EA046114B1 - ATR KINASE INHIBITOR BAY 1895344 FOR USE IN THE TREATMENT OF HYPERPROLIFERATIVE DISEASE - Google Patents

Description

The present invention relates to an ATR kinase inhibitor, 2-[(3R)-3-methylmorpholin-4-yl]-4-(1methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine, for use in the treatment of a hyperproliferative disease, which is characterized in that said compound of formula (I) is administered in an amount of 60 mg twice a day and the dosage regimen is 3 days on/11 days off, or 70 mg twice a day day and the dosage regimen is 3 days on/11 days off, or 80 mg twice a day and the dosage regimen is 3 days on/11 days off.

Prerequisites for creating the invention

2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine is is a compound of formula (I)

(I).

It is also known as BAY 1895344 and is an ATR kinase inhibitor that can be used to treat hyperproliferative diseases. The synthesis of this compound is described in international patent publication WO 2016/020320, in particular in example 111.

In accordance with the clinical trial protocol and based on data obtained in in vivo experiments following administration of BAY 1895344 to mice, rats and dogs, and based on in vitro data regarding plasma binding protein and blood/plasma partitioning, the effective dose in humans is greater than 300 mg BID , 3 days on/4 days off, meaning a dose of more than 600 mg per day, was evaluated at the start of clinical trials with BAY 1895344.

One object of the invention is to determine one or more daily doses, as well as dosage regimens, of a compound of formula (I) that are suitable for the treatment of one or more hyperproliferative diseases. Another object of the invention is to identify pharmaceutical compositions containing a compound of formula (I) that can be used for such treatment.

Despite the progress described in the art with regard to kinase inhibitors, there remains a need for improved pharmaceutical compositions for the treatment of hyperproliferative diseases, in particular pharmaceutical compositions that are suitable for oral administration to improve patient compliance.

The release profile of the pharmaceutical composition must translate into plasma levels of the active ingredient that are sufficient for effective therapy. Because the physicochemical properties of active ingredients vary widely, the types and amounts of excipients to formulate a pharmaceutical composition that is actually suitable for achieving the required plasma levels of a particular active ingredient are usually unpredictable.

In addition to the dissolution properties, the chemical and mechanical stability of the pharmaceutical composition is important.

Finally, it is important that the production method allows large-scale production of the pharmaceutical composition with high product quality.

Development of a reproducible, large-scale (>2 kg) GMP process for the production of a pharmaceutical composition that contains a compound of formula (I) has proven difficult. During the scale-up of GMP production to the 2 kg scale, pharmaceutical compositions that contain the compound of formula (I) encountered various problems such as flow and compaction problems, especially during tabletting (see Experimental section below for details).

Therefore, another object of the present invention is to provide a method for the production of a pharmaceutical composition which contains a compound of formula (I), which allows the said pharmaceutical composition to be produced, in particular on a scale >2 kg.

Description of the invention

Connection for application

According to a first aspect, the present invention relates to the use of 2-[(3R)-3methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5- yl)-1,7-naphthyridine for the treatment of a hyperproliferative disease, which is characterized in that the specified compound is administered in an amount of 60 mg twice a day and the dosage regimen is 3 days on / 11 days off, or 70 mg twice a day and the dosage regimen is 3 days on/11 days off, or 80 mg twice a day and the dosage regimen is 3 days on/11 days off.

It is very surprising that the effective human dose between 40 and 80 mg BID was more than 3 times (80 mg BID) and up to more than 7 times (40 mg BID) lower than the estimated effective dose, which is more than 300 mg BID, with regimen of 3 days on/4 days off, which was assumed at launch

- 1 046114 clinical trials of compound (I). This very significant difference between the calculated and actual dose could not be predicted and is very unexpected from the point of view of preclinical pharmacokinetic data.

2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-III-pyrazol-5-yl)-8-(III-pyrazol-5-yl)-1,7-naphthyridine is is a compound of formula (I)

The compound of formula (I) may exist as a tautomer of formula (Ia)

The compound of formula (I) may exist in various solid forms, which are described in international patent publication WO 2018/153970. The preferred polymorphic forms are called

Form A and Form B. The most preferred is Form B. Methods for preparing various solid forms of compound (I), such as, for example, Form A and Form B, are described in international patent publication WO 2018/153970. Methods for preparing the preferred Form B are described in example 111 of international patent publication WO 2016/020320A1 and in international patent publication WO 2018/153970.

In accordance with an embodiment of the first aspect of the invention (Compound for Use), Form A of the compound of formula (I) is administered. An X-ray powder diffraction pattern of Form A of the compound of formula (I) is shown in FIG. 1.

According to a preferred embodiment of the first aspect of the invention, Form B of the compound of formula (I) is administered. An X-ray powder diffraction pattern of Form B of the compound of formula (I) is shown in FIG. 2.

The compound of formula (I) may exist as a solvate, especially as a hydrate.

In addition, the compound of formula (I) may exist in the form of a salt. Said salt may be any salt, either an organic or an inorganic addition salt, especially any pharmaceutically acceptable salt commonly used in pharmaceuticals.

The term pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of formula (I). For example, see S. M. Berge, et al. Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19. A suitable pharmaceutically acceptable salt of the compound of formula (I) may be, for example, an acid addition salt of the compound (I), such as an acid addition salt with an inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, disulfuric, phosphoric or nitric acid, for example, or with an organic acid such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3hydroxy -2-naphthoic, nicotinic, pamoic, pectic, persulfuric, 3-phenylpropionic, picric, beer, 2-hydroxyethanesulfonic, itaconic acid, sulfamic acid, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalene sulfonic, naphthalene disulfonic , camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric or thiocyanic acid, for example . Preferred is the acid addition salt of the compound of formula (I) with hydrochloric acid.

The compound of formula (I) or its tautomer, solvate (eg, hydrate), pharmaceutically acceptable salt, or any of the solid forms of the compound of formula (I) can be used in micronized form. Micronization can be achieved by standard grinding methods.

The term hyperproliferative disease includes, but is not limited to, psoriasis, keloids and other skin hyperplasias, benign prostatic hyperplasia (BPH), solid tumors such as cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye , liver, skin, head and neck, thyroid gland, parathyroid gland, and their distant metastases.

The term hyperproliferative disease also includes lymphomas, sarcomas and leukemia.

- 2 046114

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 respiratory tract cancers 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 cancer include, but are not limited to, brainstem and hypophthalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, and neuroectodermal and pineal tumors.

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 cancers, as well as uterine sarcoma.

Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, stomach, pancreas, rectum, small intestine, and salivary gland cancers.

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

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

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (carcinoma of the intrahepatic bile duct), 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, lip and oral cavity, and squamous cell cancers.

Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcoma, 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 are well characterized in humans but also exist with similar etiologies in other mammals and can be treated by administration of the pharmaceutical composition of the present invention.

Hyperproliferative disease may be characterized by one or more defects in the DNA damage response (DDR) mechanism. In particular, a hyperproliferative disease may be characterized by one or more biomarkers that have been described in international patent publication WO 2018/153968, which is incorporated herein by reference. In particular, a hyperproliferative disease may be characterized by one or more deleterious mutations in one or more genes and/or proteins, as detailed in WO 2018/153968. Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the ATM gene and/or the BRCA1 gene and/or the ATM protein and/or the BRCA1 protein.

In addition, a hyperproliferative disease may be characterized by one or more deleterious mutations in the ATM gene, and/or the BRCA1 gene, and/or the BRCA2 gene, and/or the PALB2 gene, and/or the ARIDIA gene, and/or loss of the ATM protein.

Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the ATM gene, and/or the BRCA1 gene, and/or the BRCA2 gene, and/or loss of the ATM protein.

Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the ATM gene.

Preferably, the hyperproliferative disease is characterized by loss of the ATM protein.

Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the ATM gene and loss of the ATM protein.

Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the BRCA1 gene.

Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the BRCA2 gene.

In addition, a hyperproliferative disease may be characterized by one or more deleterious mutations in the PALB2 gene.

In addition, a hyperproliferative disorder may be characterized by one or more deleterious mutations in the ARID1A gene.

- 3 046114

The term deleterious mutation as used herein means a mutation of a gene that has a deleterious effect on the function of the gene or on the function of its corresponding RNA or its corresponding protein.

For example, a deleterious mutation of a gene may result in a decrease in the expression level of the gene, or a reduced amount of protein, especially loss of protein, or a decrease in the activity of the protein that corresponds to the gene, or non-functionality of the gene/protein (loss of function) compared to the corresponding wild type genome/protein.

Examples of a deleterious mutation include, but are not limited to:

The deleterious mutation may be a nonsense mutation, which is a point mutation in the corresponding gene, resulting in a premature stop codon or nonsense codon in the transcribed mRNA, and a processed, incomplete and non-functional protein that corresponds to the corresponding gene.

The deleterious mutation may be a missense mutation, which is a point mutation in the corresponding gene resulting in the production of either a non-functional protein (complete loss of function) or a protein with partial loss of function compared to the corresponding wild-type protein.

A deleterious mutation can also lead to a frameshift mutation, which is a genetic mutation in the corresponding gene caused by insertions or deletions of one or more nucleotides in such a gene, where the number of nucleotides is not divisible by three, and results in a (sometimes processed) non-functional protein. which corresponds to the corresponding gene.

A deleterious mutation may also be a large rearrangement mutation, such as a deletion of one or more exons that disrupts the reading frame or critical functional domain of the corresponding protein. Another example of a large rearrangement mutation is the duplication of one or more non-terminal exons that disrupts the reading frame or critical functional domain of the corresponding protein.

The deleterious mutation may also be a splice site mutation, which is a genetic mutation that inserts, deletes, or changes a number of nucleotides at a specific splicing site during the processing of precursor messenger RNA into mature messenger RNA. Consensus splice site sequences that govern exon recognition are located at the very ends of introns. Removal of a splice site leaves one or more introns in the mature mRNA, resulting in the production of a nonfunctional protein that corresponds to the corresponding gene.

A deleterious mutation can also be a copy number variant (CNV), especially a decrease in the number of copies of a gene (eg, homozygous or heterozygous deletion) compared to the normal copy number of the corresponding gene.

For example, deleterious mutation(s) in the ATM gene and/or ATM protein may result in loss of ATM protein and/or loss of ATM function. For example, deleterious mutation(s) in the BRCA1 gene and/or BRCA1 protein may result in loss of BRCA1 protein and/or loss of BRCA1 function.

Methods for detecting one or more deleterious mutations, for example in the ATM or BRCA1 or BRCA2 or PALB2 or ARID 1A gene and/or in the ATM or BRCA1 or BRCA2 or PALB2 or ARIDIA protein, are known to those skilled in the art and are described, for example, in WO2018 /153968, which is incorporated herein by reference.

According to an embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 160 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID). Preferably, it is administered twice daily (BID), which means that 80 mg is administered to the patient twice a day, for example the first dose of 80 mg in the morning and the second dose of 80 mg in the evening. Most preferably, the compound of formula (I) is administered twice daily (BID) every 12 ± 1 hour.

In accordance with an embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 80 mg (BID) and the dosage regimen is 3 days on/11 days off. In other words, in this embodiment, the dosing regimen is 3 days on/4 days off for one week, followed by a week off without treatment.

According to a preferred embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 80 mg (BID) and the dosage regimen is 3 days on/11 days off.

According to an embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 140 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID). Preferably, it is administered twice daily (BID), which means that 70 mg is administered to the patient twice a day, for example the first dose of 70 mg in the morning and the second dose of 70 mg in the evening. Most preferably, the compound of formula (I) is administered twice daily (BID) every 12 ± 1 hour.

In accordance with an embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 70 mg (BID) and the dosage regimen is 3 days on/11 days off

- 4 046114 va. In other words, in this embodiment, the dosing regimen is 3 days on/4 days off for one week, followed by a week off without treatment.

According to an embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 120 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID). Preferably, it is administered twice daily (BID), which means that 60 mg is administered to the patient twice a day, for example the first dose of 60 mg in the morning and the second dose of 60 mg in the evening. Most preferably, the compound of formula (I) is administered twice daily (BID) every 12 ± 1 hour.

In accordance with an embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 60 mg (BID) and the dosage regimen is 3 days on/11 days off. In other words, in this embodiment, the dosing regimen is 3 days on/4 days off for one week, followed by a week off without treatment.

According to a preferred embodiment of the first aspect of the invention, the compound of formula (I) is administered in an amount of 60 mg (BID) and the dosage regimen is 3 days on/11 days off.

According to an embodiment of the first aspect, a compound for use according to the invention is characterized in that the compound of formula (I) is in the form of a pharmaceutical composition containing said compound of formula (I) together with at least one pharmaceutically acceptable excipient.

The term pharmaceutically acceptable excipient means any excipient that is relatively non-toxic and harmless to the patient in concentrations consistent with the effective action of the active ingredient, a compound of formula (I), such that any side effects attributable to the excipient do not interfere with the beneficial effect of the active ingredient .

Pharmaceutically acceptable excipients in the context of the present invention are, for example, fillers, disintegrants, lubricants, glidants, coating agents.

According to an embodiment of the first aspect, a compound for use according to the invention is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of 3 to 25% by weight, preferably in an amount of 4 to 22% by weight, most preferably in an amount of 5 to 20% by weight.

According to an embodiment of the first aspect, a compound for use according to the invention is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of 3 to 25%, preferably in an amount of 4 to 22%, most preferably in an amount of 5 to 20% by weight, and the pharmaceutical composition contains a glidant. Preferably, the pharmaceutical composition contains colloidal silicon dioxide (as a glidant).

According to an embodiment of the first aspect, a compound for use according to the invention is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 20% by weight of the pharmaceutical composition and the pharmaceutical composition contains a glidant. Preferably, the pharmaceutical composition contains colloidal silicon dioxide (as a glidant).

The term glidant refers to a pharmaceutically acceptable excipient that is added to a pharmaceutical composition to improve granulate flow by reducing interparticle friction. It includes pharmaceutically acceptable excipients such as colloidal silicon dioxide. The preferred glidant is colloidal silica. Colloidal silicon dioxide may have a specific surface area of 50 to 600 m ² -g ^-1 , preferably a specific surface area of 100 to 300 m ² -g ^-1 , most preferably 175 to 225 m ² -g

According to an embodiment of the first aspect, a compound for use according to the invention is characterized in that the pharmaceutical composition contains lactose, preferably lactose monohydrate, most preferably spray-dried lactose monohydrate. Spray-dried lactose monohydrate preferably has a particle size distribution where 10% of the particles have a size of 30 to 70 μm, 50% of the particles have a size of 100 to 140 μm, and 90% of the particles have a size of 200 to 240 μm. The particle size distribution of spray-dried lactose monohydrate can be determined using laser diffraction.

According to an embodiment of the first aspect, a compound for use according to the invention is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 80 mg and at least one pharmaceutically acceptable excipient.

According to an embodiment of the first aspect, a compound for use according to

- 5 046114 In connection with the invention, it is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 70 mg and at least one pharmaceutically acceptable excipient.

According to an embodiment of the first aspect, a compound for use according to the invention is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 60 mg and at least one pharmaceutically acceptable excipient.

Pharmaceutical composition

Specified formula compound! (I) is administered in the form of a pharmaceutical composition which contains a compound of formula (I) in an amount of 80, 70 or 60 mg and at least one pharmaceutically acceptable excipient.

Preferably, the pharmaceutical composition contains a compound of formula (I) in an amount of 80 mg.

Preferably, the pharmaceutical composition contains a compound of formula (I) in an amount of 70 mg.

Preferably, the pharmaceutical composition contains a compound of formula (I) in an amount of 60 mg.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of from 15 to 25%, preferably in an amount of from 18 up to 22%, most preferably in an amount of 20 wt.%.

Preferably, the pharmaceutical composition according to the invention contains a compound of the formula! (I) in an amount of 3 to 10%, preferably in an amount of 4 to 8%.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of from 15 to 25%, preferably in an amount of from 18 up to 22%, most preferably in an amount of 20 wt.%, and the pharmaceutical composition contains a glidant such as colloidal silicon dioxide. The preferred glidant is colloidal silica.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 3 to 10%, preferably in an amount of 4 to 8%, and the pharmaceutical composition contains a glidant such as colloidal silicon dioxide. The preferred glidant is colloidal silica.

Preferably, the pharmaceutical composition according to the invention contains lactose, especially lactose monohydrate or lactose anhydrate, preferably spray-dried lactose monohydrate.

A particularly preferred particle size distribution of spray-dried lactose monohydrate is described above.

Preferably, the pharmaceutical composition according to the invention contains a compound of the formula! (I) in an amount from 5 to 25%, one or more fillers in an amount from 70 to 90%, one or more lubricants in an amount from 0.5 to 3%, one or more disintegrants in an amount from 2 to 10% and one or more several glidants in an amount from 0.2 to 1 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 15 to 23%, one or more excipients in an amount of 70 to 85%, one or more lubricants in an amount of 0.5 to 2%, one or more disintegrants in an amount from 2.5 to 7% and one or more glidants in an amount from 0.3 to 0.8 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 17 to 22%, one or more excipients in an amount of 73 to 82%, one or more lubricants in an amount of 0.7 to 1.5%, one or more disintegrants in an amount from 3 to 6% and one or more glidants in an amount from 0.4 to 0.6 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 3 to 10%, one or more excipients in an amount of 85 to 92%, one or more lubricants in an amount of 0.5 to 3%, one or more disintegrants in an amount from 2 to 10% and one or more glidants in an amount from 0.2 to 1 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 4 to 8%, one or more excipients in an amount of 87 to 91%, one or more lubricants in an amount of 0.5 to 3%, one or more disintegrants in an amount from 2 to 10% and one or more glidants in an amount from 0.2 to 1 wt.% of the pharmaceutical composition.

The term excipient refers to a pharmaceutically acceptable excipient,

- 6 046114 which is added to a pharmaceutical composition to increase volume and/or weight. It includes pharmaceutically acceptable excipients such as microcrystalline cellulose and/or lactose.

Preferably the filler is microcrystalline cellulose and/or lactose, especially lactose monohydrate, preferably spray-dried lactose monohydrate, or the filler is a mixture of two or more fillers, such as a mixture of microcrystalline cellulose and lactose, especially a mixture of microcrystalline cellulose and lactose monohydrate, preferably a mixture of microcrystalline cellulose and lactose. cellulose and spray-dried lactose monohydrate. A particularly preferred particle size distribution of spray-dried lactose monohydrate is described above.

Preferably, the pharmaceutical composition according to the invention contains one or more excipients in an amount of from 65 to 90% by weight of the pharmaceutical composition, preferably in an amount from 70 to 85%, most preferably in an amount from 73 to 77%.

Preferably, the pharmaceutical composition according to the invention contains one or more excipients in an amount of from 65 to 92% by weight of the pharmaceutical composition, preferably in an amount from 70 to 92%, most preferably in an amount from 73 to 91%.

The term lubricant refers to a pharmaceutically acceptable excipient that is added to a pharmaceutical composition to reduce friction, heat and wear when administered between hard surfaces. It includes pharmaceutically acceptable excipients such as magnesium stearate. Preferably the lubricant is magnesium stearate.

Preferably, the pharmaceutical composition according to the invention contains one or more lubricants in an amount of 0.5 to 3% by weight of the pharmaceutical composition, preferably in an amount of 0.6 to 2%, most preferably in an amount of 0.8 to 1.2%.

The term disintegrant refers to a pharmaceutically acceptable excipient that is added to a pharmaceutical composition to cause breakdown (disintegration) to support the release of the active ingredient from the pharmaceutical composition. It includes pharmaceutically acceptable excipients such as croscarmellose sodium, croscarmellose sodium being preferred.

Preferably, the pharmaceutical composition according to the invention contains one or more disintegrants in an amount of 2 to 10% by weight of the pharmaceutical composition, preferably in an amount of 2.5 to 6%, most preferably in an amount of 3 to 5%.

The term glidant is defined above.

Preferably, the pharmaceutical composition according to the invention contains one or more glidants in an amount of 0.2 to 1% by weight of the pharmaceutical composition, preferably in an amount of 0.3 to 0.8%, most preferably in an amount of 0.4 to 0.6%.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount from 5 to 25%, microcrystalline cellulose (as a first filler) in an amount from 40 to 51%, lactose monohydrate (as a second filler) in an amount from 30 to 51%. 38%, magnesium stearate (as a lubricant) in an amount from 0.5 to 2%, croscarmellose sodium (as a disintegrant) in an amount from 2 to 8% and colloidal silicon dioxide (as a glidant) in an amount from 0.2 to 0.8 wt. % pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount from 10 to 24%, microcrystalline cellulose (as a first filler) in an amount from 41 to 49%, lactose monohydrate (as a second filler) in an amount from 30 to 49%. 36%, magnesium stearate (as a lubricant) in an amount from 0.5 to 2%, croscarmellose sodium (as a disintegrant) in an amount from 2 to 8% and colloidal silicon dioxide (as a glidant) in an amount from 0.2 to 0.8 wt. % pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount from 13 to 23%, microcrystalline cellulose (as a first filler) in an amount from 41 to 47%, lactose monohydrate (as a second filler) in an amount from 30 to 47%. 35%, magnesium stearate (as a lubricant) in an amount from 0.5 to 2%, croscarmellose sodium (as a disintegrant) in an amount from 2 to 8% and colloidal silicon dioxide (as a glidant) in an amount from 0.2 to 0.8 wt. % pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount from 16 to 22%, microcrystalline cellulose (as a first filler) in an amount from 42 to 45%, lactose monohydrate (as a second filler) in an amount from 31 to 45%. 33%, magnesium stearate (as a lubricant) in an amount from 0.5 to 2%, croscarmellose sodium (as a disintegrant) in an amount from 2 to 8% and colloidal silicon dioxide (as a glidant) in an amount from 0.2 to 0.8 wt. % pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 19 to 21%, microcrystalline cellulose (as the first

- 7 046114 filler) in an amount from 42 to 43%, lactose monohydrate (as a second filler) in an amount from 31 to 32%, magnesium stearate (as a lubricant) in an amount from 0.5 to 2%, croscarmellose sodium (as disintegrant) in an amount from 2 to 8% and colloidal silicon dioxide (as a glidant) in an amount from 0.2 to 0.8 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 20%, microcrystalline cellulose (as a first filler) in an amount of 42.8%, lactose monohydrate (as a second filler) in an amount of 31.7%, magnesium stearate (as a lubricant) in an amount of 1%, croscarmellose sodium (as a disintegrant) in an amount of 4% and colloidal silicon dioxide (as a glidant) in an amount of 0.5 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount from 19 to 21%, microcrystalline cellulose (as a first filler) in an amount from 42 to 43%, lactose monohydrate (as a second filler) in an amount from 31 to 43%. 32%, magnesium stearate (as a lubricant) in an amount from 1.1 to 1.5%, croscarmellose sodium (as a disintegrant) in an amount from 2 to 8% and colloidal silicon dioxide (as a glidant) in an amount from 0.2 to 0.8 wt. % pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 20%, microcrystalline cellulose (as a first filler) in an amount of 42.7%, lactose monohydrate (as a second filler) in an amount of 31.7%, magnesium stearate (as a lubricant) in an amount of 1.1%, croscarmellose sodium (as a disintegrant) in an amount of 4% and colloidal silicon dioxide (as a glidant) in an amount of 0.5 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 20%, microcrystalline cellulose (as a first filler) in an amount of 42.5%, lactose monohydrate (as a second filler) in an amount of 31.7%, magnesium stearate (as a lubricant) in an amount of 1.3%, croscarmellose sodium (as a disintegrant) in an amount of 4% and colloidal silicon dioxide (as a glidant) in an amount of 0.5 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention contains a compound of formula (I) in an amount of 20%, microcrystalline cellulose (as a first filler) in an amount of 42.3%, lactose monohydrate (as a second filler) in an amount of 31.7%, magnesium stearate (as a lubricant) in an amount of 1.5%, croscarmellose sodium (as a disintegrant) in an amount of 4% and colloidal silicon dioxide (as a glidant) in an amount of 0.5 wt.% of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention is used for oral administration.

Preferably, the pharmaceutical composition according to the invention is a solid oral dosage form.

The term solid oral dosage form includes granules, pellets, tablets, dragees, pills, melts, capsules or solid dispersions. Preferably, the solid oral dosage form is selected from tablets (coated or uncoated), pellets and granules. The most preferred solid oral dosage form is a tablet.

Preferably, the pharmaceutical composition according to the invention may be an uncoated tablet or a coated tablet.

Typical pharmaceutically acceptable tablet coating agents are hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, sucrose, liquid glucose, ethylcellulose, cellulose acetate phthalate, polyethylene glycol and shellac. The coating agents may be mixed with other applicable coating agents, or commercially available ready-to-use coating mixtures may be used, such as, for example, OpadryTM 14F150002.

Preferably the tablet is coated with a mixture of hypromellose, polyethylene glycol, titanium dioxide, iron oxide, preferably red iron oxide, most preferably red Fe2O3. commercially available, for example, as Opadry 14F150002.

Preferably, the pharmaceutical composition according to the invention is an immediate release tablet.

The pharmaceutical composition according to the invention exhibits good release properties. Moreover, preference is given to dosage forms where the compound of formula (I) is rapidly released, also known as immediate release dosage forms. The term immediate release dosage form refers to a release dosage form having a Q-value (45 min) of 75%, where the Q-value is determined in accordance with the USP method of release, section <711> (USP 41-NF 36) using a device USP 2 (paddle device).

- 8 046114

Preferably a pharmaceutical composition in accordance with the 10 mg tablet described in example 1, paragraph 1.1.

Preferably a pharmaceutical composition in accordance with the 20 mg tablet described in example 1, paragraph 1.1.

Preferably a pharmaceutical composition in accordance with the 40 mg tablet described in example 1, paragraph 1.1.

Preferably a pharmaceutical composition in accordance with the 40 mg tablet (Tablet D) described in example 4.

Preferably a pharmaceutical composition in accordance with the 40 mg tablet (Tablet E) described in example 4.

Preferably a pharmaceutical composition in accordance with the 40 mg tablet (Tablet F) described in example 4.

Preferably the pharmaceutical composition is in accordance with the 60 mg tablet described in example 3.

Preferably the pharmaceutical composition is in accordance with the 80 mg tablet described in example 3.

Method of treatment according to the invention represents with the invention represents with the invention represents with the invention represents with the invention represents with the invention represents with the invention represents with the invention represents with the invention represents with Also, a method for treating a hyperproliferative disease may be considered which includes administering a compound of formula (I) in an amount of 10 to 160 mg per day to the patient, especially in an amount of 60 mg to 160 mg per day, preferably in an amount of 80 to 160 mg per day.

A patient for the purposes of the present invention is a mammal, especially a human, in need of treatment for a particular hyperproliferative disease. The patient and/or hyperproliferative disease may be characterized by one or more defects in the DNA damage response (DDR) mechanism. In particular, the patient and/or hyperproliferative disease may be characterized by one or more biomarkers that have been described in international patent publication WO 2018/153968, which is incorporated herein by reference.

In particular, the patient and/or hyperproliferative disease may be characterized by one or more deleterious mutations in one or more genes and/or proteins, further described in WO 2018/153968. Preferably, the patient and/or hyperproliferative disease is characterized by one or more deleterious mutations in the ATM gene and/or the BRCA1 gene and/or the ATM protein and/or the BRCA1 protein.

For example, deleterious mutation(s) in the ATM gene and/or ATM protein may result in loss of ATM protein and/or loss of ATM function. For example, deleterious mutation(s) in the BRCA1 gene and/or in the BRCA1 protein may result in loss of BRCA1 protein and/or loss of BRCA1 function.

In addition, a hyperproliferative disease may be characterized by one or more deleterious mutations in the ATM gene, and/or the BRCA1 gene, and/or the BRCA2 gene, and/or the PALB2 gene, and/or the ARID1A gene, and/or loss of the ATM protein.

Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the ATM gene and/or the BRCA1 gene and/or the BRCA2 gene and/or loss of the ATM protein.

Preferably, the hyperproliferative disease is characterized by one or more deleterious mutations in the ATM gene.

Preferably, the hyperproliferative disease is characterized by loss of the ATM protein.

Preferably a hyperproliferative disease with deleterious mutations in the ATM gene and loss of the ATM protein.

Preferably a hyperproliferative disease with deleterious mutations in the BRCA1 gene.

Preferably a hyperproliferative disease with deleterious mutations in the BRCA2 gene.

characterized characterized characterized one one one or or or

In addition, hyperproliferative disease may be characterized by single or deleterious mutations in the PALB2 gene.

In addition, hyperproliferative disease may be characterized by single or deleterious mutations in the ARID1A gene.

several several several several several

Methods for detecting one or more deleterious mutations in the ATM or BRCA1, BRCA2 or PALB2 or ARID1A gene and/or in the ATM or BRCA1 or BRCA2 or PALB2 or ARIDIA protein are known to those skilled in the art and are described, for example, in WO 2018/153968, which is incorporated herein by reference.

Preferably, the compound of formula (I) is administered in an amount of 20 to 120 mg per day, or in an amount of 60 to 160 mg per day, or in an amount of 20 to 80 mg per day, preferably in an amount of 80 to 160 mg per day.

Preferably, the compound of formula (I) is administered in an amount of 160 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID) as described above.

- 9 046114

Preferably, the compound of formula (I) is administered in an amount of 80 mg (BID) using one or more dosage regimens for 80 mg (BID) treatment as described above in the context of the first aspect of the invention (Compound for Use).

Preferably, the compound of formula (I) is administered in an amount of 80 mg (BID) and the dosage regimen is 3 days on/11 days off.

Preferably, the compound of formula (I) is administered in an amount of 140 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID) as described above.

Preferably, the compound of formula (I) is administered in an amount of 70 mg (BID) using one or more dosage regimens for 70 mg (BID) treatment as described above in the context of the first aspect of the invention (Compound for use).

Preferably, the compound of formula (I) is administered in an amount of 120 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID) as described above.

Preferably, the compound of formula (I) is administered in an amount of 60 mg (BID) using one or more dosage regimens for 60 mg (BID) treatment as described above in the context of the first aspect of the invention (Compound for use).

Preferably, the compound of formula (I) is administered in an amount of 60 mg (BID) and the dosage regimen is 3 days on/11 days off.

Preferably, the compound of formula (I) is contained in a pharmaceutical composition together with at least one pharmaceutically acceptable excipient.

Preferably, the compound of formula (I) is contained in a pharmaceutical composition together with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition contains the compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of 15 to 25%, preferably in an amount of 18 to 22%, most preferably in an amount of 20% by weight.

Preferably, the compound of formula (I) is contained in a pharmaceutical composition together with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition contains the compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of 15 to 25%, preferably in an amount of 18 to 22%, most preferably in an amount of 20 wt.%, and the pharmaceutical composition contains a glidant. Preferably the glidant is colloidal silica.

Preferably, the method of treating a hyperproliferative disease is characterized in that the pharmaceutical composition contains lactose, preferably lactose monohydrate, most preferably spray-dried lactose monohydrate.

Preferably, the method of treating a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 5 to 80 mg, preferably in an amount of 5 to 40 mg, more preferably in an amount of 40 to 80 mg and at least one pharmaceutically acceptable excipient.

Preferably, the method for treating a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 80 mg.

Preferably, the method for treating a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 70 mg.

Preferably, the method for treating a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 60 mg.

Preferably, the compound of formula (I) is contained in a pharmaceutical composition as further described above.

Method for producing a pharmaceutical composition

In addition, a method for preparing a pharmaceutical composition may be considered, in which a compound of formula (I) is mixed with at least one pharmaceutically acceptable excipient.

Preferably, in the method for preparing a pharmaceutical composition according to the invention, the compound of formula (I) is mixed with at least one pharmaceutically acceptable excipient by granulation.

The term granulation method includes wet granulation and dry granulation. Wet granulation methods include techniques such as fluidized bed granulation and high shear wet granulation. Dry granulation methods include methods such as direct compression, impact compaction and rolling.

Preferably, the granulation method used in the process for preparing the pharmaceutical composition according to the invention is a dry granulation method, most preferably a roller method.

Preferably a method for preparing a pharmaceutical composition according to the invention

- 10 046114 differs in that:

a) the compound of formula (I) is granulated with at least one pharmaceutically acceptable excipient,

b) the granulate obtained in step a) is mixed with a lubricant and, optionally, with one or more additional pharmaceutically acceptable excipients and, optionally,

c) the product obtained in step b) is coated with one or more other pharmaceutically acceptable coating agents.

Preferably, step a) of the process for preparing a pharmaceutical composition according to the invention is characterized in that the compound of formula (I) is granulated with a filler, preferably microcrystalline cellulose and lactose monohydrate, a lubricant, preferably magnesium stearate, and a disintegrant, preferably croscarmellose sodium, preferably by a dry granulation method , preferably by rolling.

Preferably, step b) of the process for preparing a pharmaceutical composition according to the invention is characterized in that the granulate obtained in step a) is mixed with a lubricant, preferably magnesium stearate, a glidant, preferably colloidal silica, a filler, preferably microcrystalline cellulose, and a disintegrant, preferably croscarmellose sodium. Mixing is carried out using a suitable device, such as for example a drum mixer, for a suitable period of time.

Preferably, in step c) of the process for preparing the pharmaceutical composition according to the invention, the product of step b) is coated with one or more additional pharmaceutically acceptable coating agents. Preference is given to pharmaceutically acceptable coating agents selected from the group of plasticizers, film-forming agents and colorants. Optionally, an anti-blocking agent or opacifier can be used. A plasticizer, preferably polyethylene glycol, a film-forming agent, preferably hypromellose, and dyes, preferably iron oxide and titanium dioxide, are combined with film coating liquids, preferably (purified) water, to obtain a homogeneous coating suspension, which is applied, preferably sprayed, onto the product of step b ), preferably onto tablets, using a suitable coating device, such as, for example, a perforated drum coating device. To change the color of the coating, other pigments or water-soluble dyes or combinations thereof can be used.

Preferably, after step b) of the process for preparing the pharmaceutical composition according to the invention, there is optionally a step called step b1), in which the mixture obtained in step b) is divided into individual elements and further processed into the desired dosage form, for example for filling sachets or capsules Optionally, one or more additional pharmaceutically acceptable excipients are added. Preferably, the mixture is divided into individual elements and then compressed into tablets.

Compression into tablets can be accomplished using a tablet press, such as a standard rotary tablet press.

Preferably, the method for preparing the pharmaceutical composition according to the invention is characterized in that:

a) a compound of formula (I) is mixed with one or more excipients and one or more disintegrants,

b) the mixture obtained in step a) is mixed with one or more lubricants,

c) the mixture obtained in step b) is compacted between pressing rollers to obtain strips, d) the strips obtained in step c) are sieved to obtain granulate,

e) the granulate obtained in step d) is mixed with one or more fillers, one or more disintegrants and one or more glidants,

f) the mixture obtained in step e) is mixed with one or more lubricants,

g) the mixture obtained in step f) is compressed to form a tablet, and optionally

h) the tablet obtained in step g) is coated with one or more additional pharmaceutically acceptable coating agents.

Pharmaceutically acceptable coating agents, which may optionally be used, are described above in the context of the second aspect of the invention.

Preferably, the method for preparing the pharmaceutical composition according to the invention is characterized in that the excipient(s), disintegrant(s), lubricant(s), glidant(s) of the pharmaceutical composition of the invention are used, especially as described above in the context of the second aspect of the present inventions. Preferably, the preferred excipients, preferred disintegrants, preferred lubricants and preferred glidants as defined above are used.

- 11 046114

A method for preparing a pharmaceutical composition according to the invention may also be contemplated, wherein a compound of formula (I) is mixed with at least one pharmaceutically acceptable excipient and the resulting mixture is directly compressed to form a tablet. Optionally, the tablet may be coated with one or more additional pharmaceutically acceptable excipients.

In addition, a method for preparing a pharmaceutical composition according to the invention may be considered, in which a compound of formula (I) is mixed with at least one pharmaceutically acceptable excipient and the resulting mixture is directly compressed and placed into capsules or sachets.

Use of a compound of formula (I) for the production of a medicament for the treatment of a hyperproliferative disease

The use of a compound of formula (I) may also be contemplated for the manufacture of a medicament for the treatment of a hyperproliferative disease, which is characterized in that the compound of formula (I) is administered in an amount of 10 to 160 mg per day to a patient.

Preferably, the compound of formula (I) is administered in an amount of 20 to 120 mg per day, or in an amount of 60 to 160 mg per day, or in an amount of 20 to 80 mg per day, preferably in an amount of 80 to 160 mg per day.

Preferably, the compound of formula (I) is administered in an amount of 160 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID) as described above.

Preferably, the compound of formula (I) is administered in an amount of 80 mg (BID) using one or more dosage regimens for 80 mg (BID) treatment as described above in the context of the first aspect of the invention (Compound for Use).

Preferably, the compound of formula (I) is administered in an amount of 140 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID) as described above.

Preferably, the compound of formula (I) is administered in an amount of 70 mg (BID) using one or more dosage regimens for 70 mg (BID) treatment as described above in the context of the first aspect of the invention (Compound for use).

Preferably, the compound of formula (I) is administered in an amount of 120 mg per day. The daily amount can be administered once daily (QD) or twice daily (BID) as described above.

Preferably, the compound of formula (I) is administered in an amount of 60 mg (BID) using one or more dosage regimens for 60 mg (BID) treatment as described above in the context of the first aspect of the invention (Compound for use).

Preferably, the compound of formula (I) is contained in a pharmaceutical composition together with at least one pharmaceutically acceptable excipient.

Preferably, the compound of formula (I) is contained in a pharmaceutical composition together with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition contains the compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of 15 to 25%, preferably in an amount of 18 to 22%, most preferably in an amount of 20% by weight.

Preferably, the compound of formula (I) is contained in a pharmaceutical composition together with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition contains the compound of formula (I) in an amount of 25% by weight of the pharmaceutical composition or less, or in an amount of 20% by weight of the pharmaceutical composition or less, especially in an amount of 15 to 25%, preferably in an amount of 18 to 22%, most preferably in an amount of 20% by weight, and the pharmaceutical composition contains a glidant. Preferably the glidant is colloidal silica.

Preferably, the use of a compound of formula (I) for the production of a medicament for the treatment of a hyperproliferative disease is characterized in that the pharmaceutical composition contains lactose, preferably lactose monohydrate, most preferably spray-dried lactose monohydrate.

Preferably, the use of a compound of formula (I) for the production of a medicament for the treatment of a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 5 to 80 mg, preferably in an amount of 5 to 40 mg, more preferably in an amount of 40 up to 80 mg and at least one pharmaceutically acceptable excipient.

Preferably, the use of a compound of formula (I) for the production of a medicament for the treatment of a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 80 mg.

Preferably, the use of a compound of formula (I) for the production of a medicament for the treatment of a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 70 mg.

- 12 046114

Preferably, the use of a compound of formula (I) for the production of a medicament for the treatment of a hyperproliferative disease is characterized in that the pharmaceutical composition contains a compound of formula (I) in an amount of 60 mg.

Preferably, the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a hyperproliferative disease is characterized in that the compound of formula (I) is contained in a pharmaceutical composition in accordance with the second aspect of the present invention, which is further described above.

Examples

Example 1.

Immediate release tablet containing BAY1895344 (20% drug content)

1.1 Composition of BAY 1895344 10, 20 and 40 mg film-coated tablets (drug content 20%)

Composition Tablet A 10 mg [mg] Tablet B 20 mg [mg] Tablet C 40 mg [mg] Medicinal substance BAY 1895344 micronized 10.00 20.00 40.00 Tablet core Cellulose, 21.405 42.81 85.62 microcrystalline (Avicel ® PH 102) Lactose monohydrate, dried 15.845 31.69 63.38 spray (SuperTab® USD) Croscarmellose sodium 2.000 4.00 8.00 Magnesium stearate 0.500 1.00 2.00 Colloidal dioxide 0.250 0.50 1.00 silicon CAS numbers: 112945-52-5 and 7631-86-9 Weight (tablet without 50.0 100.0 200.0

shells)

Film coating (off-the-shelf commercial coating system Opadry Dark Red 14F150002)

Hypromellose 15 cP Macrogol 1.5750 0.5250 2.10 0.70 3.60 1.20 (Polyethylene glycol 3350) Iron oxide red 0.3675 0.49 0.84 Titanium dioxide 0.1575 0.21 0.36 Mass (film 2.6250 3.50 6.00

coating)

Weight (tablet, 52.6 103.5 206.0 film-coated)

a) Micronization

BAY 1895344 was micronized in a jet mill after deagglomeration in a paddle sieve mill (mesh size 1.6 mm) with a diameter of 200 mm on an industrial scale. Grinding parameters: feed speed 3-6 kg/h and grinding pressure 3-6 bar.

b) Dry granulation and mixing kg micronized BAY 1895344, 4.061 kg microcrystalline cellulose, 3.169 kg spray-dried lactose monohydrate and 0.2 kg croscarmellose sodium were mixed in suitable equipment. 0.07 kg of magnesium stearate was then added and further mixed in suitable equipment. The mixture was roller compacted using a Gerteis Mini-Pactor (press force: 9.0 kN/cm; gap width: 2.0 mm; pressure roller speed: 2.5 rpm; granulator speed: 70 rpm). The roller compacted tapes were granulated using a 20 mesh (840 micron) screen. Thereafter, 0.22 kg of microcrystalline cellulose, 0.2 kg of croscarmellose sodium and 0.05 kg of anhydrous colloidal silica were mixed with the granule. Finally, 0.03 kg of magnesium stearate was added to the final mixture. The mixing steps were carried out in a suitable mixer.

c) Tableting

The mixture of step b) was compressed on a rotary tablet press into tablets containing 10, 20

- 13 046114 and 40 mg BAY1895344.

d) Film coating

Commercially available Opadry™ 14F150002 dark red was combined with purified water to form a uniform coating suspension, which was sprayed onto the tablets using a perforated drum coater.

The composition of example 1 was also produced on a different, ie on a larger scale. The ratio of ingredients and operating principle of the equipment were the same.

1.2 Properties of tablets

Table 1. Release study of the compound of formula (I) in % of . total mass of the composition.

15 minutes 30 min 45 min 60 min Tablet A 78% 87% 91% 92% Tablet B 79% 92% 96% 98% Tablet C 72% 88% 92% 95%

Each value represents the average of 6 individual results. USP 2 instrument (paddle instrument), 900 ml citrate buffer, pH 3.5, 50 rpm (tablet A and B), 55 rpm (tablet C).

Immediate release tablet containing BAY1895344 (drug content 33%)

2.1 Composition BAY 1895344, 40 mg film-coated tablet (drug content 33%) ________________________________________________________________

Composition Tablet 40 mg [mg] Medicinal substance BAY 1895344 micronized 40.0 Composition Tablet 40 mg [mg]

Tablet core Cellulose, microcrystalline 42.9 (Avicel ® PHI02) Lactose monohydrate, ground (not 31.2 spray dried) Croscarmellose sodium 4.8 Magnesium stearate 1.2 Weight (tablet without coating) 120.0

Hypromellose 15 cP2.2

Macrogol (Polyethylene glycol 3350)0.7

Iron oxide red0.5

Titanium dioxide0.2

Weight (film coating) 3.6

Weight (coated tablet)____123.6______________________

a) Micronization

BAY1895344 was micronized in a jet mill after deagglomeration in a paddle sieve mill (mesh size 1.6 mm) with a diameter of 200 mm on an industrial scale. Grinding parameters: feed speed 3-6 kg/h and grinding pressure 3-6 bar.

b) Dry granulation and mixing

666 g micronized BAY1895344, 264 g microcrystalline cellulose, 519 g milled lactose monohydrate and 40 g croscarmellose sodium were mixed in a suitable equipment. 14 g of magnesium stearate was then added and further mixed in suitable equipment. The mixture was compacted with a roller. The tapes produced by roller compaction were granulated using a mesh screen. After this, 450 g of microcrystalline cellulose and 40 g of croscarmellose sodium were mixed with the granule. Finally, 6 g of magnesium stearate was added to the final mixture. The mixing steps were carried out in a suitable mixer.

c) Tableting

The mixture of step b) was compressed on a one-die tabletting press into tablets containing 40 mg of BAY1895344. During pressing, serious problems with the flow of the mixture were observed. The mixture was compacted in the hopper so that it did not flow into the die of the rotary tablet press. Consequently, compression of this composition was impossible.

d) Film coating

Since tablet production was not successful, this production step was not carried out.

Example 2.

First-in-human trial of the oral ATR inhibitor BAY 1895344 in patients with advanced solid tumors.

- 14 046114

Methods:

Patients with advanced metastatic solid tumors, resistant or refractory to standard treatment, with and without DDR defects, were treated with BAY 1895344, BID, on a 3 days on/4 days off regimen continuously in 3 week cycles (ClinicalTrials.gov identifier: NCT03188965).

Results:

patients were assigned to 6 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg), including patients with colorectal cancer (4), breast cancer (3), prostate cancer (2), and ovaries (2). The median number of prior treatments was 5. No dose-limiting toxicity (DLT) was reported in the 5-40 mg cohorts. There were 2/3 DLTs in the 80 mg cohort (grade 4 [G4] neutropenia; G4 neutropenia and G4 thrombocytopenia) and 2/7 DLTs in the 60 mg cohort (G4 neutropenia; G2 fatigue). The 40 mg BID 3 on/4 off regimen was defined as the maximum tolerated dose (MTD). The most common treatment-emergent side effects included anemia, neutropenia, nausea and fatigue. Pharmacokinetics appeared to be dose proportional with pharmacodynamic analysis showing modulation of pH2AX and/or pKAP1 in paired tumor biopsies with exposures associated with preclinical antitumor activity. In 13 patients with and without DDR defects treated at dose levels >40 mg BID, the objective response rate (ORR) was 30.7%, including 2/2 of the patients in the 40 mg cohort (appendiceal cancer and urothelial cancer). 1/8 patients in the cohort receiving 60 mg of the drug (breast cancer), and 1/3 of patients in the cohort receiving 80 mg of the drug (endometrial cancer). Notably, these 4 responding patients had loss of ATM protein expression and/or ATM mutation with a median treatment duration of 347 days (range 293 days - 364 days). A patient with BRCA1-mutant olaparib-resistant ovarian cancer (60 mg) had a CA125 response and SD >10 months. An additional 41 patients were enrolled in open-label expansion cohorts with cancers with DDR defects (prostate cancer, breast cancer, gynecologic cancer, colorectal cancer) or ATM protein loss (all willing) with observed responses.

Conclusions: The ATR inhibitor BAY 1895344 can be tolerated at bioactive doses with antitumor activity against cancers with certain DDR defects, including loss of ATM protein.

Example 3.

Immediate release tablet containing BAY 1895344 (20% drug content)

Composition BAY 1895344, 60 and 80 mg film-coated tablets (drug content 20%)

Composition Tablet 60 mg [mg] Tablet 80 mg [mg] Medicinal substance BAY 1895344 micronizedbO.OO 80.00 Tablet core Cellulose, 128.43 171.24 microcrystalline (Avicel ® PHI02) Lactose monohydrate, 95.07 126.76 spray dried (SuperTab® USD) Croscarmellose sodium 12.00 16.00 Magnesium stearate 3.00 4.00 Colloidal silicon dioxide 1.50 2.00 CAS numbers: 112945-52-5 and 7631-86-9 Weight (tablet without coating) 300.0 400.0

Film coating (off-the-shelf commercial coating system Opadry Dark Red 14F150002)

Hypromellose 15 cP 5.40 7.20 Macrogol (Polyethylene glycol 3350) 1.80 2.40 Iron oxide red 1.26 1.68 Titanium dioxide 0.54 0.72 Mass (film coating) 9.00 12.00

Weight (coated tablet 309.0 412.0)

- 15 046114

a) Micronization

BAY 1895344 was micronized in a jet mill after deagglomeration in a paddle sieve mill (mesh size 1.6 mm) with a diameter of 200 mm on an industrial scale. Grinding parameters: feed speed 3-6 kg/h and grinding pressure 3-6 bar.

b) Dry granulation and mixing kg micronized BAY 1895344, 4.061 kg microcrystalline cellulose, 3.169 kg spray-dried lactose monohydrate and 0.2 kg croscarmellose sodium were mixed in suitable equipment. 0.07 kg of magnesium stearate was then added and further mixed in suitable equipment. The mixture was roller compacted using a Gerteis Mini-Pactor (press force: 9.0 kN/cm; gap width: 2.0 mm; pressure roller speed: 2.5 rpm; granulator speed: 70 rpm). The roller compacted tapes were granulated using a 20 mesh (840 micron) screen. Thereafter, 0.22 kg of microcrystalline cellulose, 0.2 kg of croscarmellose sodium and 0.05 kg of anhydrous colloidal silica were mixed with the granule. Finally, 0.03 kg of magnesium stearate was added to the final mixture. The mixing steps were carried out in a suitable mixer.

c) Tableting

The mixture of step b) was compressed on a rotary tablet press into tablets containing 60 and 80 mg of BAY 1895344.

d) Film coating

Commercially available Opadry™ 14F150002 dark red was combined with purified water to form a uniform coating suspension, which was sprayed onto the tablets using a perforated drum coater.

Example 4.

Immediate release tablet containing BAY 1895344 (20% drug content)

Composition BAY 1895344, 40 mg film-coated tablets (20% drug content) with different amounts of magnesium stearate.________________________

Composition Tablet D 40 mg Total amount of stearate magsh 1.1% (w/w) [mg] Tablet E 40 mg Total Magnesium zystearate 1.3% (mass/mass) [mg] Tablet F 40 mg Total Magnesium Stearate 1.5% (w/w) [mg] Medicinal substance BAY 1895344 micronized 40.00 40.00 40.00 Tablet core Cellulose, 85.42 85.02 84.62 microcrystalline (Avicel ® PHI02) Lactose monohydrate, dried 63.38 63.38 63.38 spray (SuperTab® USD) Croscarmellose 8.00 8.00 8.00 sodium Magnesium stearate 2.20 2.60 3.00 Colloidal dioxide 1.00 1.00 1.00 silicon CAS numbers: 112945-52-5 and 7631-86-9 Weight (tablet without 200.0 200.0 200.0

shells)

Film coating (off-the-shelf commercial coating system Opadry Dark Red 14F150002)

Hypromellose 15 cP 3.60 3.60 3.60 Macrogol (Polyethylene glycol 3350) 1.20 1.20 1.20 Iron oxide red 0.84 0.84 0.84 Titanium dioxide 0.36 0.36 0.36 Mass (film coating) 6.00 6.00 6.00

Weight (tablet, 206.0 206.0 206.0 film-coated)

- 16 046114

a) Micronization

BAY 1895344 was micronized in a jet mill after deagglomeration in a paddle sieve mill (mesh size 1.6 mm) with a diameter of 200 mm on an industrial scale. Grinding parameters: feed speed 3-6 kg/h and grinding pressure 3-6 bar.

b) Dry granulation and mixing kg micronized BAY 1895344, 4.061 kg microcrystalline cellulose, 3.169 kg spray-dried lactose monohydrate and 0.2 kg croscarmellose sodium were mixed in suitable equipment. 0.07 kg of magnesium stearate was then added and further mixed in suitable equipment. The mixture was roller compacted using a Gerteis Mini-Pactor (press force: 9.0 kN/cm; gap width: 2.0 mm; pressure roller speed: 2.5 rpm; granulator speed: 70 rpm). The roller compacted tapes were granulated using a 20 mesh (840 micron) screen. Thereafter, 0.22 kg of microcrystalline cellulose, 0.2 kg of croscarmellose sodium and 0.05 kg of anhydrous colloidal silica were mixed with the granule. Finally, 0.04 kg (tablet D)/0.06 kg (tablet E)/0.08 kg (tablet F) magnesium stearate was added to the final mixture. The mixing steps were carried out in a suitable mixer.

c) Tableting

The mixture of step b) was compressed on a rotary tablet press into tablets containing 10, 20 and 40 mg of BAY 1895344.

d) Film coating

Commercially available Opadry™ 14F150002 dark red was combined with purified water to form a uniform coating suspension, which was sprayed onto the tablets using a perforated drum coater.

Compared to the tablets of Example 1, the tablets of Example 4 were improved for relief embossing.

Example 5.

Liquid working composition that contains BAY 1895344 (1 and 4 mg/ml)

Composition BAY 1895344, 1 and 4 mg/ml liquid working compositions:

Composition Solution 1 mg/ml [g] Solution 4 mg/ml [G] Medicinal substance BAY 1895344 micronized0.040 0.160 Excipients Citric acid, anhydrous 0.800 0.800 Sucralose 0.040 0.040 1n. sodium hydroxide q.s. (establishment q.s. (establishment pH values per pH pH values per pH 1.9-2.7) 1.9-2.7) Water for injections 39.420 39.420

a) Micronization

BAY 1895344 was micronized in a jet mill after deagglomeration in a paddle sieve mill (mesh size 1.6 mm) with a diameter of 200 mm on an industrial scale. Grinding parameters: feed speed 3-6 kg/h and grinding pressure 3-6 bar.

b) Making the solution

BAY 1895344 was suspended in a partial amount of water for injection with stirring (drug concentration). Anhydrous citric acid and sucralose were dissolved in the remaining water for injection at room temperature (stock solution).

Drug concentrate BAY 1895344 was added to the main solution and dissolved with stirring. Setting the pH value using a mixture of 1 N. Sodium hydroxide/anhydrous citric acid was only needed when the pH value was not within the specified pH range of 1.9-2.7. The solution was filtered before bottling.

Example 6.

First-in-human trial of the oral ATR inhibitor BAY 1895344 in patients with advanced solid tumors - results from NCT study 03188965

Efficiency:

The majority of patients treated were on the MTD regimen and dose. (40 mg BID 3 days on/4 days off, n=134), n=20 patients were treated with different doses but the same regimen (3 days on/4 days off), and n=8 patients took an alternative dose and were on mode 60 mg BID and 80 mg BID 3 days on / 11 days off (4 weeks per cycle).

At the beginning of the dose escalation period (Part A), patients received the liquid formulation (LSF) described in Example 5. At later stages of the dose escalation period, patients were switched from LSF to tablets (see Example 1, paragraph 1.1., drug-containing tablets). funds 20%). During the maximum tolerated dose phase of treatment, some patients were transferred

- 17 046114 money from LSF for tablets, but most were treated only with tablets.

At MTD dose (40 mg BID) and treatment regimen (3 days on/4 days off) n=134:

Some patients were preselected for DDR defects (in part B) and some were not (in part A). They had multiple tumor features, including cohorts independent of ATM protein loss (including castration-resistant prostate cancer, breast cancer, gastric cholangiocarcinoma, pancreatic cancer, esophageal cancer, colorectal cancer, tongue squamous cell carcinoma), and other cohorts with tumor types such as ovarian, endometrial, cervical, breast, appendix, urothelial cancer, castration-resistant prostate cancer, bladder cancer, cholangiocarcinoma and colorectal cancer.

DDR defects were analyzed using FoundationONE® CDx from Foundation Medicine Inc., USA, to identify deleterious mutations (hereinafter abbreviated as mut, e.g. ATMmut, BRCA1mut, BRCA2mut, etc.) in one or more of the following genes: ATM, BRCA1, BRCA2 , CHEK2, FANCA, MSH2, MRE11A, PALB2, RAD51, ATRX, CDK12, CHEK1, PARP1, POLD1, XRCC2, and/or ARIDIA.

Patients/indications with ATM protein loss identified by IHC are also referred to hereafter as ATMloss.

Responses were defined as complete response (CR), partial response (PR), or long-term stable disease (SD), meaning stable disease lasting 4 months or more (= SD >4 months).

There were 5 patients with PR on the treatment regimen and at the MTD dose level (40 mg BID 3 days on/4 days off), all with documented DDR defects (specifically 2 ATMloss, 1 ATMmut, 1 BRCAlmut and 1 BRCA2mut), as indicated , including urothelial collecting duct carcinoma, appendix, ovarian, esophageal and breast cancer.

There were 22 patients with long-term SD (SD>4 months), who were distributed as follows: colorectal cancer (6 patients), ovarian cancer (5), breast cancer (4), endometrial cancer (3), castration-resistant prostate cancer glands (2), stomach cancer (1) and pancreatic cancer (1).

(81.8%) of these had a DDR defect, including 5 patients with ATMloss, 4 with ATMmut, 1 with ATMloss and ATMmut, 5 with BRCA1mut (all of the above with or without additional DDR defects), 1 with a deleterious PALB2 mutation (PALB2mut) but no ATMloss/mut, no BRCA1mut and no BRCA2mut, and finally, 2 of these 18 patients had a deleterious ARID 1A mutation (ARID1Amut) but did not have concurrent ATMloss/mut, BRCA1mut and BRCA2mut.

3 of 22 patients did not have a DDR defect on retrospective testing, and 1 of 22 patients had no data on DDR defects.

At dose levels other than 40 mg BID, but with the same treatment regimen (3 days on/4 days off) n=20:

Patients were not preselected for DDR defects (mostly part A) and were randomly assigned to various tumor indications, including colorectal cancer, breast cancer, ovarian cancer, endometrial cancer, castration-resistant prostate cancer, pancreatic cancer, cancer lung and hepatocellular carcinoma.

There were 5 responders (same definition as above). 2 of them (40%) had PR and breast and endometrial cancer, both with ATMloss and ATMmut. The remaining 3 patients had long-term SD >4 months. and were with ovarian cancer (BRCA1mut), hepatocellular carcinoma (no data on DDR defects = N/A) and colorectal cancer (N/A).

Across all dose levels (5 mcg BID - 80 mg BID) tested in a 3-day on/4-day-off regimen, 7 PRs were identified covering 6 indications: urothelial collecting duct cancer, appendix cancer, ovarian cancer, esophageal ATM protein loss (abbreviated esophageal ATMloss), endometrial cancer (1 patient per indication), and breast cancer (2 patients). Others had long-term stable disease (SD >4 months) with the following indications: colorectal cancer (7), ovarian cancer (6), breast cancer (4), endometrial cancer (3), castration-resistant prostate cancer (2 ), gastric cancer (1), hepatocellular carcinoma (1) and pancreatic cancer (1).

Patients who received doses of 5 mg BID and 10 mg BID had no response (no PR and no SD >4 months).

Biomarker

All 7 PRs mentioned above had DDR defects (2 ATMloss and ATMmut + 2 ATMloss + 1 ATMmut + 1 BRCA1mut + 1 BRCA2mut), while 19 of 25 SD >4 mo. had DDR defects (5 patients with ATMloss, 4 with ATMmut and 1 with ATMloss and ATMmut, 6 with BRCA1mut, 1 with PALB2mut, 2 with ARID1Amut), 3 of 25 were N/A, and 3 of 25 patients did not have DDR defects.

Patients of the 32 responders (including PR and SD >4 as described above) had ATMmut and/or ATMloss. Eleven of the 32 responding patients had neither ATM protein loss nor a deleterious ATM gene mutation. 3 Of the 32 responding patients did not have the DDR defect, and 3 of the 32 responding patients had an unknown mutational defect.

-

Claims (10)

tus (N/A). In the alternative treatment regimen, part A. 1: each of 60 mg BID and 80 mg BID in a 3 days on/11 days off regimen: There are currently 2 dose levels for this prolonged escalation therapy. The first dose level is 60 mg BID in a 3 days on/11 days off regimen, where 6 patients were treated, with cholangiocarcinoma (1 patient), castration-resistant prostate cancer (2) and colorectal cancer (3). 4 of 6 patients have known DDR defects (3 patients with ATMloss and 1 with ATMmut and ATMloss), but all patients met inclusion criteria for loss of ATM protein and/or ATMmut. To date, 1 responder patient with cholangiocarcinoma with SD >4 months has been identified. The second dose level is 80 mg BID in a 3 days on/11 days off regimen, where 5 patients were being treated at that time. One patient had stable disease with a -11% reduction in tumor size with treatment at 56 days (the time point for the first efficacy assessment), which was ongoing. To date, no DLT (DLT = dose-limiting toxicity) has been observed at both dose levels (60 mg BID and 80 mg BID). Conclusion Overall, the combined preclinical and clinical information indicates the promising anticancer activity and manageable risk profile of BAY 1895344, supporting the favorable risk assessment of the compound in indications with unmet medical need. CLAIM 1. Application of 2-[(^)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)- 1,7 naphthyridine of formula (I) for the treatment of a hyperproliferative disease, which is characterized in that said compound of formula (I) is administered in an amount 60 mg twice daily and the dosing regimen is 3 days on/11 days off, or 70 mg twice daily and the dosing regimen is 3 days on/11 days off, or 80 mg twice daily and the dosing regimen is 3 days on/11 days off. 2. Use according to claim 1, characterized in that said compound of formula (I) is administered in an amount of 60 mg twice a day and the dosage regimen is 3 days on/11 days off. 3. Use according to claim 1, characterized in that said compound of formula (I) is administered in an amount of 70 mg twice a day and the dosage regimen is 3 days on/11 days off. 4. Use according to claim 1, characterized in that said compound of formula (I) is administered in an amount of 80 mg twice a day and the dosage regimen is 3 days on/11 days off. 5. Use according to claim 1, characterized in that said compound of formula (I) is administered in the form of a pharmaceutical composition containing a compound of formula (I) in an amount of 60 mg and at least one pharmaceutically acceptable excipient. 6. Use according to claim 1, characterized in that said compound of formula (I) is administered in the form of a pharmaceutical composition containing a compound of formula (I) in an amount of 70 mg and at least one pharmaceutically acceptable excipient. 7. Use according to claim 1, characterized in that said compound of formula (I) is administered in the form of a pharmaceutical composition containing the compound of formula (I) in an amount of 80 mg and at least one pharmaceutically acceptable excipient. 8. Use according to any one of claims 1 to 7, characterized in that said hyperproliferative disease is selected from psoriasis, keloids and other skin hyperplasias, benign prostatic hyperplasia (BPH), solid tumors such as cancer of the breast, respiratory tract, brain , reproductive organs, digestive tract, urinary tract, eyes, liver, skin, head and neck, thyroid gland, parathyroid gland, and their distant metastases. 9. Use according to claim 8, wherein said solid tumors are breast cancer. 10. Use according to claim 8, wherein said solid tumors are cancers of the reproductive organs. -