Fumarate, tartrate, malate, and citrate salts of an EGFR inhibitor

Abstract

The present application provides salts and crystalline forms, and polymorphic crystalline forms of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, compositions thereof, methods of preparation thereof, and methods of their uses.

Description

FUMARATE, TARTRATE, MALATE, AND CITRATE SALTS OF AN EGFR INHIBITOR

[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 of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide (hereinafter referred to as "Compound I"), compositions thereof, methods of preparation thereof, and methods of their uses.

[0003] Compound I is an inhibitor of epidermal growth factor receptor (EGFR) and has use in the treatment of various cancers in individuals, including humans, in need thereof. 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 their disclosed polymorphic forms, have physical properties that make them advantageous in the development of Compound I as a therapeutic for the treatment of cancer in an individual in need thereof.

[0004] In one aspect, provided herein is a fumarate salt of Compound I.

[0005] In one aspect, provided herein is a 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 a citrate salt of Compound I.

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

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

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

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

[0013] Various embodiments are contemplated herein. For example, in Embodiment 1, provided is a fumarate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[0014] Embodiment 2: The fumarate salt of Embodiment 1, wherein the salt is a hemi-fumarate 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 in an aqueous solution having a pH of about 1.5 and at a temperature of about 25 ℃, calculated as an 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.

[0017] Embodiment 5: The fumarate salt of any one of Embodiments 1-4, wherein the fumarate salt has a solubility in an aqueous solution having a pH of about 4.7 and at a temperature of about 25 ℃, calculated as an 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.

[0018] Embodiment 6: The fumarate salt of any one of Embodiments 1-5, wherein the fumarate salt has a solubility in an aqueous solution having a pH of about 6.6 and at a temperature of about 25 ℃, calculated as an 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.

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

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

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

[0022] Embodiment 10: The fumarate salt of Embodiment 9, further comprising peaks in the XRPD pattern at 15.4±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2, and 22.0±0.2 degrees 2-theta.

[0023] Embodiment 11: The fumarate salt of Embodiment 10, further comprising peaks in the XRPD pattern at 8.4±0.2, 17.6±0.2, 21.7±0.2, 24.0±0.2, and 27.7±0.2 degrees 2-theta.

[0024] Embodiment 12: The fumarate salt of any one of Embodiments 1-11, wherein the fumarate salt exhibits a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 185 ℃.

[0025] Embodiment 13: The fumarate salt of Embodiment 12, further comprising an endotherm onset in the differential scanning calorimetry trace of from about 165 ℃ to about 180 ℃.

[0026] Embodiment 14: A fumarate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide in crystalline form, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 5.0±0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 185 ℃.

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

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

[0029] Embodiment 17: The fumarate salt of Embodiment 16, further comprising peaks in the XRPD pattern at 15.4±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2, and 22.0±0.2 degrees 2-theta.

[0030] Embodiment 18: The fumarate salt of Embodiment 17, further comprising peaks in the XRPD pattern at 8.4±0.2, 17.6±0.2, 21.7±0.2, 24.0±0.2, and 27.7±0.2 degrees 2-theta.

[0031] Embodiment 19: The fumarate salt of any one of Embodiments 14-18, further comprising an endotherm onset in the differential scanning calorimetry trace of from about 165 ℃ to about 180 ℃.

[0032] Embodiment 20: The fumarate salt of any one of Embodiments 14-19, wherein the fumarate salt has a solubility in an aqueous solution having a pH of about 1.2 and at a temperature of about 25 ℃, calculated as an 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.

[0033] Embodiment 21: The fumarate salt of any one of Embodiments 14-20, wherein the fumarate salt has a solubility in an aqueous solution having a pH of about 4.6 and at a temperature of about 25 ℃, calculated as an 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.

[0034] Embodiment 22: The fumarate salt of any one of Embodiments 14-21, wherein the fumarate salt has a solubility in an aqueous solution having a pH of about 6.8 and at a temperature of about 25 ℃, calculated as an 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.

[0035] Embodiment 23: A 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.

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

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

[0038] Embodiment 26: The tartrate salt of any one of Embodiments 23-25, wherein the tartrate salt has a solubility in an aqueous solution having a pH of about 1.4 and at a temperature of about 25 ℃, calculated as an 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.

[0039] Embodiment 27: The tartrate salt of any one of Embodiments 23-26, wherein the tartrate salt has a solubility in an aqueous solution having a pH of about 4.7 and at a temperature of about 25 ℃, calculated as an 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.

[0040] Embodiment 28: The tartrate salt of any one of Embodiments 23-27, wherein the tartrate salt has a solubility in an aqueous solution having a pH of about 6.6 and at a temperature of about 25 ℃, calculated as an 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.

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

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

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

[0044] Embodiment 32: The tartrate salt of Embodiment 31, further comprising peaks in the XRPD pattern at 16.1±0.2, 16.7±0.2, 19.1±0.2, 19.9±0.2, and 21.3±0.2 degrees 2-theta.

[0045] Embodiment 33: The tartrate salt of Embodiment 32, further comprising peaks in the XRPD pattern at 12.9±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2, and 24.0±0.2 degrees 2-theta.

[0046] Embodiment 34: The tartrate salt of any one of Embodiments 23-33, wherein the tartrate salt exhibits a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 230 ℃.

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

[0048] Embodiment 36: A 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 crystalline form, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 17.9±0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 230 ℃.

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

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

[0051] Embodiment 39: The tartrate salt of Embodiment 38, further comprising peaks in the XRPD pattern at 16.1±0.2, 16.7±0.2, 19.1±0.2, 19.9±0.2, and 21.3±0.2 degrees 2-theta.

[0052] Embodiment 40: The tartrate salt of Embodiment 39, further comprising peaks in the XRPD pattern at 12.9±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2, and 24.0±0.2 degrees 2-theta.

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

[0054] Embodiment 42: The tartrate salt of any one of Embodiments 36-41, wherein the tartrate salt has a solubility in an aqueous solution having a pH of about 1.4 and at a temperature of about 25 ℃, calculated as an 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.

[0055] Embodiment 43: The tartrate salt of any one of Embodiments 36-42, wherein the tartrate salt has a solubility in an aqueous solution having a pH of about 4.7 and at a temperature of about 25 ℃, calculated as an 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.

[0056] Embodiment 44: The tartrate salt of any one of Embodiments 36-43, wherein the tartrate salt has a solubility in an aqueous solution having a pH of about 6.6 and at a temperature of about 25 ℃, calculated as an 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.

[0057] Embodiment 45: A malate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

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

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

[0060] Embodiment 48: The malate salt of any one of Embodiments 45-47, wherein the malate salt has a solubility in an aqueous solution having a pH of about 1.4 and at a temperature of about 25 ℃, calculated as an 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.

[0061] Embodiment 49: The malate salt of any one of Embodiments 45-48, wherein the malate salt has a solubility in an aqueous solution having a pH of about 4.8 and at a temperature of about 25 ℃, calculated as an 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.

[0062] Embodiment 50: The malate salt of any one of Embodiments 45-49, wherein the malate salt has a solubility in an aqueous solution having a pH of about 6.4 and at a temperature of about 25 ℃, calculated as an 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.

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

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

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

[0066] Embodiment 54: The malate salt of Embodiment 53, further comprising peaks in the XRPD pattern at 9.7±0.2, 16.2±0.2, 18.9±0.2, 22.4±0.2, and 22.6±0.2 degrees 2-theta.

[0067] Embodiment 55: The malate salt of Embodiment 54, further comprising peaks in the XRPD pattern at 8.4±0.2, 14.5±0.2, 16.5±0.2, 18.2±0.2, and 21.9±0.2 degrees 2-theta.

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

[0069] Embodiment 57: The malate salt of Embodiment 56, further comprising an endotherm onset in the differential scanning calorimetry trace of from about 134 ℃ to about 147 ℃.

[0070] Embodiment 58: A malate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide in crystalline form, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 6.0±0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 146 ℃ to about 160 ℃.

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

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

[0073] Embodiment 61: The malate salt of Embodiment 60, further comprising peaks in the XRPD pattern at 9.7±0.2, 16.2±0.2, 18.9±0.2, 22.4±0.2, and 22.6±0.2 degrees 2-theta.

[0074] Embodiment 62: The malate salt of Embodiment 61, further comprising peaks in the XRPD pattern at 8.4±0.2, 14.5±0.2, 16.5±0.2, 18.2±0.2, and 21.9±0.2 degrees 2-theta.

[0075] Embodiment 63: The malate salt of any one of Embodiments 58-62, further comprising an endotherm onset in the differential scanning calorimetry trace of from about 134 ℃ to about 147 ℃.

[0076] Embodiment 64: The malate salt of any one of Embodiments 58-63, wherein the malate salt has a solubility in an aqueous solution having a pH of about 1.4 and at a temperature of about 25 ℃, calculated as an 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.

[0077] Embodiment 65: The malate salt of any one of Embodiments 58-64, wherein the malate salt has a solubility in an aqueous solution having a pH of about 4.8 and at a temperature of about 25 ℃, calculated as an 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.

[0078] Embodiment 66: The malate salt of any one of Embodiments 58-65, wherein the malate salt has a solubility in an aqueous solution having a pH of about 6.4 and at a temperature of about 25 ℃, calculated as an 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.

[0079] Embodiment 67: A citrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.

[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 a 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 2-theta.

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

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

[0085] Embodiment 73: The citrate salt of Embodiment 72, further comprising peaks in the XRPD pattern at 3.7±0.2, 11.2±0.2, 18.2±0.2, 21.8±0.2, and 22.4±0.2 degrees 2-theta.

[0086] Embodiment 74: The citrate salt of Embodiment 73, further comprising peaks in the XRPD pattern at 10.9±0.2, 25.5±0.2, 26.1±0.2, and 33.0±0.2 degrees 2-theta.

[0087] Embodiment 75: The citrate salt of any one of Embodiments 67-74, wherein the citrate salt exhibits a differential scanning calorimetry trace comprising a peak of from about 175 ℃ to about 179 ℃.

[0088] Embodiment 76: The citrate salt of Embodiment 75, further comprising an endotherm onset in the differential scanning calorimetry trace of from about 124 ℃ to about 128 ℃.

[0089] Embodiment 77: A citrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide in crystalline form, wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 7.3±0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 175 ℃ to about 179 ℃.

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

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

[0092] Embodiment 80: The citrate salt of Embodiment 79, further comprising peaks in the XRPD pattern at 3.7±0.2, 11.2±0.2, 18.2±0.2, 21.8±0.2, and 22.4±0.2 degrees 2-theta.

[0093] Embodiment 81: The citrate salt of Embodiment 80, further comprising peaks in the XRPD pattern at 10.9±0.2, 25.5±0.2, 26.1±0.2, and 33.0±0.2 degrees 2-theta.

[0094] Embodiment 82: The citrate salt of any one of Embodiments 77-81, further comprising an endotherm onset in the differential scanning calorimetry trace of from about 124 ℃ to about 128 ℃.

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

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

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

[0098] Embodiment 86: A pharmaceutical composition comprising the citrate salt of any one of Embodiments 67-82, 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) the fumarate salt of any one of Embodiments 1-22, (b) the tartrate salt of any one of Embodiments 23-44, (c) the malate salt of any one of Embodiments 45-66, (d) the citrate salt of any one of Embodiments 67-82, (e) the pharmaceutical composition of Embodiment 83, (f) the pharmaceutical composition of Embodiment 84, (g) the pharmaceutical composition of Embodiment 85, or (h) the pharmaceutical composition of Embodiment 86.

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

[0101] Embodiment 89: The method of Embodiment 87 or 88, wherein the cancer comprises one or more mutations selected from the group consisting of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, EGFR Exon20 ins ASV, and a mutation of ERBB2 which is Her2 Exon20 ins YVMA.

[0102] Embodiment 90: The method of any one of Embodiments 87-89, wherein 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, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenomas, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of vater 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 cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal carcinoma, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumors, gastrointestinal stromal tumors, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumors, vaginal cancer, spinal carcinoma, 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 carcinoma.

[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 metastatic brain cancer.

[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 87-94, wherein the cancer is a locally advanced cancer.

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

[0109] Embodiment 97: The method of any one of Embodiments 87-96, 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 87-97, wherein the cancer comprises one or more mutations in the epidermal growth factor receptor (EGFR) protein.

[0111] Embodiment 99: The method of Embodiment 98, wherein the one or more mutations in the EGFR protein 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 Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, and EGFR Exon20 ins ASV.

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

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

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

[0115] Embodiment 103: The method of Embodiment 102, wherein the 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 was administered to the individual in a metastatic setting.

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

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

[0119] Embodiment 107: The method of Embodiment 106, wherein the one or more additional anticancer agents comprises one or more agents selected from HER2 inhibitors, HER2-CD3 bispecific antibodies, HER2-immune targeting bispecific antibodies, anti-HER2 chimeric antigen receptor (CAR) T cells, anti-HER2 chimeric antigen receptor (CAR) cytotoxic T-lymphocytes (CTLs), anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells, anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells, epidermal growth factor receptor (EGFR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors, PD-1 inhibitors, PD-L1 inhibitors, Phosphoinositide 3-kinase (PI3K) inhibitors, and chemotherapeutic agents.

[0120] Embodiment 108: The method of Embodiment 107, wherein the one or more additional anticancer agents are selected from the group consisting of 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), zenocutuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, necitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[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 conjugates are selected from trastuzumab emtansine and trastuzumab deruxtecan.

[0123] Embodiment 111: The method of Embodiment 108, wherein the one or more additional anticancer agents comprises one or more chemotherapeutic agents.

[0124] Embodiment 112: The method of Embodiment 111, wherein the one or more chemotherapeutic agents is 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 87-113, wherein the method further comprises treating the individual in need thereof with radiation.

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

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

[0129] Embodiment 117: A method of preparing the fumarate salt of any one of Embodiments 1-22, 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; and

[0131] (2) removing the solvent from step (1) to afford 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 of preparing the tartrate salt of any one of Embodiments 23-44, 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; and

[0136] (2) removing the solvent from step (1) to afford 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 of preparing the malate salt of any one of Embodiments 45-66, 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; and

[0141] (2) removing the solvent from step (1) to afford 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 of preparing the citrate salt of any one of Embodiments 67-82, 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; and

[0146] (2) removing the solvent from step (1) to afford 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 of 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 117-135, wherein the mixture of step (1) is stirred at 20-60 ℃.

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

[0158] Embodiment 138: The method of any one of Embodiments 117-137, wherein step (2) further comprises vacuum filtration.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0197] FIG. 5 provides the bioavailability and concentrations of unbound tucatinib and Compound I in the brain or plasma at 1 hour, 4 hours, and 8 hours following oral administration of a single dose of either tucatinib (50 mg / kg) or Compound I (3 mg / kg) into mice.

[0198] FIG. 6 shows the sensitivity of 25 breast cancer cell lines, including cell lines that exhibit amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein and / or overexpression of the HER2 protein, to treatment with Compound I in comparison to tucatinib and lapatinib, as indicated by the calculated half maximal effective concentrations (EC50s).

[0199] FIG. 7A shows the average tumor volumes in the mice in the Compound 1 Group, the Tucatinib Group, and the Vehicle Control Group after 28 days of treatment from Example 20.

[0200] FIG. 7B shows the tumor volume in the individual mice in the Vehicle Control Group from Example 20.

[0201] FIG. 7C shows tumor volume in individual mice in the Compound 1 Group from Example 20.

[0202] FIG. 7D shows the tumor volume in individual mice in the Tucatinib Group from Example 20.

[0203] FIG. 7E shows the average body weights of the mice in each of the Compound 1 Group, the Tucatinib Group, and the Vehicle Control Group from Example 20 (where the Vehicle Group is represented by circles, the Compound 1 Group is represented by triangles, and the Tucatinib Group is represented by squares).

[0204] FIG. 8A shows a1H-NMR spectrum of a fumarate salt after recrystallization in deuterated methanol (CD3OD).

[0205] FIG. 8B shows a1H-NMR spectrum of a fumarate salt (fumarate scale-up) in deuterated methanol (CD3OD).

[0206] FIG. 8C shows a1H-NMR spectrum of a tartrate salt in deuterated methanol (CD3OD).

[0207] FIG. 8D shows a1H-NMR spectrum of a tartrate salt (tartrate scale-up) in deuterated methanol (CD3OD).

[0208] FIG. 8E shows a1H-NMR spectrum of a malate salt in deuterated methanol (CD3OD).

[0209] FIG. 8F shows a1H-NMR spectrum of malate salt (malate scale-up) in deuterated methanol (CD3OD).

[0210] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present application. For purposes of the present application, the following terms are defined.

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

[0212] Reference to "about" a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".

[0213] The term "about X-Y" used herein has the same meaning as "about X to about Y." The expression "about X, Y, and / or Z" used herein has the same meaning as "about X, about Y, and / or about Z."

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

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

[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, for example, melting temperatures, heats of fusion, solubilities, dissolution rates, and / or vibrational spectra as a result of the arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, such as storage stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility / dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of a crystalline form may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g., particle shape and size distribution might be different between polymorphs).

[0217] As used herein, the term "substantially as shown in" when referring, for example, to an XRPD pattern, a DSC graph, a TGA graph, or a GVS graph, includes a pattern or graph that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art.

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

[0219] As used herein, the term "substantially free of" means that the composition comprising 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 indicated substance or substances.

[0220] As used herein, "treatment" or "treating" is an approach for 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 resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g.,preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the recurrence of the disease, reducing recurrence rate of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. In some embodiments, the treatment reduces the severity of one or more symptoms associated with cancer by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the treatment. Also encompassed by "treatment" is a reduction of pathological consequence of cancer. The methods of the application contemplate any one or more of these aspects of treatment.

[0221] The term "effective amount" used herein refers to an amount of a compound or composition sufficient to treat a specified disorder, condition, or disease, such as to ameliorate, palliate, lessen, and / or delay one or more of its symptoms in an individual. In reference to cancer, an effective amount comprises an amount sufficient to cause a tumor to shrink and / or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation in cancer in an individual. In some embodiments, an effective amount is an amount sufficient to delay development of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence of cancer in an individual. In some embodiments, an effective amount is an amount sufficient to reduce recurrence rate of cancer in an individual. An effective amount can be administered to an individual in one or more administrations. The effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of tumor; (vii) reduce recurrence rate of tumor, and / or (viii) relieve to some extent one or more of the symptoms associated with the cancer in an individual.

[0222] As is understood in the art, an “effective amount” may be in one or more doses,i.e.,a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a compound or composition described herein may be considered to be given in an effective amount if, optionally in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. The components (e.g.,the first and second therapies) in a combination therapy of the application may be administered to an individual sequentially, simultaneously, or concurrently 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 produces a desired outcome in the individual.

[0223] As used herein, "therapeutically effective amount" indicates an amount administered to an individual that results in a desired pharmacological and / or physiological effect for the condition in the individual. The effect in the individual may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for the condition and / or adverse effect attributable to the condition.

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

[0225] "In conjunction with" or "in combination with" refers to administration of one treatment modality in addition to another treatment modality, such as administration of a compound or composition described herein in addition to administration of the other agent to the same individual under the same treatment plan. As such, "in conjunction with" or "in combination with" refers to administration of one treatment modality before, during or after delivery of the other treatment modality to the individual.

[0226] The term "simultaneous administration," as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes. When the first and second therapies are administered simultaneously, the first and second therapies may be contained in the same composition (e.g.,a composition comprising both a first and second therapy) or in separate compositions (e.g.,a first therapy is contained in one composition and a second therapy is contained in another composition).

[0227] As used herein, the term "sequential administration" means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the 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 the first therapy and that of a second therapy in a combination therapy overlap with each other.

[0229] As used herein, by "pharmaceutically acceptable" or "pharmacologically compatible" is meant a material that is not 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 have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U. S. Food and Drug administration.

[0230] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein 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) variants and HER2 variants. The chemical name of Compound I is N-[2-[4-(4-cyclopropyl-1-piperazinyl)-1-piperidinyl]-5-[[6-[(3R)-3-(3,5-difluorophenyl)- 2-isoxazolidinyl]-4-pyrimidinyl]amino]-4-methoxyphenyl]-2-propenamide. Compound I has the following structure:

[0233]

[0234] Compound I

[0235]

[0236] Compound I can also be named as (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 CAS Registry No. 2489185-38-6.

[0237] Compound I has been described in WO2020 / 190119, and may be prepared by methods described therein. The contents of WO2020 / 190119 are hereby incorporated by reference herein for that purpose. Alternatively, Compound I may be prepared by methods known to those having ordinary skill in the art.

[0238] Salts

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

[0240] A salt of Compound I may provide the advantages of bioavailability and stability and may be suitable for use as an active agent in a pharmaceutical composition. Variations in the salt form of a pharmaceutical drug may affect the dissolution rate (which may affect bioavailability,etc.), manufacturability (e.g.,ease of handling, ease of purification, ability to consistently prepare doses of known strength,etc.) and stability (e.g., thermal stability, shelf life (including resistance to degradation),etc.) of a pharmaceutical drug product. Such variations may affect the methods of preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage forms including tablets and capsules. Salt forms of a pharmaceutical drug may provide desired or suitable hygroscopicity, dissolution rate, solubility, absorption, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Thus, salts of a compound may provide advantages of improving the manufacturing process of an active agent or the stability or storability of a drug product form of the active agent, or having suitable bioavailability and / or stability as an active agent.

[0241] The use of certain conditions, such as the use of different solvents and / or temperatures, has been found to produce different salts of Compound I, and different polymorphic forms of those salts, including the fumarate salt, tartrate salt, malate salt, and citrate salt described herein, which may exhibit one or more favorable characteristics described herein. The processes for the preparation of the fumarate salt, tartrate salt, malate salt, and citrate salt described herein and characterization of these salts are described in greater detail below.

[0242] Fumarate Salt

[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 hemi-fumarate 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 in an aqueous solution having a pH of about 1.5 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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). In some embodiments, the fumarate salt has a solubility in an aqueous solution having a pH of about 4.7 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, of about 20 mg / mL (about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, about 20 mg / mL, about 20.5 mg / mL, about 21 mg / mL, about 21.5 mg / mL, or about 22 mg / mL). In some embodiments, the fumarate salt has a solubility in an aqueous solution having a pH of about 6.6 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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).

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

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

[0249]

[0250] In some embodiments, the fumarate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 1A or as provided in Table 1. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the fumarate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1A or as provided in Table 1 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0253]

[0254] In some embodiments, the fumarate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 1B or as provided in Table 2. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the fumarate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1B or as provided in Table 2 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0257]

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

[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 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.5±0.2 and 22.3±0.2 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at 22.3±0.2 degrees 2-theta. 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 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.5±0.4 and 22.3±0.4 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising a peaks at 22.3±0.4 degrees 2-theta. 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 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 4.5±0.6 and 22.3±0.6 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at 22.3±0.6 degrees 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1C or as provided in Table 3 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

[0260] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in FIG. 1D. Angles as measured in degrees 2-theta and peak intensities that may be observed for the fumarate salt using XRPD are shown in Table 4.

[0261]

[0262] In some embodiments, the fumarate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 1D or as provided in Table 4. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the fumarate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1D or as provided in Table 4 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

[0264] In some embodiments, the fumarate salt has an XRPD pattern substantially as shown in FIG. 1E. Angles as measured in degrees 2-theta and peak intensities that may be observed for the fumarate salt using XRPD are shown in Table 5.

[0265]

[0266] In some embodiments, the fumarate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 1E or as provided in Table 5. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the fumarate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0267] In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.2, 8.4±0.2, 8.9±0.2, 10.6±0.2, 11.0±0.2, 11.7±0.2, 12.7±0.2, 13.7±0.2, 14.2±0.2, 15.4±0.2, 16.3±0.2, 17.1±0.2, 17.6±0.2, 18.1±0.2, 18.8±0.2, 19.5±0.2, 19.8±0.2, 20.5±0.2, 21.3±0.2, 21.7±0.2, 22.0±0.2, 23.4±0.2, 24.0±0.2, 25.7±0.2, 27.2±0.2, 27.7±0.2, and 28.7±0.2 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.4, 8.4±0.4, 8.9±0.4, 10.6±0.4, 11.0±0.4, 11.7±0.4, 12.7±0.4, 13.7±0.4, 14.2±0.4, 15.4±0.4, 16.3±0.4, 17.1±0.4, 17.6±0.4, 18.1±0.4, 18.8±0.4, 19.5±0.4, 19.8±0.4, 20.5±0.4, 21.3±0.4, 21.7±0.4, 22.0±0.4, 23.4±0.4, 24.0±0.4, 25.7±0.4, 27.2±0.4, 27.7±0.4, and 28.7±0.4 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.6, 8.4±0.6, 8.9±0.6, 10.6±0.6, 11.0±0.6, 11.7±0.6, 12.7±0.6, 13.7±0.6, 14.2±0.6, 15.4±0.6, 16.3±0.6, 17.1±0.6, 17.6±0.6, 18.1±0.6, 18.8±0.6, 19.5±0.6, 19.8±0.6, 20.5±0.6, 21.3±0.6, 21.7±0.6, 22.0±0.6, 23.4±0.6, 24.0±0.6, 25.7±0.6, 27.2±0.6, 27.7±0.6, and 28.7±0.6 degrees 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 1E or as provided in Table 5 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

[0268] In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at 5.0±0.2 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.2 and 17.1±0.2 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.2, 17.1±0.2, and 20.5±0.2 degrees 2-theta. 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, 18.1±0.2, 18.8±0.2, 19.8±0.2, 20.5±0.2, and 22.0±0.2 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.2, 8.4±0.2, 15.4±0.2, 17.1±0.2, 17.6±0.2, 18.1±0.2, 18.8±0.2, 19.8±0.2, 20.5±0.2, 21.7±0.2, 22.0±0.2, 24.0±0.2, and 27.7±0.2 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at 5.0±0.4 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.4 and 17.1±0.4 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.4, 17.1±0.4, and 20.5±0.4 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising a peak at 5.0±0.6 degrees 2-theta. In some embodiments, the fumarate salt has an XRPD pattern comprising peaks at 5.0±0.6 and 17.1±0.6 degrees 2-theta. 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 2-theta. 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 2-theta. 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 2-theta.

[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 as exhibiting a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 185 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 172±4 ℃ (e.g., 172±3 ℃, 172±2 ℃, or 172±1 ℃). In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 174±4 ℃ (e.g., 174±3 ℃, 174±2 ℃, or 174±1 ℃). In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 176±4 ℃ (e.g., 176±3 ℃, 176±2 ℃, or 176±1 ℃). In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 178±4 ℃ (e.g., 178±3 ℃, 178±2 ℃, or 178±1 ℃). In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 180±4 ℃ (e.g., 180±3 ℃, 180±2 ℃, or 180±1 ℃). In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 182±4 ℃ (e.g., 182±3 ℃, 182±2 ℃, or 182±1 ℃). In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 184±4 ℃ (e.g., 184±3 ℃, 184±2 ℃, or 184±1 ℃). In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 185±4 ℃ (e.g., 185±3 ℃, 185±2 ℃, or 185±1 ℃).

[0270] In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 185 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 184 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 182 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 180 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 174 ℃ to about 184 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 174 ℃ to about 182 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 174 ℃ to about 180 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 176 ℃ to about 184 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 176 ℃ to about 182 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 176 ℃ to about 180 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 178 ℃ to about 184 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 178 ℃ to about 182 ℃. In some embodiments, the fumarate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 178 ℃ to about 180 ℃.

[0271] In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 165 ℃ to about 180 ℃. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 165±4 ℃ (e.g., 165±3 ℃, 165±2 ℃, or 165±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 167±4 ℃ (e.g., 167±3 ℃, 167±2 ℃, or 167±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 169±4 ℃ (e.g., 169±3 ℃, 169±2 ℃, or 169±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 171±4 ℃ (e.g., 171±3 ℃, 171±2 ℃, or 171±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 173±4 ℃ (e.g., 173±3 ℃, 173±2 ℃, or 173±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 175±4 ℃ (e.g., 175±3 ℃, 175±2 ℃, or 175±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 177±4 ℃ (e.g., 177±3 ℃, 177±2 ℃, or 177±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 179±4 ℃ (e.g., 179±3 ℃, 179±2 ℃, or 179±1 ℃). In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 180±4 ℃ (e.g., 180±3 ℃, 180±2 ℃, or 180±1 ℃).

[0272] In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 165 ℃ to about 180 ℃. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 165 ℃ to about 175 ℃. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 167 ℃ to about 180 ℃. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 167 ℃ to about 175 ℃. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 169 ℃ to about 180 ℃. In some embodiments, the fumarate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 169 ℃ to about 175 ℃.

[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) apply:

[0274] (a) the fumarate salt is a hemi-fumarate salt;

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

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

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

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

[0279] (f) the fumarate salt exhibits an XRPD pattern comprising:

[0280] (i) a peak at 5.0±0.2 degrees 2-theta;

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

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

[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 2-theta; 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 2-theta; and

[0285] (g) the fumarate salt exhibits a differential scanning calorimetry trace comprising:

[0286] (i) a peak of from about 172 ℃ to about 185 ℃; or

[0287] (ii) a peak of from about 172 ℃ to about 185 ℃ and an endotherm onset of from about 165 ℃ to about 180 ℃.

[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 Salt

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

[0291] In some embodiments, the tartrate salt of Compound I is a hemi-tartrate 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 in an aqueous solution having a pH of about 1.4 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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). In some embodiments, the tartrate salt has a solubility in an aqueous solution having a pH of about 4.7 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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). In some embodiments, the tartrate salt has a solubility in an aqueous solution having a pH of about 6.6 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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).

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

[0295]

[0296] In some embodiments, the tartrate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 2A or as provided in Table 6. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the tartrate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 2A or as provided in Table 6 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0299]

[0300] In some embodiments, the tartrate salt has an XRPD pattern displaying at least one of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 2B or as provided in Table 7. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the tartrate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0301] In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 26.1±0.2 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 26.1±0.4 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 26.1±0.6 degrees 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 2B or as provided in Table 7 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0303]

[0304] In some embodiments, the tartrate salt has an XRPD pattern displaying 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 of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 2C or as provided in Table 8. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the tartrate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 2C or as provided in Table 8 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0307]

[0308] In some embodiments, the tartrate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 2D or as provided in Table 9. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the tartrate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0309] In some embodiments, the tartrate salt has an XRPD pattern comprising peaks 5.8±0.2, 7.4±0.2, 8.9±0.2, 11.1±0.2, 11.6±0.2, 12.6±0.2, 12.9±0.2, 14.0±0.2, 16.1±0.2, 16.7±0.2, 17.4±0.2, 17.9±0.2, 18.2±0.2, 18.8±0.2, 19.1±0.2, 19.9±0.2, 20.7±0.2, 21.3±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2, 23.3±0.2, 23.5±0.2, 24.0±0.2, 24.3±0.2, 26.5±0.2, 27.8±0.2, and 28.3±0.2 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks 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±0.4, 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 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks 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, 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 2D or as provided in Table 9 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

[0310] In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 17.9±0.2 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.2 and 17.9±0.2 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.2, 7.4±0.2, and 17.9±0.2 degrees 2-theta. 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, and 21.3±0.2 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.2, 7.4±0.2, 12.9±0.2, 16.1±0.2, 16.7±0.2, 17.9±0.2, 19.1±0.2, 19.9±0.2, 21.3±0.2, 21.7±0.2, 22.3±0.2, 22.8±0.2, and 24.0±0.2 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 17.9±0.4 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.4 and 17.9±0.4 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.4, 7.4±0.4, and 17.9±0.4 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising a peak at 17.9±0.6 degrees 2-theta. In some embodiments, the tartrate salt has an XRPD pattern comprising peaks at 5.8±0.6 and 17.9±0.6 degrees 2-theta. 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 2-theta. 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 2-theta. 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 2-theta.

[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 as exhibiting a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 230 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 218±4 ℃ (e.g., 218±3 ℃, 218±2 ℃, or 218±1 ℃). In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 220±4 ℃ (e.g., 220±3 ℃, 220±2 ℃, or 220±1 ℃). In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 222±4 ℃ (e.g., 222±3 ℃, 222±2 ℃, or 222±1 ℃). In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 224±4 ℃ (e.g., 224±3 ℃, 224±2 ℃, or 224±1 ℃). In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 226±4 ℃ (e.g., 226±3 ℃, 226±2 ℃, or 226±1 ℃). In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 228±4 ℃ (e.g., 226±3 ℃, 226±2 ℃, or 226±1 ℃). In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 230±4 ℃ (e.g., 226±3 ℃, 226±2 ℃, or 226±1 ℃).

[0312] In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 230 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 228 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 226 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 224 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 220 ℃ to about 228 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 220 ℃ to about 226 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 220 ℃ to about 224 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 222 ℃ to about 228 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 222 ℃ to about 226 ℃. In some embodiments, the tartrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 222 ℃ to about 224 ℃.

[0313] In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset of from about 215 ℃ to about 230 ℃. In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 215±4 ℃ (e.g., 215±3 ℃, 215±2 ℃, or 215±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 217±4 ℃ (e.g., 217±3 ℃, 217±2 ℃, or 217±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 219±4 ℃ (e.g., 219±3 ℃, 219±2 ℃, or 219±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 221±4 ℃ (e.g., 221±3 ℃, 221±2 ℃, or 221±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 223±4 ℃ (e.g., 223±3 ℃, 223±2 ℃, or 223±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 225±4 ℃ (e.g., 225±3 ℃, 225±2 ℃, or 225±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 227±4 ℃ (e.g., 227±3 ℃, 227±2 ℃, or 227±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 229±4 ℃ (e.g., 229±3 ℃, 229±2 ℃, or 229±1 ℃). In some embodiments, the tartrate salt exhibits a differential scanning calorimetry trace comprising an exotherm onset at 230±4 ℃ (e.g., 230±3 ℃, 230±2 ℃, or 230±1 ℃).

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

[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) apply:

[0316] (a) the tartrate salt is a hemi-tartrate salt;

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

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

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

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

[0321] (f) the tartrate salt exhibits an XRPD pattern comprising:

[0322] (i) a peak at 17.9±0.2 degrees 2-theta;

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

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

[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 2-theta; 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 2-theta; and

[0327] (g) the tartrate salt exhibits a differential scanning calorimetry trace comprising:

[0328] (i) a peak of from about 218 ℃ to about 230 ℃; or

[0329] (ii) a peak of from about 218 ℃ to about 230 ℃ and an exotherm onset of from about 215 ℃ to about 230 ℃.

[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 Salt

[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 hemi-malate 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 in an aqueous solution having a pH of about 1.4 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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). In some embodiments, the malate salt has a solubility in an aqueous solution having a pH of about 4.8 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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).In some embodiments, the malate salt has a solubility in an aqueous solution having a pH of about 6.4 and at a temperature of about 25 ℃, calculated as an amount of the free base of Compound I, 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).

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

[0337]

[0338] In some embodiments, the malate salt has an XRPD pattern displaying at least one or at least two of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 3A or as provided in Table 10. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the malate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0339] In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.3±0.2 and 23.4±0.2 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.3±0.4 and 23.4±0.4 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 5.3±0.6 and 23.4±0.6 degrees 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 3A or as provided in Table 10 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0341]

[0342] In some embodiments, the malate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 3B or as provided in Table 11. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the malate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 3B or as provided in Table 11 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0345]

[0346] In some embodiments, the malate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 3C or as provided in Table 12. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the malate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 3C or as provided in Table 12 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0349]

[0350] In some embodiments, the malate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 3D or as provided in Table 13. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the malate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0351] In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.2, 8.4±0.2, 9.7±0.2, 11.7±0.2, 12.4±0.2, 12.8±0.2, 14.1±0.2, 14.5±0.2, 15.7±0.2, 15.9±0.2, 16.2±0.2, 16.5±0.2, 17.0±0.2, 17.7±0.2, 18.2±0.2, 18.4±0.2, 18.9±0.2, 19.5±0.2, 20.2±0.2, 21.0±0.2, 21.9±0.2, 22.4±0.2, 22.6±0.2, 23.8±0.2, 24.5±0.2, 24.9±0.2, 26.0±0.2, and 30.3±0.2 degrees 2-theta. 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 2-theta. 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 2-theta. 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, 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 2-theta. 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 2-theta. 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 2-theta. 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, 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 3D or as provided in Table 13 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

[0352] In some embodiments, the malate salt has an XRPD pattern comprising a peak at 6.0±0.2 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.2 and 20.2±0.2 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.2, 19.5±0.2, and 20.2±0.2 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising 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 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.2, 8.4±0.2, 9.7±0.2, 14.5±0.2, 16.2±0.2, 16.5±0.2, 18.2±0.2, 18.9±0.2, 19.5±0.2, 20.2±0.2, 21.9±0.2 22.4±0.2, and 22.6±0.2 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising a peak at 6.0±0.4 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.4 and 20.2±0.4 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.4, 19.5±0.4, and 20.2±0.4 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising a peak at 6.0±0.6 degrees 2-theta. In some embodiments, the malate salt has an XRPD pattern comprising peaks at 6.0±0.6 and 20.2±0.6 degrees 2-theta. 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 2-theta. 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 2-theta. 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 2-theta.

[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 as exhibiting a differential scanning calorimetry trace comprising a peak of from about 146 ℃ to about 160 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 146±4 ℃ (e.g., 146±3 ℃, 146±2 ℃, or 146±1 ℃). In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 148±4 ℃ (e.g., 148±3 ℃, 148±2 ℃, or 148±1 ℃). In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 150±4 ℃ (e.g., 150±3 ℃, 150±2 ℃, or 150±1 ℃). In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 152±4 ℃ (e.g., 152±3 ℃, 152±2 ℃, or 152±1 ℃). In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 154±4 ℃ (e.g., 154±3 ℃, 154±2 ℃, or 154±1 ℃). In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 156±4 ℃ (e.g., 156±3 ℃, 156±2 ℃, or 156±1 ℃). In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 158±4 ℃ (e.g., 158±3 ℃, 158±2 ℃, or 158±1 ℃). In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 160±4 ℃ (e.g., 160±3 ℃, 160±2 ℃, or 160±1 ℃).

[0354] In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 146 ℃ to about 160 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 146 ℃ to about 158 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 146 ℃ to about 156 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 146 ℃ to about 154 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 148 ℃ to about 158 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 148 ℃ to about 156 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 148 ℃ to about 154 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 150 ℃ to about 158 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 150 ℃ to about 156 ℃. In some embodiments, the malate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 150 ℃ to about 154 ℃.

[0355] In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 147 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 134±4 ℃ (e.g., 134±3 ℃, 134±2 ℃, or 134±1 ℃). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 136±4 ℃ (e.g., 136±3 ℃, 136±2 ℃, or 136±1 ℃). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 138±4 ℃ (e.g., 138±3 ℃, 138±2 ℃, or 138±1 ℃). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 140±4 ℃ (e.g., 140±3 ℃, 140±2 ℃, or 140±1 ℃). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 142±4 ℃ (e.g., 142±3 ℃, 142±2 ℃, or 142±1 ℃). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 144±4 ℃ (e.g., 144±3 ℃, 144±2 ℃, or 144±1 ℃). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 146±4 ℃ (e.g., 146±3 ℃, 146±2 ℃, or 146±1 ℃). In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 147±4 ℃ (e.g., 147±3 ℃, 147±2 ℃, or 147±1 ℃).

[0356] In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 147 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 146 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 144 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 136 ℃ to about 146 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 142 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 136 ℃ to about 144 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 138 ℃ to about 146 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 140 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 136 ℃ to about 142 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 138 ℃ to about 144 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 140 ℃ to about 146 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 138 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 136 ℃ to about 140 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 138 ℃ to about 142 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 140 ℃ to about 144 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 142 ℃ to about 146 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 134 ℃ to about 136 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 136 ℃ to about 138 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 138 ℃ to about 140 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 140 ℃ to about 142 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 142 ℃ to about 144 ℃. In some embodiments, the malate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 144 ℃ to about 146 ℃.

[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) apply:

[0358] (a) the malate salt is a hemi-malate salt;

[0359] (b) the malate salt is in a crystalline form;

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

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

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

[0363] (f) the malate salt exhibits an XRPD pattern comprising:

[0364] (i) a peak at 6.0±0.2 degrees 2-theta;

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

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

[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 2-theta; 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 2-theta; and

[0369] (g) the malate salt exhibits a differential scanning calorimetry trace comprising:

[0370] (i) a peak of from about 146 ℃ to about 160 ℃; or

[0371] (ii) a peak of from about 146 ℃ to about 160 ℃ and an endotherm onset of from about 134 ℃ to about 147 ℃.

[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 Salt

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

[0375] In some embodiments, the citrate salt of Compound I is a hemi-citrate 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 FIG. 4A. Angles as measured in degrees 2-theta and peak intensities that may be observed for the citrate salt using XRPD are shown in Table 14.

[0378]

[0379] In some embodiments, the citrate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, or at least six of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 4A or as provided in Table 14. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the citrate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at 7.6±0.2 and 18.9±0.2 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at 7.6±0.4 and 18.9±0.4 degrees 2-theta. 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 2-theta. 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 2-theta. In some embodiments, the citrate salt has an XRPD pattern comprising peaks at 7.6±0.6 and 18.9±0.6 degrees 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 4A or as provided in Table 14 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0382]

[0383] In some embodiments, the citrate salt has an XRPD pattern displaying 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 of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 4B or as provided in Table 15. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the citrate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 4B or as provided in Table 15 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[0386]

[0387] In some embodiments, the citrate salt has an XRPD pattern displaying at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at degrees 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 4C or as provided in Table 16. It should be understood that peak intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Peak intensities and peak assignments can vary within experimental error. In some embodiments, peak assignments listed herein, including for the citrate salt, can vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. 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 2-theta. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG. 4C or as provided in Table 16 may be observed, for instance, due to the presence of impurities, solvent, or other polymorphs or amorphic forms present in the test sample.

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

[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 as exhibiting a differential scanning calorimetry trace comprising a peak of from about 175 ℃ to about 179 ℃. In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 175±4 ℃ (e.g., 175±3 ℃, 175±2 ℃, or 175±1 ℃). In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 177±4 ℃ (e.g., 177±3 ℃, 177±2 ℃, or 177±1 ℃). In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak at 179±4 ℃ (e.g., 179±3 ℃, 179±2 ℃, or 179±1 ℃).

[0391] In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 175 ℃ to about 179 ℃. In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 175 ℃ to about 178 ℃. In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 176 ℃ to about 179 ℃. In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 175 ℃ to about 177 ℃. In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 176 ℃ to about 178 ℃. In some embodiments, the citrate salt is characterized as exhibiting a differential scanning calorimetry trace comprising a peak of from about 177 ℃ to about 179 ℃.

[0392] In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 124 ℃ to about 128 ℃. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 124±4 ℃ (e.g., 124±3 ℃, 124±2 ℃, or 124±1 ℃). In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 126±4 ℃ (e.g., 126±3 ℃, 126±2 ℃, or 126±1 ℃). In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset at 128±4 ℃ (e.g., 128±3 ℃, 128±2 ℃, or 128±1 ℃).

[0393] In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 124 ℃ to about 128 ℃. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 124 ℃ to about 127 ℃. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 125 ℃ to about 128 ℃. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 124 ℃ to about 126 ℃. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 125 ℃ to about 127 ℃. In some embodiments, the citrate salt exhibits a differential scanning calorimetry trace comprising an endotherm onset of from about 126 ℃ to about 128 ℃.

[0394] In some embodiments of the citrate salt, at least one, at least two, at least three, or all of the following (a)-(d) apply:

[0395] (a) the citrate salt is a hemi-citrate salt;

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

[0397] (c) the citrate salt exhibits an XRPD pattern comprising:

[0398] (i) a peak at 7.3±0.2 degrees 2-theta;

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

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

[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 2-theta; 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 2-theta; and

[0403] (d) the citrate salt exhibits a differential scanning calorimetry trace comprising:

[0404] (i) a peak of from about 175 ℃ to about 179 ℃; or

[0405] (ii) a peak of from about 175 ℃ to about 179 ℃ and an endotherm onset of from about 124 ℃ to about 128 ℃.

[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 on cells. The HER2 gene is found on human chromosome 17. HER2 protein is composed of four plasma membrane-bound receptor tyrosine kinases. Signaling pathways activated by 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 the human epidermal growth factor receptor 2 tyrosine kinase protein, encoded by the HER2 gene (also known as erbb2, or neu or HER2 / neu), on chromosome 17. The term “HER2” used herein refers to either i) the nucleic acid sequence that encodes the HER2 protein, or ii) the protein thereof.

[0410] As used herein, the term “HER2 amplified” or “HER2-amplified” cancer or cells refer to cancer or cells characterized by amplification of the HER2 gene that can be readily assessed by methods known to those having ordinary skill in the art,e.g.,in situhybridization (ISH) tests that are commercially available or can be conducted by methods known to those having ordinary skill in the art. It is a term commonly used and understood in the field. For purpose of this application, HER2 amplified cancer or cells encompass the following: a) the cancer or the cell exhibits at least 3, 4, 5, or 6 copies (e.g., 6 copies) of the gene encoding HER2 protein per interphase nucleus as detected by a single-probein situhybridization (ISH) test performed on a sample from the cancer (e.g., per ASCO / CAP guidelines, such as the guidelines of 2007, 2013, or 2018); b) the cancer or cell exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8, 2.0, or 2.2, as detected by a dual-probe ISH test performed on a sample from the cancer (e.g., per ASCO / CAP guidelines, such as the guidelines of 2007, 2013, or 2018); c) the cancer or cell exhibits (i) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8, 2.0, or 2.2 and (ii) at least 3, 4, 5, or 6 copies of the gene encoding HER2 protein per interphase nucleus comprising the sample, as detected by a dual-probe ISH test performed on a sample from the cancer (e.g., per ASCO / CAP guidelines, such as the guidelines of 2007, 2013, or 2018). In some cases, HER2 amplified cancer are defined according to the standard described in the ASCO / CAP guidelines of 2007, 2013 or 2018 or other widely accepted standard for the cancer (e.g., the particular cancer).

[0411] HER2 amplification has been identified in various types of cancers including, without limitation, breast, colon, endometrial, cervical, urothelial, lung (including, non-small cell lung cancer), ovarian, gastric, gastroesophageal junction (GEJ), head and neck, biliary tract, prostate, and pancreatic adenocarcinomas. HER2 amplification is present in about 18%-25% of breast cancers. HER2 amplification is also present in about 30% of GEJ cancers and about 20% of gastric cancers.

[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 relapse, shorter disease-free survival and poorer 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 fluorescence in situ hybridization (FISH), or similar methods thereof performed on a sample from the cancer. In some embodiments, the ISH technique used is a single-probe ISH, which identifies the number of HER2 gene copies on chromosome 17. In some embodiments, the ISH technique used is a dual-probe ISH, where the HER2 gene copy number is quantified in relation to the number of centromere 17 (CEP17) gene copies per nucleus. In some embodiments, protein expression of HER2 is detected via immunohistochemistry (IHC), or similar methods thereof. In some embodiments, the cancer is metastatic and the ISH test is performed on a sample of metastatic site.

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

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

[0416] As used herein, the term “HER2 overexpressed” or “HER2-overexpressed” cancer or cells refer to cancer or cells characterized by the overexpression of the HER2 protein that can be readily assessed by methods known to those having ordinary skill in the art,e.g., an immunohistochemistry (IHC) tests that are commercially available or can be conducted by methods known to those having ordinary skill in the art. It is a term commonly used and understood in the field. For purpose of this application, HER2 overexpressed cancer or cells encompass cancers or cells that exhibit at least 10% of cancer cells with 2+ or 3+ positivity per an immunohistochemistry (IHC) test performed on a sample from the cancer (e.g., per ASCO / CAP guidelines, such as the guidelines of 2007, 2013, or 2018). In some cases, HER2 overexpressed cancers are defined according to the standard described in the ASCO / CAP guidelines of 2007, 2013 or 2018 or other widely accepted standard for the cancer (e.g., the particular cancer).

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

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

[0419] As used herein, the term “HER2 positive” cancer or cell encompasses both HER2 amplified cancer or cell and HER2 overexpressed cancer or cell.

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

[0421] In some embodiments, the cancer described herein comprises an amplification of the gene encoding HER2 but does not comprise HER2 overexpression.

[0422] In some embodiments, the cancer described herein comprises HER2 overexpression but does not comprise an amplification of the gene encoding HER2.

[0423] Method of Preparation

[0424] In some embodiments, provided is a method of 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 afford 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 of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylforamide, 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 of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60 ℃. In some embodiments, the mixture of step (1) is stirred at a temperature of from about 1 ℃ to about 80 ℃. 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 of 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 afford 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 of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylforamide, 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 of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60 ℃. In some embodiments, the mixture of step (1) is stirred at a temperature of from about 1 ℃ to about 80 ℃. 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 of preparing a malate 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 afford the malate salt. In some embodiments, the molar ratio of malic acid to Compound I is about 0.5:1. In some embodiments, the molar ratio of malic acid to Compound I is about 1:1. In some embodiments, the solvent of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylforamide, 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 of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60 ℃. In some embodiments, the mixture of step (1) is stirred at a temperature of from about 1 ℃ to about 80 ℃. 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 of 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 afford 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 of step (1) comprises an aprotic solvent (e.g., acetone, toluene, hexane, ethyl acetate, methyl t-butyl ether, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylforamide, 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 of step (1) comprises an aprotic solvent. In some embodiments, the solvent of step (1) comprises acetone. In some embodiments, the solvent of step (1) comprises acetonitrile. In some embodiments, the solvent of step (1) comprises ethyl acetate. In some embodiments, the solvent of step (1) comprises a protic solvent. In some embodiments, the solvent of step (1) comprises ethanol. In some embodiments, the mixture of step (1) is stirred at 20-60 ℃. In some embodiments, the mixture of step (1) is stirred at a temperature of from about 1 ℃ to about 80 ℃. In some embodiments, removing the solvent comprises vacuum drying. In some embodiments, step (2) further comprises vacuum filtration.

[0428] Compositions

[0429] Also provided herein are compositions containing salts described herein, such as a fumarate salt, a tartrate salt, a malate salt, or a 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 compositions are pharmaceutical compositions. In some embodiments, the composition is a sterile composition.

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

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

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

[0433] In some embodiments of the composition containing a tartrate salt of Compound I, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is the tartrate salt. In some embodiments of the composition containing a tartrate salt of Compound I, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of Compound I in the composition exists as the tartrate salt.

[0434] In some embodiments, provided is a composition containing a malate salt of Compound I. In some embodiments, the composition is substantially free of other salts and non-salt forms of Compound I. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of Compound I.

[0435] In some embodiments of the composition containing a 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 the malate salt. In some embodiments of the composition containing a 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 Compound I in the composition exists as the malate salt.

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

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

[0438] Method of Treatment

[0439] In some embodiments, provided is a method of treating cancer in an individual in need thereof comprising administering to the individual a salt or pharmaceutical composition provided herein. In some embodiments, provided is a method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a salt or pharmaceutical composition provided herein. In some embodiments, provided is a method of treating cancer in an individual in need thereof 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 is a method of treating cancer in an individual in need thereof 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 is a method of treating cancer in an individual in need thereof 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 treatment of 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 is a method 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 is a method of treating cancer (e.g., a metastatic cancer) in an individual in need thereof comprising administering to the individual a salt or pharmaceutical composition provided herein, wherein the cancer comprises an epidermal growth factor receptor (EGFR) mutation, or one or more wild-type or mutant kinases selected from ERBB2 (HER2) and ERBB4. In some embodiments, the cancer comprises one or more mutations selected from the group consisting of EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, EGFR Exon20 ins ASV, and a mutation of ERBB2 which is Her2 Exon20 ins YVMA. In some embodiments, the cancer comprises a mutation which is EGFR Del19 / T790M. In some embodiments, the cancer comprises a mutation which is EGFR L858R / T790M. In some embodiments, the cancer comprises a mutation which is EGFR L858R. In some embodiments, the cancer comprises a mutation which is EGFR Exon20 ins NPH. In some embodiments, the cancer comprises a mutation which is EGFR Exon20 ins SVD. In some embodiments, the cancer comprises a mutation which is EGFR Exon20 ins FQEA. In some embodiments, the cancer comprises a mutation which is EGFR Exon20 ins H. In some embodiments, the cancer comprises a mutation which is EGFR Exon20 ins ASV. In some embodiments, the cancer comprises a mutation of ERBB2 which is Her2 Exon20 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 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, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenomas, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of vater 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 cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal carcinoma, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumors, gastrointestinal stromal tumors, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumors, vaginal cancer, spinal carcinoma, 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 carcinoma. 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 metastatic brain cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0443] 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises an amplification of 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises an amplification of the gene encoding the human epidermal growth factor receptor 2 (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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises an overexpression of the human epidermal growth factor receptor 2 (HER2) protein.

[0444] In some variations of any of the embodiments described herein, the cancer is a locally advanced cancer. In some variations, the cancer is unresectable. In some variations, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some variations, the cancer when tested using a single-probe in situ hybridization (ISH,e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence 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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some variations, the cancer when tested using a dual-probe ISH (e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence in situ hybridization (FISH)) test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0 or 2.2). In some variations, the cancer when tested using a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample. In some variations, the cancer when tested using an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some variations, the cancer when tested using (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some 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 (such as 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein (such as 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 (such as 1, 2, or 3) mutations in the HER2 protein (such as any of the mutations described herein). In some variations, the cancer comprises one or more (such as 1, 2, or 3) mutations in the HER2 protein, wherein the one or more (such as 1, 2, or 3) mutations in the HER2 protein is selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variations, the cancer does not comprise any mutation in the HER2 protein. In some variations, the cancer does not comprise HER2 overexpression. 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 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 comprise an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some variations, the cancer does not comprise 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 does not comprise any mutation in the HER2 protein. In some variations, the cancer comprises a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not comprise a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not comprise a mutation in 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 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein selected from H1047L and H1047R. In some variations, the composition is administered to the individual in need thereof orally, parentally, intravenously, subcutaneously, or intracerebrally. In some variations, the method further comprises administering to the individual in need thereof one or more additional anticancer agents (such as any of the anticancer agents described herein). In some variations, the one or more additional anticancer agents comprise a HER2 inhibitors. In some variations, the one or more additional anticancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anticancer agents comprise a HER2-immune targeting bispecific antibody. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T-lymphocytes (CTLs). In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anticancer 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 individual is a human.

[0445] In some embodiments, provided is a method 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 is 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) an 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 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) an amplification of the gene encoding the human epidermal growth factor receptor 2 (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 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) an overexpression of the human epidermal growth factor receptor 2 (HER2) protein.

[0446] 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer has been determined to exhibit one or more of (i) to (iv) prior to administration of the salt of Compound I, or a pharmaceutically acceptable salt thereof: (i) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer exhibits 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 exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8; (iii) a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere 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; (iv) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 3+ positivity; or (v) (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some embodiments, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, the cancer is a locally advanced cancer. In some embodiments, the cancer is unresectable.

[0447] In some variations of any of the embodiments described herein, the cancer when tested using a single-probe in situ hybridization (ISH,e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence 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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some variations, the cancer when tested using a dual-probe ISH (e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence in situ hybridization (FISH)) test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0 or 2.2). In some variations, the cancer when tested using a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample. In some variations, the cancer when tested using an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some variations, the cancer when tested using (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some 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 (such as 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein (such as 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 (such as 1, 2, or 3) mutations in the HER2 protein (such as any of the mutations described herein). In some variations, the cancer does not comprise HER2 overexpression. In some variations, the cancer does not comprise any mutation in the HER2 protein. 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 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 comprise an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some variations, the cancer does not comprise 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 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not comprise a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some variations, the cancer does not comprise a mutation in 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 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein selected from H1047L and H1047R. In some variations, the composition is administered to the individual in need thereof orally, parentally, intravenously, subcutaneously, or intracerebrally. In some variations, the method further comprises administering to the individual in need thereof one or more additional anticancer agents (such as any of the anticancer agents described herein). In some variations, the one or more additional anticancer agents comprise a HER2 inhibitors. In some variations, the one or more additional anticancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anticancer agents comprise a HER2-immune targeting bispecific antibody. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T-lymphocytes (CTLs). In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anticancer 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 individual is a human.

[0448] 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein a single-probe in situ hybridization (ISH) test performed on a sample from the cancer exhibits 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 as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein a single-probe in situ hybridization (ISH) test performed on a sample from the cancer exhibits 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 as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 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) an 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 exhibits 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 as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein a dual-probe ISH test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein a dual-probe ISH test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 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) an 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 exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere 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 prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere 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 prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 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) an 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 exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere 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 prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 3+ positivity prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 3+ positivity prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 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) an amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 3+ positivity prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, wherein the cancer comprises one or more central nervous system (CNS) metastases, and wherein (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. 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 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) an amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein, and wherein (i) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (ii) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein.

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

[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 (such as 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 comprises one or more (such as 1, 2, or 3) mutations selected from the group consisting of G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F, V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Del19, EGFR L858R / C797S, EGFR Del19 / C797S, EGFR Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, and EGFR Exon20 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 Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, and EGFR Exon20 ins ASV. In some variations, the cancer does not comprise any of the EGFR mutations described above. In some variations, the cancer does not comprise any mutation 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 (such as 1, 2, or 3) mutations in the HER2 protein, wherein the one or more (such as 1, 2, or 3) mutations in the HER2 protein is selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some variations, the cancer does not comprise any mutation 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 comprise an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some variations, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some variations, the cancer does not comprise 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.

[0454] In some variations of any of the embodiments described herein, the composition is administered to the individual in need thereof orally, parentally, intravenously, subcutaneously, or intracerebrally.

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

[0456] In some variations of any of the embodiments described herein, the individual has received one or more prior therapies for treatment of the cancer before administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some variations, the one or more prior therapies comprise one or more anti-HER2-based regimens. In some variations, the one or more anti-HER2-based regimens was administered to the individual in a metastatic setting. In some variations, the individual has failed the one or more prior therapies prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein.

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

[0458] In some variations of any of the embodiments described herein, the cancer does not comprise 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 comprises identifying the individual based upon the individual having a HER2-amplified or HER2 overexpressed cancer.

[0460] In some variations of any of the embodiments described herein, the cancer does not comprise a mutation in 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 anticancer agents (such as any of the anticancer agents described herein) or a second therapy (e.g., radiology). In some variations, the one or more additional anticancer agents comprise a HER2 inhibitors. In some variations, the one or more additional anticancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anticancer agents comprise a HER2-immune targeting bispecific antibody. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T-lymphocytes (CTLs). In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anticancer 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 is 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 an 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 HER2 overexpression. In some embodiments, a sample of the cancer exhibits HER2 expression of 3+ when tested using immunohistochemistry (IHC) test. 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 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) an 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 an amplification of the gene encoding HER2 protein. In some embodiments, the cancer comprises overexpression of the HER2 protein. In some embodiments, the cancer comprises one or more (such as 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 comprises one or more (such as 1, 2, or 3) mutations selected from the group consisting of G309A, G309E, S310F, R678Q, R678Q and L755W, L755S, L755W, I767M, D769H, D769Y, V777L, Y835F,V842I, R896C, G1201V, del.755-759EGFR Del19 / T790M, EGFR L858R / T790M, EGFR L858R, EGFR Del19, EGFR L858R / C797S, EGFR Del19 / C797S, EGFR Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, and EGFR Exon20 ins ASV. In some embodiments, the one or more mutations comprises a G309A mutation. In some embodiments, the one or more mutations comprises a G309E mutation. In some embodiments, the one or more mutations comprises a S310F mutation. In some embodiments, the one or more mutations comprises a R678Q mutation. In some embodiments, the one or more mutations comprises a R678Q mutation and a L755W mutation. In some embodiments, the one or more mutations comprises a L755S mutation. In some embodiments, the one or more mutations comprises a L755W mutation. In some embodiments, the one or more mutations comprises an I767M mutation. In some embodiments, the one or more mutations comprises a D769H mutation. In some embodiments, the one or more mutations comprises a D769Y mutation. In some embodiments, the one or more mutations comprises a V777L mutation. In some embodiments, the one or more mutations comprises a Y835F mutation. In some embodiments, the one or more mutations comprises a V842I mutation. In some embodiments, the one or more mutations comprises a R896C mutation. In some embodiments, the one or more mutations comprises a G1201V mutation. In some embodiments, the one or more mutations comprises a del.755-759EGFR Del19 / T790M mutation. In some embodiments, the one or more mutations comprises an EGFR L858R / T790M mutation. In some embodiments, the one or more mutations comprises an EGFR L858R mutation. In some embodiments, the one or more mutations comprises an EGFR del 19 mutation. In some embodiments, the one or more mutations comprises an EGFR L858R / C797S mutation. In some embodiments, the one or more mutations comprises an EGFR Del19 / C797S mutation. In some embodiments, the one or more mutations comprises an EGFR Exon20 ins NPH mutation. In some embodiments, the one or more mutations comprises an EGFR Exon20 ins SVD mutation. In some embodiments, the one or more mutations comprises an EGFR Exon20 ins FQEA mutation. In some embodiments, the one or more mutations comprises an EGFR Exon20 ins H mutation. In some embodiments, the one or more mutations comprises an EGFR Exon20 ins ASV mutation. In some embodiments, the cancer does not comprise any of the EGFR mutations described above. In some embodiments, the cancer does not comprise any mutation in the epidermal growth factor receptor (EGFR) protein. In some embodiments, the cancer when tested using a single-probe in situ hybridization (ISH,e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence 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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the cancer when tested using a dual-probe ISH (e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence in situ hybridization (FISH)) test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0 or 2.2). In some embodiments, the cancer when tested using a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample. In some embodiments, the cancer when tested using an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some embodiments, the cancer when tested using (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some embodiments, the cancer 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 to the individual in need thereof orally, parentally, intravenously, subcutaneously, or intracerebrally. In some embodiments, the individual has not received one or more prior therapy for treatment of the cancer prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the individual has received one or more prior therapies for treatment of the cancer before administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the one or more prior therapies comprise one or more anti-HER2-based regimens. In some embodiments, the one or more anti-HER2-based regimens was administered to the individual in a metastatic setting. In some embodiments, the individual has failed the one or more prior therapies prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the method further comprises identifying the individual based upon the individual having a HER2-amplified or HER2 overexpressed 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 is 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 an 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 HER2 overexpression. In some embodiments, a sample of the cancer exhibits HER2 expression of 3+ when tested using immunohistochemistry (IHC) test. 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 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) an 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 an amplification of the gene encoding HER2 protein. In some embodiments, the cancer comprises overexpression of the HER2 protein. In some embodiments, the cancer comprises one or more (such as 1, 2, or 3) mutations in the HER2 protein, wherein the one or more (such as 1, 2, or 3) mutations in the HER2 protein is selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments, the one or more mutations comprises a p.A775_G776insYVMA mutation. In some embodiments, the one or more mutations comprises a p.778insGCP mutation. In some embodiments, the one or more mutations comprises a p.G780_P781dupGSP mutation. In some embodiments, the one or more mutations comprises a .G778_S779insCPG mutation. In some embodiments, the cancer does not comprise any of the HER2 mutations described above. In some embodiments, the cancer does not comprise any mutation in the HER2 protein. In some embodiments according to any one of the methods described herein, the cancer does not comprise one or more mutations in the HER2 protein. In some embodiments according to any one of the methods described herein, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein. In some embodiments according to any one of the methods described herein, the cancer does not comprise one or more exon 20 insertion mutations in the HER2 protein, selected from p.A775_G776insYVMA, p.778insGCP, p.G780_P781dupGSP, and p.G778_S779insCPG. In some embodiments according to any one of the methods described herein, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.A775_G776insYVMA. In some embodiments according to 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 according to 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 according to 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 according to any one of the methods described herein, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some embodiments according to any one of the methods described herein, the cancer does not comprise a mutation in the HER2 protein that is G776C. In some embodiments, the cancer when tested using a single-probe in situ hybridization (ISH,e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence 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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the cancer when tested using a dual-probe ISH (e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence in situ hybridization (FISH)) test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0 or 2.2). In some embodiments, the cancer when tested using a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample. In some embodiments, the cancer when tested using an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some embodiments, the cancer when tested using (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some embodiments, the cancer 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 to the individual in need thereof orally, parentally, intravenously, subcutaneously, or intracerebrally. In some embodiments, the individual has not received one or more prior therapy for treatment of the cancer prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the individual has received one or more prior therapies for treatment of the cancer before administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the one or more prior therapies comprise one or more anti-HER2-based regimens. In some embodiments, the one or more anti-HER2-based regimens was administered to the individual in a metastatic setting. In some embodiments, the individual has failed the one or more prior therapies prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the method further comprises identifying the individual based upon the individual having a HER2-amplified or HER2 overexpressed 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.

[0464] 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) one or more additional anticancer agent or a second therapy, wherein the cancer comprises an 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) one or more additional anticancer agent or a second therapy, 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 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 anticancer agent or a second therapy, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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 HER2 inhibitor, wherein the cancer comprises an 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 HER2 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 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) an 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) one or more chemotherapeutic agents, wherein the cancer comprises an 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) 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 is 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, and b) one or more chemotherapeutic agents, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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) one or more additional anticancer agents comprising trastuzumab and capecitabine, wherein the cancer comprises an 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) one or more additional anticancer agents comprising trastuzumab and capecitabine, 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 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 anticancer agents comprising trastuzumab and capecitabine, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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) an EGFR inhibitor, wherein the cancer comprises an 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) an EGFR 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 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) an EGFR inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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 an 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 is 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, and b) a PARP inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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 PD-1 inhibitor, wherein the cancer comprises an 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 PD-1 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 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) a PD-1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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 PD-L1 inhibitor, wherein the cancer comprises an 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 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 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) a PD-L1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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 PI3K inhibitor, wherein the cancer comprises an 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 PI3K 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 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) a PI3K inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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 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 anticancer agents comprising a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises an 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 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 anticancer agents comprising 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 is a method 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 anticancer agents comprising a chemotherapeutic agent or a PD-1 inhibitor, wherein the cancer comprises (i) one or more central nervous system (CNS) metastases, and (ii) an 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 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 an 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 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 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) an 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 HER2 protein.

[0465] In some variations of any of the embodiments described herein, the cancer comprises 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 anticancer agents comprise a HER2 inhibitors. In some variations, the one or more additional anticancer agents comprise a HER2-CD3 bispecific antibody. In some variations, the one or more additional anticancer agents comprise a HER2-immune targeting bispecific antibody. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) T cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytotoxic T-lymphocytes (CTLs). In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells. In some variations, the one or more additional anticancer agents comprise anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells. In some variations, the one or more additional anticancer 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 selected from the group consisting of 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), zenocutuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, necitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189. In some variations, the second therapy is radiation. In some variations, the one or more chemotherapeutic agents 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 EGFR inhibitor is selected from the group consisting of erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, lapatinib, dacomitinib, necitumumab, vandetanib, afatinib, brigatinib, and icotinib. 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), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (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 (BAY 80-6946), PX-866, dactolisib, CUDC-907, voxtalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597. 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), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (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), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (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 tested using a single-probe in situ hybridization (ISH,e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence 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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some variations, the cancer when tested using a dual-probe ISH (e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence in situ hybridization (FISH)) test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0 or 2.2). In some variations, the cancer when tested using a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample. In some variations, the cancer when tested using an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some variations, the cancer when tested using (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some 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 composition is administered to the individual in need thereof orally, parentally, intravenously, subcutaneously, or intracerebrally. In some variations, the individual has not received one or more prior therapy for treatment of the cancer prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some variations, the individual has received one or more prior therapies for treatment of the cancer before administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some variations, the one or more prior therapies comprise one or more anti-HER2-based regimens. In some variations, the one or more anti-HER2-based regimens was administered to the individual in a metastatic setting. In some variations, the individual has failed the one or more prior therapies prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some variations, the method further comprises identifying the individual based upon the individual having a HER2-amplified or HER2 overexpressed cancer. 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 is locally advanced or metastatic. In some variations, the cancer is unresectable.

[0466] In some embodiments, there is provided use of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, for manufacture of a medicament for treatment of an individual having cancer, wherein the cancer comprises an 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 salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, for use in treating a human having cancer, wherein the cancer comprises an 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 a locally advanced cancer. In some embodiments, the cancer is unresectable. In some embodiments, the cancer comprises one or more central nervous system (CNS) metastases (e.g., brain metastases). In some embodiments, there is provided a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, for use in treating a human having cancer, wherein the cancer comprises one or more central nervous system (CNS) metastases. In some embodiments, there is provided use of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein, for manufacture of a medicament for the treatment of cancer in an individual, wherein the cancer comprises one or more central nervous system (CNS) metastases. In some embodiments, the cancer further comprises an amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2) protein or overexpression of the HER2 protein. In some embodiments, the cancer comprises an amplification of the gene encoding the HER2 protein. In some embodiments, the cancer comprises an overexpression of the HER2 protein. In some embodiments, the cancer does not comprise HER2 overexpression. In some embodiments, the cancer does not comprise amplification of the gene encoding the HER2 protein. In some embodiments, the cancer when tested using a single-probe in situ hybridization (ISH, e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence 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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample prior to administration of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the cancer when tested using a dual-probe ISH (e.g., a silver-enhanced in situ hybridization (SISH) or fluorescence in situ hybridization (FISH)) test performed on a sample from the cancer exhibits a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (CEP17) per interphase nucleus of at least 1.8 (e.g., at least 1.8, 2.0 or 2.2). In some embodiments, the cancer when tested using a dual-probe ISH test performed on a sample from the cancer exhibits (a) a ratio of the number of genes encoding the human epidermal growth factor receptor 2 (HER2) protein to the number of centromere of chromosome 17 (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 the human epidermal growth factor receptor 2 (HER2) protein per interphase nucleus comprising the sample. In some embodiments, the cancer when tested using an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ or 3+ positivity. In some embodiments, the cancer when tested using (a) an immunohistochemistry (IHC) test performed on a sample from the cancer exhibits at least 10% of cancer cells with 2+ positivity, and (b) a single-probe in situ hybridization (ISH) test performed on a sample from the cancer is determined to be positive. In some embodiments, the cancer 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 (such as 1, 2, or 3) mutations in the epidermal growth factor receptor (EGFR) protein (such as 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 (such as 1, 2, or 3) mutations in the HER2 protein (such as 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 comprise an exon 20 insertion mutation in the HER2 protein that is p.778insGCP. In some embodiments, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G780_P781dupGSP. In some embodiments, the cancer does not comprise an exon 20 insertion mutation in the HER2 protein that is p.G778_S779insCPG. In some embodiments, the cancer does not comprise a mutation in the HER2 protein that is L775S. In some embodiments, the cancer does not comprise a mutation in the HER2 protein that is G776C. In some embodiments, the cancer does not comprise any mutation in the HER2 protein. In some embodiments, the cancer comprises a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the cancer does not comprise a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein. In some embodiments, the cancer does not comprise a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein at histidine 1047. In some embodiments, the cancer does not comprise a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) protein selected from H1047L and H1047R. In some embodiments, the individual has not received one or more prior therapy for treatment of the cancer prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the individual has received one or more prior therapies for treatment of the cancer before administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the one or more prior therapies comprise one or more anti-HER2-based regimens (e.g., in a metastatic setting). In some embodiments, the individual has failed the one or more prior therapies prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the composition is administered to the individual in need thereof orally, parentally, intravenously, subcutaneously, or intracerebrally. In some embodiments, the method further comprises administering to the individual in need thereof one or more additional anticancer agents (such as any of the anticancer agents described herein). In some embodiments, the one or more additional anticancer agents comprises one or more agents selected from HER2 inhibitors, HER2-CD3 bispecific antibodies, HER2-immune targeting bispecific antibodies, anti-HER2 chimeric antigen receptor (CAR) T cells, anti-HER2 chimeric antigen receptor (CAR) cytotoxic T-lymphocytes (CTLs), anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells, anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells, epidermal growth factor receptor (EGFR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors, PD-1 inhibitors, PD-L1 inhibitors, Phosphoinositide 3-kinase (PI3K) inhibitors, and chemotherapeutic agents. In some embodiments, the one or more additional anticancer agents are selected from antibody-drug conjugates (e.g., trastuzumab emtansine or trastuzumab deruxtecan). In some embodiments, the one or more additional anticancer agents comprise trastuzumab and capecitabine. In some embodiments, the medicament is used in combination with radiation. In some embodiments, the method further comprises identifying the individual based upon the individual having a HER2-amplified or HER2 overexpressed cancer. In some embodiments, the individual is a human.

[0467] In some embodiments, the individual has received one or more (such as 1, 2, or 3) prior therapy for treatment of the cancer prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein. In some embodiments, the individual has failed the one or more (such as 1, 2, or 3) prior therapies prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein.

[0468] In some embodiments, the one or more prior therapies exhibit inhibitory activity against cancer comprising a T790M mutation in the epidermal growth factor receptor (EGFR) protein. In some embodiments, the one or more prior therapies exhibiting inhibitory activity against cancer comprising a T790M mutation in the epidermal growth factor receptor (EGFR) protein comprises osimertinib.

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

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

[0471] In some embodiments, the individual has not received one or more (such as 1, 2, or 3) prior therapy for treatment of the cancer prior to administration to the individual of a salt of Compound I as described herein or a pharmaceutical composition comprising a salt of Compound I as described herein.

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

[0473] Second agent or second therapy

[0474] In some embodiments, the method further comprises administering to the individual in need thereof one or more additional anticancer agents or a second therapy.

[0475] In some embodiments, the one or more additional anticancer agents comprises one or more agents selected from the group consisting of HER2 inhibitors, HER2-CD3 bispecific antibodies, HER2-immune targeting bispecific antibodies, anti-HER2 chimeric antigen receptor (CAR) T cells, anti-HER2 chimeric antigen receptor (CAR) cytotoxic T-lymphocytes (CTLs), anti-HER2 chimeric antigen receptor (CAR) natural killer (NK) cells, anti-HER2 chimeric antigen receptor (CAR) cytokine-induced killer (CIK) cells, epidermal growth factor receptor (EGFR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and chemotherapeutic agents.

[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), zenocutuzamab (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 icotinib.

[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 PD-1 inhibitors include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (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 cancer agents are selected from the group consisting of 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), zenocutuzamab (MCLA-128), ISB 1302, afatanib, poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, erlotinib, osimertinib, gefitinib, cetuximab, panitumumab, necitumumab, vandetanib, afatinib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0483] In some embodiments, the one or more additional cancer agents are selected from antibody-drug conjugates. In 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 anticancer agents comprises one or more chemotherapeutic agents. In some embodiments, the one or more chemotherapeutic agents is 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 anticancer 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 (BAY 80-6946), PX-866, dactolisib, CUDC-907, voxtalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597.

[0487] In some embodiments, the one or more additional cancer agents are selected from the group consisting of 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), zenocutuzamab (MCLA-128), ISB 1302, , poziotinib, pyrotinib, mobocertinib (TAK-788), and BDTX-189, osimertinib, cetuximab, panitumumab, necitumumab, vandetanib, brigatinib, icotinib, niraparib, olaparib, talazoparib, rucaparib, veliparib, iniparib, pamiparib (BGB-290), CEP-9722, E7016, pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

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

[0489] In some embodiments, the one or additional cancer agents comprise osimertinib.

[0490] In some embodiments, the one or additional cancer agents comprise erlotinib.

[0491] In some embodiments, the one or additional cancer agents comprise gefitinib.

[0492] In some embodiments, the one or additional cancer agents comprise afatinib.

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

[0494] Dosing and method of administration

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

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

[0497] In some embodiments, a salt of Compound I as described herein and a second agent or therapy are administered simultaneously to the individual. In some embodiments, a salt of Compound I as described herein and a second agent or therapy are administered concurrently to the individual. In some embodiments, a salt of Compound I as described herein and a second agent or therapy are administered sequentially to the individual.

[0498] In some embodiments, a dosage of from about 1 mg / kg to about 100 mg / kg of a salt of Compound I as described herein is administered into an individual, such as a human (e.g., from about 1 mg / kg to about 75 mg / kg, from about 2 mg / kg to about 75 mg / kg, from about 3 mg / kg to about 75 mg / kg, from about 4 mg / kg to about 75 mg / kg, from about 5 mg / kg to about 75 mg / kg, from about 1 mg / kg to about 50 mg / kg, from about 2 mg / kg to about 50 mg / kg, from about 3 mg / kg to about 50 mg / kg, from about 4 mg / kg to about 50 mg / kg, from about 5 mg / kg to about 50 mg / kg, from about 1 mg / kg to about 40 mg / kg, from about 2 mg / kg to about 40 mg / kg, from about 3 mg / kg to about 40 mg / kg, from about 4 mg / kg to about 40 mg / kg, from about 5 mg / kg to about 40 mg / kg, from about 1 mg / kg to about 30 mg / kg, from about 2 mg / kg to about 30 mg / kg, from about 3 mg / kg to about 30 mg / kg, from about 4 mg / kg to about 30 mg / kg, from about 5 mg / kg to about 30 mg / kg, from about 6 mg / kg to about 80 mg / kg, from about 10 mg / kg to about 80 mg / kg, from about 15 mg / kg to about 80 mg / kg, from about 20 mg / kg to about 80 mg / kg, fr...

Claims

1.A fumarate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.2.The fumarate salt of claim 1, wherein the fumarate salt is a hemi-fumarate salt.3.The fumarate salt of claim 1 or 2, wherein the fumarate salt is in a crystalline form.4.The fumarate salt of claim 3, wherein the fumarate salt exhibits (a) an XRPD pattern comprising peaks at 5.0 ± 0.2 degrees 2-theta, 17.1 ± 0.2 degrees 2-theta, and 20.5 ± 0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 172 ℃ to about 185 ℃5.A tartrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.6.The tartrate salt of claim 5, wherein the tartrate salt is a hemi-tartrate salt.7.The tartrate salt of claim 5 or 6, wherein the tartrate salt is in a crystalline form.8.The tartrate salt of claim 7, wherein the tartrate salt exhibits (a) an XRPD pattern comprising peaks at 17.9 ± 0.2 degrees 2-theta, 5.8 ± 0.2 degrees 2-theta, and 7.4 ± 0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 218 ℃ to about 230 ℃.9.A malate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.10.The malate salt of claim 9, wherein the malate salt is a hemi-malate salt.11.The malate salt of claim 9 or 10, wherein the malate salt is in a crystalline form.12.The malate salt of claim 11, wherein the malate salt exhibits (a) an XRPD pattern comprising peaks at 6.0 ± 0.2 degrees 2-theta, 20.2 ± 0.2 degrees 2-theta, and 19.5 ± 0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 146 ℃ to about 160 ℃.13.A citrate salt of (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide.14.The citrate salt of claim 13, wherein the citrate salt is a hemi-citrate salt.15.The citrate salt of claim 13 or 14, wherein the citrate salt is in a crystalline form.16.The citrate salt of claim 15, wherein the citrate salt exhibits (a) an XRPD pattern comprising peaks at 7.3 ± 0.2 degrees 2-theta, 7.4 ± 0.2 degrees 2-theta, and 18.6 ± 0.2 degrees 2-theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 175 ℃ to about 179 ℃.17.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) the fumarate salt of any one of claims 1-4, (b) the tartrate salt of any one of claims 5-8, (c) the malate salt of any one of claims 9-12, or (d) the citrate salt of any one of claims 13-16.18.A method of treating cancer in an individual in need thereof, the method comprising administering to the individual (a) the fumarate salt of any one of claims 1-4, (b) the tartrate salt of any one of claims 5-8, (c) the malate salt of any one of claims 9-12, (d) the citrate salt of any one of claims 13-16, or (e) the pharmaceutical composition of claim 17.19.The method of claim 18, wherein the cancer comprises an epidermal growth factor receptor (EGFR) mutation or one or more wild-type or mutant kinases selected from the group consisting of: ERBB2 and ERBB4.20.The method of claim 18 or 19, wherein the cancer is selected from the group consisting of: pseudomyxoma, intrahepatic 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, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenomas, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of vater 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 cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal carcinoma, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumors, gastrointestinal stromal tumors, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumors, vaginal cancer, spinal carcinoma, 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 carcinoma.

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