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WO2018153970A1 - Formes solides de 2-[(3r)-3-méthylmorpholin-4-yl]-4-(1-méthyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphtyridine - Google Patents

Formes solides de 2-[(3r)-3-méthylmorpholin-4-yl]-4-(1-méthyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphtyridine Download PDF

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Publication number
WO2018153970A1
WO2018153970A1 PCT/EP2018/054363 EP2018054363W WO2018153970A1 WO 2018153970 A1 WO2018153970 A1 WO 2018153970A1 EP 2018054363 W EP2018054363 W EP 2018054363W WO 2018153970 A1 WO2018153970 A1 WO 2018153970A1
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compound
formula
xrpd
ray powder
powder diffractogram
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PCT/EP2018/054363
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English (en)
Inventor
Philipp Rubenbauer
Jens Geisler
Jana GALBRAITH
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Bayer Pharma Aktiengesellschaft
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Publication of WO2018153970A1 publication Critical patent/WO2018153970A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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):
  • 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.
  • example 111 describes the preparation of the compound of the formula (I).
  • the compound of formula (I) crystallizes in two different polymorphic forms, which are called “Form A” and “Form B” in the following.
  • 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
  • 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).
  • stability e.g. mechanical stability, chemical stability, storage stability
  • compatibility over other ingredients e.g., 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).
  • 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.
  • solid forms e.g. either Form A, Form B, Form C, Form D or Form E
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 ( ⁇ ) 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.
  • 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 ( ⁇ ) present in the pharmaceutical composition.
  • the present invention concerns a pharmaceutical composition
  • 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 ( ⁇ ) 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.
  • 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)
  • the aforementioned combinations comprise no significant fractions of another solid form of the compound of the formula (I).
  • 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 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
  • Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 6.4, 9.3, 19.1.
  • XRPD X-ray powder diffractogram
  • Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 6.4, 9.3, 16.1, 17.0, 19.1.
  • XRPD X-ray powder diffractogram
  • Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 6.4, 9.3, 16.1,
  • Form A of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 6.4, 9.3, 14.3,
  • 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 2 ⁇ 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.
  • XRPD X-ray powder diffractogram
  • Form A of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) substantially as shown in Figure 1.
  • Form A of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table Al.
  • Form A of the compound of formula (I) is an anhydrate.
  • Form A of the compound of formula (I) is characterized by the FT-IR spectrum substantially as shown in Figure 3.
  • Form A of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table B.
  • Form A of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table C.
  • Form A of the compound of formula (I) is characterized by the Raman spectrum substantially as shown in Figure 4.
  • Form A of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table D.
  • Form A of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table E.
  • 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 2 ⁇ values: 8.3, 9.3,
  • XRPD X-ray powder diffractogram
  • Form B of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 8.3, 18.0, 19.9.
  • XRPD X-ray powder diffractogram
  • Form B of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 8.3, 9.3, 18.0,
  • Form B of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 8.3, 9.3, 13.8, 14.0, 18.0, 19.9, 20.1.
  • XRPD X-ray powder diffractogram
  • Form B of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table Al.
  • Form B of the compound of formula (I) is an anhydrate.
  • Form B of the compound of formula (I) is characterized by the FT-IR spectrum substantially as shown in Figure 7
  • Form B of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table B.
  • Form B of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table C.
  • Form B of the compound of formula (I) is characterized by the Raman spectrum substantially as shown in Figure 8.
  • Form B of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table D.
  • Form B of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table E.
  • 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 2 ⁇ values: 8.9, 12.3, 13.1, 14.5, 19.6, 20.0, 23.6.
  • XRPD X-ray powder diffractogram
  • Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 8.9, 13.1, 23.6.
  • XRPD X-ray powder diffractogram
  • Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 8.9, 12.3, 13.1, 20.0, 23.6.
  • XRPD X-ray powder diffractogram
  • Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 8.9, 12.3, 13.1, 14.5, 19.6, 20.0, 23.6.
  • Form C of the compound of formula (I) is characterized by a X-ray powder diffractogram (XRPD) comprising the following reflections, quoted as 2 ⁇ values: 8.9, 12.3, 13.1, 14.5, 19.6, 20.0, 23.6, 27.9.
  • XRPD X-ray powder diffractogram
  • Form C of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) substantially as shown in Figure 9.
  • Form C of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table Al.
  • Form C of the compound of formula (I) is characterized by the FT-IR spectrum substantially as shown in Figure 11.
  • Form C of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table B.
  • Form C of the compound of formula (I) is characterized by the FT-IR bands maxima substantially as listed in Table C.
  • Form C of the compound of formula (I) is characterized by the Raman spectrum substantially as shown in Figure 12.
  • Form C of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table D.
  • Form C of the compound of formula (I) is characterized by the Raman bands maxima substantially as listed in Table E.
  • 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).
  • 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 2 ⁇ values: 9.0, 21.5, 23.8.
  • XRPD X-ray powder diffractogram
  • XRPD X-ray powder diffractogram
  • 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 2 ⁇ values: 9.0, 10.5, 12.1, 12.9, 15.1, 21.5, 23.8.
  • XRPD X-ray powder diffractogram
  • Pattern D Mixture of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) substantially as shown in Figure 13.
  • Pattern D Mixture of the compound of formula (I) is characterized by the X-ray powder diffractogram (XRPD) described in Table A2.
  • 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 2 ⁇ values: 9.0, 10.5, 12.1, 12.9, 15.1, 21.5, 23.8
  • XRPD X-ray powder diffractogram
  • 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 2 ⁇ values: 8.8, 9.0, 12.3, 12.6, 19.0, 19.5.
  • XRPD X-ray powder diffractogram
  • 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 2 ⁇ values: 8.8, 12.3, 12.6.
  • XRPD X-ray powder diffractogram
  • 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 2 ⁇ values: 8.8, 9.0, 12.3, 12.6, 19.0.
  • XRPD X-ray powder diffractogram
  • 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 2 ⁇ values: 8.8, 9.0, 12.3, 12.6, 19.0, 19.5.
  • XRPD X-ray powder diffractogram
  • Pattern E Mixture of the compound of formula (I) is characterized by the X- ray powder diffractogram (XRPD) substantially as shown in Figure 14.
  • pseudopolymorph E of the compound of formula (I) is a hydrate.
  • 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").
  • DSC Differential Scanning Calorimetry
  • 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.
  • 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.
  • BPH benign prostate hyperplasia
  • 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.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • 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.
  • 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.
  • 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.
  • the present invention covers the treatment of lung carcinoma, in particular small-cell lung cancer, colorectal cancer, bladder cancer, lymphomas, gliomas, and ovarian cancer.
  • 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.
  • 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.
  • 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)
  • DLBC diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • prostate cancer in particular castration- resistant prostate cancer, gliomas
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • suitable anti-hyper-proliferative, cytostatic or cytotoxic combination active ingredients include:
  • amifostine aminoglutethimide, hexyl aminolevuliriate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin ⁇ , antithrombin ⁇ , 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,
  • 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.
  • 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 for example hard or soft gelatin capsules
  • sugar-coated tablets granule
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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 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®),
  • surfactants 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, Crem
  • 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 for example polyvinylpyrrolidon, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine),
  • 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®
  • modified starch carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®
  • 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®
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas such as, for example, Aerosil®
  • coating materials for example sugar, shellac
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • a pharmaceutical composition comprising Form F of the compound of formula (I) and optionally one or more pharmaceutically suitable excipient(s).
  • 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.
  • "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 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.
  • 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.
  • 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° 2 ⁇ , step size 0.013°, counting time 99 sec, ⁇ 22 min run time. All X-ray reflections are quoted as ° 2 ⁇ (theta) values with a resolution of + 0.1°.
  • 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.
  • 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:
  • Air background spectra were collected before analysis.
  • 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.
  • Figure 3 shows the FT-IR spectrum of Form A.
  • Figure 4 shows the Raman spectrum of Form A.
  • 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.
  • 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.
  • DCM dichloromethane
  • 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.
  • 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).
  • 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.
  • RH relative humidity
  • 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).
  • Figure 11 shows the FT-IR spectrum of Form C.
  • Figure 12 shows the Raman spectrum of Form C.
  • Form A was dissolved in dioxane (ImL), filtered through a 0.45 ⁇ 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.
  • 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. 3 ⁇ 4 NMR analysis of Pattern D material conformed to the molecular structure and no solvent was detected:
  • TG/DTA analysis showed a gradual weight loss of ⁇ 7.4 % between 25 °C and 205 °C and as there was no solvent detected in the 3 ⁇ 4 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 Starbucks! Verweissammlung Mé Vietnamese Strukturberichtatorium. 14. 3 ⁇ 4 NMR analysis of this mixture conformed to the molecular structure and ⁇ 0.01 molar equivalents of toluene was detected:
  • TG/DTA analysis 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.
  • the error range was established to be as standard resolution at 4 cm "1 and therefore the error range is + 2 cm 1 .
  • the error range was established to be as standard resolution at 4 cm "1 and therefore the error range is + 2 cm 1 .
  • 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 ⁇ over 4h with 1 * 10 A 6 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).
  • 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.
  • 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.

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Abstract

La présente invention concerne différentes formes solides de 2-[(3R)-3-méthylmorpholin-4-yl]-4-(1-méthyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphtyridine de formule (I) :
PCT/EP2018/054363 2017-02-24 2018-02-22 Formes solides de 2-[(3r)-3-méthylmorpholin-4-yl]-4-(1-méthyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphtyridine WO2018153970A1 (fr)

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US10729680B2 (en) 2016-01-14 2020-08-04 Bayer Pharma Aktiengesellschaft 5-substituted 2-(morpholin-4-yl)-1,7-naphthyridines
WO2020165015A1 (fr) 2019-02-11 2020-08-20 Bayer Aktiengesellschaft Inhibiteur de kinase atr bay1895344 destiné à être utilisé dans le traitement d'une maladie hyper-proliférative
US10772893B2 (en) 2014-08-04 2020-09-15 Bayer Pharma Aktiengesellschaft 2-(morpholin-4-yl)-1,7-naphthyridines
KR20210049845A (ko) * 2018-08-24 2021-05-06 바이엘 악티엔게젤샤프트 2-[(3r)-3-메틸모르폴린-4-일]-4-(1-메틸-1h-피라졸-5-일)-8-(1h-피라졸-5-일)-1,7-나프티리딘의 제조 방법
CN114423760A (zh) * 2019-11-21 2022-04-29 江苏恒瑞医药股份有限公司 吡唑并杂芳基类衍生物、其制备方法及其在医药上的应用
WO2023016529A1 (fr) * 2021-08-11 2023-02-16 微境生物医药科技(上海)有限公司 Dérivé de naphtyridine utile comme inhibiteur de l'atr et son procédé de préparation
WO2023116865A1 (fr) * 2021-12-23 2023-06-29 优领医药科技（上海）有限公司 Dérivé contenant du pyrazole, sel pharmaceutiquement acceptable de celui-ci, procédé de préparation correspondant et utilisation associée
WO2023165493A1 (fr) * 2022-03-01 2023-09-07 武汉众诚康健生物医药科技有限公司 Dérivé de naphtyridine et son utilisation

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US11529356B2 (en) 2014-08-04 2022-12-20 Bayer Pharma Aktiengesellschaft 2-(morpholin-4-yl)-1,7-naphthyridines
US10772893B2 (en) 2014-08-04 2020-09-15 Bayer Pharma Aktiengesellschaft 2-(morpholin-4-yl)-1,7-naphthyridines
US10729680B2 (en) 2016-01-14 2020-08-04 Bayer Pharma Aktiengesellschaft 5-substituted 2-(morpholin-4-yl)-1,7-naphthyridines
KR20210049845A (ko) * 2018-08-24 2021-05-06 바이엘 악티엔게젤샤프트 2-[(3r)-3-메틸모르폴린-4-일]-4-(1-메틸-1h-피라졸-5-일)-8-(1h-피라졸-5-일)-1,7-나프티리딘의 제조 방법
CN112823158A (zh) * 2018-08-24 2021-05-18 拜耳股份有限公司 制备2-[(3r)-3-甲基吗啉-4-基]-4-(1-甲基-1h-吡唑-5-基)-8-(1h-吡唑-5-基)-1,7-二氮杂萘的方法
CN112823158B (zh) * 2018-08-24 2023-08-15 拜耳股份有限公司 制备2-[(3r)-3-甲基吗啉-4-基]-4-(1-甲基-1h-吡唑-5-基)-8-(1h-吡唑-5-基)-1,7-二氮杂萘的方法
KR102797099B1 (ko) 2018-08-24 2025-04-18 바이엘 악티엔게젤샤프트 2-[(3r)-3-메틸모르폴린-4-일]-4-(1-메틸-1h-피라졸-5-일)-8-(1h-피라졸-5-일)-1,7-나프티리딘의 제조 방법
WO2020165015A1 (fr) 2019-02-11 2020-08-20 Bayer Aktiengesellschaft Inhibiteur de kinase atr bay1895344 destiné à être utilisé dans le traitement d'une maladie hyper-proliférative
CN114423760A (zh) * 2019-11-21 2022-04-29 江苏恒瑞医药股份有限公司 吡唑并杂芳基类衍生物、其制备方法及其在医药上的应用
EP4063363A4 (fr) * 2019-11-21 2023-11-29 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Dérivé pyrazolo-hétéroaryl, son procédé de préparation et son utilisation médicale
WO2023016529A1 (fr) * 2021-08-11 2023-02-16 微境生物医药科技(上海)有限公司 Dérivé de naphtyridine utile comme inhibiteur de l'atr et son procédé de préparation
WO2023116865A1 (fr) * 2021-12-23 2023-06-29 优领医药科技（上海）有限公司 Dérivé contenant du pyrazole, sel pharmaceutiquement acceptable de celui-ci, procédé de préparation correspondant et utilisation associée
WO2023165493A1 (fr) * 2022-03-01 2023-09-07 武汉众诚康健生物医药科技有限公司 Dérivé de naphtyridine et son utilisation

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