2-amino-N-[7-methoxy-2, 3-dihydroimidazo-[1,2-c] quinazolin-5-yl] pyrimidine-5-carboxamides

Patent metadata

Field	Value
Publication number	US-10844066-B2
Application number	US-201716082712-A
Country	US
Kind code	B2
Filing date	Mar 1, 2017
Priority date	Mar 8, 2016
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

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.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
R 1 is a hydrogen atom or a —C(═O)H group; and
R 1′ is a —(CH 2 ) 2 OH group;
or
R 1 and R 1′ are taken together with the N-atom to which they are attached to form a morpholinyl group which is substituted with 1 or 2 substituents independently selected from the group consisting of —OH and ═O,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

2. The compound according to claim 1 , wherein:
R 1 is a hydrogen atom; and
R 1′ is a —(CH 2 ) 2 OH group,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

3. The compound according to claim 1 , wherein:
R 1 is a —C(═O)H group; and
R 1′ is a —(CH 2 ) 2 OH group,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

4. The compound according to claim 1 , wherein:
R 1 and R 1′ are taken together with the N-atom to which they are attached to form a morpholinyl group which is substituted with 1 or 2 substituents independently selected from the group consisting of —OH and ═O,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

5. The compound according to claim 1 , wherein:
R 1 and R 1′ are taken together with the N-atom to which they are attached to form a morpholinyl group which is substituted with a —OH and a ═O substituent,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

6. The compound according to claim 1 , wherein:
R 1 and R 1′ are taken together with the N-atom to which they are attached to form a morpholinyl group which is substituted with a —OH substituent,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

7. The compound according to claim 1 , wherein:
R 1 and R 1′ are taken together with the N-atom to which they are attached to form a morpholinyl group which is substituted with a ═O substituent,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

8. The compound according to claim 1 , wherein:
R 1 and R 1′ are taken together with the N-atom to which they are attached to form a morpholinyl group which is substituted with a ═O substituent, wherein said ═O group is bound to a carbon atom adjacent to said N-atom,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

9. The compound according to claim 1 , wherein the compound is:

or a physiologically acceptable salt thereof.

10. The compound according to claim 1 , wherein the compound is:

or a physiologically acceptable salt thereof.

11. The compound according to claim 1 , wherein the compound is:

or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

12. The compound according to claim 1 , wherein the compound is:

or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.

13. The compound according to claim 1 , wherein the compound is:

or a physiologically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 , or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, and a pharmaceutically acceptable diluent or carrier.

15. The pharmaceutical composition according to claim 14 , wherein the compound of formula (I) is present in a therapeutically effective amount.

16. The pharmaceutical composition according to claim 15 , further comprising at least one additional active compound.

17. The pharmaceutical composition of claim 16 , wherein the at least one additional active compound is an anti-hyper-proliferative, anti-inflammatory, analgesic, immunoregulatory, diuretic, anti-arrhythmic, anti-hypercholesterolemic, anti-diabetic, anti-dyslipidemia, anti-diabetic or antiviral agent.

18. The pharmaceutical composition of claim 17 , wherein the at least one additional active compound is 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin+estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabixi

Assignees

• Bayer Pharma AG

Inventors

• Schwarz Thomas
• Liu Ningshu
• Politz Oliver
• Gerisch Michael
• Lang Dieter

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5355

  Non-condensed oxazines and containing further heterocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title