EGFR inhibitors fumarate, tartrate, malate, and citrate

Abstract

The present application provides salts and crystalline forms, and polymorphic crystalline forms, compositions thereof, methods for their preparation, and methods for their use 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. Compound I ((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 an inhibitor of the epidermal growth factor receptor (EGFR) and has been used to treat various cancers in individuals, including humans, in need of such treatment.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 422,361, filed November 3, 2022, and U.S. Provisional Application No. 63 / 464,130, filed 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, compositions thereof, methods for their preparation, and methods of use 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”). [Background technology]

[0003] Compound I is an inhibitor of the epidermal growth factor receptor (EGFR) and is used to treat various cancers in individuals, including humans, in need of such treatment. The present disclosure relates to the identification of novel salt forms of Compound I, and novel polymorphic forms of the disclosed salt forms. The disclosed salt forms, and the disclosed polymorphic forms, have physical properties that make them advantageous for the development of Compound I as a therapeutic agent for the treatment of cancer in individuals in need thereof. Summary of the Invention

[0004] [Means for solving the problem] In one aspect, provided herein is a fumarate salt of Compound I.

[0005] In one aspect, provided herein is the tartrate salt of Compound I.

[0006] In one aspect, provided herein is a malate salt of Compound I.

[0007] In one aspect, provided herein is the citrate salt of Compound I.

[0008] In another aspect, provided herein are compositions containing the fumarate, tartrate, malate, or citrate salts of Compound I described herein.

[0009] In another aspect, provided herein is a method of treating cancer using a fumarate, tartrate, malate, or citrate salt of Compound I in an individual in need thereof.

[0010] In another aspect, provided herein is a method of using a fumarate, tartrate, malate, or citrate salt of Compound I, or a pharmaceutical composition comprising such salts, in the treatment of cancer in an individual in need thereof.

[0011] In another aspect, provided herein is a method of using a fumarate, tartrate, malate, or citrate salt of Compound I, or a pharmaceutical composition comprising such salts, in the manufacture of a medicament for the treatment of cancer in an individual in need thereof.

[0012] In another aspect, provided herein are methods for preparing the fumarate, tartrate, malate, or citrate salts of Compound I.

[0013] Various embodiments are contemplated herein.For example, in embodiment 1, there is provided (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 fumarate salt.

[0014] Embodiment 2: The fumarate salt of embodiment 1, wherein the salt is a hemifumarate salt.

[0015] Embodiment 3: The fumarate salt of embodiment 1 or 2, wherein the salt is in a crystalline form.

[0016] Embodiment 4: The fumarate salt of any one of embodiments 1-3, wherein the fumarate salt has a solubility, 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.5 and at a temperature of about 25° C.

[0017] Embodiment 5: The fumarate salt of any one of embodiments 1-4, wherein the fumarate salt has a solubility, 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 4.7 and at a temperature of about 25° C.

[0018] Embodiment 6: The fumarate salt of any one of embodiments 1-5, wherein the fumarate salt has a solubility, 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, of about 0.2 mg / mL in an aqueous solution having a pH of about 6.6 and at a temperature of about 25° C.

[0019] Embodiment 7: The fumarate salt of any one of embodiments 3 to 6, wherein the fumarate salt exhibits an XRPD pattern comprising a peak at 5.0±0.2 degrees 2θ.

[0020] Embodiment 8: The fumarate salt of embodiment 7, further comprising a peak at 17.1±0.2 degrees 2θ in said XRPD pattern.

[0021] Embodiment 9: The fumarate salt of embodiment 8, further comprising a peak at 20.5±0.2 degrees 2θ in said XRPD pattern.

[0022] 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 degrees 2θ in the XRPD pattern.

[0023] 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 degrees 2θ in the XRPD pattern.

[0024] Embodiment 12: The fumarate salt of any one of embodiments 1 to 11, wherein the fumarate salt exhibits a differential scanning calorimetry trace comprising a peak at about 172°C to about 185°C.

[0025] Embodiment 13: The fumarate salt of embodiment 12, further comprising an endothermic onset of about 165°C to about 180°C in the differential scanning calorimetry trace.

[0026] Embodiment 14: A crystalline form 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 fumarate, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 5.0±0.2 degrees two-theta, and (b) a differential scanning calorimetry trace comprising a peak from about 172° C. to about 185° C.

[0027] Embodiment 15: The fumarate salt of embodiment 14, further comprising a peak at 17.1±0.2 degrees 2θ in said XRPD pattern.

[0028] Embodiment 16: The fumarate salt of embodiment 15, further comprising a peak at 20.5±0.2 degrees 2θ in said XRPD pattern.

[0029] 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 degrees 2θ in the XRPD pattern.

[0030] 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 degrees 2θ in the XRPD pattern.

[0031] Embodiment 19: The fumarate salt of any one of embodiments 14 to 18, further comprising an endothermic onset of about 165°C to about 180°C in the differential scanning calorimetry trace.

[0032] Embodiment 20: The fumarate salt of any one of embodiments 14-19, wherein the fumarate salt has a solubility, 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, of greater than about 9.2 mg / mL in an aqueous solution having a pH of about 1.2 and at a temperature of about 25° C.

[0033] Embodiment 21: The fumarate salt of any one of embodiments 14-20, wherein the fumarate salt has a solubility, 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, of about 7.2 mg / mL in an aqueous solution having a pH of about 4.6 and at a temperature of about 25° C.

[0034] Embodiment 22: The fumarate salt of any one of embodiments 14-21, wherein the fumarate salt has a solubility, 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, of about 0.1 mg / mL in an aqueous solution having a pH of about 6.8 and at a temperature of about 25° C.

[0035] Embodiment 23: (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 tartrate salt.

[0036] Embodiment 24: The tartrate salt of embodiment 23, wherein the salt is a hemitartrate salt.

[0037] Embodiment 25: The tartrate salt of embodiment 23 or 24, wherein the salt is in crystalline form.

[0038] Embodiment 26: The tartrate salt of any one of embodiments 23-25, wherein the tartrate salt has a solubility, calculated as the amount of 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.4 and at a temperature of about 25° C.

[0039] Embodiment 27: The tartrate salt of any one of embodiments 23 to 26, wherein the tartrate salt has a solubility, 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, of about 0.3 mg / mL in an aqueous solution having a pH of about 4.7 and at a temperature of about 25° C.

[0040] Embodiment 28: The tartrate salt of any one of embodiments 23 to 27, wherein the tartrate salt has a solubility, 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, of about 0.2 mg / mL in an aqueous solution having a pH of about 6.6 and at a temperature of about 25° C.

[0041] Embodiment 29: The tartrate salt of any one of embodiments 25 to 28, wherein the tartrate salt exhibits an XRPD pattern comprising a peak at 17.9±0.2 degrees 2θ.

[0042] Embodiment 30: The tartrate salt of embodiment 29, further comprising a peak at 5.8±0.2 degrees 2θ in the XRPD pattern.

[0043] Embodiment 31: The tartrate salt of embodiment 30, further comprising a peak at 7.4±0.2 degrees 2θ in the XRPD pattern.

[0044] 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 degrees 2θ in the XRPD pattern.

[0045] 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 degrees 2θ in the XRPD pattern.

[0046] Embodiment 34: The tartrate salt of any one of embodiments 23 to 33, wherein the tartrate salt exhibits a differential scanning calorimetry trace comprising a peak at about 218°C to about 230°C.

[0047] Embodiment 35: The tartrate salt of embodiment 34, further comprising an exotherm onset of about 215°C to about 230°C in the differential scanning calorimetry trace.

[0048] Embodiment 36: 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 in a crystalline form, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 17.9±0.2 degrees two-theta, and (b) a differential scanning calorimetry trace comprising a peak from about 218° C. to about 230° C.

[0049] Embodiment 37: The tartrate salt of embodiment 36, further comprising a peak at 5.8±0.2 degrees 2θ in the XRPD pattern.

[0050] Embodiment 38: The tartrate salt of embodiment 37, further comprising a peak at 7.4±0.2 degrees 2θ in the XRPD pattern.

[0051] 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 degrees 2θ in the XRPD pattern.

[0052] 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 degrees 2θ in the XRPD pattern.

[0053] Embodiment 41: The tartrate salt of any one of embodiments 36 to 40, further comprising an exotherm onset of about 215°C to about 230°C in the differential scanning calorimetry trace.

[0054] Embodiment 42: The tartrate salt of any one of embodiments 36-41, wherein the tartrate salt has a solubility, 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.4 and at a temperature of about 25° C.

[0055] Embodiment 43: The tartrate salt of any one of embodiments 36 to 42, wherein the tartrate salt has a solubility, 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, of about 0.3 mg / mL in an aqueous solution having a pH of about 4.7 and at a temperature of about 25° C.

[0056] Embodiment 44: The tartrate salt of any one of embodiments 36 to 43, wherein the tartrate salt has a solubility, 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, of about 0.2 mg / mL in an aqueous solution having a pH of about 6.6 and at a temperature of about 25° C.

[0057] Embodiment 45: (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 malate salt.

[0058] Embodiment 46: The malate salt of embodiment 45, wherein the salt is a hemimalate salt.

[0059] Embodiment 47: The malate salt of embodiment 45 or 46, wherein the salt is in crystalline form.

[0060] Embodiment 48: The malate salt of any one of embodiments 45 to 47, wherein the malate salt has a solubility, 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.4 and at a temperature of about 25° C.

[0061] Embodiment 49: The malate salt of any one of embodiments 45 to 48, wherein the malate salt has a solubility, 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 4.8 and at a temperature of about 25° C.

[0062] Embodiment 50: The malate salt of any one of embodiments 45 to 49, wherein the malate salt has a solubility, 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, of about 0.3 mg / mL in an aqueous solution having a pH of about 6.4 and at a temperature of about 25° C.

[0063] Embodiment 51: The malate of any one of embodiments 47 to 50, wherein the malate exhibits an XRPD pattern comprising a peak at 6.0±0.2 degrees 2θ.

[0064] Embodiment 52: The malate salt of embodiment 51, further comprising a peak at 20.2±0.2 degrees 2θ in said XRPD pattern.

[0065] Embodiment 53: The malate salt of embodiment 52, further comprising a peak at 19.5±0.2 degrees 2θ in said XRPD pattern.

[0066] 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 degrees 2θ in the XRPD pattern.

[0067] 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 degrees 2θ in the XRPD pattern.

[0068] Embodiment 56: The malate of any one of embodiments 45 to 55, wherein the malate exhibits a differential scanning calorimetry trace comprising a peak from about 146°C to about 160°C.

[0069] Embodiment 57: The malate of embodiment 56, further comprising an endothermic onset of about 134°C to about 147°C in the differential scanning calorimetry trace.

[0070] Embodiment 58: A crystalline form 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 malate, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 6.0±0.2 degrees two-theta, and (b) a differential scanning calorimetry trace comprising a peak from about 146° C. to about 160° C.

[0071] Embodiment 59: The malate salt of embodiment 58, further comprising a peak at 20.2±0.2 degrees 2θ in said XRPD pattern.

[0072] Embodiment 60: The malate salt of embodiment 59, further comprising a peak at 19.5±0.2 degrees 2θ in said XRPD pattern.

[0073] 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 degrees 2θ in the XRPD pattern.

[0074] 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 degrees 2θ in the XRPD pattern.

[0075] Embodiment 63: The malate of any one of embodiments 58 to 62, further comprising an endothermic onset of about 134°C to about 147°C in the differential scanning calorimetry trace.

[0076] Embodiment 64: The malate salt of any one of embodiments 58 to 63, wherein the malate salt has a solubility, 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.4 and at a temperature of about 25° C.

[0077] Embodiment 65: The malate salt of any one of embodiments 58-64, wherein the malate salt has a solubility, calculated as the amount of 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, of greater than about 20 mg / mL in an aqueous solution having a pH of about 4.8 and at a temperature of about 25° C.

[0078] Embodiment 66: The malate salt of any one of embodiments 58-65, wherein the malate salt has a solubility, 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, of about 0.3 mg / mL in an aqueous solution having a pH of about 6.4 and at a temperature of about 25° C.

[0079] 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.

[0080] Embodiment 68: The citrate salt of embodiment 67, wherein the salt is a hemi-citrate salt.

[0081] Embodiment 69: The citrate salt of embodiment 67 or 68, wherein the salt is in crystalline form.

[0082] Embodiment 70: The citrate salt of embodiment 69, wherein the citrate salt exhibits an XRPD pattern comprising a peak at 7.3±0.2 degrees 2θ.

[0083] Embodiment 71: The citrate salt of embodiment 70, further comprising a peak at 7.4±0.2 degrees 2θ in said XRPD pattern.

[0084] Embodiment 72: The citrate salt of embodiment 71, further comprising a peak at 18.6±0.2 degrees 2θ in said XRPD pattern.

[0085] 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 degrees 2θ in the XRPD pattern.

[0086] 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 degrees 2θ in the XRPD pattern.

[0087] Embodiment 75: The Citrate Salt of any one of embodiments 67 to 74, wherein the Citrate Salt exhibits a differential scanning calorimetry trace comprising a peak at about 175°C to about 179°C.

[0088] 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.

[0089] Embodiment 77: A crystalline form 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 citrate salt, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 7.3±0.2 degrees two-theta, and (b) a differential scanning calorimetry trace comprising a peak from about 175° C. to about 179° C.

[0090] Embodiment 78: The citrate salt of embodiment 77, further comprising a peak at 7.4±0.2 degrees 2θ in said XRPD pattern.

[0091] Embodiment 79: The citrate salt of embodiment 78, further comprising a peak at 18.6±0.2 degrees 2θ in said XRPD pattern.

[0092] 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 degrees 2θ in the XRPD pattern.

[0093] 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 degrees 2θ in the XRPD pattern.

[0094] Embodiment 82: The Citrate Salt of any one of embodiments 77 to 81, further comprising an endothermic onset of about 124°C to about 128°C in the differential scanning calorimetry trace.

[0095] Embodiment 83: A pharmaceutical composition comprising the fumarate salt of any one of embodiments 1 to 22 and a pharmaceutically acceptable carrier.

[0096] Embodiment 84: A pharmaceutical composition comprising the tartrate salt of any one of embodiments 23 to 44 and a pharmaceutically acceptable carrier.

[0097] Embodiment 85: A pharmaceutical composition comprising the malate salt of any one of embodiments 45 to 66 and a pharmaceutically acceptable carrier.

[0098] Embodiment 86: A pharmaceutical composition comprising the Citrate Salt of any one of embodiments 67 to 82 and a pharmaceutically acceptable carrier.

[0099] Embodiment 87: A method of treating cancer in an individual in need thereof, comprising administering to the individual (a) a fumarate salt according to any one of embodiments 1 to 22, (b) a tartrate salt according to any one of embodiments 23 to 44, (c) a malate salt according to any one of embodiments 45 to 66, (d) a citrate salt according to any one of embodiments 67 to 82, (e) a pharmaceutical composition according to embodiment 83, (f) a pharmaceutical composition according to embodiment 84, (g) a pharmaceutical composition according to embodiment 85, or (h) a pharmaceutical composition according to embodiment 86.

[0100] Embodiment 88: The method of embodiment 87, wherein the cancer comprises a mutation in epidermal growth factor receptor (EGFR), or one or more wild-type or mutant kinases selected from ERBB2 and ERBB4.

[0101] Embodiment 89: The method of embodiment 87 or 88, wherein the cancer comprises one or more mutations in ERBB2 selected from the group consisting of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, EGFR exon 20 ins ASV, and Her2 exon 20 ins YVMA.

[0102] Embodiment 90: The cancer is selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, 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, epithelial ovarian cancer, ovarian germ cell cancer, male breast cancer, brain tumor, 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 cavity and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cancer, kidney cancer, heart cancer, duodenal cancer, and malignant 90. The method of any one of embodiments 87-89, wherein the cancer is selected from the group consisting of soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' carcinoma, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain tumor, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

[0103] Embodiment 91: The method of embodiment 90, wherein the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.

[0104] Embodiment 92: The method of embodiment 91, wherein the cancer is a metastatic brain tumor.

[0105] Embodiment 93: The method of embodiment 91, wherein the cancer is breast cancer.

[0106] Embodiment 94: The method of embodiment 91, wherein the cancer is non-small cell lung cancer.

[0107] Embodiment 95: The method of any one of embodiments 87 to 94, wherein the cancer is a locally advanced cancer.

[0108] Embodiment 96: The method of any one of embodiments 87 to 95, wherein the cancer is unresectable.

[0109] Embodiment 97: The method of any one of embodiments 87 to 96, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).

[0110] Embodiment 98: The method of any one of embodiments 87 to 97, wherein the cancer comprises one or more mutations in the epidermal growth factor receptor (EGFR) protein.

[0111] Embodiment 99: The one or more mutations in the EGFR protein are 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 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins 99. The method of embodiment 98, comprising one or more mutations selected from the group consisting of: ASV.

[0112] Embodiment 100: The method of any one of embodiments 87 to 99, wherein the cancer comprises one or more mutations in the HER2 protein, and the one or more mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG.

[0113] Embodiment 101: The method of any one of embodiments 87 to 100, wherein the individual has not undergone one or more prior therapies for the treatment of the cancer prior to administration of the salt or pharmaceutical composition to the individual.

[0114] Embodiment 102: The method of any one of embodiments 87 to 101, wherein the individual has undergone one or more prior therapies for the treatment of the cancer prior to administration of the salt or pharmaceutical composition to the individual.

[0115] Embodiment 103: The method of embodiment 102, wherein said one or more prior therapies comprise one or more anti-HER2-based regimens.

[0116] Embodiment 104: The method of embodiment 103, wherein the one or more anti-HER2-based regimens are administered to the individual in a metastatic state.

[0117] Embodiment 105: The method of any one of embodiments 102 to 104, wherein the individual has failed the one or more prior therapies prior to administration of the salt or the pharmaceutical composition to the individual.

[0118] Embodiment 106: The method of any one of embodiments 87 to 105, wherein the method further comprises administering to the individual in need thereof one or more additional anti-cancer agents.

[0119] Embodiment 107: The method of embodiment 106, wherein the one or more additional anticancer agents comprise one or more agents selected from a HER2 inhibitor, a HER2-CD3 bispecific antibody, a HER2 immunotargeting bispecific antibody, an anti-HER2 chimeric antigen receptor (CAR) T cell, an anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocyte (CTL), an anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cell, an anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cell, an epidermal growth factor receptor (EGFR) inhibitor, a poly-ADP-ribose polymerase (PARP) inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and a chemotherapeutic agent.

[0120] Embodiment 108: The one or more additional anticancer agents are 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-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, nekitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, Veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemipillimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 108. The method of embodiment 107, wherein the medicament is selected from the group consisting of: 101), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0121] Embodiment 109: The method of embodiment 108, wherein the one or more additional anticancer agents are selected from antibody-drug conjugates.

[0122] Embodiment 110: The method of embodiment 109, wherein the antibody-drug conjugate is selected from trastuzumab emtansine and trastuzumab deruxtecan.

[0123] Embodiment 111: The method of embodiment 108, wherein the one or more additional anti-cancer agents comprise one or more chemotherapeutic agents.

[0124] Embodiment 112: The method of embodiment 111, wherein the one or more chemotherapeutic agents are selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin.

[0125] Embodiment 113: The method of embodiment 108, wherein the one or more additional anticancer agents comprise trastuzumab and capecitabine.

[0126] Embodiment 114: The method of any one of embodiments 87 to 113, wherein the method further comprises treating the individual in need thereof with radiation.

[0127] Embodiment 115: The method of embodiment 87, wherein (a) the fumarate salt according to any one of embodiments 1 to 22, (b) the tartrate salt according to any one of embodiments 23 to 44, (c) the malate salt according to any one of embodiments 45 to 66, (d) the citrate salt according to any one of embodiments 67 to 82, (e) the pharmaceutical composition according to embodiment 83, (f) the pharmaceutical composition according to embodiment 84, (g) the pharmaceutical composition according to embodiment 85, or (h) the pharmaceutical composition according to embodiment 86 is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to the individual in need thereof.

[0128] Embodiment 116: The method of any one of embodiments 87 to 115, wherein the individual is a human.

[0129] Embodiment 117: A method for preparing the fumarate salt of any one of embodiments 1 to 22, comprising:

[0130] (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;

[0131] (2) removing the solvent from step (1) to obtain the fumarate salt.

[0132] 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.

[0133] 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.

[0134] Embodiment 120: A method for preparing the tartrate salt of any one of embodiments 23 to 44, comprising:

[0135] (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;

[0136] (2) removing the solvent from step (1) to obtain the tartrate salt.

[0137] 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.

[0138] 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.

[0139] Embodiment 123: A method for preparing a malate salt according to any one of embodiments 45 to 66, comprising:

[0140] (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;

[0141] (2) removing the solvent from step (1) to obtain the malate salt.

[0142] 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.

[0143] 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.

[0144] Embodiment 126: A method for preparing the Citrate Salt of any one of embodiments 67 to 82, comprising:

[0145] (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;

[0146] (2) removing the solvent from step (1) to obtain the citrate salt.

[0147] 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.

[0148] 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.

[0149] Embodiment 129: The method of any one of embodiments 117-128, wherein the solvent in step (1) comprises an aprotic solvent or a protic solvent.

[0150] Embodiment 130: The method of embodiment 129, wherein the solvent comprises an aprotic solvent.

[0151] Embodiment 131: The method of embodiment 130, wherein the aprotic solvent is acetone.

[0152] Embodiment 132: The method of embodiment 130, wherein the aprotic solvent is acetonitrile.

[0153] Embodiment 133: The method of embodiment 130, wherein the aprotic solvent is ethyl acetate.

[0154] Embodiment 134: The method of embodiment 129, wherein the solvent comprises a protic solvent.

[0155] Embodiment 135: The method of embodiment 134, wherein the protic solvent is ethanol.

[0156] Embodiment 136: The method of any one of embodiments 117 to 135, wherein the mixture of step (1) is stirred at 20 to 60°C.

[0157] Embodiment 137: The method of any one of embodiments 117 to 135, wherein removing the solvent comprises vacuum drying.

[0158] Embodiment 138: The method of any one of embodiments 117 to 137, wherein step (2) further comprises vacuum filtration. [Brief explanation of the drawings]

[0159] [Figure 1A] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound I prepared according to Example 2.

[0160] [Figure 1B] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound I prepared according to Example 3.

[0161] [Figure 1C] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound I prepared according to Example 4.

[0162] [Figure 1D] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound I prepared according to Example 5.

[0163] [Figure 1E] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the fumarate salt of Compound I prepared according to Example 6.

[0164] [Figure 1F] 1 shows a differential scanning calorimetry (DSC) graph of the fumarate salt of Compound I prepared according to Example 2.

[0165] [Figure 1G] 1 shows a differential scanning calorimetry (DSC) graph of the fumarate salt of Compound I prepared according to Example 5.

[0166] [Figure 1H] 1 shows a differential scanning calorimetry (DSC) graph of the fumarate salt of Compound I prepared according to Example 6.

[0167] [Figure 1I] 1 shows a thermogravimetric analysis (TGA) graph of the fumarate salt of Compound I prepared according to Example 2.

[0168] [Figure 1J] 1 shows a thermogravimetric analysis (TGA) graph of the fumarate salt of Compound I prepared according to Example 5.

[0169] [Figure 1K] 1 shows a thermogravimetric analysis (TGA) graph of the fumarate salt of Compound I prepared according to Example 6.

[0170] [Figure 1L] 1 shows a thermogravimetric analysis (TGA) graph of the fumarate salt of Compound I prepared according to Example 5 after 24 hours at room temperature and 92.5% relative humidity (RH).

[0171] [Figure 1M] 1 shows a thermogravimetric analysis (TGA) graph of the fumarate salt of Compound I prepared according to Example 6 after 24 hours at room temperature and 92.5% relative humidity (RH).

[0172] [Figure 2A] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound I prepared according to Example 7.

[0173] [Figure 2B] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound I prepared according to Example 8.

[0174] [Figure 2C] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound I prepared according to Example 9.

[0175] [Figure 2D] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the tartrate salt of Compound I prepared according to Example 10.

[0176] [Figure 2E] 1 shows a differential scanning calorimetry (DSC) graph of the tartrate salt of Compound I prepared according to Example 9.

[0177] [Figure 2F] 1 shows a differential scanning calorimetry (DSC) graph of the tartrate salt of Compound I prepared according to Example 10.

[0178] [Figure 2G] 1 shows a thermogravimetric analysis (TGA) graph of the tartrate salt of Compound I prepared according to Example 9.

[0179] [Figure 2H] 1 shows a thermogravimetric analysis (TGA) graph of the tartrate salt of Compound I prepared according to Example 10.

[0180] [Figure 2I] 1 shows a thermogravimetric analysis (TGA) graph of the tartrate salt of Compound I prepared according to Example 9 after 24 hours at room temperature and 92.5% relative humidity (RH).

[0181] [Figure 2J] 1 shows a thermogravimetric analysis (TGA) graph of the tartrate salt of Compound I prepared according to Example 10, aged at room temperature for 24 hours at 92.5% relative humidity (RH).

[0182] [Figure 3A] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound I prepared according to Example 11.

[0183] [Figure 3B] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound I prepared according to Example 12.

[0184] [Figure 3C] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound I prepared according to Example 13.

[0185] [Figure 3D] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the malate salt of Compound I prepared according to Example 14.

[0186] [Figure 3E]1 shows a differential scanning calorimetry (DSC) graph of the malate salt of Compound I prepared according to Example 13.

[0187] [Figure 3F] 1 shows a differential scanning calorimetry (DSC) graph of the malate salt of Compound I prepared according to Example 14.

[0188] [Figure 3G] 1 shows a thermogravimetric analysis (TGA) graph of the malate salt of Compound I prepared according to Example 13.

[0189] [Figure 3H] 1 shows a thermogravimetric analysis (TGA) graph of the malate salt of Compound I prepared according to Example 14.

[0190] [Figure 3I] 1 shows a thermogravimetric analysis (TGA) graph of the malate salt of Compound I prepared according to Example 13 at room temperature and 92.5% relative humidity (RH) for 24 hours.

[0191] [Figure 3J] 1 shows a thermogravimetric analysis (TGA) graph of the malate salt of Compound I prepared according to Example 14 at room temperature for 24 hours at 92.5% relative humidity (RH).

[0192] [Figure 4A] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the citrate salt of Compound I prepared according to Example 15.

[0193] [Figure 4B] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the citrate salt of Compound I prepared according to Example 16.

[0194] [Figure 4C] 1 shows an experimental X-ray powder diffraction (XRPD) pattern of the citrate salt of Compound I prepared according to Example 17.

[0195] [Figure 4D] 1 shows a differential scanning calorimetry (DSC) graph of the citrate salt of Compound I prepared according to Example 17.

[0196] [Figure 4E] 1 shows a thermogravimetric analysis (TGA) graph of the citrate salt of Compound I prepared according to Example 17.

[0197] [Figure 5] The bioavailability and concentrations of unbound tucatinib and Compound I in the brain or plasma are provided at 1, 4, and 8 hours after oral administration of a single dose of either tucatinib (50 mg / kg) or Compound I (3 mg / kg) to mice.

[0198] [Figure 6] Figure 1 shows the sensitivity of 25 breast cancer cell lines, including cell lines exhibiting amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein and / or overexpression of HER2 protein, to treatment with Compound I compared to tucatinib and lapatinib, as indicated by calculated median effective concentrations (EC50).

[0199] [Figure 7A] 1 shows the mean tumor volumes in mice in the Compound 1, Tucatinib, and vehicle control groups after 28 days of treatment in Example 20.

[0200] [Figure 7B] 1 shows tumor volumes in individual mice in the vehicle control group of Example 20.

[0201] [Figure 7C] 1 shows the tumor volumes in individual mice in the Compound 1 group of Example 20.

[0202] [Figure 7D] 1 shows tumor volumes in individual mice in the tucatinib group of Example 20.

[0203] [Figure 7E] The average body weights of mice in each of the Compound 1 group of Example 20, the tucatinib group, and the vehicle control group are shown (the vehicle group is represented by circles, the Compound 1 group is represented by triangles, and the tucatinib group is represented by squares).

[0204] [Figure 8A] 1H-NMR spectrum of the fumarate salt after recrystallization in deuterated methanol (CD3OD).

[0205] [Figure 8B] 1H-NMR spectrum of fumarate salt (fumarate salt scale-up) in deuterated methanol (CD3OD).

[0206] [Figure 8C] 1H-NMR spectrum of the tartrate salt in deuterated methanol (CD3OD).

[0207] [Figure 8D] 1H-NMR spectrum of tartrate salt (tartrate salt scale-up) in deuterated methanol (CD3OD).

[0208] [Figure 8E] 1H-NMR spectrum of malate in deuterated methanol (CD3OD).

[0209] [Figure 8F] 1H-NMR spectrum of malate (malate scale-up) in deuterated methanol (CD3OD). DETAILED DESCRIPTION OF THE INVENTION

[0210] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Furthermore, any methods or materials similar or equivalent to those described herein can be used in the practice of this application. For purposes of this application, the following terms are defined:

[0211] It is understood that embodiments of the present application described herein include "consisting of" and / or "consisting essentially of" the embodiments.

[0212] Reference herein to "about" a value or parameter includes (and describes) a variation about that value or parameter itself. For example, a reference to "about X" includes a reference to "X."

[0213] As used herein, the term "about X to Y" 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."

[0214] As used herein, reference to "not being" a value or parameter generally means and describes "other than" a value or parameter. For example, not using the method to treat cancer type X means using the method to treat a type of cancer other than type X.

[0215] As used herein, the terms "a," "an," or "the" include not only embodiments with one member, but also embodiments with more than one member. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, a reference to "the agent" includes a reference to one or more agents known to those of skill in the art, and so forth.

[0216] As used herein, the term "polymorph" or "polymorphic form" refers to a 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, as a result of the arrangement or conformation of molecules or ions within the crystal lattice. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, concentration (important in formulation and product manufacturing), and dissolution rate (a key factor in bioavailability). Differences in stability can be due to changes in chemical reactivity (e.g., differential oxidation, such that a dosage form consisting of one polymorph discolors more quickly than another), mechanical changes (e.g., a tablet that crumbles on storage as a kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., a tablet of one polymorph is more susceptible to disintegration at high humidity). As a result of differences in solubility / disintegration, some polymorphic transitions may be ineffective at one extreme or toxic at the other. In addition, the physical properties of the crystalline form may be important in processing; for example, some polymorphs may be more likely to form solvates or may be difficult to filter and wash free of impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0217] As used herein, the term "substantially as shown," for example, when referring to an XRPD pattern, DSC graph, TGA graph, or GVS graph, includes patterns or graphs that are not necessarily identical to those shown herein, but that fall within the limits of experimental error or deviation as recognized by one of ordinary skill in the art.

[0218] In some embodiments, the term "substantially pure" means that the salt or polymorphic form contains less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% by weight of impurities. In other embodiments, "substantially pure" refers to a material that is free of impurities. Impurities may include, for example, by-products or residual reagents from chemical reactions, contaminants, degradation products, other salt forms, other polymorphic forms, water, and solvents.

[0219] As used herein, the term "substantially free" means that the composition, including the salt form or 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 specified substance or substances.

[0220] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. For 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 attributable to the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the worsening of the disease), preventing or slowing the spread of the disease (e.g., metastasis), preventing or slowing the recurrence of the disease, reducing the rate of disease recurrence, slowing or delaying the progression of the disease, improving the disease state, providing remission (partial or total) of the disease, reducing the dosage of one or more other drugs required to treat the disease, slowing the progression of the disease, improving quality of life, and / or extending survival. In some embodiments, treatment reduces the severity of one or more symptoms associated with cancer by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the corresponding symptoms in the same subject before treatment or compared to the corresponding symptoms in another subject not receiving treatment. Alleviation of the pathological consequences of cancer is also encompassed by “treatment.” The methods of the present application contemplate any one or more of these aspects of treatment.

[0221] As used herein, the term "effective amount" refers to an amount of a compound or composition sufficient to treat a particular disorder, condition, or disease, such as improving, alleviating, mitigating, and / or delaying one or more of its symptoms in an individual. With respect to cancer, an effective amount includes an amount sufficient to shrink a tumor and / or reduce the rate of tumor growth (such as an amount sufficient to inhibit tumor growth), or prevent or delay other undesirable cell proliferation of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to delay the onset 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. An effective amount can be administered to an individual in one or more administrations. An effective amount of a drug or composition may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, suppress, slow to some extent, and preferably stop, cancer cell invasion into peripheral organs; (iv) inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay tumor onset and / or recurrence; (vii) reduce the rate of tumor recurrence; and / or (viii) alleviate to some extent one or more symptoms associated with cancer in an individual.

[0222] As understood in the art, an effective amount may be one or more doses; i.e., a single administration or multiple administrations may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administration of one or more therapeutic agents, and the compounds or compositions described herein may be, or may be considered to be administered in an effective amount if, a desired or beneficial result is achieved, optionally in combination with one or more other agents. Components of the combination therapy of the present application (e.g., first and second therapies) may be administered sequentially, simultaneously, or concurrently to an individual using the same or different routes of administration for each component. Thus, an effective amount of a combination therapy includes an amount of the first therapy and an amount of the second therapy that, when administered sequentially, simultaneously, or concurrently to an individual, will produce a desired result in that individual.

[0223] As used herein, a "therapeutically effective amount" refers to an amount administered to an individual that produces a desired pharmacological and / or physiological effect for the individual's condition. The effect in the individual may be prophylactic, in that the condition or its symptoms are completely or partially prevented, and / or therapeutic, in that the condition and / or adverse effects resulting from the condition are partially or completely cured.

[0224] As used herein, "individual" means a mammal, including a human, dog, cat, or domestic animal. In one embodiment, "individual" means a human.

[0225] "In conjunction with" or "in combination with" refers to the administration of one therapy in addition to another therapy, e.g., the administration of a compound or composition described herein in addition to the administration of other agents to the same individual under the same treatment regimen. Thus, "in conjunction with" or "in combination with" refers to the administration of one therapy before, during, or after the delivery of another therapy to an individual.

[0226] The term "co-administration," as used herein, means that the first and second therapies in a combination therapy are administered at a time interval of about 15 minutes or less, e.g., about 10 minutes or less, 5 minutes or less, or 1 minute or less. When the first and second therapies are administered at the same time, the first and second therapies may be contained in the same composition (e.g., a composition containing both the first and second therapeutic agents) or may be contained in separate compositions (e.g., the first therapy in one composition and the second therapy in another composition).

[0227] As used herein, the term "sequential administration" means that the first and second therapies in a combination therapy are administered at an interval of more than about 15 minutes, for example, more than about 20 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, or more. Either the first or second therapy may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.

[0228] 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.

[0229] As used herein, "pharmaceutically acceptable" or "pharmaceutically compatible" means a material that is biologically or otherwise undesirable; e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients preferably have met the required standards of toxicology and manufacturing testing and / or are listed in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0230] The disclosures of all publications, patents, patent applications and published patent applications mentioned herein are hereby incorporated by reference in their entirety.

[0231] Compound I

[0232] Compound I is a compound that has been demonstrated to have inhibitory activity against epidermal growth factor receptor (EGFR) mutants and HER2 mutants. 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-propenamide. Compound I has the following structure:

[0233] [ka]

[0234] Compound I

[0235]

[0236] Compound I can 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 is described in WO2020 / 190119 and may be prepared by the methods described therein. The contents of WO2020 / 190119 are incorporated herein by reference for this purpose. Alternatively, Compound I may be prepared by methods known to those skilled in the art.

[0238] salt

[0239] In one aspect, provided herein are salts of Compound I. Salts may have chemical or physical properties that make them suitable for medical or pharmaceutical uses, such as enhanced bioavailability and stability under certain conditions.

[0240] Salts of Compound I may offer advantages in bioavailability and stability and may be suitable for use as an active agent in pharmaceutical compositions. Variations in the salt form of a drug substance can affect the drug's dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to prepare uniform doses of known strengths, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.). Such variations may affect the preparation and formulation of pharmaceutical compositions in different dosage and delivery forms, such as solid oral dosage forms, including tablets and capsules. Salt forms of drug substances may provide desirable or preferred hygroscopicity, dissolution rate, solubility, absorption, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Thus, salts of compounds may offer advantages in improving the manufacturing process of the active agent or the stability or storage of a pharmaceutical form of the active agent, or in providing suitable bioavailability and / or stability as the active agent.

[0241] It has been found that the use of certain conditions, such as the use of different solvents and / or temperatures, produces different salts of Compound I, as well as different polymorphs of those salts, including the fumarate, tartrate, malate, and citrate salts described herein, which may exhibit one or more advantageous properties described herein. The processes for preparing the fumarate, tartrate, malate, and citrate salts described herein, as well as the properties of these salts, are described in further detail below.

[0242] Fumarate

[0243] In some embodiments, provided herein is a fumarate salt of Compound I.

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

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

[0246] In some embodiments, the fumarate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 1.5 and at a temperature of about 25° C. In some embodiments, the fumarate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 4.7 and at a temperature of about 25° C. In some embodiments, the fumarate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 6.6 and at a temperature of about 25°C.

[0247] In some embodiments, the fumarate salt has a solubility of 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 as the amount of free base of Compound I, in an aqueous solution having a pH of about 1.2 and at a temperature of about 25° C. In some embodiments, the fumarate salt has a solubility of 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 as the amount of free base of Compound I, in an aqueous solution having a pH of about 4.6 and at a temperature of about 25° C. In some embodiments, the fumarate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 6.8 and at a temperature of about 25°C.

[0248] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in Figure 1A. The angles and peak intensities measured in degrees 2θ that may be observed for the fumarate salt using XRPD are shown in Table 1.

[0249] [Table 1]

[0250] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in FIG. 1A or as set forth in Table 1, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and instrumentation used to obtain the spectrum, as well as analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the fumarate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0251] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It is understood that additional peaks in the XRPD pattern other than those shown in FIG. 1A or listed in Table 1 may be observed due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0252] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in Figure 1B. The angles and peak intensities measured in degrees 2θ that may be observed for the fumarate salt using XRPD are shown in Table 2.

[0253] [Table 2]

[0254] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in FIG. 1B or as set forth in Table 2, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees with maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and instrumentation used to obtain the spectrum, as well as analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the fumarate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0255] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It is understood that additional peaks in the XRPD pattern other than those shown in FIG. 1B or listed in Table 2 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0256] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in Figure 1C. The angles and peak intensities measured in degrees 2θ that may be observed for the fumarate salt using XRPD are shown in Table 3.

[0257] [Table 3]

[0258] In some embodiments, the fumarate salt has an XRPD pattern exhibiting at least one, at least two, or all of the peaks at 2θ degrees with maximum intensity in the XRPD pattern substantially as shown in FIG. 1C or as listed in Table 3. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the fumarate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0259] 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 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.5±0.2 and 22.3±0.2 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 22.3±0.2 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.5±0.4, 8.9±0.4, and 22.3±0.4 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.5±0.4 and 22.3±0.4 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 22.3±0.4 degrees 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 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.5±0.6 and 22.3±0.6 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 22.3±0.6 degrees 2θ. It will be appreciated that additional peaks in the XRPD pattern other than those shown in FIG. 1C or listed in Table 3 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0260] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in Figure ID. The angles and peak intensities measured in degrees 2θ that may be observed for the fumarate salt using XRPD are shown in Table 4.

[0261] [Table 4]

[0262] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in FIG. 1D or as set forth in Table 4, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 peaks at 2θ degrees with maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and instrumentation used to obtain the spectrum, as well as analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the fumarate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0263] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It will be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1D or listed in Table 4 may be observed, for example, due to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0264] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in Figure IE. The angles and peak intensities measured in degrees 2θ that may be observed for the fumarate salt using XRPD are shown in Table 5.

[0265] [Table 5]

[0266] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in FIG. 1E or as set forth in Table 5, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees with maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and instrumentation used to obtain the spectrum, as well as analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the fumarate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0267] In some embodiments, the fumarate salt is 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, 19.2±0.2, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0.2, 55. It has an XRPD pattern containing peaks at 8.8±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 degrees 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 degrees 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 degrees 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, 19.8±0.2, 20.5±0.2, and 22.0±0.2 degrees 2θ. It has an XRPD pattern containing peaks at 8.8±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 degrees 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 degrees 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 degrees 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, 19.8±0.4, 20.5±0.4, and 22.0±0.4 degrees 2θ. It has an XRPD pattern containing peaks at 8.8±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 degrees 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 degrees 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 degrees 2θ.It will be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1E or listed in Table 5 may be observed, for example, due to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0268] In some embodiments, the fumarate salt has an XRPD pattern including peaks at 5.0±0.2 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern including peaks at 5.0±0.2 and 17.1±0.2 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern including peaks at 5.0±0.2, 17.1±0.2, and 20.5±0.2 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern including 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 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern including 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. In some embodiments, the fumarate salt has an XRPD pattern including peaks at 5.0±0.4 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern including peaks at 5.0±0.4 and 17.1±0.4 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern including peaks at 5.0±0.4, 17.1±0.4, and 20.5±0.4 degrees 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 degrees 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 degrees 2θ. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at 5.0±0.6 degrees 2θ.In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.6 and 17.1±0.6 degrees 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 degrees 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 degrees 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 degrees 2θ.

[0269] In some embodiments, the fumarate salt has a differential scanning calorimetry trace substantially as shown in FIG. 1F. In some embodiments, the fumarate salt has a differential scanning calorimetry trace substantially as shown in FIG. 1G. In some embodiments, the fumarate salt has a differential scanning calorimetry trace substantially as shown in FIG. 1H. In some embodiments, the fumarate salt is characterized by a differential scanning calorimetry trace including a peak at about 172°C to about 185°C. In some embodiments, the fumarate salt is characterized by a differential scanning calorimetry trace including a peak at 172±4°C (e.g., 172±3°C, 172±2°C, or 172±1°C). In some embodiments, the fumarate salt is characterized by a differential scanning calorimetry trace including a peak at 174±4°C (e.g., 174±3°C, 174±2°C, or 174±1°C). In some embodiments, the fumarate salt 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 salt 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 salt 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 salt 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 salt is characterized by exhibiting a differential scanning calorimetry trace that includes 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 that includes a peak at 185±4° C. (e.g., 185±3° C., 185±2° C., or 185±1° C.).

[0270] 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.

[0271] In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace with an endothermic onset at about 165°C to about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace with 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 with 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 with an endothermic onset at 169±4°C (e.g., 169±3°C, 169±2°C, or 169±1°C). In some embodiments, the fumarate salts exhibit a differential scanning calorimetry trace with an endothermic onset at 171±4°C (e.g., 171±3°C, 171±2°C, or 171±1°C). In some embodiments, the fumarate salts exhibit a differential scanning calorimetry trace with an endothermic onset at 173±4°C (e.g., 173±3°C, 173±2°C, or 173±1°C). In some embodiments, the fumarate salts exhibit a differential scanning calorimetry trace with an endothermic onset at 175±4°C (e.g., 175±3°C, 175±2°C, or 175±1°C). In some embodiments, the fumarate salts exhibit a differential scanning calorimetry trace with 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 with 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 with an endothermic onset at 180±4°C (e.g., 180±3°C, 180±2°C, or 180±1°C).

[0272] In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 165°C and about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 165°C and about 175°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 167°C and about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 167°C and about 175°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 169°C and about 180°C. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 169°C and about 175°C.

[0273] 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) are true:

[0274] (a) The fumarate is a hemifumarate;

[0275] (b) The fumarate salt is in crystalline form;

[0276] (c) the fumarate salt has a solubility, calculated as the amount of free base of Compound I, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.5 and at a temperature of about 25° C.;

[0277] (d) the fumarate salt has a solubility, calculated as the amount of free base of Compound I, of greater than about 20 mg / mL in an aqueous solution having a pH of about 4.7 and at a temperature of about 25° C.;

[0278] (e) the fumarate salt has a solubility, calculated as the amount of free base of Compound I, of about 0.2 mg / mL in an aqueous solution having a pH of about 6.6 and at a temperature of about 25°C;

[0279] (f) Fumarate is

[0280] (i) peak at 5.0 ± 0.2 degrees 2θ;

[0281] (ii) peaks at 5.0 ± 0.2 and 17.1 ± 0.2 degrees 2θ;

[0282] (iii) peaks at 5.0 ± 0.2, 17.1 ± 0.2, and 20.5 ± 0.2 degrees 2θ;

[0283] (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 degrees 2θ; or

[0284] (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 exhibiting an XRPD pattern comprising:

[0285] (g) Fumarate is

[0286] (i) a peak between about 172°C and about 185°C; or

[0287] (ii) a peak at about 172°C to about 185°C and an endothermic onset at about 165°C to about 180°C 1 shows a differential scanning calorimetry trace containing:

[0288] 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)(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) apply. In some embodiments, (c), (d), (e), (f)(iv), and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(v), and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(i), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(ii), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(iii), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(iv), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(v), and (g)(ii) apply.

[0289] tartrate

[0290] In some embodiments, provided herein is the tartrate salt of Compound I.

[0291] In some embodiments, the tartrate salt of Compound I is a hemitartrate salt.

[0292] In some embodiments, the tartrate salt of Compound I is in a crystalline form.

[0293] In some embodiments, the tartrate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 1.4 and at a temperature of about 25°C. In some embodiments, the tartrate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 4.7 and at a temperature of about 25°C. In some embodiments, the tartrate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 6.6 and at a temperature of about 25°C.

[0294] In some embodiments, the tartrate salt has an XRPD pattern substantially as shown in Figure 2A. The angles and peak intensities measured in degrees 2θ that may be observed for the tartrate salt using XRPD are shown in Table 6.

[0295] [Table 6]

[0296] In some embodiments, the tartrate salt has an XRPD pattern substantially as shown in FIG. 2A or as set forth in Table 6, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and instrumentation used to obtain the spectrum, as well as analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the tartrate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0297] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ.It will be understood that additional peaks in the XRPD pattern other than those shown in Figure 2A or listed in Table 6 may be observed due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0298] In some embodiments, the tartrate salt has an XRPD pattern substantially as shown in Figure 2B. The angles and peak intensities measured in degrees 2θ that may be observed for the tartrate salt using XRPD are shown in Table 7.

[0299] [Table 7]

[0300] In some embodiments, the tartrate salt has an XRPD pattern exhibiting at least one peak at a 2θ degree with maximum intensity in the XRPD pattern substantially as shown in FIG. 2B or as set forth in Table 7. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the tartrate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0301] In some embodiments, the tartrate salt has an XRPD pattern including a peak at 26.1±0.2 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including a peak at 26.1±0.4 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including a peak at 26.1±0.6 degrees 2θ. It will be understood that additional peaks in the XRPD pattern other than those shown in FIG. 2B or listed in Table 7 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0302] In some embodiments, the tartrate salt has an XRPD pattern substantially as shown in Figure 2C. The angles and peak intensities measured in degrees 2θ that may be observed for the tartrate salt using XRPD are shown in Table 8.

[0303] [Table 8]

[0304] In some embodiments, the tartrate salt has an XRPD pattern substantially as shown in FIG. 2C or as set forth in Table 8, exhibiting 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 degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the tartrate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0305] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It will be understood that additional peaks in the XRPD pattern other than those shown in Figure 2C or listed in Table 8 may be observed, for example, due to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0306] In some embodiments, the tartrate salt has an XRPD pattern substantially as shown in Figure 2D. The angles and peak intensities measured in degrees 2θ that may be observed for the tartrate salt using XRPD are shown in Table 9.

[0307] [Table 9]

[0308] In some embodiments, the tartrate salt has an XRPD pattern substantially as shown in FIG. 2D or as set forth in Table 9, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and instrumentation used to obtain the spectrum, as well as analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the tartrate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0309] In some embodiments, the tartrate salt is 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, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0.2, 55 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 degrees 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 degrees 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 degrees 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, 18.8±0.4, 19.1±0. 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 degrees 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 degrees 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 degrees 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, 18.8±0.6, 19.1±0.6 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 degrees 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 degrees 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 degrees 2θ. It is understood that additional peaks in the XRPD pattern other than those shown in FIG. 2D or listed in Table 9 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0310] In some embodiments, the tartrate salt has an XRPD pattern including peaks at 17.9±0.2 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including peaks at 5.8±0.2 and 17.9±0.2 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including peaks at 5.8±0.2, 7.4±0.2, and 17.9±0.2 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including 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 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including 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. In some embodiments, the tartrate salt has an XRPD pattern including peaks at 17.9±0.4 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including peaks at 5.8±0.4 and 17.9±0.4 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including peaks at 5.8±0.4, 7.4±0.4, and 17.9±0.4 degrees 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 degrees 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 degrees 2θ. In some embodiments, the tartrate salt has an XRPD pattern including a peak at 17.9±0.6 degrees 2θ.In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.6 and 17.9±0.6 degrees 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 degrees 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 degrees 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 degrees 2θ.

[0311] In some embodiments, the tartrate salt has a differential scanning calorimetry trace substantially as shown in FIG. 2E. In some embodiments, the tartrate salt has a differential scanning calorimetry trace substantially as shown in FIG. 2F. In some embodiments, the tartrate salt is characterized by a differential scanning calorimetry trace including a peak at about 218°C to about 230°C. In some embodiments, the tartrate salt is characterized by a differential scanning calorimetry trace including a peak at 218±4°C (e.g., 218±3°C, 218±2°C, or 218±1°C). In some embodiments, the tartrate salt is characterized by a differential scanning calorimetry trace including a peak at 220±4°C (e.g., 220±3°C, 220±2°C, or 220±1°C). In some embodiments, the tartrate salt is characterized by a differential scanning calorimetry trace including a peak at 222±4°C (e.g., 222±3°C, 222±2°C, or 222±1°C). In some embodiments, the tartrate salt 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 salt 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 salt 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 salt 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).

[0312] In some embodiments, the tartrate salt is characterized by exhibiting a differential scanning calorimetry trace comprising a peak from 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 from 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 from 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 from 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 from 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 from 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 from about 220°C to about 224°C. In some embodiments, the tartrate salt is characterized by a differential scanning calorimetry trace comprising a peak from about 222°C to about 228°C. In some embodiments, the tartrate salt is characterized by a differential scanning calorimetry trace comprising a peak from about 222°C to about 226°C. In some embodiments, the tartrate salt is characterized by a differential scanning calorimetry trace comprising a peak from about 222°C to about 224°C.

[0313] In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at about 215°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm 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 exotherm 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 exotherm 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 exotherm 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 with an onset of exotherm 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 with an onset of exotherm 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 with an onset of exotherm 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 with an onset of exotherm 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 that includes an exotherm onset at 230±4° C. (eg, 230±3° C., 230±2° C., or 230±1° C.).

[0314] In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset of about 215°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset of about 215°C to about 228°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset of about 217°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset of about 217°C to about 228°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset of about 219°C to about 230°C. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset of about 219°C to about 228°C.

[0315] 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) are true:

[0316] (a) The tartrate is a hemitartrate;

[0317] (b) The tartrate salt is in crystalline form;

[0318] (c) the tartrate salt has a solubility, calculated as the amount of free base of Compound I, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.4 and at a temperature of about 25° C.;

[0319] (d) the tartrate salt has a solubility, calculated as the amount of free base of Compound I, of about 0.3 mg / mL in an aqueous solution having a pH of about 4.7 and at a temperature of about 25° C.;

[0320] (e) the tartrate salt has a solubility, calculated as the amount of free base of Compound I, of about 0.2 mg / mL in an aqueous solution having a pH of about 6.6 and at a temperature of about 25° C.;

[0321] (f) Tartrate is

[0322] (i) peak at 17.9 ± 0.2 degrees 2θ;

[0323] (ii) peaks at 5.8 ± 0.2 and 17.9 ± 0.2 degrees 2θ;

[0324] (iii) peaks at 5.8 ± 0.2, 7.4 ± 0.2, and 17.9 ± 0.2 degrees 2θ;

[0325] (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 degrees 2θ; or

[0326] (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 exhibiting an XRPD pattern comprising:

[0327] (g) Tartrate is

[0328] (i) a peak between about 218°C and about 230°C; or

[0329] (ii) A peak of about 218°C to about 230°C and an exothermic onset of about 215°C to about 230°C 1 shows a differential scanning calorimetry trace containing:

[0330] 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)(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) apply. In some embodiments, (c), (d), (e), (f)(iv), and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(v), and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(i), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(ii), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(iii), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(iv), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(v), and (g)(ii) apply.

[0331] Malate

[0332] In some embodiments, provided herein is a malate salt of Compound I.

[0333] In some embodiments, the malate salt of Compound I is a hemimalate salt.

[0334] In some embodiments, the malate salt of Compound I is in a crystalline form.

[0335] In some embodiments, the malate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 1.4 and at a temperature of about 25° C. In some embodiments, the malate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 4.8 and at a temperature of about 25° C. In some embodiments, the malate salt has a solubility of 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 free base of Compound I, in an aqueous solution having a pH of about 6.4 and at a temperature of about 25°C.

[0336] In some embodiments, the malate salt has an XRPD pattern substantially as shown in Figure 3 A. The angles and peak intensities measured in degrees 2θ that may be observed for the malate salt using XRPD are shown in Table 10.

[0337] [Table 10]

[0338] In some embodiments, the malate salt has an XRPD pattern exhibiting at least one or at least two peaks with maximum intensity at 2θ degrees in the XRPD pattern substantially as shown in FIG. 3A or as set forth in Table 10. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the malate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0339] In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.3±0.2 and 23.4±0.2 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.3±0.4 and 23.4±0.4 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.3±0.6 and 23.4±0.6 degrees 2θ. It will be appreciated that additional peaks in the XRPD pattern other than those shown in FIG. 3A or listed in Table 10 may be observed due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0340] In some embodiments, the malate salt has an XRPD pattern substantially as shown in Figure 3B. The angles and peak intensities measured in degrees 2θ that may be observed for the malate salt using XRPD are shown in Table 11.

[0341] [Table 11]

[0342] In some embodiments, the malate salt has an XRPD pattern substantially as shown in FIG. 3B or as set forth in Table 11, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and instrumentation used to obtain the spectrum, as well as analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the malate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0343] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It will be understood that additional peaks in the XRPD pattern other than those shown in Figure 3B or listed in Table 11 may be observed due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0344] In some embodiments, the malate salt has an XRPD pattern substantially as shown in Figure 3C. The angles and peak intensities measured in degrees 2θ that may be observed for the malate salt using XRPD are shown in Table 12.

[0345] [Table 12]

[0346] In some embodiments, the malate salt has an XRPD pattern substantially as shown in FIG. 3C or as set forth in Table 12, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the malate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0347] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It will be understood that additional peaks in the XRPD pattern other than those shown in Figure 3C or listed in Table 12 may be observed due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0348] In some embodiments, the malate salt has an XRPD pattern substantially as shown in Figure 3D. The angles and peak intensities measured in degrees 2θ that may be observed for the malate salt using XRPD are shown in Table 13.

[0349] [Table 13]

[0350] In some embodiments, the malate salt has an XRPD pattern substantially as shown in FIG. 3D or as set forth in Table 13, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the malate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0351] In some embodiments, malate is 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, 17.7±0.2, 18.2±0.2, 19.2±0.2, 20.2±0.2, 21.2±0.2, 22.2±0.2, 23.2±0.2, 24.2±0.2, 25.2±0.2, 26.2±0.2, 27.2±0.2, 28.2±0.2, 29.2±0.2, 30.2±0.2, 31.2±0.2, 32.2±0.2, 33.2±0.2, 34.2±0.2, 35.2±0.2, 36.2±0.2, 37.2±0.2, 38.2±0.2, 39.2±0.2, 40.2±0.2, 41.2±0.2, 42.2±0.2, 43.2±0.2, 44.2±0.2, 45.2±0.2, 46.2±0.2, 47.2±0.2, 48.2±0.2, 49.2±0.2, 50.2±0.2, 51.2±0.2, 52.2±0.2, 53.2±0.2, 54.2±0 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 degrees 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 degrees 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 degrees 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±0.4, 17.7±0.4, 18.2±0.4 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 degrees 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 degrees 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 degrees 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, 17.7±0.6, 18.2±0.6 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 degrees 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 degrees 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 degrees 2θ.It will be understood that additional peaks in the XRPD pattern other than those shown in Figure 3D or listed in Table 13 may be observed, for example, due to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0352] In some embodiments, the malate salt has an XRPD pattern including peaks at 6.0±0.2 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern including peaks at 6.0±0.2 and 20.2±0.2 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern including peaks at 6.0±0.2, 19.5±0.2, and 20.2±0.2 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern including 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. In some embodiments, the malate salt has an XRPD pattern including 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. In some embodiments, the malate salt has an XRPD pattern including peaks at 6.0±0.4 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern including peaks at 6.0±0.4 and 20.2±0.4 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern including peaks at 6.0±0.4, 19.5±0.4, and 20.2±0.4 degrees 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 degrees 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 degrees 2θ. In some embodiments, the malate salt has an XRPD pattern comprising a peak at 6.0±0.6 degrees 2θ.In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.6 and 20.2±0.6 degrees 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 degrees 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 degrees 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 degrees 2θ.

[0353] In some embodiments, the malate salt has a differential scanning calorimetry trace substantially as shown in FIG. 3E. In some embodiments, the malate salt has a differential scanning calorimetry trace substantially as shown in FIG. 3F. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace including a peak at about 146°C to about 160°C. In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace including a peak at 146±4°C (e.g., 146±3°C, 146±2°C, or 146±1°C). In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace including a peak at 148±4°C (e.g., 148±3°C, 148±2°C, or 148±1°C). In some embodiments, the malate salt is characterized by exhibiting a differential scanning calorimetry trace including a peak at 150±4°C (e.g., 150±3°C, 150±2°C, or 150±1°C). In some embodiments, the malate salts are characterized by exhibiting a differential scanning calorimetry trace that includes a peak at 152±4°C (e.g., 152±3°C, 152±2°C, or 152±1°C). In some embodiments, the malate salts are characterized by exhibiting a differential scanning calorimetry trace that includes a peak at 154±4°C (e.g., 154±3°C, 154±2°C, or 154±1°C). In some embodiments, the malate salts are characterized by exhibiting a differential scanning calorimetry trace that includes a peak at 156±4°C (e.g., 156±3°C, 156±2°C, or 156±1°C). In some embodiments, the malate salts are characterized by exhibiting a differential scanning calorimetry trace that includes 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 that includes a peak at 160±4°C (e.g., 160±3°C, 160±2°C, or 160±1°C).

[0354] In some embodiments, the malate 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 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 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 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 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 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 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 salts are characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 150°C to about 158°C. In some embodiments, the malate salts are characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 150°C to about 156°C. In some embodiments, the malate salts are characterized by exhibiting a differential scanning calorimetry trace comprising a peak from about 150°C to about 154°C.

[0355] In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset at about 134°C to about 147°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with 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 with 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 with 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 with an endothermic onset at 140±4°C (e.g., 140±3°C, 140±2°C, or 140±1°C). In some embodiments, the malate salts exhibit a differential scanning calorimetry trace with an endothermic onset at 142±4°C (e.g., 142±3°C, 142±2°C, or 142±1°C). In some embodiments, the malate salts exhibit a differential scanning calorimetry trace with an endothermic onset at 144±4°C (e.g., 144±3°C, 144±2°C, or 144±1°C). In some embodiments, the malate salts exhibit a differential scanning calorimetry trace with an endothermic onset at 146±4°C (e.g., 146±3°C, 146±2°C, or 146±1°C). In some embodiments, the malate salts exhibit a differential scanning calorimetry trace with an endothermic onset at 147±4°C (e.g., 147±3°C, 147±2°C, or 147±1°C).

[0356] In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 134°C and about 147°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 134°C and about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 134°C and about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 136°C and about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 134°C and about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 136°C and about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 138°C and about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 134°C and about 140°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 136°C and about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 138°C and about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 140°C and about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 134°C and about 138°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 136°C and about 140°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endothermic onset between about 138°C and about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 140°C to about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 142°C to about 146°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 134°C to about 136°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 136°C to about 138°C.In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 138°C to about 140°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 140°C to about 142°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 142°C to about 144°C. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace with an endothermic onset of about 144°C to about 146°C.

[0357] 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) are true:

[0358] (a) The malate is a hemimalate;

[0359] (b) Malate is in crystalline form;

[0360] (c) the malate salt has a solubility, calculated as the amount of free base of Compound I, of greater than about 20 mg / mL in an aqueous solution having a pH of about 1.4 and at a temperature of about 25° C.;

[0361] (d) the malate salt has a solubility, calculated as the amount of free base of Compound I, of greater than about 20 mg / mL in an aqueous solution having a pH of about 4.8 and at a temperature of about 25° C.;

[0362] (e) the malate salt has a solubility, calculated as the amount of free base of Compound I, of about 0.3 mg / mL in an aqueous solution having a pH of about 6.4 and at a temperature of about 25° C.;

[0363] (f) Malate is

[0364] (i) peak at 6.0 ± 0.2 degrees 2θ;

[0365] (ii) peaks at 6.0 ± 0.2 and 20.2 ± 0.2 degrees 2θ;

[0366] (iii) peaks at 6.0 ± 0.2, 19.5 ± 0.2, and 20.2 ± 0.2 degrees 2θ;

[0367] (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

[0368] (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 exhibiting an XRPD pattern comprising:

[0369] (g) Malate is

[0370] (i) a peak between about 146°C and about 160°C; or

[0371] (ii) a peak at about 146°C to about 160°C and an endothermic onset at about 134°C to about 147°C 1 shows a differential scanning calorimetry trace containing:

[0372] 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)(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) apply. In some embodiments, (c), (d), (e), (f)(iv), and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(v), and (g)(i) apply. In some embodiments, (c), (d), (e), (f)(i), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(ii), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(iii), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(iv), and (g)(ii) apply. In some embodiments, (c), (d), (e), (f)(v), and (g)(ii) apply.

[0373] Citrate

[0374] In some embodiments, provided herein is the citrate salt of Compound I.

[0375] In some embodiments, the citrate salt of Compound I is a hemicitrate salt.

[0376] In some embodiments, the citrate salt of Compound I is in a crystalline form.

[0377] In some embodiments, the citrate salt has an XRPD pattern substantially as shown in Figure 4A. The angles and peak intensities measured in degrees 2θ that may be observed for the citrate salt using XRPD are shown in Table 14.

[0378] [Table 14]

[0379] In some embodiments, the citrate salt has an XRPD pattern substantially as shown in FIG. 4A or as set forth in Table 14, exhibiting at least one, at least two, at least three, at least four, at least five, or at least six peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the citrate salt, may vary by about ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0380] 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 degrees 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 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at 7.6±0.2 and 18.9±0.2 degrees 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 degrees 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 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at 7.6±0.4 and 18.9±0.4 degrees 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 degrees 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 degrees 2θ. In some embodiments, the Citrate Salt has an XRPD pattern comprising peaks at 7.6±0.6 and 18.9±0.6 degrees 2θ. It is understood that additional peaks in the XRPD pattern other than those shown in Figure 4A or listed in Table 14 may be observed due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0381] In some embodiments, the citrate salt has an XRPD pattern substantially as shown in Figure 4B. The angles and peak intensities measured in degrees 2θ that may be observed for the citrate salt using XRPD are shown in Table 15.

[0382] [Table 15]

[0383] In some embodiments, the citrate salt has an XRPD pattern substantially as shown in FIG. 4B or as set forth in Table 15, exhibiting 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 degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the citrate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0384] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It will be understood that additional peaks in the XRPD pattern other than those shown in Figure 4B or listed in Table 15 may be observed, for example, due to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0385] In some embodiments, the citrate salt has an XRPD pattern substantially as shown in Figure 4C. The angles and peak intensities measured in degrees 2θ that may be observed for the citrate salt using XRPD are shown in Table 16.

[0386] [Table 16]

[0387] In some embodiments, the citrate salt has an XRPD pattern substantially as shown in FIG. 4C or as set forth in Table 16, exhibiting at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks at 2θ degrees of maximum intensity in the XRPD pattern. It should be understood that peak intensities may vary depending on several factors, including sample preparation, mounting, and the instrument used to obtain the spectrum, as well as the analytical procedures and settings. Peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for the citrate salt, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2θ.

[0388] 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 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 degrees 2θ. It is understood that additional peaks in the XRPD pattern other than those shown in Figure 4C or listed in Table 16 may be observed due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0389] In some embodiments, the citrate salt has an XRPD pattern including peaks at 7.3±0.2 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern including peaks at 7.3±0.2 and 7.4±0.2 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern including peaks at 7.3±0.2, 7.4±0.2, and 18.6±0.2 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern including 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. In some embodiments, the citrate salt has an XRPD pattern including 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. In some embodiments, the citrate salt has an XRPD pattern including peaks at 7.3±0.4 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern including peaks at 7.3±0.4 and 7.4±0.4 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern including peaks at 7.3±0.4, 7.4±0.4, and 18.6±0.4 degrees 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 degrees 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 degrees 2θ. In some embodiments, the citrate salt has an XRPD pattern comprising a peak at 7.3±0.6 degrees 2θ.In some embodiments, the citrate salt has an XRPD pattern comprising peaks at 7.3±0.6 and 7.4±0.6 degrees 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 degrees 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 degrees 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 degrees 2θ.

[0390] In some embodiments, the Citrate Salt has a differential scanning calorimetry trace substantially as shown in FIG. 4D. In some embodiments, the Citrate Salt is characterized by a differential scanning calorimetry trace including a peak at about 175°C to about 179°C. In some embodiments, the Citrate Salt is characterized by a differential scanning calorimetry trace including a peak at 175±4°C (e.g., 175±3°C, 175±2°C, or 175±1°C). In some embodiments, the Citrate Salt is characterized by a differential scanning calorimetry trace including a peak at 177±4°C (e.g., 177±3°C, 177±2°C, or 177±1°C). In some embodiments, the Citrate Salt is characterized by a differential scanning calorimetry trace including a peak at 179±4°C (e.g., 179±3°C, 179±2°C, or 179±1°C).

[0391] 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.

[0392] In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace with an endothermic onset at about 124°C to about 128°C. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace with an endothermic onset at 124±4°C (e.g., 124±3°C, 124±2°C, or 124±1°C). In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace with an endothermic onset at 126±4°C (e.g., 126±3°C, 126±2°C, or 126±1°C). In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace with an endothermic onset at 128±4°C (e.g., 128±3°C, 128±2°C, or 128±1°C).

[0393] 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.

[0394] In some embodiments of the Citrate Salt, at least one, at least two, at least three, or all of the following (a)-(d) are true:

[0395] (a) The citrate is a hemicitrate;

[0396] (b) The citrate salt is in crystalline form;

[0397] (c) Citrate is

[0398] (i) peak at 7.3 ± 0.2 degrees 2θ;

[0399] (ii) peaks at 7.3±0.2 and 7.4±0.2 degrees 2θ;

[0400] (iii) peaks at 7.3 ± 0.2, 7.4 ± 0.2, and 18.6 ± 0.2 degrees 2θ;

[0401] (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

[0402] (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 exhibiting an XRPD pattern comprising:

[0403] (d) Citrate is

[0404] (i) a peak between about 175°C and about 179°C; or

[0405] (ii) a peak at about 175°C to about 179°C and an endothermic onset at about 124°C to about 128°C 1 shows a differential scanning calorimetry trace containing:

[0406] 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.

[0407] HER2

[0408] 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 in cells. The HER2 gene is found on human chromosome 17. The HER2 protein consists of four membrane-bound receptor tyrosine kinases. Signal transduction 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).

[0409] 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. As used herein, the term "HER2" refers to either i) a nucleic acid sequence encoding the HER2 protein, or ii) the protein.

[0410] As used herein, the term "HER2-amplified" or "HER2-amplified" cancer or cells refers to cancer or cells characterized by amplification of the HER2 gene, which can be easily assessed by methods known to those skilled in the art, such as commercially available in situ hybridization (ISH) tests or tests that can be performed by methods known to those skilled in the art. It is a term commonly used and understood in the field. For purposes of this application, a HER2-amplified cancer or cell is one in which: a) the cancer or cell exhibits at least 3, 4, 5, or 6 copies (e.g., 6 copies) of the gene encoding the HER2 protein per interphase nucleus, as detected by a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer (e.g., according to ASCO / CAP guidelines, such as the 2007, 2013, or 2018 guidelines); b) the cancer or cell exhibits at least 1.8, 2.0, or 2.5 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein relative to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus, as detected by a dual-probe ISH test performed on a sample derived from the cancer. c) cancers or cells (i) exhibit a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8, 2.0, or 2.2, and (ii) exhibit at least 3, 4, 5, or 6 copies of the gene encoding HER2 protein per interphase nucleus constituting the sample, as detected by a dual-probe ISH test performed on the cancer-derived sample (e.g., according to the ASCO / CAP guidelines, e.g., the 2007, 2013, or 2018 guidelines). In some cases, HER2-amplified cancers are defined according to the criteria set forth in the 2007, 2013, or 2018 ASCO / CAP guidelines, or other widely accepted criteria for the cancer (e.g., a particular cancer).

[0411] HER2 amplification has been identified in various 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, esophagogastric junction (GEJ) cancer, head and neck cancer, biliary tract cancer, prostate cancer, and pancreatic adenocarcinoma. HER2 amplification is present in approximately 18% to 25% of breast cancers. HER2 amplification is also present in approximately 30% of GEJ cancers and approximately 20% of gastric cancers.

[0412] HER2-amplified tumors are characterized by an aggressive phenotype (e.g., increased cell proliferation, increased cell survival, increased cell motility, and increased cell adhesion), increased metastasis, increased recurrence, shorter disease-free survival, and reduced overall survival.

[0413] In some embodiments, HER2 gene amplification can be detected and / or assessed via in situ hybridization (ISH) techniques, such as chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization (SISH), or fluorescent in situ hybridization (FISH), or similar methods performed on samples from cancer. 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 dual-probe ISH, in which the HER2 gene copy number is quantified in relation to the number of centromere 17 (CEP17) gene copies per nucleus. In some embodiments, HER2 protein expression is detected via immunohistochemistry (IHC) or similar methods. In some embodiments, the cancer is metastatic, and ISH testing is performed on samples from metastatic sites.

[0414] 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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus, as detected by single-probe in situ hybridization (ISH) testing (e.g., according to ASCO / CAP guidelines, such as the 2007, 2013, or 2018 guidelines) performed on a sample from the cancer. In some embodiments, the cancer has been determined to exhibit a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8, 2.0, or 2.2, as detected by dual-probe ISH testing (e.g., according to ASCO / CAP guidelines, such as the 2007, 2013, or 2018 guidelines) performed on a sample from the cancer. In some embodiments, the cancer is determined to exhibit (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus 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 comprising the sample, as detected by a dual-probe ISH test (e.g., according to ASCO / CAP guidelines, such as the 2007, 2013, or 2018 guidelines) performed on a sample derived from the cancer.

[0415] In some embodiments, the cancer comprises overexpression of the HER2 protein, which increases expression of the HER2 tyrosine kinase receptor on the cell membrane, leading to increased homo- or heterodimerization of HER2 with other family members, including HER1 / EGFR, HER3, and HER4, resulting in increased activation of HER2 signaling, resulting in increased cell cycle progression and cell proliferation, leading to cancer.

[0416] As used herein, the term "HER2-overexpressed" or "HER2-overexpressed" cancer or cells refers to cancer or cells characterized by overexpression of HER2 protein, which can be easily assessed by methods known to those skilled in the art, such as immunohistochemistry (IHC) tests that are commercially available or can be performed by methods known to those skilled in the art. This is a term commonly used and understood in the field. For purposes of this application, HER2-overexpressed cancer or cells encompasses cancer or cells that exhibit at least 10% of cancer cells that are 2+ or 3+ positive by immunohistochemistry (IHC) tests performed on samples derived from the cancer (e.g., according to the ASCO / CAP guidelines, 2007, 2013, or 2018 guidelines). In some cases, HER2-overexpressed cancer is defined according to the criteria set forth in the 2007, 2013, or 2018 ASCO / CAP guidelines, or other widely accepted criteria for the cancer (e.g., a particular cancer).

[0417] In some embodiments, a 3+ positive IHC score is associated with a test result showing a uniform, dark, and circumferential (wire mesh) pattern in at least 10% of the tumor cells, while a 2+ positive test result is associated with weak to moderate complete membrane staining in at least 10% of the tumor cells.

[0418] In some embodiments, when examined using one or more of (i)-(iv): (i) a single-probe in situ hybridization (ISH) test performed on a sample derived from a cancer shows at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (ii) a dual-probe ISH test performed on a sample derived from a cancer shows a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8; (iii) a dual-probe ISH test performed on a sample derived from a cancer shows (a) a ratio of at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus; (b) a ratio of at least 2.0 between the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein and the number of chromosome 17 centromeres (CEP17) per interphase nucleus, and (b) at least 4 copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (iv) an immunohistochemistry (IHC) test performed on the cancer-derived sample shows at least 10% 3+ positive cancer cells; or (v) (a) an immunohistochemistry (IHC) test performed on the cancer-derived sample shows at least 10% 2+ positive cancer cells, and (b) a single probe in situ hybridization (ISH) test performed on the cancer-derived sample is determined to be positive.

[0419] As used herein, the term "HER2-positive" cancers or cells encompasses both HER2-amplified cancers or cells and cancers or cells that overexpress HER2.

[0420] In some embodiments, the cancers described herein involve both amplification of the gene encoding HER2 and overexpression of the HER2 protein.

[0421] In some embodiments, the cancers described herein involve amplification of the gene encoding HER2, but do not involve overexpression of HER2.

[0422] In some embodiments, the cancers described herein involve overexpression of HER2 but do not involve amplification of the gene encoding HER2.

[0423] Method of preparation

[0424] In some embodiments, provided is a method for preparing a fumarate salt of Compound I, comprising: (1) forming a mixture of Compound I and fumaric acid in a solvent; and (2) removing the solvent from step (1) to obtain the 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 in step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methylpyrrolidinone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ammonia, or acetic acid). In some embodiments, the solvent in step (1) comprises an aprotic solvent. In some embodiments, the solvent in step (1) comprises acetone. In some embodiments, the solvent in step (1) comprises acetonitrile. In some embodiments, the solvent in step (1) comprises ethyl acetate. In some embodiments, the solvent in step (1) comprises a protic solvent. In some embodiments, the solvent in step (1) comprises ethanol. In some embodiments, the mixture in step (1) is stirred at 20 to 60°C. In some embodiments, the mixture in 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.

[0425] In some embodiments, provided is a method for preparing a tartrate salt of Compound I, comprising: (1) forming a mixture of Compound I and tartaric acid in a solvent; and (2) removing the solvent from step (1) to obtain the 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 in step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methylpyrrolidinone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ammonia, or acetic acid). In some embodiments, the solvent in step (1) comprises an aprotic solvent. In some embodiments, the solvent in step (1) comprises acetone. In some embodiments, the solvent in step (1) comprises acetonitrile. In some embodiments, the solvent in step (1) comprises ethyl acetate. In some embodiments, the solvent in step (1) comprises a protic solvent. In some embodiments, the solvent in step (1) comprises ethanol. In some embodiments, the mixture in step (1) is stirred at 20 to 60°C. In some embodiments, the mixture in 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.

[0426] In some embodiments, provided is a method for preparing a malic acid salt of Compound I, comprising: (1) forming a mixture of Compound I and malic acid in a solvent; and (2) removing the solvent from step (1) to obtain the malic acid 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 in step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methylpyrrolidinone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ammonia, or acetic acid). In some embodiments, the solvent in step (1) comprises an aprotic solvent. In some embodiments, the solvent in step (1) comprises acetone. In some embodiments, the solvent in step (1) comprises acetonitrile. In some embodiments, the solvent in step (1) comprises ethyl acetate. In some embodiments, the solvent in step (1) comprises a protic solvent. In some embodiments, the solvent in step (1) comprises ethanol. In some embodiments, the mixture in step (1) is stirred at 20 to 60°C. In some embodiments, the mixture in 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.

[0427] In some embodiments, provided is a method for preparing a citrate salt of Compound I, comprising: (1) forming a mixture of Compound I and citric acid in a solvent; and (2) removing the solvent from step (1) to obtain the 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 in step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or N-methylpyrrolidinone) or a protic solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ammonia, or acetic acid). In some embodiments, the solvent in step (1) comprises an aprotic solvent. In some embodiments, the solvent in step (1) comprises acetone. In some embodiments, the solvent in step (1) comprises acetonitrile. In some embodiments, the solvent in step (1) comprises ethyl acetate. In some embodiments, the solvent in step (1) comprises a protic solvent. In some embodiments, the solvent in step (1) comprises ethanol. In some embodiments, the mixture in step (1) is stirred at 20 to 60°C. In some embodiments, the mixture in 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.

[0428] composition

[0429] Also provided herein are compositions containing a salt described herein, such as a fumarate, tartrate, malate, or citrate salt of Compound I. In some embodiments, the composition contains a fumarate salt of Compound I. In some embodiments, the composition contains a tartrate salt of Compound I. In some embodiments, the composition contains a malate salt of Compound I. In some embodiments, the composition contains a citrate salt 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.

[0430] In some embodiments, provided are compositions containing the fumarate salt of Compound I. In some embodiments, the compositions are substantially free of other salts and non-salt forms of Compound I. In some embodiments, the compositions are substantially free of amorphous or non-crystalline forms of Compound I.

[0431] In some embodiments of a composition containing the fumarate 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 the total composition is the fumarate salt. In some embodiments of a composition containing the fumarate 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 as the fumarate salt.

[0432] In some embodiments, provided are compositions containing the tartrate salt of Compound I. In some embodiments, the compositions are substantially free of other salts and non-salt forms of Compound I. In some embodiments, the compositions are substantially free of amorphous or non-crystalline forms of Compound I.

[0433] In some embodiments of a composition containing the 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 the total composition is the tartrate salt. In some embodiments of a composition containing the 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 as the tartrate salt.

[0434] In some embodiments, provided are compositions containing the malic acid salt of Compound I. In some embodiments, the compositions are substantially free of other salts and non-salt forms of Compound I. In some embodiments, the compositions are substantially free of amorphous or non-crystalline forms of Compound I.

[0435] In some embodiments of a composition containing the malate 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 the total composition is malate salt. In some embodiments of a composition containing a 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 as the malate salt.

[0436] In some embodiments, provided are compositions containing the citrate salt of Compound I. In some embodiments, the compositions are substantially free of other salts and non-salt forms of Compound I. In some embodiments, the compositions are substantially free of amorphous or non-crystalline forms of Compound I.

[0437] In some embodiments of a composition containing the citrate 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 the total composition is the citrate salt. In some embodiments of a composition containing a 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 Compound I in the composition is present as the citrate salt.

[0438] Treatment methods

[0439] In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a salt or pharmaceutical composition provided herein. In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a therapeutically effective amount of a salt or pharmaceutical composition provided herein. In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a fumarate salt of Compound I, or a pharmaceutical composition comprising a fumarate salt of Compound I and a pharmaceutically acceptable carrier. In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a tartrate salt of Compound I, or a pharmaceutical composition comprising a tartrate salt of Compound I and a pharmaceutically acceptable carrier. In some embodiments, provided are methods of treating cancer in an individual in need of treatment, comprising administering to the individual a malate salt of Compound I, or a pharmaceutical composition comprising a malate salt of Compound I and a pharmaceutically acceptable carrier. In some embodiments, provided is a method of treating cancer in an individual in need thereof, comprising administering to the individual a citrate salt of Compound I, or a pharmaceutical composition comprising a citrate salt of Compound I and a pharmaceutically acceptable carrier.

[0440] Also provided herein is the use of a salt or composition provided herein in the manufacture 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 of treating cancer. In some embodiments, provided herein is the use of a salt or composition provided herein for treating cancer.

[0441] In some embodiments, provided are methods of treating cancer in an individual in need thereof, 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, provided are methods of treating cancer in an individual in need thereof (e.g., metastatic cancer), comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer comprises a mutation in epidermal growth factor receptor (EGFR), 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 group consisting of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, EGFR exon 20 ins ASV, and an ERBB2 mutation that is EGFR exon 20 ins YVMA. In some embodiments, the cancer comprises a mutation that is EGFR Del19 / T790M. In some embodiments, the cancer comprises a mutation that is EGFR L858R / T790M. In some embodiments, the cancer comprises a mutation that is EGFR L858R. In some embodiments, the cancer comprises a mutation that is EGFR exon 20 ins NPH. In some embodiments, the cancer comprises a mutation that is EGFR exon 20 ins SVD. In some embodiments, the cancer comprises a mutation that is EGFR exon 20 ins FQEA. In some embodiments, the cancer comprises a mutation in EGFR exon 20 ins H. In some embodiments, the cancer comprises a mutation in EGFR exon 20 ins ASV. In some embodiments, the cancer comprises a mutation in ERBB2 in Her2 exon 20 ins YVMA. In some embodiments, the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, gastric cancer, and colorectal cancer.

[0442] In some embodiments, the cancer is pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer. Biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain tumor, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer In some embodiments, the cancer is selected from the group consisting of uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain tumor, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. In some embodiments, the cancer is metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some embodiments, the cancer is metastatic brain tumor. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0443] In some embodiments, provided are methods of 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 amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of 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 amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some embodiments, provided are methods of 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 overexpression of the human epidermal growth factor receptor 2 (HER2) protein.

[0444] In some variations of any of the embodiments described herein, the cancer is locally advanced. 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). In some variations, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some variations, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some variations, when examined using a dual-probe ISH test performed on a sample from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus 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) per interphase nucleus comprising the sample. In some variations, the cancer exhibits at least 10% 2+ or 3+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample from the cancer.In some variations, (a) the cancer, when examined using an immunohistochemistry (IHC) test performed on a sample from the cancer, exhibits at least 10% 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some variations, the cancer is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations (e.g., any of the mutations described herein) in the epidermal growth factor receptor (EGFR) protein. In some variations, the cancer does not comprise a mutation in the epidermal growth factor receptor (EGFR) protein. In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations (e.g., any of the mutations described herein) in the HER2 protein. In some variations, 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 variations, the cancer does not comprise any mutations in the HER2 protein. In some variations, the cancer does not comprise overexpression of HER2. In some variations, the cancer does not comprise amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some variations, the cancer does not comprise one or more mutations in the HER2 protein. In some variations, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variations, the cancer does not contain 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 variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP.In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein, p.G780_P781dupGSP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein, p.G778_S779insCPG. In some variations, the cancer does not contain a mutation in the HER2 protein, L775S. In some variations, the cancer does not contain a mutation in the HER2 protein, G776C. In some variations, the cancer does not contain any mutations in the HER2 protein. In some variations, the cancer contains a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not contain a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, 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 variations, 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 variations, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some variations, the method further comprises administering one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein) to an individual in need thereof. In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells.In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anti-cancer agents comprise a chemotherapeutic agent. In some variations, the individual is human.

[0445] In some embodiments, provided are methods of treating 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 one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of 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 the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided are methods of 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 the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some embodiments, provided are methods of 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) overexpression of the human epidermal growth factor receptor 2 (HER2) protein.

[0446] In some embodiments, provided are methods of 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 prior to administering the salt of Compound I, or a pharmaceutically acceptable salt thereof, the cancer is characterized in that: (i) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer reveals at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (ii) a dual-probe ISH test performed on a sample from the cancer reveals at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein relative to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus; (iii) a dual-probe ISH test performed on a sample derived from the cancer shows one or more of the following: (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 2.0, and (b) at least four copies of the gene encoding human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample; (iv) an immunohistochemistry (IHC) test performed on a sample derived from the cancer shows at least 10% 3+ positive cancer cells; or (v) (a) an immunohistochemistry (IHC) test performed on a sample derived from the cancer shows at least 10% 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer includes one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the cancer is locally advanced cancer. In some embodiments, the cancer is unresectable.

[0447] In some variations of any of the embodiments described herein, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some variations, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some variations, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) protein to the number of chromosome 17 centromeres (CEP17) per interphase nucleus 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) per interphase nucleus comprising the sample. In some variations, the cancer exhibits at least 10% 2+ or 3+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer. In some variations, (a) the cancer examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer exhibits at least 10% 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some variations, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein (e.g., any of the mutations described herein). In some variations, the cancer does not comprise a mutation in the epidermal growth factor receptor (EGFR) protein. In some variations, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein (e.g., any of the mutations described herein). In some variations, the cancer does not comprise overexpression of HER2. In some variations, the cancer does not comprise any mutations in the HER2 protein. In some variations, the cancer does not comprise an amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein. In some variations, the cancer does not comprise one or more mutations in the HER2 protein. In some variations, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variations, the cancer does not contain 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 variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some variations, the cancer does not contain a mutation in the HER2 protein that is L775S. In some variations, the cancer does not comprise a mutation in the HER2 protein that is G776C. In some variations, the cancer comprises a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not comprise a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein.In some variations, 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 variations, 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 variations, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some variations, the method further comprises administering one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein) to an individual in need thereof. In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anti-cancer agents comprise a chemotherapeutic agent. In some variations, the individual is human.

[0448] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein a single-probe in situ hybridization (ISH) test performed on a sample from the cancer indicates at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and a single-probe in situ hybridization (ISH) test performed on a sample from the cancer indicates at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein a single-probe in situ hybridization (ISH) test performed on a sample from the cancer shows at least 6 copies of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample, prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein 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 to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and 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 to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein a dual-probe ISH test performed on a sample from the cancer shows a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein a dual-probe ISH test performed on a sample from the cancer shows, prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 2.0, and (b) at least 4 copies of genes encoding human epidermal growth factor receptor 2 (HER2) proteins per interphase nucleus comprising the sample. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein a dual-probe ISH test performed on a sample from the cancer shows, prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of at least 2.0, and (b) at least 4 copies of genes encoding human epidermal growth factor receptor 2 (HER2) proteins per interphase nucleus comprising the sample.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein a dual-probe ISH test performed on a sample from the cancer shows, prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromeres of chromosome 17 (CEP17) per interphase nucleus of 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 comprising the sample. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of 3+ positive cancer cells prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of 3+ positive cancer cells prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein, and wherein immunohistochemistry (IHC) testing performed on a sample from the cancer shows at least 10% of 3+ positive cancer cells prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% of cancer cells that are 2+ positive, and (b) a single in situ hybridization (ISH) test performed on a sample from the cancer determines a positive result. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (a) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% 2+ positive cancer cells, and (b) a single in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, wherein the cancer comprises (a) one or more central nervous system (CNS) metastases and (b) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein, wherein prior to administration of the salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, (i) an immunohistochemistry (IHC) test performed on a sample from the cancer shows at least 10% 2+ positive cancer cells, and (ii) a single in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive.

[0449] In some variations of any of the embodiments described herein, the cancer is locally advanced. In some variations, the cancer is unresectable. In some variations, the cancer includes one or more central nervous system (CNS) metastases (e.g., brain metastases).

[0450] In some variations, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.

[0451] In some variations of any of the embodiments described herein, the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, gastric cancer, and colorectal cancer.

[0452] In some variations of any of the embodiments described herein, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein. In some variations, the one or more mutations in the EGFR protein are G309A, G309E, S310F, R678Q, R678Q, and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759, EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Del19, EGFR L858R / C797S, EGFR Del19 / C797S, EGFR exon 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins ASV. In some variations, 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 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins ASV. In some variations, the cancer does not contain any of the above EGFR mutations. In some variations, the cancer does not contain any mutations in the epidermal growth factor receptor (EGFR) protein.

[0453] In some variations 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 variations, the cancer does not comprise any mutations in the HER2 protein. In some variations, the cancer does not comprise one or more mutations in the HER2 protein. In some variations, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some variations, 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 variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some variations, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some variations, the cancer does not contain a mutation in the HER2 protein that is L775S. In some variations, the cancer does not contain a mutation in the HER2 protein that is G776C.

[0454] 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.

[0455] In some variations of any of the embodiments described herein, the individual has not undergone one or more prior therapies for the treatment of cancer prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.

[0456] In some variations of any of the embodiments described herein, the individual has undergone one or more prior therapies for the treatment of cancer before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. 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 were administered to the individual in a metastatic state. In some variations, the individual has failed one or more prior therapies before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.

[0457] In some variations of any of the embodiments described herein, the cancer does not involve overexpression of HER2.

[0458] In some variations of any of the embodiments described herein, the cancer does not include amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein.

[0459] In some variations of any of the embodiments described herein, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer.

[0460] In some variations of any of the embodiments described herein, the cancer does not comprise a mutation in a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein (e.g., one or more mutations at histidine 1047 or cysteine ​​420, e.g., H1047L, H1047R, or C420R).

[0461] In some variations of any of the embodiments described herein, the method further comprises administering to the individual in need thereof one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein) or a second therapy (e.g., radiation therapy). In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anticancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anticancer agents comprise a chemotherapeutic agent.

[0462] In some embodiments, provided are methods of 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 amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises overexpression of HER2. In some embodiments, the cancer sample exhibits HER2 expression of 3+ when examined using an immunohistochemistry (IHC) test. In some embodiments, the present application provides methods of 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 one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the present application provides a method of 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 the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises amplification of the gene encoding the HER2 protein. In some embodiments, the cancer comprises overexpression of the HER2 protein. In some embodiments, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein.In some embodiments, the one or more mutations in the EGFR protein are 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 20 ins NPH, EGFR exon 20 ins SVD, EGFR exon 20 ins FQEA, EGFR exon 20 ins H, and EGFR exon 20 ins ASV. In some embodiments, the one or more mutations comprise a G309A mutation. In some embodiments, the one or more mutations comprise a G309E mutation. In some embodiments, the one or more mutations comprise a S310F mutation. In some embodiments, the one or more mutations comprise a R678Q mutation. In some embodiments, the one or more mutations comprise a R678Q mutation and a L755W mutation. In some embodiments, the one or more mutations comprise a L755S mutation. In some embodiments, the one or more mutations comprise a L755W mutation. In some embodiments, the one or more mutations comprise a I767M mutation. In some embodiments, the one or more mutations comprise a D769H mutation. In some embodiments, the one or more mutations comprise a D769Y mutation. In some embodiments, the one or more mutations comprise a V777L mutation. In some embodiments, the one or more mutations comprise a Y835F mutation. In some embodiments, the one or more mutations comprise a V842I mutation. In some embodiments, the one or more mutations comprise a R896C mutation. In some embodiments, the one or more mutations comprise a G1201V mutation. In some embodiments, the one or more mutations comprise a del.755-759 EGFR Del19 / T790M mutation. In some embodiments, the one or more mutations comprise an EGFR L858R / T790M mutation. In some embodiments, the one or more mutations comprise an EGFR L858R mutation. In some embodiments, the one or more mutations comprise an EGFR del 19 mutation.In some embodiments, the one or more mutations comprise an EGFR L858R / C797S mutation. In some embodiments, the one or more mutations comprise an EGFR Del19 / C797S mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins NPH mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins SVD mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins FQEA mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins H mutation. In some embodiments, the one or more mutations comprise an EGFR exon 20 ins ASV mutation. In some embodiments, the cancer does not comprise any of the EGFR mutations listed above. In some embodiments, the cancer does not comprise any mutations in the epidermal growth factor receptor (EGFR) protein. In some embodiments, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus constituting the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2).In some embodiments, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus 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) per interphase nucleus comprising the sample. In some embodiments, when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ or 3+ positive cancer cells. In some embodiments, (a) when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer is selected from the group consisting of metastatic brain tumors, 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 thereof. In some embodiments, the individual has not received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the one or more prior therapies include one or more anti-HER2-based regimens. In some embodiments, one or more anti-HER2-based regimens have been administered to the individual in a metastatic state. In some embodiments, the individual has failed one or more prior therapies before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein.In some embodiments, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer. In some embodiments, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is unresectable.

[0463] In some embodiments, provided are methods of 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 amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises overexpression of HER2. In some embodiments, the cancer sample exhibits HER2 expression of 3+ when examined using an immunohistochemistry (IHC) test. In some embodiments, the present application provides methods of 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 one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the present application provides a method of 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 a human epidermal growth factor receptor 2 (HER2) protein or overexpression of a HER2 protein. In some embodiments, the cancer comprises amplification of a gene encoding a HER2 protein. In some embodiments, the cancer comprises overexpression of a HER2 protein. In some embodiments, the cancer comprises one or more (e.g., one, two, or three) mutations in a HER2 protein, wherein the one or more (e.g., one, two, or three) mutations in the HER2 protein are selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments, the one or more mutations comprise a p.A775_G776insYVMA mutation. In some embodiments, the one or more mutations comprise a p.778insGCP mutation. In some embodiments, the one or more mutations comprise a p.G780_P781dupGSP mutation.In some embodiments, the one or more mutations include a G778_S779insCPG mutation. In some embodiments, the cancer does not include any of the HER2 mutations described above. In some embodiments, the cancer does not include any mutations in the HER2 protein. In some embodiments, according to any one of the methods described herein, the cancer does not include one or more mutations in the HER2 protein. In some embodiments, according to any one of the methods described herein, the cancer does not include one or more exon 20 insertion mutations in the HER2 protein. In some embodiments, according to any one of the methods described herein, the cancer does not include 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 one of the methods described herein, the cancer does not include an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some embodiments of any one of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some embodiments of any one of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some embodiments of any one of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some embodiments of any one of the methods described herein, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some embodiments of any one of the methods described herein, the cancer does not comprise a mutation in the HER2 protein that is G776C.In some embodiments, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus constituting the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some embodiments, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus 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) per interphase nucleus comprising the sample. In some embodiments, when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ or 3+ positive cancer cells. In some embodiments, (a) when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer is selected from the group consisting of 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 thereof. In some embodiments, the individual has not received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has received one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the one or more prior therapies include one or more anti-HER2-based regimens. In some embodiments, one or more anti-HER2-based regimens were administered to the individual in a metastatic state. In some embodiments, the individual has failed one or more prior therapies before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein. In some embodiments, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer. In some embodiments, the cancer is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is unresectable.

[0464] In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 or second therapies, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 or second therapies, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of 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, and b) one or more additional anti-cancer agents or second therapies, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a pharmaceutical composition comprising a salt of Compound I as described herein or a salt of Compound I as described herein, and b) a HER2 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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, provided are methods of 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, and b) one or more chemotherapeutic agents, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, comprising administering to the individual a) a pharmaceutical composition comprising a salt of Compound I as described herein or a salt of Compound I as described herein, and b) one or more additional anti-cancer agents, including trastuzumab and capecitabine, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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, including trastuzumab and capecitabine, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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, including trastuzumab and capecitabine, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided is a method of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 (i) one or more central nervous system (CNS) metastases, and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein.In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, provided are methods of treating cancer (e.g., breast cancer) in an individual in need thereof, 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 (i) one or more central nervous system (CNS) metastases, and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided are methods of treating gastric cancer in an individual in need of treatment, 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, including a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, provided are methods of treating gastric cancer in an individual in need of treatment, 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, including a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, provided are methods of treating gastric cancer in an individual in need thereof, 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, including a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases and (ii) amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) protein or overexpression of HER2 protein. In some embodiments, provided is a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof, 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 the group consisting of carboplatin, a taxane, pemetrexed, a PD-1 inhibitor, and a PD-L1 inhibitor, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein, overexpression of the HER2 protein, or one or more mutations in the HER2 protein. In some embodiments, provided is a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof, 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 the group consisting of carboplatin, a taxane, pemetrexed, a PD-1 inhibitor, and a PD-L1 inhibitor, wherein the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases).In some embodiments, provided is a method of treating lung cancer (e.g., NSCLC or SCLC) in an individual in need thereof, 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 the group consisting of 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 the gene encoding human epidermal growth factor receptor 2 (HER2) protein, overexpression of the HER2 protein, or one or more mutations in the HER2 protein.

[0465] In some variations of any of the embodiments described herein, the cancer comprises an amplification of the gene encoding the HER2 protein. In some variations, the cancer comprises overexpression of the HER2 protein. In some variations, the one or more additional anti-cancer agents comprise a HER2 inhibitor. In some variations, the one or more additional anti-cancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise a HER2-immunotargeting bispecific antibody. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T cells (CTLs). In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anti-cancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anti-cancer agents comprise an epidermal growth factor receptor (EGFR) inhibitor. In some variations, the one or more additional anticancer agents comprise a poly-ADP-ribose polymerase (PARP) inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PD-L1 inhibitor. In some variations, the one or more additional anticancer agents comprise a PI3K inhibitor. In some variations, the one or more additional anticancer agents comprise a chemotherapeutic agent. In some variations, the one or more additional anticancer agents are selected from antibody-drug conjugates.In some variations, the one or more additional anticancer agents are 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-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, nekitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, Selected from the group consisting of veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemipilimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variations, the second therapy is radiation. In some variations, the one or more chemotherapeutic agents are selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin. In some variations, the EGFR inhibitor is selected from the group consisting of erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, lapatinib, dacomitinib, necitumumab, vandetanib, afatinib, brigatinib, and nicotinib.In some variations, the PARP inhibitor is selected from the group consisting of niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, and E7016. In some variations, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514. In some variations, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variations, the PI3K inhibitor is selected from the group consisting of taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (BKM120), duvelisib, (IPI-145), copanlisib (BAY80-6946), PX-866, dactolisib, CUDC-907, boctalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597. In some variations, the additional anticancer agent comprises a chemotherapeutic agent. In some variations, the chemotherapeutic agent is selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin. In some variations, the additional anticancer agent comprises a PD-1 inhibitor.In some variations, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514. In some variations, the cancer comprises one or more mutations in the HER2 protein. In some variations, the one or more additional anticancer agents comprise carboplatin. In some variations, the one or more additional anticancer agents comprise a taxane. In some variations, the one or more additional anticancer agents comprise pemetrexed. In some variations, the one or more additional anticancer agents comprise a PD-1 inhibitor. In some variations, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514. In some variations, the one or more additional anticancer agents comprise a PD-L1 inhibitor. In some variations, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variations, the cancer, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus comprising the sample prior to administration of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.In some variations, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some variations, when examined using a dual-probe ISH test performed on a sample from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus 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) per interphase nucleus comprising the sample. In some variations, the cancer exhibits at least 10% 2+ or 3+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer. In some variations, (a) the cancer exhibits at least 10% 2+ positive cancer cells when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some variations, the cancer is selected from the group consisting of metastatic brain tumor, 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 thereof. In some variations, the individual has not undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some variations, the individual has undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. 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 have been administered to the individual in a metastatic state. In some variations, the individual has failed one or more prior therapies before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some variations, the method further includes identifying the individual based on the individual having a HER2-amplified or HER2-overexpressing cancer. In some variations, the cancer is selected from the group consisting of metastatic brain tumor, breast cancer, and non-small cell lung cancer. In some variations, the cancer is locally advanced or metastatic. In some variations, the cancer is unresectable.

[0466] In some embodiments, there is provided a use of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein for the manufacture of a medicament for treating an individual with cancer, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, there is provided a use of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein for the treatment of a human with cancer, wherein the cancer comprises amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer is locally advanced. 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 use of a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein for the treatment of a human with cancer, wherein the cancer comprises one or more central nervous system (CNS) metastases. In some embodiments, there is provided a use of a salt of Compound I as described herein, or a pharmaceutical composition comprising a salt of Compound I as described herein, for 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 amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises amplification of the gene encoding the HER2 protein. In some embodiments, the cancer comprises overexpression of the HER2 protein. In some embodiments, the cancer does not comprise overexpression of HER2. In some embodiments, the cancer does not comprise amplification of the gene encoding the HER2 protein.In some embodiments, when examined using a single-probe in situ hybridization (ISH, e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits at least 3, 4, 5, or 6 copies (e.g., at least 6 copies) of the gene encoding human epidermal growth factor receptor 2 (HER2) per interphase nucleus constituting the sample prior to administering a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, when examined using a dual-probe ISH (e.g., silver-enhanced in situ hybridization (SISH) or fluorescent in situ hybridization (FISH)) test performed on a sample from the cancer, the cancer exhibits a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0, or 2.2). In some embodiments, when examined using a dual-probe ISH test performed on a sample derived from the cancer, the cancer exhibits (a) a ratio of the number of genes encoding human epidermal growth factor receptor 2 (HER2) proteins to the number of chromosome 17 centromeres (CEP17) per interphase nucleus 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) per interphase nucleus comprising the sample. In some embodiments, when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ or 3+ positive cancer cells. In some embodiments, (a) when examined using an immunohistochemistry (IHC) test performed on a sample derived from the cancer, the cancer exhibits at least 10% of 2+ positive cancer cells, and (b) a single-probe in situ hybridization (ISH) test performed on a sample derived from the cancer is determined to be positive. In some embodiments, the cancer is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.In some embodiments, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein (e.g., any of the mutations described herein). In some embodiments, the cancer does not comprise a mutation in the epidermal growth factor receptor (EGFR) protein. In some embodiments, the cancer comprises one or more (e.g., 1, 2, or 3) mutations in the HER2 protein (e.g., any of the mutations described herein). In some embodiments, the cancer does not comprise one or more mutations in the HER2 protein. In some embodiments, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some embodiments, 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, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some embodiments, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some embodiments, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some embodiments, the cancer does not contain an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some embodiments, the cancer does not contain a mutation in the HER2 protein that is L775S. In some embodiments, the cancer does not contain a mutation in the HER2 protein that is G776C. In some embodiments, the cancer does not contain any mutations in the HER2 protein. In some embodiments, the cancer contains a mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the cancer does not contain 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 selected from H1047L and H1047R in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the individual has not undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has undergone one or more prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the one or more prior therapies include one or more anti-HER2-based regimens (e.g., in a metastatic setting). In some embodiments, the individual has failed one or more prior therapies before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of Compound I described herein. In some embodiments, the composition is administered orally, parenterally, intravenously, subcutaneously, or intracerebrally to an individual in need thereof. In some embodiments, the method further comprises administering to the individual in need thereof one or more additional anti-cancer agents (e.g., any of the anti-cancer agents described herein). In some embodiments, the one or more additional anti-cancer agents comprise one or more agents selected from a HER2 inhibitor, a HER2-CD3 bispecific antibody, a HER2 immunotargeting bispecific antibody, an anti-HER2 chimeric antigen receptor (CAR) T cell, an anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocyte (CTL), an anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cell, an anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cell, an epidermal growth factor receptor (EGFR) inhibitor, a poly-ADP-ribose polymerase (PARP) inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and a chemotherapeutic agent.In some embodiments, the one or more additional anti-cancer agents are selected from antibody-drug conjugates (e.g., trastuzumab emtansine or trastuzumab deruxtecan). In some embodiments, the one or more additional anti-cancer agents comprise trastuzumab and capecitabine. In some embodiments, the 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 individual is human.

[0467] In some embodiments, the individual has undergone one or more (e.g., one, two, or three) prior therapies for the treatment of cancer before administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein. In some embodiments, the individual has failed one or more (e.g., one, two, or three) prior therapies before administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein.

[0468] In some embodiments, the one or more prior therapies exhibit inhibitory activity against cancers that comprise a T790M mutation in the epidermal growth factor receptor (EGFR) protein. In some embodiments, the one or more prior therapies exhibit inhibitory activity against cancers that comprise a T790M mutation in the epidermal growth factor receptor (EGFR) protein include osimertinib.

[0469] In some embodiments, the individual has been administered osimertinib prior to administering to the individual a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein. In some embodiments, at the time the individual is administered a salt of Compound I described herein or a pharmaceutical composition comprising a salt of Compound I described herein, administration of osimertinib has been completed for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0470] In some embodiments, the one or more prior therapies include one or more standard therapies for the cancer.

[0471] In some embodiments, the individual has not undergone one or more (e.g., 1, 2, or 3) prior therapies for the treatment of cancer prior to administering to the individual a pharmaceutical composition comprising a salt of Compound I described herein or a salt of a compound described herein.

[0472] In some embodiments, the individual is a mammal, hi some embodiments, the individual is a human.

[0473] Second drug or therapy

[0474] In some embodiments, the methods further comprise administering to the individual in need thereof one or more additional anti-cancer agents or second therapies.

[0475] In some embodiments, the one or more additional anti-cancer agents comprise one or more agents selected from the group consisting of a HER2 inhibitor, a HER2-CD3 bispecific antibody, a HER2 immunotargeting bispecific antibody, an anti-HER2 chimeric antigen receptor (CAR) T cell, an anti-HER2 chimeric antigen receptor (CAR) cytotoxic T lymphocyte (CTL), an anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cell, an anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cell, an epidermal growth factor receptor (EGFR) inhibitor, a poly-ADP-ribose polymerase (PARP) inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and a chemotherapeutic agent.

[0476] Exemplary HER2 inhibitors include, but are not limited to, trastuzumab, trastuzumab and hyaluronidase, trastuzumab and capecitabine, tucatinib, lapatinib, neratinib, dacomitinib, pertuzumab, margetuximab, trastuzumab emtansine, trastuzumab deruxtecan, ZW49 (Zymeworks), A166 (Klaus Pharma), ARX788 (Ambrx), RC48-ADC (RemeGen), vic-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189.

[0477] Exemplary EGFR inhibitors include, but are not limited to, erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, lapatinib, dacomitinib, necitumumab, vandetanib, afatinib, brigatinib, and nicotinib.

[0478] Exemplary PARP inhibitors include, but are not limited to, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, and E7016.

[0479] Exemplary anti-PD-1 antibodies include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tirelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514.

[0480] Exemplary PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0481] Exemplary CTLA-4 inhibitors include ipilimumab and tremelimumab.

[0482] In some embodiments, the one or more additional anticancer agents are bevacizumab, 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-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, nekitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, bevacizumab Selected from the group consisting of riparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemipilimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0483] In some embodiments, the one or more additional anti-cancer agents are selected from antibody-drug conjugates, hi some embodiments, the antibody-drug conjugates are selected from the group consisting of trastuzumab emtansine and trastuzumab deruxtecan.

[0484] In some embodiments, the one or more additional anti-cancer agents comprise one or more chemotherapeutic agents, hi some embodiments, the one or more chemotherapeutic agents are selected from the group consisting of doxorubicin, docetaxel, pemetrexed, paclitaxel, carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, temozolomide, irinotecan, oxiplatin, and eribulin.

[0485] In some embodiments, the one or more additional anti-cancer agents comprise trastuzumab and capecitabine.

[0486] In some embodiments, the one or more additional anticancer agents comprise a PI3K inhibitor. Exemplary PI3K inhibitors include, but are not limited to, taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (BKM120), duvelisib, (IPI-145), copanlisib (BAY80-6946), PX-866, dactolisib, CUDC-907, boctalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597.

[0487] In some embodiments, the one or more additional anticancer agents are erlotinib, gefitinib, afatanib, bevacizumab, 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-trastuzumab duocarmazine, zanidatamab (ZW25), zenoctuzamab (MCLA-128), ISB 1302, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, osimertinib, cetuximab, panitumumab, nekitumumab, vandetanib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, semipilimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0488] In some embodiments, the one or more anticancer agents are selected from the group consisting of osimertinib, erlotinib, gefitinib, and afatinib.

[0489] In some embodiments, one or more anticancer agents comprises osimertinib.

[0490] In some embodiments, one or more anti-cancer agents comprises erlotinib.

[0491] In some embodiments, one or more anti-cancer agents comprises gefitinib.

[0492] In some embodiments, one or more anticancer agents comprises afatinib.

[0493] In some embodiments, the method further comprises treating the individual in need thereof with radiation.

[0494] Administration and Methods of Administration

[0495] The amount of a salt of Compound I described herein administered to an individual (e.g., a human) can vary depending on the particular composition, method of administration, and the particular cancer being treated. The amount should be sufficient to produce a desired response, such as a therapeutic response to cancer. In some embodiments, the amount of a salt of Compound I described herein is below a level that induces toxicological effects (e.g., effects above clinically acceptable toxicity levels), or is at a level at which potential side effects can be controlled or tolerated when a salt of Compound I described herein is administered to an individual.

[0496] In some embodiments, the salt of Compound I described herein is administered systemically to a subject. In some embodiments, the salt of Compound I described herein is administered parenterally to a subject. In some embodiments, the salt of Compound I described herein is administered locally (i.e., topically) to a subject. In some embodiments, the salt of Compound I described herein is administered orally, intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonary, intramuscularly, intratracheally, intracerebrally, intraocularly, transdermally, or by inhalation. In some embodiments, the salt of Compound I described herein is administered orally to a subject. In some embodiments, the salt of Compound I described herein is administered orally to a subject, while one or more additional agents may be administered to the subject by other routes, including intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonary, intramuscularly, intratracheally, intracerebrally, intraocularly, transdermally, or by inhalation. For example, in some embodiments, the salt of Compound I described herein is administered orally to a subject, while one or more additional agents are administered intravenously to a subject. In some embodiments, the salts of Compound I described herein are administered orally to an individual. In some embodiments, the salts of Compound I described herein are administered parenterally to an individual. In some embodiments, the salts of Compound I described herein are administered int...

Claims

1. (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 fumarate salt.

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

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

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

5. (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 tartrate salt.

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

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

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

9. (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 malate salt.

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

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

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

13. (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.

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

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

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

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

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

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

20. The cancers include pseudomyxoma, intrahepatic cholangiocarcinoma, 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, epithelial ovarian cancer, ovarian germ cell cancer, male breast cancer, brain tumor, 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 cavity and paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant 20. The method of claim 18 or 19, wherein the cancer is selected from the group consisting of soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' carcinoma, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain tumor, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

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