WO2018153970A1

WO2018153970A1 - Solid forms of 2-[(3r)-3-methylmorpholin-4-yl]-4-(1-methyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphthyridine

Info

Publication number: WO2018153970A1
Application number: PCT/EP2018/054363
Authority: WO
Inventors: Philipp Rubenbauer; Jens Geisler; Jana GALBRAITH
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2017-02-24
Filing date: 2018-02-22
Publication date: 2018-08-30

Abstract

The present invention covers different solid forms of 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine of formula (I).

Description

Solid Forms of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-

5-yl)- 1 ,7-naphthyridine

This present invention covers different solid forms of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l- methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)-l,7-naphthyridine of formula (I):

(D-

WO2016020320 discloses the compound of formula (I), and further describes that this and other compounds disclosed therein are inhibitors of ATR kinase, and may therefore be used as agents for the prophylaxis and/or treatment of hyper-proliferative diseases.

WO2016020320, example 111 describes the preparation of the compound of the formula (I).

It has been found that the compound of formula (I) crystallizes in two different polymorphic forms, which are called "Form A" and "Form B" in the following. In addition, the following solid forms of the compound of formula (I) are also subject to the present invention: the amorphous form; disordered polymorphic form C (in the following called "Form C"); pseudopolymorphic form D ("Form D"); a mixture of polymorphic Form B with Form D of the compound of formula (I), which mixture was isolated from various stress experiments further described in the Experimental Section with various solvents, such as acetonitrile, dimethyl sulfoxide, ethyl acetate, methanol, isopropanol or EthanolA ater (96.4% v/v), preferably with acetonitrile (in the following called "Pattern D Mixture"); pseudopolymorphic form E ("Form E"); a mixture of polymorphic Form B with Form E of the compound of formula (I), which mixture was isolated from various stress experiments further described in the Experimental Section with toluene (in the following called "Pattern E Mixture").

Aspects of some embodiments of the present invention which may be beneficial in the present pharmaceutical field may include stability (e.g. mechanical stability, chemical stability, storage stability), compatibility over other ingredients, purity, solubility, crystallization properties, properties regarding isolation during the chemical synthesis and bioavailability of the solid forms of the compound of formula (I).

Embodiments of the present invention do not only concern the amorphous form, Form A, Form B, Form C, Form D, Form E, Pattern D Mixture or Pattern E Mixture of the compound of the formula (I) but also mixtures comprising two, three, four, five or six solid forms of the aforementioned.

A pharmaceutical composition subject to the present invention comprises only one of the solid forms selected from amorphous form, Form A, Form B, Form C, Form D, Form E of the compound of the formula (I) and, preferably, no significant fractions of another solid form of the compound of the formula (I), for example of another solid form of the compound of the formula (I).

A pharmaceutical composition according to the present invention comprises preferably only one of the solid forms selected from Form A and Form B of the compound of the formula (I) and, preferably, no significant fractions of another solid form of the compound of the formula (I).

In another embodiment the pharmaceutical composition of the present invention comprises one of the aforementioned solid forms (e.g. either Form A, Form B, Form C, Form D or Form E) of the compound of the formula (I) in an amount of more than 85 percent by weight, preferably more than 90 percent by weight, more preferably more than 95 percent by weight, most preferably up to 100 percent by weight of the total amount of all solid forms of the compound of the formula (I) present in the pharmaceutical composition.

The present invention also concerns a pharmaceutical composition comprising Form A of the compound of the formula (I) according to the present invention.

Preference is given to a pharmaceutical composition comprising the compound of the formula (I) in its Form A and no significant fractions of another solid form of the compound of the formula (I), for example of Form B or of Form C or of Forms D or E of the compound of the formula (I).

The pharmaceutical composition preferably comprises Form A of the compound of the formula (I) in an amount of more than 85 percent by weight, more preferably of more than 90 percent by weight, more preferably of more than 95 percent by weight, most preferably of more than 98 percent by weight of the total amount of all solid forms of the compound of the formula (I) present in the pharmaceutical composition.

The present invention also concerns a pharmaceutical composition comprising Form B of the compound of the formula (I) according to the present invention.

Further preference is given to a pharmaceutical composition comprising the compound of the formula (I) in its Form B and no significant fractions of another solid form of the compound of the formula (I), for example of Form A or of Form C or of Forms D or E of the compound of the formula (I).

The pharmaceutical composition preferably comprises Form B of the compound of the formula (I) in an amount of more than 85 percent by weight, more preferably of more than 90 percent by weight, more preferably of more than 95 percent by weight, most preferably of more than 98 percent by weight of the total amount of all solid forms of the compound of the formula (I) present in the pharmaceutical composition.

The present invention also concerns a pharmaceutical composition comprising Form C of the compound of the formula (I) according to the present invention.

Further preference is given to a pharmaceutical composition comprising the compound of the formula (I) in its Form C and no significant fractions of another solid form of the compound of the formula (I), for example of Form A or of Form B or of Forms D or E of the compound of the formula (I).

The pharmaceutical composition preferably comprises Form C of the compound of the formula (I) in an amount of more than 85 percent by weight, more preferably of more than 90 percent by weight, more preferably of more than 95 percent by weight, most preferably of more than 98 percent by weight of the total amount of all solid forms of the compound of the formula (I) present in the pharmaceutical composition.

The present invention also concerns a pharmaceutical composition comprising Form D of the compound of the formula (I) according to the present invention.

Further preference is given to a pharmaceutical composition comprising the compound of the formula (I) in its Form D and no significant fractions of another solid form of the compound of the formula (I), for example of Form A or of Form B or of Form C or of Form E of the compound of the formula

(D-

The pharmaceutical composition preferably comprises Form D of the compound of the formula (I) in an amount of more than 85 percent by weight, more preferably of more than 90 percent by weight, more preferably of more than 95 percent by weight, most preferably of more than 98 percent by weight of the total amount of all solid forms of the compound of the formula (I) present in the pharmaceutical composition. hi another embodiment the present invention concerns a pharmaceutical composition comprising the Pattern D Mixture of the compound of the formula (I) and no significant fractions of another solid form of the compound of the formula (I), for example of Form A or Form C or of Form E of the compound of the formula (I).

The pharmaceutical composition preferably comprises Pattern D Mixture of the compound of the formula (Γ) in an amount of more than 85 percent by weight, more preferably of more than 90 percent by weight, more preferably of more than 95 percent by weight, most preferably of more than 98 percent by weight of the total amount of all solid forms of the compound of the formula (I) present in the pharmaceutical composition.

The present invention also concerns a pharmaceutical composition comprising Form E of the compound of the formula (I) according to the present invention.

Further preference is given to a pharmaceutical composition comprising the compound of the formula (I) in its Form E and no significant fractions of another solid form of the compound of the formula (I), for example of Form A or of Form C or of Form D of the compound of the formula (I).

The pharmaceutical composition preferably comprises Form E of the compound of the formula (I) in an amount of more than 85 percent by weight, more preferably of more than 90 percent by weight, more preferably of more than 95 percent by weight, most preferably of more than 98 percent by weight of the total amount of all solid forms of the compound of the formula (Γ) present in the pharmaceutical composition.

In another embodiment the present invention concerns a pharmaceutical composition comprising the Pattern E Mixture of the compound of the formula (I) and no significant fractions of another solid form of the compound of the formula (I), for example of Form A or Form C or of Form D of the compound of the formula (I).

The pharmaceutical composition preferably comprises Pattern E Mixture of the compound of the formula (Γ) in an amount of more than 85 percent by weight, more preferably of more than 90 percent by weight, more preferably of more than 95 percent by weight, most preferably of more than 98 percent by weight of the total amount of all solid forms of the compound of the formula (I) present in the pharmaceutical composition.

The solid forms of the compound of the formula (I) of the present invention are used alone or together as a mixture in high purity in pharmaceutical formulations. Aforementioned mixtures may comprise a combination of the compound of formula (I) in its Form A and the compound of formula (I) in its Form B, a combination of the compound of formula (I) in its Form A and the compound of formula (I) in its Form C, a combination of the compound of formula (I) in its Form A and the compound of formula (I) in its Form D, a combination of the compound of formula (I) in its Form A and the compound of formula (I) in its Form E, a combination of the compound of formula (I) in its Form B and the compound of formula (I) in its Form C, a combination of the compound of formula (I) in its Form B and the compound of formula (I) in its Form D, a combination of the compound of formula (I) in its Form B and the compound of formula (I) in its Form E, a combination of the compound of formula (I) in its Form C and the compound of formula (I) in its Form D, a combination of the compound of formula (I) in its Form C and the compound of formula (I) in its Form E, a combination of the compound of formula (I) in its Form D and the compound of formula (I) in its Form E, a combination of the compound of formula (I) in its Form A and the Pattern D Mixture of the compound of formula (I), a combination of the compound of formula (I) in its Form A and the Pattern E Mixture of the compound of formula (I), a combination of the compound of formula (I) in its Form B and the Pattern D Mixture of the compound of formula (I), a combination of the compound of formula (I) in its Form B and the Pattern E Mixture of the compound of formula (I), or a combination of the Pattern D Mixture of the compound of formula (I) and the Pattern E Mixture of the compound of formula (I).

Optionally the aforementioned combinations comprise no significant fractions of another solid form of the compound of the formula (I). In this context the term 'no significant fraction' shall have the meaning of an amount of no more than 10 percent by weight and preferably of no more than 5 percent by weight of the mentioned another solid form of compound of formula (I).

The different solid forms of the compound of formula (I) can be, for example, distinguished by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), FT-IR- and Raman- spectroscopy:

Figure 1 : X-ray powder diffractogram of Form A

Figure 2: DSC thermogram of Form A analysed from 30-300 °C at 10°C per minute

Figure 3: FT-IR spectrum of Form A

Figure 4: Raman spectrum of Form A

Figure 5: X-ray powder diffractogram of Form B

Figure 6: DSC thermogram of Form B analysed from 30-300 °C at 10 °C per minute

Figure 7: FT-IR spectrum of Form B Figure 8: Raman spectrum of Form B

Figure 9: X-ray powder diffractogram of Form C

Figure 10: DSC thermogram of Form C analysed from 30-300 °C at 10 °C per minute Figure 11 : FT-IR spectrum of Form C Figure 12: Raman spectrum of Form C

Figure 13: X-ray powder diffractogram of mixtures of Pattern D and Form B upon storage vs Forms A and B

Figure 14: X-ray powder diffractogram of mixtures of Pattern E and Form B upon storage vs Forms A and B

In another embodiment Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 19.1.

In another embodiment Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 16.1, 17.0, 19.1.

In another embodiment Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 16.1,

17.0, 19.1, 24.9, 25.9.

In another embodiment Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 14.3,

16.1, 17.0, 19.1, 24.9, 25.9.

In another embodiment Form A of the compound of formula (I) can be characterized by a X-ray powder diffractogram (XRPD) which displays at least 3, particularly at least 5, preferably at least 7, more preferably at least 10, most preferably at least 15 of the following reflections, quoted as 2Θ values: 6.4, 9.3, 12.4, 12.9, 14.3, 15.6, 16.1, 17.0, 19.1, 19.9, 22.6, 24.9, 25.6, 25.7, 25.9.

In another embodiment Form A of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) substantially as shown in Figure 1.

In another embodiment Form A of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table Al. In another embodiment of the present invention Form A of the compound of formula (I) is an anhydrate.

In another embodiment of the present invention Form A of the compound of formula (I) is characterized by the FT-IR spectrum substantially as shown in Figure 3.

In another embodiment of the present invention Form A of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table B.

In another embodiment of the present invention Form A of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table C.

In another embodiment of the present invention Form A of the compound of formula (I) is characterized by the Raman spectrum substantially as shown in Figure 4.

In another embodiment of the present invention Form A of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table D.

In another embodiment of the present invention Form A of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table E.

In another embodiment of the present invention Form A of the compound of formula (I) is characterized by one or more of the following: X-ray powder diffractogram as described herein; FT-IR spectrum or FT-IR bands maxima substantially as described herein; Raman spectrum or Raman bands maxima substantially as described herein.

Form B of the compound of formula (I) can be characterized by a X-ray powder diffractogram (XRPD), which displays at least 3, particularly at least 5, preferably at least 7, more preferably at least 10, most preferably at least 12 of the following reflections, quoted as 2Θ values: 8.3, 9.3,

13.8, 14.0, 18.0, 18.7, 19.6, 19.9, 20.1, 22.1, 23.9, 27.4.

In another embodiment Form B of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 18.0, 19.9.

In another embodiment Form B of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 9.3, 18.0,

19.9, 20.1.

In another embodiment Form B of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 9.3, 13.8, 14.0, 18.0, 19.9, 20.1. In another embodiment Form B of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) substantially as shown in Figure 5.

In another embodiment Form B of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table Al.

In another embodiment of the present invention Form B of the compound of formula (I) is an anhydrate.

In another embodiment of the present invention Form B of the compound of formula (I) is characterized by the FT-IR spectrum substantially as shown in Figure 7

In another embodiment of the present invention Form B of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table B.

In another embodiment of the present invention Form B of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table C.

In another embodiment of the present invention Form B of the compound of formula (I) is characterized by the Raman spectrum substantially as shown in Figure 8.

In another embodiment of the present invention Form B of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table D.

In another embodiment of the present invention Form B of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table E.

In another embodiment of the present invention Form B of the compound of formula (I) is characterized by one or more of the following: X-ray powder diffractogram as described herein; FT-IR spectrum or FT-IR bands maxima substantially as described herein; Raman spectrum or Raman bands maxima substantially as described herein.

Form C of the compound of formula (I) can be characterized by a X-ray powder diffractogram (XRPD), which displays at least 3, preferably at least 5, more preferably at least 7 of the following reflections, quoted as 2Θ values: 8.9, 12.3, 13.1, 14.5, 19.6, 20.0, 23.6.

In another embodiment Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.9, 13.1, 23.6.

In another embodiment Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.9, 12.3, 13.1, 20.0, 23.6. In another embodiment Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.9, 12.3, 13.1, 14.5, 19.6, 20.0, 23.6.

In another embodiment Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.9, 12.3, 13.1, 14.5, 19.6, 20.0, 23.6, 27.9.

In another embodiment Form C of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) substantially as shown in Figure 9.

In another embodiment Form C of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table Al.

In another embodiment of the present invention Form C of the compound of formula (I) is characterized by the FT-IR spectrum substantially as shown in Figure 11.

In another embodiment of the present invention Form C of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table B.

In another embodiment of the present invention Form C of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table C.

In another embodiment of the present invention Form C of the compound of formula (I) is characterized by the Raman spectrum substantially as shown in Figure 12.

In another embodiment of the present invention Form C of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table D.

In another embodiment of the present invention Form C of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table E.

In another embodiment of the present invention Form C of the compound of formula (I) is characterized by one or more of the following: X-ray powder diffractogram as described herein; FT-IR spectrum or FT-IR bands maxima substantially as described herein; Raman spectrum or Raman bands maxima substantially as described herein.

Pattern D Mixture is a mixture of polymorphic Form B with Form D of the compound of formula (I).

In another embodiment Form D or Pattern D Mixture of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 9.0, 21.5, 23.8. In another embodiment Form D or Pattern D Mixture of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 9.0, 10.5, 12.1, 21.5, 23.8.

In another embodiment Form D or Pattern D Mixture of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 9.0, 10.5, 12.1, 12.9, 15.1, 21.5, 23.8.

In another embodiment Pattern D Mixture of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) substantially as shown in Figure 13.

In another embodiment Pattern D Mixture of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table A2.

In another embodiment Pattern Form D or Pattern D Mixture of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 9.0, 10.5, 12.1, 12.9, 15.1, 21.5, 23.8

In another embodiment, Form D of the compound of formula (I) is a hydrate.

Pattern E Mixture is a mixture of polymorphic Form B with a pseudopolymorph E of the compound of formula (I).

Form E or Pattern E Mixture of the compound of formula (I) can be characterized by a X-ray powder diffractogram (XRPD), which displays at least 3, preferably at least 5, more preferably at least 6 of the following reflections, quoted as 2Θ values: 8.8, 9.0, 12.3, 12.6, 19.0, 19.5.

In another embodiment Form E or Pattern E Mixture of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections quoted as 2Θ values: 8.8, 12.3, 12.6.

In another embodiment Form E or Pattern E Mixture of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.8, 9.0, 12.3, 12.6, 19.0.

In another embodiment Form E or Pattern E Mixture of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.8, 9.0, 12.3, 12.6, 19.0, 19.5.

In another embodiment Pattern E Mixture of the compound of formula (I) is characterized by the X- ray powder diffractogram (XRPD) substantially as shown in Figure 14. In another embodiment, pseudopolymorph E of the compound of formula (I) is a hydrate.

In context with the present invention the X-ray powder diffractogram of the different solid forms of compound of formula (I) according to the invention are determined with Cu K alpha 1 as radiation at 25 °C according to the method further described below in the Experimental Part ("X- ray Powder Diffraction").

The characterization of the different solid forms of compound of formula (I) according to the invention can be further characterized by Differential Scanning Calorimetry (DSC) as further described in the Experimental Part ("Differential Scanning Calorimetry").

The characterization of the different solid forms of compound of formula (I) according to the invention can be further characterized by JR- or Raman Spectroscopy as further described in the Experimental Part.

The aforementioned solid forms of the compound of formula (I) according to the invention may have useful pharmacological properties and may be employed for the prevention and treatment of disorders in humans and animals. The compounds according to the invention may open up a further treatment alternative and may therefore be an enrichment of pharmacy.

The solid forms of the compound of formula (I) according to the invention show a valuable spectrum of action which could not have been predicted. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals. In particular, said compounds of the present invention have surprisingly been found to effectively inhibit ATR kinase and may therefore be used for the treatment or prophylaxis of disorders mediated by ATR kinase, in particular hyper-proliferative diseases.

The present invention covers a method for using the compounds and/or pharmaceutical compositions of the present invention, to treat diseases, in particular hyper-proliferative diseases. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, in particular a human, an amount of a compound of this invention which is effective to treat the disease. Hyper-proliferative diseases include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those diseases also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These diseases have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering compounds or pharmaceutical compositions of the present invention.

In particular, the present invention covers the treatment of lung carcinoma, in particular small-cell lung cancer, colorectal cancer, bladder cancer, lymphomas, gliomas, and ovarian cancer.

In particular, the present invention covers the treatment of lung carcinoma, in particular small-cell lung cancer, colorectal cancer, bladder cancer, lymphomas, in particular diffuse large B-cell lymphoma (DLBC) and mantle cell lymphoma (MCL), prostate cancer, in particular castration- resistant prostate cancer, gliomas, and ovarian cancer.

The present invention further provides for the use of the solid forms of the compound of formula (I) and/or of the pharmaceutical compositions of the present invention for the production of a medicament for the treatment and/or prophylaxis of a disease, especially of one or more of the aforementioned diseases, in particular of a hyper -proliferative disease.

A further subject matter of the present invention is the use of the solid forms of the compound of formula (I) and/or of the pharmaceutical compositions of the present invention in the manufacture of a medicament for the treatment and/or prophylaxis of a disorder, in particular one or more of the hyper-proliferative diseases mentioned above.

The present invention furthermore covers the solid forms of the compound of formula (I) of the present invention for use in a method for the treatment and/or prophylaxis of a disease, in particular of a hyper-proliferative disease.

The present invention further provides a method for treatment and/or prophylaxis of diseases, especially the aforementioned diseases, in particular of a hyper-proliferative disease, using an effective amount of at least one, preferably one, solid form of the compound of formula (I) and/or of the pharmaceutical compositions according to the present invention.

The present invention further provides the solid forms of the compound of formula (I) of formula (I) and/or of the pharmaceutical compositions of the present invention for use in the treatment and/or prophylaxis of diseases, especially of the aforementioned diseases, in particular of a hyper- proliferative disease.

The present invention further provides the solid forms of the compound of formula (I) and/or of the pharmaceutical compositions of the present invention for use in a method for treatment and/or prophylaxis of the aforementioned diseases, in particular of a hyper-proliferative disease.

The present invention furthermore covers a pharmaceutical combination, in particular a medicament, comprising at least one solid form of the compound of formula (I) according to the invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of the above mentioned diseases.

The present invention further provides a pharmaceutical combination comprising one or more active ingredients selected from a solid form of the compound of formula (I) according to the invention and one or more active ingredients selected from anti-hyper-proliferative, cytostatic or cytotoxic substances for treatment of cancers.

The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of -parts.

A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient and a second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein a first active ingredient and a second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein a first active ingredient and a second active ingredient are present in one unit without being in admixture.

A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a second active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The solid forms of the compound of formula (I) of this invention can be administered as the sole pharmaceutically active ingredient or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention relates also to such pharmaceutical combinations. For example, the solid forms of the compound of formula (I) of this invention may be combined with known chemotherapeutic agents and/or anti-cancer agents, e.g. anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA- intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.

For example, the solid forms of the compound of formula (I) of the present invention may be combined with known anti-hyper-proliferative, cytostatic or cytotoxic substances for treatment of cancers. Examples of suitable anti-hyper-proliferative, cytostatic or cytotoxic combination active ingredients include:

1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine,

14

] amifostine, aminoglutethimide, hexyl aminolevuliriate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin Π, antithrombin ΙΠ, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron,

15

] oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium- 103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG- epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide -K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium- 186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]- octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

The solid forms of the compound of formula (I) according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent. The solid forms of the compound of formula (I) according to the invention can be administered in administration forms suitable for these administration routes.

Suitable administration forms for oral administration are those which deliver the solid forms of the compound of formula (I) according to the invention in a rapid and/or modified manner, and contain the solid forms of the compound of formula (I) according to the invention, for example tablets (uncoated or coated tablets, for example with enteric or retarded-dissolution or insoluble coatings which control the release of the compound of general formula (I)), tablets or films/wafers which disintegrate rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions or aerosols.

Parenteral administration can be accomplished with avoidance of an absorption step (for example by an intravenous, intraarterial, intracardial, intraspinal or intralumbal route) or with inclusion of an absorption (for example by an intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal route). Suitable administration forms for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

For the other administration routes, suitable examples are pharmaceutical forms for inhalation or inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, ear or eye preparations (for example eye baths, ocular insert, ear drops, ear powders, ear-rinses, ear tampons), vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), milk, pastes, foams, dusting powders, implants, intrauterine coils, vaginal rings or stents. The solid forms of the compound of formula (I) according to the invention can be converted to the administration forms mentioned. This can be done in a manner known per se, by mixing with pharmaceutically suitable excipients.

These excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), dyes (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctants.

Pharmaceutically acceptable excipients are non-toxic, preferably they are non-toxic and inert. Pharmaceutically acceptable excipients include, inter alia: fillers and excipients (for example cellulose, microcrystalline cellulose, such as, for example, Avicel®, lactose, mannitol, starch, calcium phosphate such as, for example, Di-Cafos®),

• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat)

• solvents (for example water, ethanol, Isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),

• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyle sulphate, lecithin, phospholipids, fatty alcohols such as, for example, Lanette®, sorbitan fatty acid esters such as, for example, Span®, polyoxyethylene sorbitan fatty acid esters such as, for example, Tween®, polyoxyethylene fatty acid glycerides such as, for example, Cremophor®, polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers such as, for example, Pluronic®),

buffers and also acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine)

isotonicity agents (for example glucose, sodium chloride),

adsorbents (for example highly-disperse silicas)

viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidon, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine),

disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®),

flow regulators, lubricants, glidant and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas such as, for example, Aerosil®), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®),

capsule materials (for example gelatine, hydroxypropylmethylcellulose),

synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as, for example, Eudragit®, polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

penetration enhancers,

stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

flavourings, sweeteners, flavour- and/or odour-masking agents. The present invention further provides pharmaceutical compositions which comprise at least one of the solid forms of the compound of formula (I) according to the invention, preferably one solid form of the compound of formula (I) according to the invention, together with one or more, preferably inert, nontoxic, pharmaceutically suitable excipients, and the use thereof for the aforementioned purposes.

The present invention covers a pharmaceutical composition comprising Form A of the compound of formula (I) and optionally one or more pharmaceutically suitable excipient(s).

The present invention covers a pharmaceutical composition comprising Form B of the compound of formula (I) and optionally one or more pharmaceutically suitable excipient(s).

The present invention covers a pharmaceutical composition comprising Form C of the compound of formula (I) and optionally one or more pharmaceutically suitable excipient(s).

The present invention covers a pharmaceutical composition comprising Form D of the compound of formula (I) and optionally one or more pharmaceutically suitable excipient(s).

The present invention covers a pharmaceutical composition comprising Form E of the compound of formula (I) and optionally one or more pharmaceutically suitable excipient(s).

The present invention covers a pharmaceutical composition comprising Form F of the compound of formula (I) and optionally one or more pharmaceutically suitable excipient(s).

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative diseases by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered will generally range from about 0.001 mg kg to about 200 mg kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

In spite of this, it may be necessary to deviate from the amounts specified, specifically depending on body weight, administration route, individual behaviour towards the active ingredient, type of formulation, and time or interval of administration. For instance, less than the aforementioned minimum amount may be sufficient in some cases, while the upper limit mentioned has to be exceeded in other cases. In the case of administration of greater amounts, it may be advisable to divide them into several individual doses over the day.

The percentages in the tests and examples which follow are, unless indicated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

Experimental Section

Methods:

1. X-Ray Powder Diffraction (XRPD)

XRPD analyses were performed using a "X'Pert Pro" diffractometer from PANalytical B.V., Netherlands, equipped with a Cu X-ray tube emitting (radiation Cu K alpha 1, wavelength 1.5406 A), and a Pixcel detector system. The samples were analysed at 25°C in transmission mode and held between low density polyethylene films. The HighScore Plus software, version 2.2c, from PANalytical B.V. was used applying the following parameters: range 3 - 40° 2Θ, step size 0.013°, counting time 99 sec, ~ 22 min run time. All X-ray reflections are quoted as ° 2Θ (theta) values with a resolution of + 0.1°.

The diffraction peaks of Forms A, B and C are described in Table Al, the diffraction peaks greater of Pattern D Mixture and Pattern E Mixture than 10% relative intensity were described in Table A2.

2. Differential Scanning Calorimetry (DSC)

DSC analyses were carried out on a Perkin Elmer Jade Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminium pans (i.e. closed but not gas tight). Each sample was heated under nitrogen at a rate of 10°C/minute to a maximum of 300°C. Indium metal was used as the calibration standard.

3. ¾ Nuclear Magnetic Resonance spectroscopy (NMR)

NMR analysis was carried out on a Bruker 500MHz instrument in CDCI3.

4. Raman Spectroscopy

Raman analyses were performed using a Raman station Avalon Instruments, software version 5.4.3.4. Cyclohexane was the standard used to provide a reference spectrum prior to sample analysis (5 sec x 6 exposures). The preparation of each sample analysed by Raman is detailed below:

A small amount of each sample was placed into separate wells of a polypropylene 96 well plate. Each well was lined with a soft tin cap (5 x 8 mm) to improve signal and prevent interference from the well plate. The laser was centred on each well and automatically focused. Spectra were collected using an exposure of 5 sec x 5 exposures which produced good quality spectra without the causing any sample degradation. 5. FT-IR Spectroscopy

FT-IR analyses were performed using a Thermo Nicolet Avatar 370FT-IR instrument. FT-IR were presented using GRAMS/AI spectroscopy software version 8.00. The preparation of each sample analysed by FT-IR is detailed below:

A small amount of drug substance was placed onto the Golden Gate accessory (diamond crystal/ZnSe lens) and locked in place. The instrument parameters were as follows:

Number of sample scans: 16

Number of background scans: 16

- Resolution: 2.000

Sample gain: 8.0

- Mirror velocity: 0.6329

- Aperture: 100.00

- Range: 650 - 4000 cm ¹

Air background spectra were collected before analysis.

Examples

Example 1

Preparation of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-

5-yl)-l,7-naphthyridine - Form A a) Preparation of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-[l- (tetrahydro-2H-pyran-2-yl)- 1 H- razol-5-yl] - 1 ,7-naphthyridine :

2-[(3R)-3-methylmorpholin-4-yl]-8-[l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl]-l,7- naphthyridin-4-yl trifluoromethanesulfonate (90.0 g, 171 mmol) ("Intermediate- 10" as described in WO2016020320) was dissolved in 2250 mL cyclopentyl methyl ether. l-Methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (74.7 g, 341 mmol) was added followed by 260 mL aqueous potassium carbonate solution (2.0 M) and bis(triphenylphosphine)palladium(II)dichloride (12.0 g, 17.1 mmol). The reaction mixture was stirred under nitrogen at 110 °C for 3 hours (TLC control, ethyl acetate). After cooling the mixture was filtered over Celite^® and the filter cake was washed with cyclopentyl methyl ether. The solvent was evaporated in vacuo. The residue was suspended in a mixture of n-hexane/ethyl acetate (1 : 1) and passed through a plug of silicagel (n-hexane/ethyl acetate 1 : 1 -> ethyl acetate). The solvent was evaporated in vacuo and the darkgreen oil (78.4 g, 171 mmol, 100 % yield) was used without any further purification in the next step. b) Preparation of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5- yl)-l,7-naphthyridine - Form A:

2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-[l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-5-yl]-l,7-naphthyridine (78.4 g, 171 mmol) was dissolved in 340 mL methanol. 340 mL cone, aqueous HC1 solution (37 %) was added dropwise at room temperature and the reaction mixture was stirred 1 h at this temperature. After complete conversion (TLC control) 1500 mL 3M aqueous NaOH solution were added dropwise under cooling. The suspension was extracted twice with each 2000 mL dichloromethane. The combined organic phases were washed once with 2000 mL brine, dried over MgSC and the solvent was evaporated in vacuo. The residue was suspended in 150 mL acetonitrile and the suspension was filtered. The filter cake was washed with n-hexane and dried in vacuo at 50 °C yielding the title compound as a yellow solid (34.5 g, 91.9 mmol, 51 % yield). c) Characterisation of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH- pyrazol-5-yl)-l,7-naphthyridine Form A:

The XRPD pattern obtained for Form A is shown in Figure 1. The XRPD pattern is indicative of a crystalline material. Optical microscopy confirmed crystallinity showing birefringent irregularly shaped particles.

The DSC thermogram obtained for Form A at 10°C/min is shown in Figure 2. The ¾ NMR spectrum conformed to the molecular structure with a minimal amount of CH₂CI₂ detected: Peak [ppm] Intensity [rel]

1 12,8 0,37

2 8,42 3,18

3 8,41 3,31

4 7,73 1,95

5 7,73 1,93

6 7,67 3,29

7 7,67 3,27

8 7,34 2,25

9 7,34 2,17

10 7,26 15,63

11 7,17 3,19

12 7,17 4,95

13 7,16 3,61

14 6,46 3,67

15 6,45 3,59

16 5,3 0,31

17 4,44 0,46

18 4,43 0,48

19 4,43 0,47

20 4,42 0,47

21 4,2 0,57

22 4,19 0,61

23 4,18 0,66

24 4,17 0,66

25 4,05 0,57

26 4,04 0,59

27 4,02 0,64

28 4,02 0,63

29 3,94 0,84

30 3,92 1,63

31 3,88 1

32 3,87 0,98

33 3,85 0,52

34 3,85 0,5

35 3,75 0,56

36 3,74 0,75

37 3,74 19

38 3,73 0,96

39 3,72 0,83

40 3,7 0,67

41 3,7 0,58

42 3,6 0,53

43 3,59 0,56 44 3,57 0,81

45 3,56 0,78

46 3,55 0,39

47 3,54 0,35

48 1,58 11,25

49 1,48 5,08

50 1,46 5,01

51 0,07 0,69

52 0,01 0,6

53 0 15,64

54 -0,01 0,51

Figure 3 shows the FT-IR spectrum of Form A.

Figure 4 shows the Raman spectrum of Form A.

Example 2a

5-yl)-l,7-naphthyridine - Form B

Form B of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)- 1,7-naphthyridine was prepared according to Example 111 of International Patent Application WO2016020320.

Example 2b

5-yl)-l,7-naphthyridine - Form B

Approximately 40mg of Form A was added to an uncapped vial and placed into a heater block at 200 °C for ~ 5 minutes prior to cooling to ambient and analysis of the solid forms by XRPD. During this time the material appeared to melt and recrystallise. The resulting solids were analysed by XRPD (data not shown) and the diffractogram showed that the material had fully converted to Form B material. Example 2c

5-yl)-l,7-naphthyridine - Form B

Deprotection reaction

A reaction vessel was charged with a solution of (3R)-3-methyl-4-(4-(l-mefhyl-lH-pyrazolyl-5- yl)-8-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)-l,7-naphthyridin-2-yl)morpholine (4.0 g, 8.72 mmol) in dichloromethane (DCM) (20 ml). 2M Hydrochloric acid (20.06 ml, 40.1 mmol) (5.0 vol) was added to the stirring solution.

Work-up

The biphasic mixture was then vigorously stirred for an hour and the organic phase was separated. DCM (20 ml) and 2M NaOH (40 ml) were added to the aqueous phase. The organic phase was separated and the aqueous phase was extracted once more with DCM (20 ml). The organic phases were combined and washed with water (20 ml). The phases were separated and the organic solution was concentrated to dryness. 2-Propanol (20 ml) was added to the residue and the solvent was removed under reduced pressure. Isopropyl acetate (40 ml) was added and the mixture was stirred at 60 °C for lh. The solid was filtered off and dried in an oven at 40 °C for 18h.

Scale-up:

To scale-up the production of Form B material the deprotection reaction and the work-up described above were repeated on a larger scale using the same conditions as described above. Scale up of Form B material was carried out by dissolving about 7.0 g of 2-[(3R)-3- methylmorpholin-4-yl] -4-( 1 -methyl- 1 H-pyrazol-5-yl)-8-( 1 H-pyrazol-5-yl)- 1 ,7-naphthyridine in DCM (35 niL). Heptane (112 mL) was added dropwise and the slurry agitated for about 2 hours before isolation of the solids by filtration. The solids were dried in the vacuum oven at 40°C overnight.

The material received after scale -up was analysed by XRPD (Figure 5), ¾ NMR (see data below), DSC (Figure 6), FT-IR (Figure 7) and Raman (Figure 8). TG/DTA and optical microscopy were carried out on Form B material isolated during screening. The XRPD trace of Form B material shown in Figure 5 was indicative of crystalline material. Optical microscopy carried out on Form B material showed birefringent irregularly shaped particles.

TG/DTA analysis (data not shown) carried out on Form B material showed minimal weight loss of -0.8% (25 °C - 195 °C) indicating the material was an anhydrous form. The DSC thermogram (Figure 6) showed one endothermic melting effect, which indicates that the material was phase pure. The ¾ NMR spectrum conformed to the molecular structure and -0.09 molar equivalents of CH2CI2 was detected:

50 1,57 8,63

51 1,48 4,93

52 1,46 4,92

53 0,07 1,84

54 0,01 0,46

55 0,00 15,75

56 -0,01 0,50

Example 3

5-yl)-l,7-naphthyridine - Form C

Pattern C material was initially generated as a mixture with amorphous material by lyophilisation of Form A from dioxane (for further details see Example 4, first paragraph).

Stressing of this mixture at 98 % RH for 12 days caused a significant increase in the amount of Form C present. In a scale-up experiment Form C was finally prepared by lyophilisation of Form A (-160 mg) from dioxane (10 mL), followed by relative humidity ("RH") stressing at 98% RH for 12 days. XRPD analysis indicated Form C was a disordered polymorphic form, see Figure 9. The TG/DTA thermogram (data not shown) of Form C showed a gradual weight loss of -2.2% between 30°C-200°C. Two endothermic events were observed; the first small endothermic event is followed by a larger endothermic event. DSC analysis of Form C also showed two endothermic events (Figure 10).

The ¾ NMR spectrum conformed to the molecular structure with minimal solvent amount detected. It was noted that a broad NH peak at 12.8 ppm was present, but was not integrated.

15 4,2 0,55

16 4,19 0,6

17 4,18 0,64

18 4,17 0,64

19 4,05 0,55

20 4,04 0,59

21 4,02 0,63

22 4,02 0,64

23 3,94 0,81

24 3,92 1,59

25 3,88 0,95

26 3,87 0,96

27 3,85 0,5

28 3,74 0,63

29 3,74 19

30 3,73 0,96

31 3,72 0,85

32 3,7 1,48

33 3,7 0,58

34 3,6 0,54

35 3,59 0,58

36 3,57 0,82

37 3,56 0,8

38 1,48 5,07

39 1,46 5,02

40 0,07 2,58

41 0,01 0,64

42 0 20,92

43 -0,01 0,71

Figure 11 shows the FT-IR spectrum of Form C.

Figure 12 shows the Raman spectrum of Form C.

Example 4

Vapour and humidity stress

~ 15 mg of Form A was dissolved in dioxane (ImL), filtered through a 0.45μιη filter into an HPLC vial. The vial was rotated within a Dewar flask containing liquid nitrogen forming a frozen film on the inside of the vial. The vial was lyophilised under vacuum (0.4mbar) for -18 hours at 20°C. A sample was removed and analysed by XRPD. The material generated appeared to be a two phase mixture of XRD amorphous and disordered crystalline material. The crystalline material is Form C. The two phase mixture of this disordered (Form C) and amorphous material was exposed to air saturated in solvent vapour and various controlled humidity conditions for 7 days before analysis by XRPD. Form A material was also exposed to controlled humidity conditions. The results are shown in Table 2 below.

A number of solids were isolated from these experiments (see Table 2). Form C was obtained post humidity stressing of the two phase amorphous/disordered material (see also Example 3).

Form A material was stressed at 98 % RH and 40°C/75 % RH for 7 days. It did not show any conversion after this treatment.

Pattern D material was isolated as a mixture with Form B from a number of solvents (acetonitrile, dimethyl sulfoxide, ethyl acetate, methanol, isopropanol, and ethanol/water (96:4)). The XRPD sample was re-analysed the next day to assess if Pattern D was a metastable form. The solids showed no change in form, see XRPD's of Figure 13. ¾ NMR analysis of Pattern D material conformed to the molecular structure and no solvent was detected:

TG/DTA analysis (data not shown) showed a gradual weight loss of ~ 7.4 % between 25 °C and 205 °C and as there was no solvent detected in the ¾ NMR spectrum this can be equated to -1.6 molar equivalents of water. Pattern D material may be a hydrate but further analysis is required to confirm this designation.

Pattern E was isolated as a mixture with Form B material post vapour stressing amorphous/Pattern C material with toluene. Further analysis was run to ensure Pattern E was not a degradant. XRPD analysis was carried out on remaining solids and although the signal was weak it showed no change in form, the solids had remained as a mixture of Pattern E and Form B, see Fehler! Verweisquelle konnte nicht gefunden werden. 14. ¾ NMR analysis of this mixture conformed to the molecular structure and < 0.01 molar equivalents of toluene was detected:

32 3,87 0,91

33 3,85 0,49

34 3,85 0,47

35 3,75 0,52

36 3,74 0,61

37 3,74 19

38 3,73 0,89

39 3,72 0,81

40 3,7 2,05

41 3,7 0,53

42 3,6 0,51

43 3,59 0,56

44 3,57 0,8

45 3,56 0,73

46 3,55 0,38

47 3,54 0,33

48 2,35 0,83

49 1,54 10,9

50 1,48 4,9

51 1,46 4,83

52 0,12 0,34

53 0,01 3,07

54 0 102,5

55 -0,01 3,11

56 -0,12 0,36

TG/DTA analysis (data not shown) showed a weight loss of ~ 6.2 % between 25 - 200 °C which equates to 1.4 molar equivalents of water. Pattern E material may be a hydrate but further analysis is required to confirm this designation.

Table 2: Results from vapour and humidity stressing experiments

Amorphous + Pattern C toluene solid E + B

Amorphous + Pattern C Ethanol/water (96:4%v/v, A_w~0.25) solid B + D

Form A 98% H stress solid A

Form A 40°C/75% RH stress solid A

Amorphous + Pattern C 98% RH stress solid C

Amorphous + Pattern C 40°C/75% RH stress solid C

Example 5

Competitive slurry experiments

Preliminary interconversion experiments were carried out starting with suspensions of Form A and Form B material (50 : 50) in isopropanol (=ΓΡΑ). The experiments were carried out at 5 °C, 20 °C and 60 °C. Experiments at 20 and 60 °C were sampled after 7 and 14 days. After 7 days at 60 °C complete conversion to Form B was observed whereas at 22 °C the suspension still contained a mixture of Patterns A and B. After 14 days at 22 °C the experiment appeared to be moving towards Form B formation but the experiments at 5 °C still consisted of a 50 : 50 mixture of A + B.

These preliminary results shown in Table 3 indicated that Form B was the most stable form and given sufficient time Form A would convert to Form B.

Table 3: Competitive slurry experiments between Form A and Form B

Inter-conversion experiments involving suspensions of Form A were carried out in IPA and ΓΡΑ/water (86 : 14, % v/v) seeding with all relevant forms (Patterns A - E). The slurries were sampled at various time points and solids isolated were analysed by XRPD. The results are shown in Table 4. The results indicated that Form B material was the thermodynamically stable form at room temperature. A lot of mixtures were isolated probably due to slow kinetics of conversion to Form B and is also affected by solubility in the solvents used. Table 4: Competitive slurry experiments seeded with all forms

Example 6

Characterization of different solid forms by XRPD, FT-IR and Raman Spectroscopy

The solid forms of the present invention were characterized by XRPD, FT-IR and Raman spectroscopy according to the methods described above. The results are presented in Tables Al, A2, B, C, D and E.

Table Al: XRPD reflections listing (2Θ values) of Forms A, B and C

Form A Form B Form C

6,4 8,3 8,9

9,3 9,3 11,0

10,2 11,2 12,3

12,4 13,8 13,1

12,7 14,0 14,5 Form A Form B Form C

12,9 14,2 17,2

13,7 14,4 19,1

14,3 15,6 19,6

14,9 16,1 20,0

15,6 16,7 22,1

16,1 17,0 23,6

17,0 17,7 26,7

17,5 18,0 27,9

18,5 18,7 29,5

18,7 19,1 31,0

19,1 19,4

19,5 19,6

19,9 19,9

20,4 20,1

20,8 20,5

21,0 21,3

22,2 21,7

22,6 22,1

23,3 22,6

23,9 23,2

24,1 23,4

24,9 23,9

25,6 24,2

25,7 24,7

25,9 25,8

26,8 26,0

27,1 26,4

27,6 26,8

28,6 27,4

28,9 27,8

29,2 28,2

29,8 29,9

30,4 31,4

30,7 32,5

30,9 33,3

32,1 33,6

32,9 34,0

33,6 34,6

34,0 36,2

35,4 37,5

36,0 38,9

36,3 39,4

36,5

37,5

38,0

38,8

39,7 Table A2: XRPD reflections listing (2Θ values) of Pattern D Mixture and Pattern E Mixture

+ Characteristic reflections of pseudopolymorph D in Pattern D Mixture

** Characteristic reflections of pseudopolymorph E in Pattern E Mixture

Table B : Band listings for FT-IR analyses (cm ¹) of Form A, Form B and Form C

The error range was established to be as standard resolution at 4 cm^"1 and therefore the error range is + 2 cm ¹.

Form A Form B Form C

3744 3671 3280

3305 3305 2954

3137 2958 2854

2296 2850 2226

2258 2348 2186

2205 2234 2166

2187 2177 2050

2162 2167 2034

2119 2162 2022

2102 2086 1993

2093 2050 1984

2062 2038 1974

2050 2022 1717

2034 2015 1703

2014 1984 1613

1996 1614 1529

1984 1526 1499

1973 1507 1462

1966 1462 1434

1952 1433 1422

1679 1407 1396

1654 1385 1370

1650 1370 1271

1615 1328 1260 1527 1314 1216

1501 1266 1179

1462 1233 1141

1430 1207 1111

1406 1174 1098

1384 1138 1081

1372 1125 1069

1327 1100 1042

1313 1079 1026

1234 1060 1015

1224 1030 1001

1209 1012 979

1177 997 954

1139 976 930

1127 953 912

1099 927 880

1081 909 873

1068 882 837

1059 866 814

1027 852 791

1009 813 756

976 795 734

952 755 721

926 747 714

905 730 702

900 712 697

861 706 675

852 674 662

809 659 657

796

778

768

757

748

722

702

674

654

Table C: Most intense FT-IR bands (cm ¹) of Form A, Form and Form C

Table D : Band listings (cm ¹) for Raman analyses of Form A, Form B and Form C

527 591 759

512 567 703

472 557 676

462 544 661

444 524 649

421 511 639

389 473 591

354 459 558

329 449 521

273 423 512

255 413 460

208 390 445

173 351 419

118 325 384

287 357

271 323

249 289

192 279

175 250

129 206

113 194

181

117

Table E: Most intense Raman bands (cm ¹) of Form A, Form B and Form C

Example 7

Metabolism in vitro of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH- pyrazol-5-yl)- 1,7-naphthyridine

Test compound: 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH-pyrazol-5-yl)- 1 ,7 -naphthyridine

Test material: hepatocytes of Wistar rat, Beagle dog and human The in vitro metabolism of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH- pyrazol-5-yl)-l,7-naphfhyridine was investigated in human, rat and dog hepatocyte suspensions at 10 μΜ over 4h with 1 * 10^A6 cells per 1 mL incubation volume. Time points were taken at 0, 1, 2 and 4h.

The identified metabolic pathways in human hepatocytes were mainly various oxidations at the methylmorpholine moiety forming the metabolites M-l to M-8 (see Figure 15). In addition, dealkylation at the morpholine moiety to M-5 and direct glucuronidation of drug to M-l 0 and M-11 were observed (see Figure 15. In addition, several secondary metabolites of the oxidation at the morpholine moiety were seen, for example conjugates with glucuronic acid (M-l 2, M-l 3) (see Figure 15.

The metabolic pathways of 2-[(3R)-3-methylmorpholin-4-yl]-4-(l-methyl-lH-pyrazol-5-yl)-8-(lH- pyrazol-5-yl)-l,7-naphthyridine were highly comparable between all investigated species.

Explorative metabolite analysis in mouse plasma exhibited the highest MS response for M-5 relative to the signal of unchanged drug. Formation of the oxidative metabolites M-l, M-2, M-3, M-6, M-7 and M-8 was also observed, but with lower signal intensities. In rat plasma, formation of metabolites M-l to M-5 was detected.

Claims

A solid form of the compound of formula (I)

(I) selected from its amorphous form, Form A, Form B, Form C, Form D, Form E, Pattern D Mixture, Pattern E Mixture, or a mixture thereof.

2. The compound of claim 1, which is Form A of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 19.1.

3. The compound of claim 1, which is Form A of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 16.1, 17.0, 19.1.

4. The compound of claim 1, which is Form A of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 16.1, 17.0, 19.1, 24.9, 25.9.

5. The compound of claim 1, which is Form A of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 14.3, 16.1, 17.0, 19.1, 24.9, 25.9.

6. The compound of claim 1, which is Form A of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 6.4, 9.3, 12.4, 12.9, 14.3, 15.6, 16.1, 17.0, 19.1, 19.9, 22.6, 24.9, 25.6, 25.7, 25.9.

7. The compound of claim 1, which is Form A of the compound of formula (I) and which is characterized by the X-ray powder diffractogram substantially as shown in Figure 1.

8. The compound of claim 1, which is Form B of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 18.0, 19.9.

9. The compound of claim 1, which is Form B of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 9.3, 18.0, 19.9, 20.1.

10. The compound of claim 1, which is Form B of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 9.3, 13.8, 14.0, 18.0, 19.9, 20.1.

11. The compound of claim 1, which is Form B of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 9.3, 13.8, 14.0, 18.0, 18.7, 19.6, 19.9, 20.1, 27.4.

12. The compound of claim 1, which is Form B of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.3, 9.3, 13.8, 14.0, 18.0, 18.7, 19.6, 19.9, 20.1, 22.1, 23.9, 27.4.

13. The compound of claim 1, which is Form B of the compound of formula (I) and which is characterized by the X-ray powder diffractogram substantially as shown in Figure 5.

14. The compound of claim 1, which is Form C of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.9, 13.1, 23.6.

15. The compound of claim 1, which is Form C of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.9, 12.3, 13.1, 20.0, 23.6.

16. The compound of claim 1, which is Form C of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.9, 12.3, 13.1, 14.5, 19.6, 20.0, 23.6.

17. The compound of claim 1, which is Form C of the compound of formula (I) and which is characterized by the X-ray powder diffractogram substantially as shown in Figure 9.

18. The compound of claim 1, which is Form D or Pattern D Mixture of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 9.0, 21.5, 23.8.

19. The compound of claim 1, which is Form D or Pattern D Mixture of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 9.0, 10.5, 12.1, 21.5, 23.8.

20. The compound of claim 1, which is Form D or Pattern D Mixture of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising quoted as 2Θ values: 9.0, 10.5, 12.1, 12.9, 15.1, 21.5, 23.8.

21. The compound of claim 1, which is Pattern D Mixture of the compound of formula (I) and which is characterized by the X-ray powder diffractogram substantially as shown in Figure 13.

22. The compound of claim 1, which is Form E or Pattern E Mixture of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.8, 12.3, 12.6.

23. The compound of claim 1, which is From E or Pattern E Mixture of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.8, 9.0, 12.3, 12.6, 19.0.

24. The compound of claim 1, which is Form E or Pattern E Mixture of the compound of formula (I) and which is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2Θ values: 8.8, 9.0, 12.3, 12.6, 19.0, 19.5.

25. The compound of claim 1, which is Pattern E Mixture of the compound of formula (I) and which is characterized by the X-ray powder diffractogram substantially as shown in Figure 14.

26. A pharmaceutical composition comprising Form A of the compound of the formula (I) according to any one of claims 2 to 7.

27. A pharmaceutical composition according to claim 26 comprising Form A and no significant fractions of another solid form of the compound of formula (I).

28. A pharmaceutical composition comprising Form B of the compound of the formula (I) according to any one of claims 8 to 13.

29. A pharmaceutical composition of claim 28 comprising Form B and no significant fractions of another solid form of the compound of formula (I).

30. A pharmaceutical composition comprising Form C of the compound of the formula (I) according to any one of claims 14 to 17.

31. A pharmaceutical composition of claim 30 comprising Form C and no significant fractions of another solid form of the compound of formula (I).

32. A pharmaceutical composition comprising Form D or Pattern D Mixture of the compound of the formula (I) according to any one of claims 18 to 21.

33. A pharmaceutical composition of claim 32 comprising Form D and no significant fractions of another solid form of the compound of formula (I).

34. A pharmaceutical composition comprising Form E or Pattern E Mixture of the compound of the formula (I) according to any one of claims 22 to 25.

35. A pharmaceutical composition comprising Form A of the compound of formula (I) according to any one of claims 2 to 7 and Form B of the compound of formula (I) according to any one of claims 8 to 13 and optionally no other solid form of the compound of the formula (I).

36. A pharmaceutical composition of any of claims 26 to 35 comprising one or more pharmaceutically suitable excipient(s).