ± 0.6, 11.4 ± 0.6, 18.9 ± 0.6, and 22.7 ± 0.6 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.6±0.6 and 18.9±0.6° 2θ. It is understood that except for Figure 4A In addition to those peaks shown in or provided in Table 14, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0395] In some embodiments, the XRPD pattern of the citrate salt is substantially as follows Figure 4B Table 15 shows the angles (as measured in °2θ) and peak intensities for citrate salts observable using XRPD.

[0396] Table 15

[0397]

[0398] In some embodiments, the citrate salt has a Figure 4BIn the XRPD pattern shown in or as provided in Table 15 at least one, at least two, at least three, at least four, at least five, at least six, at least seven or at least eight peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including citrate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0399] In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.2, 7.4 ± 0.2, 9.4 ± 0.2, 11.2 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.4 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.2, 7.4 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.4 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.2, 7.4 ± 0.2, and 18.6 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.4, 7.4 ± 0.4, 9.4 ± 0.4, 11.2 ± 0.4, 18.6 ± 0.4, 18.9 ± 0.4, 20.5 ± 0.4, and 22.4 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.4, 7.4 ± 0.4, 18.6 ± 0.4, 18.9 ± 0.4, 20.5 ± 0.4, and 22.4 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.4, 7.4 ± 0.4, and 18.6 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.6, 7.4 ± 0.6, 9.4 ± 0.6, 11.2 ± 0.6, 18.6 ± 0.6, 18.9 ± 0.6, 20.5 ± 0.6, and 22.4 ± 0.6 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.6, 7.4 ± 0.6, 18.6 ± 0.6, 18.9 ± 0.6, 20.5 ± 0.6, and 22.4 ± 0.6 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 2.4 ± 0.6, 7.4 ± 0.6, and 18.6 ± 0.6 ° 2θ. It should be understood that except for Figure 4BIn addition to those peaks shown in or provided in Table 15, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0400] In some embodiments, the XRPD pattern of the citrate salt is substantially as follows Figure 4C Table 16 shows the angles (as measured in °2θ) and peak intensities for citrate salts observable using XRPD.

[0401] Table 16

[0402]

[0403] In some embodiments, the citrate salt has a Figure 4C In the XRPD pattern shown in or as provided in Table 16 at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten peaks at ° 2θ with maximum intensity. It should be understood that the peak intensity may vary according to many factors (including sample preparation, installation, and the instrument and analysis procedures and settings used to obtain the spectrum). Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including citrate) may vary by about ± 0.6 °, ± 0.4 °, ± 0.2 ° or ± 0.1 ° 2θ.

[0404] In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7±0.2, 7.3±0.2, 7.4±0.2, 10.9±0.2, 11.2±0.2, 18.2±0.2, 18.6±0.2, 21.8±0.2, 22.4±0.2, 25.5±0.2, 26.1±0.2, and 33.0±0.2° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7±0.2, 7.3±0.2, 7.4±0.2, 11.2±0.2, 18.2±0.2, 18.6±0.2, 21.8±0.2, and 22.4±0.2° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.3±0.2, 7.4±0.2, 18.2±0.2, and 18.6±0.2° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7±0.4, 7.3±0.4, 7.4±0.4, 10.9±0.4, 11.2±0.4, 18.2±0.4, 18.6±0.4, 21.8±0.4, 22.4±0.4, 25.5±0.4, 26.1±0.4, and 33.0±0.4° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7±0.4, 7.3±0.4, 7.4±0.4, 11.2±0.4, 18.2±0.4, 18.6±0.4, 21.8±0.4, and 22.4±0.4° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.3±0.4, 7.4±0.4, 18.2±0.4, and 18.6±0.4° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7±0.6, 7.3±0.6, 7.4±0.6, 10.9±0.6, 11.2±0.6, 18.2±0.6, 18.6±0.6, 21.8±0.6, 22.4±0.6, 25.5±0.6, 26.1±0.6, and 33.0±0.6° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7±0.6, 7.3±0.6, 7.4±0.6, 11.2±0.6, 18.2±0.6, 18.6±0.6, 21.8±0.6, and 22.4±0.6° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.3±0.6, 7.4±0.6, 18.2±0.6, and 18.6±0.6° 2θ. It is understood that except for Figure 4CIn addition to those peaks shown in or provided in Table 16, additional peaks may be observed in the XRPD pattern due to, for example, the presence of impurities, solvents or other polymorphs or the presence of an amorphous form in the test sample.

[0405] In some embodiments, the citrate salt has an XRPD pattern comprising a peak at 7.3 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising a peak at: 7.3 ± 0.2 and 7.4 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising a peak at: 7.3 ± 0.2, 7.4 ± 0.2, and 18.6 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising a peak at: 3.7 ± 0.2, 7.3 ± 0.2, 7.4 ± 0.2, 11.2 ± 0.2, 18.2 ± 0.2, 18.6 ± 0.2, 21.8 ± 0.2, and 22.4 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7 ± 0.2, 7.3 ± 0.2, 7.4 ± 0.2, 10.9 ± 0.2, 11.2 ± 0.2, 18.2 ± 0.2, 18.6 ± 0.2, 21.8 ± 0.2, 22.4 ± 0.2, 25.5 ± 0.2, 26.1 ± 0.2, and 33.0 ± 0.2 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising a peak at 7.3 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.3 ± 0.4 and 7.4 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.3 ± 0.4, 7.4 ± 0.4, and 18.6 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7 ± 0.4, 7.3 ± 0.4, 7.4 ± 0.4, 11.2 ± 0.4, 18.2 ± 0.4, 18.6 ± 0.4, 21.8 ± 0.4, and 22.4 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7 ± 0.4, 7.3 ± 0.4, 7.4 ± 0.4, 10.9 ± 0.4, 11.2 ± 0.4, 18.2 ± 0.4, 18.6 ± 0.4, 21.8 ± 0.4, 22.4 ± 0.4, 25.5 ± 0.4, 26.1 ± 0.4, and 33.0 ± 0.4 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising a peak at 7.3 ± 0.6 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.3±0.6 and 7.4±0.6° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 7.3±0.6, 7.4±0.6, and 18.6±0.6° 2θ.In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7 ± 0.6, 7.3 ± 0.6, 7.4 ± 0.6, 11.2 ± 0.6, 18.2 ± 0.6, 18.6 ± 0.6, 21.8 ± 0.6, and 22.4 ± 0.6 ° 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at: 3.7 ± 0.6, 7.3 ± 0.6, 7.4 ± 0.6, 10.9 ± 0.6, 11.2 ± 0.6, 18.2 ± 0.6, 18.6 ± 0.6, 21.8 ± 0.6, 22.4 ± 0.6, 25.5 ± 0.6, 26.1 ± 0.6, and 33.0 ± 0.6 ° 2θ.

[0406] In some embodiments, the citrate salt has substantially Figure 4D In some embodiments, the citrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak of about 175°C to about 179°C. In some embodiments, the citrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 175±4°C (e.g., 175±3°C, 175±2°C, or 175±1°C). In some embodiments, the citrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 177±4°C (e.g., 177±3°C, 177±2°C, or 177±1°C). In some embodiments, the citrate is characterized by exhibiting a differential scanning calorimetry trace comprising a peak at 179±4°C (e.g., 179±3°C, 179±2°C, or 179±1°C).

[0407] In some embodiments, the citrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 175°C to about 179°C. In some embodiments, the citrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 175°C to about 178°C. In some embodiments, the citrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 176°C to about 179°C. In some embodiments, the citrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 175°C to about 177°C. In some embodiments, the citrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 176°C to about 178°C. In some embodiments, the citrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 177°C to about 179°C.

[0408] In some embodiments, citrate salts exhibit a differential scanning calorimetry trace comprising an endothermic onset of about 124°C to about 128°C. In some embodiments, citrate salts exhibit a differential scanning calorimetry trace comprising an endothermic onset at 124±4°C (e.g., 124±3°C, 124±2°C, or 124±1°C). In some embodiments, citrate salts exhibit a differential scanning calorimetry trace comprising an endothermic onset at 126±4°C (e.g., 126±3°C, 126±2°C, or 126±1°C). In some embodiments, citrate salts exhibit a differential scanning calorimetry trace comprising an endothermic onset at 128±4°C (e.g., 128±3°C, 128±2°C, or 128±1°C).

[0409] In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 124°C to about 128°C. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 124°C to about 127°C. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 125°C to about 128°C. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 124°C to about 126°C. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 125°C to about 127°C. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset of about 126°C to about 128°C.

[0410] In some embodiments of the citrate salt, at least one, at least two, at least three, or all of the following (a)-(d) apply:

[0411] (a) Citrate is hemi-citrate;

[0412] (b) the citrate salt is in crystalline form;

[0413] (c) The citrate salt exhibits an XRPD pattern comprising:

[0414] (i) peak at 7.3 ± 0.2° 2θ;

[0415] (ii) peaks at 7.3 ± 0.2 and 7.4 ± 0.2° 2θ;

[0416] (iii) peaks at 7.3 ± 0.2, 7.4 ± 0.2, and 18.6 ± 0.2° 2θ;

[0417] (iv) peaks at 3.7±0.2, 7.3±0.2, 7.4±0.2, 11.2±0.2, 18.2±0.2, 18.6±0.2, 21.8±0.2, and 22.4±0.2 degrees 2θ; or

[0418] (v) peaks at 3.7±0.2, 7.3±0.2, 7.4±0.2, 10.9±0.2, 11.2±0.2, 18.2±0.2, 18.6±0.2, 21.8±0.2, 22.4±0.2, 25.5±0.2, 26.1±0.2, and 33.0±0.2 degrees 2θ; and

[0419] (d) The citrate salt exhibits a differential scanning calorimetry trace comprising:

[0420] (i) a peak from about 175°C to about 179°C; or

[0421] (ii) a peak at about 175°C to about 179°C and an endothermic onset at about 124°C to about 128°C.

[0422] In some embodiments, (a) and (b) apply. In some embodiments, (a), (b) and (c) apply. In some embodiments, (a), (b), (c) and (d) apply. In some embodiments, (c) and (d) apply. In some embodiments, (c)(i) and (d)(i) apply. In some embodiments, (c)(ii) and (d)(i) apply. In some embodiments, (c)(iii) and (d)(i) apply. In some embodiments, (c)(iv) and (d)(i) apply. In some embodiments, (c)(v) and (d)(i) apply. In some embodiments, (c)(i) and (d)(ii) apply. In some embodiments, (c)(ii) and (d)(ii) apply. In some embodiments, (c)(iii) and (d)(ii) apply. In some embodiments, (c)(iv) and (d)(ii) apply. In some embodiments, (c)(v) and (d)(ii) apply.

[0423] HER2

[0424] HER2 (human epidermal growth factor receptor 2), also known as Neu, ErbB2, CD340 (cluster of differentiation 340), and p185, is an epidermal growth factor receptor found on cells. The HER2 gene is found on human chromosome 17. The HER2 protein consists of four plasma membrane-bound receptor tyrosine kinases. The signaling pathways activated by the HER2 protein include: mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K / Akt), phospholipase Cγ, protein kinase C (PKC), and signal transducer and activator of transcription (STAT).

[0425] As used herein, the term "HER2", also known as ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) or Erbb2, or neu, p185 or CD340 (cluster of differentiation 340), is a human epidermal growth factor receptor 2 tyrosine kinase protein encoded by the HER2 gene (also known as erbb2, or neu or HER2 / neu) on chromosome 17. The term "HER2" used herein refers to i) a nucleic acid sequence encoding a HER2 protein, or ii) a protein thereof.

[0426] As used herein, the term "HER2 amplified" or "HER2-amplified" cancer or cell refers to a cancer or cell characterized by HER2 gene amplification, which can be easily assessed by methods known to those skilled in the art, for example, commercially available or in situ hybridization (ISH) tests that can be performed by methods known to those skilled in the art. It is a term commonly used and understood in the art. For the purposes of this application, HER2-amplified cancers or cells encompass the following: a) cancers or cells exhibit at least 3, 4, 5 or 6 copies (e.g., 6 copies) of genes encoding HER2 protein per interphase nucleus, as detected by a single probe in situ hybridization (ISH) test performed on a sample from cancer (e.g., according to ASCO / CAP guidelines, such as 2007, 2013 or 2018 guidelines); b) cancers or cells exhibit a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8, 2.0 or 2.2, such as by performing a single probe in situ hybridization (ISH) test on a sample from cancer. c) the cancer or cells exhibit (i) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8, 2.0, or 2.2, and (ii) at least 3, 4, 5, or 6 copies of the gene encoding HER2 protein per interphase nucleus in the sample as detected by a dual-probe ISH test performed on a sample from the cancer (e.g., according to ASCO / CAP guidelines, such as 2007, 2013, or 2018 guidelines). In some cases, HER2-amplified cancers are defined according to criteria described in the 2007, 2013, or 2018 ASCO / CAP guidelines or other widely accepted cancer (e.g., specific cancer) criteria.

[0427] HER2 amplification has been confirmed in many types of cancer, including but not limited to breast cancer, colon cancer, endometrial cancer, cervical cancer, urothelial cancer, lung cancer (including non-small cell lung cancer), ovarian cancer, gastric cancer, gastroesophageal junction (GEJ) cancer, head and neck cancer, biliary tract cancer, prostate cancer and pancreatic adenocarcinoma. HER2 amplification is present in about 18%-25% of breast cancers. HER2 amplification is also present in about 30% of GEJ cancers and about 20% of gastric cancers.

[0428] HER2-amplified tumors are characterized by an aggressive phenotype (eg, increased cell proliferation, increased cell survival, increased cell motility, and increased cell adhesion), increased metastasis, increased recurrence, shorter disease-free survival, and poor overall survival.

[0429] In some embodiments, HER2 gene amplification can be detected and / or assessed by in situ hybridization (ISH) techniques (e.g., chromogenic in situ hybridization (CISH), silver enhanced in situ hybridization (SISH), or fluorescent in situ hybridization (FISH)) or similar methods thereof from cancer samples. In some embodiments, the ISH technique used is single-probe ISH, which identifies the number of HER2 gene copies on chromosome 17. In some embodiments, the ISH technique used is double-probe ISH, in which the number of HER2 gene copies per cell nucleus is quantified relative to the number of centromere 17 (CEP17) gene copies. In some embodiments, the protein expression of HER2 is detected by immunohistochemistry (IHC) or similar methods thereof. In some embodiments, cancer is metastatic, and the ISH test is performed on samples of metastatic sites.

[0430] In some embodiments, the cancer has been determined to exhibit at least 3, 4, 5, or 6 copies (e.g., 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus, as detected by a single probe in situ hybridization (ISH) test on a sample from the cancer (e.g., according to ASCO / CAP guidelines, e.g., 2007, 2013, or 2018 guidelines). In some embodiments, the cancer has been determined to exhibit a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromere of chromosome 17 (CEP17) of at least 1.8, 2.0, or 2.2, as detected by a dual probe ISH test on a sample from the cancer (e.g., according to ASCO / CAP guidelines, e.g., 2007, 2013, or 2018 guidelines). In some embodiments, the cancer has been determined to exhibit (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromere of chromosome 17 (CEP17) of at least 1.8, 2.0, or 2.2, and (b) at least 3, 4, 5, or 6 copies of the gene encoding HER2 protein per interphase nucleus in the sample, as detected by performing a dual-probe ISH test on a sample from the cancer (e.g., according to ASCO / CAP guidelines, such as 2007, 2013, or 2018 guidelines).

[0431] In some embodiments, cancer comprises overexpression of HER2 protein. HER2 overexpression leads to increased expression of HER2 tyrosine kinase receptor on the cell membrane, increased homologous or heterologous dimerization of HER2 with other family members (including HER1 / EGFR, HER3 and HER4), increased activation of HER2 signal transduction, increased cell cycle progression and cell proliferation, and cancer.

[0432] As used herein, the term "HER2 overexpressed" or "HER2-overexpressed" cancer or cell refers to a cancer or cell characterized by overexpression of HER2 protein, which can be easily evaluated by methods known to those skilled in the art, for example, commercially available or immunohistochemistry (IHC) tests that can be performed by methods known to those skilled in the art. It is a commonly used and understood term in the art. For the purposes of this application, HER2 overexpressed cancers or cells include cancers or cells that show at least 10% of cancer cells have 2+ or 3+ positive according to an immunohistochemistry (IHC) test performed on a sample from a cancer (e.g., according to ASCO / CAP guidelines, such as 2007, 2013, or 2018 guidelines). In some cases, HER2 overexpressed cancers are defined according to the criteria described in the ASCO / CAP guidelines of 2007, 2013, or 2018 or other widely accepted cancer (e.g., specific cancer) criteria.

[0433] In some embodiments, an IHC score of 3+ positive is associated with a test result showing a homogeneous, dark, and circumferential (chicken wire) pattern in at least 10% of tumor cells, while a test result showing 2+ positive is associated with weak to moderate complete membrane staining in at least 10% of tumor cells.

[0434] In some embodiments, when one or more of (i) to (iv) are used for testing: (i) a sample from a cancer is tested by single-probe in situ hybridization (ISH), and the cancer exhibits at least 6 copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample; (ii) a sample from a cancer is tested by dual-probe ISH, and the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromere of chromosome 17 (CEP17) of at least 1.8; (iii) a sample from a cancer is tested by dual-probe ISH, and the cancer exhibits (a) 6 copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus; The ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) is at least 2.0, and (b) at least 4 copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample; (iv) the sample from the cancer is tested by immunohistochemistry (IHC), and the cancer shows 3+ positivity in at least 10% of the cancer cells; or (v) (a) the sample from the cancer is tested by immunohistochemistry (IHC), and the cancer shows 2+ positivity in at least 10% of the cancer cells, and (b) the sample from the cancer is tested by single probe in situ hybridization (ISH), and the cancer is determined to be positive.

[0435] As used herein, the term "HER2-positive" cancer or cell encompasses HER2-amplified cancers or cells and HER2-overexpressing cancers or cells.

[0436] In some embodiments, the cancers described herein comprise amplification of the gene encoding HER2 and overexpression of HER2 protein.

[0437] In some embodiments, a cancer described herein comprises amplification of a gene encoding HER2, but does not comprise overexpression of HER2.

[0438] In some embodiments, a cancer described herein comprises overexpression of HER2, but does not comprise amplification of the gene encoding HER2.

[0439] Preparation method

[0440] In some embodiments, a method for preparing a fumarate salt of Compound I is provided, comprising: (1) forming a mixture of Compound I and fumaric acid in a solvent; and (2) removing the solvent from step (1) to obtain a fumarate salt. In some embodiments, the molar ratio of fumaric acid to Compound I is about 0.5:1. In some embodiments, the molar ratio of fumaric acid to Compound I is about 1:1. In some embodiments, the solvent of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl tert-butyl ether, ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or N-methylpyrrolidone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ammonia or acetic acid). In some embodiments, the solvent of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60° C. In some embodiments, the mixture of step (1) is stirred at a temperature of about 1° C. to about 80° C. In some embodiments, removing the solvent comprises vacuum drying. In some embodiments, step (2) further comprises vacuum filtration.

[0441] In some embodiments, a method for preparing a tartrate salt of Compound I is provided, comprising: (1) forming a mixture of Compound I and tartaric acid in a solvent; and (2) removing the solvent from step (1) to obtain a tartrate salt. In some embodiments, the molar ratio of tartaric acid to Compound I is about 0.5:1. In some embodiments, the molar ratio of tartaric acid to Compound I is about 1:1. In some embodiments, the solvent of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl tert-butyl ether, ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or N-methylpyrrolidone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ammonia or acetic acid). In some embodiments, the solvent of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60° C. In some embodiments, the mixture of step (1) is stirred at a temperature of about 1° C. to about 80° C. In some embodiments, removing the solvent comprises vacuum drying. In some embodiments, step (2) further comprises vacuum filtration.

[0442] In some embodiments, a method for preparing a malate salt of Compound I is provided, comprising: (1) forming a mixture of Compound I and malic acid in a solvent; and (2) removing the solvent from step (1) to obtain a malate salt. In some embodiments, the molar ratio of malic acid to Compound I is about 0.5:1. In some embodiments, the molar ratio of malic acid to Compound I is about 1:1. In some embodiments, the solvent of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl tert-butyl ether, ethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or N-methylpyrrolidone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ammonia or acetic acid). In some embodiments, the solvent of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60° C. In some embodiments, the mixture of step (1) is stirred at a temperature of about 1° C. to about 80° C. In some embodiments, removing the solvent comprises vacuum drying. In some embodiments, step (2) further comprises vacuum filtration.

[0443] In some embodiments, a method for preparing a citrate salt of Compound I is provided, comprising: (1) forming a mixture of Compound I and citric acid in a solvent; and (2) removing the solvent from step (1) to obtain a citrate salt. In some embodiments, the molar ratio of citric acid to Compound I is about 0.5:1. In some embodiments, the molar ratio of citric acid to Compound I is about 1:1. In some embodiments, the solvent of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl tert-butyl ether, ethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or N-methylpyrrolidone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ammonia or acetic acid). In some embodiments, the solvent of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60° C. In some embodiments, the mixture of step (1) is stirred at a temperature of about 1° C. to about 80° C. In some embodiments, removing the solvent comprises vacuum drying. In some embodiments, step (2) further comprises vacuum filtration.

[0444] Composition

[0445] Also provided herein are compositions containing salts described herein, such as compositions of fumarate, tartrate, malate, or citrate of Compound I. In some embodiments, the composition contains a fumarate of Compound I. In some embodiments, the composition contains a tartrate of Compound I. In some embodiments, the composition contains a malate of Compound I. In some embodiments, the composition contains a citrate of Compound I. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a sterile composition.

[0446] In some embodiments, a composition containing a fumarate salt of Compound 1 is provided. In some embodiments, the composition is substantially free of other salts and non-salt forms of Compound 1. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of Compound 1.

[0447] In some embodiments of the composition containing the fumarate salt of Compound I, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least 99.9 wt% of the total composition is fumarate salt. In some embodiments of the composition containing a fumarate salt of Compound I, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least 99.9 wt% of Compound I in the composition is present in the form of a fumarate salt.

[0448] In some embodiments, a composition containing a tartrate salt of Compound 1 is provided. In some embodiments, the composition is substantially free of other salts and non-salt forms of Compound 1. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of Compound 1.

[0449] In some embodiments of compositions containing a tartrate salt of Compound I, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least 99.9 wt% of the total composition is tartrate salt. In some embodiments of the composition containing a tartrate salt of Compound I, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of Compound I in the composition is present in the form of a tartrate salt.

[0450] In some embodiments, compositions are provided containing a malate salt of Compound 1. In some embodiments, the composition is substantially free of other salt and non-salt forms of Compound 1. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of Compound 1.

[0451] In some embodiments of the compositions containing the malate salt of Compound I, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least 99.9 wt% of the total composition is malate. In some embodiments of the composition containing the malate salt of Compound I, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least 99.9 wt% of Compound I in the composition is present in the form of a malate salt.

[0452] In some embodiments, a composition containing a citrate salt of Compound 1 is provided. In some embodiments, the composition is substantially free of other salt and non-salt forms of Compound 1. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of Compound 1.

[0453] In some embodiments of the composition containing the citrate salt of Compound I, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least 99.9 wt% of the total composition is citrate salt. In some embodiments of the composition containing a citrate salt of Compound 1, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% of the Compound 1 by weight of the composition is present in the form of a citrate salt.

[0454] Treatment

[0455] In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a salt or pharmaceutical composition provided herein. In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a therapeutically effective amount of a salt or pharmaceutical composition provided herein. In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a fumarate of Compound I or a pharmaceutical composition comprising a fumarate of Compound I and a pharmaceutically acceptable carrier. In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a tartrate of Compound I or a pharmaceutical composition comprising a tartrate of Compound I and a pharmaceutically acceptable carrier. In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a malate of Compound I or a pharmaceutical composition comprising a malate of Compound I and a pharmaceutically acceptable carrier. In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a citrate of Compound I or a pharmaceutical composition comprising a citrate of Compound I and a pharmaceutically acceptable carrier. In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a citrate of Compound I or a pharmaceutical composition comprising a citrate of Compound I and a pharmaceutically acceptable carrier.

[0456] Also provided herein is the use of a salt or composition provided herein in the preparation of a medicament for treating cancer in a subject. In some embodiments, provided herein is a salt or composition provided herein for use in a method for treating cancer. In some embodiments, provided herein is the use of a salt or composition provided herein for treating cancer.

[0457] In some embodiments, a method of treating cancer in an individual in need thereof is provided, comprising administering to the individual a fumarate salt of Compound I, a tartrate salt of Compound I, a malate salt of Compound I, a citrate salt of Compound I, a pharmaceutical composition comprising a fumarate salt of Compound I, a pharmaceutical composition comprising a tartrate salt of Compound I, a pharmaceutical composition comprising a malate salt of Compound I, or a pharmaceutical composition comprising a citrate salt of Compound I. In some embodiments, a method of treating cancer (e.g., metastatic cancer) in an individual in need thereof is provided, comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer comprises an epidermal growth factor receptor (EGFR) mutation, or one or more wild-type or mutant kinases selected from ERBB2 (HER2) and ERBB4. In some embodiments, the cancer comprises one or more mutations selected from the following: EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR exon 20insNPH, EGFR exon 20insSVD, EGFR exon 20insFQEA, EGFR exon 20insH, EGFR exon 20ins ASV and ERBB2 (which is Her2 exon 20insYVMA) mutations. In some embodiments, the cancer comprises a mutation as EGFR Del19 / T790M. In some embodiments, the cancer comprises a mutation as EGFR L858R / T790M. In some embodiments, the cancer comprises a mutation as EGFR L858R. In some embodiments, the cancer comprises a mutation as EGFR exon 20ins NPH. In some embodiments, the cancer comprises a mutation as EGFR exon 20insSVD. In some embodiments, the cancer comprises a mutation as EGFR exon 20insFQEA. In some embodiments, the cancer comprises a mutation that is EGFR exon 20ins H. In some embodiments, the cancer comprises a mutation that is EGFR exon 20ins ASV. In some embodiments, the cancer comprises a mutation that is ERBB2 (which is Her2 exon 20ins YVMA). In some embodiments, the cancer is selected from breast cancer, colon cancer, lung cancer, gastric cancer, and colorectal cancer.

[0458] In some embodiments, the cancer is selected from pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Watt's cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, Esophageal cancer, glioma, kidney tumor, renal cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer and thymus cancer. In some embodiments, the cancer is selected from metastatic brain cancer, breast cancer and non-small cell lung cancer. In some embodiments, the cancer is metastatic brain cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0459] In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises an amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or an overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises an amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises an overexpression of a human epidermal growth factor receptor 2 (HER2) protein.

[0460] In some variants of any embodiment described herein, cancer is locally advanced cancer. In some variants, cancer is unresectable. In some variants, cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some variants, before administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, when a sample from cancer is tested using a single probe in situ hybridization (ISH, e.g., silver enhanced in situ hybridization (SISH) or fluorescence in situ hybridization (FISH)) test, cancer exhibits at least 3, 4, 5 or 6 copies (e.g., at least 6 copies) of each interphase nucleus in the sample The gene encoding human epidermal growth factor receptor 2 (HER2) protein. In some variants, when a sample from the cancer is tested using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromere of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some variants, when a sample from the cancer is tested using a dual-probe ISH test, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromere of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some variants, when the sample from cancer is tested using immunohistochemistry (IHC) test, cancer shows that at least 10% of cancer cells have 2+ or 3+ positive. In some variants, when the sample from cancer is tested using (a) immunohistochemistry (IHC) test, cancer shows that at least 10% of cancer cells have 2+ positive, and when the sample from cancer is tested using (b) single probe in situ hybridization (ISH) test, cancer is determined to be positive. In some variants, cancer is selected from metastatic brain cancer, breast cancer and non-small cell lung cancer. In some variants, cancer includes one or more (such as 1,2 or 3) mutations (such as any mutation described herein) in epidermal growth factor receptor (EGFR) protein. In some variants, cancer does not include mutations in epidermal growth factor receptor (EGFR) protein. In some variants, cancer includes one or more (such as 1,2 or 3) mutations (such as any mutation described herein) in HER2 protein.In some variants, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein, wherein one or more (e.g., 1, 2, or 3) mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variants, the cancer does not comprise any mutation in the HER2 protein. In some variants, the cancer does not comprise HER2 overexpression. In some variants, the cancer does not comprise amplification of a gene encoding human epidermal growth factor receptor 2 (HER2) protein. In some variants, the cancer does not comprise one or more mutations in the HER2 protein. In some variants, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variants, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein, selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.A775_G776insYVMA. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.778insGCP. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G780_P781dupGSP. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G778_S779insCPG. In some variants, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some variants, cancer does not include a mutation as G776C in HER2 protein. In some variants, cancer does not include any mutation in HER2 protein. In some variants, cancer includes a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein. In some variants, cancer does not include a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein. In some variants, cancer does not include a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein at histidine 1047. In some variants, cancer does not include a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein selected from H1047L and H1047R. In some variants, the composition is administered orally, parenterally, intravenously, subcutaneously or intracerebrally to an individual in need. In some variations, the method further comprises administering to an individual in need thereof one or more additional anticancer agents (eg, any anticancer agent described herein). In some variations, the one or more additional anticancer agents include a HER2 inhibitor.In some variants, one or more additional anticancer agents include HER2-CD3 bispecific antibodies. In some variants, one or more additional anticancer agents include HER2 immune-targeted bispecific antibodies. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) T cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocytes (CTL). In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variants, one or more additional anticancer agents include epidermal growth factor receptor (EGFR) inhibitors. In some variants, one or more additional anticancer agents include poly-ADP-ribose polymerase (PARP) inhibitors. In some variants, one or more additional anticancer agents include PD-1 inhibitors. In some variations, the one or more additional anticancer agents include a PD-L1 inhibitor. In some variations, the one or more additional anticancer agents include a PI3K inhibitor. In some variations, the one or more additional anticancer agents include a chemotherapeutic agent. In some variations, the individual is human.

[0461] In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) overexpression of human epidermal growth factor receptor 2 (HER2) protein.

[0462] In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein prior to administering the salt of Compound I or a pharmaceutically acceptable salt thereof, the cancer has been determined to exhibit one or more of (i) to (iv): (i) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer shows at least 6 copies of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample; (ii) a double-probe ISH test performed on a sample from the cancer shows that the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus is consistent with the centromere of chromosome 17 (CEP17). The invention relates to a method for treating a cancerous cell line comprising: (i) a ratio of at least 1.8 to the number of copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of the centromere of chromosome 17 (CEP17) by a dual probe ISH test performed on a sample from the cancer showing that (a) the ratio of the number of copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of copies of the centromere of chromosome 17 (CEP17) is at least 2.0, and (b) at least 4 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample; (iv) an immunohistochemistry (IHC) test performed on a sample from the cancer shows that at least 10% of the cancer cells have 3+ positivity; or (v) (a) an immunohistochemistry (IHC) test performed on a sample from the cancer shows that at least 10% of the cancer cells have 2+ positivity, and (b) a single probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some embodiments, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the cancer is a locally advanced cancer. In some embodiments, the cancer is unresectable.

[0463] In some variations of any of the embodiments described herein, prior to administration of a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample when tested using a single probe in situ hybridization (ISH, e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test. In some variations, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2) when tested using a dual probe ISH (e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test. In some variants, when a sample from the cancer is tested using a dual probe ISH test, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some variants, when a sample from the cancer is tested using an immunohistochemistry (IHC) test, the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some variants, when a sample from the cancer is tested using (a) an immunohistochemistry (IHC) test, the cancer exhibits at least 10% of cancer cells with 2+ positivity, and when a sample from the cancer is tested using (b) a single probe in situ hybridization (ISH) test, the cancer is determined to be positive. In some variants, cancer is selected from metastatic brain cancer, breast cancer and non-small cell lung cancer. In some variants, cancer comprises one or more (e.g., 1, 2 or 3) mutations (e.g., any mutation described herein) in epidermal growth factor receptor (EGFR) protein. In some variants, cancer does not comprise mutations in epidermal growth factor receptor (EGFR) protein. In some variants, cancer comprises one or more (e.g., 1, 2 or 3) mutations (e.g., any mutation described herein) in HER2 protein. In some variants, cancer does not comprise HER2 overexpression. In some variants, cancer does not comprise any mutation in HER2 protein. In some variants, cancer does not comprise amplification of genes encoding human epidermal growth factor receptor 2 (HER2) protein. In some variants, cancer does not comprise one or more mutations in HER2 protein. In some variants, cancer does not comprise one or more exon 20 insertion mutations in HER2 protein.In some variants, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein, selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.A775_G776insYVMA. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.778insGCP. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G780_P781dupGSP. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G778_S779insCPG. In some variants, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some variants, cancer does not include a mutation as G776C in HER2 protein. In some variants, cancer includes a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein. In some variants, cancer does not include a mutation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein. In some variants, cancer does not include a mutation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein at histidine 1047. In some variants, cancer does not include a mutation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) protein selected from H1047L and H1047R. In some variants, the composition is administered orally, parenterally, intravenously, subcutaneously or intracerebrally to an individual in need. In some variants, the method further includes administering one or more additional anticancer agents (such as any anticancer agent described herein) to an individual in need. In some variants, one or more additional anticancer agents include HER2 inhibitors. In some variants, one or more additional anticancer agents include HER2-CD3 bispecific antibodies. In some variants, one or more additional anticancer agents include HER2 immune-targeted bispecific antibodies. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) T cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocytes (CTL). In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variants, one or more additional anticancer agents include epidermal growth factor receptor (EGFR) inhibitors.In some variants, one or more additional anticancer agents include poly-ADP-ribose polymerase (PARP) inhibitors. In some variants, one or more additional anticancer agents include PD-1 inhibitors. In some variants, one or more additional anticancer agents include PD-L1 inhibitors. In some variants, one or more additional anticancer agents include PI3K inhibitors. In some variants, one or more additional anticancer agents include chemotherapeutic agents. In some variants, the individual is human.

[0464] In some embodiments, a method of treating cancer (e.g., cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein prior to administering a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a single probe in situ hybridization (ISH) test performed on a sample from the cancer shows at least 6 copies of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein prior to administering a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a single probe in situ hybridization (ISH) test performed on a sample from the cancer shows at least 6 copies of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein, and wherein prior to administering a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a single probe in situ hybridization (ISH) test performed on a sample from the cancer shows at least 6 copies of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein prior to administration of the salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a dual-probe ISH test performed on a sample from the cancer shows a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8.In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein prior to administering the salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a dual-probe ISH assay performed on a sample from the cancer shows a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein, and wherein prior to administering a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a dual-probe ISH assay performed on a sample from the cancer shows a ratio of the number of genes encoding a human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein prior to administration of the salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a dual-probe ISH test performed on a sample from the cancer shows (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 2.0 and (b) at least 4 copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample.In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein prior to administering the salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a dual-probe ISH test performed on a sample from the cancer shows (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 2.0 and (b) at least 4 copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein, and wherein prior to administering a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, a dual-probe ISH test performed on a sample from the cancer shows (a) a ratio of the number of genes encoding a human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 2.0, and (b) at least 4 copies of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein prior to administering the salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of the cancer cells to be 3+ positive. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein prior to administering the salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of the cancer cells to be 3+ positive.In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein, and wherein prior to administration of a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, an immunohistochemistry (IHC) test performed on a sample from the cancer shows that at least 10% of the cancer cells are 3+ positive. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein prior to administration of the salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, (a) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of the cancer cells to be 2+ positive, and (b) a single probe in situ hybridization (ISH) test performed on the sample from the cancer is determined to be positive. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein prior to administering the salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, (a) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of the cancer cells to be 2+ positive, and (b) a single probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein, and wherein prior to administration of a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, (i) an immunohistochemistry (IHC) test performed on a sample from the cancer showed at least 10% of the cancer cells to be 2+ positive, and (ii) a single probe in situ hybridization (ISH) test performed on a sample from the cancer was determined to be positive.

[0465] In some variations of any of the embodiments described herein, the cancer is locally advanced cancer. In some variations, the cancer is unresectable. In some variations, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).

[0466] In some variations, the cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer.

[0467] In some variations of any of the embodiments described herein, the cancer is selected from breast cancer, colon cancer, lung cancer, gastric cancer, and colorectal cancer.

[0468] In some variations of any of the embodiments described herein, the cancer comprises one or more (eg, 1, 2, or 3) mutations in an epidermal growth factor receptor (EGFR) protein. In some variants, the one or more mutations in the EGFR protein include one or more (e.g., 1, 2, or 3) mutations selected from the group consisting of G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Del19, EGFR L858R / C797S, EGFR Del19 / C797S, EGFR exon 20ins NPH, EGFR exon 20ins SVD, EGFR exon 20insFQEA, EGFR exon 20ins H and EGFR exon 20ins ASV. In some variants, the cancer comprises one or more mutations selected from the group consisting of G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Del19, EGFR L858R / C797S, EGFR Del19 / C797S, EGFR exon 20insNPH, EGFR exon 20ins SVD, EGFR exon 20ins FQEA, EGFR exon 20ins H, and EGFR exon 20ins ASV. In some variants, the cancer does not comprise any of the EGFR mutations described above. In some variants, the cancer does not comprise any mutations in the epidermal growth factor receptor (EGFR) protein.

[0469] In some variants of any of the embodiments described herein, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein, wherein the one or more (e.g., 1, 2, or 3) mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variants, the cancer does not comprise any mutation in the HER2 protein. In some variants, the cancer does not comprise one or more mutations in the HER2 protein. In some variants, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variants, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein, which are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.A775_G776insYVMA. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.778insGCP. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G780_P781dupGSP. In some variants, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G778_S779insCPG. In some variants, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some variants, the cancer does not comprise a mutation in the HER2 protein that is G776C.

[0470] In some variations of any of the embodiments described herein, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof.

[0471] In some variations of any of the embodiments described herein, the individual has not received one or more prior therapies for treating cancer prior to administration of a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein to the individual.

[0472] In some variations of any of the embodiments described herein, prior to administering a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein to an individual, the individual has received one or more prior therapies for treating cancer. In some variations, the one or more prior therapies include one or more anti-HER2-based regimens. In some variations, one or more anti-HER2-based regimens are administered to an individual in a metastatic setting. In some variations, prior to administering a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein to an individual, one or more prior therapies of the individual have failed.

[0473] In some variations of any of the embodiments described herein, the cancer does not comprise overexpression of HER2.

[0474] In some variations of any of the embodiments described herein, the cancer does not comprise amplification of a gene encoding human epidermal growth factor receptor 2 (HER2) protein.

[0475] In some variations of any of the embodiments described herein, the method further comprises identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer.

[0476] In some variations of any of the embodiments described herein, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein (eg, one or more mutations at histidine 1047 or cysteine ​​420, eg, H1047L, H1047R, or C420R).

[0477] In some variants of any of the embodiments described herein, the method further includes administering one or more additional anticancer agents (e.g., any anticancer agent described herein) or a second therapy (e.g., radiology) to an individual in need. In some variants, one or more additional anticancer agents include HER2 inhibitors. In some variants, one or more additional anticancer agents include HER2-CD3 bispecific antibodies. In some variants, one or more additional anticancer agents include HER2 immune-targeted bispecific antibodies. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) T cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocytes (CTL). In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variants, one or more additional anticancer agents include epidermal growth factor receptor (EGFR) inhibitors. In some variants, one or more additional anticancer agents include poly ADP-ribose polymerase (PARP) inhibitors. In some variants, one or more additional anticancer agents include PD-1 inhibitors. In some variants, one or more additional anticancer agents include PD-L1 inhibitors. In some variants, one or more additional anticancer agents include PI3K inhibitors. In some variants, one or more additional anticancer agents include chemotherapeutic agents.

[0478] In some embodiments, a method for treating cancer (e.g., breast cancer) in an individual in need is provided, comprising administering to an individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises amplification of a gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, the cancer comprises overexpression of HER2. In some embodiments, when tested using an immunohistochemistry (IHC) test, a sample of the cancer exhibits 3+ HER2 expression. In some embodiments, the present application provides a method for treating cancer (e.g., breast cancer) in an individual in need, comprising administering to an individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the application provides a method for treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, cancer comprises amplification of a gene encoding HER2 protein. In some embodiments, cancer comprises overexpression of HER2 protein. In some embodiments, cancer comprises one or more (e.g., 1, 2, or 3) mutations in epidermal growth factor receptor (EGFR) protein. In some embodiments, the one or more mutations in the EGFR protein include one or more (e.g., 1, 2, or 3) mutations selected from the group consisting of G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Del19, EGFR L858R / C797S, EGFR Del19 / C797S, EGFR exon 20ins NPH, EGFR exon 20ins SVD, EGFR exon 20insFQEA, EGFR exon 20ins In some embodiments, the one or more mutations include a G309A mutation. In some embodiments, the one or more mutations include a G309E mutation. In some embodiments, the one or more mutations include a S310F mutation. In some embodiments, the one or more mutations include a R678Q mutation.In some embodiments, one or more mutations include R678Q mutation and L755W mutation. In some embodiments, one or more mutations include L755S mutation. In some embodiments, one or more mutations include L755W mutation. In some embodiments, one or more mutations include I767M mutation. In some embodiments, one or more mutations include D769H mutation. In some embodiments, one or more mutations include D769Y mutation. In some embodiments, one or more mutations include V777L mutation. In some embodiments, one or more mutations include Y835F mutation. In some embodiments, one or more mutations include V842I mutation. In some embodiments, one or more mutations include R896C mutation. In some embodiments, one or more mutations include G1201V mutation. In some embodiments, one or more mutations include del.755-759EGFR Del19 / T790M mutation. In some embodiments, one or more mutations include EGFRL858R / T790M mutation. In some embodiments, one or more mutations include EGFR L858R mutation. In some embodiments, one or more mutations include EGFR del 19 mutation. In some embodiments, one or more mutations include EGFR L858R / C797S mutations. In some embodiments, one or more mutations include EGFR Del19 / C797S mutations. In some embodiments, one or more mutations include EGFR exon 20ins NPH mutations. In some embodiments, one or more mutations include EGFR exon 20ins SVD mutations. In some embodiments, one or more mutations include EGFR exon 20ins FQEA mutations. In some embodiments, one or more mutations include EGFR exon 20ins H mutations. In some embodiments, one or more mutations include EGFR exon 20ins ASV mutations. In some embodiments, cancer does not include any of the above-mentioned EGFR mutations. In some embodiments, cancer does not include any mutations in epidermal growth factor receptor (EGFR) protein. In some embodiments, prior to administration of a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample when the sample from the cancer is tested using a single probe in situ hybridization (ISH, such as silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test.In some embodiments, when a sample from a cancer is tested using a dual probe ISH (e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some embodiments, when a sample from a cancer is tested using a dual probe ISH test, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, when a sample from a cancer is tested using an immunohistochemistry (IHC) test, the cancer shows that at least 10% of the cancer cells have 2+ or 3+ positivity. In some embodiments, when a sample from a cancer is tested using (a) an immunohistochemistry (IHC) test, the cancer shows that at least 10% of the cancer cells have 2+ positivity, and when a sample from a cancer is tested using (b) a single probe in situ hybridization (ISH) test, the cancer is determined to be positive. In some embodiments, the cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some embodiments, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need. In some embodiments, prior to administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, the individual has not received one or more prior therapies for the treatment of cancer. In some embodiments, prior to administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, the individual has received one or more prior therapies for the treatment of cancer. In some embodiments, one or more previous therapies include one or more anti-HER2-based regimens. In some embodiments, one or more anti-HER2-based regimens are administered to individuals in metastatic settings. In some embodiments, before administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, one or more previous therapies of the individual have failed. In some embodiments, the method further includes identifying an individual based on an individual with HER2-amplified or HER2-overexpressed cancer. In some embodiments, cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some embodiments, cancer is locally advanced or metastatic. In some embodiments, cancer is unresectable.

[0479] In some embodiments, a method for treating cancer (e.g., breast cancer) in an individual in need is provided, comprising administering to an individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises amplification of a gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, the cancer comprises overexpression of HER2. In some embodiments, when tested using an immunohistochemistry (IHC) test, a sample of the cancer exhibits 3+ HER2 expression. In some embodiments, the present application provides a method for treating cancer (e.g., breast cancer) in an individual in need, comprising administering to an individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the present application provides a method for treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to an individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases, and (b) amplification of a gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, cancer comprises amplification of a gene encoding a HER2 protein. In some embodiments, cancer comprises overexpression of a HER2 protein. In some embodiments, cancer comprises one or more (e.g., 1, 2, or 3) mutations in a HER2 protein, wherein one or more (e.g., 1, 2, or 3) mutations in a HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments, one or more mutations comprise p.A775_G776insYVMA mutations. In some embodiments, one or more mutations comprise a p.778insGCP mutation. In some embodiments, one or more mutations comprise a p.G780_P781dupGSP mutation. In some embodiments, one or more mutations comprise a .G778_S779insCPG mutation. In some embodiments, the cancer does not comprise any of the HER2 mutations described above. In some embodiments, the cancer does not comprise any mutation in the HER2 protein. In some embodiments according to any of the methods described herein, the cancer does not comprise one or more mutations in the HER2 protein. In some embodiments according to any of the methods described herein, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein.In some embodiments according to any of the methods described herein, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments according to any of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.A775_G776insYVMA. In some embodiments according to any of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.778insGCP. In some embodiments according to any of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G780_P781dupGSP. In some embodiments according to any of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G778_S779insCPG. In some embodiments according to any one of the methods described herein, the cancer does not comprise a mutation as L775S in the HER2 protein. In some embodiments according to any one of the methods described herein, the cancer does not comprise a mutation as G776C in the HER2 protein. In some embodiments, prior to administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, when a sample from the cancer is tested using a single probe in situ hybridization (ISH, such as silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test, the cancer exhibits at least 3, 4, 5 or 6 copies (e.g., at least 6 copies) of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, when a sample from a cancer is tested using a dual probe ISH (e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some embodiments, when a sample from a cancer is tested using a dual probe ISH test, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample.In some embodiments, when a sample from a cancer is tested using an immunohistochemistry (IHC) test, the cancer shows that at least 10% of the cancer cells have 2+ or 3+ positivity. In some embodiments, when a sample from a cancer is tested using (a) an immunohistochemistry (IHC) test, the cancer shows that at least 10% of the cancer cells have 2+ positivity, and when a sample from a cancer is tested using (b) a single probe in situ hybridization (ISH) test, the cancer is determined to be positive. In some embodiments, the cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some embodiments, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need. In some embodiments, prior to administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, the individual has not received one or more prior therapies for the treatment of cancer. In some embodiments, prior to administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, the individual has received one or more prior therapies for the treatment of cancer. In some embodiments, one or more previous therapies include one or more anti-HER2-based regimens. In some embodiments, one or more anti-HER2-based regimens are administered to individuals in metastatic settings. In some embodiments, before administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, one or more previous therapies of the individual have failed. In some embodiments, the method further includes identifying an individual based on an individual with HER2-amplified or HER2-overexpressed cancer. In some embodiments, cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some embodiments, cancer is locally advanced or metastatic. In some embodiments, cancer is unresectable.

[0480] In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents or a second therapy, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents or a second therapy, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents or a second therapy, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a HER2 inhibitor, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a HER2 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a HER2 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein.In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more chemotherapeutic agents, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more chemotherapeutic agents, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more chemotherapeutic agents, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents (including trastuzumab and capecitabine), wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents (including trastuzumab and capecitabine), wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents (including trastuzumab and capecitabine), wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein.In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) an EGFR inhibitor, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) an EGFR inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) an EGFR inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PARP inhibitor, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, and b) a PARP inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, and b) a PARP inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, and b) a PD-1 inhibitor, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein.In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-L1 inhibitor, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-L1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PD-L1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PI3K inhibitor, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, methods are provided for treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, and b) a PI3K inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, a method of treating cancer (e.g., breast cancer) in an individual in need thereof is provided, comprising administering to the individual a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) a PI3K inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating gastric cancer in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents (including chemotherapeutic agents or PD-1 inhibitors), wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating gastric cancer in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents (including chemotherapeutic agents or PD-1 inhibitors), wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, a method of treating gastric cancer in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents (including chemotherapeutic agents or PD-1 inhibitors), wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents selected from carboplatin, taxanes, pemetrexed, PD-1 inhibitors, and PD-L1 inhibitors, wherein the cancer comprises amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein, overexpression of a HER2 protein, or one or more mutations in a HER2 protein. In some embodiments, a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anticancer agents selected from carboplatin, taxanes, pemetrexed, PD-1 inhibitors, and PD-L1 inhibitors, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof is provided, comprising administering to the individual a) a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, and b) one or more additional anti-cancer agents selected from carboplatin, a taxane, pemetrexed, a PD-1 inhibitor, and a PD-L1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein, overexpression of a HER2 protein, or one or more mutations in a HER2 protein.

[0481] In some variants of any of the embodiments described herein, cancer comprises amplification of a gene encoding a HER2 protein. In some variants, cancer comprises overexpression of a HER2 protein. In some variants, one or more additional anticancer agents include HER2 inhibitors. In some variants, one or more additional anticancer agents include HER2-CD3 bispecific antibodies. In some variants, one or more additional anticancer agents include HER2 immune-targeted bispecific antibodies. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) T cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocytes (CTL). In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variants, one or more additional anticancer agents include anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variants, one or more additional anticancer agents include epidermal growth factor receptor (EGFR) inhibitors. In some variants, one or more additional anticancer agents include poly ADP-ribose polymerase (PARP) inhibitors. In some variants, one or more additional anticancer agents include PD-1 inhibitors. In some variants, one or more additional anticancer agents include PD-L1 inhibitors. In some variants, one or more additional anticancer agents include PI3K inhibitors. In some variants, one or more additional anticancer agents include chemotherapeutic agents. In some variants, one or more additional anticancer agents are selected from antibody-drug conjugates.In some variations, the one or more additional anticancer agents are selected from trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, magituximab, emtansine, detrastuzumab, ZW49 (Zymeworks), A166 (KlausPharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumab duocarmazine, zenidatuzumab (ZW25), zetuzumab (MCLA-128), ISB-1 1302, afatinib, pocitinib, pyrotinib, moboceptinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, necituzumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplizumab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dotalimumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variants, the second therapy is radiation. In some variants, one or more chemotherapeutic agents are selected from doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxaliplatin and eribulin. In some variants, the EGFR inhibitor is selected from erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, lapatinib, dacomitinib, nexitozumab, vandetanib, afatinib, brigatinib and icotinib. In some variants, the PARP inhibitor is selected from niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722 and E7016.In some variants, the PD-1 inhibitor is selected from pembrolizumab, nivolumab, cemiplizumab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sindilimab (IBI308), tislelizumab (BGB-A317), toripalizumab (JS001), dotalimumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224 and AMP-514. In some variants, the PD-L1 inhibitor is selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170 and BMS-986189. In some variations, the PI3K inhibitor is selected from taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (BKM120), duvelisib (IPI-145), copanlisib (BAY80-6946), PX-866, dactolisib, CUDC-907, voxtalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474 and PWT33597. In some variations, the additional anticancer agent comprises a chemotherapeutic agent. In some variants, chemotherapeutic agents are selected from doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxaliplatin and eribulin. In some variants, other anticancer agents include PD-1 inhibitors. In some variants, PD-1 inhibitors are selected from pembrolizumab, nivolumab, cimiprilimumab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sindilimab (IBI308), tislelizumab (BGB-A317), tereprilimumab (JS001), multitalimumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224 and AMP-514. In some variants, cancer includes one or more mutations in HER2 protein. In some variations, the one or more additional anticancer agents include carboplatin. In some variations, the one or more additional anticancer agents include a taxane. In some variations, the one or more additional anticancer agents include pemetrexed. In some variations, the one or more additional anticancer agents include a PD-1 inhibitor.In some variants, the PD-1 inhibitor is selected from pembrolizumab, nivolumab, cemiplizumab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sindilimab (IBI308), tislelizumab (BGB-A317), toripalizumab (JS001), dotalimumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224 and AMP-514. In some variants, one or more additional anticancer agents include PD-L1 inhibitors. In some variants, the PD-L1 inhibitor is selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170 and BMS-986189. In some variations, prior to administration of a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample when tested using a single probe in situ hybridization (ISH, e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test. In some variations, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2) when tested using a dual probe ISH (e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test. In some variants, when a sample from the cancer is tested using a dual probe ISH test, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some variants, when a sample from the cancer is tested using an immunohistochemistry (IHC) test, the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some variants, when a sample from the cancer is tested using (a) an immunohistochemistry (IHC) test, the cancer exhibits at least 10% of cancer cells with 2+ positivity, and when a sample from the cancer is tested using (b) a single probe in situ hybridization (ISH) test, the cancer is determined to be positive. In some variations, the cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer.In some variations, the composition is administered orally, parenterally, intravenously, subcutaneously or intracerebrally to an individual in need. In some variations, before administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, the individual has not received one or more previous therapies for treating cancer. In some variations, before administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, the individual has received one or more previous therapies for treating cancer. In some variations, one or more previous therapies include one or more anti-HER2-based regimens. In some variations, one or more anti-HER2-based regimens are administered to an individual in a metastatic setting. In some variations, before administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, one or more previous therapies of the individual have failed. In some variations, the method further includes identifying an individual based on an individual with HER2-amplified or HER2-overexpressed cancer. In some variations, cancer is selected from metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some variations, cancer is locally advanced or metastatic. In some variants, the cancer is unresectable.

[0482] In some embodiments, there is provided a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein for use in the manufacture of a medicament for treating an individual with cancer, wherein the cancer comprises an amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or an overexpression of a HER2 protein. In some embodiments, there is provided a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, which is used to treat a person with cancer, wherein the cancer comprises an amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or an overexpression of a HER2 protein. In some embodiments, the cancer is a locally advanced cancer. In some embodiments, the cancer is unresectable. In some embodiments, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, there is provided a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, which is used to treat a person with cancer, wherein the cancer comprises one or more central nervous system (CNS) metastases. In some embodiments, there is provided a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein for use in the manufacture of a medicament for treating cancer in an individual, wherein the cancer comprises one or more central nervous system (CNS) metastases. In some embodiments, the cancer further comprises an amplification of a gene encoding a human epidermal growth factor receptor 2 (HER2) protein or an overexpression of a HER2 protein. In some embodiments, the cancer comprises an amplification of a gene encoding a HER2 protein. In some embodiments, the cancer comprises an overexpression of a HER2 protein. In some embodiments, the cancer does not comprise an overexpression of HER2. In some embodiments, the cancer does not comprise an amplification of a gene encoding a HER2 protein. In some embodiments, prior to administration of a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of a gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample when tested using a single probe in situ hybridization (ISH, e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test. In some embodiments, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2) when tested using a dual probe ISH (e.g., silver enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test.In some embodiments, when a sample from a cancer is tested using a dual probe ISH test, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus to the number of centromeres of chromosome 17 (CEP17) of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2), and (b) at least 3 or 4 copies (e.g., at least 3, 4, 5, or 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus in the sample. In some embodiments, when a sample from a cancer is tested using an immunohistochemistry (IHC) test, the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some embodiments, when a sample from a cancer is tested using (a) an immunohistochemistry (IHC) test, the cancer exhibits at least 10% of cancer cells with 2+ positivity, and when a sample from a cancer is tested using (b) a single probe in situ hybridization (ISH) test, the cancer is determined to be positive. In some embodiments, cancer is selected from metastatic brain cancer, breast cancer and non-small cell lung cancer. In some embodiments, cancer comprises one or more (e.g., 1, 2 or 3) mutations (e.g., any mutations described herein) in epidermal growth factor receptor (EGFR) protein. In some embodiments, cancer does not comprise mutations in epidermal growth factor receptor (EGFR) protein. In some embodiments, cancer comprises one or more (e.g., 1, 2 or 3) mutations (e.g., any mutations described herein) in HER2 protein. In some embodiments, cancer does not comprise one or more mutations in HER2 protein. In some embodiments, cancer does not comprise one or more exon 20 insertion mutations in HER2 protein. In some embodiments, cancer does not comprise one or more exon 20 insertion mutations in HER2 protein, which are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP and p.G778_S779insCPG. In some embodiments, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.A775_G776insYVMA. In some embodiments, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.778insGCP. In some embodiments, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G780_P781dupGSP. In some embodiments, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein, i.e., p.G778_S779insCPG. In some embodiments, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some embodiments, the cancer does not comprise a mutation in the HER2 protein that is G776C. In some embodiments, the cancer does not comprise any mutation in the HER2 protein.In some embodiments, the cancer comprises a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein at histidine 1047. In some embodiments, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein selected from H1047L and H1047R. In some embodiments, the individual has not received one or more prior therapies for treating cancer before administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to the individual. In some embodiments, prior to administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, the individual has received one or more prior therapies for treating cancer. In some embodiments, one or more prior therapies include one or more anti-HER2-based regimens (e.g., in a metastatic setting). In some embodiments, prior to administering a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein to an individual, one or more prior therapies of the individual have failed. In some embodiments, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need. In some embodiments, the method further comprises administering one or more additional anticancer agents (e.g., any anticancer agents described herein) to an individual in need. In some embodiments, one or more additional anticancer agents include one or more agents selected from HER2 inhibitors, HER2-CD3 bispecific antibodies, HER2 immune-targeted bispecific antibodies, anti-HER2 chimeric antigen receptor (CAR) T cells, anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocytes (CTL), anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells, anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells, epidermal growth factor receptor (EGFR) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, PD-1 inhibitors, PD-L1 inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors and chemotherapeutic agents. In some embodiments, one or more additional anticancer agents are selected from antibody-drug conjugates (e.g., trastuzumab or de trastuzumab). In some embodiments, one or more additional anticancer agents include trastuzumab and capecitabine. In some embodiments, drugs are used in combination with radiation. In some embodiments, the method further comprises identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer.In some embodiments, the subject is a human.

[0483] In some embodiments, prior to administration of a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein to the individual, the individual has received one or more (e.g., 1, 2, or 3) prior therapies for treating cancer. In some embodiments, prior to administration of a salt of Compound 1 as described herein or a pharmaceutical composition comprising a salt of Compound 1 as described herein to the individual, one or more (e.g., 1, 2, or 3) prior therapies have failed for the individual.

[0484] In some embodiments, one or more prior therapies exhibit inhibitory activity against a cancer comprising a T790M mutation in an epidermal growth factor receptor (EGFR) protein. In some embodiments, one or more prior therapies exhibiting inhibitory activity against a cancer comprising a T790M mutation in an epidermal growth factor receptor (EGFR) protein include osimertinib.

[0485] In some embodiments, osimertinib has been administered to the individual prior to administration of a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, to the individual. In some embodiments, administration of osimertinib has been completed for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months at the time a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, is administered to the individual.

[0486] In some embodiments, the one or more prior therapies include one or more standard therapies for the cancer.

[0487] In some embodiments, the individual has not received one or more (e.g., 1, 2, or 3) prior therapies for treating cancer prior to administration of a salt of Compound 1 as described herein, or a pharmaceutical composition comprising a salt of Compound 1 as described herein, to the individual.

[0488] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0489] Second agent or second therapy

[0490] In some embodiments, the method further comprises administering one or more additional anti-cancer agents or a second therapy to the individual in need thereof.

[0491] In some embodiments, the one or more additional anti-cancer agents include one or more agents selected from HER2 inhibitors, HER2-CD3 bispecific antibodies, HER2 immune-targeted bispecific antibodies, anti-HER2 chimeric antigen receptor (CAR) T cells, anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocytes (CTLs), anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells, anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells, epidermal growth factor receptor (EGFR) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and chemotherapeutic agents.

[0492] Exemplary HER2 inhibitors include, but are not limited to, trastuzumab, trastuzumab with hyaluronidase, trastuzumab with capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, makituximab, emtansine, detrastuzumab, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumab duocarmazine, zenidatuzumab (ZW25), zetuzumab (MCLA-128), ISB 1302, afatinib, pocitinib, pyrotinib, mobocitinib (TAK-788), and BDTX-189.

[0493] Exemplary EGFR inhibitors include, but are not limited to, erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, lapatinib, dacomitinib, necituzumab, vandetanib, afatinib, brigatinib, and icotinib.

[0494] Exemplary PARP inhibitors include, but are not limited to, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, and E7016.

[0495] Exemplary PD-1 inhibitors include, but are not limited to, pembrolizumab, nivolumab, cemiplizumab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalizumab (JS001), dotalimumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514.

[0496] Exemplary PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0497] Exemplary CTLA-4 inhibitors include ipilimumab and tremelimumab.

[0498] In some embodiments, the one or more additional anticancer agents are selected from bevacizumab, trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, magituximab, emtansine, detrastuzumab, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumabduocarmazine, zenidatuzumab (ZW25), zetuzumab (MCLA-128), ISB 1302, afatinib, pocitinib, pyrotinib, moboceptinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, necituzumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplizumab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dotalimumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0499] In some embodiments, the one or more additional anti-cancer agents are selected from antibody-drug conjugates. In some embodiments, the antibody-drug conjugates are selected from trastuzumab enmetuzumab and trastuzumab desmoduzumab.

[0500] In some embodiments, the one or more additional anticancer agents include one or more chemotherapeutic agents. In some embodiments, the one or more chemotherapeutic agents are selected from doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxaliplatin and eribulin.

[0501] In some embodiments, the one or more additional anti-cancer agents include trastuzumab and capecitabine.

[0502] In some embodiments, one or more additional anticancer agents include PI3K inhibitors. Exemplary PI3K inhibitors include, but are not limited to, taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, bupanisib (BKM120), duvilisib (IPI-145), clomiphene (BAY 80-6946), PX-866, dactolisib, CUDC-907, voxtalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597.

[0503] In some embodiments, the one or more additional anticancer agents are selected from erlotinib, gefitinib, afatinib, bevacizumab, trastuzumab, trastuzumab and hyaluronidase, capecitabine, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, makituximab, emtansine, detrastuzumab, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumab duocarmazine, zenidatuzumab (ZW25), zetuzumab (MCLA-128), ISB-1 1302, pocitinib, pyrotinib, mobocitinib (TAK-788), and BDTX-189, osimertinib, cetuximab, panitumumab, necituzumab, vandetanib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplizumab, JTX-4014, spartalizumab (PDR001), carrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dotalimumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189

[0504] In some embodiments, the one or more additional anticancer agents are selected from osimertinib, erlotinib, gefitinib, and afatinib.

[0505] In some embodiments, the one or more additional anti-cancer agents include osimertinib.

[0506] In some embodiments, the one or more additional anticancer agents include erlotinib.

[0507] In some embodiments, the one or more additional anticancer agents include gefitinib.

[0508] In some embodiments, the one or more additional anti-cancer agents include afatinib.

[0509] In some embodiments, the method further comprises treating the individual in need thereof with radiation.

[0510] Dosage and administration method

[0511] Administration of a salt of Compound 1 as described herein to an individual (e.g., a human) may vary with the specific composition, method of administration, and specific cancer being treated. The amount should be sufficient to produce the desired response, such as a therapeutic response against the cancer. In some embodiments, the amount of the salt of Compound 1 as described herein is below the level that causes toxicological effects (e.g., effects above a clinically acceptable toxicity level) or is at a level that can control or tolerate potential side effects when the salt of Compound 1 as described herein is administered to an individual.

[0512] In some embodiments, the salt of Compound I as described herein is administered systemically to the subject. In some embodiments, the salt of Compound I as described herein is administered parenterally to the subject. In some embodiments, the salt of Compound I as described herein is administered topically (i.e., topically) to the subject. In some embodiments, the salt of Compound I as described herein is administered orally, intravenously, intraarterially, intraperitoneally, intracapsularly, subcutaneously, intrathecally, intrapulmonaryly, intramuscularly, intratracheally, intracerebrally, intraocularly, transdermally, or by inhalation to the subject. In some embodiments, the salt of Compound I as described herein is administered orally to the subject. In some embodiments, the salt of Compound I as described herein is administered orally to the subject, while one or more additional agents may be administered to the subject by other routes, including intravenously, intraarterially, intraperitoneally, intracapsularly, subcutaneously, intrathecally, intrapulmonaryly, intramuscularly, intratracheally, intracerebrally, intraocularly, transdermally, or by inhalation. For example, in some embodiments, the salt of Compound I as described herein is administered orally to the subject, while one or more additional agents are administered intravenously to the subject. In some embodiments, a salt of Compound 1 as described herein is administered orally to a subject. In some embodiments, a salt of Compound 1 as described herein is administered parenterally to a subject. In some embodiments, a salt of Compound 1 as described herein is administered intravenously to a subject. In some embodiments, a salt of Compound 1 as described herein is administered subcutaneously to a subject. In some embodiments, a salt of Compound 1 as described herein is administered intracerebrally to a subject.

[0513] In some embodiments, a salt of Compound 1 as described herein and a second agent or therapy are administered to an individual simultaneously. In some embodiments, a salt of Compound 1 as described herein and a second agent or therapy are administered to an individual concurrently. In some embodiments, a salt of Compound 1 as described herein and a second agent or therapy are administered to an individual sequentially.

[0514] In some embodiments, a dose of about 1 mg / kg to about 100 mg / kg of a salt of Compound I as described herein is administered to an individual (e.g., a human) (e.g., about 1 mg / kg to about 75 mg / kg, about 2 mg / kg to about 75 mg / kg, about 3 mg / kg to about 75 mg / kg, about 4 mg / kg to about 75 mg / kg, about 5 mg / kg to about 75 mg / kg, about 1 mg / kg to about 50 mg / kg, about 2 mg / kg to about 50 mg / kg, about 3 mg / kg to about 50 mg / kg, about 4 mg / kg to about 50 mg / kg, about 5 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 2 mg / kg to about 40 mg / kg, about 3 mg / kg to about 40 mg / kg, about 4 mg / kg to about 4 In some embodiments, a salt of Compound 1 as described herein is administered once or twice daily to an individual (e.g., a human), optionally orally or parenterally. For oral administration, an exemplary daily dosage of a salt of Compound I as described herein is from about 0.001 to about 1000 mg per kilogram of body weight, with the course of treatment repeated at appropriate intervals.

[0515] In addition, a salt of Compound 1 as described herein can be administered according to the methods disclosed herein in an amount of about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 to about 500 mg, or about 100 mg to about 500 mg, or about 10 mg to about 750 mg, or about 10 mg to about 700 mg, or about 10 mg to about 650 mg, or about 10 mg to about 600 mg, or about 1 0 mg to about 575 mg, or about 10 mg to about 550 mg, or about 10 mg to about 500 mg, or about 10 mg to about 450 mg, or about 10 mg to about 400 mg, or about 10 mg to about 350 mg, or about 10 mg to about 300 mg, or about 10 mg to about 275 mg, or about 10 mg to about 250 mg, or about 10 mg to about 200 mg, or about 10 mg to about 150 mg, or about 10 mg to about 100 mg, or about 10 mg to about 75 mg, or about 10 mg to about 50 mg, or about 10 mg to about 25 mg.

[0516] In addition, the salt of Compound I as described herein can be administered once a day (QD) according to the methods disclosed herein. Compound I can be administered as a salt in an amount that provides about 6 mg QD, about 12 mg QD, about 20 mg QD, about 30 mg QD, about 45 mg QD, about 60 mg QD, about 75 mg QD, about 90 mg QD, or about 105 mg QD of the free base of Compound I. In one embodiment, Compound I can be administered as a salt in an amount that provides about 6 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 12 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 20 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 30 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 45 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 60 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 75 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 90 mg QD of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 105 mg QD of the free base of Compound I.

[0517] In addition, the salt of Compound I as described herein can be administered twice a day (BID) according to the methods disclosed herein. Compound I can be administered as a salt in an amount that provides about 3 mg BID, about 6 mg BID, about 10 mg BID, about 15 mg BID, about 20 mg BID, about 25 mg BID, about 30 mg BID, about 45 mg BID, or about 50 mg BID of the free base of Compound I. In one embodiment, Compound I can be administered as a salt in an amount that provides about 3 mg BID of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 6 mg BID of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 10 mg BID of the free base of Compound I. In another embodiment, Compound I can be administered as a salt in an amount that provides about 15 mg BID of the free base of Compound I. In another embodiment, Compound I may be administered as a salt in an amount that provides about 20 mg BID of the free base of Compound I. In another embodiment, Compound I may be administered as a salt in an amount that provides about 25 mg BID of the free base of Compound I. In another embodiment, Compound I may be administered as a salt in an amount that provides about 30 mg BID of the free base of Compound I. In another embodiment, Compound I may be administered as a salt in an amount that provides about 45 mg BID of the free base of Compound I. In another embodiment, Compound I may be administered as a salt in an amount that provides about 50 mg BID of the free base of Compound I.

[0518] Those skilled in the art will appreciate that, with respect to the salts of Compound 1 as described herein, the particu...

Claims

1. A fumarate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

2. The fumarate of claim 1, wherein the fumarate is a hemifumarate.

3. The fumarate salt of claim 1 or 2, wherein the fumarate salt is in crystalline form.

4. The fumarate salt of claim 3, wherein the fumarate salt exhibits (a) an XRPD pattern comprising peaks at 5.0±0.2° 2θ, 17.1±0.2° 2θ, and 20.5±0.2° 2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 172°C to about 185°C.

5. The tartrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

6. The tartrate salt of claim 5, wherein the tartrate salt is a hemi-tartrate salt.

7. The tartrate salt of claim 5 or 6, wherein the tartrate salt is in crystalline form.

8. The tartrate salt of claim 7, wherein the tartrate salt exhibits (a) an XRPD pattern comprising peaks at 17.9±0.2°2θ, 5.8±0.2°2θ, and 7.4±0.2°2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 218°C to about 230°C.

9. The malate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

10. The malate salt of claim 9, wherein the malate salt is a hemimalate salt.

11. The malate salt of claim 9 or 10, wherein the malate salt is in crystalline form.

12. The malate salt of claim 11, wherein the malate salt exhibits (a) an XRPD pattern comprising peaks at 6.0±0.2° 2θ, 20.2±0.2° 2θ, and 19.5±0.2° 2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 146°C to about 160°C.

13. The citrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

14. The citrate salt of claim 13, wherein the citrate salt is a hemi-citrate salt.

15. The citrate salt of claim 13 or 14, wherein the citrate salt is in crystalline form.

16. The citrate salt of claim 15, wherein the citrate salt exhibits (a) an XRPD pattern comprising peaks at 7.3±0.2° 2θ, 7.4±0.2° 2θ, and 18.6±0.2° 2θ, and (b) a differential scanning calorimetry trace comprising a peak at about 175°C to about 179°C.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) the fumarate salt of any one of claims 1-4, (b) the tartrate salt of any one of claims 5-8, (c) the malate salt of any one of claims 9-12, or (d) the citrate salt of any one of claims 13-16.

18. A method for treating cancer in an individual in need thereof, the method comprising administering to the individual (a) a fumarate salt as described in any one of claims 1-4, (b) a tartrate salt as described in any one of claims 5-8, (c) a malate salt as described in any one of claims 9-12, (d) a citrate salt as described in any one of claims 13-16, or (e) a pharmaceutical composition as described in claim 17.

19. The method of claim 18, wherein the cancer comprises an epidermal growth factor receptor (EGFR) mutation or one or more wild-type or mutant kinases selected from the group consisting of: ERBB2 and ERBB4.

20. The method of claim 18 or 19, wherein the cancer is selected from the group consisting of pseudomyxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Watt's cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, pediatric lymphoma, pediatric leukemia, small Bowel cancer, meningioma, esophageal cancer, glioma, kidney tumor, renal cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer and thymus cancer.

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