Salt of protein kinase mek inhibitor and use thereof

Abstract

The present invention relates to a pharmaceutically acceptable salt of compound N-(2-hydroxy-ethoxy) 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6-carboxamide and the use of said pharmaceutically acceptable salt in the treatment of cancers.

Description

Salts of a protein kinase MEK inhibitor and uses thereof TECHNICAL FIELD

[0001] The present invention relates to pharmaceutically acceptable salts of the compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide and the use of said pharmaceutically acceptable salts for the treatment of cancer. BACKGROUND

[0002] Over-activation of the Ras / Raf / Mek / Erk signaling mechanism plays an important role in the proliferation and differentiation of cancer cells; Ras / Raf / Mek / Erk signaling mechanism has been found to be continuously activated or over-activated in a variety of cancers, such as pancreatic cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, skin cancer, breast cancer, etc. Inhibiting the Ras / Raf / Mek / Erk signaling pathway helps the treatment of such over-proliferative diseases, in which Mek, a target downstream of Ras and Raf, plays a key role in the pathway, and the substrate of Mek phosphorylation is MAP kinase Erk. If Mek is inhibited, the Ras / Raf / Mek / Erk signaling pathway will be closed, and thus the proliferation of cancer cells will be inhibited. Therefore, Mek inhibitors can inhibit the growth of cancer cells, especially for cancers caused by over-activation of Ras or Raf. Meanwhile, Mek is also involved in diseases and symptoms of inflammation, including acute and chronic inflammation.

[0003] Chinese Patent Application No. 201210190520.4 discloses a number of benzothiazole compounds which exhibit protein kinase Mek inhibitory activity, including the compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide (hereinafter referred to as Compound 1). Polymorphic forms of Compound 1 are described in PCT Application No. PCT / CN2024 / 076655, filed on February 7, 2024, including Form I, Form II, Form IIIA, Form IIIB, Form IV, Form V, and Form VI.

[0004] However, there is still a need to develop different forms of compounds to meet the growing needs of the pharmaceutical field. SUMMARY

[0005] The inventors of the present application found that compound 1 forms a salt or a salt crystalline form with only hydrobromic acid, hydrochloric acid, 1,5-naphthalenedisulfonic acid, sulfuric acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid salt and p-toluenesulfonic acid among a number of acids, and the crystalline forms of benzenesulfonic acid salt, p-toluenesulfonic acid salt and sulfuric acid salt exhibit excellent properties such as non-hygroscopicity or slight hygroscopicity, etc. that satisfy pharmaceutical processes; in addition, the benzenesulfonic acid salt, p-toluenesulfonic acid salt and sulfuric acid salt also exhibit excellent or comparable light stability, mechanical properties, etc.

[0006] In a first aspect, the present application provides a pharmaceutically acceptable salt of compound 1, which is a hydrobromide, a hydrochloride, a sulfate, a 1,5-naphthalenedisulfonate, a 1,2-ethanedisulfonate, a benzenesulfonate or a p-toluenesulfonate, wherein

[0007] Compound 1 is 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6- carboxylic acid (2-hydroxy-ethoxy)-amide.

[0008] In some embodiments, the pharmaceutically acceptable salt is in solid form. In some embodiments, the pharmaceutically acceptable salt is in crystalline form. In some embodiments, the pharmaceutically acceptable salt is amorphous.

[0009] In some embodiments, the pharmaceutically acceptable salt is in crystalline form, which is a hydrobromide crystalline form I, a hydrochloride crystalline form I, a hydrochloride crystalline form II, a sulfate crystalline form I, a 1,5-naphthalenedisulfonate crystalline form I, a 1,2-ethanedisulfonate crystalline form I, a benzenesulfonate crystalline form I or a p-toluenesulfonate crystalline form I.

[0010] In some embodiments, the pharmaceutically acceptable salt is a hydrobromide salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2-theta positions: 24.0° ± 0.2°, 22.1° ± 0.2°, 16.8° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the hydrobromide salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2-theta positions: 15.8° ± 0.2°, 27.2° ± 0.2°, 32.2° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrobromide salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2-theta positions: 24.8° ± 0.2°, 30.4° ± 0.2°, 31.3° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrobromide salt Form I comprises characteristic diffraction peaks at the following 2-theta positions: 24.0° ± 0.2°, 22.1° ± 0.2°, 16.8° ± 0.2°, 15.8° ± 0.2°, 27.2° ± 0.2°, 32.2° ± 0.2°, 24.8° ± 0.2°, 30.4° ± 0.2°, 31.3° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrobromide salt Form I is substantially as shown in FIG. 2. In some embodiments, the hydrobromide salt Form I has a DSC pattern as shown in FIG. 3. In some embodiments, the hydrobromide salt Form I has a DSC pattern as shown in FIG. 3, wherein the DSC pattern of the hydrobromide salt Form I has endothermic peaks at 116 °C and 186 °C. In some embodiments, the hydrobromide salt Form I has a TGA pattern as shown in FIG. 4. In some embodiments, the TGA pattern of the hydrobromide salt Form I shows a mass loss gradient of about 4.2% upon heating to 80 °C.

[0011] In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2Θ positions: 13.9° ± 0.2°, 30.0° ± 0.2°, 26.9° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 24.3° ± 0.2°, 23.6° ± 0.2°, 28.9° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 27.7° ± 0.2°, 23.2° ± 0.2°, 18.8° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form I comprises characteristic diffraction peaks at the following 2Θ positions: 13.9° ± 0.2°, 30.0° ± 0.2°, 26.9° ± 0.2°, 24.3° ± 0.2°, 23.6° ± 0.2°, 28.9° ± 0.2°, 27.7° ± 0.2°, 23.2° ± 0.2°, 18.8° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form I is substantially as shown in FIG. 5. In some embodiments, the hydrochloride salt Form I has a DSC pattern as shown in FIG. 6. In some embodiments, the hydrochloride salt Form I has a DSC pattern as shown in FIG. 6, wherein the DSC pattern of the hydrochloride salt Form I has endothermic peaks at 125 °C, 136 °C, and 207 °C. In some embodiments, the hydrochloride salt Form I has a TGA pattern as shown in FIG. 7. In some embodiments, the TGA pattern of the hydrochloride salt Form I shows a mass loss gradient of about 1.1% upon heating to 100 °C.

[0012] In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt Form II characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2Θ positions: 25.2° ± 0.2°, 26.9° ± 0.2°, 24.2° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form II further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 16.5° ± 0.2°, 26.2° ± 0.2°, 22.3° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form II further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 25.8° ± 0.2°, 22.9° ± 0.2°, 21.9° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form II comprises characteristic diffraction peaks at the following 2Θ positions: 25.2° ± 0.2°, 26.9° ± 0.2°, 24.2° ± 0.2°, 16.5° ± 0.2°, 26.2° ± 0.2°, 22.3° ± 0.2°, 25.8° ± 0.2°, 22.9° ± 0.2°, 21.9° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form II is substantially as shown in FIG. 8. In some embodiments, the hydrochloride salt Form II has a DSC pattern as shown in FIG. 9. In some embodiments, the hydrochloride salt Form II has a DSC pattern as shown in FIG. 9, wherein the DSC pattern of the hydrochloride salt Form II has endothermic peaks at 97 °C, 159 °C, and 214 °C. In some embodiments, the hydrochloride salt Form II has a TGA pattern as shown in FIG. 10. In some embodiments, the TGA pattern of the hydrochloride salt Form II shows a mass loss gradient of about 5.2% upon heating to 80 °C.

[0013] In some embodiments, the pharmaceutically acceptable salt is sulfate salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2Θ positions: 25.3° ± 0.2°, 27.4° ± 0.2°, 23.5° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the sulfate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 17.3° ± 0.2°, 32.6° ± 0.2°, 34.2° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the sulfate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 29.7° ± 0.2°, 37.4° ± 0.2°, 9.1° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the sulfate salt Form I comprises characteristic diffraction peaks at the following 2Θ positions: 25.3° ± 0.2°, 27.4° ± 0.2°, 23.5° ± 0.2°, 17.3° ± 0.2°, 32.6° ± 0.2°, 34.2° ± 0.2°, 29.7° ± 0.2°, 37.4° ± 0.2°, 9.1° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the sulfate salt Form I is substantially as shown in Figure 11. In some embodiments, the sulfate salt Form I has a DSC pattern as shown in Figure 12. In some embodiments, the sulfate salt Form I has a DSC pattern as shown in Figure 12, wherein the DSC pattern of the sulfate salt Form I has an endothermic peak at 208 °C. In some embodiments, the sulfate salt Form I has a TGA pattern as shown in Figure 13. In some embodiments, the TGA pattern of the sulfate salt Form I shows a mass loss gradient of about 0.6% upon heating to 110 °C.

[0014] In some embodiments, the pharmaceutically acceptable salt is 1,5-naphthalene disulfonate salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2-theta positions: 23.6° ± 0.2°, 15.5° ± 0.2°, 14.0° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the 1,5-naphthalene disulfonate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2-theta positions: 17.4° ± 0.2°, 28.6° ± 0.2°, 14.5° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the 1,5-naphthalene disulfonate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2-theta positions: 32.2° ± 0.2°, 26.4° ± 0.2°, 34.3° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the 1,5-naphthalene disulfonate salt Form I comprises characteristic diffraction peaks at the following 2-theta positions: 23.6° ± 0.2°, 15.5° ± 0.2°, 14.0° ± 0.2°, 17.4° ± 0.2°, 28.6° ± 0.2°, 14.5° ± 0.2°, 32.2° ± 0.2°, 26.4° ± 0.2°, 34.3° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the 1,5-naphthalene disulfonate salt Form I is substantially as shown in FIG. 14. In some embodiments, the 1,5-naphthalene disulfonate salt Form I has a DSC pattern as shown in FIG. 15. In some embodiments, the 1,5-naphthalene disulfonate salt Form I has a DSC pattern as shown in FIG. 15, wherein the DSC pattern of the 1,5-naphthalene disulfonate salt Form I has endothermic peaks at 91 °C, 120 °C, and 199 °C. In some embodiments, the 1,5-naphthalene disulfonate salt Form I has a TGA pattern as shown in FIG. 16. In some embodiments, the TGA pattern of the 1,5-naphthalene disulfonate salt Form I shows a mass loss gradient of about 7.2% upon heating to 150 °C.

[0015] In some embodiments, the pharmaceutically acceptable salt is a 1,2-ethanedisulfonate salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2-theta positions: 23.4° ± 0.2°, 24.0° ± 0.2°, 20.7° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the 1,2-ethanedisulfonate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2-theta positions: 16.7° ± 0.2°, 26.2° ± 0.2°, 24.5° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the 1,2-ethanedisulfonate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2-theta positions: 30.9° ± 0.2°, 30.0° ± 0.2°, 34.3° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the 1,2-ethanedisulfonate salt Form I comprises characteristic diffraction peaks at the following 2-theta positions: 23.4° ± 0.2°, 24.0° ± 0.2°, 20.7° ± 0.2°, 16.7° ± 0.2°, 26.2° ± 0.2°, 24.5° ± 0.2°, 30.9° ± 0.2°, 30.0° ± 0.2°, 34.3° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the 1,2-ethanedisulfonate salt Form I is substantially as shown in FIG. 17. In some embodiments, the 1,2-ethanedisulfonate salt Form I has a DSC pattern as shown in FIG. 18. In some embodiments, the 1,2-ethanedisulfonate salt Form I has a DSC pattern as shown in FIG. 18, wherein the DSC pattern of the 1,2-ethanedisulfonate salt Form I has endothermic peaks at 102 °C and 177 °C. In some embodiments, the 1,2-ethanedisulfonate salt Form I has a TGA pattern as shown in FIG. 19. In some embodiments, the TGA pattern of the 1,2-ethanedisulfonate salt Form I shows a mass loss gradient of about 8.7% upon heating to 100 °C.

[0016] In some embodiments, the pharmaceutically acceptable salt is a besylate salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2Θ positions: 24.4° ± 0.2°, 25.7° ± 0.2°, 19.6° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the besylate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 14.1° ± 0.2°, 30.7° ± 0.2°, 6.1° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the besylate salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 27.1° ± 0.2°, 17.0° ± 0.2°, 17.7° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the besylate salt Form I comprises characteristic diffraction peaks at the following 2Θ positions: 24.4° ± 0.2°, 25.7° ± 0.2°, 19.6° ± 0.2°, 14.1° ± 0.2°, 30.7° ± 0.2°, 6.1° ± 0.2°, 27.1° ± 0.2°, 17.0° ± 0.2°, 17.7° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the besylate salt Form I is substantially as shown in FIG. 20. In some embodiments, the besylate salt Form I has a DSC pattern as shown in FIG. 21. In some embodiments, the besylate salt Form I has a DSC pattern as shown in FIG. 21, wherein the DSC pattern of the besylate salt Form I has an endothermic peak at 190 °C. In some embodiments, the besylate salt Form I has a TGA pattern as shown in FIG. 22. In some embodiments, the TGA pattern of the besylate salt Form I shows a mass loss gradient of about 0.7% upon heating to 180 °C.

[0017] In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonic acid salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2Θ positions: 22.4° ± 0.2°, 29.1° ± 0.2°, 14.1° ± 0.2°, using Cu-Ka radiation. In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 5.9° ± 0.2°, 29.6° ± 0.2°, 32.2° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt Form I further comprises characteristic diffraction peaks at one or two or three of the following 2Θ positions: 33.4° ± 0.2°, 27.2° ± 0.2°, 30.2° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt Form I comprises characteristic diffraction peaks at the following 2Θ positions: 22.4° ± 0.2°, 29.1° ± 0.2°, 14.1° ± 0.2°, 5.9° ± 0.2°, 29.6° ± 0.2°, 32.2° ± 0.2°, 33.4° ± 0.2°, 27.2° ± 0.2°, 30.2° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt Form I is substantially as shown in Figure 23. In some embodiments, the p-toluenesulfonic acid salt Form I has a DSC pattern as shown in Figure 24. In some embodiments, the p-toluenesulfonic acid salt Form I has a DSC pattern as shown in Figure 24, wherein the DSC pattern of the p-toluenesulfonic acid salt Form I has endothermic peaks at 185 °C and 194 °C. In some embodiments, the p-toluenesulfonic acid salt Form I has a TGA pattern as shown in Figure 25. In some embodiments, the TGA pattern of the p-toluenesulfonic acid salt Form I shows a mass loss gradient of about 0.5% upon heating to 180 °C.

[0018] In a second aspect, the present application provides a pharmaceutical composition comprising a pharmaceutically acceptable salt or a crystalline form of Compound 1 of the present application, and a pharmaceutically acceptable carrier and / or excipient.

[0019] In a third aspect, the present application provides a method of treating a tumor, a chronic inflammatory disease, an inflammatory bowel disease, a skin disease, diabetes, an ocular disease, a disease associated with angiogenesis or vasculogenesis in a mammal, a disease associated with chronic pain, and other diseases modulated by the Mek cascade, comprising administering to said mammal a pharmaceutically acceptable salt or a crystalline form of Compound 1. The present application provides a pharmaceutically acceptable salt or a crystalline form of Compound 1 for use in treating a tumor, a chronic inflammatory disease, an inflammatory bowel disease, a skin disease, diabetes, an ocular disease, a disease associated with angiogenesis or vasculogenesis in a mammal, a disease associated with chronic pain, and other diseases modulated by the Mek cascade. The use of a pharmaceutically acceptable salt or a crystalline form of Compound 1 in the manufacture of a medicament for treating a tumor, a chronic inflammatory disease, an inflammatory bowel disease, a skin disease, diabetes, an ocular disease, a disease associated with angiogenesis or vasculogenesis in a mammal, a disease associated with chronic pain, and other diseases modulated by the Mek cascade. In some embodiments, the mammal is a human.

[0020] In a fourth aspect, the present application provides a method of treating a RAS or RAF mutant cancer in a mammal, comprising administering to said mammal a pharmaceutically acceptable salt or a crystalline form of Compound 1. In some embodiments, the RAS or RAF mutant cancer is, for example, a KRAS mutant cancer, a NRAS mutant cancer, a HRAS mutant cancer, or a BRAF mutant cancer. In some embodiments, the RAS mutant cancer is pancreatic cancer, colorectal cancer, lung cancer, melanoma, acute myeloid leukemia, bladder cancer, or head and neck cancer, among others. In preferred embodiments, the cancer is a NRAS mutant cancer. In some embodiments, the NRAS mutant cancer is a NRAS mutant melanoma.

[0021] In some embodiments, KRAS comprises a mutation at one or more positions selected from codons 12, 13, 59, and 61. In some embodiments, the KRAS mutant form has a mutation at one or more amino acid positions selected from G12, G13, S17, P34, A59, and Q61. In some embodiments, the KRAS mutant form has one or more amino acid substitutions selected from G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, G12V, G13C, G13S, G13D, G13V, G13P, S17G, P34S, A59E, A59G, A59T, Q61K, Q61L, Q61R, and Q61H. In some embodiments, the KRAS mutant form has a mutation at one or more amino acid positions selected from G12, G13, A59, Q61, K117, and A146. In some embodiments, the KRAS mutant form has one or more amino acid substitutions selected from G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, A59E, A59G, A59T, Q61K, Q61L, Q61R, Q61H, K117N, K117R, K117E, A146P, A146T, and A146V. In some embodiments, the BRAF mutation is a BRAF V600E mutation.

[0022] In some embodiments, NRAS comprises a mutation at one or more positions selected from codons 12, 13, 59, 61, and 146. In some embodiments, the NRAS mutant form has a mutation at one or more amino acid positions selected from G12, G13, A59, Q61, K117, and A146. In some embodiments, the NRAS mutant form has one or more amino acid substitutions selected from G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, A59D, A59T, Q61K, Q61L, Q61R, Q61H, K117N, K117R, K117E, A146P, A146T, and A146V.

[0023] In some embodiments, the cancer is an early stage, intermediate stage, or late stage cancer. The cancer can be locally advanced or metastatic. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, melanoma, acute myelogenous leukemia, bladder cancer, or head and neck cancer. In some embodiments, the mammal has previously received an immunotherapy. In some embodiments, the mammal has previously received an immunotherapy and has a NRAS-mutated advanced melanoma. In some embodiments, the melanoma is selected from the group consisting of: advanced melanoma, unresectable melanoma, metastatic melanoma, melanoma with a BRAF mutation, melanoma with a NRAS mutation, cutaneous melanoma, or intraocular melanoma.

[0024] In some embodiments, a pharmaceutically acceptable salt or crystalline form of Compound 1 is used in combination with a chemotherapeutic agent, a KRAS inhibitor, a SHP2 inhibitor, a RAF inhibitor, or the chemotherapeutic agent and / or KRAS inhibitor and / or RAF inhibitor for the treatment of a cancer described above. In some embodiments, the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed; the KRAS inhibitor is AMG-510, MRTX849, or BI 1701963; the RAF inhibitor is LY3009120, PLX4032, LGX818, GSK2118436, BI 882370, TAK580, or Vemurafenib; and the SHP2 inhibitor is JAB-3068, TNO155, BBP-398 (IACS-15509), JAB-3312, or SHP099.

[0025] In some embodiments, a pharmaceutically acceptable salt or crystalline form of Compound 1 is in the form of a tablet, powder, granule, patch, inhaler, or capsule. In some embodiments, Compound 1 is in the form of a capsule. In some embodiments, a pharmaceutically acceptable salt or crystalline form of Compound 1 is administered at a dose of 3-50 mg of Compound 1 per time, once or twice a day. In some embodiments, Compound 1 is administered at a dose of 12 mg or 6 mg per time, twice a day. BRIEF DESCRIPTION OF DRAWINGS

[0026] The following drawings show embodiments of the present application, but the present application is not limited thereto.

[0027] Figure 1 shows the X-ray powder diffraction pattern of crystalline Form I of Compound 1 as a free base.

[0028] Figure 2 shows the X-ray powder diffraction pattern of the hydrobromide salt Form I.

[0029] Figure 3 shows the DSC pattern of the hydrobromide salt Form I.

[0030] Figure 4 shows a TGA plot of the hydrobromide salt Form I.

[0031] Figure 5 shows an X-ray powder diffraction pattern of the hydrochloride salt Form I.

[0032] Figure 6 shows a DSC plot of the hydrochloride salt Form I.

[0033] Figure 7 shows a TGA plot of the hydrochloride salt Form I.

[0034] Figure 8 shows an X-ray powder diffraction pattern of the hydrochloride salt Form II.

[0035] Figure 9 shows a DSC plot of the hydrochloride salt Form II.

[0036] Figure 10 shows a TGA plot of the hydrochloride salt Form II.

[0037] Figure 11 shows an X-ray powder diffraction pattern of the sulfate salt Form I.

[0038] Figure 12 shows a DSC plot of the sulfate salt Form I.

[0039] Figure 13 shows a TGA plot of the sulfate salt Form I.

[0040] Figure 14 shows an X-ray powder diffraction pattern of the 1,5-naphthalene disulfonic acid salt Form I.

[0041] Figure 15 shows a DSC plot of the 1,5-naphthalene disulfonic acid salt Form I.

[0042] Figure 16 shows a TGA plot of the 1,5-naphthalene disulfonic acid salt Form I.

[0043] Figure 17 shows an X-ray powder diffraction pattern of the 1,2-ethanedisulfonic acid salt Form I.

[0044] Figure 18 shows a DSC plot of the 1,2-ethanedisulfonic acid salt Form I.

[0045] Figure 19 shows a TGA plot of the 1,2-ethanedisulfonic acid salt Form I.

[0046] Figure 20 shows an X-ray powder diffraction pattern of the benzenesulfonic acid salt Form I.

[0047] Figure 21 shows a DSC plot of the benzenesulfonic acid salt Form I.

[0048] Figure 22 shows a TGA plot of the benzenesulfonic acid salt Form I.

[0049] Figure 23 shows an X-ray powder diffraction pattern of the p-toluenesulfonic acid salt Form I.

[0050] Figure 24 shows a DSC plot of the benzenesulfonic acid salt Form I.

[0051] Figure 25 shows a TGA plot of the benzenesulfonic acid salt Form I.

[0052] Figure 26 shows the DVS of the hydrobromide salt Form I.

[0053] Figure 27 shows the DVS of the hydrochloride salt Form I.

[0054] Figure 28 shows the DVS of the hydrochloride salt Form II.

[0055] Figure 29 shows the DVS of the sulfate salt Form I.

[0056] Figure 30 shows the DVS of the 1,5-napthalenesulfonic acid salt Form I.

[0057] Figure 31 shows the DVS of the 1,2-ethanedisulfonic acid salt Form I.

[0058] Figure 32 shows the DVS of the benzenesulfonic acid salt Form I.

[0059] Figure 33 shows the DVS of the p-toluenesulfonic acid salt Form I. DETAILED DESCRIPTION

[0060] The present application will be further described by way of specific examples, which are not intended to limit the scope of the application. Those skilled in the art will appreciate improvements and modifications of the described methods and apparatuses within the scope of the claims. Therefore, the scope of the patent is defined not by the specific examples, but by the appended claims.

[0061] The following abbreviations are used in the present application:

[0062] XRPD: X-ray powder diffraction

[0063] DSC: differential scanning calorimetry

[0064] TGA: thermogravimetric analysis

[0065] DVS: dynamic vapor sorption

[0066] This application includes the singular forms "a," "an," and "the" of words such as "crystal form" and "the method" include their corresponding plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a crystal form" includes one or more such different crystal forms and reference to "the method" includes reference to equivalent steps and methods known to those with ordinary skill in the art that could be substituted or in addition to the methods described herein.

[0067] Throughout the entire description and claims, the terms "comprise" and variations such as "comprising" and "comprises" will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. As used herein, the term "comprising" can be replaced by the term "containing" or, at times, by the term "having."

[0068] The term "about" means plus or minus 10% or 5% or 2% of the indicated term.

[0069] A "therapeutically effective amount" refers to the amount of a compound that will elicit the pharmacological or physiological effects for which it is administered, including an amount sufficient to prevent the onset of or to alleviate to some extent one or more of the symptoms of the disorder or condition being treated. A "therapeutically effective amount" can vary with the compound, the disease, condition, and / or symptoms of the disease or condition, the severity of the disease or condition, and / or symptoms, the age of the subject to be treated, and / or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined using routine experimentation. In the context of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination that is effective for the treatment of the disease, condition, or disorder.

[0070] An "excipient" refers to an ingredient other than the therapeutic agent itself, which is used as a diluent, vehicle, binder, and / or medium in the manufacture of a pharmaceutical composition, to improve its handling or storage properties, or to allow or facilitate the formation of a unit dosage form of a compound or pharmaceutical composition for administration.

[0071] A "crystal form" or "crystal" or "polymorph" refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0072] The crystal forms disclosed herein are substantially pure crystals. The term "substantially pure" as used herein refers to at least 85% by weight, preferably at least 95% by weight, more preferably at least 99% by weight of a crystal form disclosed herein, and also includes about 100% by weight of a certain crystal form. The remainder of the material includes other form(s) of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystalline form of a pharmaceutically acceptable salt of Compound 1 can be considered substantially pure because it has a purity greater than 90% by weight, as measured by means known and generally accepted in the art at the time.

[0073] An "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters, data or values derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate). For the crystalline forms disclosed herein, only the major peaks (i.e., the most characteristic, significant, unique and / or reproducible peaks) are summarized; other peaks can be obtained from the diffraction pattern by routine methods. The major peaks described above can be reproduced within the margin of error (±2 in the last decimal place given, or ±0.2 of the value given).

[0074] "2Θ" refers to the peak position expressed in degrees (°) based on the experimental setup in an X-ray diffraction experiment, and is typically the unit of abscissa in a diffraction pattern. The experimental setup requires that the reflected beam be recorded at a 2Θ angle if the reflection is diffracted when the incident beam forms a Θ angle with a certain lattice plane. It should be understood that the specific 2Θ values mentioned in the present application for a particular crystalline form are intended to represent the 2Θ values (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0075] The term "substantially the same" or "essentially as shown in Figure XX" with respect to an X-ray diffraction peak means that representative peak positions and intensity variations are taken into account. For example, one skilled in the art will appreciate that peak positions (2Θ) can show some variation, typically up to 0.1-0.2°, and that the instrument used to measure the diffraction can also cause some variation. In addition, one skilled in the art will appreciate that relative peak intensities can vary from instrument to instrument and also as a result of the degree of crystallinity, preferred orientation, surface of the sample prepared, and other factors known to those skilled in the art, and should be taken as only a qualitative measure.

[0076] Differential scanning calorimetry (DSC) is well known in the art, and the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the present application have a DSC pattern with a characteristic peak position having substantially the same properties as the DSC pattern provided in the figures herein, with a margin of error of ±5°C in the measured value, typically ±3°C.

[0077] The numerical values described and claimed herein are approximations. Variations to the numerical values embodied in this specification, and / or to other values deemed to be the same can result from tolerances in the instruments, measurement error, impurities in the materials, the specification for the relative sizes of components, variations among batches, and the like.

[0078] Pharmaceutical compositions comprising a pharmaceutically acceptable salt of Compound 1 disclosed herein can be administered orally, inhalationally, rectally, parenterally, or topically to a subject in need thereof. For oral administration, the pharmaceutical composition can be in the form of regular solid preparations such as tablets, powders, granules, capsules, etc., liquid preparations such as aqueous or oily suspensions, or other liquid preparations such as syrups, solutions, suspensions, etc.; for parenteral administration, the pharmaceutical composition can be in the form of solutions, aqueous solutions, oily suspension concentrates, lyophilized powders, etc. Preferably, the preparation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition can be administered as a single unit with a precise dose. In addition, the pharmaceutical composition can further comprise additional active ingredients.

[0079] All preparations of the pharmaceutical composition disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients and then prepared into the desired preparation. The "pharmaceutically acceptable excipient" refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical preparation, for example: diluents, vehicles such as water, various organic solvents, etc., fillers such as starch, sucrose, etc., binders such as cellulose derivatives, alginate, gelatin and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as decentralized agents, stabilizers, thickening agents, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes.

[0080] "Pharmaceutical composition" refers to a composition comprising a crystalline form of a compound of the present application and at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, including, i.e., adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispensing agents, depending on the nature of the mode of administration and the dosage form.

[0081] Pharmaceutically acceptable carriers are formulated in accordance with a number of factors well within the purview of the ordinarily skilled artisan. These include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the composition containing the agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can also include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., stabilization of the active agent, binder, etc.). A description of suitable pharmaceutically acceptable carriers, as well as factors involved in their selection, can be found in a variety of readily available sources, such as, for example, Allen, Jr., L.V. et al., Remington: The Science and Practice of Pharmacy (2 volumes), 22ndedition, Pharmaceutical Press (2012).

[0082] The dosage regimen of the solid forms of the present application will, of course, vary according to such factors as the pharmacokinetic properties of the particular agent; and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment(s) with which it is used in combination; the frequency with which it is to be administered; the route of administration, the renal and hepatic function of the patient, and the effect desired. In general, oral daily dosage ranges for each active ingredient will be from about 0.001 to about 5000 mg / day, preferably from about 0.01 to about 1000 mg / day, and most preferably from 0.1 to about 250 mg / day. Intravenously, the most preferred dosage ranges will be from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. The compounds of the present application can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily.

[0083] The dosage form (pharmaceutical composition) for administration can contain from about 1 mg to about 2000 mg of the active ingredient (i.e., Compound 1) per dosage unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.1% to 95% by weight based on the total weight of the composition.

[0084] The crystalline forms of the present application are not limited to those having exactly the same characteristic spectra, such as XRPD, DSC, TGA, DVS, isotherm, as described in the figures disclosed herein, any crystalline form having substantially the same or essentially the same characteristic spectra as those described in the figures fall within the scope of the present application.

[0085] X-ray powder diffraction patterns described herein were collected on a PANalytical Empyrean or X’Pert3 X-ray powder diffractometer. Method parameters for X-ray powder diffraction described herein are as follows:

[0086] X-ray source: Cu, K

[0087] K 1.54060; K 1.54443

[0088] K / K intensity ratio: 0.50

[0089] Voltage: 45 kilovolts (kV)

[0090] Current: 40 milliamps (mA)

[0091] Scan range: from 3.0 to 40.0 degrees

[0092] Differential scanning calorimetry (DSC) patterns described herein were collected on a TA Discovery 2500. Method parameters for differential scanning calorimetry (DSC) described herein are as follows:

[0093] Scan rate: 10 °C / min

[0094] Protective gas: N2

[0095] Thermogravimetric analysis (TGA) patterns described herein were collected on a TA Discovery 5500. Method parameters for thermogravimetric analysis (TGA) described herein are as follows:

[0096] Scan rate: 10 °C / min

[0097] Protective gas: N2

[0098] High performance liquid chromatography (HPLC) purity data in this disclosure were acquired on a Thermo Vanquish Core with a diode array detector (DAD). Method parameters for HPLC to test purity described herein are as follows:

[0099] 1. Column: Xbridge Shield RP18, 150 x 4.6 mm, 5 pm

[0100] 2. Mobile phase: A: 10 mM ammonium acetate (pH = 8.5): acetonitrile (95:5, v:v)

[0101] B: 50 mM ammonium acetate (pH = 8.5): acetonitrile (2:8, v:v)

[0102] Elution gradient as follows:

[0103] 3. Flow rate: 1.0 mL / min

[0104] 4. Injection volume: 5 μL

[0105] 5. Detection wavelength: 270 nm

[0106] 6. Column temperature: 40 °C

[0107] 7. Autosampler temperature: room temperature

[0108] 8. Diluent: Ethanol

[0109] Unless otherwise specified, the following examples were operated at room temperature.

[0110] Example 1: Crystalline Form I of Free Base Compound 1

[0111] The preparation of crystalline Form I of free base Compound 1 can be found in PCT application PCT / CN2024 / 076655, Example 2a. Specifically, to about 21 mg of amorphous sample of Compound 1 (prepared according to the method of Example 1 of Chinese patent application No. 201210190520.4), 4 mL of absolute ethanol was added, and the mixture was heated and stirred in an 85 °C oil bath for 5 minutes until the solution was clear; then, the resulting clear solution was allowed to cool to room temperature (25 °C) over 2.5 h while stirring, and the stirring was continued at room temperature for 24 h; the resulting solid sample was filtered off and subjected to XRPD measurement, which was designated as crystalline Form I of free base Compound 1 (sometimes simply referred to as crystalline Form I of Compound 1). The XRPD diffraction peak data of the sample are shown in Table 1 and Figure 1 below. The examples shown in Figure 1 and Table 1 are embodiments of the present application, but the present application is not limited thereto.

[0112] Figure 1 shows.

[0113] Table 1

[0114] Example 2: Preliminary screening of salt forms

[0115] Using the crystalline Form I of free base Compound 1 prepared in Example A as the starting material, salt / co-crystal screening tests were performed with one of the following acids (hydrobromic acid, hydrochloric acid, 1,5-naphthalene disulfonic acid, sulfuric acid, 1,2-ethanedisulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, myricetin, quercetin, resveratrol, kaempferol, p-toluenesulfonic acid, phosphoric acid, fuscocerine, pamoic acid, cyclamic acid, fumaric acid, gentisic acid, 1-hydroxy-2-naphthoic acid, citric acid, salicylic acid, and tartaric acid) in five solvents (acetone, IPAc, ACN, THF, and EtOAc). The samples of all tests were subjected to XRPD characterization.

[0116] The results of the tests revealed that only hydrobromic acid, hydrochloric acid, 1,5-naphthalenedisulfonic acid, sulfuric acid, 1,2-ethanedisulfonic acid, benzenesulfonate and p-toluenesulfonic acid were able to form salts or salt crystalline forms. The other results were either the free base crystalline form I and the acid, or amorphous, or degradation products. The results are shown in Tables 2, 3 and 4.

[0117] Table 2

[0118] Notes:

[0119] NA: Not performed.

[0120] *: Clear after stirring at room temperature for three days, still clear after transfer to stirring at 5°C for one day and at -20°C for two days, transferred to evaporation at room temperature.

[0121] #: Transferred to stirring at 50°C for five days after stirring at room temperature for twelve days, still clear after addition of one equivalent of methanesulfonic acid and continued stirring at 50°C.

[0122] &: Clear after stirring at room temperature for twelve days, transferred to stirring at 50°C for four days, still clear, transferred to stirring at 5°C for three days, still clear, transferred to stirring at -20°C for

[0123] Table 3

[0124] Notes:

[0125] [1]: Transferred to stirring at 50°C for six days after stirring at room temperature for 6-13 days.

[0126] [2]: Two equivalents of the corresponding ligand were added after stirring at room temperature for 6-12 days and the stirring at room temperature was continued for six days.

[0127] Table 4

[0128] Notes:

[0129] [1]: Two equivalents of the corresponding ligand were added after stirring at room temperature for 6-12 days and the stirring at room temperature was continued for six days.

[0130] [2]: Transferred to stirring at 50°C for six days after stirring at room temperature for 6-13 days

[0131] Example 3: Preparation of hydrobromide salt crystalline form I (large scale)

[0132] About 3 grams of Compound 1 Form I (Compound 1 Form I of this application refers to the free base Form I prepared as described in Example A, unless otherwise explicitly indicated) was weighed into a 60 mL glass jar and suspended in 25 mL of ethyl acetate. To this suspension was added 957 μL of 40% hydrobromic acid. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day. To this suspension was added 15 mL of ethyl acetate and the stirring was continued at room temperature for about 2 days. The solid was collected by centrifugation and dried under vacuum at room temperature for about 3 days.

[0133] The solid obtained in this example was determined to be hydrobromide Form I. The X-ray powder diffraction data for the solid obtained is shown in Table 5 and Figure 2. The hydrobromide Form I sample was tested by DSC and TGA and the data is shown in Figures 3 and 4.

[0134] Table 5

[0135] Example 4: Preparation of hydrochloride Form I

[0136] About 3 grams of Compound 1 Form I was weighed into a 60 mL glass jar and suspended in 25 mL of ethyl acetate. To this suspension was added 561 μL of 4 Molar hydrochloric acid in ethyl acetate. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day. To this suspension was added 15 mL of ethyl acetate and the stirring was continued at room temperature for about 2 days. The solid was collected by centrifugation and dried under vacuum at room temperature for about 3 days. The solid was transferred to the mother liquor and 561 μL of 38% concentrated hydrochloric acid was added and stirred magnetically at room temperature for about 1 day. The solid was collected by centrifugation and dried under vacuum at room temperature for about 1 day and then transferred to a nitrogen atmosphere and dried at room temperature for 2 days.

[0137] The solid obtained in this example was determined to be hydrochloride Form I. The X-ray powder diffraction data for the solid obtained is shown in Table 6 and Figure 5. The hydrochloride Form I sample was tested by DSC and TGA and the data is shown in Figures 6 and 7.

[0138] Table 6

[0139] Example 5: Preparation of hydrochloride Form II (large scale)

[0140] About 3 grams of Compound 1 Form I solids were weighed into a 60 mL glass jar, and 25 mL of ethyl acetate was added to form a suspension. To the suspension was added 1.683 mL of concentrated sulfuric acid. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day. To the suspension was added 15 mL of ethyl acetate, and the stirring was continued at room temperature for about 2 days. The solids were collected by centrifugation and dried under vacuum at room temperature for about 3 days.

[0141] The solid obtained in this example was determined to be the hydrochloride salt Form II. The X-ray powder diffraction data for the solid obtained is shown in Table 7 and Figure 8. The hydrochloride salt Form II sample was tested by DSC and TGA, and the data is shown in Figures 9 and 10.

[0142] Table 7

[0143] Example 6: Preparation of Sulfate Salt Form I (large scale)

[0144] About 3 grams of Compound 1 Form I solids were weighed into a 60 mL glass jar, and 25 mL of ethyl acetate was added to form a suspension. To the suspension was added 1.683 mL of concentrated sulfuric acid. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day. To the suspension was added 15 mL of ethyl acetate, and the stirring was continued at room temperature for about 2 days. The solids were collected by centrifugation and dried under vacuum at room temperature for about 3 days.

[0145] The solid obtained in this example was determined to be the sulfate salt Form I. The X-ray powder diffraction data for the solid obtained is shown in Table 8 and Figure 11. The sulfate salt Form I sample was tested by DSC and TGA, and the data is shown in Figures 12 and 13.

[0146] Table 8

[0147] Example 7: Preparation of 1,5-naphthalene disulfonate salt Form I (large scale)

[0148] About 3 grams of Compound 1 Form I solids and 1.849 grams of 1,5-naphthalene disulfonic acid were weighed into a 60-milliliter glass bottle and 25 milliliters of ethyl acetate was added to form a suspension. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day, then 15 milliliters of ethyl acetate was added and stirring was continued at room temperature for about 2 days. The solids were collected by centrifugation and placed in a vacuum oven at room temperature for about 3 days. The resulting solids were transferred to the mother liquor, and 320.2 milligrams of 1,5-naphthalene disulfonic acid and 150.7 milligrams of Compound 1 Form I solids were added and stirred magnetically at room temperature for about 3 days and then at 50 °C for 3 days. The solids were collected by filtration and dried at ambient temperature for 3 hours and then in a vacuum oven at room temperature for about 1 hour.

[0149] The solids obtained in this example were determined to be 1,5-naphthalene disulfonic acid salt Form I. The X-ray powder diffraction data for the solids obtained are shown in Table 9 and Figure 14. The 1,5-naphthalene disulfonic acid salt Form I sample was tested by DSC and TGA, and the data are shown in Figures 15 and 16.

[0150] Table 9

[0151] Example 8: Preparation of 1,2-ethanedisulfonic acid salt Form I

[0152] About 3 grams of Compound 1 Form I solids and 1.276 grams of 1,2-ethanedisulfonic acid were weighed into a 60-milliliter glass bottle and 25 milliliters of ethyl acetate was added to form a suspension. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day, then 15 milliliters of ethyl acetate was added and stirring was continued at room temperature for about 2 days. The solids were collected by centrifugation and placed in a vacuum oven at room temperature for about 3 days.

[0153] The solids obtained in this example were determined to be 1,2-ethanedisulfonic acid salt Form I. The X-ray powder diffraction data for the solids obtained are shown in Table 10 and Figure 17. The 1,2-ethanedisulfonic acid salt Form I sample was tested by DSC and TGA, and the data are shown in Figures 18 and 19.

[0154] Table 10

[0155] Example 9: Preparation of benzenesulfonic acid salt Form I

[0156] About 3 grams of Compound 1 Form I solids and 1.062 grams of benzenesulfonic acid were weighed into a 60-milliliter glass bottle and 25 milliliters of ethyl acetate was added to form a suspension. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day, and then 15 milliliters of ethyl acetate was added and stirring was continued at room temperature for about 2 days. The solids were collected by centrifugation and dried under vacuum at room temperature for about 3 days.

[0157] The solids obtained in this example were determined to be benzenesulfonic acid salt Form I. The X-ray powder diffraction data for the solids obtained are shown in Table 11 and Figure 20. The benzenesulfonic acid salt Form I sample was tested by DSC and TGA, and the data are shown in Figures 21 and 22.

[0158] Table 11

[0159] Example 10: Preparation of p-toluenesulfonic acid salt Form I

[0160] About 3 grams of Compound 1 Form I solids and 1.158 grams of p-toluenesulfonic acid were weighed into a 60-milliliter glass bottle and 25 milliliters of ethyl acetate was added to form a suspension. The suspension was stirred magnetically at room temperature (about 1000 rpm) for about 1 day, and then 15 milliliters of ethyl acetate was added and stirring was continued at room temperature for about 2 days. The solids were collected by centrifugation and dried under vacuum at room temperature for about 3 days.

[0161] The solids obtained in this example were determined to be p-toluenesulfonic acid salt Form I. The X-ray powder diffraction data for the solids obtained are shown in Table 12 and Figure 23. The p-toluenesulfonic acid salt Form I sample was tested by DSC and TGA, and the data are shown in Figures 24 and 25.

[0162] Table 12

[0163] Example 11: Hygroscopicity

[0164] To evaluate the hygroscopicity of the hydrobromide salt Form I, the hydrochloride salt Form I, the hydrochloride salt Form II, the sulfate salt Form I, the 1,5-naphthalenedisulfonate salt Form I, the 1,2-ethanedisulfonate salt Form I, the benzenesulfonate salt Form I and the p-toluenesulfonate salt Form I, the dynamic vapor sorption (DVS) curves of the hydrobromide salt Form I prepared in Example 3, the hydrochloride salt Form I prepared in Example 4, the hydrochloride salt Form II prepared in Example 5, the sulfate salt Form I of Example 6, the 1,5-naphthalenedisulfonate salt Form I prepared in Example 7, the 1,2-ethanedisulfonate salt Form I prepared in Example 8, the benzenesulfonate salt Form I prepared in Example 9 and the p-toluenesulfonate salt Form I prepared in Example 10 were tested, and the experimental results are shown in Table 13.

[0165] The DVS of the hydrobromide salt Form I is shown in Figure 26, the DVS of the hydrochloride salt Form I is shown in Figure 27, the DVS of the hydrochloride salt Form II is shown in Figure 28, the DVS of the sulfate salt Form I is shown in Figure 29, the DVS of the 1,5-naphthalenedisulfonate salt Form I is shown in Figure 30, the DVS of the 1,2-ethanedisulfonate salt Form I is shown in Figure 31, the DVS of the benzenesulfonate salt Form I is shown in Figure 32, and the DVS of the p-toluenesulfonate salt Form I is shown in Figure 33.

[0166] Table 13

[0167] According to the definition of drug hygroscopicity in the Chinese Pharmacopoeia 2020 edition, the benzenesulfonate salt Form I and the p-toluenesulfonate salt Form I of the present application have almost no hygroscopicity, and the sulfate salt Form I has slight hygroscopicity, so they can still maintain stable properties under high humidity conditions, and do not need special humidity control conditions during production, storage and use, which can well meet the requirements of drug production and use.

[0168] Definition of hygroscopicity characteristics and hygroscopic weight gain (Guidelines for Drug Hygroscopicity Test in Chinese Pharmacopoeia 2020 Edition):

[0169] Deliquescence: Absorbing sufficient moisture to form a liquid

[0170] Extremely hygroscopic: hygroscopic weight gain is not less than 15%

[0171] Hygroscopic: hygroscopic weight gain is less than 15% but not less than 2%

[0172] Slightly hygroscopic: hygroscopic weight gain is less than 2% but not less than 0.2%

[0173] No or almost no hygroscopicity: hygroscopic weight gain is less than 0.2%

[0174] Example 12: Solubility

[0175] About 50 to 70 mg of the hydrobromide salt Form I prepared in Example 3, the hydrochloride salt Form I prepared in Example 4, the hydrochloride salt Form II prepared in Example 5, the sulfate salt Form I of Example 6, the 1,5-naphthalene disulfonate salt Form I prepared in Example 7, the 1,2-ethane disulfonate salt Form I prepared in Example 8, the benzenesulfonate salt Form I prepared in Example 9 and the p-toluenesulfonate salt Form I prepared in Example 10 were weighed into a 5 mL graduated cylinder, respectively, and suspended in 5 mL of purified water, SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid), respectively. After equilibration at 37°C for 0.5 h, 1 h, 2 h and 4 h, the solutions were filtered to obtain clear solutions. The contents of the samples in the solutions were determined by HPLC. The results are shown in Table 14.

[0176] The results show that in purified water, the solubility of the 1,5-naphthalene disulfonate salt Form I at 0.5 h, 1 h and 4 h is higher than that of the other salt forms; in SGF, the solubility of the 1,5-naphthalene disulfonate salt Form I at 0.5 h, 1 h and 2 h is higher than that of the other salt forms; in FaSSIF, the solubility of the 1,5-naphthalene disulfonate salt Form I at 0.5 h, 1 h and 2 h is higher than that of the other salt forms; in FeSSIF, the solubility of the 1,5-naphthalene disulfonate salt Form I at 0.5 h, 1 h, 2 h and 4 h is higher than that of the other salt forms.

[0177] Table 14

[0178] Example 13: Bulk and tapped densities

[0179] About 500 mg of the hydrobromide salt Form I prepared in Example 3, the hydrochloride salt Form I prepared in Example 4, the hydrochloride salt Form II prepared in Example 5, the sulfate salt Form I of Example 6, the 1,5-naphthalene disulfonate salt Form I prepared in Example 7, the 1,2-ethane disulfonate salt Form I prepared in Example 8, the benzenesulfonate salt Form I prepared in Example 9 and the p-toluenesulfonate salt Form I prepared in Example 10 were weighed into a 5 mL graduated cylinder, respectively, and the volumes at this time were recorded. The graduated cylinders were tapped on the table 200 times and the volumes at this time were recorded. The tests were carried out in triplicate. The results are shown in Table 15.

[0180] Table 15

[0181] Example 14: Angle of repose

[0182] Approximately 20 mg of each of the hydrobromide salt Form I prepared in Example 3 (starting purity 99.87 area %), the hydrochloride salt Form I prepared in Example 4 (starting purity 99.84 area %), the hydrochloride salt Form II prepared in Example 5 (starting purity 99.88 area %), the sulfate salt Form I of Example 6 (starting purity 100.00 area %), the 1,5-naphthalene disulfonate salt Form I prepared in Example 7 (starting purity 96.75 area %), the 1,2-ethane disulfonate salt Form I prepared in Example 8 (starting purity 99.75 area %), the benzenesulfonate salt Form I prepared in Example 9 (starting purity 99.84 area %), and the p-toluenesulfonate salt Form I prepared in Example 10 (starting purity 99.90 area %) were placed in 5 mL clear glass vials, closed and placed in a light stability chamber with temperature set at 5 °C. When the light intensity reached white light 352000 Lux-hrs + ultraviolet 51 W-hrs / m 2 and white light 1414000 Lux-hrs + ultraviolet 208 W-hrs / m 2 , samples were taken for XRPD and HPLC purity testing. Approximately 20 mg of each of the above eight samples were placed in 5 mL clear glass vials, wrapped with aluminum foil, closed and placed in a light stability chamber with temperature set at 5 °C. When the light intensity reached white light 352000 Lux-hrs + ultraviolet 51 W-hrs / m 2 and white light 1414000 Lux-hrs + ultraviolet 208 W-hrs / m 2 , samples were taken for XRPD and HPLC purity testing.

[0183] Table 16

[0184] Example 15: Comparison of Light Stability

[0185] Approximately 20 mg of each of the hydrobromide salt Form I prepared in Example 3 (starting purity 99.87 area %), the hydrochloride salt Form I prepared in Example 4 (starting purity 99.84 area %), the hydrochloride salt Form II prepared in Example 5 (starting purity 99.88 area %), the sulfate salt Form I of Example 6 (starting purity 100.00 area %), the 1,5-naphthalene disulfonate salt Form I prepared in Example 7 (starting purity 96.75 area %), the 1,2-ethane disulfonate salt Form I prepared in Example 8 (starting purity 99.75 area %), the benzenesulfonate salt Form I prepared in Example 9 (starting purity 99.84 area %), and the p-toluenesulfonate salt Form I prepared in Example 10 (starting purity 99.90 area %) were placed in 5 mL clear glass vials, closed and placed in a light stability chamber with temperature set at 5 °C. When the light intensity reached white light 352000 Lux-hrs + ultraviolet 51 W-hrs / m 2 and white light 1414000 Lux-hrs + ultraviolet 208 W-hrs / m 2 , samples were taken for XRPD and HPLC purity testing. Approximately 20 mg of each of the above eight samples were placed in 5 mL clear glass vials, wrapped with aluminum foil, closed and placed in a light stability chamber with temperature set at 5 °C. When the light intensity reached white light 352000 Lux-hrs + ultraviolet 51 W-hrs / m 2 and white light 1414000 Lux-hrs + ultraviolet 208 W-hrs / m 2 , samples were taken for XRPD and HPLC purity testing.XRPD and HPLC purity were tested at different time. The results are shown in Table 17. The purity of hydrobromide Form I, hydrochloride Form I, hydrochloride Form II, sulfate Form I, benzenesulfonate Form I and p-toluenesulfonate Form I decreased slightly after being placed under the condition of white light 1414000 Lux hrs + ultraviolet 208 W hrs / m 2 The purity decreased slightly after being placed under the condition, and the sample purity / initial purity was 96.0% ~ 99.3%; the purity of 1,5-naphthalenedisulfonate Form I and 1,2-ethanedisulfonate Form I decreased significantly after being placed under the condition, and the sample purity / initial purity was 91.6% and 81.6%; the hydrobromide Form I, hydrochloride Form II, sulfate Form I, 1,5-naphthalenedisulfonate Form I, 1,2-ethanedisulfonate Form I, benzenesulfonate Form I and p-toluenesulfonate Form I did not change significantly in crystal form after being placed under all conditions, and the hydrochloride Form I changed in crystal form after being placed under all conditions. 2 The purity decreased slightly after being placed under the condition, and the sample purity / initial purity was 96.0% ~ 99.3%; the purity of 1,5-naphthalenedisulfonate Form I and 1,2-ethanedisulfonate Form I decreased significantly after being placed under the condition, and the sample purity / initial purity was 91.6% and 81.6%; the hydrobromide Form I, hydrochloride Form II, sulfate Form I, 1,5-naphthalenedisulfonate Form I, 1,2-ethanedisulfonate Form I, benzenesulfonate Form I and p-toluenesulfonate Form I did not change significantly in crystal form after being placed under all conditions, and the hydrochloride Form I changed in crystal form after being placed under all conditions.

[0186] Table 17

[0187] Illumination-1: white light 352000 Lux hrs + ultraviolet 51 W hrs / m 2 ;

[0188] Illumination-2: white light 1414000 Lux hrs + ultraviolet 208 W hrs / m 2 ;

[0189] Light shielding control-1: the glass bottle was wrapped with aluminum foil and placed under white light 352000 Lux hrs + ultraviolet 51 W hrs / m 2 ;

[0190] Light shielding control-2: the glass bottle was wrapped with aluminum foil and placed under white light 1414000 Lux hrs + ultraviolet 208 W hrs / m 2 .

[0191] The above examples are only for illustrating the technical concept and characteristics of the present application, and the purpose is to enable the person skilled in the art to understand the content of the present application and to implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made according to the spirit and essence of the present application shall be covered within the protection scope of the present application.

Claims

1. A pharmaceutically acceptable salt of Compound 1 which is a hydrobromide, hydrochloride, sulfate, 1,5-naphthalenedisulfonate, 1,2-ethanedisulfonate, benzenesulfonate, or p-toluenesulfonate, wherein Compound 1 is 4-fluoro-5-(2-fluoro-4-iodophenylamino)-lH- benzo[d]thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide.

2. The pharmaceutically acceptable salt of claim 1, wherein the pharmaceutically acceptable salt is in solid form.

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

4. The pharmaceutically acceptable salt of claim 3, wherein the pharmaceutically acceptable salt is in crystalline form which is hydrobromide Form I, hydrochloride Form I, hydrochloride Form II, sulfate Form I, 1,5-naphthalenedisulfonate Form I, 1,2-ethanedisulfonate Form I, benzenesulfonate Form I, or p-toluenesulfonate Form I.

5. The pharmaceutically acceptable salt of claim 4, wherein the X-ray powder diffraction pattern of the hydrobromide Form I includes characteristic diffraction peaks at the following 2Θ positions: 24.0° ± 0.2°, 22.1° ± 0.2°, 16.8° ± 0.2°, using Cu-Kα radiation; (a) the pharmaceutically acceptable salt is a hydrobromide salt Form I characterized by (b) the pharmaceutically acceptable salt is hydrochloride Form I, characterized by an X-ray powder diffraction pattern including characteristic diffraction peaks at the following 2Θ positions: 13.9° ± 0.2°, 30.0° ± 0.2°, 26.9° ± 0.2°, using Cu-Kα radiation; (c) the pharmaceutically acceptable salt is hydrochloride Form II, characterized by an X-ray powder diffraction pattern including characteristic diffraction peaks at the following 2Θ positions: 25.2° ± 0.2°, 26.9° ± 0.2°, 24.2° ± 0.2°, using Cu-Kα radiation; (d) the pharmaceutically acceptable salt is sulfate Form I, characterized by an X-ray powder diffraction pattern including characteristic diffraction peaks at the following 2Θ positions: 25.3° ± 0.2°, 27.4° ± 0.2°, 23.5° ± 0.2°, using Cu-Kα radiation (e) the pharmaceutically acceptable salt is 1,5-naphthalenedisulfonate Form I, characterized by an X-ray powder diffraction pattern including characteristic diffraction peaks at the following 2Θ positions: 23.6° ± 0.2°, 15.5° ± 0.2°, 14.0° ± 0.2°, using Cu-Kα radiation (f) the pharmaceutically acceptable salt is 1,2-ethanedisulfonate Form I, characterized by an X-ray powder diffraction pattern including characteristic diffraction peaks at the following 2Θ positions: 23.4° ± 0.2°, 24.0° ± 0.2°, 20.7° ± 0.2°, using Cu-Kα radiation (g) the pharmaceutically acceptable salt is benzenesulfonate Form I, characterized by an X-ray powder diffraction pattern including characteristic diffraction peaks at the following 2Θ positions: 24.4° ± 0.2°, 25.7° ± 0.2°, 19.6° ± 0.2°, using Cu-Kα radiation ​ (h) the pharmaceutically acceptable salt is p-toluenesulfonic acid salt Form I characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at the following 2Θ positions: 22.4° ± 0.2°, 29.1° ± 0.2°, 14.1° ± 0.2°, using Cu-Kα radiation 6. The pharmaceutically acceptable salt of claim 5, wherein (a) the X-ray powder diffraction pattern of the hydrobromide salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 15.8° ± 0.2°, 27.2° ± 0.2°, 32.2° ± 0.2°; (b) the X-ray powder diffraction pattern of the hydrochloride salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 24.3° ± 0.2°, 23.6° ± 0.2°, 28.9° ± 0.2°; (c) the X-ray powder diffraction pattern of the hydrochloride salt Form II further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 16.5° ± 0.2°, 26.2° ± 0.2°, 22.3° ± 0.2° (d) the X-ray powder diffraction pattern of the sulfate salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 17.3° ± 0.2°, 32.6° ± 0.2°, 34.2° ± 0.2° (e) the X-ray powder diffraction pattern of the 1,5-naphthalene disulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 17.4° ± 0.2°, 28.6° ± 0.2°, 14.5° ± 0.2° (f) the X-ray powder diffraction pattern of the 1,2-ethanedisulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 16.7° ± 0.2°, 26.2° ± 0.2°, 24.5° ± 0.2° (g) the X-ray powder diffraction pattern of the benzenesulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 14.1° ± 0.2°, 30.7° ± 0.2°, 6.1° ± 0.2° (h) the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 5.9° ± 0.2°, 29.6° ± 0.2°, 32.2° ± 0.2° 7. The pharmaceutically acceptable salt of claim 6, wherein (a) the X-ray powder diffraction pattern of the hydrobromide salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 24.8° ± 0.2°, 30.4° ± 0.2°, 31.3° ± 0.2°; (b) the X-ray powder diffraction pattern of the hydrochloride salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 27.7° ± 0.2°, 23.2° ± 0.2°, 18.8° ± 0.2°; (c) the X-ray powder diffraction pattern of the hydrochloride salt Form II further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 25.8°±0.2°, 22.9°±0.2°, 21.9°±0.2° (d) the X-ray powder diffraction pattern of the sulfate salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 29.7°±0.2°, 37.4°±0.2°, 9.1°±0.2° (e) the X-ray powder diffraction pattern of the 1,5-naphthalenedisulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 32.2°±0.2°, 26.4°±0.2°, 34.3°±0.2° (f) the X-ray powder diffraction pattern of the 1,2-ethanedisulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 30.9°±0.2°, 30.0°±0.2°, 34.3°±0.2° (g) the X-ray powder diffraction pattern of the benzenesulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 27.1°±0.2°, 17.0°±0.2°, 17.7°±0.2° (h) the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt Form I further comprises one or two or three characteristic diffraction peaks at the following 2Θ positions: 33.4°±0.2°, 27.2°±0.2°, 30.2°±0.2° 8. The pharmaceutically acceptable salt of claim 4, wherein (a) the X-ray powder diffraction pattern of the hydrobromide salt Form I comprises characteristic diffraction peaks at the following 2Θ positions: 24.0°±0.2°, 22.1°±0.2°, 16.8°±0.2°, 15.8°±0.2°, 27.2°±0.2°, 32.2°±0.2°, 24.8°±0.2°, 30.4°±0.2°, 31.3°± 0.2°； (b) the X-ray powder diffraction pattern of the hydrochloride salt Form I comprises characteristic diffraction peaks at the following 2Θ positions: 13.9°±0.2°, 30.0°±0.2°, 26.9°±0.2°, 24.3°±0.2°, 23.6°±0.2°, 28.9°±0.2°, 27.7°±0.2°, 23.2°±0.2°, 18.8°±0.2°; (c) the X-ray powder diffraction pattern of the hydrochloride salt Form II comprises characteristic diffraction peaks at the following 2Θ positions: 25.2°±0.2°, 26.9°±0.2°, 24.2°±0.2°, 16.5°±0.2°, 26.2°±0.2°, 22.3°±0.2°, 25.8°±0.2°, 22.9°±0.2°, 21.9°±0.2° (d) the X-ray powder diffraction pattern of the sulfate Form I comprises characteristic diffraction peaks at the following 2Θ positions: 25.3° ± 0.2°, 27.4° ± 0.2°, 23.5° ± 0.2°, 17.3° ± 0.2°, 32.6° ± 0.2°, 34.2° ± 0.2°, 29.7° ± 0.2°, 37.4° ± 0.2°, 9.1° ± 0.2° (e) the X-ray powder diffraction pattern of the 1,5-naphthalenedisulfonic acid Form I comprises characteristic diffraction peaks at the following 2Θ positions: 23.6° ± 0.2°, 15.5° ± 0.2°, 14.0° ± 0.2°, 17.4° ± 0.2°, 28.6° ± 0.2°, 14.5° ± 0.2°, 32.2° ± 0.2°, 26.4° ± 0.2°, 34.3° ± 0.2° (f) the X-ray powder diffraction pattern of the 1,2-ethanedisulfonic acid Form I comprises characteristic diffraction peaks at the following 2Θ positions: 23.4° ± 0.2°, 24.0° ± 0.2°, 20.7° ± 0.2°, 16.7° ± 0.2°, 26.2° ± 0.2°, 24.5° ± 0.2°, 30.9° ± 0.2°, 30.0° ± 0.2°, 34.3° ± 0.2° (g) the X-ray powder diffraction pattern of the benzenesulfonic acid Form I comprises characteristic diffraction peaks at the following 2Θ positions: 24.4° ± 0.2°, 25.7° ± 0.2°, 19.6° ± 0.2°, 14.1° ± 0.2°, 30.7° ± 0.2°, 6.1° ± 0.2°, 27.1° ± 0.2°, 17.0° ± 0.2°, 17.7° ± 0.2° (h) the X-ray powder diffraction pattern of the p-toluenesulfonic acid Form I comprises characteristic diffraction peaks at the following 2Θ positions: 22.4° ± 0.2°, 29.1° ± 0.2°, 14.1° ± 0.2°, 5.9° ± 0.2°, 29.6° ± 0.2°, 32.2° ± 0.2°, 33.4° ± 0.2°, 27.2° ± 0.2°, 30.2° ± 0.2° 9. The pharmaceutically acceptable salt of claim 4, wherein (a) the X-ray powder diffraction pattern of the hydrobromide Form I is substantially as shown in Figure 2; (b) the X-ray powder diffraction pattern of the hydrochloride Form I is substantially as shown in Figure 5; (c) the X-ray powder diffraction pattern of the hydrochloride Form II is substantially as shown in Figure 8 (d) the X-ray powder diffraction pattern of the sulfate Form I is substantially as shown in Figure 11 (e) the X-ray powder diffraction pattern of the 1,5-naphthalenedisulfonic acid Form I is substantially as shown in Figure 14 (f) the X-ray powder diffraction pattern of the 1,2-ethanedisulfonic acid Form I is substantially as shown in Figure 17 (g) the X-ray powder diffraction pattern of the benzenesulfonic acid Form I is substantially as shown in Figure 20 (h) the X-ray powder diffraction pattern of the p-toluenesulfonic acid Form I is substantially as shown in Figure 23 10. The pharmaceutically acceptable salt of claim 4, wherein (a) the hydrobromide salt Form I has a DSC pattern as shown in Figure 3; (b) the hydrochloride salt Form I has a DSC pattern as shown in Figure 6; (c) the hydrochloride salt Form II has a DSC pattern as shown in Figure 9 (d) the sulfate salt Form I has a DSC pattern as shown in Figure 12 (e) the 1,5-naphtalenedisulfonic acid salt Form I has a DSC pattern as shown in Figure 15 (f) the 1,2-ethanedisulfonic acid salt Form I has a DSC pattern as shown in Figure 18 (g) the benzenesulfonic acid salt Form I has a DSC pattern as shown in Figure 21 (h) the p-toluenesulfonic acid salt Form I has a DSC pattern as shown in Figure 24 11. The pharmaceutically acceptable salt of claim 4, wherein (a) the hydrobromide salt Form I has a DSC pattern as shown in Figure 3, wherein the DSC pattern of the hydrobromide salt Form I has endothermic peaks at 116°C and 186°C; (b) the hydrochloride salt Form I has a DSC pattern as shown in Figure 6, wherein the DSC pattern of the hydrochloride salt Form I has endothermic peaks at 125°C, 136°C and 207°C; (c) the hydrochloride salt Form II has a DSC pattern as shown in Figure 9, wherein the DSC pattern of the hydrochloride salt Form II has endothermic peaks at 97°C, 159°C and 214°C (d) the sulfate salt Form I has a DSC pattern as shown in Figure 12, wherein the DSC pattern of the sulfate salt Form I has an endothermic peak at 208°C (e) the 1,5-naphtalenedisulfonic acid salt Form I has a DSC pattern as shown in Figure 15, wherein the DSC pattern of the 1,5-naphtalenedisulfonic acid salt Form I has endothermic peaks at 91°C, 120°C and 199°C (f) the 1,2-ethanedisulfonic acid salt Form I has a DSC pattern as shown in Figure 18, wherein the DSC pattern of the 1,2-ethanedisulfonic acid salt Form I has endothermic peaks at 102°C and 177°C (g) the benzenesulfonic acid salt Form I has a DSC pattern as shown in Figure 21, wherein the DSC pattern of the benzenesulfonic acid salt Form I has an endothermic peak at 190°C (h) the p-toluenesulfonic acid salt Form I has a DSC pattern as shown in Figure 24, wherein the DSC pattern of the p-toluenesulfonic acid salt Form I has endothermic peaks at 185°C and 194°C 12. The pharmaceutically acceptable salt of claim 4, wherein (a) the hydrobromide salt Form I has a TGA pattern as shown in Figure 4; (b) the hydrochloride salt Form I has a TGA pattern as shown in Figure 7; (c) the hydrochloride salt Form II has a TGA pattern as shown in Figure 10 (d) the sulfate salt Form I has a TGA pattern as shown in Figure 13 (e) the 1,5-naphtalenedisulfonic acid salt Form I has a TGA as shown in Figure 16 (f) the 1,2-ethanedisulfonic acid salt Form I has a TGA pattern as shown in Figure 19 (g) the benzenesulfonic acid salt Form I has a TGA pattern as shown in Figure 22 (h) the p-toluenesulfonic acid salt Form I has a TGA pattern as shown in Figure 25 13. In a second aspect, the present application provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of any one of claims 1-12, and a pharmaceutically acceptable carrier and / or excipient.

14. A method of treating neoplasms, chronic inflammatory diseases, inflammatory bowel diseases, skin diseases, diabetes, ocular diseases, diseases associated with angiogenesis or vasculogenesis in a mammal, diseases associated with chronic pain, and other diseases modulated by the Mek cascade in a mammal, comprising administering to said mammal a pharmaceutically acceptable salt of any one of claims 1-12.

15. A method of treating RAS or RAF mutant cancer in a mammal, comprising administering to said mammal a pharmaceutically acceptable salt of any one of claims 1-12.

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