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Last Updated: January 16, 2021

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Claims for Patent: 9,902,727

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Summary for Patent: 9,902,727
Title:Aminoalcohol substituted 2,3-dihydroimidazo[1,2-C]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
Abstract: This invention relates to novel 2,3-dihydroimidazo[1,2-c]quinazoline compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for phosphotidylinositol-3-kinase (PI3K) inhibition and treating diseases associated with phosphotidylinositol-3-kinase (PI3K) activity, in particular treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.
Inventor(s): Scott; William (Guilford, CT), Liu; Ningshu (Berlin, DE), Mowes; Manfred (Berlin, DE), Hagebarth; Andrea (Berlin, DE), Monning; Ursula (Woltersdorf, DE), Bomer; Ulf (Glienicke, DE)
Assignee: Bayer Intellectual Property GmbH (Monheim, DE)
Application Number:14/553,280
Patent Claims:1. A compound of formula (I): ##STR00104## wherein: R.sup.1 is -(CH.sub.2).sub.n-(CHR.sup.4)-(CH.sub.2).sub.m-N(R.sup.5)(R.sup.5); R.sup.2 is a heteroaryl of structure: ##STR00105## wherein: * indicates the point of attachment of said heteroaryl with the rest of the compound of formula (I); R.sup.3 is methyl; R.sup.4 is hydroxy in the (R)-configuration; R.sup.5 and R.sup.5' are the same or different and are, independently of each other, a hydrogen atom, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, or R.sup.5 and R.sup.5' are taken together with the nitrogen atom to which they are bound to form a 3- to 7- membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen, and sulfur, and which is optionally substituted with 1 or more R.sup.6' groups; R.sup.6 is a hydrogen atom, a halogen atom, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, aryl, aryl-C.sub.1-C.sub.6-alkyl, heteroaryl, heteroaryl-C.sub.1-C.sub.6-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C.sub.1-C.sub.6-alkyl, -C.sub.1-C.sub.6-alkyl-OR.sup.7, -C.sub.1-C.sub.6-alkyl-SR.sup.7, -C.sub.1-C.sub.6-alkyl-N(R.sup.7)(R.sup.7'), -C.sub.1-C.sub.6-alkyl-C(.dbd.O)R.sup.7, -CN, -C(.dbd.O)OR.sup.7, -C(.dbd.O)N(R.sup.7)(R.sup.7'), -OR.sup.7, -SR.sup.7, -N(R.sup.7)(R.sup.7'), or -NR.sup.7C(.dbd.O)R.sup.7, each of which is optionally substituted with 1 or more R.sup.8 groups; each occurrence of R.sup.6' is the same or different and is independently C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-alkyl-OR.sup.7; each occurrence of R.sup.7 and R.sup.7' is the same or different and is independently a hydrogen atom, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkenyl, aryl, aryl-C.sub.1-C.sub.6-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C.sub.1-C.sub.6-alkyl, or heteroaryl-C.sub.1-C.sub.6-alkyl; each occurrence of R.sup.8 is independently a halogen atom, nitro, hydroxy, cyano, formyl, acetyl, amino, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-cycloalkenyl, aryl, aryl-C.sub.1-C.sub.6-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-C.sub.1-C.sub.6-alkyl, or heteroaryl-C.sub.1-C.sub.6-alkyl; and n is an integer of 1 and m is an integer of 1; with the proviso that when: - said R.sup.5 and R.sup.5' are taken together with the nitrogen atom to which they are bound to form: ##STR00106## wherein * indicates the point of attachment with the rest of the structure of formula (I), then - R.sup.2 is not: ##STR00107## wherein * indicates the point of attachment with the rest of the structure of formula (I), or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

2. The compound according to claim 1, wherein: R.sup.5 and R.sup.5' are taken together with the nitrogen atom to which they are bound to form a 3- to 7- membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen and nitrogen and which is optionally substituted with 1 or more R.sup.6' groups, or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

3. The compound according to claim 1, wherein: R.sup.5 and R.sup.5' are taken together with the nitrogen atom to which they are bound to form morpholinyl, or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

4. The compound according to claim 1, wherein R.sup.6 is C.sub.1-C.sub.6-alkyl optionally substituted with 1 or more R.sup.8 groups, or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

5. The compound according to claim 1, wherein R.sup.6 is C.sub.1-C.sub.3-alkyl, or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

6. The compound according to claim 1, wherein R.sup.6 is methyl, or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

7. The compound according to claim 1, wherein: R.sup.5 and R.sup.5' are taken together with the nitrogen atom to which they are bound to form piperidinyl, pyrrolidinyl, or azetidinyl, or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

8. A method of preparing the compound of formula (I) according to claim 1, comprising reacting an intermediate compound of formula (XI): ##STR00108## wherein R.sup.1 and R.sup.3 are as defined in claim 1, with a compound of formula (XIa): R.sup.2COOH (XIa) wherein R.sup.2 is as defined in claim 1, to give the compound of formula (I): ##STR00109## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1.

9. A pharmaceutical composition comprising the compound of formula (I), or a stereoisomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing, according to claim 1, and a pharmaceutically acceptable diluent or carrier.

10. A pharmaceutical combination comprising: one or more compounds of formula (I), or a stereoisomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing, according to claim 1; and one or more agents selected from: a taxane, Docetaxel, Paclitaxel, or Taxol; an epothilone, Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2'-deoxyadenosine; Thioguanine; an anti-androgen, Flutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinum derivative, Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; and Rituximab.

11. A method for treatment of a disease of uncontrolled cell growth, proliferation or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response comprising administering to a human or animal in need thereof the compound of formula (I), or a stereoisomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing, according to claim 1.

12. A compound of formula (XI): ##STR00110## wherein R.sup.1 and R.sup.3 are as defined in claim 1.

13. The method according to claim 11, wherein the disease of uncontrolled cell growth, proliferation or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response is mediated by the phosphotidylinositol-3-kinase (PI3K) pathway.

14. The method according to claim 11, wherein the disease of uncontrolled cell growth, proliferation or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour or metastases thereof.

15. The method according to claim 14, wherein the haemotological tumour, solid tumour and/or metastases thereof is selected from leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours, brain tumours and brain metastases, tumours of the thorax, non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, renal, bladder and prostate tumours, skin tumours, and sarcomas, and metastases thereof.

Details for Patent 9,902,727

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Genentech RITUXAN rituximab SOLUTION;INTRAVENOUS 103705 001 1997-11-26   Start Trial Bayer Intellectual Property GmbH (Monheim, DE) 2030-11-11 RX search
Genentech RITUXAN rituximab SOLUTION;INTRAVENOUS 103705 002 1997-11-26   Start Trial Bayer Intellectual Property GmbH (Monheim, DE) 2030-11-11 RX search
Genentech Inc RITUXAN HYCELA rituximab; hyaluronidase (human recombinant) SOLUTION;SUBCUTANEOUS 761064 001 2017-06-22   Start Trial Bayer Intellectual Property GmbH (Monheim, DE) 2030-11-11 RX Orphan search
Genentech Inc RITUXAN HYCELA rituximab; hyaluronidase (human recombinant) SOLUTION;SUBCUTANEOUS 761064 002 2017-06-22   Start Trial Bayer Intellectual Property GmbH (Monheim, DE) 2030-11-11 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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