WO2015083059A1

WO2015083059A1 - Forms of the egfr inhibitor

Info

Publication number: WO2015083059A1
Application number: PCT/IB2014/066475
Authority: WO
Inventors: Vijay SETHURAMAN; Liladhar Waykole; Runyan LI; Liang MAO; Wenxian Pan; Xiaoyang Wang; Yubo ZHANG
Original assignee: Novartis Ag
Priority date: 2013-12-02
Filing date: 2014-12-01
Publication date: 2015-06-11

Abstract

The present disclosure generally relates to polymorphic form(s) of (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi). The present disclosure also generally relates to a pharmaceutical composition comprising the form(s), as well of methods of using the form(s) in the treatment of cancer indications, and methods for obtaining such forms.

Description

FORMS OF THE EGFR INHIBITOR

FIELD OF INDUSTRIAL APPLICABILITY

The present disclosure generally relates to polymorphic form(s) of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi). The present disclosure also generally relates to a pharmaceutical composition comprising the form(s), as well of methods of using the form(s) in the treatment of cancer indications, use of said forms and methods for obtaining such forms.

BACKGROUND OF THE DISCLOSURE

The epidermal growth factor receptor (EGFR, Erb-Bl) belongs to a family of proteins involved in the proliferation of normal and malignant cells. Overexpression of EGFR is found in over 70 percent of human cancers, including without limitation non-small cell lung carcinomas (NSCLC), breast cancers, gliomas, squamous cell carcinoma of the head and neck, and prostate cancer. The identification of EGFR as an oncogene has led to the development of anti-EGFR targeted molecules, such as gefitinib and erlotinib. SUMMARY OF THE DISCLOSURE

The object of the present disclosure was to provide novel forms of a more potent EGFR inhibitor, the inhibitor of formula 1 :

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi), that also has a better therapeutic index. The forms exhibit improved hygroscopicity, stability and/or solubility. In one embodiment the form affords better handling characteristic. In another embodiment, the forms can be better used in formulating pharmaceutical compositions. The novel forms of the Compound can be mixed with specific excipients, or, alternatively, be formulated in compositions free of other specific excipients, to further bolster their advantageous characteristics. Particularly good stability is achieved when the Compound EGFRi, or its specific forms are kept at a pH between 1 and 9, particularly between 1 and 6.8. The compound and its form exhibit the best stability at about pH 4.5.

Embodiments of these crystalline forms include those characterized herein as Compound EGFRi free form A, free form B, mesylate form A, mesylate form B (when in combination with other forms), mesylate form C, amorphous form and HC1 salt form. The names used herein to characterize a specific form, e.g. "free form A", "free form B", "mesylate form A", "mesylate form B", "mesylate form C", "amorphous form" or "HCl salt form" etc., should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.

Specifically, the present disclosure provides the following aspects, advantageous features and specific embodiments, respectively alone or in combination, as listed in the following items: 1. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is free form A. 2. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is free form B.

3. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is mesylate form A.

4. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is mesylate form C.

5. A HCl salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide.

6. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is mesylate form B, wherein the form further comprises any form as defined in any one of items 1 to 4 or HCl salt as defined in item 6.

7. The crystalline form according to item 1, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30, measured at a temperature of about 22°C. 8. The crystalline form according to item 1 or 7, wherein the x-ray powder diffraction pattern measured at a temperature of about 22°C of the crystalline form is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 1, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 2, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 2.

9. The crystalline form according to item 2, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

11.24, 14.68, 15.66, 18.64, 19.63, 20.05, 20.31, 22.41, 24.91, 25.43, 26.03, 27.18 and 28.07± 0.30, measured at a temperature of about 22°C.

10. The crystalline form according to item 2 or 9, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 4, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 5 or Fig. 6, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 7.

11. The crystalline form according to item 3, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

9.12, 12.19, 16.25, 17.38, 18.42, 19.91, 20.85, 22.43, 22.92, 24.10, 26.64 and 27.78 ± 0.30, measured at a temperature of about 22°C.

12. The crystalline form according to item 3 or 11, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 8, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 9, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 9.

13. The crystalline form according to item 4, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

11.51, 13.19, 16.23, 17.50, 19.14, 23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30, measured at a temperature of about 22°C. 14. The crystalline form according to item 4 or 13, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 14, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 15, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 15.

15. The HC1 salt of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to item 5, wherein the compound is crystalline and the x-ray powder diffraction pattern comprises 4 or 5 2Θ values (CuKa) selected from the group consisting of:

14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30, measured at a temperature of about 22°C. 16. The HC1 salt of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to item 5 or 15, wherein the salt is crystalline and the x-ray powder diffraction pattern measured at a temperature of about 22°C of the salt is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 17, a differential scanning calorimetry (DSC) thermogram of the salt is essentially the same as that shown in FIG. 18, or a thermo gravimetric analysis (TGA) diagram of the salt is essentially the same as that shown in figure FIG. 18.

17. The crystalline form according to item 6, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

11.76, 13.832, 14.41, 15.9, 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30, measured at a temperature of about 22°C.

18. The crystalline form according to item 6 or 17, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 11, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 12, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 12.

19. The crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of items 1 to 4, 6 to 14, 17 or 18, or HC1 salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of items 5, 15 or 16, comprising:

(i) free form A, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30;

(ii) free form B, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 11.24, 14.68, 15.66, 18.64, 19.63, 20.05, 20.31, 22.41, 24.91, 25.43, 26.03, 27.18 and 28.07± 0.30;

(iii) mesylate form A, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 9.12, 12.19, 16.25, 17.38, 18.42, 19.91, 20.85, 22.43, 22.92, 24.10, 26.64 and 27.78 ± 0.30;

(iv) mesylate form B, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 11.76, 13.832, 14.41, 15.9, 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30;

(v) mesylate form C, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 11.51, 13.19, 16.23, 17.50, 19.14,

23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30;

(vi) HC1 salt form wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30, all measured at a temperature of about 22°C, or

(vii) amorphous form,

wherein when the crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide comprises mesylate form B, the crystalline form further comprises also at least one of the forms selected from the group of free form A, free form B, mesylate form A, mesylate form C and HC1 salt form.

20. The crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of items 1 to 4 or 7 to 14, or HC1 salt of (R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of items 5, 15 or 16, wherein the crystalline form or a salt consist essentially of respective form or a salt.

21. The crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide or HC1 salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to item 20, wherein said forms or salt are in substantially pure form. 22. The crystalline form or the salt form according to item 19, wherein x-ray powder diffraction pattern comprises five, six, seven, eight or more 2Θ values (CuKa) selected from the group. 23. The crystalline form or the salt form according to item 19, wherein x-ray powder diffraction pattern comprises all 2Θ values selected from the group for a respective form.

24. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide having a X-ray diffraction spectrum essentially the same as the X-ray powder diffraction spectrum shown in FIG. 1, FIG. 4, FIG. 8, FIG. 11, FIG. 14, or FIG. 17.

25. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide having a differential scanning calorimetry (DSC) thermogram essentially the same as that shown in any one of figures FIG. 2, FIG. 5, FIG. 6, FIG. 9, FIG. 12, FIG. 15, or FIG 18. 26. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide having a thermo gravimetric analysis (TGA) diagram essentially the same as that shown in any one of figures FIG. 2, FIG. 7, FIG. 9, FIG. 12, FIG. 15, or FIG 18.

27. A mesylate salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, wherein the salt excludes the crystalline form B of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide with the x-ray powder diffraction pattern of 15 2Θ values (CuKa) selected from the group consisting of 11.76, 13.832, 14.41, 15.9, 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.20, measured at 22°C.

28. A pharmaceutical composition comprising the crystalline form according to any one of items 1 to 4, 6 to 14, 17 to 26, HC1 salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of items 5, 15, 16 or 19 to 23, or mesylate salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to item 27. 29. The pharmaceutical composition according to item 28, further comprising a

pharmaceutically acceptable carrier or diluent.

30. The pharmaceutical composition according to item 28 or 29, wherein the crystal form is as defined in any one of items 1 to 4, or 6 to 26.

31. The pharmaceutical composition according to item 28 or 29, wherein said form is free form A, free form B, mesylate form A, mesylate form C or HCl salt form and wherein x-ray powder diffraction pattern comprises four 2Θ values (CuKa) selected from the group consisting of:

(a) 5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30 for free form A,

(b) 11.24, 14.68, 15.66, 18.64, 19.63, 20.05, 20.31, 22.41, 24.91, 25.43, 26.03, 27.18 and 28.07± 0.30 for free form B,

(c) 9.12, 12.19, 16.25, 17.38, 18.42, 19.91, 20.85, 22.43, 22.92, 24.10, 26.64 and 27.78 ± 0.30 for mesylate form A,

(e) 11.51, 13.19, 16.23, 17.50, 19.14, 23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30 for mesylate form C, or

(f) 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 for HCl salt form,

all at a temperature of about 22°C, respectively.

32. The pharmaceutical composition according to item 31, wherein said form is free form A, free form B, mesylate form A, mesylate form C or HCl salt form and wherein x-ray powder diffraction pattern comprises five 2Θ values (CuKa) selected from the group consisting of: (a) 5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30 for free form A,

(f) 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 for HCl salt form,

all at a temperature of about 22°C, respectively.

33. The pharmaceutical composition according to item 32, wherein said form is free form A, free form B, mesylate form A, mesylate form C or HCl salt form and wherein x-ray powder diffraction pattern comprises all 2Θ values selected from the group consisting of:

(a) 5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30 for free form A, (b) 11.24, 14.68, 15.66, 18.64, 19.63, 20.05, 20.31, 22.41, 24.91, 25.43, 26.03, 27.18 and 28.07± 0.30 for free form B,

(f) 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 for HC1 salt form,

all at a temperature of about 22°C, respectively. 34. A pharmaceutical composition comprising

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide and a pH modifier.

35. The pharmaceutical composition according to item 34, wherein

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide is a mesylate salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide. 36. The pharmaceutical composition according to item 34 or 35 comprising mesylate form B of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide. 37. The pharmaceutical composition according to item 34 comprising amorphous form of

38. The pharmaceutical composition according to any one of items 28 to 33, further comprising a pH modifier.

39. The pharmaceutical composition according to any one of items 28 to 38, wherein the pH modifier is a pharmaceutically acceptable acid, base, salt or mixtures thereof. 40. The pharmaceutical composition according to any one of items 28 to 38, wherein the composition is liquid.

41. The pharmaceutical composition according to item 34, wherein the

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide is in any form as defined in any one of items 1 to 27. 42. The pharmaceutical composition according to any one of items 28 to 41, wherein the pH of the formulation is between pH 1 and pH 9, measured at 25°C.

43. The pharmaceutical composition according to any one of items 28 to 41, wherein the pH of the formulation is between pH 2 and pH 9, measured at 25°C.

44. The pharmaceutical composition according to any one of items 28 to 41, wherein the pH of the formulation is between pH 2 and pH 6.8, measured at 25°C. 45. The pharmaceutical composition according to any one of items 28 to 41, wherein the pH of the formulation is between pH 2 and pH 4.7, measured at 25°C.

46. The pharmaceutical composition according to any one of items 28 to 41, wherein the pH of the formulation is about 4.5, or pH is 4.5, measured at 25°C.

47. A pharmaceutical formulation comprising

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, wherein 1 g of the pharmaceutical formulation dissolved, suspended or slurried in 1 mL of water has a pH of between pH 1 and pH 9.

48. A pharmaceutical formulation comprising

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, wherein 1 w/w % solution or suspension of the pharmaceutical formulation, relative to the

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide in the pharmaceutical formulation, has a pH of between pH 1 and pH 9.

49. The pharmaceutical formulation according 47 or 48, wherein pH is between pH 1 and pH 6.8, measured at 25°C.

50. The pharmaceutical formulation according 47 or 48, wherein pH is between pH 2 and pH 6.8, measured at 25°C. 51. The pharmaceutical formulation according 47 or 48, wherein pH is between pH 2 and pH 4.7, measured at 25°C.

52. The pharmaceutical formulation according 47 or 48, wherein pH is about pH 4.5, measured at 25°C.

53. A crystalline form according to any one of items 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of items 5, 15, 16 or 19 to 23, mesylate salt according to item 27, a pharmaceutical composition according to any one of items 28 to 46, or a pharmaceutical formulation according to any one of items 47 to 52, for use as a medicine. 54. A crystalline form according to any one of items 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of items 5, 15, 16 or 19 to 23, mesylate salt according to item 27, a pharmaceutical composition according to any one of items 28 to 46, or a pharmaceutical formulation according to any one of items 47 to 52, for use in the treatment of a proliferative disease.

55. The crystalline form according to any one of items 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of items 5, 15, 16 or 19 to 23, mesylate salt according to item 27, the pharmaceutical composition according to any one of items 28 to 46, or the pharmaceutical formulation according to any one of items 47 to 52 for use according to item 54, wherein the proliferative disease is non-small cell lung cancer, head and neck cancer, colorectal cancer, breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, glioma or prostate cancer.

56. The crystalline form according to any one of items 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of items 5, 15, 16 or 19 to 23, mesylate salt according to item 27, the pharmaceutical composition according to any one of items 28 to 46, or the pharmaceutical formulation according to any one of items 47 to 52 for use according to item 54 or 55, wherein the proliferative disease is non-small cell lung cancer.

57. The crystalline form according to any one of items 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of items 5, 15, 16 or 19 to 23, mesylate salt according to item 27, the pharmaceutical composition according to any one of items 28 to 46, or the pharmaceutical formulation according to any one of items 47 to 52 for use according to item 54 or 55, wherein

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide is administered to a human.

58. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide comprising:

(i) free form A,

(ii) free form B,

(iii) mesylate form A,

(iv) mesylate form B,

(v) mesylate form C,

(vi) HC1 salt form, or

(vii) amorphous form, wherein when the crystalline form of

59. The crystalline form according to item 58 consisting essentially of

(i) free form A,

(ii) free form B,

(iii) mesylate form A,

(v) mesylate form C, or

(vi) HC1 salt form.

60. The crystalline form according to item 59, wherein said forms are in substantially pure form.

61. The crystalline form according to any one of items 58 to 60, wherein x-ray powder diffraction pattern comprises 4 or more 2Θ values selected from the group consisting of:

(d) 11.76, 13.832, 14.41, 15.9 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30 for mesylate form B,

(f) 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 for HC1 salt form,

all at a temperature of about 22°C.

62. The crystalline form according to item 61, wherein x-ray powder diffraction pattern comprises five or more 2Θ values selected from the group. 63. The crystalline form according to item 61, wherein x-ray powder diffraction pattern comprises all 2Θ values selected from the group for a respective form.

64. A crystalline form of

65. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide having a differential scanning calorimetry (DSC) thermogram essentially the same as that shown in shown in any one of figures FIG. 2, FIG. 5, FIG. 6, FIG. 9, FIG. 12, FIG. 15, or FIG 18. 66. A crystalline form of

67. A pharmaceutical composition comprising the crystalline form according to any one of items 58 to 66.

68. The pharmaceutical composition according to item 67, further comprising a

pharmaceutically acceptable carrier or diluent.

Definitions

As used herein "amorphous" refers to a solid form of a molecule and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.

As used herein, "substantially pure," when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of Compound EGFRi, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of Compound EGFRi may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of Compound EGFRi and/or reaction impurities and/or processing impurities. In alternative, the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical forms of the Compound EGFRi. In one embodiment, the "substantially pure" can also mean that that the compound includes cumulatively less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical forms of the compound and/or other impurities.

The term "free form" refers to the compound per se without salt formation or association with a solvent (e.g., solvate; if solvent water - hydrate).

The term "essentially the same" with reference to X-ray diffraction peak positions, or Figures means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2Θ) or other peak positions in a Figure will show some inter-apparatus variability, depending on the method used; in case of XRPD typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, temperature, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. illustrates the x-ray powder diffraction pattern of the crystalline free form A of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi).

FIG. 2. illustrates the differential scanning calorimetry (DSC) and the thermogravimetric analysis (TGA) of the crystalline free form A of the compound

FIG. 3. illustrates the microscopic picture of the crystalline free form A of the compound (R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi).

FIG. 4. illustrates the x-ray powder diffraction pattern of the crystalline free form B of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi) (recorded by Bruker D8 Discover X-ray diffractometer).

FIG. 5. illustrates the differential scanning calorimetry (DSC) of the crystalline free form B of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi) recorded by TA Discovery Series DSC in open pan DSC (a hole in DSC lid) test; the free form B lost water and changed to free form A, then the free form A melted at 112.2 °C

FIG. 6. illustrates the differential scanning calorimetry (DSC) of the crystalline free form B of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi) by TA Discovery Series DSC in the closed pan DSC, the free form B was tested in a sealed DSC pan, which was isolated from outside.

FIG. 7. illustrates the thermogravimetric analysis (TGA) of the crystalline free form B of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi) by TA Discovery Series TGA.

FIG. 8. illustrates the x-ray powder diffraction patterns of the crystalline mesylate form A of the compound

FIG. 9. illustrates the differential scanning calorimetry (DSC) and the thermogravimetric analysis (TGA) of the crystalline mesylate form A of the compound

FIG. 10. illustrates the microscopic picture of the crystalline mesylate form A of the compound

FIG. 11. illustrates the x-ray powder diffraction pattern of the crystalline mesylate form B of the compound

FIG. 12. illustrates the differential scanning calorimetry (DSC) and the thermogravimetric analysis (TGA) of the crystalline mesylate form B of the compound

FIG. 13. illustrates the microscopic picture of the crystalline mesylate form B of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi). FIG. 14. illustrates the x-ray powder diffraction patterns of the crystalline mesylate form C of the compound

FIG. 15. illustrates the differential scanning calorimetry (DSC) and the thermogravimetric analysis (TGA) of the crystalline mesylate form C of the compound

FIG. 16. illustrates the x-ray powder diffraction patterns of the amorphous form, free form A and free form B of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide (Compound EGFRi) superimposed.

FIG. 17. illustrates the x-ray powder diffraction patterns of the HC1 salt form of the compound

FIG. 18. illustrates the differential scanning calorimetry (DSC) and the thermogravimetric analysis (TGA) of the HC1 salt form of the compound

DETAILED DESCRIPTION OF THE DISCLOSURE

The disclosure relates to crystalline forms of the Compound EGFRi, which are described and characterized herein. The Compound EGFRi act as inhibitor of EGFR It can be employed in different forms for use in the treatment of cancer diseases. The forms of the compound have pronounced different characteristics and can thus be appropriately selected when, for example, formulating the compound in the pharmaceutical formulation. The Compound EGFRi exhibits EGFR kinase activity and can be thus, particularly in specific forms as disclosed herein, used for treating proliferative disease. Inhibition of cell proliferation can be measured using methods known to those skilled in the art. For example, a convenient assay for measuring cell proliferation is the CellTiter-Glo™ Luminescent Cell Viability Assay, which is commercially available from Promega (Madison, Wis.). That assay determines the number of viable cells in culture based on quantitation of ATP present, which is an indication of metabolically active cells. See Crouch et al (1993) J. Immunol. Meth. 160:81-88, U.S. Pat. No. 6,602,677. The assay may be conducted in 96- or 384-well format, making it amenable to automated high-throughput screening (HTS). See Cree et al (1995) Anticancer Drugs 6:398-404. The assay procedure involves adding a single reagent

(CellTiter-Glo® Reagent) directly to cultured cells. This results in cell lysis and generation of a luminescent signal produced by a luciferase reaction. The luminescent signal is

proportional to the amount of ATP present, which is directly proportional to the number of viable cells present in culture. Data can be recorded by luminometer or CCD camera imaging device. The luminescence output is expressed as relative light units (RLU). Inhibition of cell proliferation may also be measured using colony formation assays known in the art.

Furthermore, the Compound EGFRi can be used in a method of treating a condition mediated by EGFR in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of Compound EGFRi. In one embodiment, the condition is a cell proliferative disease. In a more specific embodiment, the condition is cancer, for example, non-small cell lung cancer (NSCLC), head and neck cancer, colorectal cancer, breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, glioma and prostate cancer. In a specific embodiment the condition is non-small cell lung cancer (NSCLC).

Treatment of the cell proliferative disorder by administration of the Compound EGFRi results in an observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of cancer cells or absence of the cancer cells; reduction in the tumor size; inhibition of cancer cell infiltration into peripheral organs including the spread of cancer into soft tissue and bone; inhibition of tumor metastasis; inhibition, to some extent, of tumor growth; and/or relief to some extent, one or more of the symptoms associated with the specific cancer; reduced morbidity and mortality, and improvement in quality of life issues. To the extent the Compound EGFRi may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. Reduction of these signs or symptoms may also be felt by the patient.

The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TDP) and/or determining the response rate (RR). Metastasis can be determined by staging tests and by bone scan and tests for calcium level and other enzymes to determine spread to the bone. CT scans can also be done to look for spread to the pelvis and lymph nodes in the area. Chest X-rays and measurement of liver enzyme levels by known methods are used to look for metastasis to the lungs and liver, respectively. Other routine methods for monitoring the disease include transrectal ultrasonography (TRUS) and transrectal needle biopsy (TRNB).

The therapeutically effective dosage of the compound, the pharmaceutical composition, or the combinations of the compound with other pharmaceutically active ingredients (e.g. other anticancer drugs) thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g. in divided doses up to four times a day. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.

In certain embodiments, a therapeutic amount or dose of the compound of the present disclosure may range from about 0.1 mg/kg to about 500 mg/kg, alternatively from about 1 to about 50 mg/kg. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses (such as two, three, or four times daily). Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment may cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

It has been found that several forms of the

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide exist. For example, the amorphous form has been found to have very good solubility at lower pH. However, the compound as such is sticky and hard to formulate. Therefore, crystalline forms are deemed more suitable for formulating. The following crystalline forms were found: crystalline free form A (temperature of melting (Tm) 114.6 °C), crystalline free form B (Tm 112.2 °C), crystalline mesylate form A (Tm 168.9 °C) and crystalline mesylate form B (Tm 170.1 °C). Mesylate Form C is an anhydrate form. It is crystalline. In the DSC curve, it shows one endotherm occurring at Tonset = 187.2 °C, but the peak is split into two. In the TGA curve, it shows a small weight loss, about 0.8%, up to 185 °C. Although better for formulating, crystalline free form A (anhydrous) is unstable as bulk, but is less hygroscopic than other crystalline forms. Crystalline free form B is a dihydrate and more stable than free form A. The free form dihydrate Form B is more stable in 0.1 N HC1 than the mesylate trihydrate form B. Free form B can be prepared in good yield by using a simple, inexpensive and mild procedure, and in excellent purity retaining consistent water content from 30% to 90% relative humidity at 25°C. Also the dihydrate allows the use of choice of analytical methods, especially the X-ray methods, the usage of which permits clear and straightforward analysis of its release in pharmaceutical

compositions. Crystalline mesylate form A of the compound is a monohydrate. It is more stable in bulk than free forms, but more hygroscopic. The best form for handling and formulating in pharmaceutical composition is mesylate form B. The mesylate form B is a trihydrate. It is more stable in solid state than free forms (free base forms A and B) and mesylate form A, more soluble in aqueous media, and better compatible with certain excipients. Compound EGFRi HC1 salt form behaves better in liquid formulations. It does not form gels with solvents.

In one embodiment, the present disclosure provides the mesylate salt of the compound (R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-meth lisonicotinamide of the following structure

N-(7-Chloro-l-{(3R)-l-[(2E)-4-(dimethylamino)but-2-enoyl]azepan-3-yl}-lH-benzimidazol- 2-yl)-2-methylpyridine-4-carboxamide methanesulfonate (1 : 1) can be also trihydrate. In particular embodiment the mesylate salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide or

N-(7-Chloro-l-{(3R)-l-[(2E)-4-(dimethylamino)but-2-enoyl]azepan-3-yl}-lH-benzimidazol- 2-yl)-2-methylpyridine-4-carboxamide methanesulfonate trihydrate exclude the crystal form with the following x-ray powder diffraction pattern: 11.76, 13.832, 14.41, 15.9 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30 2Θ (CuKa λ= 1.54056A).

In another embodiment, the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide is a HC1 salt. The Compound EGFRi crystalline free form A, which is an anhydrous form, has the following characteristic x-ray powder diffraction pattern: 5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30 2Θ (CuKa λ= 1.54056A). It may be characterized by a x-ray powder diffraction pattern (PXRD) comprising 5 or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 5.46, 15.84, 20.42, 22.56, 23.77, 25.09, 25.73 ± 0.30, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.54056A. Preferably, the Compound EGFRi crystalline free form A may be characterized by a x-ray powder diffraction pattern comprising 6 or more 2Θ values (CuKa λ=1.54056Α) selected from the group consisting of : 5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30, at a temperature of about 22°C.

In one embodiment, a representative XRPD pattern for the free form A is presented in the following table:

Free form A (anhydrous form):

Angle d value Intensity %

2-Theta ° Angstrom %

5.46287 16.16386 100

9.24225 9.56081 15.1

11.20646 7.88906 20.7

14.82315 5.97135 38.4

15.83617 5.59158 44

17.02289 5.20435 20

18.66506 4.75 75.3

19.63889 4.51661 21.8

20.42329 4.34487 54.1

21.12807 4.20151 18.1

22.55916 3.9381 25

23.76851 3.7404 25.9

25.09203 3.54602 40.5

25.72761 3.45984 28.3

26.35253 3.3792 30.1

27.55552 3.23434 29.6

28.11551 3.17118 21.3

30.93583 2.8882 16.2

34.67523 2.58482 15.3

38.62941 2.32884 15.2

40.05239 2.24932 16.4

The Compound EGFRi crystalline free form B, which is a dihydrate, has the following characteristic x-ray powder diffraction pattern: 11.24±0.30, 14.68±0.30, 15.66±0.30, 18.64±0.30, 19.63±0.30, 20.05±0.30, 20.31±0.30, 22.41±0.30, 24.91±0.3025.43±0.30, 26.03±0.30, 27.18±0.30, and 28.07± 0.30 (CuKa λ= 1.54056A). It may be characterized by a x-ray powder diffraction pattern (PXRD) comprising four or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 18.64, 25.43, 20.31 , 26.03, 27.18, and

28.07± 0.30, measured at a temperature of about 22°C and an x-ray wavelength, λ, of

1.54056A. Preferably, the Compound EGFRi crystalline free form B may be characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values (CuKa λ=1.54056Α) selected from the group consisting of 18.64, 25.43, 20.31, 26.03, 27.18, and 28.07± 0.30, at a temperature of about 22°C. In one embodiment, a representative XRPD pattern for the free form B is presented in the following table:

Free form B (dihydrate)

Angle Intensity %

-Theta ° %

11.24 38

14.68 47

15.66 48

18.64 100

19.63 42

20.05 47

20.31 61

22.41 45

24.91 50

25.43 65

26.03 55

27.18 50

28.07 35 The Compound EGFRi crystalline mesylate form A, which is a monohydrate, has the following characteristic x-ray powder diffraction pattern: 9.12, 12.19, 16.25, 17.38, 18.42, 19.91, 20.85, 22.43, 22.92, 24.10, 26.64 and 27.78 ± 0.30 2Θ (CuKa λ= 1.54056A). It may be characterized by a x-ray powder diffraction pattern (PXRD) comprising four or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 9.12, 12.19, 16.25, 17.38, 18.42, 19.91, 20.85, 22.43, 22.92, 24.10, 26.64 and 27.78 ± 0.30, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.54056A. Preferably, the Compound EGFRi crystalline mesylate form A may be characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 9.12, 12.19, 16.25, 17.38, 18.42, 19.91, 20.85, 22.43, 22.92, 24.10, 26.64 and 27.78 ± 0.30, at a temperature of about 22°C. In one embodiment, a representative XRPD pattern for the mesylate form A is presented in the following table:

Mesylate form A (monohydrate):

Angle d value Intensity %

2-Theta ° Angstrom %

9.12147 9.68713 25.9

12.19287 7.25295 100

13.43312 6.58597 8.6

14.14358 6.2567 10.9

16.24641 5.45129 14.2

17.3816 5.09775 12.5

18.41949 4.81277 74.2

19.90531 4.45675 12.4

20.85497 4.2559 13.1

21.86745 4.06109 9.5

22.43198 3.96014 14.1

22.92317 3.87639 13

23.32961 3.80976 11.7

23.79896 3.73568 9.7

24.09837 3.68994 14.2

25.43377 3.49915 10

25.85028 3.4437 10

26.63696 3.34376 14.2

27.78252 3.20843 21.8

30.98983 2.88329 8.1

34.23538 2.61701 6.7

35.4115 2.53274 6.4

36.98372 2.4286 10.4

37.26719 2.41078 10.1

38.17953 2.35524 7.1

39.10431 2.30165 7.6

39.79202 2.26344 7.4

41.64976 2.16667 6.3

43.98388 2.05695 7.1

The Compound EGFRi crystalline mesylate form B, which is trihydrate, has the following characteristic x-ray powder diffraction pattern: 11.76, 13.832, 14.41, 15.9 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30 2Θ (CuKa λ= 1.54056A). It may be characterized by a x-ray powder diffraction pattern (PXRD) comprising five or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 11.76, 13.832, 14.41, 15.9 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.54056A. Preferably, the Compound EGFRi crystalline mesylate form B may be characterized by a x-ray powder diffraction pattern comprising six or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 11.76, 13.832, 14.41, 15.9 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30, at a temperature of about 22°C.

In one embodiment, a representative XRPD pattern for the mesylate form B is presented in the following table:

Mesylate form B (trihydrate):

Angle d value Intensity %

2-Theta ° Angstrom %

5.79532 15.23733 33.2

11.75526 7.52196 51.2

13.82942 6.39811 48.8

14.41049 6.1414 50.8

15.18888 5.82838 57.3

16.30465 5.43196 26.2

17.65193 5.02028 59

18.47867 4.79749 35.8

18.78755 4.71931 61.2

19.61655 4.5217 30.4

20.29133 4.37283 25

21.4551 4.1382 64.7

21.83466 4.06711 40.8

22.30375 3.98262 54.9

23.35057 3.80639 35.7

23.82335 3.73191 38.8

24.50774 3.62923 100

24.89097 3.57421 53

25.56678 3.48124 53.2

26.65771 3.3412 94.2

27.77467 3.20932 65.3

29.06548 3.06966 27.8

30.59466 2.91963 22.3

31.82663 2.80937 24.2

34.81147 2.57501 17.4

36.02644 2.49091 22.9

41.51816 2.17324 18.3

44.6646 2.02717 17.8 The Compound EGFRi crystalline mesylate form C has the following characteristic x-ray powder diffraction pattern: 11.51, 13.19, 16.23, 17.50, 19.14, 23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30 2Θ (CuKa λ= 1.54056A). It may be characterized by a x-ray powder diffraction pattern (PXRD) comprising five or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 11.51, 13.19, 16.23, 17.50, 19.14, 23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.54056A. Preferably, the Compound EGFRi crystalline mesylate form C may be characterized by a x-ray powder diffraction pattern comprising six or more 2Θ values (CuKa λ= 1.54056A) selected from the group consisting of 11.51, 13.19, 16.23, 17.50, 19.14, 23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30, at a temperature of about 22°C.

In one embodiment, a representative XRPD pattern for the mesylate form C is presented ^' the following table:

Mesylate form C (anhydrous form):

Angle d value Intensity %

2-Theta ° Angstrom %

5.67913 15.54881 13.4

10.81411 8.17439 14.5

11.5087 7.68255 25.3

12.2189 7.23757 17.6

13.1893 6.70716 26.1

13.77973 6.42107 17.5

14.41634 6.13893 13.9

16.23088 5.45648 26.1

17.50003 5.06351 22.6

19.14178 4.63277 41.9

19.5925 4.5272 19.3

20.43204 4.34303 15.5

21.77114 4.07883 22.3

22.03055 4.03139 17.1

22.53925 3.94154 19.5

23.15277 3.83846 42.6

23.80439 3.73484 26.5

24.64689 3.60905 100

25.81205 3.44872 33.8

26.06282 3.4161 23.8

26.69553 3.33655 21.9

27.27977 3.26641 14.5

27.91729 3.19325 15.3 28.97184 3.07937 22.7

29.98749 2.97735 11.7

32.8838 2.72143 15.6

35.64795 2.51648 9.5

The Compound EGFRi crystalline HCl salt form has the following characteristic x-ray powder diffraction pattern: 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 2Θ (CuKa λ= 1.54056A), measured at a temperature of about 22°C.

In one embodiment, a representative XRPD pattern for the HCl salt form is presented in the following table:

HCl salt form:

Angle d value Intensity %

2-Theta ° Angstrom %

14.88934 5.94495 90.1

15.54683 5.69499 52

18.02516 4.91716 63.2

19.69317 4.50428 90.5

20.15181 4.40279 62.6

20.87353 4.25216 55.8

22.21493 3.99834 48.5

25.61463 3.47485 100

26.12697 3.40786 72.1

26.79442 3.32446 63.3

27.78255 3.20843 78.2

32.53383 2.7499 40.2

All tables above contain most pronounced and characteristic peaks for each of the forms in bold.

In one embodiment of the disclosure, the form of the Compound EGFRi is provided in substantially pure form. This crystalline form of the Compound EGFRi in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure.

Preferably, the crystalline form has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, a composition is provided consisting essentially of any one of the forms presented above, except when the form is mesylate form B, the compound contains other forms as well. The composition of this embodiment may comprise at least 90 weight % of the respective form, based on the weight of the Compound EGFRi in the composition. The presence of reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.

The disclosed forms of the Compound EGFRi can be formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical compositions can be formulated for oral, intravenous, intradermal, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, intraventricular, intrathecal, epidural, transdermal, rectal, by inhalation, or topical administration. In one embodiment, the pharmaceutical composition is formulated for oral administration. The pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. The compositions can be formulated for immediate release, sustained release, or controlled release of the compounds of the invention. Suitable pharmaceutical excipients include, for example, a) diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine); b) lubricants (e.g., silica, talcum, stearic acid, its magnesium or calcium salt); for tablets also c) binders (e.g., magnesium aluminum silicate, starch, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone); if desired d) disintegrants, e.g., starches, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Additional suitable pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The

pharmaceutical excipients can be saline, starch, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when the compound of the invention is administered intravenously. The present compositions can also contain minor amounts of wetting or emulsifying agents, or pH modifier.

Particularly pH modifier, also called pH buffering agent, can improve the stability of the Compound EGFRi, or its specific forms, namely free Form A, free Form B, mesylate from A, mesylate form B, mesylate form C, amorphous form and HC1 salt form. In solid dosage forms modulation of the pH through the use of pH modifiers can be very effective in improving solid dosage form stability. The same applies to liquid dosage forms. Particularly beneficial is when the pH is above pH 1 and below pH 9, particularly above pH 1 and below pH 6.8. In this range the 0.1% aqueous solutions or suspensions of the Compound EGFRi or its forms are most stable. Best result in terms of improved stability is reached at pH between pH 2 and pH 4.7. Acidic or basic ingredients (pH modifiers) can be intentionally added to a formulation to modify the pH and increase the composition's stability, for example measured by amount of the Compound EGFRi degradation products or impurities. pH modifier in oral solid dosage forms can be selected for example on the basis of knowing pH of their saturated solution. Without wishing to be bound to any theory, it can be assumed that solid pH, or the pH in a solid formulation, is reflective of the pH of the adsorbed moisture layer on the surface of particles or crystals in the formulation. Therefore, when a water soluble pH modifier dissolves in the moisture layer it achieves the pH of a saturated solution. The effect of a pH modifier on the solid pH is hence dependent on both its ionization constant (pKa) as well as its aqueous solubility. Limiting the pH in a liquid formulations is much more straightforward and a skilled person would be able to avail himself with many known buffers, acids, bases, and their salts. In case of lyophilized parenteral formulations, the solution used for the freeze drying process can usually be buffered to the desired pH using common buffering systems and buffer concentrations used for solution formulations. Again, without wishing to be bound to any theory, the pH of the reconstituted lyophile should generally correspond to solution pH prior to freeze drying.

Suitable pH modifiers used to enhance the stability of the forms are for example acids, bases or their salts (e.g. citric acid, fumaric acid, acetic acid, HC1, boric acid, phosphoric acid, malic, formic, lactic, succinic acid, malic acid, picolinic acid or succinic acid, etc. ,or mixtures thereof), or mixtures thereof. Particularly HC1, boric acid, phosphoric acid, acetic acid, or mixtures thereof, can be used. pH can be measured by a pH meter using a glass electrode or micro pH electrode. In alternative, pH can be measured by any other suitable means, like for example neutralization titration. In case of liquid samples, their pH can be measured directly. In order to measure pH of solid samples, they first need to be dissolved or suspended in a suitable solvent. For example, a 1 g sample of solid pharmaceutical composition comprising Compound EGFRi can be dissolved or suspended in a volume of 1 mL of water in order to prepare a solution, suspension or slurry of the pharmaceutical composition comprising Compound EGFRi and optionally also other excipients of the pharmaceutical formulation (e.g. pH modifier). The pH of said solution, suspension or slurry of the pharmaceutical composition comprising

Compound EGFRi should be between pH 1 and pH 9, preferably between pH 2 and pH 6.8, particularly around pH 4.5; measured at 20°C. In alternative, a sample can be dissolved or suspended in water to prepare 1 w/w % solution or suspension of the Compound EGFRi and H measured. The pH of said 1% solution or suspension of the Compound EGFRi should be between pH 1 and pH 9, preferably between pH 2 and pH 6.8, particularly around pH 4.5; measured at 25°C. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,

tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In another embodiment, the compositions can be formulated for parenteral administration by various routes, including but not limited to, intravenous (including bolus injection), subcutaneous, intramuscular, and intra-arterial administration. Such parenteral dosage forms are administered in the form of sterile or sterilisable injectable solutions, suspensions, dry and/or lyophilized products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection (reconstitutable powders) and emulsions. Vehicles used in such dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles.

Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1 percent to about 99 percent; and in another embodiment from about 1 percent to about 70 percent of the compound of the invention by weight or volume.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.

Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.

In another aspect, the pharmaceutical compositions further comprise one or more additional therapeutic agents. The compounds of the invention and the additional therapeutics agent(s) may act additively or synergistically. Preparation of Crystalline Materials:

Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (counter-solvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs. Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2^nd Edition, SSCI, West Lafayette, Indiana (1999).

For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapour pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility. In one method to prepare crystals, a compound is suspended and/or stirred in a suitable solvent to afford slurry, which may be heated to promote dissolution. The term "slurry", as used herein, means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature. Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by

micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph). A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analysed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be co-milled or passed through a mesh screen to delump the product, if necessary.

Crystalline forms may be prepared directly from the reaction medium of the final process for preparing EGFRi. This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which Compound EGFRi may be crystallized.

Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones. It is also possible to obtain one form of the compound and then transform it into another form, or mixture thereof, by the methods described above. The presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (PXRD) or solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in the comparison of an

experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one polymorph in the sample. The simulated PXRD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963) or TOPAS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).

The following non-limiting examples are illustrative of the disclosure.

EXAMPLES Details about methodology, instruments and standards used

1 pH value

The pH of 1% solution or suspension of the drug substance in water was recorded at 25°C. Mettler Toledo pH-meter with Orion Micro-pH combination electrode was used.

2 Determination of solubility

Solubility was determined using UPLC. 20 mg of drug substance were equilibrated in 1 mL media at room temperature for 24 h. The solution/suspension was filtrated and the saturated solution was analysed with UPLC.

3 Hygroscopicity

Water sorption curves were recorded using Surface Measurement Systems dynamic vapour sorption instrument at 25 °C.

4 Polymorphism behaviour

Slurries of drug substance were stirred at room temperature for 24 hours. The slurries were filtrated and the solids were analysed with XRD instrument.

5 UPLC method

Wave length: 225 nm

Column: Waters ACQUITY HSS T3, 50 x 2.1 mm, 1.8 μηι

Column temperature: 40 °C

Flow rate: 0.60 mL/min

Mobile phase A: 0.05% TFA in 95% water/5% acetonitrile

Mobile phase B: 0.05% TFA in 95% acetonitrile 15% water

Injection volume: 1.0 μL

Gradient:

6. X-ray Powder Diffraction Measurements One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present disclosure. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.

XRPD-method used to scan the samples as disclosed herein was as follows:

Instrument: Bruker D8 Discover with XYZ stage

Detector: GADDS (2D 'area' detector with 20° window)

Radiation: CuKa (0.15406 nm)

X-ray generator: power 40kV, 40 mA (1600 Watts)

Step size, resolution: 0.02 degrees

Measuring slice: 0.3 mm and 0.2 mm

Scan range: 2° - 45° (2 theta value)

Scan time: 2min

X-ray optics: Parallel (Goebel mirror)

Source slit: Fixed, 0.5mm

Detector distance: ~30cm

Sample amount of ca 2-5 mg was placed on an objective slide and centred in the X-ray beam.

7. Differential Scanning Calorimetry (DSC)

The DSC instrument used to test the crystalline forms was a TA Instrument® Differential Scanning Calorimetry Model 2910, TA Instruments® Modulated Differential Scanning Calorimetry Model 2920, TA Discovery series DSC or TA Instruments® Modulated

Differential Scanning Calorimetry Model Q1000. The DSC cell/sample chamber was purged with 100 ml/min of ultra- high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about ± 1°C, and the heat of fusion can be measured within a relative error of about ±5%. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. About 2-6 mg of sample powder was placed into the bottom of the pan and lightly tapped down to make contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10°C per minute in the temperature range between 25 and 300°C.

The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram ("W/g"). The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.

8. Thermogravimetric Analysis (TGA)

The TGA instruments used to test the crystalline forms was TA instruments, High Resolution Thermogravimetric Analyzer Q5000. 0.5-1.0 mg of test substance was weighted and placed on the open sample pan. The TGA

thermogram was recorded as follows: the sample was loaded into the furnace, the temperature equilibrated to 30 °C and heated to 300 °C at a heating rate of 10 °C/min under a flow of nitrogen at 25 m L/min. The instrument was calibrated for temperature with nickel and aluminum, and calibrated for weight with a 100 mg standard.

9. Polarized light microscope

Instrument: Olympus BX51 -P polarizing microscope. 0.1 -0.5 mg of test substance was dispersed in one drop of silicon oil on a glass slide.

Example 1.

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidaz ol-2-yl)-2-methylisonicotinamide

Intermediate 15

Step A: A stirred solution of (S)-feri-butyl 3-aminopiperidine-l-carboxylate (0.500 g, 2.49 mmol), l-fluoro-4-methyl-2-nitrobenzene (0.387 g, 2.49 mmol) and

N,N-diisopropylethylamine (0.482 g, 3.74 mmol) in DMF under argon was heated to 110°C for 6 h (reaction completion monitored by TLC). The mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford (S)-ieri-butyl

3-((4-methyl-2-nitrophenyl) amino) piperidine-l-carboxylate (I-15a). MS calculated for Ci₇H₂₄N₃0₄ (M-H^") 334.18, found 334.0.

Step B: To a stirred solution of I-15a (0.550 g, 1.64 mmol) in MeOH (35mL) was added Pd/C (0.090 g) and the mixture was stirred at room temperature under hydrogen atmosphere (balloon) for 2h (reaction completion monitored by TLC). The mixture was filtered through Celite, washed with MeOH and concentrated under reduced pressure to afford (S)-ieri-butyl 3-((2-amino-4-methylphenyl)amino)piperidine-l-carboxylate (I-15b). MS calculated for C17H28N3O2 (M+H⁺) 306.22, found 306.2.

Step C: To a stirred solution of (5 -tert-butyl

3-((2-amino-4-methylphenyl)amino)piperidine-l-carboxylate (I-15b) (0.500 g, 1.63 mmol) in MeOH (20 mL) was added a solution of cyanogen bromide (0.208 g, 1.96 mmol) in 1 :2 MeCN:H₂0 (20 mL) for a period of 5 min. The mixture was heated to 50°C for 2h (reaction completion monitored by TLC), cooled to 0°C and pH was adjusted to 10 by adding aqueous Na₂C03 solution. The mixture was stirred for 30 min at room temperature, the resulting solid was collected and dried under vacuum to afford the title compound (Intermediate 15). 1H-NMR (400 MHz, CDCI₃): d 7.24 (s, 1H), 7.17 (d, J= 7.6 Hz, 1H), 6.85 (d, J= 8 Hz, 1H), 4.64 (br s, 2H), 4.17 (t, J = 14.8 Hz, 2H), 3.99-3.93 (m, 1H), 3.32 (d, J= 11.6 Hz, 1H), 2.79 (t, J= 12.4 Hz, 1H), 2.41 (s, 3H), 2.38-2.37 (m, 1H), 2.34 (d, J= 3.2 Hz, 1H), 1.91 (d, J = 13.6 Hz, 3H), 1.69-1.61 (m, 1H), 1.47 (s, 9H); MS calculated for Ci₈H₂₇N₄0₂ (M+H⁺) 331.21, found 331.0.

Intermediate 26

(RVtert-butyl 3-(2-amino-7-chloro-lH-benzo[dlimidazol-l-vf)azepane-l-carboxylate

Step A: (R)-tert- butyl 3-((2-chloro-6-nitrophenyl)amino)azepane-l-carboxylate (I-26a) was prepared following procedures analogous to 1-15, Step A, using the appropriate starting materials. 1H-NMR (400MHz, CDC1₃): d 8.00-7.91 (m, 1H), 7.58-7.49 (m, 1H), 7.02-6.51 (m, 2H), 4.31-4.03 (m, 1H), 3.84-2.98 (m, 4H), 1.98-1.60 (m, 5H), 1.46-1.39 (m, 10H); MS calculated for Ci₇H₂₅ClN₃0₄ (M+H⁺) 370.15, found 370.10.

Step B: A mixture of I-26a (7.5 g, 19.5 mmol) and Zn (12.8 mg, 195 mmol) in AcOH

(22 mL) was stirred at room temperature for 2 h. The reaction was basified with saturated aqueous Na₂CC>3 solution, filtered, and extracted with EtOAc (3 x 80 mL). The combined organic phase was washed with brine, dried with Na₂S0₄ and concentrated in vacuum to afford (R)-tert-butyl 3-((2-amino-6-chlorophenyl)amino)azepane-l-carboxylate (I-26b). MS calculated for C17H27CIN3O2 (M+H⁺) 340.17, found 340.10. The crude was used in the next step without further purification.

Step C: The title compound (Intermediate 26) was prepared from I-26b following procedures analogous to 1-15, Step C. 'H-NMR (400MHZ, CDCI3): d 7.34-7.26 (m, 1H), 7.04-6.97 (m, 2H), 6.05-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.50-5.37 (m, 0.5H), 5.10-4.80(m, 0.5H), 4.41-4.23(m, 1H), 4.09-3.96(m, 0.5H), 3.94-3.81 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.14 (m, 0.5H), 2.84-2.63 (m, 1H), 2.34-2.17 (m, 1H), 2.07-1.84 (m, 1H), 1.82-1.64 (m, 2H), 1.53 (s, 9H), 1.48-1.37 (m, 1H); MS calculated for Ci₈H₂₆ClN₄0₂ (M+H⁺) 365.17, found 365.10.

Intermediate 27

(R)-N-(l-(azepan-3-yl)-7-chloro-lH-benzo[dlimidazol-2-yl)-2-methylisonicotinamide hydrochloride

5-26 step A l~27a intermediate 27

Step A: A mixture of 2-methylisonicotinic acid (3.371 g, 24.6 mmol) and 2-(7-aza-lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (9.345 g, 24.6 mmol) in CH₂C1₂ (120 ml) was treated at room temperature with NEt₃ (4.1 mL, 29.4 mmol). The reaction was stirred for 1 hour before it was slowly added into a CH₂C1₂ solution (45 ml) of 1-26 (5.98 g, 16.4 mmol). Ten minutes later, more NEt₃ (4.1 mL, 29.4 mmol) was added and the mixture stirred for 2 h. The mixture was then diluted with CH₂C1₂ (240 mL), washed with H₂0 (2 x 80 mL), saturated aqueous NaHCC solution (70 mL), and brine (70 mL). The organic phase was dried with Na₂S0₄, and concentrated under reduced pressure. The crude material was purified by column chromatography (55% EtOAc/hexanes) to afford

(R)-tert-butyl

3-(7-chloro-2-(2-methylisonicotinamido)-lH-benzo[d]imidazol-l-yl)azepane-l-carboxylate (I-27a) as a light yellow foam. 1H-NMR (400MHz, CDCI3): d 12.81 (br s, 1H), 8.65-8.62 (m, 1H), 7.95-7.85 (m, 2H), 7.27-7.11 (m, 3H), 5.64 - 5.51 (m, 1H), 4.56-4.44 (m, 1H),

4.07-3.92 (m, 1H), 3.79-3.71 (m, 0.5H), 3.41-3.35 (m, 0.5H), 3.29-3.23 (m, 1H), 2.71-2.59 (m, 1H), 2.65 (s, 3H), 2.22-2.00 (m, 3H), 1.93-1.80 (m, 1H), 1.51-1.45 (m, 1H), 1.50 (s, 3.5H), 1.41 (s, 5.5H); MS calculated for C₂₅H₃iClN₅03 (M+H⁺) 484.20, found 484.20.

Step B: A solution of I-27a (8.62 g, 16.4 mmol) in MeOH (67 mL) was treated with HCI in dioxane (4M, 67 mL) and the mixture was stirred at room temperature for 7 h. The mixture was then concentrated under reduced pressure to afford the title compound (Intermediate 27). The product was used in the next step without further purification. A sample was treated with 1M NaOH, extracted with EtOAc, dried with Na₂S0₄ and concentrated under reduced pressure to afford 1-27 as a free base. 'H-NMR (400MHZ, CD₃CN): d 8.49 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.50 (br d, J=7.52 Hz, 1H), 7.16 - 7.09 (m, 2H), 5.66-5.59 (m, 1H), 3.77 (dd, J = 6.54, 14.3 Hz, 1H), 3.18 (dd, J = 5.3, 14.3 Hz, 1H), 3.05 - 2.98 (m, 1H), 2.76-2.69 (m, 1H), 2.63-2.53 (m, 1H), 2.47 (s, 3H), 2.10-2.03 (m, 1H), 1.96-1.93 (m, 2H), 1.86 - 1.75 (m, 2H), 1.61 - 1.54 (m, 2H); MS calculated for

C20H23CIN5O (M+H⁺) 384.15, found 384.20. (i?,£^,)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[dlimidazol-2

-νΠ-2-methylisonicotinamide

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (58 mg, 0.35 mmol) and l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol) in DMF (2 mL) was treated with hydroxybenzotriazole (54 mg, 0.35 mmol) and stirred at room temperature for 1 h. The resulting mixture was added to a solution of 1-27 (100 mg, 0.22 mmol) in DMF (2 mL). Triethylamine (199 mg, 1.97 mmol) was then added and the mixture was stirred for 5 days. Water (2 mL) was added and the mixture was concentrated under reduced pressure. The residue was diluted with IN NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), dried over Na₂S0₄, and concentrated under reduced pressure. The crude was purified by column chromatography (9: 1 :0.175N CH₂Cl₂/MeOH/NH₃ in CH₂C1₂, 0% to 100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.30-7.22 (m, 2H), 6.71-6.65 (m, 1H), 6.57-6.54 (m, 1H), 5.54 (br. s, 1H), 4.54 (br. s, 1H), 4.20 (br s, 1H), 3.95 (br s, 1H), 3.48 (br s, 1H), 2.98 (br s, 2H), 2.72 (d, J = 12.0 Hz, 1H), 2.58 (s, 3H), 2.14 (br s, 6H), 2.05 (d, J = 6.7 Hz, 3H), 1.88 (br s, 1H), 1.46 (d, J=11.3 Hz, 1H); MS calculated for C₂₆H₃₂C1N₆0₂ (M+H⁺) 495.22, found 495.10. Melting point (114.6 °C). Example 2.

(i?,^-iV-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidaz ol-2-yl)-2-methylisonicotinamide (EGFRi) Biochemical Assays

IC50 determinations. All EGFR biochemical assays were carried out by HTRF method. The EGFR(L858R/T790M) enzyme was purchased from Carna (GST-a.a. 669-1210). The substrate peptide Biotin-TK-peptide was purchased from Cis-Bio. The reaction mixtures contained 1 μΜ peptide substrate, 10 μΜ ATP, and 0.036 nM EGFR(L858R/T790M) in the reaction buffer (50 mM HEPES pH 7.1, lOmM MgC12, 0.01% BSA, 1 mM TCEP and 0.1 mM Na3V04) at a final volume of 10 μΕ. All reactions were carried out at room temperature in white ProxiPlate™ 384- well Plus plates (PerkinElmer) and were quenched with 5 μΕ of 0.2 M EDTA at 60 min. Five μΕ of the detection reagents (2.5 ng PT66K and 0.05 μg SAXL per well) were added, the plates were incubated at room temperature for 1 h and then read in En Vision reader. EGFRi was diluted into assay mixture (final DMSO 0.5%), and IC50 values were determined by 12-point (from 50 to 0.000282 μΜ) inhibition curves in duplicate under the assay conditions as described above. For no-preincubation condition, the compound was added to the assay solution containing ATP and peptide, and the reaction was initiated by addition of enzyme. For pre-incubation conditions, the compound was added to the assay solution containing enzyme and peptide, and pre-incubated at room temperature for desired period of time, then the reaction was initiated by addition of ATP.

EGFR Target Modulation in Engineered NTH/3 T3 Cell Lines

Tissue Culture. NTH/3 T3 cell lines expressing human EGFR (WT, L858R, and

L858R T790M) (obtained from Matthew Meyerson's Lab at DFCI) were maintained in 10% FBS/DMEM supplemented with 100 μ^πιΐ Penicillin/Streptomycin (Hyclone #SV30010) and 2 μg/ml Puromycin. The cells were harvested with 0.05% Trypsin/EDTA (Hyclone #SH30236.01), re-suspended in 5% FBS/DMEM Pen/Strep without Puromycin and plated at 9,000 cells per well in 50 μΐ of media in a 384-well black plate with clear bottoms (Greiner #789068G). The cells were allowed to incubate overnight in a 37°C, 5% C02 humidified tissue culture incubator. A 12-point test compound curve was prepared by serial diluting a 10 μΜ stock 1 :3 in DMSO in a 384-well compound plate (Greiner #789201L). The serial diluted compound was transferred to the plate containing cells by using a 50 nl Pin Head device (Perkin Elmer) and the cells were placed back in the incubator for 3 hours. Only the EGFR WT-expressing cells were induced with 50 ng/ml EGF (Preprotech #AF-100-15) for 5 minutes before lysis. The media was removed and cells were lysed in 25 μΐ of Lysis buffer containing protease and phosphatase inhibitors (1% Triton X-100, 20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 150 mM NaCl, IX complete cocktail inhibitor (Roche #1 1 697 498 001), IX Phosphatase Inhibitor Cocktail Set II and Set III (Sigma #P5726 and #P0044)). The plates were shaken at 4°C for 5 minutes with foil top at maximum speed. An aliquot of 5 μΐ from each well was transferred to ProxiPlate™ 384- well Plus plates (PE #6008289). The plates were sealed with a foil top and frozen at -80°C and thawed when needed.

AlphaLISA. The frozen aliquots were thawed and briefly centrifuged. All antibodies and beads were diluted in IX AlphaLISA HiBlock Buffer (PE #AL004C). Biotinylated anti-phospho-EGFR (Y1068) (Cell Signaling #4031) was incubated with the lysate for 1 hour at room temperature at 1 nM final concentration. Goat anti-total EGFR (R&D Systems

#AF231) was added and allowed to equilibrate for 1 hour at room temperature at 1 nM final concentration. Then, 10 μΐ of mixed beads (AlphaScreen Streptavidin Donor Beads (PE #6760002S) and AlphaLISA anti-goat IgG Acceptor Beads (PE #AL107C)) was equilibrated for 1.5 hours before reading on En Vision plate reader using the built-in settings for

AlphaScreen.

Data Analysis. Cells untreated (L858R and L858R/T790M) or EGF-induced (WT) were set to 100% maximum response. For a negative control, 10 μΜ HKI-272 was used to normalize data to 0% of maximum response. With these parameters, the IC50's for each compound in each cell line was calculated using non-linear curve fitting analysis. EGFR Target Modulation in HI 975, H3255 and HCC827 Cell Lines

Tissue Culture. Cells were maintained in 10% FBS/RPMI supplemented with 100 μg/ml Penicillin/Streptomycin (Hyclone #SH30236.01). The cells were harvested with 0.25% Trypsin/EDTA (Hyclone #SH30042.1), re-suspended in 5% FBS/DMEM Pen/Strep and plated at 10,000 cells per well in 50 μΐ of media in a 384-well black plate with clear bottoms (Greiner #789068G). The cells were allowed to incubate overnight in a 37°C, 5% C02 humidified tissue culture incubator. A 12-point test compound curve was prepared by serial diluting a 10 μΜ stock 1 :3 in DMSO in a 384-well compound plate (Greiner #789201L). The serial diluted compound was transferred to the plate containing cells by using a 50 nl Pin Head device (Perkin Elmer) and the cells were placed back in the incubator for 3 hours. Phospho-EGFR (Yl 173) Target Modulation Assay. The media was reduced to 20 μΐ using a Bio-Tek ELx 405 SelectTM plate washer. Cells were lysed with 20 μΐ of 2X Lysis buffer containing protease and phosphatase inhibitors (2% Triton X-100, 40 mM Tris, pH 7.5, 2 mM EDTA, 2 mM EGTA, 300 mM NaCl, 2X complete cocktail inhibitor (Roche #11 697 498 001), 2X Phosphatase Inhibitor Cocktail Set II and Set III (Sigma #P5726 and #P0044)). The plates were shaken at 4°C for 20 minutes. An aliquot of 25 μΐ from each well was transferred to pEGFR(Yl 173) ELISA plates for analysis.

Phospho-EGFR (Yl 173) ELISA. Solid white high-binding ELISA plates (Greiner #781074) were coated with 5 μg/ml anti-EGFR capture antibody (R&D Systems #AF231) overnight in 50 mM carbonate/bicarbonate pH 9.5 buffer. Plates were blocked with 1% BSA (Sigma #A7030) in PBS for 1 hour at room temperature. Wash steps were carried out with a Bio-Tek ELx405 SelectTM using 4 cycles of 100 μΐ TBS-T (20 mM Tris, 137 mM NaCl, 0.05% Tween-20) per well. Media was drained and cells were lysed in 40 μΐ Lysis buffer containing protease and phosphatase inhibitors (1% Triton X-100, 20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 150 mM NaCl, IX complete cocktail inhibitor (Roche #11 697 498 001), IX Phosphatase Inhibitor Cocktail Set II and Set III (Sigma #P5726 and #P0044)). Lysis was allowed to occur for 20 minutes on ice. A 25 μΐ aliquot was added to each well of the blocked ELISA plate and incubated overnight at 4°C with gentle shaking. A 1 :500

anti-phospho-EGFR (Cell Signaling #4407) in 0.2% BSA/TBS-T was added and incubated for 1 hour at room temperature. After washing, 1 :2,000 anti-rabbit-HRP (Cell Signaling #7074) in 0.2% BSA/TBS-T was added and incubated for 1 hour at room temperature.

Chemiluminescent detection was carried out with SuperSignal ELISA Pico substrate (ThermoScientific #37069). Signal was read on En Vision plate reader using built-in

UltraLUM setting.

Data Analysis. Control cells treated with EGF were set to 100% maximum response. For a negative control, 10 μΜ afatinib (BIBW2992) was used to normalize data to 0% of maximum response. With these parameters, the IC50's for each compound in each cell line was calculated using non-linear curve fitting analysis.

EGFR Target Modulation in HEKn (EGFR-WT) Cell Line

Tissue Culture. Human neonatal epithelial keratinocytes (Invitrogen #C-001-5C) were maintained in EpiLife media (Invitrogen #M-EPI-500-CA) supplemented with growth factors (Invitrogen #S-001-5). Cells were harvested with 0.05% Trypsin/EDTA (Hyclone

#SH30236.01) and quenched with 5% FBS/EpiLife media. A density of 7500 cells in 50 μΐ of EpiLife media (no growth factors) was plated in each well of a 384- well solid black tissue culture plate (Greiner #789168G) and incubated overnight at 37°C, 5% C02 in a humidified tissue culture incubator. A 12-point test compound curve was prepared by serial diluting a 10 μΜ stock 1 :3 in DMSO in a 384-well compound plate (Greiner #789201L). The serial diluted compound was transferred to the plate containing cells by using a 50 nl Pin Head device (Perkin Elmer) and the cells were placed back in the incubator for 3 hours.

Stimulation of EGFR autophosphorylation was carried out with 10 ng/ml EGF (Preprotech #AF-100-15) for 5 minutes in the tissue culture incubator.

Phospho-EGFR (Yl 173) ELISA. Solid white high-binding ELISA plates (Greiner #781074) were coated with 5 μg/ml anti-EGFR capture antibody (R&D Systems #AF231) overnight in 50 mM carbonate/bicarbonate pH 9.5 buffer. Plates were blocked with 1% BSA (Sigma #A7030) in PBS for 1 hour at room temperature. Wash steps were carried out with a Bio-Tek ELx405 SelectTM using 4 cycles of 100 μΐ TBS-T (20 mM Tns, 137 mM NaCl, 0.05%

Tween-20) per well. Media was drained and cells were lysed in 40 μΐ Lysis buffer containing protease and phosphatase inhibitors (1% Triton X-100, 20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 150 mM NaCl, IX complete cocktail inhibitor (Roche #11 697 498 001), IX Phosphatase Inhibitor Cocktail Set II and Set III (Sigma #P5726 and #P0044)). Lysis was allowed to occur for 20 minutes on ice. A 25 μΐ aliquot was added to each well of the blocked ELISA plate and incubated overnight at 4°C with gentle shaking. A 1 :500

UltraLUM setting.

Data Analysis. Control cells treated with EGF were set to 100% maximum response. For a negative control, 10 μΜ afatinib (BIBW2992) was used to normalize data to 0% of maximum response. With these parameters, the IC50's for each compound in each cell line was calculated using non-linear curve fitting analysis. EGFR Target Modulation in HaCaT (EGFR-WT) Cell Line

Tissue Culture. HaCaT cells were maintained in 10% FBS/RPMI supplemented with 100 μg/ml Penicillin/Streptomycin (Hyclone #SH30236.01). The cells were harvested with 0.25% Trypsin/EDTA (Hyclone #SH30042.1 ), re-suspended in 5% FBS/DMEM Pen/Strep and plated at 10,000 cells per well in 50 μΐ of media in a 384-well black plate with clear bottoms (Greiner #789068G). The cells were allowed to incubate overnight in a 37°C, 5% C02 humidified tissue culture incubator, with A 12-point test compound curve was prepared by serial diluting a 10 μΜ stock 1 :3 in DMSO in a 384-well compound plate (Greiner

#789201L). The serial diluted compound was transferred to the plate containing cells by using a 50 nl Pin Head device (Perkin Elmer) and the cells were placed back in the incubator for 3 hours. Stimulation of EGFR autophosphorylation was carried out with 10 ng/ml EGF (Preprotech #AF-100-15), prepared in 2% FBS/PBS for 5 minutes in the tissue culture incubator.

Phospho-EGFR (Yl 173) ELISA. Solid white high-binding ELISA plates (Greiner #781074) were coated with 5 μg/ml anti-EGFR capture antibody (R&D Systems #AF231) overnight in 50 mM carbonate/bicarbonate pH 9.5 buffer. Plates were blocked with 1% BSA (Sigma #A7030) in PBS for 1 hour at room temperature. Wash steps were carried out with a Bio-Tek ELx405 SelectTM using 4 cycles of 100 μΐ TBS-T (20 mM Tns, 137 mM NaCl, 0.05% Tween-20) per well. Media was drained and cells were lysed in 40 μΐ Lysis buffer containing protease and phosphatase inhibitors (1% Triton X-100, 20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 150 mM NaCl, IX complete cocktail inhibitor (Roche #11 697 498 001), IX Phosphatase Inhibitor Cocktail Set II and Set III (Sigma #P5726 and #P0044)). Lysis was allowed to occur for 20 minutes on ice. A 25 μΐ aliquot was added to each well of the blocked ELISA plate and incubated overnight at 4°C with gentle shaking. A 1 : 500

UltraLUM setting.

Biological Results

- IC₅₀ determinations for the

(i?,£^')-N-(7-chloro-l-(l -(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide obtained from a EGFR biochemical assay as described above from EGFR (L858R T790M) without and with 90-minute pre- incubation were 0.008μΜ and <0.001 μΜ, respectively.

- The compound of the disclosure shows an inhibition IC₅₀ determinations obtained from EGFR target modulation in engineered NIH/3T3 cell lines for L858R/T790M and L858R, 0.01 Ι μΜ and 0.015μΜ, respectively. For wt the value was 0.259μΜ.

- The IC₅₀ determinations obtained from EGFR target modulation in HI 975 (EGFR

L858/T790M), H3255 (EGFR L858R), and HEKn (EGFR WT) cell lines were 0.013μΜ, 0.030μΜ and 1.180μΜ respectively.

Further EGFR target modulation experiments with certain forms yielded following IC₅₀ results in the respective cells lines:

Target Modulation EC50 (μΜ)

Form Batch HaCaT H1975 H3255 HCC827

HC1 1 N.D. 0.004 0.008 N.D.

HC1 2 0.125 0.003 0.007 N.D.

HC1 3 0.100 0.003 0.004 0.001

HC1 4 N.D. 0.003 0.005 N.D.

HC1 5 0.396 0.008 0.008 N.D.

Mesylate form A 1 0.169 0.003 0.002 N.D.

All forms of

(i?,£^')-N-(7-chloro-l-(l -(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide compound are expected to be effective in the same range as shown in the results.

Example 3. Crystalline Mesylate form B (mesylate trihydrate form) (i?,£^')-N-(7-chloro-l-(l -(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide as obtained in Example 1 (1.0 g) was dissolved in acetone (30 mL) by heating to 55°C to form a solution. Methanesulfonic acid (325 μΕ) was added to acetone (50 mL), and the methanesulfonic acid/acetone (22.2 mL) was added to the solution at 0.05ml/min. Following precipitation, the resulting suspension was cooled to room temperature at 0.5 °C/min, and crystals were collected by filtration, and dried for 4 hours at 40°C under vacuum. The collected crystals (300 mg) were suspended in acetone/H^O (6 mL; v/v=95/5) by heating to 50°C. The suspension was kept slurrying for 16 hours, and cooled to room temperature at 0.5 °C/min. The crystal was collected by filtration and dried for 4 hours at 40°C under vacuum.

The structure of

(i?,£^')-N-(7-chloro-l-(l -(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide mesylate was confirmed by Differential Scanning Calorimetry, X-Ray Powder Diffraction, and Elemental Analyses. Melting point (170.1 °C). Theoretical calculated: %C (54.8); %H (5.9); %N (14.2); %0 (13.5); %S (5.4); and %C1 (6.0); C:N ratio: 3.86. Found: %C (52.0); %H (5.8); %N (13.3); %C1 (5.9); C:N ratio: 3.91. Stoichiometry: 1.01.

In addition, crystalline mesylate form B was prepared by suspending 300mg of crystalline mesylate form A in 6mL of acetone/H20 (v/v=95/5) by heating to 50°C. The suspension was kept slurrying for 16 hours, and then the suspension was allowed to cool to room temperature at 0.5 °C/min. The crystal was collected by filtration and afterwards dried for 4 hours at 40°C under vacuum. Example 4. Crystalline Mesylate form A (mesylate monohydrate form)

5.0 mL of dried acetone and 800 mg of mesylate form B (mesylate trihydrate Form) as obtained in example 3 were added into a glass vial. The suspension was heated to 55 °C for 5 hours. DSC was checked to see if the transformation was complete. Another 800 mg of the mesylate form B was converted to mesylate form A with the same method, the only difference was that the suspension was allowed to equilibrate at 20 °C (the ambient temperature in the lab), overnight.

In addition, crystalline mesylate form A was prepared by dissolving l .Og of free form A in 30mL of acetone by heating to 55°C. 325μΕ of methansulfonic acid was added to 50mL of acetone and then 22.2mL of methansulfonic acid acetone was added to free form solution at 0.05ml/min. Precipitation was formed during the addition of methansulfonic acid, and the suspension was allowed to cool to room temperature at 0.5 °C/min. The crystal was collected by filtration and afterwards dried for 4 hours at 40°C under vacuum.

Example 5. Crystalline free form A (anhydrous form)

750mg of EGFRi HC1 salt form (purity: 99%) were dissolved in 15mL of mixed solvent (EtOH/H20, v/v=l/9) by heating to 60°C. 7.42mL sodium hydroxide (0.2mol/L in

EtOH/H20, v/v=l 19) was added to the HC1 salt form EtOH/ H20 solution at 0.05ml/min. Precipitation was formed during the addition of sodium hydroxide, and the suspension was allowed to cool to room temperature at 0.5 °C/min. The crystal was collected by filtration and afterwards dried for 4 hours at 40°C under vacuum. Example 6. Crystalline free form B (dihydrate form)

Crystalline free form A or the compound obtained in example 1 (2.5 g, 5.0 mmol) was dissolved into 4 mL acetone: water 5: 1 (v/v) at r.t. to result a clear solution. The solution was stirred for 24 h and white precipitate appeared after the first 1 h. The white solid was separated with filtration then washed with 500 μΕ acetone: water 5: 1 (v/v) three times to remove black colour. After dried under vacuum at 40 °C overnight, EGFRi free form B (2.0 g, 4.0 mmol) was obtained as white solid in 80% yield.

Example 7. Crystalline HC1 salt form l.Og of amorphous form or free form of the Compound EGFRi was dissolved in 50mL of acetone by heating to 55°C. 22.2mL of hydrochloride acid in acetone (O. lmol/L) was added to free form solution at 0.05ml/min. Precipitation was formed during the addition of hydrochloride acid, and the suspension was allowed to cool to room temperature at

0.5°C/min. The crystal was collected by filtration and afterwards dried for 4 hours at 40°C under vacuum.

Also, 850mg of amorphous form or free form of the EGFRi compound were weighed out in a 20ml vial. 4.25ml of Acetonitrile were added to completely dissolve the compound. To this solution 6.86 ml of 0.6 N HC1 were slowly added while stirring the solution. The solution turned yellow and solids precipitated out after 15mins. The solution was stirred for 15 minutes and then let to stand without stirring overnight. The solution was filtered and dried under vacuum at 40 °C for 8hrs. A yellow solid was obtained as the final product.

Example 8. Evaporation of completely dissolved samples at 25 degree C

Mesylate form B of the EGFRi compound was completely dissolved in various solvents. The solvent was then evaporated and the obtained from measured by XRPD.

Solvents XRPD

acetonitrile/H20 = 1/1 (v/v) Mesylate form B

acetone/water = 1/1 (v/v) Mesylate form B

isopropyl alcohol/water = 1/1 (v/v) Mesylate form B

acetonitrile Mesylate form B

ethanol Mesylate form B

water Mesylate form B

propyl alcohol Mesylate form B

dichloromethane Mesylate form A

methanol Mesylate form B Example 9. Precipitation by addition of antisolvent at 25 degree C

Mesylate form B of the EGFRi compound was completely dissolved in various solvents. The compound was then precipitated by addition of an antisolvent and the obtained from measured by XRPD. The following solvent additions were performed at 25°C

Solvent Antisolvent Ratio XRPD

Methanol tetrahydrofuran 1 :4 Mesylate forms A and B

Ethyl acetate 1 :5 Mesylate form B tert-butylmethylether 1 10 Mesylate form A

DMF tetrahydrofuran 1 5 Mesylate form B

ethyl acetate 1 1.5 Mesylate form B

tert-butylmethylether 1 10 Mesylate form B

toluene 1 10 Mesylate form B

95% EtOH ethyl acetate 1 3.8 Mesylate form B

Example 10. Stability data for free form B and mesylate form B, both crystalline forms

Test Conditions Salt Form

Form free Form B mesylate Form B

Initial UPLC purity (%), ₉9.9, white solid 99.5, yellow solid

colour

Tl (total impurity) CL (color) Tl (total impurity) CL (color)

[%] [%]

0.1 % solutions or suspensions, 1 week, 80 °C

pH 1 (0.1 N HCI) 27.0 ^*C 90.4 ^*C pH 2 (0.01 N HCI) 7.4 ^*A 10.3 ^*A pH 4.7 acetate buffer 4.7 ^*C 4.9 ^*A pH 6.8 phosphate buffer 55.0 51.0 ^*A pH 9.0 borate buffer 81.1 88.9

pH 10.0 borate buffer 86.7 93.8

Water 83.3 20.1

Ethanol 25.5 *c 4.7

I PA 50.7 ^*A 37.1 *c

Acetone 9.1 ^*A 5.1 *c

THF 44.1 ^*A 94.2 *c

DCM 81.7 ^*C 7.2 ^*A

5% solutions, 1 day, r.t. (room temperature)

DMSO

0.7 ^*A 0.2 ^*A

Dilution, pH 6.8

Solid state, 1 week, 80 °C, tight container

Bulk (UPLC) 40.5 C 0.6 A

Bulk (XRPD) change to free Form A change to Mesylate Form A

Solid state, 1 week, 50 °C, tight container

Bulk (UPLC) 2.1 0.4

Bulk (XRPD) no change no change

Mixture, 1 week, 50 °C, tight container

1% in mixture 1 11.3 A 0.5 A

1% in mixture 2 42.7 A 3.1 A Test Conditions Salt Form

Form free Form B mesylate Form B

Initial UPLC purity (%),

99.9, white solid 99.5, yellow solid

colour

Tl (total impurity) CL (color) Tl (total impurity) CL (color) [%] [%]

Solid state, 1 week, 80 °C, 75% RH

Bulk (UPLC) 4.0 B 1.0

Bulk (XRPD) no change no change

Solid state, 1 week, 50 °C, 75% RH

Bulk (UPLC) 0.8 0.4

Bulk (XRPD) no change no change

Mixture, 1 week, 50 °C, 75% RH

1 % in mixture 1 2.2 A 0.5 A

1 % in mixture 2 1.6 A 0.3 A

Total impurity(TI) and color (CL)

Suspension * Clear solution after stress test

Test not performed A No change of color

B Slight discoloration C Medium discoloration

D Strong discoloration

TIs are analysed by UPLC (method as described above). They are calculated as area-% products or against external standard 1%).

Purity: 100% - sum by- and total impurity

Compositions of the excipient mixtures [mass-%]

Mixture 1 : Lactose, spray dried (53.7%), Microcrystalline cellulose PH102 (40%),

Crospovidone XL (5%), Aerosil (0.3%), Mg stearate (1%)

Mixture 2: Mannitol DC (68.7%), Microcrystalline cellulose PH102 (26%), Ac-di-Sol

(4%), Aerosil (0.3%), Ca stearate (1%)

Neither the free Form B nor the Mesylate Form B is stable in tested aqueous solutions at 80 °C for 1 week. Significant degradation occurred in pH 1.0 (0.1 N HCl), pH 6.8, pH 9.0 and pH 10.0 buffer solutions, and in water with more than 20% Tl (total impurity) after the test. Both forms are relatively more stable in pH 2.0 (0.01 N HCl) solution and pH 4.7 acetate buffer solution with 7.4% and 4.7% Ή for the free Form B, and 10.3% and 4.9% Tl for the Mesylate Form B, respectively. The free Form B and the Mesylate Form B are also unstable in tested organic solvents of ethanol, IP A, acetone, THF and DCM at 80 °C for 1 week. The free Form B degraded by 9.1% in acetone. The Mesylate Form B degraded by 4.7%, 5.1% and 4.2% in ethanol, acetone and DCM, respectively. The two forms degraded by more than 20% in the other organic solvents. Therefore, both forms should be avoided to contact the tested solvents at high temperature for a long period.

Example 11. Stability data for free form A and mesylate form A, both crystalline forms

Test Conditions Salt Form

Form free Form A mesylate Form A

Initial UPLC purity (%),

99.9, white solid 99.5, yellow solid

color

Tl (total impurity) CL (color) Tl (total impurity) CL (color) [%] [%]

0.1 % solutions or suspensions, 1 week, 80 °C

pH 1 (0.1 N HCI) 97.34 ^*A 97.84 ^*A pH 2 (0.01 N HCI) 8.34 ^*B 1 1.44 ^*B pH 4.5 acetate buffer 1 .58 ^*B 6.23 ^*B pH 6.8 phosphate buffer 34.95 43.23

pH 9.0 borate buffer 85.18 74.81

Water 84.07 14.42

Acetone 0.36 ^*A 0.62 ^*A

Total impurity(TI) and color (CL)

Suspension * Clear solution after stress test

Test not performed A No change of color

B Slight discoloration C Medium discoloration

D Strong discoloration

Purity: 100% - sum by- and total impurity

Examples 10 and 11 show that stability of the EGFRi forms deteriorates significantly at pH below 1 and above 6.8, and even more so above pH 9. Therefore, it is best to modulate pH in a pharmaceutical composition to keep pH within the range between pH 1 and pH 9, even better within the range between pH 1 and pH 6.8. This can be achieved by using a pH modifier. As a pH modifier can be used for example buffers as exemplified in the examples. Excipients attaining the same effect are expected to work as well. Best stability is achieved if the microenvironment of the EGFRi is between pH 2 and pH 4.7±0.2, particularly pH 2 and pH 4.7. Example 12. Solubility and pH of forms pH of 1% solution or suspension

Free form A Mesylate form A

In water 8.13 5.38

Solubility (approx. at 25°C, mg/ml) [pH final]

Free form A Mesylate form A

0.1N HC1 > 11.99 [1.66] > 9.92 [1.84]

Citrate buffer, pH 3 > 11.06 [3.92] > 10.13 [3.40]

Acetate buffer, pH 4.5 > 10.20 [5.01] > 9.87 [4.91]

Phosphate buffer, pH 6.8 0.51 [7.37] > 9.62 [7.16]

Water 0.29 [7.65] > 9.97 [5.45]

Example 13. In vivo exposure of HCl salt form and mesylate forms

PK studies for mesylate form and HCl salt form were conducted in rat. Both forms were dosed orally at 10 and 30 mg/kg in 0.5% MC/Tween 80 formulation. Both salt forms were soluble at both dose levels in the formulation. Plasma exposures of both forms and its active metabolite were determined. The mesylate form showed very similar PK profiles in the rats at both 10 and 30 mg/kg as those of HCL salt form. The exposures of both parent compound forms and active metabolite are summarized below.

Salt Form Dose (mg/kg) AUC (nM*hr) Metabolite to parent ratio

HCl salt 10 9923 12%

30 23687 13%

Mesylate forms 10 8267 1 1 %

30 24092 14%

The mesylate crystalline forms show dose proportionality from 10 to 30mg/kg, and the exposure is comparable to HCl salt.

Claims

1. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is free form A.

2. A crystalline form of

3. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is mesylate form A. 4. A crystalline form of

5. A HC1 salt of

6. A crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide, which is mesylate form B, wherein the form further comprises any form as defined in any one of claims 1 to 4 or HC1 salt as defined in claim 5.

7. The crystalline form according to claim 1 , wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77, 25.09, 25.73, 26.35 and 27.56 ± 0.30, measured at a temperature of about 22°C.

8. The crystalline form according to claim 1 or 7, wherein the x-ray powder diffraction pattern measured at a temperature of about 22°C of the crystalline form is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 1, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 2, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 2. 9. The crystalline form according to claim 2, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

10. The crystalline form according to claim 2 or 9, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 4, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 5 or Fig. 6, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 7.

11. The crystalline form according to claim 3, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

12. The crystalline form according to claim 3 or 11, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 8, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 9, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 9.

13. The crystalline form according to claim 4, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

11.51, 13.19, 16.23, 17.50, 19.14, 23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30, measured at a temperature of about 22°C.

14. The crystalline form according to claim 4 or 13, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 14, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 15, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 15. 15. The HC1 salt of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to claim 5, wherein the compound is crystalline and the x-ray powder diffraction pattern comprises 4 or 5 2Θ values (CuKa) selected from the group consisting of:

14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30, measured at a temperature of about 22°C.

16. The HC1 salt of the compound

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to claim 5 or 15, wherein the salt is crystalline and the x-ray powder diffraction pattern measured at a temperature of about 22°C of the salt is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 17, a

differential scanning calorimetry (DSC) thermogram of the salt is essentially the same as that shown in FIG. 18, or a thermo gravimetric analysis (TGA) diagram of the salt is essentially the same as that shown in figure FIG. 18.

17. The crystalline form according to claim 6, wherein the x-ray powder diffraction pattern comprises 4, 5, 6, 7, 8 or all 2Θ values (CuKa) selected from the group consisting of:

18. The crystalline form according to claim 6 or 17, wherein the x-ray powder diffraction pattern of the crystalline form measured at a temperature of about 22°C is essentially the same as the X-ray powder diffraction spectrum shown in FIG. 11, a differential scanning calorimetry (DSC) thermogram of the crystalline form is essentially the same as that shown in FIG. 12, or a thermo gravimetric analysis (TGA) diagram of the crystalline form is essentially the same as that shown in figure FIG. 12.

19. The crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of claims 1 to 4, 6 to 14, 17 or 18, or HC1 salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of claims 5, 15 or 16, comprising:

(i) free form A, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 5.46, 14.82, 15.84, 18.67, 20.42, 22.56, 23.77,

25.09, 25.73, 26.35 and 27.56 ± 0.30;

(iv) mesylate form B, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 11.76, 13.832, 14.41, 15.9, 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.30; (v) mesylate form C, wherein the x-ray powder diffraction pattern comprises 4 or more 2Θ values (CuKa) selected from the group consisting of 11.51, 13.19, 16.23, 17.50, 19.14, 23.15, 23.80, 24.65, 25.81, 26.06, 26.70 and 28.97 ± 0.30;

(vii) amorphous form,

wherein when the crystalline form of

20. The crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of claims 1 to 4 or 7 to 14, or HC1 salt of (R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of claims 5, 15 or 16,wherein the crystalline form or the salt consist essentially of the respective form or the salt.

21. The crystalline form of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to claim 20, wherein said forms or salt are in substantially pure form.

22. The crystalline form or the salt form according to claim 19, wherein x-ray powder diffraction pattern comprises five or more 2Θ values (CuKa) selected from the group.

23. The crystalline form or the salt form according to claim 19, wherein x-ray powder diffraction pattern comprises all 2Θ values selected from the group for a respective form.

24. A crystalline form of

25. A crystalline form of (R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide having a differential scanning calorimetry (DSC) thermogram essentially the same as that shown in any one of figures FIG. 2, FIG. 5, FIG. 6, FIG. 9, FIG. 12, FIG. 15, or FIG 18.

26. A crystalline form of

27. A mesylate salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide with the x-ray powder diffraction pattern of 15 2Θ values (CuKa) selected from the group consisting of 11.76, 13.832, 14.41, 15.9, 17.65, 18.79, 21.46, 21.83, 22.30, 23.82, 24.51, 24.89, 25.57, 26.66 and 27.77 ± 0.20, measured at 22°C. 28. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 4, 6 to 14, 17 to 26, HCl salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to any one of claims 5, 15, 16 or 19 to 23, or mesylate salt of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide according to claim 27.

29. The pharmaceutical composition according to claim 28, further comprising a

pharmaceutically acceptable carrier or diluent.

30. The pharmaceutical composition according to claim 28 or 29, wherein the crystal form is as defined in any one of claims 1 to 4, or 6 to 26.

31. The pharmaceutical composition according to claim 28 or 29, wherein said form is free form A, free form B, mesylate form A, mesylate form C or HCl salt form and wherein x-ray powder diffraction pattern comprises four 2Θ values (CuKa) selected from the group consisting of:

(b) 11.24, 14.68, 15.66, 18.64, 19.63, 20.05, 20.31, 22.41, 24.91, 25.43, 26.03, 27.18 and 28.07± 0.30 for free form B, (c) 9.12, 12.19, 16.25, 17.38, 18.42, 19.91, 20.85, 22.43, 22.92, 24.10, 26.64 and 27.78 ± 0.30 for mesylate form A,

(f) 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 for HC1 salt form,

all at a temperature of about 22°C, respectively.

32. The pharmaceutical composition according to claim 31, wherein said form is free form A, free form B, mesylate form A, mesylate form C or HC1 salt form and wherein x-ray powder diffraction pattern comprises five 2Θ values (CuKa) selected from the group consisting of:

(f) 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 for HC1 salt form,

all at a temperature of about 22°C, respectively.

33. The pharmaceutical composition according to claim 32, wherein said form is free form A, free form B, mesylate form A, mesylate form C or HC1 salt form and wherein x-ray powder diffraction pattern comprises all 2Θ values selected from the group consisting of:

(f) 14.89, 19.69, 25.61, 26.13 and 27.78 ± 0.30 for HC1 salt form,

all at a temperature of about 22°C, respectively.

34. A pharmaceutical composition comprising

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide and a pH modifier. 35. The pharmaceutical composition according to claim 34, wherein

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide. 36. The pharmaceutical composition according to claim 34 or 35 comprising mesylate form B of

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide. 37. The pharmaceutical composition according to claim 34 comprising amorphous form of (R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide.

38. The pharmaceutical composition according to any one of claims 28 to 33, further comprising a pH modifier.

39. The pharmaceutical composition according to any one of claims 28 to 38, wherein the pH modifier is a pharmaceutically acceptable acid, base, salt or mixtures thereof. 40. The pharmaceutical composition according to any one of claims 28 to 39, wherein the composition is liquid.

41. The pharmaceutical composition according to claim 34, wherein the

(R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide is in any form as defined in any one of claims 1 to 27.

42. The pharmaceutical composition according to any one of claims 28 to 41, wherein the pH of the formulation is between pH 1 and pH 9, measured at 25°C. 43. The pharmaceutical composition according to any one of claims 28 to 41, wherein the pH of the formulation is between pH 2 and pH 9, measured at 25°C.

44. The pharmaceutical composition according to any one of claims 28 to 41, wherein the pH of the formulation is between pH 2 and pH 6.8, measured at 25°C.

45. The pharmaceutical composition according to any one of claims 28 to 41, wherein the pH of the formulation is between pH 2 and pH 4.7, measured at 25°C.

46. The pharmaceutical composition according to any one of claims 28 to 41, wherein the pH of the formulation is about 4.5, or pH is 4.5, measured at 25°C.

47. A pharmaceutical formulation comprising

48. A pharmaceutical formulation comprising

53. The pharmaceutical formulation according to any one of claims 47 to 52 comprising (R,E)-N-(7-chloro-l-(l-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-lH-benzo[d]imidazol-2 -yl)-2-methylisonicotinamide in any form as defined in any one of claims 1 to 27. 54. A crystalline form according to any one of claims 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of claims 5, 15, 16 or 19 to 23, mesylate salt according to claim 27, a pharmaceutical composition according to any one of claims 28 to 46, or a pharmaceutical formulation according to any one of claims 47 to 53, for use as a medicine. 55. A crystalline form according to any one of claims 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of claims 5, 15, 16 or 19 to 23, mesylate salt according to claim 27, a pharmaceutical composition according to any one of claims 28 to 46, or a pharmaceutical formulation according to any one of claims 47 to 53, for use in the treatment of a

proliferative disease.

56. The crystalline form according to any one of claims 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of claims 5, 15, 16 or 19 to 23, mesylate salt according to claim 27, the pharmaceutical composition according to any one of claims 28 to 46, or the pharmaceutical formulation according to any one of claims 47 to 53 for use according to claim 55, wherein the proliferative disease is non-small cell lung cancer, head and neck cancer, colorectal cancer, breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, glioma or prostate cancer.

57. The crystalline form according to any one of claims 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of claims 5, 15, 16 or 19 to 23, mesylate salt according to claim 27, the pharmaceutical composition according to any one of claims 28 to 46, or the pharmaceutical formulation according to any one of claims 47 to 53 for use according to claim 55 or 56, wherein the proliferative disease is non-small cell lung cancer.

58. The crystalline form according to any one of claims 1 to 4, 6 to 14 or 17 to 26, HC1 salt according to any one of claims 5, 15, 16 or 19 to 23, mesylate salt according to claim 27, the pharmaceutical composition according to any one of claims 28 to 46, or the pharmaceutical formulation according to any one of claims 47 to 53 for use according to any one of claims 55 to 57, wherein