OA19085A - Pharmaceutical salts of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-(1methyl-1H-indol-3-yl)pyrimidin-2-yl)amino) phenyl)acrylamide and crystalline forms thereof - Google Patents

Abstract

Crystalline forms of N-(2-(2-(dimethylamino) ethoxy)-4-methoxy-5-((4-(1-methyl-1H- indol-3yl)pyrimidin-2-yl)amino)phenyl)acrylamide (1) and its pharmaceutically acceptable salts and compositions thereof useful for the treatment or prevention of diseases or medical conditions mediated through mutated forms of epidermal growth factor receptor (EGFR), such as various cancers, are disclosed.

Description

PHARMACEUTICAL SALTS OF W-(2-(2-(DIMETHYLAMINO)ETHOXY)-4METHOXY-5-((4-(l -METHYL-U/-INDOL-3 -YL)PYRIMIDIN-2YL)AMINO)PHENYL)ACRYLAMIDE AND CRYSTALLINE FORMS THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e] to U.S. Provisional Application No. .62/351,749, filed on June 17, 2016, which is incorporated herein by reference , in its entirety.

FIELD OF THE INVENTION

The present invention relates to crystalline forms of 7V-(2-(2-(dimetliylamino)ethoxy)4-methoxy-5-((4-(l-methyl-lH-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (see below, compound 1) and its pharmaceutically acceptable salts and compositions thereof useful for the treatment or prévention of diseases or medical conditions mediated through mutated forms of epidermal growth factor receptor (EGFR), such as various cancers.

B ACKGROUND OF THE INVENTION

The epidermal growth factor receptor (EGFR, Herl, ErbBl) is a principal member of the ErbB family of four structurally-related cell surface receptors with the other members being Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4). EGFR exerts its primary cellular fonctions though its intrinsic catalytic tyrosine protein kinase activity. The receptor is activated by binding with growth factor ligands, such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), which transform the catalytically inactive EGFR monomer into catalytically active homo- and hetero- dimers. These catalytically active dimers then initiate intracellular tyrosine kinase activity, which leads to the autophosphorylation of spécifie EGFR tyrosine residues and elicits the downstream activation of signaling proteins. Subsequently, the signaling proteins initiate multiple signal transduction cascades (MAPK, Akt and INK), which ultimately médiate the essential biological processes of cell growth, prolifération, motility and survj val.

EGFR is found at :abnormally high levels on the surface of many types of cancer cells and increased levels of EGFR bave been associated with advanced disease, cancer spread and poor clinical prognosis. Mutations in EGFR can lead to receptor overexpression, perpétuai activation or sustained hyperactivity and resuit in uncontrolled cell growth, i.e. cancer. Consequently, EGFR mutations hâve been identified in several types of malignant tumors, including metastatic lung, head and neck, colorectal and pancreatic cancers. In lung cancer, i i

I mutations mainly occur in exons 18 to 21, which encode the adenosine triphosphate (ATP)binding pocket of the kinase domain. The most clinically relevant drug-sensitive EGFR mutations are délétions in exon 19 that eliminate a common amino acid motif (LREA) and point mutations in exon 21, which lead to a substitution of arginine for leucine at position 858 (L858R). Together, these two mutations account for nearly 85% of the EGFR mutations observed in lung cancer. Both mutations hâve perpétuai tyrosine kinase activity and as a resuit they are oncogenic. In at least 50% of patients who are initially responsive to current therapy, disease progression is associated with the development of a secondary mutation, T790M in exon 20 of EGFR (referred to as the gatekeeper mutation).

Compound 1 effectively inhibits the kinase domain of the T790M double mutant and therefore overcomes the résistance observed with the currently used therapy of réversible inhibitors. See WO2016/092841 and International Application No. PCT/US17/32066, both of which are herein incorporated by reference in their entireties. However, to make compound 1 a viable therapeutic agent for treatment of diseases associated with T790M double mutation, there remains a need to find a suitable sait and/or crystalline form that would provide desired physical and mechanical properties, among others, for formulation. Because crystallinity and crystalline forms of a drug substance and their physical and mechanical properties, such as solubility, melting point, hardness, and compressability, are in general unpredictable, so are their effects on the properties of a corresponding drug product, such as dissolution rate and bioavailability, the present invention sought to identify such a suitable sait and/or crystalline form of compound 1.

SUMMARY OF THE INVENTION

The present invention provides crystalline forms of compound 1 and its various pharmaceutical salts. In one aspect, the présent invention provides a crystalline form of compound 1 (free base):

In one aspect, the present invention provides a crystalline form of the compound of formula 1, namely N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-lH-indol-3yl)pyrimidin-2-yl)amino)phenyl)acrylamide (free base), having an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 8.5°±0.2°,

16.7°±0.2°, and 25.2°±0.2°.

In another aspect, the présent invention provides a crystalline form of N-(2-(2(dimethylamino) ethoxy)-4-methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2yl)amino)phenyl)acrylamide methanesulfonate sait (formula 2) having a molar ratio of about 1:1 between methanesulfonic acid and free base.

In another aspect, the présent invention provides a crystalline form of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2 yl)amino)phenyl)acrylamide hydrochloride sait (formula 3) having a molar ratio of about 1:1 between hydrochloride acid and free base.

i

In another aspect, the présent invention provides a crystalline form of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide sulfate sait (formula 4) having a molar ratio of about 1:1 between sulfuric acid and free base.

In another aspect, the présent invention provides a crystalline form of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2yl)amino)phenyl)acrylamide p-toluenesulfonate (p-tosylate) sait (formula 5) having a molar ratio of about 1:1 between p-toluenesulfonic acid andfrcc base.

In another aspect, the présent invention provides a crystalline form of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2yl)amino)phenyl)acrylamide citrate sait (formula 6) having a molar ratio of about 1:1 between citric acid and free base.

OH

HO₂C^''^j<'CO₂H co₂h

In another aspect, the présent invention provides a pharmaceutical composition comprising a crystalline form according to any of embodiments disclosed here, or a combination thereof, and a pharmaceutically acceptable carrier, adjuvant, diluent, and/or vehicle.

In another aspect, the présent invention provides a method of treating a disease or disorder associated with an EGFR activity, comprising administration of a therapeutically effective amount of a crystalline form according to any one of the embodiments disclosed herein, or a combination thereof, or a pharmaceutical composition thereof, to a patient in need of treatment.

In another aspect, the présent invention provides a method of inhibiting a mutant of EGFR in a subject, comprising contacting a biological sample of said subject with a crystalline forais of compounds according to any embodiments disclosed herein, or a combination thereof, or a pharmaceutical composition thereof.

In another aspect, the présent invention provides use of a crystalline form according to any embodiments disclosed herein, or a combination thereof, in the manufacture of a médicament for treatment of a disease or disorder associated with an EGFR activity.

In another aspect, the présent invention provides processes of preparing a crystalline form according to any embodiments disclosed herein as substantially described and shown.

Other aspects or advantages of the présent invention will be better appreciated in view of the detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures IA and IB illustrate (Fig. IA) XRPD pattern of compound 1 (free base); and (Fig. IB) XRPD data of pattern of compound 1 (free base).

Figure 2 illustrâtes PLM image of compound 1 (free base).

Figure 3 illustrâtes DSC thermogram of compound 1 (free base).

Figure 4 illustrâtes TGA Thermogram of compoundl (free base).

Figures 5A and 5B illustrate (Fig. 5A) XRPD pattern of compound 2 (Form 2A); and (Fig. 5B) XRPD data of compound 2 (Form 2A).

Figure 6 illustrâtes PLM image of compound 2 (Form 2A) (50x).

Figure 7 illustrâtes DSC thermogram of compound 2 (Form 2A).

Figure 8 illustrâtes TGA thermogram of compound 2 (Form 2A).

Figures 9 A and 9B illustrate (Fig. 9A) XRPD pattern of compound 2 (Form 2B); and (Fig. 9B) XRPD data of compound 2 (Form 2B).

Figure 10 illustrâtes PLM image of compound 2 (Form 3) (50x).

Figure 11 illustrâtes TGA-MS of compound 2 (Form 2A).

Figure 12 illustrâtes DSC thermogram of compound 2 (Form 2B).

Figure 13 illustrâtes Overlay ofDSC and TGA thermograms for compound 3.

Figures 14A and 14B illustrate (Fig. 14A) Overlay of compound 3 XRPD patterns before and after dynamic vapor sorption (DVS). (Fig. 14B) XRPD data of compound 3.

Figure 15 illustrâtes Overlay ofDSC and TGA thermograms for compound 4.

Figures 16A and 16B illustrate (16A) Overlay of XRPD patterns for compound 4 before (bottom) and after (top) DVS. (16B) XRPD data of compound 4 before DVS.

Figure 17 illustrâtes Overlay ofDSC and TGA üieimograms for compound 4.

Figures 18A and 18B illustrate (Fig. 18A) Overlay of XRPD patterns for compound 5 before (bottom) and after (top) DVS; and (Fig. 18B) XRPD data of compound 5 before DVS.

Figure 19 illustrâtes Overlay ofDSC and TGA thermograms for compound 5.

Figure 20 illustrâtes Overlay of DSC and TGA thermograms for compound 6.

Figures 21A and 21B illustrate (Fig. 21 A) XRPD pattern for compound 6; and (Fig.

B) XRPD data of compound 6.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a crystalline form of the compound of formula 1, namely N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indol-3yl)pyrimidin-2-yl)amino)phenyl)acryIamide (free base), having an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 8.5°±0.2°, 16.7°±0.2°, and 25.2°±0.2°.

In one embodiment, the X-ray powder diffraction pattern further comprises any two or more of the following 2Θ values measured using CuKa radiation: 9.5°±0.2°, 12.2°±0.2°, 12.5°±0.2°, 15.7°±0.2°, 16.0°±0.2°, 19.4°±0.2°, 19.7°±0.2°, 20.0°±0.2°, 23.2°±0.2°, 24.4°±0.2°, and 28.5°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 2Θ values along 8.5°±0.2°, 16.7°±0.2°, and 25.2°±0.2°.

In another embodiment, the crystalline form of compound 1 has a melting point with an onset température at about 169.6 °C and/or a peak température at about 171.7 “Cas measured by differential scaiming calorimetry.

In another embodiment, the crystalline form of compound 1 has an X-ray powder diffraction pattern substantially as depicted in FIG. 1.

In another embodiment, the crystalline form of compound 1 has a differential scanning calorimetric thermogram substantially as depicted in FIG. 3.

In another embodiment, the crystalline form of compound 1 has a thermal gravimétrie analysis thermogram substantially as depicted in FIG. 4.

In another aspect, the present invention provides a crystalline form of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2yl)amino)phenyl)acrylamide methanesulfonate sait (formula 2) having a molar ratio of about 1:1 between methanesulfonic acid and free base.

In one embodiment, the crystalline form of compound 2 , designated as crystalline Form 2A, has an X-ray powder diffraction pattern comprising any three or more of the following 20 values measured using CuKa radiation: 12.6°±0.2°, 15.5°±0.2°, 17.9°±0.2°, 22.1°±0.2°, and 25.2°±0.2°.

In another embodiment, the X-ray powder diffraction pattern of the crystalline form of compound 2 further comprises any two or more of the following 2Θ values measured. using CuKa radiation: ll.l°±0.2°, 13.8°±0.2°, 14.7°±0.2°, 16.7°±0.2°, 19.3°±0.2°, 20.9°±0.2°, 23.2°±0.2°, and 25.8°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 20 values along 12.6°±0.2°, 15.5°±0.2°, 17.9°±0.2°, 22.1°±0.2°, and 25.2°±0.2°.

In another embodiment, the crystalline form 2A has a melting point with an onset température at about 233.3 °C and/or a peak température at about 238.1 °C as measured by differential scanning calorimetry.

In another embodiment, the crystalline form 2A has an X-ray powder diffraction pattern substantially as depicted in FIG. 5.

In another embodiment, the crystalline form 2A has a differential scanning calorimetric thermogram substantially as depicted in FIG. 7.

In another embodiment, the crystalline form 2A has a thermal gravimétrie analysis thermogram substantially as depicted in FIG. 8.

In another embodiment, the X-ray powder diffraction pattern of the crystalline form of compound 2, designated as crystalline Form 2B, has an X-ray powder diffraction pattern comprising any three or more of the following 20 values measured using CuKa radiation: 9.7°±0.2°, 12.8°±0.2°, 15.7°±0.2°, 18.2°±0.2°, 20.3°±0.2°, 25.1°±0.2°, 25.6°±0.2°, and 26.8°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 20 values.

In another embodiment, the X-ray powder diffraction pattern of the crystalline form 2B has an X-ray powder diffraction pattern substantially as depicted in FIG. 9.

In another embodiment, the crystalline form 2B has a differential scanning calorimetric thermogram substantially as depicted in FIG. 12.

In another embodiment, the crystalline, form 2B has a thermal gravimétrie analysis thermogram substantially as depicted in FIG. 11.

iïi another aspect, the present invention provides a crystalline form of N-(2-(2(dfrnethylamino)ethoxy)-4-methoxy-5 -((4-(1 -methyl-1 H-indol-3 -yl)pyrimidin-2yl)amino)phenyl)acrylamide hydrochloride sait (formula 3) having a molar ratio of about 1:1 between hydrochloride acid and free base.

N„ -HCI

In one embodiment, the crystalline form of compound 3 has an X-ray powder diffraction pattern comprising any three or more of the following 2Θ values measured using CuKa radiation: 8.5°±0.2°, 11.2°±0.2°, 18.1°±0.2°, 22.4°±0.2°, 23.5°±0.2°, and 26.3°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 2Θ values.

In another embodiment, the X-ray powder diffraction pattern of the crystalline form of compound 3 further comprises any two or more of the following 2Θ values measured using CuKa radiation: 9.0°±0.2°, 12.7°±0.2°, 16.1°±0.2°, 17.3°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 25.4°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 2Θ values along 8.5°±0.2°, 11.2°±0.2°, 18.1°±0.2°, 22.4°±0.2°, 23.5°±0.2°, and 26.3°±0.2°.

In another embodiment, the crystalline form of compound 3 has a melting point with an onset température at about 266.6 °C and/or a peak température at about 269.5 °C as measured by differential scanning calorimetry.

In another embodiment, the crystalline form of compound 3 has an X-ray powder diffraction pattern substantially as depicted in FIG. 14.

In another embodiment, the crystalline form of compound 3 has a differential scanning calorimetric thermogram and/or a thermal gravimétrie analysis thermogram substantially as depicted in FIG. 13.

In another aspect, the present invention provides a crystalline form of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-( 1 -methyl-1 H-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide sulfate sait (formula 4) having a molar ratio of about 1:1 between sulfuric acid and free base.

I

In one embodiment, the crystalline form of compound 4 has an X-ray powder diffraction pattern comprising any three or more of the following 2Θ values measured using CuKa radiation: 5.6°±0.2°, 7.3°±0.2°, 11.0°±0.2°, 11.9°±0.2°, 14.3°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.6°±0.2°, 19.9°±0.2°, 22.2°±0.2°, 24.9°±0.2°, and 26.3°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 2Θ values.

In another embodiment, the crystalline form of compound 4 has a melting point with an onset température at about 152.3 °C and/or a peak température at about 167.1 °C as measured by differential scanning calorimetry.

In another embodiment, the crystalline form of compound 4 has an X-ray powder diffraction pattern substantially as depicted in FIG. 16.

In another embodiment, the crystalline form of compound 4 has a differential scanning calorimetric thermogram and/or a thermal gravimétrie analysis thermogram substantially as depicted in FIG. 17.

In another aspect, the présent invention provides a crystalline form of N-(2-(2(dimethylamino)ethoxy)-4-methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2yl)amino)phenyl)acrylamide p-toluenesulfonate (p-tosylate) sait (formula 5) having a molar ratio of about 1:1 between p-toluenesulfonic acid and free base.

In one embodiment, the crystalline form of compound 5 has an X-ray powder diffraction pattern comprising any three or more of the following 2Θ values measured using CuKa radiation: 6.8°±0.2°, 7.3°±0.2°, 10.3°±0.2°, 11.3°±0.2°, 13.1°±0.2°, 15.6°±0.2°, 18.2°±0.2°, 20.5°±0.2°, 19.9°±0.2°, 22.7°±0.2°, 23.3°±0.2°, 27.1°±0.2°, and 29.7°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 2Θ values.

In another embodiment, the crystalline form of compound 4 has a melting point with an onset température at about 152.3 °C and/or a peak température at about 167.1 °C as measured by differential scanning calorimetry.

In another embodiment, the crystalline form of compound 4 has an X-ray powder diffraction pattern substantially as depicted in FIG. 18.

In another embodiment, the crystalline form of compound 4 has a differential scanning calorimetric thermogram and/or a thermal gravimétrie analysis thermogram substantially as depicted in FIG. 19.

In another aspect, the présent invention provides a crystalline form of N-(2-(2(dimethylamino) ethoxy)-4-methoxy- 5 -((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2yl)amino)phenyl)acrylamide citrate sait (formula 6) having a molar ratio of about 1:1 between citric acid and free base.

In one embodiment, the crystalline form of compound 6 has an X-ray powder diffraction pattern comprising any three or more of the following 2Θ values measured using CuKa radiation: 5.9°±0.2°, 8.0°±0.2°, 13.2°±0.2°, 19.0°±0.2°, 25.6°±0.2°, and 26.5°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 20 values.

In another embodiment, the X-ray powder diffraction pattern of the crystalline form of compound 6 further comprises any two or more of the following 20 values measured using CuKa radiation: 12.6°±0.2°, I6.0°±0.2°, 16.6°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 20.3°±0.2°, 23.2°±0.2°, and 25.8°±0.2°. In one embodiment, the X-ray powder diffraction pattern comprises ail of these 20 values along 5.9°±0.2°, 8.0°±0.2°, 13.2°±0.2°, 19.0°±0.2°, 25.6°±0.2°, and 26.5°±0.2°.

In another embodiment, the crystalline form of compound 6 has an X-ray powder diffraction pattern substantially as depicted in FIG. 22.

In another embodiment, the crystalline form of compound 6 has a differential scanning calorimetric thermogram and/or a thermal gravimétrie analysis thermogram substantially as depicted in FIG. 21.

In another aspect, the présent invention provides a pharmaceutical composition comprising a crystalline form according to any of embodiments disclosed here, or a combination thereof, and a pharmaceutically acceptable carrier, adjuvant, diluent, and/or vehicle.

In another aspect, the present invention provides a method of treating a disease or disorder associated with an EGFR activity, comprising administration of a therapeutically effective amount of a crystalline form according to any one of the embodiments disclosed herein, or a combination thereof, or a pharmaceutical composition thereof, to a patient in need of treatment.

In one embodiment, the disease or disorder is associated with one or more mutants of EGFR.

In another embodiment, the mutant or mutants of EGFR are selected from L858R activating mutants L858R, delE746-A750, G719S; the Exon 19 délétion activating mutant; and the T790M résistance mutant.

In another embodiment, the disease or disorder is a cancer.

In another embodiment, the cancer is selected from brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectum cancer, breast cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma, and thyroid tumors and their complications.

In another embodiment, the cancer is brain cancer or lung cancer.

In another embodiment, the cancer is a metastatic brain cancer.

In another embodiment, the any embodiment of the method of treating diseases or disorders is used in combination with administering to the patient a second therapeutic agent.

In another embodiment, the second therapeutic agent is a chemotherapeutic agent.

In another embodiment, the second therapeutic agent is a different EGFR modulator.

In another aspect, the present invention provides a method of inhibiting a mutant of EGFR in a subject, comprising contacting a biological sample of said subject with a crystalline forms of compounds according to any embodiments disclosed herein, or a combination thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides use of a crystalline form according to any embodiments disclosed herein, or a combination or mixture thereof, in the manufacture of a médicament for treatment of a disease or disorder associated with an EGFR activity.

In one embodiment of this aspect, the disease or disorder is a cancer selected from the group consisting of brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectum cancer, breast cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma, and thyroid tumors and their complications.

In another embodiment of this aspect, the disease or disorder is brain cancer or lung cancer.

In another aspect, the present invention provides pro cesses of preparing a crystalline form according to any embodiments disclosed herein as substantially described and shown.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingrédient per unit dose. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuons infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingrédient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excrétion of the compound employed, the duration of treatment, and the âge, gender, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or subdose, as herein above recited, or an appropriate fraction thereof, of an active ingrédient. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small incréments untii the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally afford effective results without causing substantial harmful or deleterious side effects.

When the compositions of this disclosure comprise a combination of a crystalline form of compound 1 or sait of the present disclosure and one or more, preferably one or two, additional therapeutic or prophylactic agent, both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example, by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parentéral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingrédient with the carrier(s) or excipient(s). Oral administration or administration by injection is preferred.

Pharmaceutical formulations adapted for oral administration may be presented as discrète units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid émulsions or water-in-oil émulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as éthanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be présent.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths, Glidants and lubricants such as colloïdal silica, talc, magnésium stéarate, calcium stéarate, or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the médicament when. the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a résorption accelerator such as a quatemary sait and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the resuit is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stéarate sait, talc, or minerai oil. The lubricated mixture is then compressed into tablets. The compounds of the présent disclosure can also be combîned with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polytneric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding p articulaie material in polymers, wax, or the like.

It should be understood that in addition to the ingrédients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The term patient or “subject” inciudes both human and other mammals.

The term mammal or “mammalian animal” inciudes, but is not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits and mice. The preferred mammals are humans.

The term “therapeutically effective amount refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A therapeutically effective amount can vary depending on, inter alia, the compound, the disease and its severity, and the âge, weight, or other factors of the subject to be treated. When applied to an individual active ingrédient, administered alone, the term refers to that ingrédient alone. When applied to a combination, the term refers to combîned amounts of the active ingrédients that resuit in the therapeutic effect, whether administered in combination, serially, or simultaneously.

The term treating or “treatment” refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; (ii) relieving the disease, disorder, or condition, i.e., causing régression of the disease, disorder, and/or condition; or (iii) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it. Thus, in one embodiment, “treating or treatment refers to ameliorating a disease or disorder, which may include ameliorating one or more physical parameters, though maybe indiscemible by the subject being treated. In another embodiment, treating or treatment inciudes modulating the disease or disorder, either physîcally (e.g., stabilization of a discemible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, treating or treatment includes delaying the onset of the disease or disorder.

When the terni “about” is applied to a parameter, such as amount, température, time, or the like, it indicates that the parameter can usually vary by ±10%, preferabiy within ±5%, and more preferabiy within ±2%. As would be understood by a person skilled in the art, when a parameter is not critical, a number provided in the Examples is often given only for illustration purpose, instead of being limiting.

The tenu “a,” “an,” or “the,” as used herein, represents both singular and plural forms. In general, when either a singular or a plural form of a noun is used, it dénotés both singular and plural forms of the noun.

The following non-limiting Examples further illustrate certain aspects of the present invention.

EXAMPLES

Example 1

7V-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide (1)

A 1

Step 1. A solution of 4-(2-(dimethylamino)ethoxy)-6-methoxy-jV-1-(4-(1-methyl-1Hindol-3-yl)pyrimidin-2-yl)benzene-l,3 diamine (A, prepared as in International Application No. PCI7US15/65286; 1 equiv, 16.8 g, 26.2 mmol) in THF (550 mL) and water (120 mL) was cooled to 0-5 °C. Acryloyl chloride (1.0 equiv., 3.3 mL) was added dropwise over 30 minutes. After 2 hours, additional acryloyl chloride (0.4 mL) was added over 10 minutes and the mixture was stirred for 1 h. NaOH (2 equiv., 2.8 g, 68.0 mmol) was added, and the mixture was stirred for 30 minutes, and then partially concentrated to remove THF. The aqueous phase was extracted with dichloromethane (900 mL), and the organic phase was dried Na₂SÛ4 and concentrated. The crude product was purified via column chromatography (silica gel; dichloromethane/MeOH, 80:1 to 20:1 gradient) to afford 1 (14.0 g). Further purification of 1, according to Step 2, was necessary in order to obtaîn compound 1.

Step 2. To a solution of 1, prepared as in Step 1, (1 eq, 22.5 g, 46.3 mmol), in 850 mL of THF was added NaOH (9 g dissolved in 203 mL of H₂O) over 5 min. The mixture was heated to 60°C with stirring for 50 min, then cooled to 10-20°C and IN HCl (180 mL) was added over 20 min. The layers were separated and the aqueous phase was extracted with dichloromethane (2 X 400 mL). The organic phases were combined, dried (Na₂SO4) and concentrated. The crude product was purified via column chromatography (silica gel; 20:1 dichloromethane/MeOH) to afford a solid, which was dissolved in dichloromethane/heptane (2:3) then concentrated to afford 19.5 g of compound 1 as a crystalline solid. Ή NMR (400 MHz, CD₃OD) δ ppm 2.42 (s, 6 H), 2.80 (br t, >5.0 Hz, 2 H), 3.98 (s, 3 H), 3.92 (s, 3 H), 4.21 (br t, >5.0 Hz, 2 H), 5.79 (dd, >10.2, 1.4 Hz, 1 H), 6.39 (dd, >16.9, 1.4 Hz, 1 H), 6.64 (dd, >16.9, 10.2 Hz, 1 H), 6.83 (s, 1 H), 7.15-7.30 (m, 3 H), 7.46 (d, >7.6 Hz, 1 H), 8.16-8.30 (m, 2 H), 8.52 (s, 1 H), 9.29 (s, 1 H).

The crystalline form of compound 1 was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA); Figures 1-4. It is a crystalline powder that displays biréfringence and irregular shape with some agglomérations under the PLM (Figure 2). The crystalline form of compound 1 has a melting point with onset température at 169.6°C, -0.35% weight loss before the melting point and -1.62% weight loss from 137°C to 185°C (Figures 3-4).

£xample 2 jV-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide methanesulfonate (1:1) (2)

To a solution of 100 mg of compound 1 (free base) in 4mL of THF was added a solution of 21.7 mg of methanesulfonic acid in 0.164 mL of water, and the solution was stirred at room température ovemight. The precipitate was isolated by centrifugation at 8000 rpm for 5 mins. After drying under vacuum at 30°C ovemight, 60 mg of methanesulfonate sait, crystalline Form 2A, was obtained. NMR (400 MHz, CD₃OD) δ ppm 2.73 (s, 3 H), 3.06 (s, 6 H), 3.65-3.72 (m, 2 H), 3.94 (s, 3 H), 4.00 (s, 3 H), 4.54-4.60 (m, 2 H), 5.86 (br d, >10.0 Hz, 1 H), 6.40-6.48 (m, 1 H), 6.56-6.66 (m, 1 H), 6.98 (s, 1 H), 7.20-7.34 (m, 3 H), 7.50 (d, >8.0 Hz, 1 H), 8.11 (br d, >6.0 Hz, 1 H), 8.35 (br d, >7.8 Hz, 1 H), 8.42 (s, 1 H), 8.50 (br s, 1 H). Anal. Calcd. for C₂8H₃₄N₆O₆S: C, 57.72; H, 5.88; N, 14.42; O, 16.47; S, 5.50. Found: C, 57.76; H, 5.85; N, 14.45; 0,16.34; S, 5.60; C₂₇H₃₀N₆O₃ · 1.0 CH₃SO₃H.

Form 2A is a beige crystalline powder; its XRPD pattern is shown in Figure 5. It shows biréfringence and has a melting point with onset température at 233.3°C, -0.40% weight loss before the melting point and -0.035% weight loss from 170°C to 210°C. (PLM, Figure 6; DSC, Figure 7; TGA, Figure. 8).

A polymorph screening study was performed on Form 2A by the slurry, solventthermal heating/cooling, anti-solvent précipitation, solid heating-cooling and grinding methods. One new crystal form, Form 2B, was found. Form 2B may be a hydrate form of Form 2A and shows low crystallinity, low melting point and high weight loss compared with the Form 2A. XRPD, PLM, DSC, and TGA-MS analyses of Form 2B are shown in Figures 9-12.

Example 3

JV-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-177-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide hydrochloride (1:1) (3)

A dilute hydrochloric acid solution was prepared by dissolving 650.6 mg of a 38% HCl solution in 5 mL of THF. This solution (0.167 mL) was added to a solution of 100 mg of compound 1 (free base) dissolved in 4 mL of THF. The solution was stirred at room température ovemight. The resulting solid precipitate was isolated by centrifugation at 8000 rpm for 5 min. After drying under vacuum at 30°C ovemight, 70 mg of HCl sait (3) was obtained. An overlay of DSC and TGA curves is shown in Figure 13, and an overlay of

XRPD patterns before and after DVS is shown in Figure 14.

The methods of Examples 1 and 2 were used to préparé sulfate (4), tosylate (5), and citrate (6) salts.

Example 4

A^r-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l -methyl- 177-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide sulfate (1:1) (4)

N< H₂SO₄

Example 5

7V-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-177-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide/j-toluenesulfonate (1:1) (5)

H Y n₀O₀-„n

SO₃H 'HNMR (400 MHz, DMSO-î/₆) δ ppm 2.29 (s, 3 H), 2.92 (s, 6 H), 3.50-3.62 (m, 2 H), 3.89 (s, 3 H), 3.91 (s, 3 H), 4.37-4.48 (m, 2 H), 5.79 (dd, >10.2, 1.5 Hz, 1 H), 6.29 (dd, >16.9, 1.5 Hz, 1 H), 6.59 (br dd, >16.9, 10.2 Hz, 1 H), 6.94 (s, 1 H), 7.09-7.17 (m, 3 H), 7.18-7.27 (m, 2 H), 7.48 (d, >8.0 Hz, 2 H), 7.52 (d, >8.0 Hz, 1 H), 7.95 (s, 1 H), 8.26-8.38 (m, 2 H), 8.48 (s, 1 H), 8.66 (s, 1 H), 9.38 (s, 1 H).

Example 6

7V-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-177-indol-3-yl)pyrimidin-2yl)amino)phenyl)acrylamide citrate (1:1) (6)

’H NMR (400 MHz, DMSO-7Ù δ ppm 2.58 (br d, J=\7.8 Hz, 4H), 2.70 (s, 6 H), 3.21 (br t, 7=4.9 Hz, 2 H), 3.88 (s, 3 H), 3.90 (s, 3 H), 4.36 (br t, 7=4.9 Hz, 2 H), 5.78 (dd, 7=10.2, 1.6 Hz, 1 H), 6.28 (dd, 7=16.9, 1.6 Hz, 1 H), 6.56 (dd, 7=16.9, 10.2 Hz, 1H), 6.94 (s, 1 H), 7.117.28 (m, 3 H), 7.52 (d, 7=8.0 Hz, 1 H), 7.93 (s, 1 H), 8.23-8.38 (m, 2 H), 8.50 (s, 1 H), 8.73 (s, 1 H), 9.55 (s, 1 H).

Summary of XRPD/DSC/TGA Analysis of Crystalline Forms of Compounds 2 to 6

Based on the XRPD/DSC/TGA results of the five salts, namely compounds 3 (HCl), 4 (sulfate), 2 (mesylate), 5 (tosylate) and 6 (citrate), Compound 3 showed the best crystallinity, the highest melting point (266.6°C) and the least weight loss 0.14%. Compounds 4-6 showed a melting point range from 130°C to 180°C with variable weigh loss from 1.8% to 6.2% on TGA. The degree of crystallinity is compound 3 (HCl) > 4 (sulfate) ~ 2(mesylate) ~ 4 (tosylate) > 6 (citrate). According to DVS results, compounds 3 and 5 could be classified as slightly hygroscopic (0.76% and 1.86% weight gain from 0 to 80% RH, respectively) while compounds 4 and 2 are hygroscopic (10.60% and 14.44% weight gain from 0 to 80% RH, respectively). No form transformation was observed after DVS test for any of the salts.

Table 1. Detailed Information of Sait Forms

Ex.	Compound (Form)	DSC	TGA (wt% loss)	DVS Sorption (%)	Stoichiometry (free base : acid)
lst peak (°C)/H (J/g)	2ndpeak (°C)/H (J/g)a	3rd peak (°C)/H (J/g)
1	1 (free base)	169.6/78.7	-	-	0.35 (30.6-137.0 °C) 1.6 (137.0185.0 °C)	-	-
2	2 (Form 2A) (methanesulfonate)	239.8/105.3	-	-	0.27 (26.5-210.0 °C)	0.91	1:1.0
3	3 (Form 2B) (methanesulfonate)	31.2/65.0	159.1/26.3		2.8 (29.7-144.0 °C) 0.51 (144.0204.0 °C)	14.44	1:1.1
4	3 (hydrochloride)	266.6/167.8	-	-	0.14 (28.2-150.0 °C)	0.76	1:1.0
5	4 (sulfate)	69.9/59.4	180.2/31.8	-	6.2 (31.1138.0 °C) 2.5 (138.0225.0 °C)	10.60	1:1.0
6	5 (ptoluenesulfonate)	152.3/35.7	-	-	1.8 (28.7125.0 °C)	1.86	1:1.0
7	6 (citrate)	43.6/47.3	134.5/38.2	179.0/88.7	2.2 (26.3-100.0 °C) 24.2 (100.0- 212.0 °C)	-	1:1.0

indicates either no data available or not determined

Table 2. Solubility Data for Various Sait Forms

Example	Sait	Solubility (mg/mL)	Final pH	HPLC Purity (%)
1	1 (free base)	0.05	6.2	-
2	2 (methanesulfonate)	>53	. 4.9	95.7
4	3 (hydrochloride)	0.81	6.0	91.2
5	4 (sulfate)	>79	2.4	99.5
6	5 (p-toluenesulfonate)	0.53	5.8	92.8
7	6 (citrate)	6.9	4.6	97.1

Définitions

X-ray Powder Diffractometer (XRPD)

Differential Scanning Calorimetry (DSC)

Thermal Gravimétrie Analysis (TGA)

Polarized Light Micros copy (PLM)

Dynamic Vapor Sorption (DVS)

Thermogravimetric Analyzer/ Mass Spectrometer (TGA-MS)

I

Table 3. Instrumentation

Name	Model	Manufacture
X-ray Powder Difïractometer(XRPD)	D8 advance	Bruker
Polarized Light Microscopy (PLM)	LV100PL	Nikon
Differential Scanning Calorimetry (DSC)	Q2000	TA
Thermal Gravimétrie Analysis (TGA)	Q5000IR	TA
Mass Spectrometer (MS)	QGA	Hiden
Dynamic Vapor Sorption System (DVS)	Advantage-1	SMS
Nuclear Magnetic Résonance (NMR)	AVANCE III (400MHz)	Bruker
High Performance Liquid Chromatograph (HPLC)	Agilent 1200 and 1260	Agilent

The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the présent invention as defined by the claims. As will 5 be readily appreciated, numerous variations and combinations of the featufes set forth above can be utilized without departing from the présent invention as set forth in the claims.

Claims (16)

1. A crystalline form of the compound of formula 1, namely AZ-(2-(2(dimethyl amino)ethoxy)-4-methoxy- 5 -((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2 yl)amino)phenyl)acrylamide (free base), or a pharmaceutically acceptable sait thereof.

2. The crystalline form of claim 1, wherein the compound of formula 1 is a free base having an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 8.5°±0.2°, 16.7°±0.2°, and 25.2°±0.2°, and optionally two or more of the following 2Θ values measured using CuKa radiation: 9.5°±0.2°, 12.2°±0.2°, 12.5°±0.2°, 15.7°±0.2°, 16.0°±0.2°, 19.4°±0.2°, 19.7°±0.2°, 20.0°±0.2°, 23.2°±0.2°, 24.4°±0.2°, and 28.5°+0.2°; and/or having a melting point with an onset température at about 169.6 °C and/or a peak température at about 171.7 °C as measured by differential scanning calorimetry.

3. The crystalline form of claim 1, which is /V-(2-(2-(dimethylamino)ethoxy)-4methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2-yl)amino)phenyl)acrylamide methanesulfonate sait (formula 2) having a molar ratio of about 1:1 between methanesulfonic acid and free base.

4. The crystalline form of claim 3, designated as Form 2A, having an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 12.6°±0.2°, 15.5°±0.2°, 17.9°±0.2°, 22.1°±0.2°, and 25.2°±0.2°, and optionally two or more of the following 2Θ values measured using CuKa radiation: ll.l°±0.2°, 13.8°±0.2°, 14.7°±0.2°, 16.7°±0.2°, 19.3°±0.2°, 20.9°±0.2°, 23.2°±0.2°, and 25.8°±0.2°; and/or having a melting point with an onset température at about 233.3 °C and/or a peak température at about

238,1 °C as measured by differential scanning calorimetry.

5. The crystalline form of claim 3, designated as Form 2B, having an X-ray powder diffraction pattern comprising three or more of the following 2Θ values measured using CuKa radiation: 9.7°±0.2°, 12.8°±0.2°, 15.7°±0.2°, 18.2°±0.2°, 20.3°±0.2°, 25.1°±0.2°_} 25.6°±0.2°, and 26.8°±0.2°; and/or having a diffractional scanning calorimetric thermogram substantially as depicted in FIG. 12.

6. The crystalline form of claim 1, which is a AI-(2-(2-(dimethylamino)ethoxy)-4methoxy-5 -((4-(1 -methyl-1 H-indol-3 -yl)pyrimidin-2-yl) amino)phenyl)acryl amide hydrochloride sait (formula 3) having a molar ratio of about 1:1 between hydrochloride acid and free base.

7. The crystalline form of claim 6, having an X-ray powder diffraction pattern comprising three or more of the following 2Θ values measured using CuKa radiation: 8.5°±0.2°, 11.2°±0.2°, 18.1°±0.2°, 22.4°±0.2°, 23.5°±0.2°, and 26.3°±0.2°, and optionally two or more of the following 2Θ values measured using CuKa radiation: 9.0°±0.2°, 12.7°±0.2°, 16.1°±0.2°, 17.3°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 25.4°±0.2°; and/or having a melting point with an onset température at about 169.6 °C and/or a peak température at about 171.7 °C as measured by differential scanning calorimetry.

8. The crystalline form of claim 1, which is 7V-(2-(2-(dimethylamino)ethoxy)-4methoxy-5 -((4-(1 -methyl-1 H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acryl amide sulfate sait (formula 4) having a molar ratio of about 1:1 between sulfuric acid and free base.

9. The crystalline form of claim 8, having an X-ray powder diffraction pattern comprising three or more of the following 2Θ values measured using CuKa radiation:

i

19085 |

5.6°±0.2°, 7.3°±0.2°, 11.0°±0.2°, 11.9°±0.2°, 14.3°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.6°±0.2°,

19.9°±0.2°, 22.2°±0.2°, 24.9°±0.2°, and 26.3°±0.2°; and/or having a melting point with an onset température at about 152.3 °C and/or a peak température at about 167.1 °C as measured by differential scanning calorimetry.

10. The crystalline form of claim 1, which is JV-(2-(2-(dimethylamino)ethoxy)-4mcthoxy-5-((4-(1-methyl-lH-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide p- toluenesulfonate (p-tosylate) sait (formula 5) having a molar ratio of about 1:1 between ptoluenesulfonic acid and free base.

11. The crystalline form of claim 10, having an X-ray powder diffraction pattern comprising three or more of the following 2Θ values measured using CuKa radiation: 6.8°±0.2°, 7.3°±0.2°, 10.3°±0.2°, 11.3°±0.2°, 13.1°±0.2°, 15.6°±0.2°, 18.2°±0.2°, 20.5°±0.2°, 19.9°±0.2°, 22.7°±0.2°, 23.3°±0.2°, 27.1°±0.2°, and 29.7°±0.2°; and/or having a melting point with an onset température at about 152.3 °C and/or a peak température at about 167.1 °C as measured by differential scanning calorimetry.

12. The crystalline form of daim 1, which is N-(2-(2-(dimethylamino)ethoxy)-4methoxy-5-((4-( 1 -methyl-1 H-indol-3 -yl)pyrimidin-2-yl)amino)phenyl)acrylamide citrate sait (formula 6) having a molar ratio of about 1:1 between citric acid and free base.

13. The crystalline form of claim 12, having an X-ray powder diffraction pattern comprising three or more of the following 2Θ values measured using CuKa radiation: 5.9°±0.2°, 8.0°±0.2°, 13.2°±0.2°, 19.0°±0.2°, 25.6°±0.2°, and 26.5°±0.2°, and optionally two or more of the following 2Θ values measured using CuKa radiation: 12.6°±0.2°, 16.0°±0.2°, 16.6°±0.2°, 17.0°±0.2°, 18.5°±0.2°, 20.3°±0.2°, 23.2°±0.2°, and 25.8°±0,2°; and/or having a diffractional scanning calorimetric thermogram substantially as depicted in FIG. 21.

14. A pharmaceutical composition comprising a crystalline form of any one of claims 1 to 13, and a pharmaceutically acceptable carrier, adjuvant, diluent, and/or vehicle.

15. Use of a crystalline form according to any one of claims 1 to 13, or a pharmaceutical composition of claim 14, in the manufacture of a médicament for the treatment

5 of a disease or disorder associated with one or more mutants of EGFR selected from L858R activating mutants L858R, delE746-A750, G719S; the Exon 19 délétion activating mutant; and the T790M résistance mutant.

16. The use of claim 15, wherein said disease or disorder is a cancer selected from brain cancer, lung cancer, kidney cancer, b one cancer, liver cancer, bladder cancer, head and

10 neck cancer, esophageal cancer, stomach cancer, colon cancer, rectum cancer, breast cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma, and thyroid tumors and their complications.